Note: Descriptions are shown in the official language in which they were submitted.
WO 2022/177557 - 1 -
PCT/US2021/018381
CRYSTALLINE SOLIDS OF MEK INHIBITOR N-((R)-2,3-
DIHYDROXYPROPDXY)-3,4-DIFLUOR0-2-(2-FLUOR0-4-IODO-
PHENYLAMINO)-BENZAMIDE AND USES THEREOF
FIELD OF THE INVENTION
[0001] The present disclosure relates to: a) methods of synthesizing N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b)
crystalline forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide; c) pharmaceutical compositions comprising one or more
crystalline forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide, and, optionally, one or more pharmaceutically
acceptable
carriers; and d) methods of treating a tumor, a cancer, or a Rasopathy
disorder by
administering one or more crystalline forms of N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide to a subject in need
thereof.
BACKGROUND
[0002] N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide ("mirdametinib", or "PD-0325901") is a small molecule drug which has
been
designed to inhibit mitogen-activated protein kinase kinase 1 ("MEK1") and
mitogen-
activated protein kinase kinase 2 ("MEK2"). MEK1 and MEK2 are proteins that
play key
roles in the mitogen-activated protein kinase ("MAPK") signaling pathway. The
MAPK
pathway is critical for cell survival and proliferation, and overactivation of
this pathway,
has been shown to lead to tumor development and growth. Mirdametinib is a
highly
potent and specific allosteric non-ATP-competitive inhibitor of MEK1 and MEK2.
By
virtue of its mechanism of action, mirdametinib leads to significantly
inhibited
phosphorylation of the extracellular regulated MAP kinases ERK1 and ERK2,
thereby
leading to impaired growth of tumor cells both in vitro and in vivo. In
addition, evidence
indicates that inflammatory cytokine-induced increases in MEK/ERK activity
contribute
to the inflammation, pain, and tissue destruction associated with rheumatoid
arthritis and
other inflammatory diseases.
CA 03207513 2023- 8- 4
WO 2022/177557 _ 2 _
PCT/US2021/018381
100031 Crystal forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-
phenylamino)-benzamide have been described previously. W02002/006213 describes
crystalline Forms land II. U.S. Patent No. 7,060,856 ("the '856 patent")
describes a
method of producing Form IV. The '856 patent indicates that the material
produced by
this method was greater than 90% Form IV (The '856 patent, Example 1). The
'856 patent
also states that the differential scanning calorimetry ("DSC") of the material
produced
shows an onset of melting at 110 C as well as a small peak with an onset at
117 C,
consistent with the material being a mixture of two forms.
100041 WO 2006/134469 ("the '469 PCT publication") also describes a
method of
synthesizing N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide. The '469 PCT publication reports the method yields a
product
conforming to the polymorphic Form IV disclosed in U.S. Patent Application No.
10/969,681 which issued as the '856 patent.
100051 Differences in the characteristics of different polymorphic
forms can lead to
differences in the effective dose or physical properties affecting
processability of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
caused
by differences in solubility or bioavailability. Thus, there is a need for
compositions of
polymorphic forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide, for use in treatment of a tumor, a cancer, or a
Rasopathy
disorder.
BRIEF DESCRIPTION OF THE FIGURES
100061 FIG. IA is a X-ray powder diffraction pattern ("XRPD")
corresponding to
essentially pure crystalline Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide.
100071 FIG. 1B is a thermogravimetric analysis thermogram ("TGA") and a
differential
scanning calorimetry thermogram ("DSC") corresponding to essentially pure
crystalline
Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide.
100081 FIG. 2A is a X-ray powder diffraction pattern ("XRPD")
corresponding to
crystalline Form V.
CA 03207513 2023- 8- 4
WO 2022/177557 - 3 -
PCT/US2021/018381
[0009] FIG. 2B is a thermogravimetric analysis thermogram ("TGA") and a
differential
scanning calorimetry thermogram ("DSC") corresponding to crystalline Form V.
[0010] FIG. 3A is an XRPD corresponding to crystalline Form VI.
[0011] FIG. 3B is a DSC and a TGA corresponding to crystalline
Form VI.
[0012] FIG. 4A is an XRPD corresponding to crystalline Form VII.
[0013] FIG. 4B is a DSC and a TGA corresponding to crystalline
Form VII.
100141 FIG. 5A is an XRPD corresponding to crystalline Form
VIII.
[0015] FIG. 5B is a DSC and a TGA corresponding to crystalline
Form VIII.
[0016] FIG. 6A is an XRPD corresponding to crystalline Form IX.
100171 FIG. 6B is a DSC and a TGA corresponding to crystalline
Form IX.
[0018] FIG. 7A is an XRPD corresponding to crystalline Form X.
[0019] FIG. 7B is a DSC and a TGA corresponding to crystalline
Form X.
[0020] FIG. 8A is an XRPD corresponding to crystalline Form XI.
[0021] FIG. 8B is a DSC and a TGA corresponding to crystalline
Form XI.
[0022] FIG. 9A is an XRPD corresponding to crystalline Form XII.
[0023] FIG. 9B is a DSC and a TGA corresponding to crystalline
Form XII.
[0024] FIG. 10A is an XRPD corresponding to crystalline Form
XIII.
[0025] FIG. 10B is a DSC and a TGA corresponding to crystalline
Form XIII.
[0026] FIG. 11A is an XRPD corresponding to crystalline Form XIV
overlaid with an
XRPD corresponding to crystalline Form IV.
[0027] FIG. 11B is a DSC and a TGA corresponding to crystalline
Form XIV.
[0028] FIG. 12A is an XRPD corresponding to crystalline Form XV.
100291 FIG. 12B is a DSC and a TGA corresponding to crystalline
Form XV.
[0030] FIG. 13A is an XRPD corresponding to crystalline Form
XVI.
[0031] FIG. 13B is a DSC and a TGA corresponding to crystalline
Form XVI.
[0032] FIG. 14A is an XRPD corresponding to crystalline Form
XVII.
[0033] FIG. 14B is a DSC and a TGA corresponding to crystalline
Form XVII.
[0034] FIG. 15A is an XRPD corresponding to crystalline Form
XVIII.
[0035] FIG. 15B is a DSC and a TGA corresponding to crystalline
Form XVIII.
[0036] FIG. 16A is an XRPD corresponding to crystalline Form
XIX.
[0037] FIG. 16B is a DSC and a TGA corresponding to crystalline
Form XIX.
[0038] FIG. 17A is an XRPD corresponding to crystalline Form XX.
[0039] FIG. 17B is a DSC and a TGA corresponding to crystalline
Form XX.
CA 03207513 2023- 8- 4
WO 2022/177557 - 4 -
PCT/US2021/018381
[0040] FIG. 18A is an XRPD corresponding to crystalline Form
XXI.
100411 FIG. 18B is a DSC and a TGA corresponding to crystalline
Form XXI.
100421 FIG. 19A is an XRPD corresponding to crystalline Form
XXII.
100431 FIG. 19B is a DSC and a TGA corresponding to crystalline
Form XXII.
100441 FIG. 20A is an XRPD corresponding to crystalline Form
XXIII.
100451 FIG. 20B is a DSC and a TGA corresponding to crystalline
Form XXIII.
100461 FIG. 21A is an XRPD corresponding to crystalline Form
XXIV.
100471 FIG. 21B is a DSC and a TGA corresponding to crystalline
Form XXIV.
100481 FIG. 22A is an XRPD corresponding to amorphous
mirdametinib.
100491 FIG. 22B is a DSC and a TGA corresponding to amorphous
mirdametinib.
BRIEF SUMMARY OF THE INVENTION
Crystalline Forms and Amorphous Solids
100501 The present disclosure features useful compositions and methods
to treat disorders
whereby aberrant MEK1 or MEK2 activity is implicated, e.g., a cancer, a tumor,
or a
Rasopathy disorder, such as neurofibromatosis type 1, in a subject in need
thereof. In
some aspects, the present disclosure features novel polymorphic forms of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and
methods of producing them using pure Form IV, which is substantially free of
contaminating forms, e.g., Form I.
100511 In some aspects, the present disclosure features novel methods
of synthesizing N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide. In
some aspects, the methods of synthesizing N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide described herein are useful in
producing pure
Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide.
100521 In some aspects, the methods and compositions described herein
are useful in
treating patients who struggle to swallow whole capsules or tablets, e.g.,
pediatric patients
or subjects suffering from dysphagia, such as patients with esophageal cancer,
Parkinson's disease, amyotrophic lateral sclerosis, stroke, achalasia, or
esophageal
narrowing.
CA 03207513 2023- 8- 4
WO 2022/177557 - 5 -
PCT/US2021/018381
[0053] In some aspects, the present disclosure provides a crystalline
form of N-((R)-2,3-
di hy droxyprop oxy)-3 ,4-difluoro-2-(2-fluoro-4 odo-ph enyl amino)-b enzami
de of Formula
(I)
H
6F1 N,
I ,
(I),
selected from the group consisting of:
a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.4 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta;
b) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.9 0.2, 7.2 0.2, and 21.2 0.2 degrees two theta;
c) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.3 0.2, 10.6 0.2, and 16.1 0.2 degrees two theta;
d) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.4 0.2, 10.7 0.2, and 18.7 0.2 degrees two theta;
e) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 6.7 0.2, 13.5 0.2, and 22.2 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 10.6 0.2, 19.6 0.2, and 24.8 0.2 degrees two theta;
g) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-
3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.5 0.2, 6.9 0.2, and 10.1 0.2 degrees two theta;
CA 03207513 2023- 8- 4
WO 2022/177557 - 6 -
PCT/US2021/018381
h) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 10.1 0.2, 17.3 0.2, and 22.6 0.2 degrees two theta;
i) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 4.6 0.2, 5.1 0.2, and 14.6 0.2 degrees two theta;
j) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 4.6 0.2, 23.4 0.2, and 25.2 0.2 degrees two theta;
k) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.5 0.2, 14.7 0.2, and 20.9 0.2 degrees two theta;
1) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-
3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 6.0 + 0.2, 17.1 + 0.2, and 20.61 0.2 degrees two theta;
m) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.9 + 0.2, 10.1 + 0.2, and 15.5 + 0.2 degrees two theta;
n) a crystalline form of N-((R)-2,3 -di hydroxyprop oxy)-3 ,4-di uoro-2-(2-
fluoro-4-iodo-phenylamino)-b enzamide characterized by an XRPD pattern having
peaks
at 4.6 0.2, 10.7 0.2, and 15.9 0.2 degrees two theta;
o) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 10.2 0.2, 11.6 0.2, and 20.0 0.2 degrees two theta;
1)) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-
3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 7.8 0.2, 14.0 0.2, and 17.1 0.2 degrees two theta;
cl) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-
3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.5 0.2, 8.2 0.2, and 16.7 0.2 degrees two theta;
r) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-
3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 7.2 0.2, 21.7 0.2, and 29.1 0.2 degrees two theta;
CA 03207513 2023- 8- 4
WO 2022/177557 - 7 -
PCT/US2021/018381
s) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.4 0.2, 9.7 0.2, and 10.7 0.2 degrees two theta; and
t) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 7.2 0.2, 20.6 0.2, and 23.0 0.2 degrees two theta.
100541 In some aspects, the crystalline form of N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks 5.4 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta.
In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
5.4
0.2, 12.5 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 2A.
100551 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
2.7 wt% between about 35 C and about 100 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-
benzami de
exhibits a DSC thermogram that has an endotherm onset at about 77 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 95 C. In some aspects, the crystalline form of N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram
that
has a first endotherm onset at about 77 C and a second endotherm onset at
about 95 C.
In some aspects, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a
TGA
profile substantially as shown in FIG. 2B; and/or b) a DSC profile
substantially as shown
in FIG. 2B.
100561 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form V.
100571 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de is characterized by an
XRPD
CA 03207513 2023- 8- 4
WO 2022/177557 - 8 -
PCT/US2021/018381
pattern haying peaks at 5.9 0.2, 7.2 0.2, and 21.2 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 5.9
0.2, 7.2 0.2, 9.3 0.2, and 21.2 0.2 degrees two theta. In some aspects,
the crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
3A.
100581 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
2.4 wt% between about 25 C and about 125 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 41 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 70 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram
that
has an endotherm onset at about 109 C. In some aspects, the crystalline form
of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits a DSC thermogram that has an endotherm onset at about 41 C and an
endotherm
onset at about 70 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits a
DSC thermogram that has an endotherm onset at about 41 C and an endotherm
onset at
about 109 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has an endotherm onset at about 70 C and an endotherm onset at about 109
C. In
some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a
first
endotherm onset at about 41 C, a second endotherm onset at about 70 C, and a
third
endotherm onset at about 109 C. In some aspects, the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by: a) a TGA profile substantially as shown in FIG. 3B; and/or
b) a DSC
profile substantially as shown in FIG. 3B.
100591 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is Form VI.
CA 03207513 2023- 8- 4
WO 2022/177557 - 9 -
PCT/US2021/018381
[0060] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 5.3 0.2, 10.6 0.2, and 16.1 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 5.3
0.2, 10.6 0.2, 13.9 0.2, and 16.1 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 4A.
100611 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
5.2 wt% between about 40 C and about 120 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 85 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endothermic event
at
about 110 'C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has a first endotherm onset at about 85 C and a second endothermic event
at about
110 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a
TGA
profile substantially as shown in FIG. 4B; and/or b) a DSC profile
substantially as shown
in FIG. 4B.
[0062] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VII.
[0063] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 5.4 0.2, 10.7 0.2, and 18.7 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 5.4
0.2, 10.7 + 0.2, 18.7 + 0.2, and 23.9 + 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
CA 03207513 2023- 8- 4
WO 2022/177557 - 10 -
PCT/US2021/018381
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 5A.
100641 In some aspects, the TGA exhibits that the crystalline
form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
3.3 wt% between about 40 C and about 112 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 81 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 110 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has a first endotherm onset at about 81 C and a second endotherm onset
at about 110
C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile
substantially as shown in FIG. 5B; and/or b) a DSC profile substantially as
shown in FIG.
5B.
100651 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VIII.
100661 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 6.7 0.2, 13.5 0.2, and 22.2 0.2 degrees two
theta. In some
aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 6.7
0.2, 8.0 0.2, 13.5 0.2, and 22.2 0.2 degrees two theta. In some aspects,
the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 6A.
100671 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
4.6 wt% between about 28 C and about 128 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 84 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-i odo-
CA 03207513 2023- 8- 4
WO 2022/177557 - 11 -
PCT/US2021/018381
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 107 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has an endotherm onset at about 114 C. In some aspects, the crystalline
form of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 84 C and an
endotherm
onset at about 107 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits a
DSC thermogram that has an endotherm onset at about 84 C and an endotherm
onset at
about 114 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has an endotherm onset at about 107 C and an endotherm onset at about
114 C. In
some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a
first
endotherm onset at about 84 C, a second endotherm onset at about 107 C, and
a third
endotherm onset at about 114 C. In some aspects, the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by: a) a TGA profile substantially as shown in FIG. 6B; and/or
b) a DSC
profile substantially as shown in FIG. 6B.
[0068] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form IX.
[0069] In some aspects, the crystalline form of N-((R)-2,3-dihy
droxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 10.6 0.2, 19.6 0.2, and 24.8 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 5.5
0.2, 10.6 0.2, 19.6 0.2, and 24.8 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 7A.
[0070] In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
2.9 wt% between about 40 C and about 115 C. In some aspects, the crystalline
form of
CA 03207513 2023- 8- 4
WO 2022/177557 - 12 -
PCT/US2021/018381
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 89 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide is characterized by: a) a TGA profile substantially as
shown in
FIG. 7B; and/or b) a DSC profile substantially as shown in FIG. 7B.
[0071] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form X.
[0072] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 5.5 0.2, 6.9 0.2, and 10.1 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern haying peaks
at 5.5
0.2, 6.9 0.2, 10.1 0.2, and 19.2 0.2 degrees two theta. In some aspects,
the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 8A.
[0073] In some aspects, the TGA exhibits that the crystalline
form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
7.6 wt% between about 40 C and about 175 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 69 C. In some
aspects,
the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 104 C. In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has a first endotherm onset at about 69 C and a second endotherm onset
at about 104
C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile
substantially as shown in FIG. 8B; and/or b) a DSC profile substantially as
shown in FIG.
8B.
[0074] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XI.
CA 03207513 2023- 8- 4
WO 2022/177557 - 13 -
PCT/US2021/018381
[0075] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 10.1 0.2, 17.3 0.2, and 22.6 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 10.1
0.2, 17.3 0.2, 21.5 0.2, and 22.6 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 9A.
100761 In some aspects, the TGA exhibits that the crystalline
form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
8.5 wt% between about 40 C and about 160 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 72 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 109 'C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has a first endotherm onset at about 72 C and a second endotherm onset
at about 109
C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile
substantially as shown in FIG. 9B; and/or b) a DSC profile substantially as
shown in FIG.
9B.
100771 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XII.
100781 In some aspects, the crystalline form of N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 4.6 0.2, 5.1 0.2, and 14.6 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 4.6
0.2, 5.1 + 0.2, 6.41 0.2, and 14.61 0.2 degrees two theta. In some aspects,
the crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
10A.
CA 03207513 2023- 8- 4
WO 2022/177557 - 14 -
PCT/US2021/018381
[0079] In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
3.1 wt% between about 20 C and about 100 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 55 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 109 C. In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has a first endotherm onset at about 55 C and a second endotherm onset
at about 109
C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile
substantially as shown in FIG. 10B; and/or b) a DSC profile substantially as
shown in
FIG. 10B.
[0080] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIII.
100811 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 4.6 0.2, 23.4 0.2, and 25.2 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 4.6
0.2, 23.4 0.2, 25.2 0.2, and 30.6 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 11A.
100821 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
0.15 wt% between about 40 C and about 150 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about ii 1 C. In
some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by: a) a TGA profile
substantially as
shown in FIG. 11B; and/or b) a DSC profile substantially as shown in FIG. 11B.
CA 03207513 2023- 8- 4
WO 2022/177557 - 15 -
PCT/US2021/018381
[0083] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIV.
[0084] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 5.5 0.2, 14.7 0.2, and 20.9 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 5.5
0.2, 14.7 0.2, 20.9 0.2, and 26.6 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 12A.
[0085] In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
3.8 wt% between about 40 C and about 150 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 104 C. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by: a) a TGA profile
substantially as
shown in FIG. 12B; and/or b) a DSC profile substantially as shown in FIG. 12B.
[0086] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XV.
[0087] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 6.0 0.2, 17.1 0.2, and 20.6 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 6.0
0.2, 12.8 0.2, 17.1 0.2, and 20.6 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 13A.
[0088] In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
2.1 wt% between about 40 C and about 150 C. In some aspects, the crystalline
form of
CA 03207513 2023- 8- 4
WO 2022/177557 - 16 -
PCT/US2021/018381
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 74 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 102 C. In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has an endotherm onset at about 114 C. In some aspects, the crystalline
form of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 74 C and an
endotherm
onset at about 102 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits a
DSC thermogram that has an endotherm onset at about 74 C and an endotherm
onset at
about 114 C. In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has an endotherm onset at about 102 C and an endotherm onset at about
114 C. In
some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a
first
endotherm onset at about 74 C, a second endotherm onset at about 102 C, and
a third
endotherm onset at about 114 C. In some aspects, the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by: a) a TGA profile substantially as shown in FIG. 13B, and/or
b) a DSC
profile substantially as shown in FIG. 13B.
100891 In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVI.
100901 In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern haying peaks at 5.9 0.2, 10.1 0.2, and 15.5 0.2 degrees two
theta. In some
aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 5.9
0.2, 10.1 0.2, 11.7 0.2, and 15.5 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 14A.
CA 03207513 2023- 8- 4
WO 2022/177557 - 17 -
PCT/US2021/018381
[0091] In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
2.7 wt% between about 40 C and about 100 C. In some aspects, crystalline
form of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 89 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide is characterized by: a) a TGA profile substantially as
shown in
FIG. 14B; and/or b) a DSC profile substantially as shown in FIG. 14B.
[0092] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVII.
[0093] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 4.6 0.2, 10.7 0.2, and 15.9 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 4.6 +
0.2, 10.7 0.2, 15.9 0.2, and 19.6 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 15A.
[0094] In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
1.6 wt% between about 30 C and about 150 C. In some aspects, the crystalline
form of
N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 83 C. In some
aspects,
the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by: a) a TGA profile substantially as
shown in
FIG. 15B; and/or b) a DSC profile substantially as shown in FIG. 15B.
[0095] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVIII.
[0096] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 10.2 0.2, 11.6 0.2, and 20.0 0.2 degrees two
theta. In some
aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
CA 03207513 2023- 8- 4
WO 2022/177557 - 18 -
PCT/US2021/018381
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 10.2
+ 0.2, 11.6 0.2, 17.1 + 0.2, and 20.0 + 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 16A.
[0097] In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
1.85 wt% between about 23 C and about 92 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 69 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 98 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram
that
has an endotherm onset at about 115 C. In some aspects, the crystalline form
of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits a DSC thermogram that has an endotherm onset at about 69 'V and an
endotherm
onset at about 98 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de
exhibits a
DSC thermogram that has an endotherm onset at about 69 C and an endotherm
onset at
about 115 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has an endotherm onset at about 98 C and an endotherm onset at about 115
C. In
some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a
first
endotherm onset at about 69 C, a second endotherm onset at about 98 C, and a
third
endotherm onset at about 115 C. In some aspects, the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by: a) a TGA profile substantially as shown in FIG. 16B; and/or
b) a DSC
profile substantially as shown in FIG. 16B.
[0098] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIX.
CA 03207513 2023- 8- 4
WO 2022/177557 - 19 -
PCT/US2021/018381
[0099] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 7.8 0.2, 14.0 0.2, and 17.1 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 7.8
0.2, 14.0 0.2, 15.6 0.2, and 17.1 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 17A.
101001 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
2.6 wt% between about 29 C and about 126 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 77 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 92 'C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram
that
has an endotherm onset at about 110 C. In some aspects, the crystalline form
of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits a DSC thermogram that has an endotherm onset at about 77 C and an
endotherm
onset at about 92 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits a
DSC thermogram that has an endotherm onset at about 77 C and an endotherm
onset at
about 110 C. In some aspects, the crystalline form of N4R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has an endotherm onset at about 92 C and an endotherm onset at about 110
C. In
some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a
first
endotherm onset at about 77 C, a second endotherm onset at about 92 C, and a
third
endotherm onset at about 110 C. In some aspects, the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
CA 03207513 2023- 8- 4
WO 2022/177557 - 20 -
PCT/US2021/018381
characterized by: a) a TGA profile substantially as shown in FIG. 17B; and/or
b) a DSC
profile substantially as shown in FIG. 17B.
101011 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XX.
101021 In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 5.5 0.2, 8.2 0.2, and 16.7 0.2 degrees two
theta. In some
aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 5.5
0.2, 8.2 0.2, 16.7 0.2, and 17.7 0.2 degrees two theta. In some aspects,
the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 18A.
101031 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
14.1 wt% between about 30 C and about 110 C. In some aspects, the
crystalline form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram has an endotherm onset at about 52 C. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 90 C. In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram
that
has a first endotherm onset at about 52 C and a second endotherm onset at
about 90 C.
In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile
substantially as shown in FIG. 18B; and/or b) a DSC profile substantially as
shown in
FIG. 18B.
101041 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXI.
101051 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 7.2 0.2, 21.7 0.2, and 29.1 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
CA 03207513 2023- 8- 4
WO 2022/177557 - 21 -
PCT/US2021/018381
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 7.2
0.2, 18.6 + 0.2, 21.7 + 0.2, and 29.1 10.2 degrees two theta. In some aspects,
the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 19A.
[0106] In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
13.8 wt% between about 26 C and about 135 C. In some aspects, the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 65
C. In
some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an
endotherm onset at about 89 C. In some aspects, the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits a
DSC thermogram that has an endotherm onset at about 102 C. In some aspects,
the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 65 C and an endotherm onset at about 89 C. In some aspects, the
crystalline form
of N-((R)-2,3 -di hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl ami
no)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 65 C
and an
endotherm onset at about 102 C. In some aspects, the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits a
DSC thermogram that has an endotherm onset at about 89 C and an endotherm
onset at
about 102 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has a first endotherm onset at about 65 C, a second endotherm onset at
about 89 C,
and a third endotherm onset at about 102 C. In some aspects, the crystalline
form of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
characterized by: a) a TGA profile substantially as shown in FIG. 19B; and/or
b) a DSC
profile substantially as shown in FIG. 19B.
[0107] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXII.
CA 03207513 2023- 8- 4
WO 2022/177557 - 22 -
PCT/US2021/018381
[0108] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 5.4 0.2, 9.7 0.2, and 10.7 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 5.4
0.2, 6.5 0.2, 9.7 0.2, and 10.7 0.2 degrees two theta. In some aspects,
the crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
20A.
[0109] In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
4.4 wt% between about 27 C and about 137 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 81 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 101 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has a first endotherm onset at about 81 C and a second endotherm onset
at about 101
C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile
substantially as shown in FIG. 20B; and/or b) a DSC profile substantially as
shown in
FIG. 20B.
101101 In some aspects, the crystalline form of N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXIII.
[0111] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 7.2 0.2, 20.6 0.2, and 23.0 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 7.2
0.2, 9.5 0.2, 20.6 0.2, and 23.0 0.2 degrees two theta. In some aspects,
the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 21A.
CA 03207513 2023- 8- 4
WO 2022/177557 - 23 -
PCT/US2021/018381
[0112] In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
1.2 wt% between about 30 C and about 119 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 104 C. In some
aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is characterized by: a) a TGA profile
substantially as
shown in FIG. 21B; and/or b) a DSC profile substantially as shown in FIG. 21B.
[0113] In some aspects, the crystal form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXIV.
[0114] In some aspects, the present disclosure provides an amorphous
form of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
of
Formula (I)
' H 7
OH N
I
1
[0115] In some aspects, the amorphous form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern substantially as shown in FIG. 22A.
[0116] In some aspects, the amorphous form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a
TGA
profile substantially as shown in FIG. 22B; and/or b) a DSC profile
substantially as
shown in FIG. 22B.
[0117] In some aspects, the XRPD pattern is generated using a
PANALYTICAL X'Pert
Pro diffractometer using Ni-filtered Cu Ka (45 kV/40 mA) radiation and a step
size of
0.03 20 with a X'CELERATOR Real Time Multi-Strip detector, configured (a) on
the
incidental beam side as follows: variable divergence slits (10 mm irradiated
length), 0.04
rad Soller slits, fixed anti-scatter slit (0.50 ), and 10 mm beam mask, and
(b) on the
diffracted beam side as follows: variable anti-scatter slit (10 mm observed
length) and
0.04 rad Soller slit or a BRUKER D8 ADVANCETM system using Cu Ka (40 kV/40
CA 03207513 2023- 8- 4
WO 2022/177557 - 24 -
PCT/US2021/018381
mA) radiation and a step size of 0.03 20 with a LYNXEYE detector, configured
(a) on
the incidental beam side as follows: Goebel mirror, mirror exit slit (0.2 mm),
2.5 Soller
slit, beam knife, and (b) on the diffracted beam side as follows: anti-scatter
slit (8 mm)
and 2.5 Soller slit; wherein samples are mounted flat on zero-background Si
wafers. In
some aspects, the DSC pattern is generated using a TA Instruments Q100 or
Q2000
differential scanning calorimeter at a rate of temperature increase of about
15 C/min.
Pharmaceutical Composition
[0118] In some aspects, the present disclosure is directed to a
pharmaceutical
composition (e.g., capsule, tablet, powder, granules, minitablets, or pellets)
comprising a
crystalline form or amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide described herein and one or more
pharmaceutically acceptable carriers.
[0119] In some aspects, the pharmaceutical composition is for oral
administration. In
some aspects, the pharmaceutical composition is a solid dosage form. In some
aspects, the
pharmaceutical composition is a capsule, tablet (e.g., dispersible tablet or
orodispersible
tablet), powder (e.g., dispersible powder), granules (e.g., dispersible
granules),
minitablets (e.g., dispersible minitablets), or pellets (e.g., dispersible
pellets). In some
aspects, the pharmaceutical composition is a tablet (e.g., dispersible tablet
or
orodispersible tablet) or a capsule.
101201 In some aspects, the pharmaceutical composition is a capsule. In
some aspects, the
capsule comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-
4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as
follows:
(a) about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the
amorphous solid of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide;
(b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1
wt/wt% to
about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt%
of one or
more lubricants; and (e) a gelatin capsule which encapsulates components (a)-
(d). In
some aspects, the capsule comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of
the
capsule is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt% of the
crystalline form
or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or
more
CA 03207513 2023- 8- 4
WO 2022/177557 - 25 -
PCT/US2021/018381
diluents; (c) about 3.5 wt/wt% to about 6 wt/vv-t% of one or more
disintegrants; (d) about
0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) a gelatin
capsule which
encapsulates components (a)-(d).
101211 In some aspects, the capsule comprises about 2 mg of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,
wherein
each component of the capsule is as follows: (a) about 0.1 wt/wt% to about 7
wt/wt% of
the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to
about 98
wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one
or more
disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or more lubricants; and
(e) a gelatin
capsule which encapsulates components (a)-(d). In some aspects, the capsule
comprises
about 2 mg of NAR)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide, wherein each component of the capsule is as follows:
(a) about
0.25 wt/wt% to about 1.5 wt/wt% of the crystalline form or the amorphous solid
of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide;
(b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5
wt/wt% to
about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2
wt/wt% of
one or more lubricants; and (e) a gelatin capsule which encapsulates
components (a)-(d).
101221 In some aspects, the capsule comprises about 5 mg of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,
wherein
each component of the capsule is as follows: (a) about 2.5 wt/wt% to about 7.0
wt/wt% of
the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to
about 98
wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one
or more
disintegrants; and (d) a gelatin capsule which encapsulates components (a)-
(c). In some
aspects, the capsule comprises about 5 mg of N4R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of
the
capsule is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt% of the
crystalline form or
the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
and (d) a
gelatin capsule which encapsulates components (a)-(c).
CA 03207513 2023- 8- 4
WO 2022/177557 - 26 -
PCT/US2021/018381
[0123] In some aspects, the pharmaceutical composition is a tablet. In
some aspects, the
tablet comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide, wherein each component of the tablet is as
follows: (a)
about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous
solid of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide;
(b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1
wt/wt% to
about 10 wt/wt% of one or more disintegrants; and (d) 0 wt/wt% to about 5
wt/wt% of
one or more lubricants. In some aspects, the tablet comprises about 1 mg of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,
wherein
each component of the tablet is as follows: (a) about 0.25 wt/wt% to about 1.5
wt/wt% of
the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to
about 95
wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one
or more
disintegrants; and (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more
lubricants.
[0124] In some aspects, the tablet comprises about 2 mg of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,
wherein
each component of the tablet is as follows: (a) about 0.1 wt/wt% to about 7
wt/wt% of the
crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-i odo-phenylamino)-benzami de; (b) about 50 wt/wt% to about 98
wt/wt% of
one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more
disintegrants; and (d) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
In some
aspects, the tablet comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the
tablet is as
follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt% of the crystalline form or
the
amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
and (d)
about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
[0125] In some aspects, the tablet comprises about 5 mg of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,
wherein
each component of the tablet is as follows: (a) about 2.5 wt/wt% to about 7.0
wt/wt% of
the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to
about 98
CA 03207513 2023- 8- 4
WO 2022/177557 - 27 -
PCT/US2021/018381
wt/wt% of one or more diluents; and (c) about 1 wt/wt% to about 10 wt/wt% of
one or
more disintegrants. In some aspects, the tablet comprises about 5 mg of N-((R)-
2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,
wherein
each component of the tablet is as follows: (a) about 2.5 wt/wt% to about 7.0
wt/wt% of
the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to
about 95
wt/wt% of one or more diluents; and (c) about 3.5 wt/wt% to about 6 wt/wt% of
one or
more disintegrants.
101261 In some aspects, the pharmaceutical composition is for oral
administration. In
some aspects, the pharmaceutical composition is dispersible orodispersible.
101271 In some aspects, the pharmaceutical composition is a tablet, a
powder, granules,
minitablets, or pellets (also called beads).
101281 In some aspects, the pharmaceutical composition is a powder. In
some aspects,
the pharmaceutical composition is a dispersible powder. In some aspects, a
capsule or
sachet comprises the dispersible powder.
101291 In some aspects, the pharmaceutical composition is in the form
of granules. In
some aspects, the granules are dispersible granules. In some aspects, a
capsule or sachet
comprises the dispersible granules.
101301 In some aspects, the pharmaceutical composition is in the form
of minitablets. In
some aspects, the minitablets are dispersible minitablets. In some aspects, a
capsule or
sachet comprises the dispersible minitablets.
101311 In some aspects, the pharmaceutical composition is in the form
of pellets. In some
aspects, the pellets are dispersible pellets. In some aspects, a capsule or
sachet comprises
the dispersible pellets.
101321 In some aspects, the pharmaceutical composition is a tablet. In
some aspects, the
tablet is a dispersible tablet. In some aspects, the tablet is an
orodispersible tablet.
101331 In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the
pharmaceutical composition is as follows: (a) about 0.1 wt/wt% to about 7
wt/wt% of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide;
(b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1
wt/wt% to
CA 03207513 2023- 8- 4
WO 2022/177557 - 28 -
PCT/US2021/018381
about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt%
of one or
more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more
sweeteners; and
(f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
101341 In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the
pharmaceutical composition is as follows: (a) about 0.2 wt/wt% to about 1.5
wt/wt% of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide;
(b) about 75 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 3
wt/wt% to
about 8 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of
one or
more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more
sweeteners; and
(f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
101351 In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the
pharmaceutical composition is as follows: (a) about 0.5 wt/wt% to about 1.2
wt/wt% of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-
benzami de;
(b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5
wt/wt% to
about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt%
of one or
more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more
sweeteners; and
(f) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
101361 In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition
comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide. In some aspects, the pharmaceutical composition that
is a
dispersible tablet, dispersible powder, dispersible granules, dispersible
minitablets, or
dispersible pellets comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical
composition that is a dispersible tablet, dispersible powder, dispersible
granules,
CA 03207513 2023- 8- 4
WO 2022/177557 - 29 -
PCT/US2021/018381
dispersible minitablets, or dispersible pellets comprises about 3 mg of N-((R)-
2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In
some
aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible powder,
dispersible granules, dispersible minitablets, or dispersible pellets
comprises about 4 mg
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide.
101371 In some aspects, at least one of the diluents is selected from
the group consisting
of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose,
pregelatinized
starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium
phosphate. In some
aspects, at least one of the diluents is microcrystalline cellulose.
101381 In some aspects, at least one of the disintegrants is selected
from the group
consisting of croscarmellose sodium, sodium starch glycolate, crospovidone,
microcrystalline cellulose, starch, pregelatinized starch, low substituted
hydroxypropyl
cellulose, and alginic acid. In some aspects, at least one of the
disintegrants is
croscarmellose sodium.
101391 In some aspects, at least one of the flavoring agents is
selected from the group
consisting of natural or synthetic flavors including but not limited to, grape
flavoring,
bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring,
strawberry
flavoring, raspberry flavoring, mint flavoring, peppermint flavoring,
grapefruit flavoring,
pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring,
banana flavoring,
or cherry flavoring. In some aspects, at least one of the flavoring agents is
grape
flavoring.
101401 In some aspects, at least one of the sweeteners is selected from
the group
consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol,
sorbitol,
glucose, fructose, and aspartame. In some aspects, at least one of the
sweeteners is
sucralose.
101411 In some aspects, at least one of the lubricants is selected from
the group consisting
of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic
acid,
hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax,
colloidal silicon
dioxide, and talc. In some aspects, at least one of the lubricants is
magnesium stearate.
CA 03207513 2023- 8- 4
WO 2022/177557 - 30 -
PCT/US2021/018381
Methods of Treatment
101421 In some aspects, the present disclosure provides a method of
treating a tumor, a
cancer, or a Rasopathy disorder comprising administering to a subject in need
of such
treatment a pharmaceutical composition (e.g., capsule, tablet, powder,
granules,
minitablets, or pellets) described herein.
101431 In some aspects, the present disclosure provides use of a
pharmaceutical
composition (e.g., capsule, tablet, powder, granules, minitablets, or pellets)
described
herein for the manufacture of a medicament for treating a tumor, a cancer, or
Rasopathy
disorder.
101441 In some aspects, the tumor is a neurofibroma. In some aspects,
the tumor is a
neurofibroma associated with Neurofibromatosis Type 1. In some aspects, the
tumor is
selected from the group consisting of cutaneous neurofibroma, plexiform
neurofibroma,
optic pathway glioma, low grade glioma, high grade glioma, or malignant
peripheral
nerve sheath tumor. In some aspects, the tumor is plexiform neurofibroma.
101451 In some aspects, the subject has been diagnosed with a Rasopathy
disorder
selected from the group consisting of neurofibromatosis type 1,
neurofibromatosis type 2,
cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan
syndrome, and Noonan syndrome with multiple lentigines.
101461 In some aspects, the cancer is selected from the group
consisting of skin cancer,
malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic
neoplasm,
lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer,
thyroid cancer,
cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer,
sarcoma, bladder
cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid
cystic
carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer,
pancreatic
cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous
carcinoma of the
peritoneum. In some aspects, the leukemia is selected from the group
consisting of acute
lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic
leukemia, and
chronic myelogenous leukemia. In some aspects, the lymphoma is selected from
the
group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma,
follicular
lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small
lymphocytic lymphoma, and Waldenstrom macroglobulinemia. In some aspects, the
lung
cancer is selected from the group consisting of lung adenocarcinoma, squamous
non-
CA 03207513 2023- 8- 4
WO 2022/177557 - 31 -
PCT/US2021/018381
small cell lung cancer, non-squamous non-small cell lung cancer, and small
cell lung
cancer.
101471 In some aspects, the subject bears a mutation or other
aberration in one or more
genes for which the mutation or other aberration causes a gain or loss of
function
characteristic of certain cancers, wherein the mutation or other aberration in
one or more
genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS,
BRAF,
MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
101481 In some aspects, an individual dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as more
than one
capsule, more than one tablet (e.g., dispersible tablet), more than one dose
of powder
(e.g., dispersible powder), more than one dose of granules (e.g., dispersible
granules),
more than one dose of minitablets (e.g., dispersible minitablets), more than
one dose of
pellets (e.g., dispersible pellets), or a combination thereof.
101491 In some aspects, the pharmaceutical composition is a dispersible
tablet, dispersible
powder, dispersible granules, dispersible minitablets, or dispersible pellets,
wherein the
pharmaceutical composition is dispersed in a potable liquid prior to
administration to the
subject. For example, a dose of 3 mg of the N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide can be administered as two
dispersible
tablets ¨ one containing 2 mg and the other containing 1 mg or as three
dispersible tablets
each containing 1 mg. As another example, a dose of 1.5 mg of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide can
be
administered as two dispersible dosage forms ¨ one dispersible tablet
containing 1 mg
and a separate unit of dispersible powder containing 0.5 mg or as three units
of
dispersible powder each containing 0.5 mg.
101501 In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered in a total daily dose that does
not exceed
20 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is administered in a total daily dose that does
not exceed
mg. In some aspects, the NAR)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide is administered in a total daily dose that does
not exceed 8
mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide is administered in a total daily dose that does not
exceed 6 mg.
In some aspects, the N-((R)-2,3-di hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
i odo-
CA 03207513 2023- 8- 4
WO 2022/177557 - 32 -
PCT/US2021/018381
phenylamino)-benzamide is administered in a total daily dose that does not
exceed 2 mg.
In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is administered in a total daily dose that does not
exceed 1 mg.
101511 In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 0.1 mg to about 20
mg. In
some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is about 0.5 mg. In some aspects, the
total daily
dose of the N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is about 1 mg. In some aspects, the total daily dose of
the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
about 2 mg. In some aspects, the total daily dose of N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 4 mg. In some
aspects, the
total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide is about 6 mg. In some aspects, the total daily dose of
the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
about 8 mg. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered about
20 mg.
101521 In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is administered two
times daily.
101531 In some aspects, the total daily dose of the N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times
daily at a
dose of about 0.1 mg to about 10 mg each. In some aspects, the total daily
dose of the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
administered two times daily at a dose of about 0.5 mg each. In some aspects,
the total
daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is administered two times daily at a dose of about 1 mg
each. In
some aspects, the total daily dose of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose
of about
2 mg each. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two
times daily
at a dose of about 3 mg each. In some aspects, the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 4 mg each. In some aspects,
the total daily
CA 03207513 2023- 8- 4
WO 2022/177557 - 33 -
PCT/US2021/018381
dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is administered two times daily at a dose of about 10
mg each.
101541 In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily
In some
aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of
about 0.1
mg to about 20 mg. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 0.5 mg. In some aspects, the total
daily dose of
the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is administered once daily at a dose of about 1 mg. In some aspects,
the total
daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is administered once daily at a dose of about 2 mg. In
some
aspects, the total daily dose of the N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of
about 4
mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily
at a dose
of about 8 mg. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is administered once
daily at a
dose of about 10 mg. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 20 mg.
101551 In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered in a total daily dose that does
not exceed
20 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is administered in a total daily dose that does
not exceed
mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-
iodo-phenylamino)-benzamide is administered in a total daily dose that does
not exceed 8
mg. In some aspects, the N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is administered in a total daily dose that does not
exceed 6 mg.
In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is administered in a total daily dose that does not
exceed 4 mg.
In some aspects, the N-((R)-2,3-di hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
i odo-
CA 03207513 2023- 8- 4
WO 2022/177557 - 34 -
PCT/US2021/018381
phenylamino)-benzamide is administered in a total daily dose that does not
exceed 2 mg.
In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is administered in a total daily dose that does not
exceed 1 mg.
[0156] In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle
comprising: (a)
21 days in which the total daily dose is administered; and (b) 7 days in which
no N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle
comprising: (a) 21 consecutive days in which the total daily dose is
administered;
followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
[0157] In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle
comprising: (a)
three 7-day periods each comprising (i) 5 days in which the total daily dose
is
administered and (ii) 2 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide; and (b) 7 days in which no N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle
comprising: (a) three 7-day periods each comprising (i) 5 consecutive days in
which the
total daily dose is administered and (ii) 2 consecutive days in which no N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
followed
by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered.
[0158] In some aspects, the 28-day dosing cycle is repeated up to a
total of 24
consecutive 28-day dosing cycles.
[0159] In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle
comprising 28
days in which the total daily dose is administered.
[0160] In some aspects, the subject experiences dysphagia. In some
aspects, the subject
experiences dysphagia caused by one or more of: disease of the nervous system,
muscle
CA 03207513 2023- 8- 4
WO 2022/177557 - 35 -
PCT/US2021/018381
weakening, developmental disability, stroke, injury, anatomical defect,
cancer, treatment
for cancer, allergic reaction, dementia, memory loss, or cognitive decline.
101611 In some aspects, the subject is a pediatric subject.
Methods of Preparing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide and Essentially Pure Form IV
101621 Novel methods of producing NAR)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide of Formula (I)
N -0
HO
H
OH
(0,
that comprise reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a
coupling
reagent that is 1-propylphosphonic anhydride ("T3P to obtain 901 Acetonide, as
shown
in Scheme I below are disclosed herein.
Scheme 1
HO 0
__\\_cr cy
/
__r..NH 0
0õ)0.NH2 + 110 T3P
NI
PD 0337792
(IPGA)
MW 147.17 PD-0315209
(FIPFA)
MW 393.10 901
Acetonide
MW 522.26
101631 In some aspects, the T3P is in solution. In some aspects, T3P is
provided as a
solution in ethyl acetate.
101641 In some aspects, the method of producing essentially pure Form
IV N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of
Formula
(I) comprises (a) reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a
coupling
reagent that is T3P to obtain 901 Acetonide; and (b) treating 901 Acetonide
with acid to
form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide, as shown in Scheme II below.
CA 03207513 2023- 8- 4
WO 2022/177557 - 36 -
PCT/US2021/018381
Scheme II
+ HO 0
F H
H
00,
01 F T3P
-(5 N
NH2 0 1.1
PD-0337792 F
F I
(IPGA) PD-0315209 F
MW 147.17 (FIPFA)
MW 393.10 901 Acetonide
MW 522.26
_
_
"acid''
H H
HOO-N 0 ,---......--., ,N
0
H F HO . 0 F
H
OH N
0 0 -...- OH N so --, _____
F I F I
F F
Mirdametinib
(PD-0325901) Crude PD-0325901
M
MW 482.20 W 482.20
101651 In some aspects, the synthesis for essentially pure crystalline
Form IV of N-((R)-
2,3-dihy droxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
of
Formula (I) comprises the reaction set forth according to Scheme III.
CA 03207513 2023- 8- 4
WO 2022/177557
PCT/US2021/018381
- 37 -
Scheme III
HO 0
F H
*0 H
N T3P , , _
0 N 0
0
F
F I
ON.)-0,,NH2 + 110 0 (50% in Et0Ac)
.---6 H
N
i-Pr2NEt la 101
._
PD-0337792 F THF, toluene
F I
(IPGA) PD-0315209
MTBE, aq. NaOH F
MW 147.17 (FIPFA)
901 Acetonide
MW 393.10
MW 522.26
aq. HCI
toluene, ACN
H H
H0-0- N 0
HOO' H
N 0
H F F Et0H
-
OH N
1401 0 . F I Et0H OH N ________ .
water I* 110
F I
F F
Mirdametinib Crude PD-0325901
(PD-0325901) MW 482.20
MW 482.20
101661 In some aspects, the synthesis for essentially pure Form IV of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of
Formula
(I) is as shown below in Scheme IV.
CA 03207513 2023- 8- 4
n
>
o
u,
r.,
o
,i
u,
,
u,
9,
4, Scheme IV
Step 1 0
1 0
N
N
tj
HON- 110 -4
-4
!A
0
!A
-
--1
o, xxO MW 163.13
______________________________________________________________ 0o
. i)---0
J,
N 0
, N)-- 0
C
\0H
0.
6P-0F3
NH2
0
_
MW: 132.16 MW: 264.22 MW: 277.28
MW: 147.17
(S)-Glycerol Acetonide PF-03714421 PD-0333760 P0-
0337792
( IPGAP )
( IPGA )
Step 2
HO 0 HO 0
.
NH2 H F
L.)
,6 F + so F N
oo
_____________________________________________________________ ,... 40 40
.
F F
I
F I F
MW: 176.09 MW: 237.02 MW:
393.10
TFBA FIA P0-
0315209 Step 3 ,
( FIPFA )
Step 4
¨
H H
H
H00- N 0 H F HOO- N H
H F /-..õõ,,..N 0 F t
0. i u
n
OH N
40 10 ..,_ OH N
I-7,
cp
N
= 40
4 /..'.-C) AI N la
F I F I
igr F lir I
ts.)
F F
F
O'
MW: 482.20 MW: 482.20 MW: 522.26
oo
Crude P0-0325901
w
PD-0325901 PD-0321920
x
( Mirdametinib )
( 901 Acetonide )
WO 2022/177557 - 39 -
PCT/US2021/018381
[0167] In some aspects, the methods provided herein provide a
crystalline composition
that is essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-
fluoro-4-iodo-phenylamino)-benzamide that contains < 0.2% of dimeric impurity
PF-
00191189
F
HN
H 0
N 0
8H N
P F-00191189
Exact Mass: 856.93
101681 In some aspects, the crystalline composition contains about
0.05% to about 0.19%
by weight of dimeric impurity PF-00191189. In some aspects, the crystalline
composition contains no detectable amount of dimeric impurity PF-00191189.
Definitions
101691 To facilitate understanding of the disclosure set forth herein,
a number of terms
are defined below.
101701 Generally, the nomenclature used herein and the laboratory
procedures in organic
chemistry, medicinal chemistry, and pharmacology described herein are those
well-
known and commonly employed in the art. Unless defined otherwise, all
technical and
scientific terms used herein generally have the same meaning as commonly
understood by
one of ordinary skill in the art to which this disclosure belongs.
101711 In this specification and the appended claims, the singular
forms "a," "an" and
"the" include plural referents unless the context clearly dictates otherwise.
The terms "a"
(or "an"), as well as the terms "one or more," and "at least one" can be used
interchangeably herein. In certain aspects, the term "a" or "an" means
"single." In other
aspects, the term "a" or "an" includes "two or more" or "multiple."
101721 Furthermore, "and/or" where used herein is to be taken as
specific disclosure of
each of the two specified features or components with or without the other.
Thus, the term
"and/or" as used in a phrase such as "A and/or B" herein is intended to
include "A and B,"
CA 03207513 2023- 8- 4
WO 2022/177557 - 40 -
PCT/US2021/018381
"A or B," "A" (alone), and "B" (alone). Likewise, the term "and/or" as used in
a phrase
such as "A, B, and/or C" is intended to encompass each of the following
aspects: A, B,
and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A
(alone); B
(alone); and C (alone).
101731 The terms "mirdametinib" and "PD-0325901" refer to the single
enantiomer N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide.
101741 The term "subject" refers to an animal, including, but not
limited to, a primate
(e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The
terms "subject"
and "patient" are used interchangeably herein in reference, for example, to a
mammalian
subject, such as a human subject.
101751 The term "pediatric" refers to a human subject under the age of
21 years at the
time of treatment. The term "pediatric" can be further divided into various
subpopulations
including- neonates (from birth through the first 28 days of life); infants
(29 days of age
to less than two years of age); children (two years of age to less than 12
years of age); and
adolescents (12 years of age through 21 years of age (up to, but not
including, the twenty-
second birthday)). See, e.g., Berhman R E, Kliegman R, Arvin A M, Nelson W E.
Nelson
Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996;
Rudolph
AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and
Avery M
D, First L R. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.
Younger
pediatric patients in particular, such as neonates, infants and young
children, can have
difficulty swallowing whole capsules or tablets.
101761 The term "dispersible" as used herein refers to a composition
(e.g., a tablet,
powder, granules, minitablets, or pellets (also known as "beads") which
disintegrates
and/or dissolves when combined with water or another potable liquid (e.g., a
non-water
beverage), or a subject's own saliva when placed in the subject's mouth, with
or without
the addition of agitation or temperature modification. In some aspects, the
dispersible
composition disintegrates or dissolves within 10 minutes, 9 minutes, 8
minutes, 7
minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute
after being
combined with water or another potable liquid. Such disintegration or
dissolution need
not be complete. For example, a dispersible tablet may dissolve almost
entirely, but some
undissolved particulate matter may remain.
101771 The term "orodispersible- refers to a composition which is
capable of dissolving
or disintegrating in a subject's mouth (i.e., dissolving or disintegrating in
a subject's
CA 03207513 2023- 8- 4
WO 2022/177557 - 41 -
PCT/US2021/018381
saliva) if administered orally, without a requirement of first dissolving or
disintegrating in
a separate container.
101781 As used herein, the terms "treat," "treated," and "treating"
mean both therapeutic
treatment and prophylactic or preventative measures wherein the object is to
prevent or
slow down (lessen) an undesired physiological condition, disorder, or disease,
or obtain
beneficial or desired clinical results. Thus, those in need of treatment
include those
already diagnosed with or suspected of having the disorder. Beneficial or
desired clinical
results include, but are not limited to, alleviation of symptoms; diminishment
of the
extent of a condition, disorder, or disease; stabilized (i.e., not worsening)
state of
condition, disorder, or disease; delay in onset or slowing of condition,
disorder, or disease
progression; amelioration of the condition, disorder, or disease state or
remission
(whether partial or total), whether detectable or undetectable; an
amelioration of at least
one measurable physical parameter, not necessarily discernible by the patient,
or
enhancement or improvement of condition, disorder, or disease. Treatment
includes
eliciting a clinically significant response without excessive levels of side
effects.
Treatment also includes prolonging survival as compared to expected survival
if not
receiving treatment. The term "therapeutically effective amount" is meant to
include the
amount of a compound that, when administered, is sufficient to prevent
development of,
or alleviate to some extent, one or more of the symptoms of a disorder,
disease, or
condition being treated. The term "therapeutically effective amount" also
refers to the
amount of a compound that is sufficient to elicit the biological or medical
response of a
cell, tissue, system, animal, or human, which is being sought by a researcher,
veterinarian,
medical doctor, or clinician.
[0179] In certain aspects, a subject is successfully "treated" for a
tumor, according to the
methods described herein if the patient shows one or more of the following: a
reduction in
the size of the tumor; relief of one or more symptoms associated with the
specific tumor;
a reduction in the volume of the tumor; improvement in quality of life;
increased
progression-free survival (PFS), disease-free survival (DFS), overall survival
(OS),
metastasis-free survival (MFS), complete response (CR), minimal residual
disease
(MRD), partial response (PR), stable disease (SD), a decrease in progressive
disease
(PD), an increased time to progression (TTP), or any combination thereof. In
some
aspects, nationally or internationally accepted standards of treatment
outcomes in a given
tumor can be used to determine whether an effective amount of mirdametinib
meets any
of these particular endpoints (e.g., CR, PFS, PR).
CA 03207513 2023- 8- 4
WO 2022/177557 - 42 -
PCT/US2021/018381
101801 In certain aspects, a subject is successfully "treated" for
cancer, e.g., lung cancer
or ovarian cancer, according to the methods disclosed herein if the patient
shows one or
more of the following: a reduction in the number of or complete absence of
cancer cells;
relief of one or more symptoms associated with the specific cancer; reduced
morbidity
and mortality; improvement in quality of life; increased progression-free
survival (PFS),
disease-free survival (DFS), overall survival (OS), metastasis-free survival
(1\SFS),
complete response (CR), minimal residual disease (MRD), partial response (PR),
stable
disease (SD), a decrease in progressive disease (PD), an increased time to
progression
(TTP), or any combination thereof In some aspects, nationally or
internationally accepted
standards of treatment outcomes in a given cancer can be used to determine
whether an
effective amount of mirdametinib meets any of these particular endpoints
(e.g., CR, PFS,
PR).
101811 The terms "pharmaceutically acceptable carrier,"
"pharmaceutically acceptable
excipient," "physiologically acceptable carrier," or "physiologically
acceptable excipient"
refer to a pharmaceutically acceptable material, composition, or vehicle, such
as a liquid
or solid excipient, solvent, or encapsulating material. In one aspect, each
component is
"pharmaceutically acceptable" in the sense of being compatible with the other
ingredients
of a pharmaceutical formulation, and suitable for use in contact with the
tissue or organ of
humans and animals without excessive toxicity, irritation, allergic response,
immunogenicity, or other problems or complications, commensurate with a
reasonable
benefit/risk ratio. See Remington: The Science and Practice of Pharmacy, 21'
Edition,
Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of
Pharmaceutical
Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the
American
Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives,
Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical
Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL,
2004
(incorporated herein by reference). Excipients can include, for example:
antiadherents,
antioxidants, binders, coatings, compression aids, disintegrants, dyes
(colors), emollients,
emulsifiers, fillers (diluents), film formers or coatings, flavors,
fragrances, glidants (flow
enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or
dispersing
agents, sweeteners, and waters of hydration. Exemplary excipients include, but
are not
limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium
phosphate
(dibasic), calcium stearate, calcium sulfate, croscarmellose, crosslinked
polyvinyl
pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin,
hydroxypropyl
CA 03207513 2023- 8- 4
WO 2022/177557 - 43 -
PCT/US2021/018381
cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate,
maltitol,
mannitol, methionine, methylcellulose, methyl paraben, microcrystalline
cellulose,
polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch,
propyl
paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl
cellulose,
sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic
acid, sucrose, talc,
titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.
101821 The term "pharmaceutical composition," as used herein,
represents a composition
containing a compound described herein formulated with one or more
pharmaceutically
acceptable excipients (carriers), and can be manufactured or sold with the
approval of a
governmental regulatory agency as part of a therapeutic regimen for the
treatment of
disease in a mammal. Pharmaceutical compositions can be formulated, for
example, for
oral administration in unit dosage form (e.g., a tablet (e.g., dispersible
tablet), powder
(e g , dispersible powder) capsule, granules, minitablets, pellets, caplet,
gelcap, or syrup)
101831 The terms "about" or "approximately" means within a range of an
acceptable error
for a particular value as determined by one of ordinary skill in the art,
which depends in
part on how the value is measured or determined. In some aspects, the term
"about" or
"approximately" means within 1, 2, 3, or 4 standard deviations. In some
aspects, the term
"about" or "approximately" means a quantity, level, value, number, frequency,
percentage, dimension, size, amount, weight or length that varies by as much
as 30, 25,
20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% to a reference quantity, level,
value, number,
frequency, percentage, dimension, size, amount, weight or length.
101841 As used herein, the term "administration" refers to the
administration of a
composition (e.g., a compound or a preparation that includes a compound as
described
herein) to a subject or system. Administration to an animal subject (e.g., to
a human) can
be by any appropriate route, such as one described herein.
101851 The term "solvate" refers to a compound provided herein or a
salt thereof, which
further includes a stoichiometric or non-stoichiometric amount of solvent
bound by non-
covalent intermolecular forces. Where the solvent is water, the solvate is a
hydrate.
Where the solvent includes ethanol, the compound can be an ethanol solvate.
101861 The term "crystalline," as used herein, refers to a solid-state
form which consists
of orderly arrangement of structural units. Different crystalline forms of the
same
compound, or a salt, hydrate, or solvate thereof, arise from different packing
of the
molecules in the solid-state, which results in different crystal symmetries
and/or unit cell
parameter. Different crystalline forms usually have different X-ray
diffraction patterns,
CA 03207513 2023- 8- 4
WO 2022/177557 - 44 -
PCT/US2021/018381
infrared spectra, melting points, density, hardness, crystal shape, optical
and electrical
properties, stability, and solubility. See, e.g., Remington'.s' Pharmaceutical
Sciences, 18th
ed., Mack Publishing, Easton PA, 173 (1990); lhe United States Pharmacopeia,
23rd ed.,
1843-1844 (1995) (incorporated herein by reference).
101871 Crystalline forms are commonly characterized by X-ray powder
diffraction
(XRPD). An XRF'D pattern of reflections (peaks, typically expressed in degrees
2-theta)
is commonly considered a fingerprint of a particular crystalline form. The
relative
intensities of the XRPD peaks can widely vary depending on, inter alia, the
sample
preparation technique, crystal size distribution, filters, the sample mounting
procedure,
and the particular instrument employed. In some instances, new peaks may be
observed
or existing peaks may disappear, depending on the type of instrument or the
settings. In
some instances, any particular peak in an XRPD pattern may appear as a
singlet, doublet,
triplet, quartet, or multiplet, depending on the type of instrument or the
settings, the
sensitivity of the instrument, measuring conditions, and/or purity of the
crystalline form.
In some instances, any particular peak in an XRPD may appear in a symmetric
shape or
in an asymmetric shape, e.g., having a shoulder. Moreover, instrument
variation and other
factors can affect the 2-theta values. A skilled artisan understanding these
variations is
capable of discriminating or ascertaining the defining features or
characteristics of a
particular crystal form using XRPD, as well as using other known
physicochemical
techniques.
101881 The term "anhydrate" as applied to a compound refers to a
crystalline form
wherein the compound contains no structural water within the crystal lattice.
101891 As used herein, the term "essentially pure" with respect to Form
IV means that the
composition comprising Form IV contains no detectable amount of another
polymorphic
form (e.g., Form I or Form II), as determined by observing no detectable
differences in an
XRPD and/or DSC pattern between a single Form IV crystal and the crystalline
composition of N4(R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide. However, "essentially pure" Form IV of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de can
include
impurities, such as, but not limited to, synthetic reactants or by-products
generated during
the chemical synthesis.
101901 As used herein, the term "aberration- as applied to a gene
refers to a mutation,
chromosomal loss or fusion, epigenetic chemical modification, or other event
which alters
the sequence, level of expression, or processed mRNA sequence associated with
a gene
CA 03207513 2023- 8- 4
WO 2022/177557 - 45 -
PCT/US2021/018381
relative to the sequence, level of expression, or processed mRNA sequence
associated
with the wild-type gene.
101911 It is understood that wherever aspects are described herein with
the language
"comprising," otherwise analogous aspects described in terms of "consisting
of' and/or
"consisting essentially of" are also provided.
101921 The details of one or more aspects are set forth in the
description below. Other
features, objects, and advantages will be apparent from the description and
from the
claims.
DETAILED DESCRIPTION OF THE INVENTION
101931 Novel crystalline forms and amorphous solids of N4R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide are described herein.
Pharmaceutical compositions (e.g., capsules, tablets, dispersible and non-
dispersible
dosage forms) and methods to treat a patient in need of therapeutic
administration of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
are also described herein. Additionally, a novel method of producing a pure
composition
of crystalline Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-
phenylamino)-benzamide is described herein.
Crystalline Forms and Amorphous Solids
101941 The present disclosure relates in part to novel crystalline
forms of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. As
with all
pharmaceutical compounds and compositions, the chemical and physical
properties of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
are important in its commercial development. These properties include, but are
not
limited to: (1) packing properties such as molar volume, bulk density and
hygroscopicity,
(2) thermodynamic properties such as melting temperature, vapor pressure and
solubility,
(3) kinetic properties such as dissolution rate and stability (including
stability at ambient
conditions, especially to moisture and under storage conditions), (4) surface
properties
such as surface area, wettability, interfacial tension and shape, (5)
mechanical properties
such as hardness, tensile strength, compactibility, handling, flow and blend;
and (6)
filtration properties. These properties can affect, for example, the
processing and storage
of the compound and pharmaceutical compositions comprising the compound.
CA 03207513 2023- 8- 4
WO 2022/177557 - 46 -
PCT/US2021/018381
[0195] In some aspects, the present disclosure provides a crystalline
form of N-((R)-2,3-
dihy droxypropoxy)-3 ,4-difluoro-2-(2-fluoro-44 odo-phenylamino)-b enzami de
of Formula
(I)
HOONO H r
OH
selected from the group consisting of:
a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.4 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta;
b) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.9 0.2, 7.2 0.2, and 21.2 0.2 degrees two theta;
c) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.3 + 0.2, 10.6 + 0.2, and 16.1 + 0.2 degrees two theta;
d) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.4 0.2, 10.7 0.2, and 18.7 0.2 degrees two theta;
e) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 6.7 0.2, 13.5 0.2, and 22,2 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 10.6 0.2, 19.6 0.2, and 24.8 0.2 degrees two theta;
g) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.5 0.2, 6.9 0.2, and 10.1 0.2 degrees two theta;
h) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 10.1 0.2, 17.3 0.2, and 22.6 0.2 degrees two theta;
CA 03207513 2023- 8- 4
WO 2022/177557 - 47 -
PCT/US2021/018381
i) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 4.6 0.2, 5.1 0.2, and 14.6 0.2 degrees two theta;
j) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 4.6 0.2, 23.4 0.2, and 25.2 0.2 degrees two theta;
k) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.5 0.2, 14.7 0.2, and 20.9 0.2 degrees two theta;
1) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-
3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 6.0 0.2, 17.1 0.2, and 20.6 0.2 degrees two theta;
m) a crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.9 0.2, 10.1 0.2, and 15.5 0.2 degrees two theta;
n) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 4.6 0.2, 10.7 0.2, and 15.9 0.2 degrees two theta;
o) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 10.2 0.2, 11.6 0.2, and 20.0 0.2 degrees two theta;
P) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-
3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 7.8 0.2, 14.0 0.2, and 17.1 0.2 degrees two theta;
cl) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-
3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.5 0.2, 8.2 0.2, and 16.7 0.2 degrees two theta;
r) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 7.2 0.2, 21.7 0.2, and 29.1 0.2 degrees two theta;
s) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 5.4 0.2, 9.7 0.2, and 10.7 0.2 degrees two theta; and
CA 03207513 2023- 8- 4
WO 2022/177557 - 48 -
PCT/US2021/018381
t) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-
3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 7.2 0.2, 20.6 0.2, and 23.0 0.2 degrees two theta.
101961 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks 5.4 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta.
In some
aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
5.4 +
0.2, 12.5 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 2A.
101971 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
2.7 wt% between about 35 C and about 100 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 77 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 95 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram
that
has a first endotherm onset at about 77 C and a second endotherm onset at
about 95 C.
In some aspects, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a
TGA
profile substantially as shown in FIG. 2B; and/or b) a DSC profile
substantially as shown
in FIG. 2B.
101981 In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form V.
101991 In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 5.9 0.2, 7.2 0.2, and 21.2 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 5.9
0.2, 7.2 0.2, 9.3 0.2, and 21.2 0.2 degrees two theta. In some aspects,
the crystalline
CA 03207513 2023- 8- 4
WO 2022/177557 - 49 -
PCT/US2021/018381
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
3A.
102001 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
2.4 wt% between about 25 C and about 125 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 41 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 70 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram
that
has an endotherm onset at about 109 C. In some aspects, the crystalline form
of N-((R)-
2,3 -di hydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-4-i odo-phenyl am i no)-
benzami de
exhibits a DSC thermogram that has an endotherm onset at about 41 C and an
endotherm
onset at about 70 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits a
DSC thermogram that has an endotherm onset at about 41 C and an endotherm
onset at
about 109 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has an endotherm onset at about 70 C and an endotherm onset at about 109
C. In
some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a
first
endotherm onset at about 41 C, a second endotherm onset at about 70 C, and a
third
endotherm onset at about 109 C. In some aspects, the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by: a) a TGA profile substantially as shown in FIG. 3B; and/or
b) a DSC
profile substantially as shown in FIG. 3B.
102011 In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VI.
102021 In some aspects, the crystalline form of N-((R)-2,3-dihy
droxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern haying peaks at 5.3 0.2, 10.6 0.2, and 16.1 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern haying peaks
at 5.3
CA 03207513 2023- 8- 4
WO 2022/177557 - 50 -
PCT/US2021/018381
0.2, 10.6 0.2, 13.9 0.2, and 16.1 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 4A.
102031 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
5.2 wt% between about 40 C and about 120 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 85 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endothermic event
at
about 110 C. In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has a first endotherm onset at about 85 C and a second endothermic event
at about
110 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a
TGA
profile substantially as shown in FIG. 4B; and/or b) a DSC profile
substantially as shown
in FIG. 4B.
102041 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VII.
102051 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 5.4 1 0.2, 10.7 1 0.2, and 18.7 1 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 5.4
0.2, 10.7 0.2, 18.7 0.2, and 23.9 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 5A.
102061 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
3.3 wt% between about 40 C and about 112 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 81 C. In some
aspects,
CA 03207513 2023- 8- 4
WO 2022/177557 - 51 -
PCT/US2021/018381
the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 110 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has a first endotherm onset at about 81 C and a second endotherm onset
at about 110
C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile
substantially as shown in FIG. 5B; and/or b) a DSC profile substantially as
shown in FIG.
5B.
102071 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VIII.
102081 In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 6.7 0.2, 13.5 0.2, and 22.2 0.2 degrees two
theta. In some
aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 6.7
0.2, 8.0 0.2, 13.5 0.2, and 22.2 0.2 degrees two theta. In some aspects,
the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 6A.
102091 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
4.6 wt% between about 28 C and about 128 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 84 C. In some
aspects,
the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 107 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de exhibits a DSC
thermogram
that has an endotherm onset at about 114 C. In some aspects, the crystalline
form of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 84 C and an
endotherm
onset at about 107 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits a
CA 03207513 2023- 8- 4
WO 2022/177557 - 52 -
PCT/US2021/018381
DSC thermogram that has an endotherm onset at about 84 C and an endotherm
onset at
about 114 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has an endotherm onset at about 107 C and an endotherm onset at about
114 C. In
some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a
first
endotherm onset at about 84 C, a second endotherm onset at about 107 C, and
a third
endotherm onset at about 114 C. In some aspects, the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by: a) a TGA profile substantially as shown in FIG. 6B; and/or
b) a DSC
profile substantially as shown in FIG. 6B.
102101 In some aspects, the crystalline form of N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is Form IX
102111 In some aspects, the crystalline form of N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 10.6 0.2, 19.6 0.2, and 24.8 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern haying peaks
at 5.5
0.2, 10.6 0.2, 19.6 0.2, and 24.8 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 7A.
102121 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
2.9 wt% between about 40 C and about 115 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-
benzami de
exhibits a DSC thermogram that has an endotherm onset at about 89 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide is characterized by: a) a TGA profile substantially as
shown in
FIG. 7B; and/or b) a DSC profile substantially as shown in FIG. 7B.
102131 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form X.
102141 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
CA 03207513 2023- 8- 4
WO 2022/177557 - 53 -
PCT/US2021/018381
pattern having peaks at 5.5 0.2, 6.9 0.2, and 10.1 0.2 degrees two
theta. In some
aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 5.5
0.2, 6.9 0.2, 10.1 0.2, and 19.2 0.2 degrees two theta. In some aspects,
the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 8A.
[0215] In some aspects, the TGA exhibits that the crystalline
form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
7.6 wt% between about 40 C and about 175 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 69 C. In some
aspects,
the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 104 C. In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has a first endotherm onset at about 69 C and a second endotherm onset
at about 104
C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile
substantially as shown in FIG. 8B; and/or b) a DSC profile substantially as
shown in FIG.
8B.
[0216] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XI.
[0217] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 10.1 0.2, 17.3 0.2, and 22.6 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 10.1
0.2, 17.3 0.2, 21.5 0.2, and 22.6 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 9A.
[0218] In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
CA 03207513 2023- 8- 4
WO 2022/177557 - 54 -
PCT/US2021/018381
8.5 wt% between about 40 C and about 160 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 72 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 109 C. In some aspects, the crystalline form of N4R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has a first endotherm onset at about 72 C and a second endotherm onset
at about 109
C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile
substantially as shown in FIG. 9B; and/or b) a DSC profile substantially as
shown in FIG.
9B.
102191 In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XII.
102201 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 4.6 0.2, 5.1 0.2, and 14.6 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern haying peaks
at 4.6
0.2, 5.1 0.2, 6.4 0.2, and 14.6 0.2 degrees two theta. In some aspects,
the crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
10A.
102211 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
3.1 wt% between about 20 C and about 100 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-
benzami de
exhibits a DSC thermogram that has an endotherm onset at about 55 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 109 C. In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has a first endotherm onset at about 55 C and a second endotherm onset
at about 109
C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile
CA 03207513 2023- 8- 4
WO 2022/177557 - 55 -
PCT/US2021/018381
substantially as shown in FIG. 10B; and/or b) a DSC profile substantially as
shown in
FIG. 10B.
102221 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIII.
[0223] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 4.6 0.2, 23.4 0.2, and 25.2 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 4.6
0.2, 23.4 0.2, 25.2 0.2, and 30.6 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
11A.
[0224] In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
0.15 wt% between about 40 C and about 150 C. In some aspects, the
crystalline form of
N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 111 C. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by: a) a TGA profile
substantially as
shown in FIG. 11B; and/or b) a DSC profile substantially as shown in FIG. 11B.
[0225] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIV.
[0226] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 5.5 0.2, 14.7 0.2, and 20.9 0.2 degrees two
theta. In some
aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 5.5
0.2, 14.7 0.2, 20.9 0.2, and 26.6 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 12A.
[0227] In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
CA 03207513 2023- 8- 4
WO 2022/177557 - 56 -
PCT/US2021/018381
3.8 wt% between about 40 C and about 150 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 104 C. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by: a) a TGA profile
substantially as
shown in FIG. 12B; and/or b) a DSC profile substantially as shown in FIG. 12B.
102281 In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XV.
102291 In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 6.0 + 0.2, 17.1 + 0.2, and 20.6 + 0.2 degrees two
theta. In some
aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 6U
0.2, 12.8 0.2, 17.1 0.2, and 20.6 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 13A.
102301 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
2.1 wt% between about 40 C and about 150 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 74 C. In some
aspects,
the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 102 C. In some aspects, the crystalline form of NAR)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has an endotherm onset at about 114 C. In some aspects, the crystalline
form of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 74 C and an
endotherm
onset at about 102 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits a
DSC thermogram that has an endotherm onset at about 74 C and an endotherm
onset at
about 114 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
CA 03207513 2023- 8- 4
WO 2022/177557 - 57 -
PCT/US2021/018381
that has an endotherm onset at about 102 C and an endotherm onset at about
114 C. In
some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a
first
endotherm onset at about 74 C, a second endotherm onset at about 102 C, and
a third
endotherm onset at about 114 C. In some aspects, the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by: a) a TGA profile substantially as shown in FIG. 13B; and/or
b) a DSC
profile substantially as shown in FIG. 13B.
102311 In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVI.
102321 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 19 02, 10 1 02, and 115 01 degrees two theta In
some
aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern haying peaks
at 5.9
0.2, 10.1 0.2, 11.7 0.2, and 15.5 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 14A.
102331 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
2.7 wt% between about 40 C and about 100 C. In some aspects, crystalline
form of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 89 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide is characterized by: a) a TGA profile substantially as
shown in
FIG. 14B; and/or b) a DSC profile substantially as shown in FIG. 14B.
102341 In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVII.
102351 In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern haying peaks at 4.6 0.2, 10.7 0.2, and 15.9 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern haying peaks
at 4.6
CA 03207513 2023- 8- 4
WO 2022/177557 - 58 -
PCT/US2021/018381
0.2, 10.7 0.2, 15.9 0.2, and 19.6 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 15A.
[0236] In some aspects, the TGA exhibits that the crystalline form of
NAR)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
1.6 wt% between about 30 C and about 150 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 83 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide is characterized by: a) a TGA profile substantially as
shown in
FIG. 15B; and/or b) a DSC profile substantially as shown in FIG. 15B.
[0237] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVIII.
[0238] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 10.2 0.2, 11.6 0.2, and 20.0 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 10.2
0.2, 11.6 0.2, 17.1 0.2, and 20.0 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 16A.
[0239] In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
1.85 wt% between about 23 C and about 92 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 69 C. In some
aspects,
the crystalline form of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 98 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram
that
has an endotherm onset at about 115 C. In some aspects, the crystalline form
of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
CA 03207513 2023- 8- 4
WO 2022/177557 - 59 -
PCT/US2021/018381
exhibits a DSC thermogram that has an endotherm onset at about 69 C and an
endotherm
onset at about 98 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits a
DSC thermogram that has an endotherm onset at about 69 C and an endotherm
onset at
about 115 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has an endotherm onset at about 98 C and an endotherm onset at about 115
C. In
some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a
first
endotherm onset at about 69 C, a second endotherm onset at about 98 C, and a
third
endotherm onset at about 115 C. In some aspects, the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by: a) a TGA profile substantially as shown in FIG 16B; and/or
b) a DSC
profile substantially as shown in FIG. 16B.
102401 In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIX.
102411 In some aspects, the crystalline form of N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 7.8 0.2, 14.0 0.2, and 17.1 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 7.8
0.2, 14.0 0.2, 15.6 0.2, and 17.1 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 17A.
102421 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
2.6 wt% between about 29 C and about 126 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-
benzami de
exhibits a DSC thermogram that has an endotherm onset at about 77 C. In some
aspects,
the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 92 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram
that
CA 03207513 2023- 8- 4
WO 2022/177557 - 60 -
PCT/US2021/018381
has an endotherm onset at about 110 C. In some aspects, the crystalline form
of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits a DSC thermogram that has an endotherm onset at about 77 C and an
endotherm
onset at about 92 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits a
DSC thermogram that has an endotherm onset at about 77 C and an endotherm
onset at
about 110 C. In some aspects, the crystalline form of N4R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has an endotherm onset at about 92 C and an endotherm onset at about 110
C. In
some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a
first
endotherm onset at about 77 C, a second endotherm onset at about 92 C, and a
third
endotherm onset at about 110 C In some aspects, the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by: a) a TGA profile substantially as shown in FIG. 17B, and/or
b) a DSC
profile substantially as shown in FIG. 17B.
102431 In some aspects, the crystalline form of N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XX.
102441 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 5.5 0.2, 8.2 0.2, and 16.7 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 5.5 +
0.2, 8.2 + 0.2, 16.7 + 0.2, and 17.7 + 0.2 degrees two theta. In some aspects,
the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 18A.
102451 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de
loses about
14.1 wt% between about 30 C and about 110 C. In some aspects, the
crystalline form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram has an endotherm onset at about 52 C. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
CA 03207513 2023- 8- 4
WO 2022/177557 - 61 -
PCT/US2021/018381
about 90 C. In some aspects, the crystalline form of NAR)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram
that
has a first endotherm onset at about 52 C and a second endotherm onset at
about 90 C.
In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile
substantially as shown in FIG. 18B; and/or b) a DSC profile substantially as
shown in
FIG. 18B.
102461 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXI.
102471 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 7.2 0.2, 21.7 0.2, and 29.1 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 7.2
0.2, 18.6 0.2, 21.7 0.2, and 29.1 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 19A.
102481 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
13.8 wt% between about 26 C and about 135 C. In some aspects, the
crystalline form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 65 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 89 C. In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram
that
has an endotherm onset at about 102 C. In some aspects, the crystalline form
of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de
exhibits a DSC thermogram that has an endotherm onset at about 65 C and an
endotherm
onset at about 89 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits a
DSC thermogram that has an endotherm onset at about 65 C and an endotherm
onset at
about 102 C. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-
CA 03207513 2023- 8- 4
WO 2022/177557 - 62 -
PCT/US2021/018381
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has an endotherm onset at about 89 C and an endotherm onset at about 102
C. In
some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a
first
endotherm onset at about 65 C, a second endotherm onset at about 89 C, and a
third
endotherm onset at about 102 C. In some aspects, the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by: a) a TGA profile substantially as shown in FIG. 19B; and/or
b) a DSC
profile substantially as shown in FIG. 19B.
102491 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXII.
102501 In some aspects, the crystalline form of N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 5.4 0.2, 9.7 0.2, and 10.7 0.2 degrees two
theta. In some
aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 5.4
0.2, 6.5 0.2, 9.7 0.2, and 10.7 0.2 degrees two theta. In some aspects,
the crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
20A.
102511 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses
about
4.4 wt% between about 27 C and about 137 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 81 C. In some
aspects,
the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset
at
about 101 C. In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram
that has a first endotherm onset at about 81 C and a second endotherm onset
at about 101
C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile
substantially as shown in FIG. 20B; and/or b) a DSC profile substantially as
shown in
FIG. 20B.
CA 03207513 2023- 8- 4
WO 2022/177557 - 63 -
PCT/US2021/018381
102521 In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXIII.
102531 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 7.2 0.2, 20.6 0.2, and 23.0 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 7.2
0.2, 9.5 + 0.2, 20.6 + 0.2, and 23.0 + 0.2 degrees two theta. In some aspects,
the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 21A.
102541 In some aspects, the TGA exhibits that the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de
loses about
1.2 wt% between about 30 C and about 119 C. In some aspects, the crystalline
form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 104 C. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by: a) a TGA profile
substantially as
shown in FIG. 21B; and/or b) a DSC profile substantially as shown in FIG. 21B.
102551 In some aspects, the crystal form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXIV.
102561 In some aspects, the present disclosure provides an amorphous
form of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
of
Formula (I)
HOONO ,
H 7
OH N
= F
(I).
102571 In some aspects, the amorphous form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern substantially as shown in FIG. 22A.
CA 03207513 2023- 8- 4
WO 2022/177557 - 64 -
PCT/US2021/018381
102581 In some aspects, the amorphous form of N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a
TGA
profile substantially as shown in FIG. 22B; and/or b) a DSC profile
substantially as
shown in FIG. 22B.
102591 In some aspects, the XRPD pattern is generated using a
PANALYTICAI?) X'Pert
Pro diffractometer using Ni-filtered Cu Ka (45 kV/40 mA) radiation and a step
size of
0.03 20 with a X'CELERATOR Real Time Multi-Strip detector, configured (a) on
the
incidental beam side as follows: variable divergence slits (10 mm irradiated
length), 0.04
rad Soller slits, fixed anti-scatter slit (0.50 ), and 10 mm beam mask, and
(b) on the
diffracted beam side as follows: variable anti-scatter slit (10 mm observed
length) and
0.04 rad Soller slit or a BRUKER D8 ADVANCETM system using Cu Ka (40 kV/40
mA) radiation and a step size of 0.03 20 with a LYNX:EYE detector, configured
(a) on
the incidental beam side as follows- Goebel mirror, mirror exit slit (0.2 mm),
2.5 Soller
slit, beam knife, and (b) on the diffracted beam side as follows: anti-scatter
slit (8 mm)
and 2.5 Soller slit; wherein samples are mounted flat on zero-background Si
wafers. In
some aspects, the DSC pattern is generated using a TA Instruments Q100 or
Q2000
differential scanning calorimeter at a rate of temperature increase of about
15 C/min.
Pharmaceutical Compositions
102601 In some aspects, the present disclosure provides a
pharmaceutical composition
comprising a crystalline form or amorphous solid of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein and one or
more
pharmaceutically acceptable carriers.
102611 In some aspects, the desired crystalline form or amorphous solid
comprises less
than 10% by weight total of one or more other crystalline forms and/or
amorphous solid.
In some aspects, the desired crystalline form or amorphous solid comprises
less than 9%
by weight total of one or more other crystalline forms and/or amorphous solid.
In some
aspects, the desired crystalline form or amorphous solid comprises less than
8% by
weight total of one or more other crystalline forms and/or amorphous solid. In
some
aspects, the desired crystalline form or amorphous solid comprises less than
7% by
weight total of one or more other crystalline forms and/or amorphous solid. In
some
aspects, the desired crystalline form or amorphous solid comprises less than
6% by
weight total of one or more other crystalline forms and/or amorphous solid. In
some
aspects, the desired crystalline form or amorphous solid comprises less than
5% by
CA 03207513 2023- 8- 4
WO 2022/177557 - 65 -
PCT/US2021/018381
weight total of one or more other crystalline forms and/or amorphous solid. In
some
aspects, the desired crystalline form or amorphous solid comprises less than
4% by
weight total of one or more other crystalline forms and/or amorphous solid. In
some
aspects, the desired crystalline form or amorphous solid comprises less than
3% by
weight total of one or more other crystalline forms and/or amorphous solid. In
some
aspects, the desired crystalline form or amorphous solid comprises less than
2% by
weight total of one or more other crystalline forms and/or amorphous solid. In
some
aspects, the desired crystalline form or amorphous solid comprises less than
1% by
weight total of one or more other crystalline forms and/or amorphous solid. In
some
aspects, the desired crystalline form or amorphous solid comprises less than
0.5% by
weight total of one or more other crystalline forms and/or amorphous solid. In
some
aspects, the desired crystalline form or amorphous solid comprises less than
0.4% by
weight total of one or more other crystalline forms and/or amorphous solid In
some
aspects, the desired crystalline form or amorphous form is essentially pure of
other
crystalline forms and/or amorphous solid.
102621 In some aspects, the pharmaceutical composition is for oral
administration. In
some aspects, the pharmaceutical composition is a solid dosage form. In some
aspects, the
pharmaceutical composition is a capsule, tablet (e.g., dispersible tablet),
powder (e.g.,
dispersible powder), granules (e.g., dispersible granules), minitablets (e.g.,
dispersible
minitablets), or pellets (e.g., dispersible pellets). In some aspects, the
pharmaceutical
composition (e.g., a dispersible tablet, dispersible powder, dispersible
granules,
dispersible minitablets, or dispersible pellets) further comprises one or more
pharmaceutically acceptable carriers. In some aspects, the pharmaceutical
composition is
for oral administration. In some aspects, the pharmaceutical composition is
orodispersible.
102631 In some aspects, the potable liquid is water, milk or a juice
(e.g., orange juice or
apple juice). In some aspects, the potable liquid is water. In some aspects,
the potable
liquid is a juice.
102641 In some aspects, the pharmaceutical composition is a tablet, a
powder, granules,
minitablets, or pellets.
102651 In some aspects, the pharmaceutical composition is a powder. In
some aspects,
the powder is a dispersible powder. In some aspects, a capsule or sachet
comprises the
dispersible powder.
CA 03207513 2023- 8- 4
WO 2022/177557 - 66 -
PCT/US2021/018381
102661 In some aspects, the pharmaceutical composition is in the form
of granules. In
some aspects, the granules are dispersible granules. In some aspects, a
capsule or sachet
comprises the dispersible granules.
102671 In some aspects, the pharmaceutical composition is in the form
of minitablets. In
some aspects, the minitablets are dispersible minitablets. In some aspects, a
capsule or
sachet comprises the dispersible minitablets.
102681 In some aspects, the pharmaceutical composition is in the form
of pellets. In some
aspects, the pellets are dispersible pellets. In some aspects, a capsule or
sachet comprises
the dispersible pellets.
102691 In some aspects, the pharmaceutical composition is a tablet. In
some aspects, the
tablet is a dispersible tablet. In some aspects, the dispersible tablet is an
orodispersible
tablet.
102701 In some aspects, the pharmaceutical composition comprises about
0 1 mg, about
0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg,
about 0.8
mg, about 0.9 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3
mg,
about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg,
about 6.5
mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5
mg, or
about 10 mg of one or more crystalline or amorphous forms of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In
some
aspects, the pharmaceutical composition comprises about 0.5 mg of one or more
crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical
composition
comprises about 1 mg of one or more crystalline or amorphous forms of N-((R)-
2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In
some
aspects, the pharmaceutical composition comprises about 2 mg of one or more
crystalline
or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide. In some aspects, the pharmaceutical composition
comprises
about 3 mg of one or more crystalline or amorphous forms of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de. In
some
aspects, the pharmaceutical composition comprises about 4 mg of one or more
crystalline
or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide. In some aspects, the pharmaceutical composition
comprises
about 5 mg of the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide.
CA 03207513 2023- 8- 4
WO 2022/177557 - 67 -
PCT/US2021/018381
[0271] In some aspects, the pharmaceutical composition comprises about
0.1 wt/wt% to
about 7 wt/wt% of one or more crystalline or amorphous forms of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In
some
aspects, the pharmaceutical composition comprises about 0.1 wt/wt% to about 5
wt/wt%
of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the
pharmaceutical composition comprises about 0.1 wt/wt%, about 0.2 wt/wt%, about
0.3
wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7
wt/wt%,
about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about
1.2
wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6
wt/wt%,
about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2 wt/wt%, about
2.1
wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5
wt/wt%,
about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about
3
wt/wt%, about 3.1 wt/wt%, about 3.2 wt/wt%, about 3.3 wt/wt%, about 3.4
wt/wt%,
about 3.5 wt/wt%, about 3.6 wt/wt%, about 3.7 wt/wt%, about 3.8 wt/wt%, about
3.9
wt/wt%, about 4 wt/wt%, about 4.1 wt/wt%, about 4.2 wt/wt%, about 4.3 wt/wt%,
about
4.4 wt/wt%, about 4.5 wt/wt%, about 4.6 wt/wt%, about 4.7 wt/wt%, about 4.8
wt/wt%,
about 4.9 wt/wt%, about 5 wt/wt%, about 5.1 wt/wt%, about 5.2 wt/wt%, about
5.3
wt/wt%, about 5.4 wt/wt%, about 5.5 wt/wt%, about 5.6 wt/wt%, about 5.7
wt/wt%,
about 5.8 wt/wt%, about 5.9 wt/wt%, about 6 wt/wt%, about 6.1 wt/wt%, about
6.2
wt/wt%, about 6.3 wt/wt%, about 6.4 wt/wt%, about 6.5 wt/wt%, about 6.6
wt/wt%,
about 6.7 wt/wt%, about 6.8 wt/wt%, about 6.9 wt/wt%, or about 7 wt/wt% of one
or
more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical
composition
comprises about 0.5 wt/wt% of one or more crystalline or amorphous forms of N-
((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl ami no)-benzami
de. In
some aspects, the pharmaceutical composition comprises about 0.8 wt/wt% of one
or
more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzami de.
102721 In some aspects, the pharmaceutical composition comprises one or
more diluents.
In some aspects, the pharmaceutical composition comprises about 50 wt/wt% to
about 98
wt/wt% of one or more diluents. In some aspects, the pharmaceutical
composition
comprises about 70 wt/wt% to about 98 wt/wt% of one or more diluent. In some
aspects,
the pharmaceutical composition comprises about 85 wt/wt% to about 95 wt/wt% of
one
CA 03207513 2023- 8- 4
WO 2022/177557 - 68 -
PCT/US2021/018381
or more diluents. In some aspects, the pharmaceutical composition comprises
about 50
wt/wt%, about 51 wt/wt%, about 52 wt/wt%, about 53 wt/wt%, about 54 wt/wt%,
about
55 wt/wt%, about 56 wt/wt%, about 57 wt/wt%, about 58 wt/wt%, about 59 wt/wt%,
about 60 wt/wt%, about 61 wt/wt%, about 62 wt/wt%, about 63 wt/wt%, about 64
wt/wt%, about 65 wt/wt%, about 66 wt/wt%, about 67 wt/wt%, about 68 wt/wt%,
about
69 wt/wt%, about 70 wt/wt%, about 71 wt/wt%, about 72 wt/wt%, about 73 wt/wt%,
about 74 wt/wt%, about 75 wt/wt%, about 76 wt/wt%, about 77 wt/wt%, about 78
wt/wt%, about 79 wt/wt%, about 80 wt/wt%, about 81 wt/wt%, about 82 wt/wt%,
about
83 wt/wt%, about 84 wt/wt%, about 85 wt/wt%, about 86 wt/wt%, about 87 wt/wt%,
about 88 wt/wt%, about 89 wt/wt%, about 90 wt/wt%, about 91 wt/wt%, about 92
wt/wt%, about 93 wt/wt%, about 94 wt/wt%, about 95 wt/wt%, about 96 wt/wt%,
about
97 wt/wt%, or about 98 wt/wt% of one or more diluents. In some aspects, the
pharmaceutical composition comprises about 90 wt/wt% of one or more diluents
In
some aspects, the pharmaceutical composition comprises about 93 wt/wt% of one
or more
diluents.
102731 In some aspects, at least one of the diluents is selected from
the group consisting
of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose,
pregelatinized
starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium
phosphate. In some
aspects, at least one of the diluents is microcrystalline cellulose.
102741 In some aspects, the pharmaceutical composition comprises about
50 wt/wt% to
about 98 wt/wt% microcrystalline cellulose. In some aspects, the
pharmaceutical
composition comprises about 70 wt/wt% to about 95 wt/wt% microcrystalline
cellulose.
In some aspects, the pharmaceutical composition comprises about 85 wt/wt % to
about 95
wt/wt % microcrystalline cellulose. In some aspects, the pharmaceutical
composition
comprises about 50 wt/wt%, about 51 wt/wt%, about 52 wt/wt%, about 53 wt/wt%,
about
54 wt/wt%, about 55 wt/wt%, about 56 wt/wt%, about 57 wt/wt%, about 58 wt/wt%,
about 59 wt/wt%, about 60 wt/wt%, about 61 wt/wt%, about 62 wt/wt%, about 63
wt/wt%, about 64 wt/wt%, about 65 wt/wt%, about 66 wt/wt%, about 67 wt/wt%,
about
68 wt/wt%, about 69 wt/wt%, about 70 wt/wt %, about 71 wt/wt %, about 72 wt/wt
%,
about 73 wt/wt %, about 74 wt/wt %, about 75 wt/wt %, about 76 wt/wt %, about
77
wt/wt %, about 78 wt/wt %, about 79 wt/wt %, about 80 wt/wt %, about 81 wt/wt
%,
about 82 wt/wt %, about 83 wt/wt %, about 84 wt/wt %, about 85 wt/wt %, about
86
wt/wt %, about 87 wt/wt %, about 88 wt/wt %, about 89 wt/wt %, about 90 wt/wt
%,
about 91 wt/wt%, about 92 wt/wt%, about 93 wt/wt%, about 94 wt/wt%, about 95
wt/wt
CA 03207513 2023- 8- 4
WO 2022/177557 - 69 -
PCT/US2021/018381
%, about 96 wt/wt%, about 97 wt/wt%, or about 98 wt/wt % microcrystalline
cellulose.
In some aspects, the pharmaceutical composition comprises about 90 wt/wt%
microcrystalline cellulose. In some aspects, the pharmaceutical composition
comprises
about 93 wt/wt% microcrystalline cellulose.
102751 In some aspects, the pharmaceutical composition comprises about
1 wt/wt% to
about 10 wt/wt% of one or more disintegrants. In some aspects, the
pharmaceutical
composition comprises about 3.5 wt/wt% to about 6 wt/wt% of one or more
disintegrants.
In some aspects, the pharmaceutical composition comprises about 1.0 wt/wt%,
about LI
wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5
wt/wt%,
about 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about
2.0
wt/wt%, about 2.1 wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4
wt/wt%,
about 2.5 wt/wt%, about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about
2.9
wt/wt%, about 3.0 wt/wt%, about 11 wt/wt%, about 12 wt/wt%, about 3.3 wt/wt%,
about 3.4 wt/wt%, about 3.5 wt/wt%, about 3.6 wt/wt%, about 3.7 wt/wt%, about
3.8
wt/wt%, about 3.9 wt/wt%, about 4.0 wt/wt%, about 4.1 wt/wt%, about 4.2
wt/wt%,
about 4.3 wt/wt%, about 4.4 wt/wt%, about 4.5 wt/wt%, about 4.6 wt/wt%, about
4.7
wt/wt%, about 4.8 wt/wt%, about 4.9 wt/wt%, about 5.0 wt/wt%, about 5.1
wt/wt%,
about 5.2 wt/wt%, about 5.3 wt/wt%, about 5.4 wt/wt%, about 5.5 wt/wt%, about
5.6
wt/wt%, about 5.7 wt/wt%, about 5.8 wt/wt%, about 5.9 wt/wt%, about 6.0
wt/wt%,
about 6.1 wt/wt%, about 6.2 wt/wt%, about 6.3 wt/wt%, about 6.4 wt/wt%, about
6.5
wt/wt%, about 6.6 wt/wt%, about 6.7 wt/wt%, about 6.8 wt/wt%, about 6.9
wt/wt%,
about 7.0 wt/wt%, about 7.1 wt/wt%, about 7.2 wt/wt%, about 7.3 wt/wt%, about
7.4
wt/wt%, about 7.5 wt/wt%, about 7.6 wt/wt%, about 7.7 wt/wt%, about 7.8
wt/wt%,
about 7.9 wt/wt%, about 8.0 wt/wt%, about 8.1 wt/wt%, about 8.2 wt/wt%, about
8.3
wt/wt%, about 8.4 wt/wt%, about 8.5 wt/wt%, about 8.6 wt/wt%, about 8.7
wt/wt%,
about 8.8 wt/wt%, about 8.9 wt/wt%, about 9.0 wt/wt%, about 9.1 wt/wt%, about
9.2
wt/wt%, about 9.3 wt/wt%, about 9.4 wt/wt%, about 9.5 wt/wt%, about 9.6
wt/wt%,
about 9.7 wt/wt%, about 9.8 wt/wt%, about 9.9 wt/wt%, or about 10.0 wt/wt% of
one or
more disintegrants. In some aspects, the pharmaceutical composition comprises
about 5
wt/wt% of one or more disintegrants.
102761 In some aspects, at least one of the disintegrants is selected
from the group
consisting of croscarmellose sodium, sodium starch glycolate, crospovidone,
microcrystalline cellulose, starch, pregelatinized starch, low substituted
hydroxypropyl
cellulose, and alginic acid. In some aspects, at least one of the
disintegrants is
CA 03207513 2023- 8- 4
WO 2022/177557 - 70 -
PCT/US2021/018381
croscarmellose sodium. In some aspects, the disintegrant is croscarmellose
sodium. In
some aspects, the pharmaceutical composition comprises about 1 wt/wt % to
about 10
wt/wt % croscarmellose sodium. In some aspects, the pharmaceutical composition
comprises about 3.5 wt/wt % to about 6 wt/wt % croscarmellose sodium. In some
aspects,
the pharmaceutical composition comprises about 1.0 wt/wt%, about 1.1 wt/wt%,
about
1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6
wt/wt%,
about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2.0 wt/wt%, about
2.1
wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5
wt/wt%,
about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about
3.0
wt/wt%, about 3.1 wt/wt%, about 3.2 wt/wt%, about 3.3 wt/wt%, about 3.4
wt/wt%,
about 3.5 wt/wt %, about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %,
about 3.9
wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3
wt/wt %,
about 4.4 wt/wt%, about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %,
about 4.8
wt/wt %, about 4.9 wt/wt %, about 5 wt/wt %, about 5.1 wt/wt %, about 5.2
wt/wt %,
about 5.3 wt/wt %, about 5.4 wt/wt %, about 5.5 wt/wt %, about 5.6 wt/wt %,
about 5.7
wt/wt %, about 5.8 wt/wt %, about 5.9 wt/wt %, about 6.0 wt/wt %, about 6.1
wt/wt%,
about 6.2 wt/wt%, about 6.3 wt/wt%, about 6.4 wt/wt%, about 6.5 wt/wt%, about
6.6
wt/wt%, about 6.7 wt/wt%, about 6.8 wt/wt%, about 6.9 wt/wt%, about 7.0
wt/wt%,
about 7.1 wt/wt%, about 7.2 wt/wt%, about 7.3 wt/wt%, about 7.4 wt/wt%, about
7.5
wt/wt%, about 7.6 wt/wt%, about 7.7 wt/wt%, about 7.8 wt/wt%, about 7.9
wt/wt%,
about 8.0 wt/wt%, about 8.1 wt/wt%, about 8.2 wt/wt%, about 8.3 wt/wt%, about
8.4
wt/wt%, about 8.5 wt/wt%, about 8.6 wt/wt%, about 8.7 wt/wt%, about 8.8
wt/wt%,
about 8.9 wt/wt%, about 9.0 wt/wt%, about 9.1 wt/wt%, about 9.2 wt/wt%, about
9.3
wt/wt%, about 9.4 wt/wt%, about 9.5 wt/wt%, about 9.6 wt/wt%, about 9.7
wt/wt%,
about 9.8 wt/wt%, about 9.9 wt/wt%, or about 10.0 wt/wt% croscarmellose
sodium. In
some aspects, the pharmaceutical composition comprises about 5 wt/wt %
croscarmellose
sodium.
102771 In some aspects, the pharmaceutical composition comprises 0
wt/wt % to about 5
wt/wt % of one or more lubricants. In some aspects, the pharmaceutical
composition
comprises about 0.1 wt/wt % to about 5 wt/wt % of one or more lubricants. In
some
aspects, the pharmaceutical composition comprises 0 wt/wt % to about 2 wt/wt %
of one
or more lubricants. In some aspects, the pharmaceutical composition comprises
about 0.1
wt/wt % to about 2 wt/wt % of one or more lubricants. In some aspects, the
pharmaceutical composition comprises 0 wt/wt %, about 0.1 wt/wt %, about 0.2
wt/wt %,
CA 03207513 2023- 8- 4
WO 2022/177557 - 71 -
PCT/US2021/018381
about 0.3 wt/wt %, about 0.4 wt/wt %, about 0.5 wt/wt %, about 0.6 wt/wt %,
about 0.7
wt/wt %, about 0.8 wt/wt %, about 0.9 wt/wt %, about 1 wt/wt %, about 1.1
wt/wt %,
about 1.2 wt/wt %, about 1.3 wt/wt %, about 1.4 wt/wt %, about 1.5 wt/wt %,
about 1.6
wt/wt %, about 1.7 wt/wt %, about 1.8 wt/wt %, about 1.9 wt/wt %, about 2
wt/wt %,
about 2.1 wt/wt %, about 2.2 wt/wt %, about 2.3 wt/wt %, about 2.4 wt/wt %,
about 2.5
wt/wt %, about 2.6 wt/wt %, about 2.7 wt/wt %, about 2.8 wt/wt %, about 2.9
wt/wt %,
about 3.0 wt/wt %, about 3.1 wt/wt %, about 3.2 wt/wt %, about 3.3 wt/wt %,
about 3.4
wt/wt %, about 3.5 wt/wt %, about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8
wt/wt %,
about 3.9 wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %,
about 4.3
wt/wt %, about 4.4 wt/wt %, about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7
wt/wt %,
about 4.8 wt/wt %, about 4.9 wt/wt %, or about 5.0 wt/wt % of one or more
lubricants. In
some aspects, the pharmaceutical composition comprises about 1 wt/wt % of one
or more
lubricants.
102781 In some aspects, at least one of the lubricants is selected from
the group consisting
of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic
acid,
hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax,
colloidal silicon
dioxide, and talc. In some aspects, at least one of the lubricants is
magnesium stearate. In
some aspects, the lubricant is magnesium stearate. In some aspects, the
pharmaceutical
composition comprises 0 wt/wt % to about 5 wt/wt % of magnesium stearate. In
some
aspects, the pharmaceutical composition comprises about 0.1 wt/wt % to about 5
wt/wt %
of magnesium stearate. In some aspects, the pharmaceutical composition
comprises 0
wt/wt % to about 2 wt/wt % of magnesium stearate. In some aspects, the
pharmaceutical
composition comprises about 0.1 wt/wt % to about 2 wt/wt % of magnesium
stearate. In
some aspects, the pharmaceutical composition comprises 0 wt/wt %, about 0.1
wt/wt %,
about 0.2 wt/wt %, about 0.3 wt/wt %, about 0.4 wt/wt %, about 0.5 wt/wt %,
about 0.6
wt/wt %, about 0.7 wt/wt %, about 0.8 wt/wt %, about 0.9 wt/wt %, about 1
wt/wt %,
about 1.1 wt/wt %, about 1.2 wt/wt %, about 1.3 wt/wt %, about 1.4 wt/wt %,
about 1.5
wt/wt %, about 1.6 wt/wt %, about 1.7 wt/wt %, about 1.8 wt/wt %, about 1.9
wt/wt %,
about 2 wt/wt %, about 2.1 wt/wt %, about 2.2 wt/wt %, about 2.3 wt/wt %,
about 2.4
wt/wt %, about 2.5 wt/wt %, about 2.6 wt/wt %, about 2.7 wt/wt %, about 2.8
wt/wt %,
about 2.9 wt/wt %, about 3.0 wt/wt %, about 3.1 wt/wt %, about 3.2 wt/wt %,
about 3.3
wt/wt %, about 3.4 wt/wt %, about 3.5 wt/wt %, about 3.6 wt/wt %, about 3.7
wt/wt %,
about 3.8 wt/wt %, about 3.9 wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %,
about 4.2
wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt %, about 4.5 wt/wt %, about 4.6
wt/wt %,
CA 03207513 2023- 8- 4
WO 2022/177557 - 72 -
PCT/US2021/018381
about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %, or about 5.0 wt/wt %
magnesium stearate. In some aspects, the pharmaceutical composition comprises
0 wt/wt
% magnesium stearate. In some aspects, the pharmaceutical composition
comprises about
0.1 wt/wt % magnesium stearate. In some aspects, the pharmaceutical
composition
comprises about 1 wt/wt % magnesium stearate.
102791 In some aspects, the pharmaceutical composition comprises 0
wt/wt% to about 5
wt/wt% of one or more flavoring agents. In some aspects, the pharmaceutical
composition
comprises 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents. In
some
aspects, the pharmaceutical composition comprises 0 wt/wt%, about 0.1 wt/wt%,
about
0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6
wt/wt%,
about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about
1.1
wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5
wt/wt%,
about 1 6 wt/wt%, about 1 7 wt/wt%, about 1 8 wt/wt%, about 1 9 wt/wt%, about
2
wt/wt%, about 2.1 wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4
wt/wt%,
about 2.5 wt/wt%, about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about
2.9
wt/wt%, about 3.0 wt/wt%, about 3.1 wt/wt%, about 3.2 wt/wt%, about 3.3
wt/wt%,
about 3.4 wt/wt%, about 3.5 wt/wt%, about 3.6 wt/wt%, about 3.7 wt/wt%, about
3.8
wt/wt%, about 3.9 wt/wt%, about 4.0 wt/wt%, about 4.1 wt/wt%, about 4.2
wt/wt%,
about 4.3 wt/wt%, about 4.4 wt/wt%, about 4.5 wt/wt%, about 4.6 wt/wt%, about
4.7
wt/wt%, about 4.8 wt/wt%, about 4.9 wt/wt%, or about 5.0 wt/wt% of one or more
flavoring agents. In some aspects, the pharmaceutical composition comprises
about 2
wt/wt% of one or more flavoring agents.
102801 In some aspects, at least one of the flavoring agents is
selected from the group
consisting of natural or synthetic flavors including but not limited to, grape
flavoring,
bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring,
strawberry
flavoring, raspberry flavoring, mint flavoring, peppermint flavoring,
grapefruit flavoring,
pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring,
banana flavoring,
or cherry flavoring. In some aspects, at least one of the flavoring agents is
grape
flavoring. In some aspects, the pharmaceutical composition comprises 0 wt/wt%
to about
5.0 wt/wt% grape flavoring. In some aspects, the pharmaceutical composition
comprises
0 wt/wt% to about 2.5 wt/wt% grape flavoring. In some aspects, the
pharmaceutical
composition comprises 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3
wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7
wt/wt%,
about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about
1.2
CA 03207513 2023- 8- 4
WO 2022/177557 - 73 -
PCT/US2021/018381
wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6
wt/wt%,
about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2 wt/wt%, about
2.1
wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5
wt/wt%,
about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about
3.0
wt/wt%, about 3.1 wt/wt%, about 3.2 wt/wt%, about 3.3 wt/wt%, about 3.4
wt/wt%,
about 3.5 wt/wt%, about 3.6 wt/wt%, about 3.7 wt/wt%, about 3.8 wt/wt%, about
3.9
wt/wt%, about 4.0 wt/wt%, about 4.1 wt/wt%, about 4.2 wt/wt%, about 4.3
wt/wt%,
about 4.4 wt/wt%, about 4.5 wt/wt%, about 4.6 wt/wt%, about 4.7 wt/wt%, about
4.8
wt/wt%, about 4.9 wt/wt%, or about 5.0 wt/wt% grape flavoring. In some
aspects, the
pharmaceutical composition comprises about 2 wt/wt% grape flavoring.
102811 In some aspects, the pharmaceutical composition comprises 0
wt/wt% to about 5
wt/wt% of one or more sweeteners. In some aspects, the pharmaceutical
composition
comprises 0 wt/wt% to about 2 wt/wt% of one or more sweeteners In some
aspects, the
pharmaceutical composition comprises 0 wt/wt%, about 0.1 wt/wt%, about 0.2
wt/wt%,
about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about
0.7
wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%,
about
1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6
wt/wt%,
about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2 wt/wt%, about
2.1 wt/wt
%, about 2.2 wt/wt %, about 2.3 wt/wt %, about 2.4 wt/wt %, about 2.5 wt/wt %,
about
2.6 wt/wt %, about 2.7 wt/wt %, about 2.8 wt/wt %, about 2.9 wt/wt %, about
3.0 wt/wt
%, about 3.1 wt/wt %, about 3.2 wt/wt %, about 3.3 wt/wt %, about 3.4 wt/wt %,
about
3.5 wt/wt %, about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %, about
3.9 wt/wt
%, about 4.0 wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3 wt/wt %,
about
4.4 wt/wt %, about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %, about
4.8 wt/wt
%, about 4.9 wt/wt %, or about 5.0 wt/wt % of one or more sweeteners. In some
aspects,
the pharmaceutical composition comprises about 1 wt/wt% of one or more
sweeteners.
102821 In some aspects, at least one of the sweeteners is selected from
the group
consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol,
sorbitol,
glucose, fructose, and aspartame. In some aspects, at least one of the
sweeteners is
sucralose. In some aspects, the sweetener is sucralose. In some aspects, the
pharmaceutical composition comprises 0 wt/wt% to about 5 wt/vv-t% sucralose.
In some
aspects, the pharmaceutical composition comprises 0 wt/wt% to about 2 wt/wt%
sucralose. In some aspects, the pharmaceutical composition comprises 0 wt/wt%,
about
0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5
wt/wt%,
CA 03207513 2023- 8- 4
WO 2022/177557 - 74 -
PCT/US2021/018381
about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about
1
wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4
wt/wt%,
about 1.5 wt/wt%, 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9
wt/wt%,
about 2 wt/wt%, about 2.1 wt/wt %, about 2.2 wt/wt %, about 2.3 wt/wt %, about
2.4
wt/wt %, about 2.5 wt/wt %, about 2.6 wt/wt %, about 2.7 wt/wt %, about 2.8
wt/wt %,
about 2.9 wt/wt %, about 3.0 wt/wt %, about 3.1 wt/wt %, about 3.2 wt/wt %,
about 3.3
wt/wt %, about 3.4 wt/wt %, about 3.5 wt/wt %, about 3.6 wt/wt %, about 3.7
wt/wt %,
about 3.8 wt/wt %, about 3.9 wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %,
about 4.2
wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt %, about 4.5 wt/wt %, about 4.6
wt/wt %,
about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %, or about 5.0 wt/wt %
sucralose. In some aspects, the pharmaceutical composition comprises about 1
wt/wt%
sucralose.
102831 In some aspects, the pharmaceutical composition is a capsule In
some aspects, the
capsule comprises about 1 mg of one or more crystalline or amorphous forms of
N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,
wherein each component of the capsule is as follows: (a) about 0.1 wt/wt% to
about 7
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more
diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 5 wt/wt% of one or more lubricants; and (e) a gelatin capsule
which
encapsulates components (a)-(d).
102841 In some aspects, the capsule comprises about 1 mg of one or more
crystalline or
amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide, wherein each component of the capsule is as follows:
(a) about
0.25 wt/wt% to about 1.5 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95
wt/wt% of
one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more
disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more
lubricants; and (e)
a gelatin capsule which encapsulates components (a)-(d).
102851 In some aspects, the capsule comprises about 2 mg of one or more
crystalline or
amorphous forms of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide, wherein each component of the capsule is as follows:
(a) about
0.1 wt/wt% to about 7 wt/wt% of the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt%
of one
CA 03207513 2023- 8- 4
WO 2022/177557 - 75 -
PCT/US2021/018381
or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more
disintegrants; (d)
0 wt/wt% to about 5 wt/wt% of one or more lubricants; and (e) a gelatin
capsule which
encapsulates components (a)-(d).
102861 In some aspects, the capsule comprises about 2 mg of one or more
crystalline or
amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide, wherein each component of the capsule is as follows:
(a) about
0.25 wt/wt% to about 1.5 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95
wt/wt% of
one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more
disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more
lubricants; and (e)
a gelatin capsule which encapsulates components (a)-(d). In some aspects, the
capsule
comprises about 3 mg of one or more crystalline or amorphous forms of N-((R)-
2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de
described
herein, wherein each component of the capsule is as follows: (a) about 0.1
wt/wt% to
about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more
diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 5 wt/wt% of one or more lubricants; and (e) a gelatin capsule
which
encapsulates components (a)-(d).
102871 In some aspects, the capsule comprises about 3 mg of one or more
crystalline or
amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide described herein, wherein each component of the capsule
is as
follows: (a) about 0.25 wt/wt% to about L5 wt/wt% of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b)
about
85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to
about 6
wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of
one or
more lubricants; and (e) a gelatin capsule which encapsulates components (a)-
(d). In
some aspects, the capsule comprises about 4 mg of one or more crystalline or
amorphous
forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide, wherein each component of the capsule is as follows: (a) about 0.1
wt/wt% to
about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more
diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0
CA 03207513 2023- 8- 4
WO 2022/177557 - 76 -
PCT/US2021/018381
wt/wt% to about 5 wt/wt% of one or more lubricants; and (e) a gelatin capsule
which
encapsulates components (a)-(d).
102881 In some aspects, the capsule comprises about 4 mg of one or more
crystalline or
amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide, wherein each component of the capsule is as follows:
(a) about
0.25 wt/wt% to about 1.5 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95
wt/wt% of
one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more
disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more
lubricants; and (e)
a gelatin capsule which encapsulates components (a)-(d).
102891 In some aspects, the capsule comprises about 5 mg of one or more
crystalline or
amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide, wherein each component of the capsule is as follows:
(a) about
2.5 wt/wt% to about 7.0 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt%
of one
or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more
disintegrants;
and (d) a gelatin capsule which encapsulates components (a)-(c).
102901 In some aspects, the capsule comprises about 5 mg of one or more
crystalline or
amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide, wherein each component of the capsule is as follows:
(a) about
2.5 wt/wt% to about 7.0 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt%
of one
or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more
disintegrants;
and (d) a gelatin capsule which encapsulates components (a)-(c).
102911 In some aspects, the pharmaceutical composition is a tablet
(e.g., dispersible
tablet). In some aspects, the tablet is a dispersible tablet. In some aspects,
the tablet (e.g.,
dispersible tablet) comprises about 0.5 mg of a crystalline or amorphous form
of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
described herein, and wherein each component of the tablet (e.g., dispersible
tablet) is as
follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to
about
98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of
one or
more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring
agents; (e) 0
CA 03207513 2023- 8- 4
WO 2022/177557 - 77 -
PCT/US2021/018381
wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about
5
wt/wt% of one or more lubricants.
102921 In some aspects, the tablet (e.g., dispersible tablet) comprises
about 0.5 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the tablet (e.g., dispersible tablet) is as follows: (a) about 0.5 wt/wt% to
about 1.2 wt/wt-13/0
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c)
about
3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to
about 2.5
wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one
or more
sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more
lubricants.
102931 In some aspects, the tablet (e.g., dispersible tablet) comprises
about 1 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the tablet (e.g., dispersible tablet) is as follows: (a) about 0.1 wt/wt% to
about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c)
about 1
wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about
5
wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one
or more
sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
102941 In some aspects, the tablet (e.g., dispersible tablet) comprises
about 1 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the tablet (e.g., dispersible tablet) is as follows: (a) about 0.5 wt/wt% to
about 1.2 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzami de; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents;
(c) about
3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to
about 2.5
wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one
or more
sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more
lubricants
102951 In some aspects, the tablet (e.g, dispersible tablet) comprises
about 2 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the tablet (e.g., dispersible tablet) is as follows: (a) about 0.1 wt/wt% to
about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
CA 03207513 2023- 8- 4
WO 2022/177557 - 78 -
PCT/US2021/018381
benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c)
about 1
wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about
5
wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one
or more
sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
102961 In some aspects, the tablet (e.g, dispersible tablet) comprises
about 2 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the tablet (e.g., dispersible tablet) is as follows: (a) about 0.5 wt/wt% to
about 1.2 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c)
about
3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) 0 wt/we/0 to
about 2.5
wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one
or more
sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more
lubricants
102971 In some aspects, the tablet (e.g., dispersible tablet) comprises
about 3 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the tablet (e.g., dispersible tablet) is as follows: (a) about 0.1 wt/wt% to
about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c)
about 1
wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about
5
wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one
or more
sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
102981 In some aspects, the tablet (e.g., dispersible tablet) comprises
about 3 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the tablet (e.g., dispersible tablet) is as follows: (a) about 0.5 wt/wt% to
about 1 .2 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c)
about
3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to
about 2.5
wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one
or more
sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more
lubricants.
102991 In some aspects, the tablet (e.g., dispersible tablet) comprises
about 4 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
CA 03207513 2023- 8- 4
WO 2022/177557 - 79 -
PCT/US2021/018381
the tablet (e.g, dispersible tablet) is as follows: (a) about 0.1 wt/wt% to
about 7 wt/wt% of
the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c)
about 1
wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about
5
wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one
or more
sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103001 In some aspects, the tablet (e.g., dispersible tablet) comprises
about 4 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the tablet (e.g, dispersible tablet) is as follows: (a) about 0.5 wt/wt% to
about 1.2 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c)
about
3.5 wt/wt% to about 6 wt/wt% of one or more di sintegrants; (d) 0 wt/wt% to
about 2 5
wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one
or more
sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more
lubricants.
103011 In some aspects, the tablet (e.g., dispersible tablet) comprises
about 5 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the tablet (e.g., dispersible tablet) is as follows: (a) about 0.1 wt/wt% to
about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c)
about 1
wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about
5
wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one
or more
sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103021 In some aspects, the tablet (e.g., dispersible tablet) comprises
about 5 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the tablet (e.g., dispersible tablet) is as follows: (a) about 0.5 wt/wt% to
about 1.2 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c)
about
3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to
about 2.5
wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one
or more
sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more
lubricants.
CA 03207513 2023- 8- 4
WO 2022/177557 - 80 -
PCT/US2021/018381
[0303] In some aspects, the tablet (e.g., dispersible tablet) comprises
about 0.1 mg to
about 5 mg of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible
in a
potable liquid; and wherein each component of the pharmaceutical composition
is as
follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of a crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b)
about
50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to
about 10
wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or
more
flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners;
and (f) 0
wt/wt% to about 5 wt/wt% of one or more lubricants.
103041 In some aspects, the tablet (e.g., dispersible tablet) comprises
about 0.1 mg to
about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible
in a
potable liquid; and wherein each component of the pharmaceutical composition
is as
follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of a crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b)
about
85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to
about 6
wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt% of one
or more
flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners;
and (0
about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
103051 In some aspects, the tablet (e.g., dispersible tablet) is
dissolved in a potable liquid
before administration. In some aspects, the potable liquid is water, milk or a
juice (e.g.,
orange juice or apple juice). In some aspects, the potable liquid is water. In
some aspects,
the potable liquid is a juice. In some aspects, the tablet is orodispersible
in a subject's
saliva.
103061 In some aspects, the pharmaceutical composition is a powder
(e.g., dispersible
powder). In some aspects, the powder (e.g., dispersible powder) is a
dispersible powder.
In some aspects, a capsule or sachet comprises the dispersible powder. In some
aspects,
the powder (e.g., dispersible powder) comprises about 0.5 mg of a crystalline
or
amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide described herein, and wherein each component of the
powder
(e.g., dispersible powder) is as follows: (a) about 0.1 wt/wt% to about 7
wt/wt% of the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide;
(b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1
wt/wt% to
CA 03207513 2023- 8- 4
WO 2022/177557 - 81 -
PCT/US2021/018381
about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt%
of one or
more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more
sweeteners; and
(f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0307] In some aspects, the powder (e.g., dispersible powder) comprises
about 0.5 mg of
a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the powder (e.g., dispersible powder) is as follows: (a) about 0.5 wt/wt% to
about 1.2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 2.5 wt/vv-t% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
[0308] In some aspects, the powder (e.g., dispersible powder) comprises
about 1 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the powder (e.g., dispersible powder) is as follows: (a) about 0.1 wt/wt% to
about 7
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more
diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d)
wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
[0309] In some aspects, the powder (e.g., dispersible powder) comprises
about 1 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-i odo-phenylamino)-benzami de described herein, and wherein each
component of
the powder (e.g., dispersible powder) is as follows: (a) about 0.5 wt/wt% to
about 1.2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzami de; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 2.5 wt/vv-t% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
CA 03207513 2023- 8- 4
WO 2022/177557 - 82 -
PCT/US2021/018381
[0310] In some aspects, the powder (e.g, dispersible powder) comprises
about 2 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the powder (e.g., dispersible powder) is as follows: (a) about 0.1 wt/wt% to
about 7
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more
diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
103111 In some aspects, the powder (e.g, dispersible powder) comprises
about 2 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the powder (e.g., dispersible powder) is as follows: (a) about 0.5 wt/wt% to
about 1.2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
10M21 In some aspects, the powder (e.g., dispersible powder) comprises
about 3 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the powder (e.g., dispersible powder) is as follows: (a) about 0.1 wt/wt% to
about 7
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzami de; (b) about 50 wt/wt% to about 98 wt/wt% of one or more
diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
103131 In some aspects, the powder (e.g., dispersible powder) comprises
about 3 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the powder (e.g., dispersible powder) is as follows: (a) about 0.5 wt/wt% to
about 1.2
CA 03207513 2023- 8- 4
WO 2022/177557 - 83 -
PCT/US2021/018381
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 2.5 wt/vv-t% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
103141 In some aspects, the powder (e.g., dispersible powder) comprises
about 4 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the powder (e.g, dispersible powder) is as follows: (a) about 0.1 wt/wt% to
about 7
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more
diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
103151 In some aspects, the powder (e.g., dispersible powder) comprises
about 4 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the powder (e.g, dispersible powder) is as follows: (a) about 0.5 wt/wt% to
about 1.2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/vv-t% of one or more
disintegrants; (d) 0
wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (t) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
103161 In some aspects, the powder (e.g., dispersible powder) comprises
about 5 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the powder (e.g., dispersible powder) is as follows: (a) about 0.1 wt/wt% to
about 7
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more
diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
CA 03207513 2023- 8- 4
WO 2022/177557 - 84 -
PCT/US2021/018381
wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
103171 In some aspects, the powder (e.g., dispersible powder) comprises
about 5 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the powder (e.g., dispersible powder) is as follows: (a) about 0.5 wt/wt% to
about 1.2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
103181 In some aspects, the powder (e g , dispersible powder) comprises
about 0.1 mg to
about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible
in a
potable liquid; and wherein each component of the pharmaceutical composition
is as
follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of a crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b)
about
50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to
about 10
wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or
more
flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners;
and (f) 0
wt/wt% to about 5 wt/wt% of one or more lubricants.
103191 In some aspects, the powder (e.g., dispersible powder) comprises
about 0.1 mg to
about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible
in a
potable liquid; and wherein each component of the pharmaceutical composition
is as
follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of a crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b)
about
85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to
about 6
wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt% of one
or more
flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners;
and (f)
about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
103201 In some aspects, the powder (e.g., dispersible powder) is
dissolved in a potable
liquid before administration. In some aspects, the potable liquid is water,
milk or a juice
CA 03207513 2023- 8- 4
WO 2022/177557 - 85 -
PCT/US2021/018381
(e.g., orange juice or apple juice). In some aspects, the potable liquid is
water. In some
aspects, the potable liquid is a juice. In some aspects, the powder is
orodispersible in a
subject's saliva.
103211 In some aspects, the pharmaceutical composition is in the form
of granules (e.g.,
dispersible granules). In some aspects, the granules (e.g., dispersible
granules) are
dispersible granules. In some aspects, a capsule or sachet comprises the
dispersible
granules. In some aspects, the granules (e.g., dispersible granules) comprise
about 0.5 mg
of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the granules (e.g., dispersible granules) is as follows: (a) about 0.1 wt/wt%
to about 7
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more
diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
103221 In some aspects, the granules (e.g., dispersible granules)
comprise about 0.5 mg of
a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the granules (e.g., dispersible granules) is as follows: (a) about 0.5 wt/wt%
to about 1.2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (t) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
103231 In some aspects, the granules (e.g., dispersible granules)
comprise about 1 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-i odo-phenylamino)-benzami de described herein, and wherein each
component of
the granules (e.g., dispersible granules) is as follows: (a) about 0.1 wt/wt%
to about 7
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more
diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
CA 03207513 2023- 8- 4
WO 2022/177557 - 86 -
PCT/US2021/018381
wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
103241 In some aspects, the granules (e.g., dispersible granules)
comprise about 1 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the granules (e.g., dispersible granules) is as follows: (a) about 0.5 wt/wt%
to about 1.2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
103251 In some aspects, the granules (e g, dispersible granules)
comprise about 2 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the granules (e.g., dispersible granules) is as follows: (a) about 0.1 wt/wt%
to about 7
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more
diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d)
wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
103261 In some aspects, the granules (e.g, dispersible granules)
comprise about 2 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the granules (e.g., dispersible granules) is as follows: (a) about 0.5 wt/wt%
to about 1.2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
103271 In some aspects, the granules (e.g., dispersible granules)
comprise about 3 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
CA 03207513 2023- 8- 4
WO 2022/177557 - 87 -
PCT/US2021/018381
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the granules (e.g., dispersible granules) is as follows: (a) about 0.1 wt/wt%
to about 7
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more
diluents; (c) about 1 wt/wt% to about 10 -wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
103281 In some aspects, the granules (e.g., dispersible granules)
comprise about 3 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the granules (e.g., dispersible granules) is as follows: (a) about 0.5 wt/wt%
to about 1.2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
103291 In some aspects, the granules (e.g., dispersible granules)
comprise about 4 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the granules (e.g, dispersible granules) is as follows: (a) about 0.1 wt/wt%
to about 7
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more
diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
103301 In some aspects, the granules (e.g., dispersible granules)
comprise about 4 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the granules (e.g, dispersible granules) is as follows: (a) about 0.5 wt/wt%
to about 1.2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
CA 03207513 2023- 8- 4
WO 2022/177557 - 88 -
PCT/US2021/018381
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
103311 In some aspects, the granules (e.g., dispersible granules)
comprise about 5 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the granules (e.g., dispersible granules) is as follows: (a) about 0.1 wt/wt%
to about 7
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more
diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d)
wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
103321 In some aspects, the granules (e.g., dispersible granules)
comprise about 5 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the granules (e.g., dispersible granules) is as follows: (a) about 0.5 wt/wt%
to about 1.2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/vv-t% of one or more
disintegrants; (d) 0
wt/wt% to about 2.5 wt/vv-t% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
103331 In some aspects, the granules (e.g., dispersible granules)
comprise about 0.1 mg to
about 5 mg of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible
in a
potable liquid; and wherein each component of the pharmaceutical composition
is as
follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of a crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b)
about
50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to
about 10
wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or
more
flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners;
and (f) 0
wt/wt% to about 5 wt/wt% of one or more lubricants.
CA 03207513 2023- 8- 4
WO 2022/177557 - 89 -
PCT/US2021/018381
[0334] In some aspects, the granules (e.g., dispersible granules)
comprise about 0.1 mg to
about 5 mg of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible
in a
potable liquid; and wherein each component of the pharmaceutical composition
is as
follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of a crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b)
about
85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to
about 6
wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt% of one
or more
flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners;
and (f)
about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
103351 In some aspects, the granules (e.g., dispersible granules) are
dissolved in a potable
liquid before administration. In some aspects, the potable liquid is water,
milk or a juice
(e g , orange juice or apple juice) In some aspects, the potable liquid is
water In some
aspects, the potable liquid is a juice. In some aspects, the granules are
orodispersible in a
subject's saliva.
103361 In some aspects, the pharmaceutical composition is in the form
of minitablets
(e.g., dispersible minitablets). In some aspects, the minitablets are
dispersible
minitablets. In some aspects, the minitablets (e.g., dispersible minitablets)
comprise about
0.5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and
wherein each
component of the minitablets (e.g., dispersible minitablets) is as follows:
(a) about 0.1
wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt%
of one
or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more
disintegrants; (d)
0 wt/wt% to about 5 wt/vv-t% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
103371 In some aspects, the minitablets (e.g., dispersible minitablets)
comprise about 0.5
mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of the minitablets (e.g., dispersible minitablets) is as follows:
(a) about 0.5
wt/wt% to about 1.2 wt/vv-t% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-
fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt%
of one
or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more
disintegrants;
CA 03207513 2023- 8- 4
WO 2022/177557 - 90 -
PCT/US2021/018381
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt%
to about
2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one
or more lubricants.
[0338] In some aspects, the minitablets (e.g., dispersible minitablets)
comprise about 1
mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of the minitablets (e.g., dispersible minitablets) is as follows:
(a) about 0.1
wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/vv-t%
of one
or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more
disintegrants; (d)
0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
[0339] In some aspects, the minitablets (e.g., dispersible minitablets)
comprise about 1
mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of the minitablets (e.g., dispersible minitablets) is as follows:
(a) about 0.5
wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt%
of one
or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more
disintegrants;
(d) 0 wt/vv-t% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0
wt/wt% to about
2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/vv-
t% of one
or more lubricants.
[0340] In some aspects, the minitablets (e.g, dispersible minitablets)
comprise about 2 mg
of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-i odo-phenylamino)-benzami de described herein, and wherein each
component of
the minitablets (e.g., dispersible minitablets) is as follows: (a) about 0.1
wt/wt% to about
7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzami de; (b) about 50 wt/wt% to about 98 wt/wt% of one or more
diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
CA 03207513 2023- 8- 4
WO 2022/177557 - 91 -
PCT/US2021/018381
[0341] In some aspects, the minitablets (e.g, dispersible minitablets)
comprise about 2 mg
of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the minitablets (e.g., dispersible minitablets) is as follows: (a) about 0.5
wt/wt% to about
1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
103421 In some aspects, the minitablets (e.g., dispersible minitablets)
comprise about 3
mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of the minitablets (e.g., dispersible minitablets) is as follows:
(a) about 0.1
wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt%
of one
or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more
disintegrants; (d)
0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
103431 In some aspects, the minitablets (e.g., dispersible minitablets)
comprise about 3
mg of a crystalline or amorphous form of N4R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of the minitablets (e.g., dispersible minitablets) is as follows:
(a) about 0.5
wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt%
of one
or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more
disintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt%
to about
2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one
or more lubricants.
103441 In some aspects, the minitablets (e.g., dispersible minitablets)
comprise about 4
mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of the minitablets (e.g, dispersible minitablets) is as follows: (a)
about 0.1
CA 03207513 2023- 8- 4
WO 2022/177557 - 92 -
PCT/US2021/018381
wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt%
of one
or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more
disintegrants; (d)
0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
103451 In some aspects, the minitablets (e.g., dispersible minitablets)
comprise about 4
mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of the minitablets (e.g, dispersible minitablets) is as follows: (a)
about 0.5
wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt%
of one
or more diluents; (c) about 3 5 wt/wt% to about 6 wt/wt% of one or more di
sintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt%
to about
2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one
or more lubricants.
103461 In some aspects, the minitablets (e.g., dispersible minitablets)
comprise about 5
mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of the minitablets (e.g., dispersible minitablets) is as follows:
(a) about 0.1
wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt%
of one
or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more
disintegrants; (d)
0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 5
wt/wt% of one or more sweeteners; and (t) 0 wt/wt% to about 5 wt/wt% of one or
more
lubricants.
103471 In some aspects, the minitablets (e.g., dispersible minitablets)
comprise about 5
mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of the minitablets (e.g., dispersible minitablets) is as follows:
(a) about 0.5
wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt%
of one
or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more
disintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt%
to about
CA 03207513 2023- 8- 4
WO 2022/177557 - 93 -
PCT/US2021/018381
2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/vv-
t% of one
or more lubricants.
103481 In some aspects, the minitablets (e.g., dispersible minitablets)
comprise about 0.1
mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible
in a
potable liquid; and wherein each component of the pharmaceutical composition
is as
follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of a crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b)
about
50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to
about 10
wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or
more
flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners;
and (f) 0
wt/wt% to about 5 wt/wt% of one or more lubricants.
103491 In some aspects, the minitablets (e g , dispersible minitablets)
comprise about 0 1
mg to about 5 mg of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible
in a
potable liquid; and wherein each component of the pharmaceutical composition
is as
follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of a crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b)
about
85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to
about 6
wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt% of one
or more
flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners;
and (f)
about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
103501 In some aspects, the minitablets (e.g., dispersible minitablets)
are dissolved in a
potable liquid before administration. In some aspects, the potable liquid is
water, milk or
a juice (e.g., orange juice or apple juice). In some aspects, the potable
liquid is water. In
some aspects, the potable liquid is a juice. In some aspects, the minitablets
are
orodispersible in a subject's saliva.
103511 In some aspects, the pharmaceutical composition is in the form
of pellets (e.g.,
dispersible pellet). In some aspects, the pellets are dispersible pellets. In
some aspects,
the pellets (e.g., dispersible pellets) comprise about 0.5 mg of a crystalline
or amorphous
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide described herein, and wherein each component of the pellets (e.g.,
dispersible
pellets) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-
2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b)
about
CA 03207513 2023- 8- 4
WO 2022/177557 - 94 -
PCT/US2021/018381
50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to
about 10
wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or
more
flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners;
and (f) 0
wt/wt% to about 5 wt/wt% of one or more lubricants.
[0352] In some aspects, the pellets (e.g., dispersible pellets)
comprise about 0.5 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the pellets (e.g., dispersible pellets) is as follows: (a) about 0.5 wt/wt% to
about 1.2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
[0353] In some aspects, the pellets (e.g., dispersible pellets)
comprise about 1 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the pellets (e.g., dispersible pellets) is as follows: (a) about 0.1 wt/wt% to
about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c)
about 1
wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about
5
wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one
or more
sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0354] In some aspects, the pellets (e.g., dispersible pellets)
comprise about 1 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the pellets (e.g., dispersible pellets) is as follows: (a) about 0.5 wt/wt% to
about 1.2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
CA 03207513 2023- 8- 4
WO 2022/177557 - 95 -
PCT/US2021/018381
[0355] In some aspects, the pellets (e.g, dispersible pellets) comprise
about 2 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the pellets (e.g., dispersible pellets) is as follows: (a) about 0.1 wt/wt% to
about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c)
about 1
wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about
5
wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one
or more
sweeteners; and (0 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103561 In some aspects, the pellets (e.g, dispersible pellets) comprise
about 2 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the pellets (e g , dispersible pellets) is as follows- (a) about 05 wt/wt% to
about 1 2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 2.5 wt/vv-t% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
103571 In some aspects, the pellets (e.g., dispersible pellets)
comprise about 3 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the pellets (e.g., dispersible pellets) is as follows: (a) about 0.1 wt/wt% to
about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c)
about 1
wt/wt% to about 10 wt/wt% of one or more di sintegrants; (d) 0 wt/wt% to about
5
wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one
or more
sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103581 In some aspects, the pellets (e.g., dispersible pellets)
comprise about 3 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the pellets (e.g., dispersible pellets) is as follows: (a) about 0.5 wt/wt% to
about 1.2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
CA 03207513 2023- 8- 4
WO 2022/177557 - 96 -
PCT/US2021/018381
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
[0359] In some aspects, the pellets (e.g., dispersible pellets)
comprise about 4 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the pellets (e.g, dispersible pellets) is as follows: (a) about 0.1 wt/wt% to
about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c)
about 1
wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about
5
wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one
or more
sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants
[0360] In some aspects, the pellets (e.g., dispersible pellets)
comprise about 4 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the pellets (e.g, dispersible pellets) is as follows: (a) about 0.5 wt/wt% to
about 1.2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0
wt/wt% to about 2.5 wt/vv-t% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
[0361] In some aspects, the pellets (e.g., dispersible pellets)
comprise about 5 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the pellets (e.g., dispersible pellets) is as follows: (a) about 0.1 wt/wt% to
about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c)
about 1
wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about
5
wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one
or more
sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0362] In some aspects, the pellets (e.g., dispersible pellets)
comprise about 5 mg of a
crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
CA 03207513 2023- 8- 4
WO 2022/177557 - 97 -
PCT/US2021/018381
fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each
component of
the pellets (e.g., dispersible pellets) is as follows: (a) about 0.5 wt/wt% to
about 1.2
wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
diluents; (c) about 3.5 wt/wt% to about 6 wt/vv-t% of one or more
disintegrants; (d) 0
wt/wt% to about 2.5 wt/vv-t% of one or more flavoring agents; (e) 0 wt/wt% to
about 2
wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or
more lubricants.
103631 In some aspects, the pellets (e.g., dispersible pellets)
comprise about 0.1 mg to
about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible
in a
potable liquid; and wherein each component of the pharmaceutical composition
is as
follows- (a) about 0.1 wt/wt% to about 7 wt/wt% of a crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b)
about
50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to
about 10
wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or
more
flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners;
and (f) 0
wt/wt% to about 5 wt/wt% of one or more lubricants.
103641 In some aspects, the pellets (e.g., dispersible pellets)
comprise about 0.1 mg to
about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible
in a
potable liquid; and wherein each component of the pharmaceutical composition
is as
follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of a crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b)
about
85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to
about 6
wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt% of one
or more
flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners;
and (f)
about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
103651 In some aspects, the pellets (e.g., dispersible pellets) are
dissolved in a potable
liquid before administration. In some aspects, the potable liquid is water,
milk or a juice
(e.g., orange juice or apple juice). In some aspects, the potable liquid is
water. In some
aspects, the potable liquid is a juice. In some aspects, the pellets are
orodispersible in a
subject's saliva.
CA 03207513 2023- 8- 4
WO 2022/177557 - 98 -
PCT/US2021/018381
Methods of Treatment
[0366] In some aspects, the present disclosure provides a method of
treating a tumor, a
cancer, or a Rasopathy disorder comprising administering to a subject in need
of such
treatment a pharmaceutical composition described herein.
[0367] In some aspects, the tumor is a neurofibroma. In some aspects,
the tumor is a
neurofibroma associated with Neurofibromatosis Type 1. In some aspects, the
tumor is
selected from the group consisting of cutaneous neurofibroma, plexiform
neurofibroma,
optic pathway glioma, low grade glioma, high grade glioma, or malignant
peripheral
nerve sheath tumor. In some aspects, the tumor is plexiform neurofibroma.
[0368] In some aspects, the subject has been diagnosed with a Rasopathy
disorder
selected from the group consisting of neurofibromatosis type 1,
neurofibromatosis type 2,
cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan
syndrome, and Noonan syndrome with multiple lentigines.
103691 In some aspects, the cancer is selected from the group
consisting of skin cancer,
malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic
neoplasm,
lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer,
thyroid cancer,
cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer,
sarcoma, bladder
cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid
cystic
carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer,
pancreatic
cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous
carcinoma of the
peritoneum. In some aspects, the leukemia is selected from the group
consisting of acute
lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic
leukemia, and
chronic myelogenous leukemia. In some aspects, the lymphoma is selected from
the
group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma,
follicular
lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small
lymphocytic lymphoma, and Waldenstrom macroglobulinemia. In some aspects, the
lung
cancer is selected from the group consisting of lung adenocarcinoma, squamous
non-
small cell lung cancer, non-squamous non-small cell lung cancer, and small
cell lung
cancer.
[0370] In some aspects, the subject bears a mutation or other
aberration in one or more
genes for which the mutation or other aberration causes a gain or loss of
function
characteristic of certain cancers, wherein the mutation or other aberration in
one or more
CA 03207513 2023- 8- 4
WO 2022/177557 - 99 -
PCT/US2021/018381
genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS,
BRAF,
MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
103711 In some aspects, an individual dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as more
than one
capsule, tablet (e.g., dispersible tablet), dose of powder (e.g, dispersible
powder), dose of
granules (e.g., dispersible granules), dose of minitablets (e.g., dispersible
minitablets),
dose of pellets (e.g., dispersible pellets), or a combination thereof. For
example, a dose of
3 mg of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide can be administered as two capsules ¨ one containing 2
mg and
the other containing 1 mg or as three capsules each containing 1 mg. As
another example,
a dose of 1.5 mg of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide can be administered as two dispersible dosage forms ¨
one
dispersible tablet containing 1 mg and a separate unit of dispersible powder
containing
0.5 mg or as three units of dispersible powder each containing 0.5 mg.
[0372] In some aspects, if the N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide is to be administered more than one time a day,
the total
daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide can be divided so the patient receives different doses
at each
administration. For example, if the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is to be 2 mg
administered two
times per day, the patient can receive 0.5 mg (e.g., as one 0.5 mg tablet
(e.g., dispersible
tablet)) in the morning and 1.5 mg (e.g., as one 0.5 mg dose of powder (e.g.,
dispersible
powder) and one 1 mg capsule) in the evening.
[0373] In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is provided in an amount of about 0.1 mg to about
20 mg
per dose of the pharmaceutical compositions described herein. In some aspects,
one or
more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is provided in an amount of about 0.1 mg,
about
0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg,
about U.S
mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg,
about 6
mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg,
about
13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about
19 mg,
or about 20 mg per dose. In some aspects, one or more crystalline or amorphous
forms of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
CA 03207513 2023- 8- 4
WO 2022/177557 - 100 -
PCT/US2021/018381
is provided in an amount of about 0.5 mg per dose. In some aspects, one or
more
crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide is provided in an amount of about 1 mg
per dose.
In some aspects, one or more crystalline or amorphous forms of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
provided
in an amount of about 2 mg per dose. In some aspects, one or more crystalline
or
amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is provided in an amount of about 3 mg per dose. In
some
aspects, one or more crystalline or amorphous forms of N#R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in an
amount of
about 4 mg per dose. In some aspects, one or more crystalline or amorphous
forms of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
provided in an amount of about 5 mg per dose In some aspects, one or more
crystalline
or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is provided in an amount of about 10 mg per dose. In
some
aspects, one or more crystalline or amorphous forms of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in an
amount of
about 20 mg per dose.
103741 In some aspects, the pharmaceutical composition comprising one
or more
crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide is administered one time, two times,
three times,
or four times per day. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times per day.
103751 In some aspects, the present disclosure provides a method of
treating a tumor, a
cancer, or a Rasopathy disorder comprising administering to a patient in need
of such
treatment a pharmaceutical composition described herein, wherein the total
daily dose of
the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is administered two times daily of about 0.1 mg to about 10 mg each.
103761 In some aspects, the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered via a pharmaceutical composition
described herein, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is provided at a total daily dose that does not
exceed 0.5
mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg,
13
CA 03207513 2023- 8- 4
WO 2022/177557 - 101 -
PCT/US2021/018381
mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some aspects, the N-
((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered in a total daily dose that does not exceed 20 mg. In some
aspects, the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
administered in a total daily dose that does not exceed 15 mg. In some
aspects, the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
administered in a total daily dose that does not exceed 12 mg. In some
aspects, the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
administered in a total daily dose that does not exceed 10 mg. In some
aspects, the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
administered in a total daily dose that does not exceed 8 mg. In some aspects,
the N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered in a total daily dose that does not exceed 6 mg. In some aspects,
the N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered in a total daily dose that does not exceed 4 mg. In some aspects,
the N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered in a total daily dose that does not exceed 2 mg. In some aspects,
the N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered in a total daily dose that does not exceed 1 mg.
103771 In some aspects, the present disclosure provides a method of
treating a tumor, a
cancer, or a Rasopathy disorder comprising administering to a patient in need
of such
treatment a pharmaceutical composition described herein, wherein the total
daily dose of
the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is administered once daily at a dose of about 0.1 mg to about 20 mg.
103781 In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is administered once
daily. In some
aspects, the total daily dose of the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of
about 0.1
mg to about 20 mg. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg,
about 0.4
mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg,
about 1 mg,
about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about
8 mg,
about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg,
about 15
CA 03207513 2023- 8- 4
WO 2022/177557 - 102 -
PCT/US2021/018381
mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg. In
some
aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of
about 0.5
mg.
In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily
at a dose
of about 1 mg. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 2 mg. In some aspects, the total
daily dose of
the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is administered once daily at a dose of about 3 mg. In some aspects,
the total
daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is administered once daily at a dose of about 4 mg. In
some
aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of
about 5
mg. In some aspects, the total daily dose of the N#R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily
at a dose
of about 6 mg. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once
daily at a
dose of about 7 mg. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 8 mg. In some aspects, the total
daily dose of
the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is administered once daily at a dose of about 9 mg. In some aspects,
the total
daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is administered once daily at a dose of about 10 mg. In
some
aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of
about 11
mg.
In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily
at a dose
of about 12 mg. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 13 mg. In some aspects, the total
daily dose
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is administered once daily at a dose of about 14 mg. In some
aspects, the
CA 03207513 2023- 8- 4
WO 2022/177557 - 103 -
PCT/US2021/018381
total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide is administered once daily at a dose of about 15 mg. In
some
aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of
about 16
mg.
In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily
at a dose
of about 17 mg. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 18 mg. In some aspects, the total
daily dose
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is administered once daily at a dose of about 19 mg. In some
aspects, the
total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide is administered once daily at a dose of about 20 mg
103791 In some aspects, the total daily dose of the N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times
daily. In
some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose
of about
0.1 mg to about 10 mg each. In some aspects, the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 0.1 mg, about 0.2 mg, about
0.3 mg,
about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about
0.9 mg,
about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about
7 mg,
about 8 mg, about 9 mg, or about 10 mg each. In some aspects, the total daily
dose of the
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
is administered two times daily at a dose of about 0.25 mg each. In some
aspects, the total
daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is administered two times daily at a dose of about 0.5
mg each.
In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a
dose of
about 1 mg each. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 2 mg each. In some aspects,
the total daily
dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is administered two times daily at a dose of about 3 mg
each. In
CA 03207513 2023- 8- 4
WO 2022/177557 - 104 -
PCT/US2021/018381
some aspects, the total daily dose of the NAR)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose
of about
4 mg each. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two
times daily
at a dose of about 5 mg each. In some aspects, the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 6 mg each. In some aspects,
the total daily
dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is administered two times daily at a dose of about 7 mg
each. In
some aspects, the total daily dose of the N4R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose
of about
8 mg each. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de is administered two
times daily
at a dose of about 9 mg each. In some aspects, the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 10 mg each.
103801 In some aspects, the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle
comprising: (a)
21 days in which the total daily dose is administered; and (b) 7 days in which
no N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle
comprising: (a) 21 consecutive days in which the total daily dose is
administered;
followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
103811 In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle
comprising: (a)
three 7-day periods each comprising (i) 5 days in which the total daily dose
is
administered and (ii) 2 days in which no N#R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide; and (b) 7 days in which no N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle
comprising: (a) three 7-day periods each comprising (i) 5 consecutive days in
which the
CA 03207513 2023- 8- 4
WO 2022/177557 - 105 -
PCT/US2021/018381
total daily dose is administered and (ii) 2 consecutive days in which no N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
followed
by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered.
103821 In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle
comprising 28
days in which the total daily dose is administered.
103831 In some aspects, the 28-day dosing cycle is repeated up to a
total of 24
consecutive 28-day dosing cycles.
103841 In some aspects, the pharmaceutical composition is a dispersible
tablet, dispersible
powder, dispersible granules, dispersible minitablets, or dispersible pellets,
and wherein
the pharmaceutical composition is dispersed in a potable liquid (e.g., water
or a juice
(e g , orange juice or apple juice)) prior to administration to the subject
103851 In some aspects, the composition is an orodispersible dosage
form (e.g.,
dispersible tablet, dispersible powder, dispersible granules, dispersible
minitablets, or
dispersible pellets) which is administered to the subject without first
dissolving the
dosage form in a separate container.
103861 In some aspects, the subject experiences dysphagia. In some
aspects, the subject
experiences dysphagia caused by one or more of: disease of the nervous system,
muscle
weakening, developmental disability, stroke, injury, anatomical defect,
cancer, treatment
for cancer, allergic reaction, dementia, memory loss, or cognitive decline. In
some
aspects, the subject has been diagnosed with an autism spectrum disorder. In
some
aspects, the subject has been diagnosed with a craniofacial disorder. In some
aspects, the
subject has been diagnosed with myasthenia gravis. In some aspects, the
subject has been
diagnosed with tardive dyskinesia.
103871 In some aspects, the subject is a pediatric subject In some
aspects, the subject is
less than 18 years old, less than 17 years old, less than 16 years old, less
than 15 years
old, less than 14 years old, less than 13 years old, less than 12 years old,
less than 11
years old, less than 10 years old, less than 9 years old, less than 8 years
old, less than 7
years old, less than 6 years old, less than 5 years old, less than 4 years
old, less than 3
years old, less than 2 years old, or less than 1 year old. In some aspects,
the subject is 1
year old, 2 years old, 3 years old, 4 years old, 5 years old, 6 years old, 7
years old, 8 years
old, 9 years old, 10 years old, 11 years old, 12 years old, 13 years old, 14
years old, 15
years old, 16 years old, or 17 years old. In some aspects, the subject is less
than 13 years
CA 03207513 2023- 8- 4
WO 2022/177557 - 106 -
PCT/US2021/018381
old. In some aspects, the subject is less than 12 years old. In some aspects,
the subject is
less than 11 years old. In some aspects, the subject is less than 10 years
old. In some
aspects, the subject is less than 9 years old. In some aspects, the subject is
less than 8
years old. In some aspects, the subject is less than 7 years old. In some
aspects, the
subject is less than 6 years old. In some aspects, the subject is less than 5
years old. In
some aspects, the subject is less than 4 years old. In some aspects, the
subject is less than
3 years old. In some aspects, the subject is less than 2 years old. In some
aspects, the
subject is less than 1 year old. In some aspects, the subject is about 2 to
about 18 years
old. In some aspects, the subject is about 3 to about 17 years old. In some
aspects, the
subject is about 4 to about 16 years old. In some aspects, the subject is
about 5 to about
15 years old. In some aspects, the subject is about 6 to about 14 years old.
In some
aspects, the subject is about 7 to about 13 years old. In some aspects, the
subject is about
8 to about 12 years old
103881 In some aspects, the subject is a geriatric subject. In some
aspects, the subject is
more than 30 years old, more than 35 years old, more than 40 years old, more
than 45
years old, more than 50 years old, more than 55 years old, more than 60 years
old, more
than 65 years old, more than 70 years old, more than 75 years old, more than
80 years old,
more than 85 years old, more than 90 years old, more than 95 years old, or
more than 100
year old. In some aspects, the subject is more than 50 years old. In some
aspects, the
subject is more than 60 years old. In some aspects, the subject is more than
70 years old.
In some aspects, the subject is more than 80 years old. In some aspects, the
subject is
more than 90 years old. In some aspects, the subject is more than 100 years
old.
103891 In some aspects, the present disclosure provides use of a
pharmaceutical
composition described herein for the manufacture of a medicament for treating
a cancer, a
tumor, or a Rasopathy disorder.
Methods of Preparing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide and Essentially Pure Form IV
103901 Novel methods of producing N4R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide of Formula (I)
CA 03207513 2023- 8- 4
WO 2022/177557 - 107 -
PCT/US2021/018381
HOONO H
6H
N
F
(I),
that comprise reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a
coupling
reagent that is 1-propylphosphonic anhydride ("T3P") to obtain 901 Acetonide,
as shown
in Scheme I below, are disclosed herein.
Scheme 1
HO 0
,N 0
0
H2 + 10 T3P
PD-0337792
101
(IPGA)
MW 147.17 PD-0315209
(FIPFA)
MW 393.10 901 Acetonide
MW 522.26
103911 In some aspects, the T3P is in solution. In some aspects, T3P is
provided as a
solution in ethyl acetate.
103921 In some aspects, the method of producing essentially pure Form
IV N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of
Formula
(I) comprises (a) reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a
coupling
reagent that is T3P to obtain 901 Acetonide; and (b) treating 901 Acetonide
with acid to
form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide, as shown in Scheme II below.
CA 03207513 2023- 8- 4
WO 2022/177557
PCT/US2021/018381
- 108 -
Scheme II
¨
_
HO 0
*0 H F
0 H
H F
ON,õ1-0.NH2 + N T3P k6
N
101 0
PD-0337792 F
F I
(IPGA) PD-0315209 F
MW 147.17 (FIPFA)
901 Acetonide
MW 393.10
MW 522.26
¨
_
'acid''
H H
HO0.-N 0 õ....,õ _........_ ,N
0
H
H F HO- 0 F
OH N 0 (51-1 _..,_
F I F I
F F
Mirdametinib
(PD-0325901) Crude PD-0325901
MW 482.20
MW 482.20
103931 In some aspects, the synthesis for essentially pure crystalline
Form IV of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
of
Formula (I) comprises the reaction set forth according to Scheme III.
CA 03207513 2023- 8- 4
WO 2022/177557
PCT/US2021/018381
- 109 -
Scheme III
¨
_
HO 0
+0 H
N F
T3P 0,.." -
H
...---.... ,N
0
.õ 0
H F
ON.).0,NH2 + 0 0 (50% in Et0Ae)
F I
i-Pr2NEt
N
__________________________________________________________ . 110
0
PD-0337792 F THF, toluene
F I
(IPGA) PD-0315209
MTBE, aq. NaOH F
MW 147.17 (FIPFA) 901
Acetonide
MW 393.10
MW 522.26
aq. HCI
toluene, ACN
H H
0
HOO'N F HOON ". F
Et0H
H H
61-I N F I Et0H OH N .
_______
0 0 . _____________________________________
water 0 0
F I
F F
Mirdametinib Crude PD-0325901
(PD-0325901) MW 482.20
MW 482.20
103941 In some aspects, the synthesis for essentially pure Form IV of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of
Formula
(I) is as shown below in Scheme IV.
CA 03207513 2023- 8- 4
n
>
o
u,
r.,
o
,4
u,
,
u,
9,
4, Scheme IV
Step 1 0
1 o
1 N
0
N
-.)
HON . --.1
--1
Pli
0 MW 163.13
!A
00 ,c)
___________________________________________________________ .. ----c)
oO,N
0\,1,70H '',
00,NH2
II CF
0 3 0
MW: 132.16 MW: 264.22 MW: 277.28 MW:
147.17
(S)-Glycerol Acetonide PF-03714421 P0-0333760 PD-
0337792
( IPGAP )
( IPGA )
Step 2
HO 0 HO 0
.
NH2 H F
la F
F + I. F N
'8
lµF 40 40
F
I .
F I F
MW: 176.09 MW: 237.02 MW:
393.10
TFBA FIA P0-
0315209 Step 3
( FIPFA )
Step 4
-
H H
H
HeO'N 0 H F
HO"N!"O'N H 0 F /,,,_/,õN 0 H
F t
0 ; `-'
n
OH N
1101
OH Nlei _______________ z\-0 t!
Cl)N
---
la N ra
F I F I
11 V F I1V I o
ts.)
F F F
17-OL-
MW: 482.20
MW: 482.20 MW: 522.26
oo
Crude PD-0325901
w
PD-0325901 PD-0321920
x
( Mirdametinib )
( 901 Acetonide )
WO 2022/177557 - 1 1 1 -
PCT/US2021/018381
10395] In some aspects, the methods of preparing N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide yields a crystalline
composition
that is essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-
fluoro-4-iodo-phenylamino)-benzamide.
103961 In some aspects, the essentially pure Form IV crystalline
composition contains <
0.2% of dimeric impurity PF-00191189
141)
HN
H 0
-N 0
HO - 0
OH
PF-00191189
Exact Mass: 856.93
103971 In some aspects, the essentially pure Form IV crystalline
composition contains
about 0.05% to about 0.19% by weight of dimeric impurity PF-00191189. In some
aspects, the essentially pure Form IV crystalline composition contains about
0.05% to
about 0.15% by weight of dimeric impurity PF-00191189. In some aspects, the
essentially pure Form IV crystalline composition contains about 0.05% to about
0.10% by
weight of dimeric impurity PF-00191189. In some aspects, the essentially pure
Form IV
crystalline composition contains no detectable amount of dimeric impurity PF-
00191189.
103981 In some aspects, the amount of dimeric impurity PF-00191189 is
determined
using High Performance Liquid Chromatography ("HPLC"). In some aspects,
reversed-
phase liquid chromatography using an ultraviolet detector at 275 nm is used.
EXAMPLES
103991 Abbreviations and Acronyms
ACN Acetonitrile
CC Controlled cooling
DCM Dichloromethane
DMF N,N-Dimethyl formamide
DMSO Dimethyl sulfoxide
DSC Differential scanning calorimetry
CA 03207513 2023- 8- 4
WO 2022/177557 - 112 -
PCT/US2021/018381
Et0Ac Ethyl acetate
Et0H Ethanol
Exp Experiment
FEV Fast evaporation
FIA 2-fluoro-4-idodoaniline
FT Fourier Transform
GVS Gravimetric Vapor Sorption
HC1 Hydrochloric acid
HOAc Acetic acid
i-Pr2NEt N,N-diisopropylethylamine
IPA 2-Propanol
IPE Isopropyl ether
LiNH2 Lithium amide
MeCN Acetonitrile
Me0H Methanol
MIBK 4-Methyl-2-pentanone
min Minutes
MTBE Methyl t-butyl ether
n/a Not Applicable
NaOH Sodium hydroxide
NH40H Ammonium hydroxide
NHP N-hydroxyphthalimide
PLM Polarized light microscopy
PXRD Powder X-ray diffraction (also known as XRPD (X-ray
powder diffraction)
RC Rapid cooling
RT Room temperature
SAS Solvent-anti solvent
SEV Slow evaporation
SGA (S)-(+)-2,2-dimethy1-1,3-dioxolane-4-methanol
SU Scale Up
t-BuOH Tert-butanol
TC Temperature cycling
T3P 1-propylphosphonic anhydride solution
TEA triethylamine
Tf20 Trifluoromethanesulfonic anhydride
TFBA 2,3,4-trifluorobenzoic acid
TFE 2,2,2-Trifluoroethanol
TGA Thermogravimetric analyzer
TGA-IR Thermogravi metric analysis interfaced with infrared spectrophotometer
THF Tetrahydrofuran
v/v Volume/volume
Example!: Production of Seed Crystals of Form IV
Step 1: Preparation of "Side Chain", PD-0337792
104001 14.4 kg alcohol (chemical purity 99.4%, optical purity 99.6%
enantiomeric
excess) was converted to 97.5 kg 9.7% w/w PD-0337792 (IPGA) solution in
toluene
CA 03207513 2023- 8- 4
WO 2022/177557 - 113 -
PCT/US2021/018381
(overall yield ¨60%). The triflate activation was performed in the 200 L
reactor by
maintaining temperatures under ¨20 C during triflic anhydride addition. The
resulting
activated alcohol was then transferred to a 400 L reactor containing solid N-
hydroxypthalimide (NHP) and the reaction was allowed to occur at ambient
temperature
to completion. The final base de-protection was performed by adding aqueous
ammonia
(-28% soln, 5 equiv., 34 kg). After reaction completion, water was removed by
distillation from toluene, and the resulting solid side product was filtered
out to yield the
product solution.
Step 2: Preparation of PD-0315209
104011 The process yielded 2L4 kg (99.4% w/w assay), which is 80% of
theoretical from
starting materials 2,3,4-trifluorobenzoic acid (12 kg, 1 eq.) and 2-fluoro-4-
iodoaniline
(16.4 kg, 1.02 eq.) with lithium amide base (5 kg, 3.2 eq.). The reaction was
initiated by
adding 5% of total solution of TFBA and FIA into lithium amide slurry at 50
C. This
reaction demonstrated a minimal initiation period of ¨10 minutes, which was
observed by
color change and slight exotherm. The remaining TFBA/FIA solution in THF was
slowly
added through a pressure can in an hour while maintaining the reaction
temperatures
within 45-55 C. There was no appreciable pressure rise (due to ammonia gas
release)
observed during the entire operation.
Step 3: Preparation of PD-0325901
104021 A modification was made to the CDI charging to mitigate
potential gas
generation. Two equal portions of CDI were added into solid FIPFA before and
after
solvent addition (through a shot loader). The timing between the two solid CDI
additions
(4.6 kg each) should not exceed 30 minutes. Then two intermediate filter cakes
were
dissolved with ethanol. The excess ethanol was distilled and replaced with
toluene to
approximately 5% v/v ethanol prior to PD-0325901 recrystallization. Lab
studies
suggested that the crystallization from toluene and acetonitrile and
recrystallization from
ethanol in toluene would not be able to reduce impurities which is essential
for the
polymorph transformation. The presence of a dimeric impurity (PF-00191189) at
a level
greater than 0.2% has been known to result in the formation of undesired
polymorph.
CA 03207513 2023- 8- 4
WO 2022/177557 - 114 -
PCT/US2021/018381
101
HN
H 0
-N 0
HO - 0
z
OH
PF-00191189
Exact Mass: 856.93
[0403] The crude crystallization from the final reaction mixture
reduced dimeric impurity
PF-00191189 to approximately 1.9% and the subsequent recrystallization further
reduced
it to approximately 0.4%. As a consequence, undesired polymorphs were
produced. The
DSC patterns indicated two different melting points ¨80 C (low melt Form II)
and
¨117 C (Form I). Also during the processing, the solids crystallized at a much
lower
temperature than expected (actual ¨10 C, expected ¨40 C). It is suspected that
the
unsuccessful recrystallization is due to a change in the solvent composition
as a result of
incomplete drying of the crude. Drying of the crude wet cake prior to ethanol
dissolution
was stopped after about 36 hours when the crude product was ¨28 kg (26 kg
theoretical).
Polymorph Transformation
[0404] Approximately 7.4 kg of PD-0325901 (mixed polymorphs) from the
final
Et0H/Water crystallization and precipitated materials from the earlier
Et0H/Toluene
filtrate were taken forward to the polymorph transformation. Both crops were
separately
dried in the filter until constant weights and each was dissolved in Et0H. The
combined
Et0H solution was analyzed by TIPLC and resulted in an estimated amount of
16.4 kg
PD-0325901. The recrystallization was started after removing Et0H via vacuum
distillation and adjusting the solvent composition to about 5% Et0H in Toluene
at 65 C
(i.e., Et0H is added dropwise at 65 C until complete solids dissolution).
[0405] A slow 4-hour cooling ramp to 5 C followed by 12 h stirring was
performed to
ensure satisfactory results. The resulting slurry was filtered and again it
was completely
dried in the filter until constant weight (approximately 3 days). The purified
solid showed
99.8% pure PD-0325901 with not detected level of dimeric impurity PF-00191189.
CA 03207513 2023- 8- 4
WO 2022/177557 - 115 -
PCT/US2021/018381
[0406] The dried solid (15.4 kg) was re-dissolved in exactly 4 volumes
of Et0H (62 L)
off of the filter, transferred to the reactor and precipitated by a slow (-3
h) water addition
(308 L) at 30-35 C, cooled to 20 C and stirred for 12 h. The DSC analysis of
a slurry
sample taken at 2 h shows the solids to be completely Form IV (desired
polymorph).
104071 21.4 kg PD-0315209, 9.7 kg CDI (1.05 equiv.), 91 kg solution of
9.7% PD-
0337792 in Toluene (1.1 equiv.) were used and resulted in 12.74 kg of PD-
0325901
(assay 99.4%, 100% Form IV, Yield ¨ 48%).
Example 2: Assay/Impurities and Identification of PD-0325901
104081 PD-0325901 is separated from process impurities and degradants
by reversed-
phase liquid chromatography with UV detection at 275 nm Identification of PD-
0325901 is performed by obtaining either an infrared or proton NMR spectrum,
in
addition to the HPLC retention time. For purity evaluation, process impurities
and
degradants are identified by their characteristic relative retention times and
quantitated by
area normalization.
104091 Chromatographic Conditions: Agilent Zorbax SB C18, 5 p.m, 4.6 x
250 mm (or
equivalent); flow rate is 1.0 mL/min; column temperature is 30 C; detector
wavelength is
275 nm; diluent is 50/50 acetonitrile/water; mobile phase A is 0.1%
trifluoroacetic acid
(TFA) in water; mobile phase B is methanol; and the gradient conditions below.
The
assay is determined against a reference standard and reported on an anhydrous,
solvent
free basis. Quantification of specified and unspecified impurities is reported
by area
percent. Total impurities is the sum of all impurities present above the
reporting
threshold of 0.05%.
Time (minutes) 0 15 40 45 46
% mobile phase B 70 70 100 100 70
Example 3: Improved Process for Preparation of Form IV
104101 As described in Example 1, synthetic methods of producing
mirdametinib as Form
IV produced Form IV with dimeric impurity PF-00191189, and further steps were
required to transform the product into essentially pure Form IV without
undesired
polymorphs Form I and Form II. Therefore, it was necessary to develop a method
of
producing essentially pure Form IV without additional processing steps.
CA 03207513 2023- 8- 4
WO 2022/177557 - 116 -
PCT/US2021/018381
Mirdametinib Manufacturing Process
104111 The route is a convergent four step synthesis with six chemical
steps overall, using
the proposed starting materials (S)-( )-2,2-dimethy1-1,3-dioxolane-4-methanol
(SGA),
2,3,4-trifluorobenzoic acid (TFBA), 2-fluoro-4-idodoaniline (FIA), and N-
hydroxyphthalimide (NRP). The final step (Step 4) provides essentially pure
Form IV of
mirdametinib.
CA 03207513 2023- 8- 4
n
>
o
L.
r.,
o
-.1
u,
,--
u,
r,
o
r,
9'
4,
Scheme for Preparation of Mirdametinib :
0
Step I
t,)
0
0
1 t,)
I--L
.,1
.,1
Pli
- HO-N NHP _
--..1
OOH Tf20 NI-0 MW 163.13 0
ON)C), ,,C
NH4OH 00.,NH2
(S)-(+)-2,2-dimethy1-1,3- TEA II CF3
0 toluene, TEA 0
dioxolane-4-methanol toluene
toluene PD-0337792
(SGA) (S)-glycerol acetonide
(IPGA)
triflate P0-0333760
MW 132.16 - -
(IPGAP) MW 147.17
MW 264.22
MW 277.28
Step 2
HO 0
1
N -I 2 HO
0 T3P --,
I. F
H F
(50% in Et0Ac) -.I
(01
______________________________________________________________________ .
N i-Pr2NEt
F
F LiNH2
1
+ THF, MTBE
. 110 THF, toluene
F
F I
I toluene, aq. HCI MTBE, aq. NaOH
2,3,4-trifluoro-benzoic acid 2-fluoro-4-iodoaniline
F
(TFBA) (FIA)
PD-0315209
MW 176.09 MW 237.02
(FIPFA)
MW 393.10
Step 3
Step 4 ¨ ¨
H H
H
,N 0,N 0
aq. HCI ., --,,.......õ, , N 0
F
"0
HO . 0 F HO , 0 F
0 H n
H H toluene, ACN
F OH 40 N s Et0H _____________________ OH si N io 110 110
ci)
water Et0H F
F I I
F F
F r.)
1--L
CB
Mirdametinib 901 Acetonide
Crude P0-0325901 oc
(P0-0325901) MW 522.26 ca
MW 482.20
XMW 482.20 - - 1-L
WO 2022/177557 - 118 -
PCT/US2021/018381
[0412] Step 1 (Preparation of PD-0337792 (IPGA)): A clean, dry 100-
gallon reactor was
charged with toluene (139.3 kg, 8 volumes) and (S)-(+)-2,2-Dimethy1-1,3-
dioxolane-4-
methanol (SGA; 20.0 kg, 1.0 equivalents). Triethylamine (18.8 kg, 1.22
equivalents) was
charged to the reactor. The reactor contents were agitated and cooled to -10
10 C.
Trifluoromethanesulfonic anhydride (43.5 kg, 1.02 equivalents) was added to a
clean 50-
L round bottom flask under nitrogen then cooled to a temperature of < -10 'C.
The cooled
trifluoromethanesulfonic anhydride was slowly transferred to the 100-gallon
reactor while
maintaining the internal temperature at -10 + 10 C. The reaction mixture was
agitated at
-10 10 C for 30 minutes. Reaction monitoring by TLC indicated the
conversion to be
complete. While maintaining the internal temperature at -10 10 C, anhydrous
toluene
(99.8 kg, 5.75 volumes) was charged to the reactor followed by N-
hydroxyphthalimide
(26.4 kg, 1.07 equivalents). The contents were warmed to 20 5 C then
agitated at this
temperature for at least 5 hours, until the triflate intermediate was not
detectable by TLC
The reaction mixture was split into two equal portions. Each toluene solution
was
quenched with USP purified water (66 kg, 6.7 volumes). The toluene solution
was then
washed twice with USP purified water (66 kg, 6.7 volumes).
104131 The toluene solutions were recombined in a 100-gallon reactor.
The organic
solution was treated with 28% ammonium hydroxide solution (41.5 kg, 7.8
equivalents).
The contents were heated to 35 5 C then agitated for not less than ("NLT")
12 hours.
Upon reaction completion, the lower, aqueous phase was removed. The toluene
solution
was dried via azeotropic distillation of toluene. The toluene solution was
then
concentrated to minimum stir volume. The concentrated solution was filtered to
remove
by-product solids. The cake was washed with toluene and the filtrates were
combined.
Assay of the toluene solution indicated 8.6 kg (36.7% yield) of PD-0337792
(IPGA) was
present.
104141 Step 2 (Preparation of PD-0315209): A clean, dry 100-gallon
reactor was purged
with nitrogen then charged with lithium amide (LiNH2, 8.8 kg, 3,4 equivalents)
followed
by tetrahydrofuran (THF, 56.8 kg, 3.2 volumes). The mixture was cooled to 10
10 C
then additional TI-IF (15.1 kg, 0.85 volumes) was charged to the reactor,
followed by a
solution of 2,3,4-trifluorobenzoic acid (TFBA, 20.0 kg, 1.0 equivalent) in THF
(26.4 kg,
1.15 volumes). The reaction mixture was heated to NMT ("not more than") 50 C.
A
solution of 2-flouro-4-iodoaniline (FIA, 27.5 kg, 1.02 equivalents) in THF
(17.8 kg, 1
volumes) was added portion wise to the reactor, maintaining the batch
temperature at
NMT 50 C and stirring for 1 hour between additions. After completing the
additions, the
CA 03207513 2023- 8- 4
WO 2022/177557 - 119 -
PCT/US2021/018381
reaction mixture stirred for an additional 3 hours at 50 10 C. Upon
reaction
completion, the mixture was cooled to NMT 10 C then quenched with USP
purified
water (120.3 kg, 6 volumes). The reaction mixture was distilled to
approximately 30
gallons after which methyl t-butyl ether (MTBE, 118.6 kg, 8 volumes) was
added. The
MTBE solution was then quenched with 2M hydrochloric acid solution (89.5 kg)
to a pH
= 7. The aqueous phase was then removed. The MTBE solution was filtered
through
celite then washed twice with 5% brine solution (104.1 kg, 5.2 volumes)
followed by 1M
hydrochloric acid solution (77.4 kg). The MTBE solution was solvent swapped
with
toluene followed by volume adjustment to approximately 50 gallons. This
mixture was
heated to 75 5 C for 1 hour then cooled to 20 5 C and stirred for 1
hour. The
product was filtered, washed with toluene (68.1 kg, -4 volumes), then dried
under
vacuum at 40 C to obtain 25.2 kg of PD-0315209 (56.4% yield).
104151 Step 3 (Preparation of crude PD-0325901): A clean, dry 100-
gallon reactor was
purged with nitrogen then charged with PD-0315209 (18.0 kg, 1 equivalent) and
THF
(113.0 kg, 7 volumes). The mixture was cooled to 5 5 C. N,N-
diisopropylethylamine
(15.1 kg, 2.55 equivalents) was charged maintaining the temperature NIVIT 25
C. The
mixture was cooled to 5 5 C then stirred for 10 minutes. PD-0337792
solution in
toluene (121.7 kg total, 1.3 equivalents) was charged to the reactor at 5 5
C, followed
by 50% T3P in ethyl acetate (42.0 kg, 1.45 equivalents). The reaction mixture
stirred at
5 C for NLT 3 hours. An additional charge of N,N-dii sopropylethylamine (1.9
kg,
0.3 equivalents) and 50% T3P in ethyl acetate (4.1 kg, 0.15 equivalents) were
made to
advance the coupling to completion. The reaction was reverse quenched into a
5% sodium
hydroxide solution (50 kg), followed by washing with 5% brine (55.4 kg). The
organic
solution was concentrated then solvent swapped with toluene. Acetonitrile
(43.0 kg, 2.4
volumes) was added to the reactor followed by 2M hydrochloric acid (117.6 kg,
5.1
equivalents). The mixture stirred at 25 5 C until reaction completion after
16 hours
The bottom aqueous was removed then the reaction mixture was washed with 5%
brine
(75.2 kg). The organic phase was concentrated then solvent swapped with
toluene to an
appropriate volume. The mixture was then heated to 75 5 C for 30 minutes
then slowly
cooled to 20 C. The solids were filtered then washed with toluene (31.1 kg,
1.7 volumes)
104161 The crude solids were charged back to the 100-gallon reactor,
followed by 5%
ethanol in toluene (170.0 kg). The mixture was heated to 75 5 C for 60
minutes to
achieve a solution then slowly cooled to 20 C. The solids were filtered then
washed
CA 03207513 2023- 8- 4
WO 2022/177557 - 120 -
PCT/US2021/018381
twice with toluene (31 kg, 1.7 volumes). The wet cake was dried under vacuum
at 45 C
to obtain 8.2 kg of crude PD-0325901 (37.1% yield).
104171 Step 4 (Preparation of Essentially Pure Form Ifr' Mirdametinib):
A clean, dry
100-gallon reactor was purged with nitrogen then charged with USP Purified
Water
(164.1 kg, 20 volumes) followed by ethanol (200 proof, 20.8 kg, 3.25 volumes).
The
solution was heated to 35 5 C. In a separate vessel, crude PD-0325901 (8.1
kg, 1
equivalent) was dissolved in ethanol (200 proof, 40.5 kg, 6.3 volumes). A
portion of this
solution (14.4 kg) was added to the 100-gallon reactor over 60 minutes. PD-
0325901
Form IV seeds as prepared in Example 1 (82.6 g, 1%wt) was added to the reactor
to
facilitate precipitation. The remainder of the crude PD-0325901/ethanol
solution (34.3
kg) was added to the reactor over 90 minutes as the mixture stirred at 35 + 5
C. The
reactor contents continued to stir at 35 5 C for 5.5 hours then were slowly
cooled to 20
C. The solids were then filtered, washed with USP purified water (16 5 kg, 2
volumes),
then dried under vacuum at 45 C for 16 hours. The dried solids were screened
through a
10-mesh sieve to obtain 5.7 kg PD-0325901 Form IV (70.4% yield).
104181 An XRPD pattern for essentially pure Form IV used herein is
shown in FIG. 1A.
TGA and DSC analysis of essentially pure Form IV used herein are shown in FIG.
1B.
Example 4: Approximate Kinetic Solubility
104191 Solubility of mirdametinib prepared by Example 3 was assessed in
30 solvents.
The solubility was visually estimated at room temperature (RT; ¨23 C) by
dosing small
aliquots of solvent into a fixed amount of solid (-10 mg) until the
dissolution point or a
maximum volume (1.8 mL) was reached. Samples that contained undissolved solids
at
RT were heated to 40 C for 1 hour and the dissolution was assessed visually.
The
solubility data are shown below in Table 1.
Table 1
Solvent v/v
Solubility (mg/mL)at Solubility(mg/mL)
( )
RT (23 C) at
40 C
1 Ethanol/Water (9:1 v/v) >
424 n/a
2 MeCN/water (8:2 v/v) >
412 n/a
3 MeCN/Water (7:3 v:v)
>408 n/a
4 Dioxane >408
n/a
DMF (dimethylformamide) > 408 n/a
6 2-Propanol:water (9:1 v/v) > 400
n/a
CA 03207513 2023- 8- 4
WO 2022/177557 - 121 -
PCT/US2021/018381
7 Acetone > 400
n/a
8 Tetrahydrofuran (THY) > 396
n/a
9 Acetic acid (HOAc) > 388
n/a
Dimethyl sulfoxide (DMSO) > 388 n/a
11 Methanol (Me0H) > 380
nia
12 Ethanol/Toluene (9:1) 210 - 420
n/a
13 Ethanol 208 -416
n/a
14 1-Propanol 101 - 202
n/a
2-Propanol (IPA) 98 - 196 n/a
16 2-Methyl-2-Butanol 97 - 194
n/a
17 Ethyl Acetate (Et0Ac) 48 - 95
n/a
18 M1BK (4-methyl-2-pentanone) 48 - 95
n/a
19 Acetonitrile (MeCN) 19 - 49
n/a
Nitromethane 10-20 n/a
21 Dimethylcarbonate (DMC) 10-19
n/a
22 Trifluoroethanol (TFE) 7-12
n/a
23 Tert-butanol (t-BuOH) 6-10*
n/a
24 MTBE (methyl-t-butyl ether) <6
> 6
Dichloromethane (DCM) <6 > 6
26 Cyclohexane <6
<6
27 Chloroform <6
<6
28 Isopropyl ether (IPE) <6
<6
29 Toluene <6
<6
Water <6 <6
n/a ¨ not applicable
*solubility determined at 30 C
Example 5: Comprehensive Crystal-Form Screening
104201 About 450 crystallization experiments were performed using the
mirdametinib prepared
in Example 3 to identify novel polymorphs and solvates/hydrates of
mirdametinib. The
description of crystallization methods and solid-state forms of the input
materials are
described here.
Crystallization Modes
104211 Four main types of crystallization modes were employed in
the screening study:
Slurry equilibration:
o Isothermal at 5, 25, and 50 C for 48-72 hours
CA 03207513 2023- 8- 4
WO 2022/177557
PCT/US2021/018381
- 122 -
o Thermocycling between 40-5 C (in one-hour periods) for 48 hours
Rapid and controlled cooling of clarified solutions of mirdametinib:
o Controlled cooling from 50 C to 5 C at a rate of 0.1 C/min with one
hour
hold every 5 C followed by hold at 5 C for 5 days, followed by hold at -20
C (for remaining solutions) for 6 to 9 days
o Rapid cooling from 50 C to -20 C at an uncontrolled rate followed by
hold at
-20 C for 4 to 14 days
Rapid and slow evaporation of clarified solutions of mirdametinib:
o Slow evaporation over up to 30 days at ambient conditions
o Rapid evaporation for up to 3 days at reduced pressure at ambient
temperature
Addition of antisolvent to saturated and clarified mirdametinib solutions at
room
temperature:
o Rapid anti solvent addition and stirring at ambient temperature for up to
11
days
Crystallization Experimental
# Exps. Description
Input Forms
Mode Mode
Slurry of mirdametinib stirred
Thermo-cycled 48 while cycling temperature
Amorphous
between 5-40 C for 48 hours
Isothermal at
Slurry of excess mirdametinib
Elevated 48
Amorphous
stirred at 50 C for 48 hours
Temperature
Slurry
Isothermal at
Slurry of excess mirdametinib
Ambient 48
Amorphous
stirred at 25 C for >48 hours
Temperature
Isothermal at
Slurry of excess mirdametinib
Low 48
Amorphous
stirred at 5 C for 72 hours
Temperature
Mirdametinib solution
equilibrated at ¨50 C, filtered,
cooled at 0.1 C/min to 5 C with
Controlled
48 1 hour hold every 5 C and hold
Form IV
Cooling
days at 5 C, followed by -
Solution
20 C storage for 6-9 days for
Cooling
remaining solutions
Mirdametinib solution
equilibrated at ¨50 C, filtered,
Rapid Cooling 48
Form IV
crash cooled to -20 C and hold
4-14 days at -20 C
Solution of mirdametinib
Solution Fast
48 equilibrated at ambient is
filtered Form IV
Evaporation Evaporation
and rapidly evaporated under
CA 03207513 2023- 8- 4
WO 2022/177557 - 123 -
PCT/US2021/018381
reduced pressure at ambient
temperature
Solution of mirdametinib
Slow equilibrated at ambient is
slowly
48
Form IV
Evaporation evaporated over up to 30 days at
ambient conditions
Solution Rapid (but Precipitation of the
mirdametinib
Antisolvent dropwise) 48 from saturated solution induced
Form IV
Addition Addition by the addition of an
antisolvent.
Slurry of Toluene Solvate in
Water/Ethanol Spiked with
Process Solvent Toluene to Evaluate Solvate Risk
Experiments to in Mirdametinib Process.
Evaluate
Solvate Risk, Vacuum-Oven Drying of
Focused Vacuum-Oven Important Solvates and Hydrates
11
Various
Experiments Drying, to Determine Stability.
Desolvation/
Dehydration by Desolvation/Dehydration by
Heating Heating of Important Solvates
Experiments and Hydrates to Investigate
Potential New Non-Solvated
Forms
Total 443
Example 6: Amorphous Material Preparation and Experiments
[0422] Amorphous mirdametinib was prepared on a 100 mg scale by rapid
evaporation
under reduced pressure (Genevac vacuum centrifuge) of 100 mg/mL solutions of
the
mirdametinib in methanol and THF (A-1 and A-2, respectfully).
[0423] Solutions of mirdametinib (100 mg/mL) were prepared in methanol
and THE, and
each solution was divided into three equal parts to be used for 1) open at RI
stability
evaluation, 2) closed at RI stability evaluation, and 3) closed at -20 C
stability
evaluation. Observations after rapid evaporation revealed that the samples
from methanol
were mostly dry, glassy materials, and the samples from THE were mostly
sticky, dark
amber gums.
104241 PXRD analyses of all six samples (three from both methanol and
THF) following
rapid evaporation indicated an amorphous state. Other analyses (e.g. PLM, TGA-
1R,
DSC) were performed on one sample from each solvent. Following initial
analyses, one
sample from each solvent was stored at RI in an open vial, at RI in a capped
vial, and at -
20 C in a capped vial.
[0425] PXRD and PLM analyses after one day showed no crystallization in
A-la (open at
RI), and A-lb (capped at RI) from methanol. A-lc (capped at -20 C) was not
analyzed.
CA 03207513 2023- 8- 4
WO 2022/177557 - 124 -
PCT/US2021/018381
[0426]
PXRD and PLM analyses after one day showed crystallization to Form IV
in A-2a
(open at RT) from THF. A-2b (capped at RT) and A-2c (capped at -20 C) were
not
analyzed.
104271 Since amorphous mirdametinib (A-1) was successfully prepared at
100 mg scale
by rapid evaporation at reduced pressure from a methanol solution, this method
was used
to prepare vials containing amorphous material for use as the input material
for slurry-
ripening experiments in the screen.
Amorphous Mirdametinib Experiments
Experiment Procedure
Results
A-1: Combined 299.8 mg of mirdametinib with 3 mL of
Amorphous
A-1 methanol and stirred for 1 hour yielding a solution.
Filtered the
solution through 2 p.m PTFE filter to clarify.
(after 1 day at
ambient)
Pipetted 900 ILIL of A-1 above into 3 separate 2 mL vials: A-la,
A-lb, and A-1c. Rapidly evaporated the solvent under reduced
pressure in a vacuum centrifuge (GeneVac ) for 20 hours.
Products were mostly glassy with a thin film of dark amber on
bottom.
PXRD and PLM analyses of all 3 samples indicated they were
initially amorphous. Analyzed A-la by PLM, TGA-IR, and DSC.
DSC data was consistent with an amorphous state. TGA-IR
showed 1.3% wt. water and Me0H evolved upon heating to 200
"C.
PXRD and PLM analyses of A-la, after one day open at RT
indicated an amorphous state.
A-2 A-2: Combined 298.9 mg of mirdametinib with 3 mL of THF
and Form IV
stirred for 1 hour yielding a solution. Filtered the solution
through 2 p.m PTFE filter to clarify.
(after 1 day at
ambient)
Pipetted 900 juL of A-2 above into 3 separate 2 mL vials: A-2a,
A-2b, and A-2c. Rapidly evaporated the solvent under reduced
pressure in a vacuum centrifuge (GeneVac ) for 20 hours.
Product was a dark amber clear gum with some glassy material
on top.
PXRD and PLM analyses of all three samples indicated they
were initially amorphous. Analyzed A-2a by PLM and TGA-IR.
TGA-IR showed 7.8% wt. water and THF evolved upon heating
to 200 C. PXRD and PLM analyses of A-2a after one day open
at RT showed crystallization to the supplied Form IV.
CA 03207513 2023- 8- 4
WO 2022/177557 - 125 -
PCT/US2021/018381
Characterization of Amorphous Material (A-1)
104281 PXRD and PLM analyses indicated the material was non-
crystalline. DSC
analysis showed no melting endotherm up to 200 C, which is consistent with an
amorphous phase. TGA-IR analysis showed about 1.3% wt. loss of water and
methanol
upon heating from 26-200 C. Amorphous mirdametinib was physically stable in
both
open and closed vials for at least 24 hours at RT.
Example 7: Results of Crystal-Form Screen
104291 The crystal-form screen consisted of about 450 crystallization
experiments
covering crystalline and amorphous input materials, and various
crystallization modes,
solvents, and temperatures.
104301 Four hydrates (designated Forms VI, XIII, XIX and XX) were
observed and
appear to be novel forms. Water activity experiments conducted between non-
solvated
Form IV and two stable hydrates (Forms VI and XIX) indicated that Form IV is
more
stable at water activities (aw) 0.6 ¨ 0.99 than hydrate Forms VI and XIX.
104311 Fifteen solvates (designated Forms V, VII-XII, XV-XVIII, and XXI-
XXIV)
observed included process-related toluene (Form V), toluene/MIBK (Form VIII),
and
unstable toluene (Form IX) solvates.
104321 Mirdametinib/process solvent conversion studies involving
stirring the toluene
solvate (Form V) in 1.1/0.5 (v/v) water/ethanol at RT with varying amounts of
added
toluene indicated that if crude mirdametinib from toluene/ethanol was the pure
toluene
solvate, controlling toluene levels going into the final crystallization could
be critical
However, if the crude API is mostly Form IV with lesser amounts of the toluene
solvate,
it may not be as critical to monitor toluene levels in the crude mirdametinib.
CA 03207513 2023- 8- 4
n
>
o
1. .
r . ,
o
-4
r . ,
o
r . ,
9'
4,
Summary of Slurry-Ripening and Evaporative Screening Results
0
kµ.)
Amorph Amorph Amorph Amorph
Fast Slow o
# Solvent
Solvent kµ.)
5C 25C TC 50C
Evap Evap t.).
i--,
1 water C C A R A
Ethanol A A -4
-4
2 water:ethanol (80:20 v/v) A A
A A ethanol:water (95:5 v/v) A C !A
!A
-1
3 water:ethanol (90:10 v/v) A A
A A ethanol:water (90:10 v/v) A C
4 water:ethanol (95:5 v/v) A A A
A ethanol:water (80:20 v/v) A C
watermethanol (95:5 v/v) A A A
ethanol:toluene (90:10 v/v) A A
6 water:THF (95:5 ITN) A A A A
ethanol:toluene (50:50 v/v) A A
7 water:dimethylformamide (95:5 v/v) A A A A
ethanol:TFE (90:10 v/v) A A
8 water:dioxane (95:5) A A A A
ethanol:DMF (80:20 v/v) A A
9 water:acetone (95:5 v/v) A A A
A ethanol:dimethylcarbonate (70:30 v/v) A A
water:2-propanol (99:1 v/v) C C R A A
Acetone A A
11 cyclohexane A A A A
acetone:water (95:5 v/v) A A
12 chloroform A A A A
acetone:water (90:10 v/v) A C
13 isopropyl ether (IPE) D D D A D
acetone:water (80:20 v/v) A A 1
14 toluene X B F B
acetone:dichloromethane (90:10 v/v) X A
toluene:ethanol (95:5 v/v) B B B
acetone:chloroform (90:10 v/v) X ,
16 toluene:ethanol (85:15 v/v) B B
B acetone:isopropyl ether (90:10 v/v) X A
17 toluene:acetone (80:20 v/v) A B
B B acetone:tetrahydrofuran (50:50 v/v) A A
18 toluene:4-methyl-2-pentanone (80:20 v/v) E F B
B acetone:nitromethane (70:30 v/v) N A
19 toluene:ethyl acetate (80:20 v/v) B B F B
acetone:methyl-t-butyl ether (90:10 v/v) A A
toluene:2-propanol (80:20 v/v) F B A acetone:DMF
(80:20 v/v) A 2
21 dimethylcarbonate:ethanol (95:5 NW) A A A
Acetonitrile A A
22 trifluoroethanol (TFE) A A A
acetonitrile:water (90:10 v/v) A A
23 MTBE (methyl-t-butyl ether) G A G
acetonitrile:water (80:20 v/v) A C
24 acetonitrile A A A
acetonitrile:water (70:30 v/v) C
acetonitrile:toluene (50:50 v/v) B B B B
acetonitrile:DMSO (80:20 v/v) 2 ro
n
26 acetontrile:isopropyl ether (50:50 v/v) A A A
acetonitrile:DMF (80:20 v/v) A 2
27 acetontrile:dichloromethane (50:50 v/v) A A
Methanol A A
cp
28 dichloromethane:methanol (80:20 v/v) A
methananitromethane (80:20 v/v) A C iµ.)
o
29 dichloromethane:tetrahydrofuran (80:20 v/v) A A
methanol:methyl acetate (50:50 v/v) A C 1--,
C---,
dichloromethane:ethanol (80:20 v/v) J 2-propanol
A A
oc
31 isopropyl ether:methanol (80:20 v/v) A J 2-
propanolloluene (90:10 v/v) A A w
oc
32 isopropyl ether:tetrahydrofuran (80:20 v/v) J 2-
propanol:cyclohexane (90:10 v/v) A A 1--,
n
>
o
L.
r.,
o
,4
u,
,
u,
r.,
o
r.,
9'
4,
Amorph Amorph Amorph Amorph
Fast Slow
# Solvent
Solvent
5C 25C TC 50C
Evap Evap 0
33 chloroform:2-propanol (60:40 v/v) J
2-propanol: dichloromethane (90:10 v/v) A A tµ.)
o
34 chloroform:dimethylformamide (90:10 v/v) A J 2-
propanol:chloroform (90:10 v/v) A A tµ.)
t.).
35 dichloromethane 2-propanol (60:40 v/v) J 2-methy1-2-
butanol 0 0 i--,
-4
-4
36 dichloromethane:DMSO (90:10 v/v) A
A ethyl acetate:dimethyl formamide (70:30 v/v) A 2 !A
!A
37 heptane A A A
ethyl acetate A A --.1
38 heptane:ethyl acetate (50:50 v/v)
A A A A methyl acetate A A
39 heptane:2-propanol (80:20 v/v) A A A A
4-methyl-2-pentanone (MIBK) A Q
40 heptane:tetrahydrofuran (90:10 v/v) A
A A A J tetrahydrofuran (THF) A
41 heptane:2-butanone (80:20 v/v) A A A A
tetrahydrofurarrwater (90:10 v/v) A A
42 cyclohexane:acetone (90:10 v/v) A A A A
tetrahydrofuran:2-butanol (90:10 v/v) A A
43 cyclohexane:2-butanone (90:10 v/v) A
A A M tetrahydrofuran:cyclohexane (90:10 v/v) A A
44 trifluoroethanol (TFE):ethanol (95:5 v/v) A J J
dioxane:water (90:10 v/v) A A
45 trifluoroethanol (TFE):ethanol (90:10 v/v) A J A
dioxane:toluene (90:10 v/v) A A
46 nitromethane A A A
dioxane:toluene (80:20 v/v) A A
47 nitromethane:1-propanol (95:5 v/v) A
A A dioxane:dichloromethane (90:10 v/v) A A .
48 dimethylcarbonate (DMC) A A
dioxane:cyclohexane (90:10 v/v) A A
-...1
A Form IV Non-solvated Form IV N Form XVI Poorly
crystalline Nitromethane solvate .
B Form V Toluene solvate 0 Form XVII 2-
Methyl-2-Butanol solvate
C Form VI Hydrate P Form XVIII
Chloroform/Water solvate
D Form VII IPE or IPE/Water solvate Q Form II Non-
solvated Form II
E Form VIII TolueneNIIBK solvate R Form XIX Hydrate
F Form IX Unstable Toluene solvate S Form XX
Hydrate (unstable)
G Form X MTBE/Water solvate T Form XXI 2-
Methyl-2-Butanol solvate 2 (unstable)
H Form XI Chloroform/IPA solvate U Form XXII IPE or
IPE/Water solvate 2
I Form XII IPA solvate (isostructural to Form XI) V Form
XXIII Cyclohexane/Et0Ac solvate
J Form I Non-solvated Form I W Form XIV IPE
Solvate (unstable to desolvation) it
K Form X111 Hydrate X Amorphous
n
L Form XIV Transient Non-solv. form (similar to Form No Solid
IV)
cp
tµ.)
o
M Form XV Cyclohexane solvate
ts.)
1¨,
Notes:
C---,
1¨,
1. Some extra peaks of unknown transient form observed. Some conversion to
Form IV observed at ambient conditions. oc
w
2. Sample was a solution after 30 days of evaporation.
oc
1¨,
3. Sample was a solution after 11 days mixing.
n
>
o
1. .
r . ,
o
-4
r . ,
o
r . ,
9'
4,
Summary of Cooling and Solvent-Antisolvent Screening Results
0
k..)
# Solvent RC CC # Solvent
Anti-Solvent SAS o
kµ.)
t.).
1 water:ethanol (60:40 v/v) C A C 1
ethanol water A i--,
-4
2 water:ethanol (50:50 v/v) A C 2
ethanol toluene 3 --I
!A
!A
3 water:ethanol (40:60 v/v) 3
ethanol cyclohexane 3 -4
4 watermethanol (40:60 v/v) R A 4
ethanol chloroform 3
water:THF (50:50 v/v) C 5 ethanol IPE 3
6 water:dimethylformamide (50:50 v/v) 6
MIBK toluene F
7 water:dioxane (50:50) 7
MIBK cyclohexane A
8 water:acetone (50:50 v/v) 8
MIBK chlorofoim 3
9 2-propanol I I 9
MIBK IPE 3
cyclohexane 10 MeCN water A
11 chloroform 11 MeCN
toluene 3
12 isopropyl ether (IPE) 12
MeCN cyclohexane 3
13 toluene 13 MeCN
chloroform 3 .
14 toluene:ethanol (70:30 v/v) B 14
MeCN DCM 3
t'-::)
toluene:ethanol (80:20 v/v) B B 15 MeCN IPE
3 oo
16 toluene:ethanol (90:10 v/v) B B 16
Et0Ac toluene A -- .
17 toluene:acetone (70:30 v/v) 17
Et0Ac cyclohexane V
18 toluene:4-methyl-2-pentanone (50:50 v/v) E
18 Et0Ac chloroform A
19 toluene:ethyl acetate (50:50 v/v) 19
Et0Ac IPE D
toluene:2-propanol (50:50 v/v) 20 Et0Ac DCM 3
21 dimethylcarbonate:ethanol (70:30 v/v) A
22 trifluoroethanol (TFE): ethanol (70:30 v/v) A
A
23 MTBE (methyl-t-butyl ether):2-propanol (50:50 v/v)
24 acetonitrile S S
acetonitrile:toluene (50:50 v/v)
it
26 acetontrile:isopropyl ether (50:50 v/v)
A D W n
27 acetontrile:dichloromethane (50:50 v/v) S
28 dicliloromethane:methanol (80:20 v/v)
cp
k.)
o
29 dichloromethane:tetrahydrofuran (80:20 v/v)
I-.
dichloromethane:ethanol (80:20 v/v)
C---,
1--,
31 isopropyl ether:methanol (80:20 v/v)
U 00
w
32 isopropyl ethertetrahydrofuran (80:20 v/v)
oo
I-.
33 chloroform:2-propanol (60:40 v/v) H H
n
>
o
L.
r.,
o
,4
u,
,
u,
r.,
o
r.,
9'
4,
# Solvent RC CC # Solvent
Anti-Solvent SAS
0
34 chloroform:dimethylformamide (90:10 v/v)
o
35 dichloromethane:2-propanol (40:60 viv)
iµ.)
t.).
36 dichloromethane:dimethyl sulfoxide (50:50 vAT)
i--,
-4
37 methyl acetate
--I
Pli
38 heptane:ethyl acetate (50:50 v/v) A
Pli
--I
39 heptane:2-propanol (50:50 v/v) I I
40 heptane:tetrahydrofuran (50:50 v/v)
41 heptane:2-butanone (50:50 v/v) A A
42 cyclohexane:acetone (40:60 v/v)
43 cyclohexane:2-butanone (40:60 v/v)
44 MIBK (4-methyl-2-pentanone)
45 Ethyl Acetate (Et0Ac)
46 2-methyl-2-butanol T T
47 nitromethane:1-propanol (40:60 v/v)
48 dimethylcarbonate (DMC) A 1 A 1
,
A Form IV Non-solvated Form IV N Form XVI Poorly
crystalline Nitromethane solvate
B Form V Toluene solvate 0 Form XVII 2-
Methyl-2-Butanol solvate '
C Form VI Hydrate P Form XVIII
Chloroform! Water solvate
D Form VII IPE or IPE/Water solvate Q Form II Non-
solvated Form II
E Form VIII Toluene/MIBK solvate R Form XIX
Hydrate
F Form IX Unstable Toluene solvate S Form XX
Hydrate (unstable)
G Form X MTBE/Water solvate T Form XXI 2-
Methyl-2-Butanol solvate 2 (unstable)
H Form XI Chloroform/IPA solvate U Form XXII IPE
or IPE/Water solvate 2
I Form XII IPA solvate (isostructural to Form XI) V
Form XXIII Cyclohexane/Et0Ac solvate
J Form I Non-solvated Form I W Form XXIV IPE
Solvate (unstable to desolvation)
K Form XIII Hydrate X Amorphous
ro
n
Form XIV Transient Non-solv. form
(similar to Form No Solid
L
IV)
Cl)
M Form XV Cyclohexane solvate
iµ.)
o
Notes:
1--,
C---,
1. Some extra peaks of unknown transient form observed. Some conversion to
Form IV observed at ambient conditions.
oc
2. Sample was a solution after 30 days of evaporation. w
oc
3. Sample was a solution after 11 days mixing. 1--,
WO 2022/177557 - 130 -
PCT/US2021/018381
Example 8: Description of the Obtained Crystal Forms of Mirdametinib
[0433] The following sections deserig117be and summarize the physical
properties of
each of the crystal forms observed for mirdametinib.
Transient Non-Solvated Form XIV
[04341 The characterization data for Form XIV, a transient non-solvated
form very
similar to Form IV, are presented in FIG. 12A and FIG. 12B. PXRD and PLM
analysis
indicates that the material is crystalline. DSC analysis shows a single sharp
endotherm
with onset at about 111 C (AH= 85.6 J/g). TGA-IR analysis shows about 0.15%
wt. loss
to 150 C, indicating a non-solvated form. Form XIV was found to convert to
Form IV
within four days at ambient conditions. Form XIV was not scaled up to be used
for
further studies (e.g. relative stability studies).
Toluene Solvate Form V
[04351 The characterization data for Form V, a process-relevant toluene
solvate, are
presented in FIG. 3A and FIG. 3B. PXRD and PLM analysis indicates that the
material is
crystalline. DSC analysis shows two overlapping endotherms with onsets at
about 77 C
(AH= 44.3 J/g) and about 95 C (AH= 33.2 J/g). TGA-1R analysis shows about
2.7% wt.
(0.15 eq) loss of toluene upon heating to 100 C and about 4.7% wt. (0.26 eq)
total loss of
toluene upon heating to 185 C, indicating a solvated form. Form V was found
to be
stable at ambient conditions for > 10 days. Form V was scaled up to be used
for focused
studies around the mirdametinib crystallization process.
Preparation of Form V
[0436] Mirdametinib (308.0 mg) was dissolved in 3.0 mL of methanol and
the solution
was filtered through a 0.2 tim PTFE filter. The solution was rapidly
evaporated under
reduced pressure (GeneVac0) overnight to yield amorphous material. Toluene
(150 tiL)
and a stir disc was added to the amorphous product and the mixture was stirred
at 25 C
for 35 min. Seeds ( --1 mg) were added, and the sample was stirred at 25 C
for 23 hours.
The damp solids were dried in a nitrogen flow chamber for 3 hours. The batch
weight was
about 212 mg, and the yield was about 69% wt. of Form V.
CA 03207513 2023- 8- 4
WO 2022/177557 - 131 -
PCT/US2021/018381
Form VIII (Toluene/MIBK Solvate)
[0437] The characterization data for Form VIII, a toluene/MIBK solvate,
are presented
FIG. 6A and FIG. 6B. PXRD and PLM analysis indicates that the material is
crystalline.
DSC analysis shows a broad endotherm with onset at about 81 C (AH= 67.1 J/g)
followed by a small broad endotherm with onset at about 110 C (AH= 7.1 J/g).
TGA-IR
analysis shows about 3.3% wt. loss of toluene and MIBK upon heating to 112 C
and
about 0.8% wt. additional loss of toluene and MIBK upon heating from 112 to
150 C,
indicating a solvated form. Form VIII was stable at ambient conditions for > 2
days. Form
VIII was not scaled up for further studies (e.g., focused studies around the
mirdametinib
crystallization process).
Unstable Toluene Solvate Form IX
[0438] The characterization data for Form IX, an unstable toluene
solvate, are presented
in FIG. 7A and FIG. 7B. PXRD and PLM analysis indicates that the material is
crystalline. DSC analysis shows a broad endotherm with onset at about 84 C
(AH= 17.1
J/g), an endotherm at about 107 C (AH=12.4 J/g), and a sharper endotherm with
onset at
about 114 C (AH= 39.6 J/g). TGA-IR analysis shows about 4.6% wt. loss of
toluene
upon heating to 128 C, indicating a solvated form. Form IX exhibited
significant
conversion toward Form IV after 20 hours at ambient conditions. Form IX was
not scaled
up for further studies (e.g. focused studies around the mirdametinib
crystallization
process).
Hydrate Form VI
[0439] The characterization data for Form VI, a hydrate, are presented
in FIG. 4A and
FIG. 4B. PXRD and PLM analysis indicates that the material is crystalline. DSC
analysis
shows three broad endotherms with onsets at about 41 C (AH= 11.4 J/g), about
70 C
(AH= 48.1 J/g), and about 109 C (AH= 21.3 J/g). TGA-IR analysis shows about
2.4% wt.
(0.7 eq) loss of water upon heating to 125 C, indicating a hydrated form.
Form VI was
found to be stable for > 2 weeks in solid-state at ambient conditions. Form VI
was scaled
up to be used for water activity studies between non-solvated Form IV and the
stable
hydrates.
CA 03207513 2023- 8- 4
WO 2022/177557 - 132 -
PCT/US2021/018381
Preparation of Form VI/ Form IV Mixture
[0440] Mirdametinib (120.8 mg) was dissolved in 1.0 mL of methanol. The
solution was
filtered through a 0.2 lam PTFE filter and rapidly evaporated under reduced
pressure
(GeneVac8) overnight. Water (1.0 mL) and a stir disc were added to the dry
solids,
followed by seeds (-0.1 mg). The suspension was mixed at 25 C for 24 hours,
and the
solids were isolated by vacuum-filtration. The batch weight was about 58 mg,
and the
yield was an about 48% wt. of a mixture of Form VI and Form IV.
Hydrate Form IX
[04411 The characterization data for Form IX, a hydrate, are presented
in FIG. 7A and
FIG. 7B. PXRD and PLM analysis indicates that the material is crystalline and
contains
some Form IV. DSC analysis shows two broad endotherms with onsets at about 55
C
(AH= 66.8 J/g) and about 109 C (AH= 25.5 J/g). TGA-lR analysis shows about
3.1% wt.
(0.9 eq) loss of water upon heating to 100 C, indicating a hydrated form.
Form IX was
observed only once (as phase-pure) during screening, and it was observed to
slowly
convert to Form IV in solid-state at ambient conditions. Form IX was not
scaled up for
further studies (e.g., water activity studies).
Hydrate Form XIX
[04421 The characterization data for Form XIX, a hydrate, are presented
in FIG. 17A and
FIG. 17B. PXRD and PLM analysis indicates that the material is crystalline.
DSC
analysis shows a broad endotherm with onset at about 69 C (AH= 28.5 J/g),
followed by
an exotherm with onset at about 98 C (AH= 13.5 J/g), and a sharp endotherm
with onset
at about 115 C (AH= 59.6 J/g). TGA-IR analysis shows about 1.85% wt. (0.5 eq)
loss of
water upon heating to 92 C, indicating a hydrated form. Form XIX was found to
be
stable in a capped vial for > 2 weeks. Form XIX was scaled up to be used for
water
activity studies between non-solvated Form IV and the stable hydrates.
Preparation of Form XIX
[04431 Mirdametinib (about 497 mg) was dissolved in 3.0 mL of
water:Me0H (40:60
v/v) by mixing at 50 C for 10 min. The solution was filtered hot through a
0.2 lam PTFE
filter into a second vial at 50 C. The solution was rapidly cooled to -20 C,
and seeds (1-
2 mg) were added and dispersed by swirling. After 30 min., the product was a
thick paste,
CA 03207513 2023- 8- 4
WO 2022/177557 - 133 -
PCT/US2021/018381
so 1.0 mL more solvent was added, and the suspension cooled at -20 C for 30
min. The
solids in the cold suspension were isolated by vacuum-filtration, then allowed
to air dry
for 16 hours. The batch weight was about 278 mg, and the yield was about 56%
wt. of
Form XIX.
Hydrate Form XX
[0444] The characterization data for Form XX, a hydrate, are presented
in FIG. 18A and
FIG. 18B. PXRD and PLM analysis indicates that the material is crystalline.
DSC
analysis shows three broad endotherms with onsets at about 77 C (AH= 29.0
J/g), about
92 C (AH= 9.8 J/g) and about 110 C (AH= 6.8 J/g). TGA-IR analysis shows
about 2.6%
wt. (0.7 eq) loss of mostly water with a small amount of acetonitrile upon
heating to 126
C, indicating a hydrated form. TGA-IR analysis of a second less-crystalline
sample of
Form XX showed only water evolved upon heating. Form XX was found to convert
to
Form IV within 10 days at ambient conditions. Form XX was not scaled up for
further
studies (e.g., water activity studies).
Other Non-Process Related Solvates (Forms VII, X-XII, XV-XVIII, XXI-XXIV)
[0445]
A summary of the non-process related solvates (Forms VII, X-XII, XV-
XVIII, and
XXI-XXIV) is shown in Table 2. The characterization data for these solvates
are shown in
FIGs. 5A-5B, 8A-8B, 9A-9B, 10A-10B, 13A-13B, 14A-14B, 15A-15B, 16A-16B, 19A-
19B, 20A-20B, 21A-21B, and 22A-22B.
Table 2 - Summary of Non-Process Solvates
DSC Endotherm
Form Nature of Solvate
Onsets (approximate TGA-IR Data (Wt. Loss)
C)
VII IPE or IPE/water 85, 110
5.2% isopropyl ether
X MTBE/water 89 (2 merged)
2.9% MTBE and water
XI Chloroform/IPA 69, 104
7.6% chloroform and IPA
XII IPA 72 109
8.5% IPA (low sample
,
quantity)
XV Cyclohexane 104
3.8% (0.2 eq.) cyclohexane
XVI Nitromethane (poorly 74, 102 21% (0.2
eq.)
crystalline) (2 merged), 114
nitromethane
CA 03207513 2023- 8- 4
WO 2022/177557 - 134 -
PCT/US2021/018381
XVII 2-Methyl-2-Butanol 89
2.7% (0.15 eq.) 2-methyl-
2- butanol
XVIII Likely Chloroform 83
1.6% chloroform and water
2-Methyl-2-Butanol 52 (overlap of two), 90
14.1% (0.9 eq.) 2-methyl-
(converts to Form IV) 2-
butanol
XXII IPE or IPE/water 65, 89, 102
13.8% isopropyl ether and
water
XXIII Cyclohexane/Et0Ac 81, 101
4.4% cyclohexane and
Et0Ac
XXIV IPE or IPE/water 104 (multiple
1.2% isopropyl ether and
overlapping endotherms) water
[0446] PXRD, TGA, and DSC data for each form presented herein are shown
in FIGs.
2A-2B, 3A-3B, 4A-4B, 5A-5B, 6A-6B, 7A-7B, 8A-8B, 9A-9B, 10A-10B, 11A-11B,
12A-12B, 13A-13B, 14A-14B, 15A-15B, 16A-16B, 17A-17B, 18A-18B, 19A-19B, 20A-
20B, 21A-21B, 22A-22B, and 23A-23B.
Example 9: Water Activity Studies of Hydrates at 23 C
[0447]
Water activity studies of the stable hydrated Forms VI and XIX were
conducted to
determine their relative thermodynamic stabilities. The studies were conducted
at 23 C
in various water/ethanol mixtures to provide water activities (aw) from 0.6 ¨
0.99. The
water activity range includes the approximate water activity of the current
final isolation
step of the mirdametinib manufacturing process. Saturated suspensions were
prepared by
stirring an excess of mirdametinib in the test solvents for 16 hours. The
suspensions were
filtered and transferred onto mixtures containing equivalent amounts of Form
VI and
Form XIX.
[0448] The suspensions were stirred at the target temperatures, sampled
at three and five
days and analyzed by PXRD. The results are summarized below and show that all
experiments produced Form IV. The hydrates may be kinetically favored at
higher water
activities.
Example 10: Drying of Certain Forms Via Vacuum Oven
[0449]
Drying studies for certain forms were conducted overnight in a vacuum
oven at 45
C. After drying, samples were equilibrated to RT for 10 min. and analyzed by
PXRD at
about 70% ambient lab humidity. The results are summarized below.
= Form V (Toluene Solvate): Remained unchanged.
CA 03207513 2023- 8- 4
WO 2022/177557 - 135 -
PCT/US2021/018381
= Form VI (Hydrate): Partially converted to Form A.
= Form XIII (Hydrate): Form XIII/Form IV mixture converted to Form IV.
= Form XIX (Hydrate): Remained unchanged.
[0450] Desolvation/dehydration studies of certain forms were conducted
in a TGA pan
with loose lid at a heating rate of 15 C/min from 25 to 100 C with a 5 min.
hold at 100
C. Samples were air-cooled to RT on the TGA and analyzed by PXRD if
crystalline. The
results are summarized below.
= Form V (Toluene Solvate): After cooling, observed sample to be molten and
transparent dark amber in appearance (melted and solidified in molten,
amorphous
state, possible decomposition).
= Form VI (Hydrate): After cooling, observed sample to be molten and
transparent
dark amber in appearance (melted and solidified in molten, amorphous state,
possible decomposition).
= Form XIX (Hydrate): After cooling, observed sample to be very slightly
sticky,
but solid particles (not melted). PXRD indicated Form I.
Example 11: Toluene-Spiked Slurry Studies
[0451] The process-relevant toluene solvate (Form V) was stirred in
water:ethanol
(1.1/0.5 v/v) overnight at RT with varying amounts of added toluene. The
suspensions
were filtered, and solids analyzed by PXRD. The results are summarized below.
= With no added toluene, Form V converted to phase-pure Form IV.
= With 0.5% added toluene (relative to mirdametinib weight), Form V
converted
to mostly Form IV with some lesser amount of Form V.
= With 1% and 2% added toluene, higher relative amounts of Form V were
observed, but difficult to distinguish between 1% and 2% toluene, since PXRD
data was qualitative and variable.
[0452] The results of the toluene-spiked slurry studies suggest that if
crude mirdametinib
from toluene/ethanol was the pure toluene solvate, controlling toluene levels
going into
the final crystallization would be critical. However, if the crude
mirdametinib is mostly
Form IV with lesser amounts of the toluene solvate, it may not be as critical
to monitor
toluene levels in the crude mirdametinib.
CA 03207513 2023- 8- 4
WO 2022/177557 - 136 -
PCT/US2021/018381
Example 12: Single Crystal X-Ray Diffraction Analysis of Form IV
[0453] A suitable single Form IV crystal was analyzed using a Bruker D8
Venture
Photon II CPAD diffractometer equipped with a CuKa INCOATEC Imus micro-focus
source (X = 1.54178 A). The simulated PXRD pattern was calculated from the low
temperature (100 K) structure and room temperature (298 K, 25 C) unit cell
parameters
shown below. Unit cell at room temperature was initially determined by
Difference
Vectors method based on 235 reflections harvested from 151, 10 diffraction
frames. Unit
cell parameters were subsequently refined during data integration by Saint
(Bruker
(2020). SAINT. Data Reduction Software) and are based on 903 reflections
recorded
between 19.1 and 1.1 A resolution. The simulated pattern was consistent with
an
experimental Form IV pattern as shown in FIG. 1A.
Table 3: Initially Determined Unit Cell Parameters at Room Temperature
a[A] b[A] c[A] an V[A3]
27.080(2) 27.080(2) 4.6971(5) 90 90 90
3444.5(8)
Table 4: Form IV Crystal Data and Structure Refinement
Crystal system Tetragonal
Space group P41
a/A 26.9861(4)
b/A 26.9861(4)
c/A 4.66600(10)
cdo 90
90
Volume/A3 3398.01(12)
8
pcalcg/cm3 1.885
Wmm-1 15.351
F(000) 1888
Example 13: Capsule Formulations
Formulation Composition
1 mg 2 mg 5 mg
Ingredient
mg/cap (w/w) mg/cap (w/w) mg/cap
(w/w)
Mirdametinib a 0.77 1 0.77 2 5.26 5
Microcrystalline Cellulose b 93.23 121.2 93.23 242.4 89.74
85.25
Croscarmellose sodium 5 6.5 5 13 5
4.75
CA 03207513 2023- 8- 4
WO 2022/177557 - 137 -
PCT/US2021/018381
Magnesium Stearate 1 1.3 1 2.6 0 0
Total 100 130 100 260 100 95
Size #3 Size #1 Size #2
Capsule Shells HG HG HG
capsules capsules capsules
HG = Hard Gelatin
a Based on a theoretical potency of 1.000. Actual quantity may be adjusted
based on the actual potency.
b Quantity of microclystalline cellulose may be adjusted for slight potency
changes of PD-0325901.
Example 14: Dispersible Tablets
Formulation Composition
0.5 mg 1.0 mg
Ingredient
mg/ta %
mg/tab
(w/w) b (w/w)
Mirdametinib a 0.75 0.50 0.75 1.00
Microcrystalline Cellulose b 90.52 60.60 90.52
121.20'
Croscarmellose sodium 4.85 3.25 4.85 6.50
Grape flavor 1.94 1.30 1.94 2.60
Sucralose 0.97 0.65 0.97 1.30
Magnesium Stearate 0.97 0.65 0.97 1.30
Total 100.0 66.95 100.0
133.90
a = Based on theoretical potency of 1.000. Quantity may be adjusted based on
the actual potency.
b = Quantity of microcrystalline cellulose may be adjusted for slight potency
changes of
mirdametinib
c = Excipients are present at the same mg/unit as the 1 mg capsule
[0454] All publications, patents, and patent applications mentioned in
this specification
are incorporated herein by reference in their entirety to the same extent as
if each
individual publication, patent, or patent application was specifically and
individually
indicated to be incorporated by reference in its entirety. Where a term in the
present
application is found to be defined differently in a document incorporated
herein by
reference, the definition provided herein is to serve as the definition for
the term.
[0455] While the invention has been described in connection with
specific aspects
thereof, it will be understood that invention is capable of further
modifications and this
application is intended to cover any variations, uses, or adaptations
following, in general,
the principles and including such departures from the present disclosure that
come within
known or customary practice within the art to which the invention pertains and
can be
applied to the essential features hereinbefore set forth, and follows in the
scope of the
claimed.
[0456] In addition to the various embodiments described herein, the
present disclosure
includes the following embodiments numbered El through E275. This list of
CA 03207513 2023- 8- 4
WO 2022/177557 - 138 -
PCT/US2021/018381
embodiments is presented as an exemplary list and the application is not
limited to these
embodiments.
[0457] El. A crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-
4-iodo-phenylamino)-benzamide of Formula (1)
HOON
OH
F I
(I),
selected from the group consisting of:
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern haying peaks at
5.4
0.2, 17.5 + 0.2, and 22.8 + 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
5.9
0.2, 7.2 0.2, and 21.2 0.2 degrees two theta;
a crystalline form of N-((R)-2,3 -di hydroxypropoxy)-3,4 -di fluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
5.3
0.2, 10.6 0.2, and 16.1 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern haying peaks at
5.4
0.2, 10.7 0.2, and 18.7 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern haying peaks at
6.7
0.2, 13.5 0.2, and 22.2 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
10.6
0.2, 19.6 0.2, and 24.8 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
5.5 1
0.2, 6.9 0.2, and 10.1 0.2 degrees two theta;
CA 03207513 2023- 8- 4
WO 2022/177557 - 139 -
PCT/US2021/018381
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
10.1
0.2, 17.3 0.2, and 22.6 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
4.6
0.2, 5.1 0.2, and 14.6 0.2 degrees two theta;
a crystalline form of N-((R)-2,3 -di hydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-
4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
4.6
0.2, 23.4 0.2, and 25.2 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
5.5
0.2, 14.7 0.2, and 20.9 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
6.0
0.2, 17.1 0.2, and 20.6 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
5.9 +
0.2, 10.1 0.2, and 15.5 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
4.6 +
0.2, 10.7 0.2, and 15.9 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
10.2
0.2, 11.6 0.2, and 20.0 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
7.8
0.2, 14.0 0.2, and 17.1 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
5.5
0.2, 8.2 0.2, and 16.7 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
7.2
0.2, 21.7 + 0.2, and 29.1 + 0.2 degrees two theta;
CA 03207513 2023- 8- 4
WO 2022/177557 - 140 -
PCT/US2021/018381
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern haying peaks at
5.4
0.2, 9.7 0.2, and 10.7 0.2 degrees two theta; and
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
7.2
0.2, 20.6 0.2, and 23.0 0.2 degrees two theta.
[0458] E2. The crystalline form of El, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks 5.4 0.2, 17.5 0.2, and 22.8
0.2
degrees two theta.
[0459] E3. The crystalline form of E2, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks 5.4 0.2, 12.5 0.2, 17.5
0.2, and 22.8
0.2 degrees two theta.
[0460] E4. The crystalline form of E2 or E3, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 2.7 wt% between about 35 C and about 100
C.
[0461] E5. The crystalline form of any one of E2-E4, wherein the
crystalline form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 77 C.
[0462] E6. The crystalline form of any one of E2-E5, wherein the
crystalline form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 95 C.
[0463] E7. The crystalline form of any one of E2-E6, wherein the
crystalline form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has a first endotherm onset at about 77 C and
a second
endotherm onset at about 95 C.
[04641 E8. The crystalline form of any one of E2-E7, wherein the
crystalline form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
is characterized by an XRPD pattern substantially as shown in FIG. 2A.
[0465] E9. The crystalline form of any one of E2-E8, wherein the
crystalline form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-
benzami de
is characterized by:
CA 03207513 2023- 8- 4
WO 2022/177557 - 141 -
PCT/US2021/018381
a) a TGA profile substantially as shown in FIG. 2B; and/or
b) a DSC profile substantially as shown in FIG. 2B.
[0466] E10. The crystalline form of any one of E2-E9, wherein the
crystalline form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
is Form V.
[0467] El 1. The crystalline form of El, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is
characterized by an XRPD pattern having peaks at 5.9 0.2, 7.2 0.2, and
21.2 0.2
degrees two theta.
[0468] E12. The crystalline form of Ell, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 5.9 0.2, 7.2 0.2, 9.3
0.2, and 21.2
0.2 degrees two theta.
[0469] E13. The crystalline form of Ell or E12, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 2.4 wt% between about 25 C and about 125
C.
[0470] E14. The crystalline form of any one of El 1-E13, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 41
C.
[0471] E15. The crystalline form of any one of Ell-E14, wherein the
crystalline form
of N-((R)-2,3 -di hydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-4-i odo-phenyl
amino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 70
C.
[0472] E16. The crystalline form of any one of Ell-E15, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 109
C.
[0473] E17. The crystalline form of any one of Ell-E16, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has a first endotherm onset at about
41 'V, a
second endotherm onset at about 70 C, and a third endotherm onset at about
109 C.
[0474] E18. The crystalline form of Ell-E17, wherein the crystalline
form of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
characterized by an XRPD pattern substantially as shown in FIG. 3A.
CA 03207513 2023- 8- 4
WO 2022/177557 - 142 -
PCT/US2021/018381
[0475] E19. The crystalline form of Ell-E18, wherein the crystalline
form of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
characterized by:
a) a TGA profile substantially as shown in FIG. 3B; and/or
b) a DSC profile substantially as shown in FIG. 3B.
[0476] E20. The crystalline form of any one of El 1-E1 9, wherein the
crystalline form
of N-((R)-2,3 -di hydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-4-i odo-phenyl ami
no)-
benzamide is Form VI.
[0477] E21. The crystalline form of El, wherein the crystalline form of
N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 5.3 0.2, 10.6 0.2, and
16.1 0.2
degrees two theta.
[0478] E22. The crystalline form of E21, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 5.3 0.2, 10.6 0.2, 13.9
0.2, and
16.1 0.2 degrees two theta.
[0479] E23. The crystalline form of E21 or E22, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 5.2 wt% between about 40 C and about 120
C.
[0480] E24. The crystalline form of any one of E21-E23, wherein the
crystalline form
of N-((R)-2,3 -di hydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-4-i odo-phenyl
amino)-
benzamide exhibits a DSC thermogram that an endotherm onset at about 85 C.
[0481] E25. The crystalline form of any one of E21-E24, wherein the
crystalline form
of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 110
C.
[0482] E26. The crystalline form of any one of E21-E25, wherein the
crystalline form
of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has a first endotherm onset at about
85 'V
and a second endotherm onset at about 110 C.
[0483] E27. The crystalline form of any one of E21-E26, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzami de is characterized by an XRPD pattern substantially as shown in FIG.
4A.
CA 03207513 2023- 8- 4
WO 2022/177557 - 143 -
PCT/US2021/018381
[0484] E28. The crystalline form of any one of E21-E27, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 4B; and/or
b) a DSC profile substantially as shown in FIG. 4B.
[0485] E29. The crystalline form of any one of E21-E28, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl ami
no)-
benzamide is Form VII.
[0486] E30. The crystalline form of El, wherein the crystalline form of
N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 5.4 0.2, 10.7 0.2, and
18.7 0.2
degrees two theta.
[0487] E31. The crystalline form of E30, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 5.4 0.2, 10.7 0.2, 18.7
0.2, and
23.9 0.2 degrees two theta.
[0488] E32. The crystalline form of E30 or E31, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 3.3 wt% between about 40 C and about 112
C.
[0489] E33. The crystalline form of any one of E30-E32, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 81
C.
[0490] E34. The crystalline form of any one of E30-E33, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 110
C.
[0491] E35. The crystalline form of any one of E30-E34, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has a first endotherm onset at about
81 'V
and a second endotherm onset at about 110 C.
[0492] E36. The crystalline form of any one of E30-E35, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzami de is characterized by an XRPD pattern substantially as shown in FIG.
5A.
CA 03207513 2023- 8- 4
WO 2022/177557 - 144 -
PCT/US2021/018381
[0493] E37. The crystalline form of any one of E30-E36, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 5B; and/or
b) a DSC profile substantially as shown in FIG. 5B.
[0494] E38. The crystalline form of any one of E30-E37, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl ami
no)-
benzamide is Form VIII.
[0495] E39. The crystalline form of El, wherein the crystalline form of
N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 6.7 0.2, 13.5 0.2, and
22.2 0.2
degrees two theta.
[0496] E40. The crystalline form of E39, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 6.7 0.2, 8.0 0.2, 13.5
0.2, and
22.2 0.2 degrees two theta.
[0497] E41. The crystalline form of E39 or E40, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 4.6 wt% between about 28 C and about 128
C.
[0498] E42. The crystalline form of any one of E39-E41, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 84
C.
[0499] E43. The crystalline form of any one of E39-E42, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 107
C.
[0500] E44. The crystalline form of any one of E39-E43, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 114
C.
[0501] E45. The crystalline form of any one of E39-E44, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has a first endotherm onset at about
84 'V, a
second endotherm onset at about 107 C, and a third endotherm onset at about
114 C.
CA 03207513 2023- 8- 4
WO 2022/177557 - 145 -
PCT/US2021/018381
[0502] E46. The crystalline form of any one of E39-E45, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
6A.
[0503] E47. The crystalline form of any one of E39-E46, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzami de is characterized by:
a) a TGA profile substantially as shown in FIG. 6B; and/or
b) a DSC profile substantially as shown in FIG. 6B.
[0504] E48. The crystalline form of any one of E39-E47, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is Form IX.
[0505] E49. The crystalline of El, wherein the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 10.6 0.2, 19.6 0.2, and
24.8 0.2
degrees two theta.
[0506] E50. The crystalline of E49, wherein the crystalline form of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 5.5 0.2, 10.6 0.2, 19.6
0.2, and
24.8 0.2 degrees two theta.
[0507] E51. The crystalline form of E49 or E50, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 2.9 wt% between about 40 C and about 115
C.
[0508] E52. The crystalline form of any one of E49-E51, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 89
C.
[0509] E53. The crystalline form of any one of E49-E52, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
7A.
[0510] E54. The crystalline form of any one of E49-E53, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 7B; and/or
b) a DSC profile substantially as shown in FIG. 7B.
CA 03207513 2023- 8- 4
WO 2022/177557 - 146 -
PCT/US2021/018381
[0511] E55. The crystalline form of any one of E49-E54, wherein the
crystalline form
of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is Form X.
[0512] E56. The crystalline form of El, wherein the crystalline form of
N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 5.5 0.2, 6.9 0.2, and
10.1 0.2
degrees two theta.
[0513] E57. The crystalline form of E56, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 5.5 0.2, 6.9 0.2, 10.1
0.2, and
19.2 0.2 degrees two theta.
[05141 E58. The crystalline form of E56 or E57, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 7.6 wt% between about 40 C and about 175
C.
[0515] E59. The crystalline form of any one of E56-E58, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 69
C.
[0516] E60. The crystalline form of any one of E56-E59, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 104
C.
[0517] E61. The crystalline form of any one of E56-E60, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has a first endotherm onset at about
69 C
and a second endotherm onset at about 104 C.
[0518] E62. The crystalline form of any one of E56-E61, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
8A.
[05191 E63. The crystalline form of any one of E56-E62, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 8B; and/or
b) a DSC profile substantially as shown in FIG. 8B.
CA 03207513 2023- 8- 4
WO 2022/177557 - 147 -
PCT/US2021/018381
[0520] E64. The crystalline form of any one of E56-E63, wherein the
crystalline form
of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
b enzami de is Form XI.
[0521] E65. The crystalline form of El, wherein the crystalline form of
N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 10.1 0.2, 17.3 0.2, and
22.6 0.2
degrees two theta.
[0522] E66. The crystalline form of E65, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 10.1 0.2, 17.3 0.2, 21.5
0.2, and
22.6 0.2 degrees two theta.
[0523] E67. The crystalline form of E65 or E66, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 8.5 wt% between about 40 C and about 160
C.
[0524] E68. The crystalline form of any one of E65-E67, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 72
C.
[0525] E69. The crystalline form of any one of E65-E68, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 109
C.
[0526] E70. The crystalline form of any one of E65-E69, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has a first endotherm onset at about
72 C
and a second endotherm onset at about 109 C.
[0527] E71. The crystalline form of any one of E65-E70, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
9A.
[0528] E72. The crystalline form of any one of E65-E71, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 9B; and/or
b) a DSC profile substantially as shown in FIG. 9B.
CA 03207513 2023- 8- 4
WO 2022/177557 - 148 -
PCT/US2021/018381
[0529] E73. The crystalline form of any one of E65-E72, wherein the
crystalline form
of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
b enzami de is Form XII.
[0530] E74. The crystalline form of El, wherein the crystalline form of
N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 4.6 0.2, 5.1 0.2, and
14.6 0.2
degrees two theta.
[0531] E75. The crystalline form of E74 wherein the crystalline form of
N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 4.6 0.2, 5.1 0.2, 6.4
0.2, and 14.6
0.2 degrees two theta.
[0532] E76. The crystalline form of E74 or E75, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 3.1 wt% between about 20 C and about 100
C.
[0533] E77. The crystalline form of any one of E74-E76, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 55
C.
[0534] E78. The crystalline form of any one of E74-E77, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 109
C.
[0535] E79. The crystalline form of any one of E74-E78, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has a first endotherm onset at about
55 C
and a second endotherm onset at about 109 C.
[0536] E80. The crystalline form of any one of E74-E79, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
10A.
[0537] E81. The crystalline form of any one of E74-E80, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 10B; and/or
b) a DSC profile substantially as shown in FIG. 10B.
CA 03207513 2023- 8- 4
WO 2022/177557 - 149 -
PCT/US2021/018381
[05381 E82. The crystalline form of any one of E74-E81, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is Form XIII.
[0539] E83. The crystalline form of El, wherein the crystalline form of
N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 4.6 0.2, 23.4 0.2, and
25.2 0.2
degrees two theta.
[05401 E84. The crystalline form of E83, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 4.6 0.2, 23.4 0.2, 25.2
0.2, and
30.6 0.2 degrees two theta.
[05411 E85. The crystalline form of E83 or E84, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 0.15 wt% between about 40 C and about 150
C.
[0542] E86. The crystalline form of any one of E83-E85, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 111
C.
[05431 E87. The crystalline form of any one of E83-E86, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
11A.
[05441 E88. The crystalline form of any one of E83-E87, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 11B; and/or
b) a DSC profile substantially as shown in FIG. 11B.
[0545] E89. The crystalline form of any one of E83-E88, wherein the
crystalline form
of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
b enzami de is Form XIV.
[0546] E90. The crystalline form of El, wherein the crystalline form of
N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 5.5 0.2, 14.7 0.2, and
20.9 0.2
degrees two theta.
CA 03207513 2023- 8- 4
WO 2022/177557 - 150 -
PCT/US2021/018381
[0547] E91. The crystalline form of E90, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 5.5 0.2, 14.7 0.2, 20.9
0.2, and
26.6 + 0.2 degrees two theta.
[0548] E92. The crystalline form of E90 or E91, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 3.8 wt% between about 40 C and about 150
C.
[0549] E93. The crystalline form of any one of E90-E92, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 104
C.
[0550] E94. The crystalline form of any one of E90-E93, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
12A.
[0551] E95. The crystalline form of any one of E90-E94, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 12B; and/or
b) a DSC profile substantially as shown in FIG. 12B.
[0552] E96. The crystalline form of any one of E90-E95, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzami de is Form XV.
[0553] E97. The crystalline form of El, wherein the crystalline form of
N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 6.0 0.2, 17.1 0.2, and
20.6 0.2
degrees two theta.
[0554] E98. The crystalline form of E97, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 6.0 0.2, 12.8 0.2, 17.1
0.2, and
20.6 0.2 degrees two theta.
[0555] E99. The crystalline form of E97 or E98, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 2.1 wt% between about 40 C and about 150
C.
CA 03207513 2023- 8- 4
WO 2022/177557 - 151 -
PCT/US2021/018381
[0556] E100. The crystalline form of any one of E97-E99, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 74
C.
[0557] E101. The crystalline form of any one of E97-E100, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzami de exhibits a DSC thermogram that has an endotherm onset at about 102
C.
[0558] E102. The crystalline form of any one of E97-E101, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 114
C.
[0559] E103. The crystalline form of any one of E97-E102, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has a first endotherm onset at about
74 'V, a
second endotherm onset at about 102 C, and a third endotherm onset at about
114 C.
[0560] E104. The crystalline form of any one of E97-E103, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
13A.
[0561] E105. The crystalline form of any one of E97-E104, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 13B; and/or
b) a DSC profile substantially as shown in FIG. 13B.
[0562] E106. The crystalline form of any one of E97-E105, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is Form XVI.
[0563] E107. The crystalline form of El, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 5.9 0.2, 10.1 0.2, and
15.5 0.2
degrees two theta.
[0564] E108. The crystalline form of E107, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 5.9 0.2, 10.1 0.2, 11.7
0.2, and
15.5 0.2 degrees two theta.
CA 03207513 2023- 8- 4
WO 2022/177557 - 152 -
PCT/US2021/018381
[0565] E109. The crystalline form of E107 or E108, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 2.7 wt% between about 40 C and about 100
C.
[0566] E110. The crystalline form of any one of E107-E109, wherein
crystalline form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits a DSC thermogram that has an endotherm onset at about 89 C.
[0567] El 11. The crystalline form of any one of El 07-El 10, wherein
the crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
14A.
[0568] E112. The crystalline form of any one of E107-E111, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 14B; and/or
b) a DSC profile substantially as shown in FIG. 14B.
[0569] E113. The crystalline form of any one of E107-E112, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is Form XVII.
[0570] E114. The crystalline form of El, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 4.6 + 0.2, 10.7 + 0.2, and
15.9 + 0.2
degrees two theta.
[0571] E115. The crystalline form of E114, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 4.6 0.2, 10.7 0.2, 15.9
0.2, and
19.6 0.2 degrees two theta.
[0572] E116. The crystalline form of E114 or E115, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 1.6 wt% between about 30 C and about 150
C.
[0573] E117. The crystalline form of any one of E114-E116, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 83
C.
CA 03207513 2023- 8- 4
WO 2022/177557 - 153 -
PCT/US2021/018381
[0574] E118. The crystalline form of any one of E114-E117, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
15A.
[0575] E119. The crystalline form of any one of E114-E118, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 15B; and/or
b) a DSC profile substantially as shown in FIG. 15B.
[0576] E120. The crystalline form of any one of E114-E119, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is Form XVIII.
[05771 E121. The crystalline form of El, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 10.2 0.2, 11.6 0.2, and
20.0 0.2
degrees two theta.
[0578] E122. The crystalline form of E121, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 10.2 0.2, 11.6 0.2, 17.1
0.2, and
20.0 0.2 degrees two theta.
[0579] E123. The crystalline form of E121 or E122, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 1.85 wt% between about 23 C and about 92
C.
[0580] E124. The crystalline form of any one of E121-E123, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 69
C.
[0581] E125. The crystalline form of any one of E121-E124, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 98
C.
[0582] E126. The crystalline form of any one of E121-E125, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 115
C.
[0583] E127. The crystalline form of any one of E121-E126, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
CA 03207513 2023- 8- 4
WO 2022/177557 - 154 -
PCT/US2021/018381
benzamide exhibits a DSC thermogram that has a first endotherm onset at about
69 C, a
second endotherm onset at about 98 C, and a third endotherm onset at about
115 'C.
[0584] E128. The crystalline form of any one of E121-E127, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
16A.
[0585] E129. The crystalline form of any one of E121-E128, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 16B; and/or
b) a DSC profile substantially as shown in FIG. 16B.
[0586] E130. The crystalline form of any one of E121-E129, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is Form XIX.
[0587] E131. The crystalline form of El, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 7.8 0.2, 14.0 0.2, and
17.1 0.2
degrees two theta.
[0588] E132. The crystalline form of E131, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 7.8 + 0.2, 14.0 + 0.2, 15.6 +
0.2, and
17.1 0.2 degrees two theta.
[0589] E133. The crystalline form of E131 or E132, wherein the TGA
exhibits that the
crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide loses about 2.6 wt% between about 29 C and about 126
C.
[0590] E134. The crystalline form of any one of E131-133, wherein the
crystalline form
of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 77
C.
[05911 E135. The crystalline form of any one of E131-E134, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 92
C.
[0592] E136. The crystalline form of any one of E131-E135, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 110
C.
CA 03207513 2023- 8- 4
WO 2022/177557 - 155 -
PCT/US2021/018381
[0593] E137. The crystalline form of any one of E131-E136, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has a first endotherm onset at about
77 C, a
second endotherm onset at about 92 C, and a third endotherm onset at about
110 C.
[0594] E138. The crystalline form of any one of E131-E137, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
17A.
[0595] El 39. The crystalline form of any one of E131-E138, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 17B; and/or
b) a DSC profile substantially as shown in FIG. 17B.
[0596] E140. The crystalline form of any one of E131-E139, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is Form XX.
[0597] E141. The crystalline form of El, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 5.5 0.2, 8.2 0.2, and
16.7 0.2
degrees two theta.
[0598] E142. The crystalline form of E141, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is
characterized by an XRPD pattern having peaks at 5.5 0.2, 8.2 0.2, 16.7
0.2, and
17.7 0.2 degrees two theta.
[0599] E143. The crystalline form of E141 or E142, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 14.1 wt% between about 30 C and about 110
C.
[0600] E144. The crystalline form of any one of E141-E143, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 52
C.
[0601] E145. The crystalline form of any one of E141-E144, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 90
C.
CA 03207513 2023- 8- 4
WO 2022/177557 - 156 -
PCT/US2021/018381
[0602] E146. The crystalline form of any one of E141-E145, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has a first endotherm onset at about
52 C
and a second endotherm onset at about 90 C.
[0603] E147. The crystalline form of any one of E141-E146, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
18A.
[0604] E148. The crystalline form of any one of E141-E147, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 18B; and/or
b) a DSC profile substantially as shown in FIG. 18B.
[0605] E149. The crystalline form of any one of E141-E148, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is Form XXI.
[0606] E150. The crystalline form of El, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 7.2 0.2, 2L7 0.2, and
29.1 0.2
degrees two theta.
[0607] E151. The crystalline form of E150, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is
characterized by an XRPD pattern having peaks at 7.2 0.2, 18.6 0.2, 21.7
0.2, and
29.1 0.2 degrees two theta.
[0608] E152. The crystalline form of E150 or E151, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 13.8 wt% between about 26 C and about 135
C.
[0609] E153. The crystalline form of any one of E150-E152, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 65
C.
[0610] E154. The crystalline form of any one of E150-E153, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 89
C.
CA 03207513 2023- 8- 4
WO 2022/177557 - 157 -
PCT/US2021/018381
[0611] E155. The crystalline form of any one of E150-E154, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 102
C.
[0612] E156. The crystalline form of any one of E150-E155, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has a first endotherm onset at about
65 C, a
second endotherm onset at about 89 C, and a third endotherm onset at about
102 C.
[0613] E157. The crystalline form of any one of E150-E156, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
19A.
[0614] E158. The crystalline form of any one of E150-E157, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 19B; and/or
b) a DSC profile substantially as shown in FIG. 19B.
[0615] E159. The crystalline form of any one of E150-E158, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is Form XXII.
[0616] E160. The crystalline form of El, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 5.4 0.2, 9.7 0.2, and
10.7 0.2
degrees two theta.
[0617] E161. The crystalline form of E160, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 5.4 0.2, 6.5 0.2, 9.7
0.2, and 10.7
0.2 degrees two theta.
[0618] E162. The crystalline form of E160 or E161, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 4.4 wt% between about 27 C and about 137
C.
[0619] E163. The crystalline form of any one of E160-E162, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 81
C.
CA 03207513 2023- 8- 4
WO 2022/177557 - 158 -
PCT/US2021/018381
[0620] E164. The crystalline form of any one of E160-E163, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 101
C.
[0621] E165. The crystalline form of any one of E160-E164, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has a first endotherm onset at about
81 C
and a second endotherm onset at about 101 C.
[0622] E166. The crystalline form of any one of E160-E165, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by an XRPD pattern substantially as shown in FIG.
20A.
[0623] E167. The crystalline form of any one of E160-E166, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 20B; and/or
b) a DSC profile substantially as shown in FIG. 20B.
[0624] E168. The crystalline form of any one of E160-E167, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is Form XXIII.
[0625] E169. The crystalline form of El, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 7.2 0.2, 20.6 0.2, and
23.0 0.2
degrees two theta.
[0626] E170. The crystalline form of E169, wherein the crystalline form
of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
characterized by an XRPD pattern having peaks at 7.2 0.2, 9.5 0.2, 20.6
0.2, and
23.0 0.2 degrees two theta.
[0627] E171. The crystalline form of E169 or E170, wherein the TGA
exhibits that the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide loses about 1.2 wt% between about 30 C and about 119
C.
[0628] E172. The crystalline form of any one of E169-E171, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide exhibits a DSC thermogram that has an endotherm onset at about 104
C.
CA 03207513 2023- 8- 4
WO 2022/177557 - 159 -
PCT/US2021/018381
[0629] E173. The crystalline form of any one of E169-E172, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by an XRF'D pattern substantially as shown in FIG.
21A.
[0630] E174. The crystalline form of any one of E169-E173, wherein the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 21B; and/or
b) a DSC profile substantially as shown in FIG. 21B.
[0631] E175. The crystalline form of any one of E169-E174, wherein the
crystal form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
is Form XXIV.
[06321 E176. Amorphous solid of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-
fluoro-4-iodo-phenylamino)-benzamide of Formula (I)
HOO N
OH H
N
(I).
[0633] E177. The amorphous solid of claim 176, wherein the amorphous
solid of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
characterized by an XRPD pattern substantially as shown in FIG. 22A.
[0634] E178. The amorphous solid of E176 or E177, wherein the amorphous
solid of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
characterized by:
a) a TGA profile substantially as shown in FIG. 22B; and/or
b) a DSC profile substantially as shown in FIG. 22B.
[0635] El 79. A pharmaceutical composition comprising: the crystalline
form of any one
of claims 1-175 or the amorphous solid of any one of claims 176-178; and one
or more
pharmaceutically acceptable carriers.
[0636] E180. The pharmaceutical composition of E179, wherein the
crystalline form or
the amorphous solid comprises less than 10% by weight total of one or more
other
crystalline forms and/or amorphous solid.
CA 03207513 2023- 8- 4
WO 2022/177557 - 160 -
PCT/US2021/018381
[0637] E181. The pharmaceutical composition of E179, wherein the
crystalline form or
the amorphous solid comprises less than 5% by weight total of one or more
other
crystalline forms and/or amorphous solid.
[0638] E182. The pharmaceutical composition of E179, wherein the
crystalline form or
the amorphous solid comprises less than 2% by weight total of one or more
other
crystalline forms and/or amorphous solid.
[0639] E183. The pharmaceutical composition of E179, wherein the
crystalline form or
the amorphous solid comprises less than 1% by weight total of one or more
other
crystalline forms and/or amorphous solid.
[0640] E184. The pharmaceutical composition of E179, wherein the
crystalline form or
the amorphous solid comprises less than 0.5% by weight total of one or more
other
crystalline forms and/or amorphous solid.
[0641] E185. The pharmaceutical composition of E179, wherein the
crystalline form or
the amorphous solid comprises less than 0.1% by weight total of one or more
other
crystalline forms and/or amorphous solid.
[0642] E186. The pharmaceutical composition of any one of E179-E185,
wherein the
pharmaceutical composition is for oral administration.
[0643] E187. The pharmaceutical composition of any one of E179-E186,
wherein the
pharmaceutical composition is a solid dosage form.
[0644] E188. The pharmaceutical composition of any one of E179-E187,
wherein the
pharmaceutical composition is a capsule, tablet, powder, granules, minitablet,
or pellet.
[0645] E189. The pharmaceutical composition of E188, wherein the
pharmaceutical
composition is a capsule.
[0646] E190. The pharmaceutical composition of E189, wherein the
capsule comprises
about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide, wherein each component of the capsule is as follows:
a) about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the
amorphous solid of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide;
b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d) 0 wt/wt% to about 5 wt/wt% of one or more lubricants; and
e) a gelatin capsule which encapsulates components a-d.
CA 03207513 2023- 8- 4
WO 2022/177557 - 161 -
PCT/US2021/018381
[0647] E191. The pharmaceutical composition of E189, wherein the
capsule comprises
about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide, wherein each component of the capsule is as follows:
a) about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the
amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzami de;
b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants,
d) 0 wt/wt% to about 5 wt/wt% of one or more lubricants; and
e) a gelatin capsule which encapsulates components a-d.
[0648] E192. The pharmaceutical composition of E189, wherein the
capsule comprises
about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide, wherein each component of the capsule is as follows:
a) about 2.5 wt/wt% to about 7.0 wt/wt% of the crystalline form or the
amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide;
b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; and
d) a gelatin capsule which encapsulates components a-c.
[0649] E193. The pharmaceutical composition of any one of E190-E192,
wherein at
least one of the diluents is selected from the group consisting of
microcrystalline
cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized
starch, calcium
sulfate, calcium carbonate, starch, and dibasic calcium phosphate.
[0650] E194. The pharmaceutical composition of E193, wherein at least
one of the
diluents is microcrystalline cellulose.
[0651] E195. The pharmaceutical composition of any one of E190-E194,
wherein at
least one of the disintegrants is selected from the group consisting of
croscarmellose
sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose,
starch,
pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic
acid.
[0652] E196. The pharmaceutical composition of E195, wherein at least
one of the
disintegrants is croscarmellose sodium.
[0653] E197. The pharmaceutical composition of any one of E190-E196,
wherein at
least one of the lubricants is selected from the group consisting of magnesium
stearate,
CA 03207513 2023- 8- 4
WO 2022/177557 - 162 -
PCT/US2021/018381
sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated
vegetable oil,
calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
[0654] E198. The pharmaceutical composition of E197, wherein at least
one of the
lubricants is magnesium stearate.
[0655] E199. The pharmaceutical composition of E188, wherein the
pharmaceutical
composition is a tablet.
[0656] E200. The pharmaceutical composition of E199, wherein the tablet
is a
dispersible tablet.
[0657] E201. The pharmaceutical composition of E200, wherein the
dispersible tablet
comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide, and wherein each component of the dispersible
tablet is
as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the
amorphous solid of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and
f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0658] E202. The pharmaceutical composition of E200, wherein the
dispersible tablet
comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide, and wherein each component of the dispersible tablet
is as
follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the
amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and
f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
CA 03207513 2023- 8- 4
WO 2022/177557 - 163 -
PCT/US2021/018381
[0659] E203. The pharmaceutical composition of E201 or E202, wherein at
least one of
the diluents is selected from the group consisting of microcrystalline
cellulose, lactose,
mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate,
calcium
carbonate, starch, and dibasic calcium phosphate.
[0660] E204. The pharmaceutical composition of E203, wherein at least
one of the
diluents is microcrystalline cellulose.
[0661] E205. The pharmaceutical composition of any one of E201-E204,
wherein at
least one of the disintegrants is selected from the group consisting of
croscarmellose
sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose,
starch,
pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic
acid.
[0662] E206. The pharmaceutical composition of E205, wherein at least
one of the
disintegrants is croscarmellose sodium.
[0663] E207. The pharmaceutical composition of any one of E201-E206,
wherein at
least one of the flavoring agents is selected from the group consisting of
natural or
synthetic flavors including but not limited to, grape flavoring, bubble gum
flavoring,
caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring,
raspberry
flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring,
pineapple flavoring,
pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or
cherry flavoring.
[0664] E208. The pharmaceutical composition of E207, wherein at least
one of the
flavoring agents is grape flavoring.
[0665] E209. The pharmaceutical composition of any one of E201-E208,
wherein at
least one sweetener of the dispersible tablet is selected from the group
consisting of
sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol,
glucose, fructose,
and aspartame.
[0666] E210. The pharmaceutical composition of E209, wherein the
sweetener is
sucralose.
[0667] E211. The pharmaceutical composition of any one of E201-E210,
wherein at
least one of the lubricants is selected from the group consisting of magnesium
stearate,
sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated
vegetable oil,
calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
[0668] E212. The pharmaceutical composition of E211, wherein at least
one of the
lubricants is magnesium stearate.
CA 03207513 2023- 8- 4
WO 2022/177557 - 164 -
PCT/US2021/018381
[0669] E213. The pharmaceutical composition of any one of E199-E212,
wherein the
tablet is an orodispersible tablet.
[0670] E214. The pharmaceutical composition of E188, wherein the
pharmaceutical
composition is a powder.
[0671] E215. The pharmaceutical composition of E214, wherein the powder
is a
dispersible powder.
[0672] E216. The pharmaceutical composition of E215, wherein the
dispersible powder
comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide, and wherein each component of the dispersible
powder is
as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous
solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and
f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0673] E217. The pharmaceutical composition of E215, wherein the
dispersible powder
comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide, and wherein each component of the dispersible powder
is as
follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the
amorphous solid of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and
f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0674] E218. The pharmaceutical composition of E216 or E217, wherein at
least one of
the diluents is selected from the group consisting of microcrystalline
cellulose, lactose,
CA 03207513 2023- 8- 4
WO 2022/177557 - 165 -
PCT/US2021/018381
mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate,
calcium
carbonate, starch, and dibasic calcium phosphate.
[0675] E219. The pharmaceutical composition of E218, wherein at least
one of the
diluents is microcrystalline cellulose.
[0676] E220. The pharmaceutical composition of any one of E216-E219,
wherein at
least one of the di sintegrants is selected from the group consisting of
croscarmellose
sodium, sodium starch glycol ate, crospovi done, microcrystalline cellulose,
starch,
pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic
acid.
[0677] E221. The pharmaceutical composition of E220, wherein at least
one of the
disintegrants is croscarmellose sodium.
[0678] E222. The pharmaceutical composition of any one of E216-E221,
wherein at
least one of the flavoring agents is selected from the group consisting of
natural or
synthetic flavors including but not limited to, grape flavoring, bubble gum
flavoring,
caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring,
raspberry
flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring,
pineapple flavoring,
pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or
cherry flavoring.
[0679] E223. The pharmaceutical composition of E222, wherein at least
one of the
flavoring agents is grape flavoring.
[0680] E224. The pharmaceutical composition of any one of E216-E223,
wherein at
least one sweetener of the dispersible powder is selected from the group
consisting of
sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol,
glucose, fructose,
and aspartame.
[0681] E225. The pharmaceutical composition of E224, wherein the
sweetener is
sucralose.
[0682] E226. The pharmaceutical composition of any one of E216-E225,
wherein at
least one of the lubricants is selected from the group consisting of magnesium
stearate,
sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated
vegetable oil,
calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
[0683] E227. The pharmaceutical composition of E226, wherein at least
one of the
lubricants is magnesium stearate.
[0684] E228. The pharmaceutical composition of any one of E215-E227,
wherein the
powder is an orodispersible powder.
CA 03207513 2023- 8- 4
WO 2022/177557 - 166 -
PCT/US2021/018381
[0685] E229. The pharmaceutical composition of E188, wherein the
pharmaceutical
composition is granules.
[0686] E230. The pharmaceutical composition of E229, wherein the
granules are
dispersible granules.
[0687] E231. The pharmaceutical composition of E230, wherein the
dispersible granules
comprise about 0.5 mg of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide, and wherein each component of the dispersible granules
is as
follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the
amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and
f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0688] E232. The pharmaceutical composition of E230, wherein the
dispersible granules
comprise about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide, and wherein each component of the dispersible granules
is as
follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the
amorphous solid of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and
f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0689] E233. The pharmaceutical composition of E231 or E232, wherein at
least one of
the diluents is selected from the group consisting of microcrystalline
cellulose, lactose,
mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate,
calcium
carbonate, starch, and dibasic calcium phosphate.
CA 03207513 2023- 8- 4
WO 2022/177557 - 167 -
PCT/US2021/018381
[0690] E234. The pharmaceutical composition of E233, wherein at least
one of the
diluents is microcrystalline cellulose.
[0691] E235. The pharmaceutical composition of any one of E231-E234,
wherein at
least one of the disintegrants is selected from the group consisting of
croscarmellose
sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose,
starch,
pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic
acid.
[0692] E236. The pharmaceutical composition of E235, wherein at least
one of the
disintegrants is croscarmellose sodium.
[0693] E237. The pharmaceutical composition of any one of E231-E236,
wherein at
least one of the flavoring agents is selected from the group consisting of
natural or
synthetic flavors including but not limited to, grape flavoring, bubble gum
flavoring,
caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring,
raspberry
flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring,
pineapple flavoring,
pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or
cherry flavoring.
[0694] E238. The pharmaceutical composition of E237, wherein at least
one of the
flavoring agents is grape flavoring.
[0695] E239. The pharmaceutical composition of any one of E231-E238,
wherein at
least one sweetener of the dispersible granules is selected from the group
consisting of
sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol,
glucose, fructose,
and aspartame.
[0696] E240. The pharmaceutical composition of E239, wherein the
sweetener is
sucralose.
[0697] E241. The pharmaceutical composition of any one of E231-E240,
wherein at
least one of the lubricants is selected from the group consisting of magnesium
stearate,
sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated
vegetable oil,
calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
[0698] E242. The pharmaceutical composition of E241, wherein at least
one of the
lubricants is magnesium stearate.
[0699] E243. The pharmaceutical composition of any one of E229-E242,
wherein the
granules are orodispersible granules.
[0700] E244. The pharmaceutical composition of E188, wherein the
pharmaceutical
composition is a minitablet.
CA 03207513 2023- 8- 4
WO 2022/177557 - 168 -
PCT/US2021/018381
[0701] E245. The pharmaceutical composition of E244, wherein the
minitablets are
dispersible minitablets.
[0702] E246. The pharmaceutical composition of E245, wherein the
dispersible
minitablets comprise about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-
fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the
dispersible
minitablets is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the
amorphous solid of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and
f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0703] E247. The pharmaceutical composition of E245, wherein the
dispersible
minitablets comprise about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the
dispersible
minitablets is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the
amorphous solid of NAR)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzami de;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and
f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0704] E248. The pharmaceutical composition of E246 or E247, wherein at
least one of
the diluents is selected from the group consisting of microcrystalline
cellulose, lactose,
mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate,
calcium
carbonate, starch, and dibasic calcium phosphate.
[0705] E249. The pharmaceutical composition of E248, wherein at least
one of the
diluents is microcrystalline cellulose.
CA 03207513 2023- 8- 4
WO 2022/177557 - 169 -
PCT/US2021/018381
[0706] E250. The pharmaceutical composition of any one of E246-E249,
wherein at
least one of the disintegrants is selected from the group consisting of
croscarmellose
sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose,
starch,
pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic
acid.
[0707] E251. The pharmaceutical composition of E250, wherein at least
one of the
di sintegrants is croscarmellose sodium.
[0708] E252. The pharmaceutical composition of any one of E246-E251,
wherein at
least one of the flavoring agents is selected from the group consisting of
natural or
synthetic flavors including but not limited to, grape flavoring, bubble gum
flavoring,
caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring,
raspberry
flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring,
pineapple flavoring,
pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or
cherry flavoring.
[0709] E253. The pharmaceutical composition of E252, wherein at least
one of the
flavoring agents is grape flavoring.
[0710] E254. The pharmaceutical composition of any one of E246-E253,
wherein at
least one sweetener of the dispersible minitablets is selected from the group
consisting of
sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol,
glucose, fructose,
and aspartame.
[0711] E255. The pharmaceutical composition of E254, wherein the
sweetener is
sucralose.
[0712] E256. The pharmaceutical composition of any one of E246-E255,
wherein at
least one of the lubricants is selected from the group consisting of magnesium
stearate,
sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated
vegetable oil,
calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
[0713] E257. The pharmaceutical composition of E256, wherein at least
one of the
lubricants is magnesium stearate.
[0714] E258. The pharmaceutical composition of any one of E244-E257,
wherein the
minitablets are orodispersible minitablets.
[0715] E259. The pharmaceutical composition of E188, wherein the
pharmaceutical
composition is a pellet.
[0716] E260. The pharmaceutical composition of E259, wherein the
pellets are
dispersible pellets.
CA 03207513 2023- 8- 4
WO 2022/177557 - 170 -
PCT/US2021/018381
[0717] E261. The pharmaceutical composition of E260, wherein the
dispersible pellets
comprise about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide, and wherein each component of the dispersible pellets
is as
follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the
amorphous solid of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-
phenylamino)-benzami de;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and
f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0718] E262. The pharmaceutical composition of E260, wherein the
dispersible pellets
comprise about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide, and wherein each component of the dispersible pellets
is as
follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the
amorphous solid of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more di sintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and
f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0719] E263. The pharmaceutical composition of E261 or E262, wherein at
least one of
the diluents is selected from the group consisting of microcrystalline
cellulose, lactose,
mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate,
calcium
carbonate, starch, and dibasic calcium phosphate.
[0720] E264. The pharmaceutical composition of E263, wherein at least
one of the
diluents is microcrystalline cellulose.
[0721] E265. The pharmaceutical composition of any one of E261-E264,
wherein at
least one of the di sintegrants is selected from the group consisting of
croscarmellose
CA 03207513 2023- 8- 4
WO 2022/177557 - 171 -
PCT/US2021/018381
sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose,
starch,
pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic
acid.
[0722] E266. The pharmaceutical composition of E265, wherein at least
one of the
disintegrants is croscarmellose sodium.
[0723] E267. The pharmaceutical composition of any one of E261-E266,
wherein at
least one of the flavoring agents is selected from the group consisting of
natural or
synthetic flavors including but not limited to, grape flavoring, bubble gum
flavoring,
caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring,
raspberry
flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring,
pineapple flavoring,
pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or
cherry flavoring.
[0724] E268. The pharmaceutical composition of E267, wherein at least
one of the
flavoring agents is grape flavoring.
[0725] E269. The pharmaceutical composition of any one of E261-E268,
wherein at
least one sweetener of the dispersible pellets is selected from the group
consisting of
sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol,
glucose, fructose,
and aspartame.
[0726] E270. The pharmaceutical composition of E269, wherein the
sweetener is
sucralose.
[0727] E271. The pharmaceutical composition of any one of E261-E270,
wherein at
least one of the lubricants is selected from the group consisting of magnesium
stearate,
sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated
vegetable oil,
calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
[0728] E272. The pharmaceutical composition of E271, wherein at least
one of the
lubricants is magnesium stearate.
[0729] E273. The pharmaceutical composition of any one of E259-E272,
wherein the
pellets are orodispersible pellets.
[0730] E274. A method of treating a tumor, cancer, or Rasopathy
disorder comprising
administering to a subject in need of such treatment the pharmaceutical
composition of
any one of E179-E273.
[0731] E275. The method of E274, wherein the tumor is a
neurofibroma.
[0732] E276. The method of E274 or E275, wherein the tumor is a
neurofibroma
associated with Neurofibromatosis Type 1.
CA 03207513 2023- 8- 4
WO 2022/177557 - 172 -
PCT/US2021/018381
[0733] E277. The method of any one of claims E274-E276, wherein the
tumor is
selected from the group consisting of cutaneous neurofibroma, plexiform
neurofibroma,
optic pathway glioma, low grade glioma, high grade glioma, and malignant
peripheral
nerve sheath tumor.
[0734] E278. The method of E277, wherein the tumor is plexiform
neurofibroma.
[0735] E279. The method of any one of E274-E278, wherein the subject
has been
diagnosed with a Rasopathy disorder selected from the group consisting of
neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous
syndrome,
Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with
multiple lentigines.
[0736] E280. The method of any one of E274-E279, wherein the cancer is
selected from
the group consisting of skin cancer, malignant peripheral nerve sheath cancer,
leukemia,
lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer,
renal cancer,
colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer,
uterine
neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer,
endometrial
cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer,
prostate cancer,
oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular
cancer, biliary
tract cancer, and serous carcinoma of the peritoneum.
[0737] E281. The method of E280, wherein the leukemia is selected from
the group
consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic
lymphocytic leukemia, and chronic myelogenous leukemia.
[0738] E282. The method of E280, wherein the lymphoma is selected from
the group
consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular
lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small
lymphocytic lymphoma, and Waldenstrom macroglobulinemia.
[0739] E283. The method of E280, wherein the lung cancer is selected
from the group
consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-
squamous
non-small cell lung cancer, and small cell lung cancer.
[0740] E284. The method of any one of E274-E283, wherein the subject
bears a
mutation or other aberration in one or more genes for which the mutation or
other
aberration causes a gain or loss of function characteristic of certain
cancers, wherein the
mutation or other aberration in one or more genes is a mutation or other
aberration in one
CA 03207513 2023- 8- 4
WO 2022/177557 - 173 -
PCT/US2021/018381
or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or
NF2.
[0741] E285. The method of any one of E274-E284, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 20 mg.
[0742] E286. The method of any one of E274-E284, wherein the N-((R)-2,3-
di hydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-4-i odo-phenyl ami n o)-b en zami
de is
administered in a total daily dose that does not exceed 10 mg.
[0743] E287. The method of any one of E274-E284, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 8 mg.
[07441 E288. The method of any one of E274-E284, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 6 mg.
[0745] E289. The method of any one of E274-E288, wherein the total
daily dose of the
N-((R)-2,3 -dihydroxypropoxy)-3 ,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-b
enzami de
is administered once daily.
[0746] E290. The method of E289, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 0.1 mg to about 20 mg.
[0747] E291. The method of E290, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3 ,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-b enzami de
is
administered once daily at a dose of about 0.5 mg.
[0748] E292. The method of E290, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 1 mg.
[0749] E293. The method of E290, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 2 mg.
[0750] E294. The method of E290, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 4 mg.
CA 03207513 2023- 8- 4
WO 2022/177557 - 174 -
PCT/US2021/018381
[0751] E295. The method of E290, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 6 mg.
[0752] E296. The method of E290, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3 ,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-b enzami de
is
administered once daily at a dose of about 8 mg.
[0753] E297. The method of E290, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 20 mg.
[0754] E298. The method of any one of E274-E288, wherein the total
daily dose of the
N-((R)-2,3 -dihydroxypropoxy)-3 ,4-difluoro-2-(2-fluoro-44 odo-phenylamino)-b
enzami de
is administered two times daily.
[0755] E299. The method of E298, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 0.1 mg to about 10 mg each.
[0756] E300. The method of E298, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 0.5 mg each.
[0757] E301. The method of E298, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 1 mg each.
[0758] E302. The method of E298, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 2 mg each.
[0759] E303. The method of E298, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 3 mg each.
[07601 E304. The method of E298, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 4 mg each.
[0761] E305. The method of E298, wherein the total daily dose of the N-
((R)-2,3-
di hydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-4-i odo-phenyl ami n o)-b en zami
de is
administered two times daily at a dose of about 10 mg each.
CA 03207513 2023- 8- 4
WO 2022/177557 - 175 -
PCT/US2021/018381
[0762] E306. The method of any one of E274-E305, wherein an individual
dose of the
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
is administered as more than one capsule, more than one tablet, more than one
dose of
dispersible powder, more than one dose of granules, more than one dose of
minitablets,
more than one dose of pellets, or a combination thereof.
[0763] E307. The method of any one of E274-E306, wherein the
pharmaceutical
composition is a dispersible tablet, a dispersible powder, dispersible
granules, dispersible
minitablets, or dispersible pellets, and wherein the dispersible tablet,
dispersible powder,
dispersible granules, dispersible minitablets, or dispersible pellets is
dispersed in a
potable liquid prior to administration to the subject.
[0764] E308. The method of E307, wherein the subject experiences
dysphagia caused by
one or more of: disease of the nervous system, muscle weakening, developmental
disability, stroke, injury, anatomical defect, cancer, treatment for cancer,
allergic reaction,
dementia, memory loss, or cognitive decline.
[0765] E309. The method of E307 or E308, wherein the subject is a
pediatric subject.
[0766] E310. The method of any one of E274-E309, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising: (a) 21 days in which the
total daily
dose is administered; and (b) 7 days in which no N4R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
[0767] E311. The method of any one of E274-E309, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising: (a) 21 consecutive days in
which the
total daily dose is administered; followed by (b) 7 consecutive days in which
no N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered.
[0768] E312. The method of any one of E274-E309, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising: (a) three 7-day periods each
comprising (i) 5 days in which the total daily dose is administered and (ii) 2
days in
which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered.
CA 03207513 2023- 8- 4
WO 2022/177557 - 176 -
PCT/US2021/018381
[0769] E313. The method of any one of E274-E309, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising: (a) three 7-day periods each
comprising (i) 5 consecutive days in which the total daily dose is
administered and (ii) 2
consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide; followed by (b) 7 consecutive days in which no N-
((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami
de is
administered.
[0770] E314. The method of any one of E310-E313, wherein the 28-day
dosing cycle is
repeated up to a total of 24 consecutive 28-day dosing cycles.
[0771] E315. Use of the pharmaceutical composition of any one of E179-
E273 for the
manufacture of a medicament for treating a tumor, cancer, or Rasopathy
disorder.
[0772] E316. The use of E315, wherein the tumor is a neurofibroma.
[0773] E317. The use of E315 or E316, wherein the tumor is a
neurofibroma associated
with Neurofibromatosis Type 1.
[0774] E318. The use of any one of E315-E317, wherein the tumor is
selected from the
group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic
pathway
glioma, low grade glioma, high grade glioma, and malignant peripheral nerve
sheath
tumor.
[0775] E319. The use of E318, wherein the tumor is plexiform
neurofibroma.
[0776] E320. The use of any one of E315-E319, wherein the subject has
been diagnosed
with a Rasopathy disorder selected from the group consisting of
neurofibromatosis type 1,
neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome,
Legius
syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
[0777] E321. The use of any one of E315-E320, wherein the cancer is
selected from the
group consisting of skin cancer, malignant peripheral nerve sheath cancer,
leukemia,
lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer,
renal cancer,
colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer,
uterine
neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer,
endometrial
cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer,
prostate cancer,
oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular
cancer, biliary
tract cancer, and serous carcinoma of the peritoneum.
CA 03207513 2023- 8- 4
WO 2022/177557 - 177 -
PCT/US2021/018381
[0778] E322. The use of E321, wherein the leukemia is selected from the
group
consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic
lymphocytic leukemia, and chronic myelogenous leukemia.
[0779] E323. The use of E321, wherein the lymphoma is selected from the
group
consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular
lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small
lymphocytic lymphoma, and Waldenstrom macrogl obulinemi a.
[0780] E324. The use of E321, wherein the lung cancer is selected from
the group
consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-
squamous
non-small cell lung cancer, and small cell lung cancer.
[0781] E325. The use of any one of E315-E324, wherein the subject bears
a mutation or
other aberration in one or more genes for which the mutation or other
aberration causes a
gain or loss of function characteristic of certain cancers, wherein the
mutation or other
aberration in one or more genes is a mutation or other aberration in one or
more of
KRAS, NRAS, BRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
[0782] E326. The use of any one of E315-E325, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 20 mg.
[0783] E327. The use of any one of E315-E325, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 10 mg.
[0784] E328. The use of any one of E315-E325, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 8 mg.
[0785] E329. The use of any one of E315-E325, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 6 mg.
[07861 E330. The use of any one of E315-E329, wherein the total daily
dose of the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
administered once daily.
[0787] E331. The use of E330, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de is
administered once daily at a dose of about 0.1 mg to about 20 mg.
CA 03207513 2023- 8- 4
WO 2022/177557 - 178 -
PCT/US2021/018381
[0788] E332. The use of E331, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 0.5 mg.
[0789] E333. The use of E331, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3 ,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-b enzami de
is
administered once daily at a dose of about 1 mg.
[0790] E334. The use of E331, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 2 mg.
[0791] E335. The use of E331, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 4 mg.
[0792] E336. The use of E331, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 6 mg.
[0793] E337. The use of E331, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 8 mg.
[0794] E338. The use of E331, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 20 mg.
[0795] E339. The use of any one of E315-E329, wherein the total daily
dose of the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
administered two times daily.
[0796] E340. The use of E339, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 0.1 mg to about 10 mg each.
[0797] E341. The use of E340, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 0.5 mg each.
[0798] E342. The use of E340, wherein the total daily dose of the N-
((R)-2,3-
di hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl ami n o)-b en zami
de is
administered two times daily at a dose of about 1 mg each.
CA 03207513 2023- 8- 4
WO 2022/177557 - 179 -
PCT/US2021/018381
[07991 E343. The use of E340, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 2 mg each.
[0800] E344. The use of E340, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 3 mg each.
[08011 E345. The use of E340, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 4 mg each.
[0802] E346. The use of E340, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 10 mg each.
[08031 E347. The use of any one of E315-E346, wherein an individual
dose of the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
administered as more than one capsule, more than one tablet, more than one
dose of
dispersible powder, more than one dose of granules, more than one dose of
minitablets,
more than one dose of pellets, or a combination thereof.
[08041 E348. The use of any one of E315-E347, wherein the
pharmaceutical
composition is a dispersible tablet, a dispersible powder, dispersible
granules, a
dispersible minitablet, or a dispersible pellet, and wherein the dispersible
tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets is
dispersed in a potable liquid prior to administration to the subject.
[0805] E349. The use of E348, wherein the subject experiences dysphagia
caused by one
or more of: disease of the nervous system, muscle weakening, developmental
disability,
stroke, injury, anatomical defect, cancer, treatment for cancer, allergic
reaction, dementia,
memory loss, or cognitive decline.
[0806] E350. The use of E348 or E349, wherein the subject is a
pediatric subject.
[08071 E351. The use of any one of E315-E350, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising: (a) 21 days in which the
total daily
dose is administered; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-
3,4-
di fluoro-2-(2-fluoro-4-i odo-phenyl am i no)-benzami de is administered.
CA 03207513 2023- 8- 4
WO 2022/177557 - 180 -
PCT/US2021/018381
[0808] E352. The use of any one of E315-E350, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising: (a) 21 consecutive days in
which the
total daily dose is administered; followed by (b) 7 consecutive days in which
no N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered.
[0809] E353. The use of any one of E315-E350, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising: (a) three 7-day periods each
comprising (i) 5 days in which the total daily dose is administered and (ii) 2
days in
which no N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered.
[0810] E354. The use of any one of E315-E350, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising: (a) three 7-day periods each
comprising (i) 5 consecutive days in which the total daily dose is
administered and (ii) 2
consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide; followed by (b) 7 consecutive days in which no N-
((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered.
[0811] E355. The use of any one of E351-E354, wherein the 28-day dosing
cycle is
repeated up to a total of 24 consecutive 28-day dosing cycles.
[0812] E356. A method of producing N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide of Formula (I)
0, N H F
OH N
F
(I),
CA 03207513 2023- 8- 4
WO 2022/177557 - 181 -
PCT/US2021/018381
the method comprising reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a
coupling reagent 1-propylphosphonic anhydride (T3P) to obtain 901 Acetonide as
shown
in Scheme 1:
Scheme 1
HO 0
,N 0
0 0
00,N H2 + T3P
I. PD-0337792
(IPGA)
MW 147 17 PD-0315209
.
(FIPFA)
MW 393.10 901
Acetonide
MW 522.26
[0813] E357. The method of E356, wherein the 1-propylphosphonic
anhydride is in
solution.
[0814] E358. The method of E356 or E357, wherein the 1-propylphosphonic
anhydride
is provided as a solution in ethyl acetate.
[0815] E359. The method of E356, wherein the method of producing N-((R)-
2,3-
dihydroxypropoxy)-3,4-ditluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of
Formula
(I), comprises a) reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a
coupling
reagent that is 1-propylphosphonic anhydride (T3P) to obtain 901 Acetonide;
and b)
treating 901 Acetonide with acid to form N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide as shown in Scheme II:
CA 03207513 2023- 8- 4
WO 2022/177557 - 182 -
PCT/US2021/018381
Scheme II
HO 0
õN 0
0 - 0
0õ3Ø,NH2 10 T3P
PD-0337792
(IPGA) PD-0315209
MW 147.17 (FIPFA)
MW 393.10 901
Acetonide
MW 522.26
"acid"
HOON 0
H F
OH N 401 OH N
Mirdametinib
(PD-0325901) Crude P0-0325901
M
MW 482.20 W 482.20
[0816] E360. The method of E356, wherein the method of producing N-((R)-
2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of
Formula
(I)
HOON
H
OHLL N
F I
(I),
comprises:
reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent
to obtain 901 Acetonide; and
treating 901 Acetonide with acid to form N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-tluoro-4-iodo-phenylamino)-benzamide according to Scheme III:
CA 03207513 2023- 8- 4
WO 2022/177557
PCT/US2021/018381
- 183 -
Scheme III
HO 0
F H
H õ,---
.......õõ--., ,N 0
T3P 0 - 0
F
F I 110 (50% in Et0AG) ,,..)--C-
25 H
N
NH2 + i-Pr2NEt la 01
___________________________________________________________ i.-
PD-0337792 F THF, toluene F I
(IPGA) PD-0315209
MTBE, aq. NaOH F
MW 147.17 (FIPFA) 901
Acetonide
MW 393.10
MW 522.26
aq. HCI
toluene, ACN
H H
HO 0 F HO ON H H F
,N õN 0 EtOH
- - -
OH N
110 0 Et0H OH N
water 4 ________
101 110
F I F I
F F
Mirdametinib Crude PD-0325901
(PD-0325901) MW 482.20
MW 482.20
[0817] E361. A crystalline composition that is essentially pure Form IV N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
prepared
by the method of any one of E356-E360.
[0818] E362. The crystalline composition of E361, wherein the crystalline
composition
contains < 0.2% of dimeric impurity PF-00191189.
I
el
F F
HN 0 F
H 0
0
HO---0N F
OH N
la 0
F I
F
PF-00191189
Exact Mass: 856.93
CA 03207513 2023- 8- 4
WO 2022/177557 - 184 -
PCT/US2021/018381
[0819] E363. The crystalline composition of E361 or E362, wherein the
crystalline
composition contains about 0.05% to about 0.19% by weight of dimeric impurity
PF-
00191189.
[0820] E364. The crystalline composition of any one of E361-E363,
wherein the
crystalline composition contains no detectable amount of dimeric impurity PF-
00191189.
CA 03207513 2023- 8- 4
