Note: Descriptions are shown in the official language in which they were submitted.
TITLE OF THE INVENTION
NOVEL CRYSTALLINE FORMS OF SUGAMMADEX
FIELD OF THE INVENTION
The present disclosure provides novel crystalline forms of sugammadex,
designated herein as
crystalline form Type 7 of sugammadex, crystalline form Type 10 of sugammadex,
crystalline
form Type 12 of sugammadex, and crystalline form Type 13 of sugammadex,
pharmaceutical
compositions thereof, and methods for their use in the reversal of
neuromuscular blockade
induced by recuronium bromide and vecuronium bromide in adults undergoing
surgery
BACKGROUND OF THE INVENTION
Sugammadex is a modified cyclodextrin having the following structure:
0
0
Na0)\--
Na0
oomo
OH
HOCt:)
OH 0
8 0
0 0 H
OH
NaOSH
....<vg) 0
0
ONa
o
0 Oit H
Na0--C" S
0
sugammadex
Sugammadex was approved in 2008 by the EMEA and in 2015 by the USFDA (and
elsewhere) for the reversal of neuromuscular blockade induced by rocuronium
bromide and
vecuronium bromide in adults undergoing surgery. It is administered
intravenously by injection
in the form of a sterile solution under the brand name BRIDION . Sugammadex is
disclosed in
W02001/040316, published June 7, 2001, together with a method for its
synthesis. An
improved synthesis of sugammadex is disclosed in PCT International Patent
Application No.
W02019/236436, filed June 03, 2019. Other methods of producing sugammadex are
also
disclosed in the art Once produced, the active ingredient is typically
isolated as a wet cake and
then dried under vacuum to obtain a powder meeting purity and residual solvent
specifications.
The powder is then dissolved in water for injection, the pH adjusted, and the
resulting solution is
filtered and filled into vials, sterilized and stored for use.
1
Date Recue/Date Received 2024-04-19
SUMMARY OF THE INVENTION
In one aspect, the present disclosure provides novel crystalline forms of
sugammadex. In
one embodiment, there is provided crystalline form type 7 of sugammadex. In
another
embodiment, there is provided crystalline form type 10 of sugammadex. In
another embodiment,
there is provided crystalline form type 12 of sugammadex. In another
embodiment, there is
provided crystalline form type 13 of sugammadex.
In another aspect, the present disclosure provides methods for the use of each
of the
aforementioned crystalline forms of sugammadex in the preparation of a
medicament for use in
the reversal of neuromuscular blockade induced by rocuronium bromide and
vecuronium
bromide in adults undergoing surgery in accordance with its approved label.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph of a Powder X-Ray Diffraction ("PXRD") pattern of sugammadex
Type
7 crystalline form, generated using the equipment and methods described
herein. The graph plots
the intensity of the peaks as defined by counts per second versus the
diffraction angle 2 theta
(20) in degrees.
FIG. 2 is a graph of a Powder X-Ray Diffraction ("PXRD") pattern of sugammadex
Type
10 crystalline form, generated using the equipment and methods described
herein. The graph
plots the intensity of the peaks as defined by counts per second versus the
diffraction angle 2
theta (20) in degrees.
FIG, 3 is a graph of a Powder X-Ray Diffraction ("PXRD") pattern of sugammadex
Type
12 crystalline form, generated using the equipment and methods described
herein. The graph
plots the intensity of the peaks as defined by counts per second versus the
diffraction angle 2
theta (20) in degrees.
FIG. 4 is a graph of a Powder X-Ray Diffraction ("PXRD") pattern of sugammadex
Type
13 crystalline form, generated using the equipment and methods described
herein. The graph
plots the intensity of the peaks as defined by counts per second versus the
diffraction angle 2
theta (20) in degrees.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
The terms used herein have their ordinary meaning and the meaning of such
terms is
independent at each occurrence thereof That notwithstanding and except where
stated otherwise,
2
Date Recue/Date Received 2024-04-19
the following definitions apply throughout the specification and claims.
C means degrees Celsius
FIG (or FIG. or Fig. or Fig or fig. or fig) means Figure (or figure) and
refers to the
corresponding figure
g means gram (or grams)
mL means milliliter (or milliliters)
"PXRD" is an abbreviation for powder x-ray diffraction
CRYSTALLINE FORMS OF SUGAMMADEX
The crystalline forms of sugammadex described herein may be prepared according
to the
procedures described below. For each procedure, starting quantities of
sugammadex may be
obtained from any suitable synthesis, including those described in PCT
Publication No.
W02001/040316, published June 07, 2001; W02019/236436, filed June 07, 2018 and
U.S.
Provisional Application No. 62/737140, Attorney Docket No. 24604, filed
September 27, 2018
all incorporated by reference in their entirety.
PXRD
As those of ordinary skill in the art readily appreciate, the physical
characteristics of a
crystal may be effectively characterized by powder x-ray diffraction (PXRD)
analysis. Such
characterizations may be used to distinguish such crystals from other
crystals. For each of the
crystalline forms of sugammadex described herein, PXRD analysis was completed
on a wet cake
sample since drying the material leads to significant loss of crystallinity
and to form change.
PXRD data reported herein were acquired on a Bruker D8 Advance System
configured in the
Bragg-Brentano configuration and equipped with a Cu radiation source with
monochromatization to Ka achieved using a nickel filter. A fixed slit optical
configuration was
employed for data acquisition. Data were acquired between 3 and 40 20 and a
step size of
0.018 . Samples were prepared by gently pressing the samples onto a shallow
cavity zero
background silicon holder. Wet cake samples were covered with Kaptonk
(polyimide film,
DuPont, USA) foil in order to maintain the wet-sample-condition throughout
data collection.
Those skilled in the art will recognize that the measurements of the PXRD peak
locations
for a given crystalline form of the same compound will vary within a margin of
error. The
margin of error for the 2-theta values measured as described herein is
typically +/- 0.2 20.
Variability can depend on such factors as the system, methodology, sample, and
conditions used
3
Date Recue/Date Received 2024-04-19
for measurement. As will also be appreciated by the skilled crystallographer,
the intensities of
the various peaks reported in the figures herein may vary due to a number of
factors such as
orientation effects of crystals in the x-ray beam, the purity of the material
being analyzed, and/or
the degree of crystallinity of the sample. The skilled crystallographer also
will appreciate that
measurements using a different wavelength will result in different shifts
according to the Bragg-
Brentano equation. Such further PXRD patterns generated by use of alternative
wavelengths are
considered to be alternative representations of the PXRD patterns of the
crystalline material of
the present disclosure and as such are within the scope of the present
disclosure.
Preparative Example 1: Crystalline Form Type 1 of Sugammadex
Crystalline form Type 1 of sugammadex was prepared as follows:
1 g of sugammadex was added to 10 mL of a methanol/water mixture with a 10:1
ratio by
volume at 25 C and while applying magnetic stirring, resulting in a slurry.
The slurry was kept
at ambient temperature while stirring for 20 hours. A wet cake sample was
produced by
centrifuging an aliquot of the slurry to a wet paste. PXRD analysis of the wet
cake produced the
Type 1 pattern.
Preparative Example 2: Crystalline Foul' Type 11 of Sugammadex
Crystalline form Type 11 of sugammadex was prepared as follows:
30 g of Sugammadex was dissolved in 90 ml purified water and the solution
filtered
through a lab glass frit filter. The solution was transferred into a clean 1L
glass reactor equipped
with an overhead stirrer. The solution was heated to 40 C while stirring at
200 rpm. 350 ml of
Me0H was added linearly over 70 min at what stage primary nucleation of Type-1
was
observed. The agitation was increased to 350 rpm and the batch seeded with
Type 2 particles
triggering turnover of the entire batch to Type 2 within minutes. 550 mL of
Me0H were finally
added linearly over 110 min. The batch was cooled to 23 C over 1 h and further
aged 1 h. The
freshly crystallized batch of Type-2 was filtered on a Rosenmund pocket filter
and displace-
washed with 6V of a 86:4:10 (v:v:v) Et0H:MeOH:Water mixture. The resulting
cake was then
dried under a dry Nitrogen flow at 50 C for a minimum of 18 hours (h). PXRD
analysis of the
dried cake produced the Type 11 pattern.
CRYSTALLINE FORM TYPE 7 OF SUGAMMADEX
Crystalline form Type 7 of sugammadex was prepared as follows:
500 mg of sugammadex Type-1 was added to 5 mL of a ethanol/water/methanol
mixture
4
Date Recue/Date Received 2024-04-19
with a respective 86:10:4 ratio by volume at 25 C and while applying magnetic
stirring, resulting
in a slurry. The slurry was kept at ambient temperature while stirring for 12
hours. A wet cake
sample was produced by centrifuging an aliquot of the slurry to a wet paste.
PXRD analysis of
the wet cake produces the Type 7 pattern.
Physical characterization of crystalline form Type 7 of sugammadex:
A PXRD pattern of crystalline form Type 7 of sugammadex generated using the
equipment and procedures described above is displayed in FIG. 1. Thus, in
another aspect, there
is provided a crystalline form Type 7 of sugammadex characterized by a powder
x-ray
diffraction pattern substantially as shown in FIG. 1.
The intensity of the peaks (y-axis is in counts per second) were plotted
versus the 2 theta
angle (x-axis is in degrees 2 theta). In addition, the data were plotted with
detector counts
normalized for the collection time per step versus the 2-theta angle. Peak
locations (on the 2-
theta x-axis) consistent with these profiles are displayed in Table 1 (+/- 0.2
2 theta). The
locations of these PXRD peaks are characteristic of the crystalline form Type
7 of sugammadex.
Thus, in another aspect, crystalline form Type 7 of sugammadex is
characterized by a powder x-
ray diffraction pattern having each of the peak positions listed in Table 1,
+/- 0.2 2-theta.
Table 1: Diffraction peaks and corresponding d-spacings for crystalline form
Type 7 of
sugammadex
Position [ Two
Diagnostic Peak
Peak Number d-spacing [Al Rel. Int. [%]
Theta] Set
-
1 5.64 15.66 48.22 1
2 6.07 14.55 42.56 1
3 6.83 12.93 27.54 1
4 7.19 1128 27.55 1
5 9.25 9.55 35.54 2
6 9.88 8.94 29.53 2
7 10.72 8.25 27.92 1
8 13.64 6.49 59.32 1
9 14.84 5.96 39.05 2
10 15.17 5.84 28.93 3
11 16.39 5.40 39.96 2
12 16.97 5.22 66.27 2
13 17.81 4.98 58.58 2
14 18.27 4.85 43.98 3
15 19.16 4.63 65.59 2
16 19.31 4.59 63.33 2
17 19.65 4.51 72.44 2
18 20.71 4.29 100.00 1
19 21.14 4.20 57.91 3
5
Date Recue/Date Received 2024-04-19
Position [ Two
Diagnostic Peak
Peak Number d-spacing [A] Rel. Int. [%]
Theta] Set
20 21.90 4.06 65.35 2
21 22.63 3.93 49.89 3
22 23.20 3.85 35.69 3
In a further aspect, the PXRD peak locations displayed in Table 1 and/or FIG.
1 most
characteristic of crystalline form Type 7 of sugammadex can be selected and
grouped as
"diagnostic peak sets" to conveniently distinguish this crystalline form from
others. Selections
of such characteristic peaks are set out in Table 1 in the column labeled
Diagnostic Peak Set.
Thus, in another aspect, there is provided a crystalline form Type 7 of
sugammadex
characterized by a powder x-ray diffraction pattern comprising each of the 2-
theta values listed
in Diagnostic Peak Set 1 in Table 1, +/- 0.2 2-theta.
In another aspect, there is provided a crystalline form Type 7 of sugammadex
characterized by a powder x-ray diffraction pattern comprising each of the 2-
theta values listed
in Diagnostic Peak Set 2 in Table 1, +/- 0.2 2-theta.
In another aspect, there is provided a crystalline form Type 7 of sugammadex
characterized by a powder x-ray diffraction pattern comprising each of the 2-
theta values listed
in Diagnostic Peak Set 3 in Table 1, +/- 0.2 2-theta.
A further aspect of the disclosure is realized and characterized by a powder x-
ray
diffraction pattern with at least peaks at diffraction angles degrees 2 theta
(+/- 0.2 ) of
Diagnostic Peak Set 1 plus Set 2. A further aspect of the disclosure is
realized and characterized
by a powder x-ray diffraction pattern with at least peaks at diffraction
angles degrees 2 theta (+/-
0.2 ) of Diagnostic Peak Set 1 plus Set 2 plus Set 3. Still another aspect of
the disclosure is
realized where there are at least 3 peaks of Diagnostic Peak Set 1. Another
aspect of the
disclosure is realized where there are at least 4 peaks of Diagnostic Peak Set
1. Another aspect of
the disclosure is realized where there are at least 5 peaks of Diagnostic Peak
Set 1. Another
aspect of the disclosure is realized where there are at least 6 peaks of
Diagnostic Peak Set 1.
Another aspect of the disclosure is realized where there are at least 7 peaks
of Diagnostic Peak
Set 1. Another aspect of the disclosure is realized where there are at least 3
peaks of Diagnostic
Peak Set 1 and 2. Another aspect of the disclosure is realized where there are
at least 3 peaks of
Diagnostic Peak Set 1 and 2 and 1 of Set 3.
CRYSTALLINE FORM TYPE 10 OF SUGAMMADEX
6
Date Recue/Date Received 2024-04-19
Crystalline form Type 10 of sugammadex was prepared as follows:
In a IL glass reactor, 30 g of sugammadex were added to 90 mL of water at 25
C while
applying overhead stirring at 200 rpm, resulting in a clear solution. Under
continued overhead
stirring at 200 rpm, the solution was heated to 40 C and then kept at these
conditions for 10 min.
Subsequently, 450 mL of methanol were added at constant rate over two hours
while overhead
stirring at 200 rpm. The batch was then aged for 6 days at 300 rpm overhead
stirring, triggering
crystallization of large particles. An additional 453 mL of Me0H were added
linearly over 3h
while overhead stirring. The freshly crystallized batch of Type 3 was filtered
on a glass filter and
displace-washed with 3V of a 86:4:10 Et0H:MeOH:Water mixture by volume. The
resulting wet
cake was then quickly transferred to a 100 mL reactor and slurry-washed in 3V
of a 86:4:10
Et0H:MeOH:Water by volume under overhead stirring (350 rpm, 23 C) for 8 days.
A wet cake
sample was produced by centrifuging an aliquot of the slurry to a wet paste.
PXRD analysis of
the wet cake produces the Type 10 pattern.
Physical characterization of crystalline form Type 10 of sugammadex:
A PXRD pattern of crystalline form Type 10 of sugammadex generated using the
equipment and procedures described above is displayed in FIG. 2. Thus, in
another aspect, there
is provided a crystalline form Type 10 of sugammadex characterized by a powder
x-ray
diffraction pattern substantially as shown in FIG. 2.
The intensity of the peaks (y-axis is in counts per second) were plotted
versus the 2-theta
angle (x-axis is in degrees 2 theta). In addition, the data were plotted with
detector counts
normalized for the collection time per step versus the 2-theta angle. Peak
locations (on the 2-
theta x-axis) consistent with these profiles are displayed in Table 2 (+/- 0.2
2 theta). The
locations of these PXRD peaks are characteristic of the crystalline form Type
10 of
sugammadex. Thus, in another aspect, crystalline form Type 10 of sugammadex is
characterized
by a powder x-ray diffraction pattern having each of the peak positions listed
in Table 2, +/- 0.2
2-theta.
Table 2: Diffraction peaks and corresponding d-spacings for crystalline form
Type 10 of
sugammadex
Position [ Two
Diagnostic Peak
Peak Number d-spacing [A] Rel. Int. [%]
Theta] Set
1 3.61 24.48 3.77 3
2 5.98 14.76 56.27 1
3 8.45 10.46 100.00 1
4 13.94 6.35 5.84 3
5 15.38 5.76 3.22 3
7
Date Recue/Date Received 2024-04-19
Position [ Two
Diagnostic Peak
Peak Number d-spacing [A] Rel. Int. [%]
Theta] Set
6 16.76 5.28 21.76 2
7 17.75 4.99 56.84 1
8 18.55 4.78 7.88 3
9 18.92 4.69 6.80 3
20.08 4.42 11.78 2
11 21.30 4.17 60.58 1
12 22.11 4.02 4.11 3
"
13 22.67 3.92 7.75 3
In a further aspect, the PXRD peak locations displayed in Table 2 and/or FIG.
2 most
characteristic of crystalline form Type 10 of sugammadex can be selected and
grouped as
"diagnostic peak sets" to conveniently distinguish this crystalline form from
others. Selections
5 of such characteristic peaks are set out in Table 2 in the column labeled
Diagnostic Peak Set.
Thus, in another aspect, there is provided a crystalline form Type 10 of
sugammadex
characterized by a powder x-ray diffraction pattern comprising each of the 2-
theta values listed
in Diagnostic Peak Set 1 in Table 2, +/- 0.2 2-theta.
In another aspect, there is provided a crystalline form Type 10 of sugammadex
10 characterized by a powder x-ray diffraction pattern comprising each of
the 2-theta values listed
in Diagnostic Peak Set 2 in Table 2, +/- 0.2 2-theta.
In another aspect, there is provided a crystalline form Type 10 of sugammadex
characterized by a powder x-ray diffraction pattern comprising each of the 2-
theta values listed
in Diagnostic Peak Set 3 in Table 2, +/- 0.2 2-theta.
A further aspect of the disclosure is realized and characterized by a powder x-
ray
diffraction pattern with at least peaks at diffraction angles degrees 2 theta
(+/- 0.2 ) of
Diagnostic Peak Set 1 plus Set 2. A further aspect of the disclosure is
realized and characterized
by a powder x-ray diffraction pattern with at least peaks at diffraction
angles degrees 2 theta (+/-
0.2 ) of Diagnostic Peak Set 1 plus Set 2 plus Set 3. Still another aspect of
the disclosure is
realized where there are at least 2 peaks of Diagnostic Peak Set 1. Another
aspect of the
disclosure is realized where there are at least 3 peaks of Diagnostic Peak Set
1. Another aspect of
the disclosure is realized where there are at least 4 peaks of Diagnostic Peak
Set 1. Another
Another aspect of the disclosure is realized where there are at least 3 peaks
of Diagnostic Peak
Set 1 and 1 peak of Diagnostic Peak 2. Another aspect of the disclosure is
realized where there
are at least 3 peaks of Diagnostic Peak Set 1 and 1 of Diagnostic Peak Set 2
and 1 of Diagnostic
Peak Set 3.
8
Date Recue/Date Received 2024-04-19
CRYSTALLINE FORM TYPE 12 OF SUGAMMADEX
Crystalline form Type 12 of sugammadex was prepared as follows:
A solution of sugammadex in water with a concentration of 200 mg/mL was
prepared.
The solution was heated to 60 C and the water slowly evaporated, producing a
white powder. A
dry sample was produced after the water had evaporated. PXRD analysis of the
dry sample
produced the Type 12 pattern.
Physical characterization of crystalline form Type 12 of sugammadex:
A PXRD pattern of crystalline form Type 12 of sugammadex generated using the
equipment and procedures described above is displayed in FIG. 3. Thus, in
another aspect, there
is provided a crystalline form Type 12 of sugammadex characterized by a powder
x-ray
diffraction pattern substantially as shown in FIG. 3.
The intensity of the peaks (y-axis is in counts per second) were plotted
versus the 2-theta
angle (x-axis is in degrees 2 theta). In addition, the data were plotted with
detector counts
normalized for the collection time per step versus the 2-theta angle. Peak
locations (on the 2-
theta x-axis) consistent with these profiles are displayed in Table 3 (+/- 0.2
2 theta). The
locations of these PXRD peaks are characteristic of the crystalline form Type
12 of
sugammadex. Thus, in another aspect, crystalline form Type 12 of sugammadex is
characterized
by a powder x-ray diffraction pattern having each of the peak positions listed
in Table 3, +/- 0.2
2-theta.
Table 3: Diffraction peaks and corresponding d-spacings for crystalline form
Type 12 of
sugammadex
Position [ Two Diagnostic Peak
Peak Number d-spacing [Al Rel. Int. ro]
Theta] Set
1 4.60 19.21 13.63 2
2 5.50 16.07 14.57 2
3 6.40 13.81 36.33 1
4 7.55 11.70 100.00 1
5 8.12 10.88 9.87 2
6 9.06 9.75 6.03 3
7 10.00 8.84 11.70 2
8 10.43 8.48 11.37 2
9 11.94 7.41 11.05 2
10 12.17 7.26 31.55 1
11 12.59 7.03 17.66 2
12 12.84 6.89 20.52 2
13 13.79 6.41 6.25 3
14 14.75 6.00 4.29 3
15 15.27 5.80 5.60 3
9
Date Recue/Date Received 2024-04-19
Position [ Two
Diagnostic Peak
Peak Number d-spacing [A] Rel. Int. [%]
Theta] Set
16 15.92 5.56 20.51 2
17 16.40 5.40 14.38 2
18 16.94 5.23 12.60 2
19 17.12 5.17 13.29 2
20 17.65 5.02 14.38 2
21 18.17 4.88 19.82 2
22 18.62 4.76 9.96 2
23 19.28 4.60 12.23 2
24 20.20 4.39 7.20 3
25 20.49 4.33 9.09 2
26 21.10 4.21 5.25 3
27 21.43 4.14 6.65 3
28 22.16 4.01 9.10 2
29 22.52 3.94 7.73 3
30 22.67 3.92 8.25 3
31 22.97 3.87 8.23 3
32 24.16 3.68 6.51 3
33 24.63 , 3.61 5.97 3
34 37.07 2.42 17.47 2
In a further aspect, the PXRD peak locations displayed in Table 3 and/or FIG.
3 most
characteristic of crystalline form Type 12 of sugammadex can be selected and
grouped as
"diagnostic peak sets" to conveniently distinguish this crystalline form from
others. Selections
of such characteristic peaks are set out in Table 3 in the column labeled
Diagnostic Peak Set.
Thus, in another aspect, there is provided a crystalline form Type 12 of
sugammadex
characterized by a powder x-ray diffraction pattern comprising each of the 2-
theta values listed
in Diagnostic Peak Set 1 in Table 3, +/- 0.2 2-theta.
In another aspect, there is provided a crystalline form Type 12 of sugammadex
.. characterized by a powder x-ray diffraction pattern comprising each of the
2-theta values listed
in Diagnostic Peak Set 2 in Table 3, +/- 0.2 2-theta.
In another aspect, there is provided a crystalline form Type 12 of sugammadex
characterized by a powder x-ray diffraction pattern comprising each of the 2-
theta values listed
in Diagnostic Peak Set 3 in Table 3, +/- 0.2 2-theta.
A further aspect of the disclosure is realized and characterized by a powder x-
ray
diffraction pattern with at least peaks at diffraction angles degrees 2 theta
(+/- 0.2 ) of
Diagnostic Peak Set 1 plus Set 2. A further aspect of the disclosure is
realized and characterized
Date Recue/Date Received 2024-04-19
by a powder x-ray diffraction pattern with at least peaks at diffraction
angles degrees 2 theta (+/-
0.2 ) of Diagnostic Peak Set 1 plus Set 2 plus Set 3. Still another aspect of
the disclosure is
realized where there are at least 1 peaks of Diagnostic Peak Set 1. Another
aspect of the
disclosure is realized where there are at least 2 peaks of Diagnostic Peak Set
1. Another aspect of
the disclosure is realized where there are at least 3 peaks of Diagnostic Peak
Set 1. Another
aspect of the disclosure is realized where there are at least 2 peaks of
Diagnostic Peak Set 1 and
3 peaks of Diagnostic Peak 2. Another aspect of the disclosure is realized
where there are at
least 2 peaks of Diagnostic Peak Set 1, 4 peaks of Diagnostic Peak 2 and 3 of
Diagnostic Peak
Set 3.
CRYSTALLINE FORM TYPE 13 OF SUGAMMADEX
Crystalline form Type 13 of sugammadex was prepared as follows:
A 1 g sample of dried Sugammadex Type 11 was placed in a humidity chamber
exhibiting
75% relative humidity at 25 C for 24 hours. PXRD analysis of the dry cake
after 24 hours
produced the Type 13 pattern.
Physical characterization of crystalline form Type 13 of sugammadex:
A PXRD pattern of crystalline form Type 13 of sugammadex generated using the
equipment and procedures described above is displayed in FIG. 4. Thus, in
another aspect, there
is provided a crystalline form Type 13 of sugammadex characterized by a powder
x-ray
diffraction pattern substantially as shown in FIG. 4.
The intensity of the peaks (y-axis is in counts per second) were plotted
versus the 2-theta
angle (x-axis is in degrees 2 theta). In addition, the data were plotted with
detector counts
normalized for the collection time per step versus the 2-theta angle. Peak
locations (on the 2-
theta x-axis) consistent with these profiles are displayed in Table 4 (+/- 0.2
2 theta). The
locations of these PXRD peaks are characteristic of the crystalline form Type
13 of
sugammadex. Thus, in another aspect, crystalline form Type 13 of sugammadex is
characterized
by a powder x-ray diffraction pattern having each of the peak positions listed
in Table 4, +/- 0.2
2-theta.
Table 4: Diffraction peaks and corresponding d-spacings for crystalline form
Type 13 of
sugammadex
Position [ Two
Diagnostic Peak
Peak Number d-spacing [A] Rel. Int. 1%1
Theta] Set
1 6.83 12.94 11.45 2
2 10.12 8.74 30.89 1
11
Date Recue/Date Received 2024-04-19
Position [ Two
Diagnostic Peak
Peak Number d-spacing [A] Rel. Int. ['Vol
Theta] Set
3 10.72 8.25 13.45 3
4 11.37 7.78 14.79 3
13.90 6.37 26.92 1
6 14.59 6.07 36.09 1
7 16.32 5.43 52.60 1
8 16.73 5.30 77.09 1
9 17.26 5.14 100.00 1
18.39 4.82 55.94 1
11 19.42 4.57 70.29 1
12 20.86 4.26 49.54 1
13 21.70 4.09 32.53 3
14 22.12 4.02 52.63 3
22.52 3.95 51.04 3
16 22.98 3.87 41.30 3
17 23.34 3.80 40.57 3
In a further aspect, the PXRD peak locations displayed in Table 4 and/or FIG.
4 most
characteristic of crystalline form Type 13 of sugammadex can be selected and
grouped as
"diagnostic peak sets" to conveniently distinguish this crystalline form from
others. Selections
5 of such characteristic peaks are set out in Table 4 in the column labeled
Diagnostic Peak Set.
Thus, in another aspect, there is provided a crystalline form Type 13 of
sugammadex
characterized by a powder x-ray diffraction pattern comprising each of the 2-
theta values listed
in Diagnostic Peak Set 1 in Table 4, +/- 0.2 2-theta.
In another aspect, there is provided a crystalline form Type 13 of sugammadex
10 characterized by a powder x-ray diffraction pattern comprising each of
the 2-theta values listed
in Diagnostic Peak Set 2 in Table 4, +/- 0.2 2-theta.
In another aspect, there is provided a crystalline form Type 13 of sugammadex
characterized by a powder x-ray diffraction pattern comprising each of the 2-
theta values listed
in Diagnostic Peak Set 3 in Table 4, +/- 0.2 2-theta.
15 A further
aspect of the disclosure is realized and characterized by a powder x-ray
diffraction pattern with at least peaks at diffraction angles degrees 2 theta
(+/- 0.2 ) of
Diagnostic Peak Set 1 plus Set 2. A further aspect of the disclosure is
realized and characterized
by a powder x-ray diffraction pattern with at least peaks at diffraction
angles degrees 2 theta (+/-
0.2 ) of Diagnostic Peak Set 1 plus Set 2 plus Set 3. Still another aspect of
the disclosure is
realized where there are at least 3 peaks of Diagnostic Peak Set 1. Another
aspect of the
disclosure is realized where there are at least 4 peaks of Diagnostic Peak Set
1. Another aspect of
12
Date Recue/Date Received 2024-04-19
the disclosure is realized where there are at least 5 peaks of Diagnostic Peak
Set 1. Another
aspect of the disclosure is realized where there are at least 6 peaks of
Diagnostic Peak Set 1.
Another aspect of the disclosure is realized where there are at least 7 peaks
of Diagnostic Peak
Set 1. Another aspect of the disclosure is realized where there are at least 8
peaks of Diagnostic
Peak Set I. Another aspect of the disclosure is realized where there are at
least 9 peaks of
Diagnostic Peak Set 1. Another aspect of the disclosure is realized where
there are at least 3
peaks of Diagnostic Peak Set 1 and one of Diagnostic Peak set 2. Another
aspect of the
disclosure is realized where there are at least 3 peaks of Diagnostic Peak Set
1, one of Diagnostic
Peak Set 2 and 3 of Diagnostic Peak Set 3.
PREPARATION OF DRUG PRODUCT
Crystallized Type 7, Type 10, Type 12 and Type 13 forms of sugammadex were
prepared
as described above, then isolated as a wet cake and then dried to obtain a
powder meeting purity
and residual solvent specifications. The drug product is then produced by a
formulation and
filling process. The dried sugammadex powder is dissolved in water for
injection and the pH
adjusted to 7.5. The resulting solution is then filtered and filled into
vials, stoppered and capped.
The bulk drug product is then terminally sterilized and stored for use.
13
Date Recue/Date Received 2024-04-19
