Note: Descriptions are shown in the official language in which they were submitted.
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POLYMORPHIC FORMS OF NATEGLINIDE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. provisional applications Serial
Nos.
60/396,904 filed July 18, 2002; 60/413,622, filed September 25, 2002;
60/414,199, filed
September 26, 2002; 60/423,750, filed November 5, 2002; 60/432,093, filed
December 10,
2002; 60/432,962, filed December 12, 2002; 60/442,109, filed January 23, 2003;
60/449,791, filed February 24, 2003; 60/479,016, filed June 16, 2003, and 10/
,
filed July 3, 2003 (attorney docket No. 1662/60606, the contents of all of
which are
to incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to the solid state chemistry of nateglinide.
15 BACKGROUND OF THE INVENTION
Nateglinide, known as (-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-
Phenylalanine, has the following structure and characteristics:
(CH3)2CH~~".. H
I
N C02H
C
I I
O
Formula C 19H27N03
Molecular Weight 317.42
Exact Mass 317.199093
Composition C 71.89% H 8.57% N 4.41% O 15.12%
2o Nateglinide is marketed as STARLIX, which is prescribed as oral tablets
having a
dosage of 60mg and 120mg for the treatment of type II diabetes. STARLIX may be
used
as monotherapy or in combination with metaformin to stimulate the pancreas to
secrete
insulin. According to the maker of STARLIX, nateglinide is a white powder that
is freely
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soluble in methanol, ethanol, and chloroform, soluble in ether, sparingly
soluble in
acetonitrile and octanol, and practically insoluble in water.
Nateglinide may be crystallized out of a mixture of water and methanol, and
further dried, as disclosed in U.S. Pat. No. 4,816,484. The procedure of the
'484 patent
results in a hydrate labeled by the present Applicants) as Form Z, or in a
methanolate
lablelled by the Applicants) as Form E. Drying of the wet sample results in
Form B
The present invention relates to the solid state physical properties of
nateglinide.
These properties may be influenced by controlling the conditions under which
nateglinide
is obtained in solid Form. Solid state physical properties include, for
example, the
io flowability of the milled solid. Flowability affects the ease with which
the material is
handled during processing into a pharmaceutical product. When particles of the
powdered
compound do not flow past each other easily, a formulation specialist must
take that fact
into account in developing a tablet or capsule formulation, which may
necessitate the use
of glidants such as colloidal silicon dioxide, talc, starch or tribasic
calcium phosphate.
15 Another important solid state property of a pharmaceutical compound is its
rate of
dissolution in aqueous fluid. The rate of dissolution of an active ingredient
in a patient's
stomach fluid may have therapeutic consequences since it imposes an upper
limit on the
rate at which an orally-administered active ingredient may reach the patient's
bloodstream.
The rate of dissolution is also a consideration in formulating syrups, elixirs
and other
20 liquid medicaments. The solid state Form of a compound may also affect its
behavior on
compaction and its storage stability:
These practical physical characteristics are influenced by the conformation
and
orientation of molecules in the unit cell, which defines a particular
polymorphic Form of a
substance. The polymorphic Form may give rise to thermal behavior different
from that of
25 the amorphous material or another polymorphic Form. Thermal behavior is
measured in
the laboratory by such techniques as capillary melting point,
thermogravimetric analysis
(TGA) and differential scanning calorimetry (DSC) and may be used to
distinguish some
polymorphic forms from others. A particular polymorphic Form may also give
rise to
distinct spectroscopic properties that may be detectable by powder X-ray
crystallography,
3o solid state C NMR spectrometry and infrared spectrometry.
Nateglinide exists in various crystalline forms. U.S. Pat. Nos. 5,463,116 and
5,488,150 disclose two crystal forms ofnateglinide, designated B-type and H-
type, and
processes for their preparation. These patents are incorporated herein by
reference for
2
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their disclosure of the forms. Both forms are characterized by melting point,
X-Ray
Powder Diffraction ("XRPD") pattern, IR spectrum in KBr and DSC thermogram.
According to these patents, B-type has a melting point of 129-130 °C
while H-type has a
melting point of 136-142°C. The H-type crystals are characterized in
these patents by an
XRPD pattern with peaks at 8.1, 13.1, 19.6 and 19.9 X0.2 degrees 28, and a
strong
reflection between 15 and 17 X0.2 degrees 20. The B-type crystal is reported
to lack these
peaks and have a weak reflection between 15 and 17 X0.2 degrees 28. H-type
crystals are
reported to have an IR spectrum with characteristic absorptions at about 1714,
1649, 1542
and 1214crri I. These absorptions are reported to be missing in the spectrum
of B-type
1o crystals.
According to U.S. Pat. No. 5,463,116, B-type crystals are unstable and
susceptible
to change during grinding as demonstrated by DSC. The DSC thermogram of B-type
shows a sharp endotherm at 131.4°C before grinding while that of H-type
shows a sharp
endotherm at 140.3°C. After grinding, the DSC thermogram of B-type
shows a second
15 endotherm at 138.2°C, suggesting a solid-solid transformation during
grinding.
According to U.S. Pat. No. 5,463,116, the temperature during crystallization
and
filtration determines whether the crystal Form is B-type or H-type.
Temperatures above
10°C, more preferably above 15°C, lead to formation of H-type,
while those below 10°C
lead to formation of B-type.
20 Another crystalline form of nateglinide designated Type-S is disclosed in
two
Chinese articles: ACTA Pharm. Sinica 2001, 36(7), 532-34 and Yaowu Fenxi
Zazhi, 2001,
21 (5), 342-44. Form S is reported to be distinguisheable from Forms B and H
by a
melting point of 172.0°C, a Fourier Transform IR with a peak at
3283crri 1 (as supposed to
3257cni' and 3306crri 1 for Forms B and H respectively) and an XRPD pattern
with a
25 strong peak at 3.78 X0.2 degrees 20.
U.S. Pat. No. 5,463,116 ("the '116 patent") lists the methanolate, ethanolate,
isopropanolate and acetonitrilate solvates of nateglinide. According to the
'116 patent,
amorphous nateglinide may be obtained by drying the hydrate and the solvates.
The
hydrate may be crystallized by dissolving B-type crystals in a 1.5:1 mixture
of ethanol and
3o water, followed by crystallization, as disclosed in Example B-3 of the '116
patent.
The present Applicants obtained a hydrate of nateglinide which the Applicants
labeled as Form Z. However, repeating of Example B-3 or comparative Example A3
of
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the '116 patent also results in Form Z, as well as the crystallization
procedure of the '484
patent. Form Z is obtained when only water is present, but Form E methanolate
or
ethanolate when both methanol or ethanol and water are present.
WO 02134713, a PCT publication in Japanese, provides in its abstract: "A
process
for preparing B form nateglinide crystals containing substantially no H-form
crystals,
which comprises the step of drying wet crystals of a nateglinide solvate at a
low
temperature until the solvent disappears and then causing them to undergo a
crystal
transition." According to the Applicant's translation of Example 1 of the WO
publication:
"Nateglinide H-form crystals (24.5 kg) were added to ethanol (360 L) and
stirred to
dissolution at room temperature. After dissolution was confirmed (the mixture)
was
cooled to 5 °C and allowed to mature at 5 °C for one hour. The
deposited crystals were
separated and damp crystals (43.0 kg) obtained. These were dried at 45
°C in a rack drier
for 24 hours (water content ca. 1 %) and then heated for 12 hours at 90
° C to bring about a
crystal transformation, when dry crystals (13.3 kg) were obtained. When these
crystals
were measured by DSC, the characteristic B-form peak was detected (mp ca.
130°C) but
the characteristic H-form peak (mp ca. 139°C) was not detected. Hence
the crystals
obtained were of the B-form only and the H-form was concluded to be
essentially absent."
According to the Applicants' translation of Page 3, Line 2 of the WO
publication:
"The moist solvate crystals obtained (BS: from the cooled solution) are dried
till the
2o solvent disappears. The temperature for this will differ depending on the
type and duantity~
of solvent, but usually lies below 60°C and preferably below
50°C. Although there is no
lower limit to the temperature, [the drying] is usually carried out at
20°C or more for
economic reasons. Drying is favorably carried out at usual reduced pressure;
at
industrially attainable reduced pressures the drying will be complete in a
short time.
Though the drying at low temperature can be continued to virtual disappearance
of the
solvent it is not necessary to clear it completely. Even if solvent to the
extent of 5% by
weight is present this is no problem because it will disappear during the
crystal
transformation. By heating the dried crystals at 60-110°C, preferably
70-100°C, a crystal
transformation into the B-form is brought about. Though the crystal
transformation is
3o usually favorably carried out in 0.5 to 4~ hours, a period of 1-24 hours is
most favored."
Another PCT publication, WO 03/022251 discloses a crystalline form of
nateglinide labeled "AL-type". The crystalline form is characterized as having
a melting
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point of 174-178 ° C, an XRPD pattern with peaks at 7.5, 15.5, 19.8 and
20.2 degrees 2A,
and an infra red spectrum with absorption bands in the region 1711.5, 1646.5,
1538.7,
1238.8, 1215.1 and 700.5 cm 1. The crystalline form is obtained in the
examples from a
solution of acetonitrile under a specific temperature range.
Processes for preparation of nateglinide are disclosed in WO/0232854.
The discovery of new polymorphic forms of a pharmaceutically useful compound
provides a new opportunity to improve the performance characteristics of a
pharmaceutical product. It enlarges the repertoire of materials that a
formulation scientist
has available for designing, for example, a pharmaceutical dosage form of a
drug with a
targeted release profile or other desired characteristic. New polymorphic
forms of
nateglinide have now been discovered.
SUMMARY OF THE INVENTION
The present invention provides for 26 crystalline forms of nateglinide,
denominated Forms A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, U, V, Y, a
(alpha), (3
(beta), y (gamma), S (delta), s (epsilon), 6 (sigma), 8 (theta) and S2
(omega).
Some of these crystalline forms have bound solvents, that is solvents that are
part
of the crystalline structure (solvates). These solvates having bound solvent
include Form
A (xylene), C (dimethylacetamide- "DMA"), D (ethanol- "EtOH"), E (ethanol and
methanol-"MeOH"), F (n-propanol- "n-PrOH"), G (isopropyl alcohol- "IPA"), I (n-
2o butanol- "n-BuOH"), J (N-methylpyrrolidone- "NMI'"), K (dimethylformamide-
"DMF"),
M (carbon tetrachloride- "CTC"), N (dichlaroethane-"DCE"), O (methanol), Q
(chloroform- "CHC13"), T (methanol), V (dimethoxyethane- "DME"), Y
(chloroform;
dichloromethane), (3 (N-methyl pyrolidone), 'y (N-methylpyrolidone) and s
(acetone;
acetonitrile- "MeCN"; nitromethane-"NM") and 8 (heptane). Form Z is a hydrate,
having
water in the crystalline structure. Form S2 is a solvate of both water and
isopropyl alcohol.
Other crystalline forms do not have bound solvents, i. e., less than about 2%
as
measured by loss on drying ("LOD"), and are anhydrates. These anhydrates
include
crystalline Forms L, P, U, a, S and ~.
3o The XRPD pattern of these forms as substantially depicted is disclosed in
Figures
1-27 and 63, with the characteristic peaks listed in Table I. The DSC
thermograms for the
forms is disclosed in Figures 36 to 62, and the characteristic DSC peaks are
listed in Table
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II. The FTIR spectrum of the anhydrite and hydrate Forms and their
characteristic peaks
are also provided. The LOD values from the TGA analysis of some of these Forms
is
listed in Table III. Preparation of the various Forms by crystallization
procedure is listed
in Table IV, while preparation by trituration is listed in Tables V and VI,
data on
absorption of solvent vapors is listed in Table VII, data on preparation by
solvent removal
is listed in Table VIII and data on crystallization from a solventlanti-
solvent system is
listed in Tables IX-XI. Figure 28 summarizes the thermal stability of the
various forms.
The present invention also provides for pharmaceutical formulations of the
various
crystalline forms and their administration.
to BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is an XRPD pattern for nateglinide Form A.
Figure 2 is an XRPD pattern for nateglinide Form C.
Figure 3 is an XRPD pattern for nateglinide Form D.
Figure 4 is an XRPD pattern for nateglinide Form E.
i5 Figure 5 is an XRPD pattern for nateglinide Form F.
Figure 6 is an XRPD pattern for nateglinide Form G.
Figure 7 is an XRPD pattern for nateglinide Form I.
Figure 8 is an XRPD pattern for nateglinide Form J.
Figure 9 is an XRPD pattern for nateglinide Form K.
2o Figure 10 is an XRPD pattern for nateglinide Form L.
Figure 11 is an XRPD pattern for nateglinide Form M.
Figure 12 is an XRPD pattern for nateglinide Form N.
Figure 13 is an XRPD pattern for nateglinide Form O.
Figure 14 is an XRPD pattern for nateglinide Form P.
25 Figure 15 is an XRPD pattern for nateglinide Form Q.
Figure 16 is an XRPD pattern for nateglinide Form T.
Figure 17 is an XRPD pattern for nateglinide Form U.
Figure 18 is an XRPD pattern for nateglinide Form V.
Figure 19 is an XRPD pattern for nateglinide Form Y.
30 Figure 20 is an XRPD pattern for nateglinide Form Z.
Figure 21 is an XRPD pattern for nateglinide Form a.
Figure 22 is an XRPD pattern for nateglinide Form (3.
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Figure 23 is an XRPD pattern for nateglinide Form y.
Figure 24 is an XRPD pattern for nateglinide Form ~.
Figure 25 is an XRPD pattern for nateglinide Form s.
Figure 26 is an XRPD pattern of nateglinide Form a.
Figure 27 is an XRPD pattern of nateglinide Form 8.
Figure 28 is a thermal stability chart showing transformation of the forms
during drying,
and is a summary of a comparison between the wet and the dry forms illustrated
in various
tables in the present invention.
Figure 29 is an FTIR spectrum of nateglinide Form L.
Figure 30 is an FTIR spectrum of nateglinide Form P.
Figure 31 is an FTIR spectrum of nateglinide Form U.
Figure 32 is an FTIR spectrum of nateglinide Form Z.
Figure 33 is an FTIR spectrum of nateglinide Form a.
Figure 34 is an FTIR spectrum of nateglinide Form 8.
Figure 35 is an FTIR spectrum of nateglinide Form ~.
Figure 36 is a DSC thermogram of nateglinide Form A.
Figure 37 is a DSC thermogram of nateglinide Form D.
Figure 38 is a DSC thermogram of nateglinide Form E.
Figure 39 is a DSC thermogram of nateglinide Form F.
2o Figure 40 is a DSC thermogram of nateglinide Form G.
Figure 41 is a DSC thermogram of nateglinide Form I.
Figure 42 is a DSC thermogram of nateglinide Form J.
Figure 43 is a DSC thermogram of nateglinide Form I~.
Figure 44 is a DSC thermogram of nateglinide Form L.
Figure 45 is a DSC thermogram of nateglinide Form M.
Figure 46 is a DSC thermogram of nateglinide Form N.
Figure 47 is a DSC thermogram of nateglinide Form O.
Figure 48 is a DSC thermogram of nateglinide Form P.
Figure 49 is a DSC thermogram of nateglinide Form Q.
3o Figure 50 is a DSC thermogram of nateglinide Form T.
Figure 51 is a DSC thermogram of nateglinide Form U.
Figure 52 is a DSC thermogram of nateglinide Form V.
7
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Figure 53 is a DSC thermogram of nateglinide Form Y (chloroform solvate).
Figure 54 is a DSC thermogram of nateglinide Form Y (dichloromethane solvate).
Figure 55 is a DSC thremogram of nateglinide Form Z.
Figure 56 is a DSC thermograrn of nateglinide Form a.
Figure 57 is a DSC thermogram of nateglinide Form (3.
Figure 58 is a DSC thermogram of nateglinide Form y.
Figure 59 is a DSC thermogram of nateglinide Form 8.
Figure 60 is a DSC thermogram of nateglinide Form s.
Figure 61 is a DSC thermogram of nateglinide Form a.
l0 Figure 62 is a DSC thermogram of nateglinide Form 8.
Figure 63 is a XRPD pattern of nateglinide Form s~.
Figure 64 is a determination of purity of Form B prepared by Example 15.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides for 26 crystalline forms of
nateglinide
15 ("NTG"), denominated Form A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, U,
V, Y, a, (3, y,
8, s, 6, 8 and SI. These crystalline forms are characterized by their XRPD
pattern, DSC
thermogram and TGA analysis, among others. Also provided are processes for
preparation of other polymorphic forms such as Form B, E, H, S and Z.
The various crystalline forms are characterized by their XRPD pattern, which
2o differs from one polymorph to another. Form E is rather similar by XRPD to
Form Z,
although some differences may be observed. The peak at 3.7 is characteristic
of Form E
and is not observed in the XRPD of Form Z. The pattern in the range of 19-22
degrees
two theta is also somewhat different between these two forms. Table I lists
the most
characteristic peaks for the new crystalline forms. The XRPD patterns are
illustrated in
25 figures 1-27 and 63.
Table I: XRPD characteristic peaks for the nateglinide crystalline forms
Crystal FormCharacteristic XRD peaks- Within about t 0.2
degrees two theta
A 6.6, 13.3, 13.9, 16.8, 27.2, 28.0 (Fig. 1)
C 5.2, 8.2,8.8 (Fig. 2)
D 6.6, 7.5, 13.1, 16.5, 17.4, 21.1 (Fig. 3)
E 3.7, 4.6, 14.9, 15.6, 16.1 (Fig. 4)
F 4.8, 5.3, 15.2, 18.9, 19.6 (Fig. 5)
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G 14.4, 15.3, 19.3, 20.3 (Fig. 6)
I 5.5, 7.4, 16.8 (Fig. 7)
J 8.0, 11.2, 12.0, 15.9, 16.1, 17.7, 28.1 (Fig.
8)
I~ 9.5, 15.4, 17.1, 21.2 (Fig. 9)
L 17.6, 17.9, 19.6 (Fig. 10)
M 16.2, 16.4, 17.0, 17.8, 18.6, 19.4, 19.6 (Fig.l
l)
N 5.3, 5.5, 8.9, 9.9, 20.4, 21.1 (Fig. 12)
O 4.4, 5.2, 15.7, 16.6 (Fig. 13)
P 4.0, 4.6, 13.4, 13.9, 19.1 (Fig. 14)
Q 5.1, 5.6, 16.2, 19.8 (Fig. 15)
T 7.2, 7.9, 8.3, 10.7 (Fig. 16)
U 4.7, 7.4, 13.8, 17.0 (Fig. 17)
V 4.5, 5.8, 11.4, 16.4 (Fig. 18)
Y 6.1, 14.2, 15.1, 18.7 (Fig. 19)
Z 4.7, 5.3, 13.5, 13.9, 15.1, 15.7, 16.1, 18.7,
19.5, 21.5 (Fig. 20)
4.8, 5.1, 19.0, 19.4, 27.7, 28.9, 31.2 (Fig.
21)
(3 4.6, 9.4, 13.9, 18.8 (Fig. 22)
y 4.4, 8.9, 18.4, 18.8, 19.5 (Fig. 23)
5.6, 14.5, 18.2, 18.9, 19.5 (Fig. 24)
s 4.2, 13.0, 13.6, 14.3, 16.2, 16.7, 19.6 (Fig.
25)
A 4.8, 7.8, 15.5, 17.7 (Fig. 26)
a 5.5, 6.1, 6.7, 14.3 (Fig. 27)
S2 4.5, 7.8, 15.5, 16.9, 17.8, 19.2, 19.7 (Figure
63)
The various crystalline forms of nateglinide are also characterized by their
DSC
therrnograms. Table II lists the DSC peaks (endotherms). In addition to the
peaks listed
in Table II, many of the various crystalline forms show an exotherm at about
165°C
followed by an endotherm at about 174°C, probably due to
recrystallization into S-Type
Form.
Table II: DSC peaks of the nateglinide crystalline forms
Crystal Form ~ DSC Peaks (°C)
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A (Fig 36) 70 98 138 -
D (Fig 37) 66 130
E (Fig. 38) 75 86 104 129
F (Fig 39) 53 103 128
G (Fig 40) 106 127 - -
I (Fig 41) 46 121 - -
J (Fig 42) 49 105 168 -
K (Fig 43) 79 105 145 170
L (Fig 44) 131 138 -
M (Fig 45) 90 102 128 -
N (Fig 46) 77 100 130 137
O (Fig 47) 106 126 137 -
P (Fig 48) 106 113 (exotherm)128 -
Q (Fig 49) 102 126 - -
T (Fig 50) 68 106 130 -
U (Fig 51) 128 138 - -
V (Fig 52) 81 139 - -
Y dichloromethane 122 130 - -
solvate
(Fig 54)
Z (Fig. 53) 90 95
a (Fig 56) 129 - - -
(3 (Fig 57) 91 100 - -
y (Fig 58) 93 136 - -
8 (Fig 59) 100 107 (exotherm)130 -
E (Fig 60) 64 108 129 -
6 (Fig 61) - - - 127
B (Fig 62) 70 104 115 130
(exo)
The various crystalline forms are also analyzed by Thermal Gravimetric
Analysis
(TGA). TGA measurements show that Forms A, D, E, F, G, I, J, K, M, N, O, Q, T,
U, V,
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Y, Z, (3, y, s, A and S~ contain significant amounts of bound solvents and may
be
considered as solvated forms of nateglinide. The XRPD analysis of some of
these
solvated forms show that some of them are unstable when left in an open bottle
for 24
hours. In contrast to the above listed forms, TGA profiles of forms L, P, U,
a, 8 and 6
show no significant weight loss. These polymorphic forms ofnateglinide are
free of
bound solvents, i. e., less than about 2% LOD. Table III lists the solvents
used for the
preparation for nateglinide solvated forms, as well as LOD values based on TGA
analysis.
The ethanol solvate of nateglinide disclosed herein has an ethanol content of
from
about 10% to about 30% by weight. The ethanol solvate of nateglinide ethanol
solvate is
1o represented by formula NTG~3/2 EtOH. Specifically, the solvate is
nateglinide Form D.
The methanol solvates of nateglinide disclosed herein have a methanol content
of
from about 2 to about 60% by weight. Specifically, nateglinide methanol
solvate exists as
nateglinide Form E, Form O and Form T methanol solvate. Nateglinide methanol
solvate
is represented by the formula NTG* 1/4 MeOH (Form O) or by the formula NTG*
1/2
15 MeOH (form E). Nateglinide Form T contains more than about 20% methanol by
weight.
The methanol content of Form T is from about 20% to about 60% by weight.
The isopropyl solvate of nateglinide disclosed herein has an isopropyl alcohol
content of from about 12% to about 30% by weight. Specifically, isopropyl
solvate of
nateglinide exists as nategli'nide Form G.
2o A hydrate of nateglinide, Form Z, has a water content of about 10 to about
50%,
more preferably about 10% to about 40%, and most preferably from about 15% to
about
25%, measured either by the Karl Fischer method or LOD. Form S~, is a hydrate-
solvate
of isopropanol and contains about SO% LOD water and isopropanol.
The heptane solvated form of nateglinide, Form 8, has about 7 to about ~%
heptane
25 by weight, and is represented by the formula NTG~ 1/4Heptane.
Table III: LOD values by TGA and solvents used for the preparation of
nateglinide
solvated forms
Crystal Form Solvent LOD by TGA Comments
(weight %)
Storage at RT for
24h is
A Xylene g0 results in a partial
conversion to Form
B
11
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C DMA >5
D Ethanol 25
E MeOH 4
F n-PrOH 16-24
G Isopropyl Alcohol22-28
20 Storage at RT for
24h
I n-BnOH results in a conversion
to
Form L
2-3
XRD pattern slightly
up to 100C.
J N-Methyl Pyrolidone changed after storage
at RT
sharp weight
loss at
for overnight
100C
K Dimethyl formamide34
M Carbon tetra 2
chloride
N Dichloroethane 8
O MeOH 2
Storage at RT for
24h
results in a conversion
to
Q Chloroform 10
Form Y, which contains
chloroform.
>20 Storage at RT for
24h
T MeOH results in a conversion
to
Form E
V Dimethoxyethane 8-16 A sharp weight loss
step of
7-8% is observed
at 70C
Y Dichloromethane/2-8
Chloroform
Beta N-Methyl Pyrolidone
No significant weight
loss
Gamma N-Methyl Pyrolidone- up to 90C
Sharp weight loss
at 90C
12
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Acetone/
Nitromethane/ Above 4
Epsilon
Acetonitrile
Theta Heptane 7.4%
Omega IPA and Water 50%
The anhydrate forms and the hydrated Form Z, are also characterized by their
FTIR spectrum. Form Z is characterized by a FT1R spectrum (Figure 31) with
peaks at
about 699, 1542, 1645, 1697, 2848, 2864, 2929, 3279 and 3504 cm 1. The more
characteristic peaks are observed at about 1645, 1697, 3279 and 3504 cni 1.
Characteristic
FTIR peaks are for the anhydrates, specifically Forms L, U, P, a, 8 and a are
disclosed in
the following table.
nateglinide form Characteristic FTIR Peaks
Form Alfa: 3283, 1711, 1646, 1420, 1238 cm (Fig.
32)
Form L: 1741, 1726, 1621, 1600, 1538, 1211, 1191
cm (Fig. 28)
Form U: 3350, 1711, 1646, 1291 cm (Fig. 30)
Form 8: 3306, 1729, 1704, 1275 cm 1 (Fig. 34)
Form a~ 3303, 1705, 1640 cm ' (Fig. 35)
Form P: ~ 3309, 1748, 1589 ciri 1 (Fig. 29)
The various crystalline forms are related to each other in that drying of one
form
i0 may result in a transformation to another form, namely nateglinide Forms A,
B, D, E, F,
G, H, I, J, K, L, M, N, Q, S, T, V, Z, a, (3, b, y, s, 0 and S2. The drying is
carned out by
heating a sample under ambient or reduced pressure. Generally, a preferred
temperature is
from about 40°C to about 80°C, more preferably under reduced
pressure. Of these forms,
Forms B, H, L, U and sigma are thermally stable, and do not convert to another
form upon
heating. Many of the above forms convert to Form B upon drying, namely Forms
A, C, D,
E, F, G, J, K, P, Q, T, Z, a, (3, b, 0 and S2. Of these forms, Form a, 6, Y
and O are
somewhat stable, and usually retain their crystalline structure after heating,
unless heated
to a high temperature. For example, Form 8 is stable when heated to
60°C overnight (at
least about 8 hours), but heating of Form b at 120°C and 1 atmosphere
results in Form B.
zo Thus, heating at a temperature above about 80°C may cause a
transformation in these
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forms. The term "stable" as used herein refers to a polymorphic change of less
than about
5% by weight, more preferably less than about 2%, particularly for Form 8.
The conversion of some of the forms to Form B goes through another form. For
example, the conversion of Form S2 and E to Form B may go through Form ~.
Form G may represent a link between Forms F, T on the one hand, and Form B on
the other hand. Forms T and F, upon drying, convert to a mixture of Form B and
G, which
makes is probable that Forms F and T convert to Fonn B by going through Form
G.
Of the forms that convert to Form B, some of them sometimes under drying
convert to other forms. Form K may convert to Forms a or S, while Form C may
convert
1o to Form B or a. Form a may convert to Form S upon heating, but the presence
of seeds of
Form B in the sample of Form a results in Form B. Probably Forms C and K
transform to
Form a first, and that it is through Form a that they transform to Form B or
S. Form J
may convert to Form B or (3, though its conversion to Form B may go through
Form (3.
The Form J used in preparing Form (3 is preferably obtained by crystallization
from N-
15 methylpyrrolidone. When Form J contains some seeds of Form y, heating
results in Form
Y.
The acetonitrile solvate of Form Epsilon, when dried, results in Form B. While
the
nitromethane solvates of Form Epsilon when dried result in Forms H or P. When
Form P
is dried, Form H is obtained, which makes it probable that conversion of Form
Epsilon to
20 Form H goes through Form P.
Another thermally stable Form of nateglinide is Form L. Form L may be obtained
by heating Forms M, N and D. To obtain Form L, these various forms are
preferably
heated for about 3-10 hours at a preferred temperature range of from about
40°C to about
80°C, more preferably about 50°C under reduced pressure. Form y
may also be prepared
25 by heating Form J containing seeds of Form y under similar conditions.
Another thermally stable form of nateglinide is Form H which may be prepared
by
heating nateglinide Forms P, V and s. Form S may be prepared by heating Forms
a and
K, though the transition of Form K to Form S may go through Form a.
Form U is another thermally stable Form of nateglinide, and does not undergo a
3o transition after being heated at about 100°C for at least about 8.5
hours.
Storage at room temperature and pressure may also cause a transition of one
form
to another. Form A partially converts to Form B during storage at room
temperature for
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about a day. Form I converts to Form L under the same conditions. Also under
the same
conditions, Form Q converts to Form Y (containing chloroform), while Form T
converts to
Form E.
Form a is related to Forms F, G, I and s in that it may be crystallized out of
the
same solvent as those forms, n-propanol, isopropyl alcohol, n-butanol and
acetonitrile,
respectively. Form a however is crystallized under different conditions, see
e.g., Table
N. Form a is often obtained with prolonged crystallization step (at least
about 2-3 days).
Not being bound by any theory, this phenomenon may point to a possible
conversion of
another crystalline form, such as those obtained from the same solvent, to
Form a
overtime in the solvent.
Forms E and D are also related in that both of the forms may be crystallized
out of
ethanol; but these forms crystallize under different conditions, see e.g.,
Table IV. The
crystallization of Form E in ethanol is prolonged, for at least about 5 days,
more preferably
at least about 1 month. Not being bound by any theory, it might be possible
that initially
Form D crystallizes out, followed by a conversion to Form E overtime in the
solvent.
To prepare Form S, the wet sample obtained after crystallization has to be
dried
Crystallization from a solution of nateglinide in n-butanol and DMF results in
a solvate,
which needs to be dried to obtain Form S. The wet samples are nateglinide
Forms K, I
and alpha.
Some of the forms may first appear as a gel, and then transform into crystals
during the filtration step (e.g. form epsilon from nitromethane, and form A
from xylene) or
overtime (e.g. Form M from carbon tetrachloride and Form J from N-
methylpyrrolidone).
Generally, gels are unstable forms which crystallize over time.
Some of the crystalline forms may be obtained by trituration. As used herein,
trituration refers to obtaining a solid from a mixture of nateglinide in a
solvent without
complete dissolution. A form of nateglinide is mixed in a particular solvent
and agitated
for a suf~'icient time to allow for transformation to another crystalline
form. After
agitation, a suspension or a paste forms. A solid may then be separated from
the
suspension by techniques well known in the art, such as filtration. The paste
may be
3o filtered, to name one technique, to remove excess solvent. The result of
this trituration
procedure is various forms of nateglinide.
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The trituration of Form delta in water may result in Form Z after about 5
hours,
and Form E after about 8 hours, which may also point to a transition of Form Z
to Form E.
All three forms may be heated to obtain Form B.
Some of the crystalline forms may be obtained by solvent removal. First a
solution
of nateglinide in a suitable solvent is prepared. The solvent may be heated to
obtain a
clear solution. The solvent may be heated from about 40°C to about
70°C, with about
55°C being preferred. The solvent is then removed to obtain a residue,
preferably at
elevated temperature within the said range. The solvent is preferably removed
by
evaporation, with evaporation under reduced pressure being particularly
preferred. The
to resulting residue is then examined. Suitable solvents include esters,
ketones, amines,
amides, alcohols and nitriles. Removal of acetonitrile, acetone, ethyl acetate
and iso-
propyl alcohol as solvents results in nateglinide Form B.
Some of the crystalline forms are obtained by absorption of solvent vapors.
Nateglinide is contacted with vapors of a particular solvent, resulting in
absorption of the
solvent. Absorption of ethanol results in Form D, methanol in Form O, and DCM
in Form
Y. Form H was stable in the presence of vapors of water and acetone.
Some of the crystalline forms may be obtained by crystallization from a
suitable
solvent. Form omega is obtained by crystallization of nateglinide out of a
mixture of
water and isopropanol. Preferably, the ratio of the water to isopropanol is
from about 1/2
2o to about 1/5, more preferably 1/3 (vol/vol).
Nateglinide Form Z is generally prepared by acidification of a solution of an
alkali
metal or alkaline earth metal salt of nateglinide in an aqueous solvent.
Preferred solvent is
water free of a co-solvent. Preferred salts are sodium and potassium salts,
with the sodium
salt being most preferred. Before acidification, the solution preferably has a
pH of above
about 8, while after acidification, the pH is preferable from about 1 to about
5, most
preferably from about 2 to about 5. Acidification results in precipitation of
nateglinide,
which may be recovered by techniques well known in the art, such as
filtration.
Nateglinide Forms B and U may be prepared by crystallization from an organic
solvent such as ethyl acetate or acetone. In the procedure for the preparation
of form B,
3o crystallization is preferably induced by concentration of the solvent,
while for Form U, by
seeding of the solution.
Nateglinide Forms B, H, U, Z, 8, 8 and 6 are related in that all of them may
be
prepared from a two solvent system. The two solvent system used is a mixture
of a
16
CA 02492644 2005-O1-17
WO 2004/009532 PCT/US2003/022375
solvent and an anti-solvent. Example of suitable antisolvents are CS to C12
aromatic
hydrocarbons such as toluene and xylene, and CS to C12 saturated hydrocarbons
such as
hexane and heptane. Examples of suitable solvents are C1 to CS alcohols such
as
methanol, ethanol, isopropanol, n-butanol and n-propanol, lower ketones (C3 to
C6) such
as acetone and lower esters ( C3 to C6) such as ethyl acetate. After
crystallization, the
crystals are recovered by techniques well known in the art, such as filtration
and
centrifugation, and may be dried. To dry, the temperature may be increased or
the
pressure reduced. In one embodiment, the crystals are dried at about
40°C to 60°C, at a
pressure of less than about 50 mmHg.
When nateglinide is crystallized out of a binary mixture, particularly in the
absence
of stirnng, the crystalline product is often Form B, as illustrated in Table
IX. The binary
mixture is prepared by suspending nateglinide in the anti-solvent, and then
adding the
solvent to form a solution. Nateglinide Form B may be obtained at different
crystallization temperatures, such as at room temperature and at about
0°C, particularly in
the absence of stirring.
Crystallization from a binary mixture of the above solvents and anti-solvents
may
lead to other forms of nateglinide other than Form B. Crystallization out of a
toluene/methanol mixture may result in nateglinide Form E, which may be
converted to
Form B by heating. Additionally, a heptane/ethyl acetate combination may
sometimes
lead to a mixture of Forms B and Z, especially with longer period of
crystallization (over
about 3 days), while a toluene/ethyl acetate mixture may result in a mixture
of Form B and
H. A mixture of Form B and Z may be converted to one containing substantially
Form B
through heating, since Form Z converts to Form B through heating.
In another embodiments, rather than preparing a solution by first suspending
nateglinide in the anti-solvent, a solution is prepared in the solvent,
followed by
combining with the anti-solvent. The combining is carried out in this
embodiment in such
a way where upon additon a solution is formed, and any precipitated solids go
back into
solution. Preferrably, the anti-solvent is heated so that upon mixing of the
solution and the
anti-solvent, immediate precipitation does not take place.
3o The different forms may be obtained depending on the solvent/anti-solvent
ratio,
crystallization conditions and the time of stirring. Generally, Form Z is
crystallized from
an ethyl acetate/heptane ratio of about 2 to 4, form H a ratio of about 4 to
about 7, Form B
a ratio of about 6 to about 8, Form U a ratio of about 1 to about ~, Farm 8 a
ratio of about
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1 and Form 8 a ratio of about 1 to about 8, more preferably from about 1 to
about 2
(vol/vol).
Of these, some forms may crystallize as other forms, and convert after being
stirred
for a sufficient time in the solvents. Stirnng the resulting slurry from
crystallization at a
temperature of from about -15°C to about 10°C, preferably about
5 °C, may result in Form
S. Form 8 seems to result from stirring of forms such as Form U, Form 8, Form
H and
even Form B. Preferably the stirring to obtain Form ~ is carried out for at
least about 2-3
hours, more preferably for at least about 10 hours.
Other than a solvent:antisolvent ratio of about 1, formation of Form 8 seems
to be
1o favored at lower crystallization and filtering temperatures, from about -
15°C to about 10°C
preferably 5°C. As previously noted, stirring of Form 8, preferably at
the specified
temperature range, results in Form b.
Form U may be obtained by stirnng with Form B or H in an organic solvent.
Stirring for about 1 hour is sufficient to obtain Form U. However, additional
stirring, such
15 as above about 5 hours, may result in a transition to Form S. Form U may
also be obtained
by crystallization, preferably at the specified ratio, more preferably at a
crystallization and
filtering temperature of about -15°C to about 10° C. Form U is
generally favored when
starting with a temperature of from about 25°C to about 35°C,
followed by cooling in less
than about 1 hour to a temperature of from about 0°C to about
10°C, with about 5°C being
2o preferred, followed by filtering in less than about 1 hour. Higher solvent
to anti-solvent
ratio may favor form U over 0.
Form H may be obtained under both low and high crystallization temperatures,
preferably under the specified solvent/anti-solvent ratio. Form B, on the
other hand, tends
to crystallize at a temperature of at least about 15 °C.
25 Forms Z generally crystallizes after about a day at a final cxystallization
temperature of at least about 15 °C, more preferably from about 15
°C to about 30°C, and
rnostpreferably from about 20°C to about 25°C. The initial
crystallization temperature
for these forms is preferably above 35 °C, followed by cooling in a few
hours, more
preferably about 1 hour, to about 20°C to about 25 °C. These
conditions may lead to Form
30 Z, which converts to Form B by drying.
Form ~ may also be obtained by stirring of crystals of Form B. Not being bound
by any theory, it may be possible that Form a is obtained through Form U, that
is stirring
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results in a transition of Form B to Form U followed to Form a. Prolonged
crystallization
and filtration is preferred for obtaining Form 6, i.e., preferably at least
about 10 hours.
Table X does not show a transition of Form B to other forms despite prolonged
stirring in the anti-solvent/solvent system due to use of a high ratio of
ethyl acetate.
Preferably about a 1:1 ratio of solvent to anti-solvent is used for obtaining
other forms
through stirring of Form B in a solvent/antisolvent mixture.
The results of the processes may vary when precipitating a solid after
combining
the solution and the anti-solvent. In this embodiment, the solution is
combined with the
anti-solvent in such a way to result in precipitation, in contrast with the
other embodiments
l0 that result in a solution after the combining step. To cause substantial
precipitation,
preferably, the solution is combined with a cold anti-solvent. More
preferably, the
antisolvent is from about 20°C to about 40°C colder than the
solution, particularly when
an ethyl acetate/heptane system is used. Most preferably, the heptane has a
temperature of
from about 0 ° C to about 10 ° C and the ethyl acetate a
temperature of from about 30 ° C to
15 about 40 ° C.
In this embodiment, Form U may be obtained within a wide range of solvent/anti-
solvent ratios and crystallization temperatures. For example, table XI shows
that Form U
may be obtained from a solvent to anti-solvent ratio of frpm about 1 to about
6, and final
crystallization temperatures from about 0°C to about 30°C. Not
being bound by any
2o theory, the presence of other forms, particularly Form 8 and Q, especially
after long
crystallization step, points to possible a transition of Form U to these
forms. The presence
of a mixture of Form B and U after 1 hour also points to the possibility that
Form B might
be immediately crystallized out of the solution, followed by a transition to
Form U, which
itself may change overtime to Forms 8 or 6.
25 The following table provides guidance on obtaining Forms B, H, U, Z, ~, 8
and a
from a solvent:anti-solvent system:
V/V ratio Filtration Crystal
temp.
(EA/l3eptane)(about) form
(about) obtained
i :1 15 C - 3 No stirring B
0 C
preferably
20-25 C
15 C - 30 Immediately after B
C crystallization
1: I With stirring
preferably
20-25 C
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Stirring for at
least about 21h
1:1 1 S C - PrecipitationImmediately after B
30 C crystallization
preferably without
20-25 C going
into solutionStirring for at U
least about lh
after combining
1:1 -15C -10 Immediately after
C crystallization
D,y~s
preferably a -~
5C B
Stirring at about g
5C
1.5:1 -15C -10
C
preferably Immediately after U
5C crystallization
Stirring at about g
5C
2:1 - 8:1 -15C - 10 Immediately after H (95%
C crystallization
preferably yield)
5C
Stirring for about
1-5h
U
Stirring for at
least about Sh
8
2:1 - 8:1 15 C - Wet crude
30 C
p
preferably material Z ~ B
20-25 C
2:1 - 8:1 15 C - Dry crude H
3 0 C
preferably material
20-25 C
Depending on the preparation procedure, nateglinide Form ~ may contain from
about 0.5% to about 3 % of residual heptane by weight. The removal of heptane
without
changing the crystal form may be carried out in a fluidized bed drier,
preferably at a
temperature of from about 60 to about 70°C, more preferably for at
least about 3 hours.
The residual Heptane may be also removed under stirnng, preferably at a
temperature of at
least about 40°C under vacuum. The 8 Form is preferably polymorphically
pure and
contains less than about 5% Form H (wtlwt), more preferably less than about 2%
(wt/wt),
and most preferably less than about 0.5% (wt/wt).
10, Crystalline Form 8 is stable at a temperature of about 40°C and a
relative humidity
of about 75% for at least about 3 months.
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Trituration of Form 8 in ethyl acetate may result in other polymorphic forms
of
nateglinide. Triturating nateglinide Form 8 at a temperature of from about 20
to about
30°C in ethyl acetate results in Form U, while triturating at higher
temperatures (above
40°C), such as at about 50°C, results in Form B.
The processes of the present invention allow for obtaining Forms b and B with
a
purity of at least about 95%, more preferably at least about 98% wt/wt
compared to other
polymorphic forms. These forms may be produced particularly free of the H
Form.
The starting material used for the processes of the present invention may be
any
crystalline or amorphous form of nateglinide, including various solvates and
hydrates.
to With crystallization processes, the crystalline form of the starting
material does not usually
affect the final result. With trituration, the final product may very
depending on the
starting material. One of skill in the art would appreciate the manipulation
of the starting
material within skill in the art to obtain a desirable form with trituration.
The processes of the present invention may also be practiced as the last step
of
15 prior art processes that synthesize nateglinide.
Many processes of the present invention involve crystallization out of a
particular
solvent, i.e., obtaining a solid material from a solution. One skilled in the
art would
appreciate that the conditions concerning crystallization may be modified
without
affecting the form of the polymorph obtained. For example, when mixing
nateglinide in a
2o solvent to form a solution, warming of the mixture may be necessary to
completely
dissolve the starting material. If warming does not clarify the mixture, the
mixture may be
diluted or filtered. To filter, the hot mixture may be passed through paper,
glass fiber or
other membrane material, or a clarifying agent such as celite. Depending upon
the
equipment used and the concentration and temperature of the solution, the
filtration
25 apparatus may need to be preheated to avoid premature crystallization.
The conditions may also be changed to induce precipitation. A preferred way of
inducing precipitation is to reduce the solubility of the solvent. The
solubility of the
solvent may be reduced, for example, by cooling the solvent.
In one embodiment, an anti-solvent is added to a solution to decrease its
solubility
30 for a particular compound, thus resulting in precipitation. Another way of
accelerating
crystallization is by seeding with a crystal of the product or scratching the
inner surface of
the crystallization vessel with a glass rod. Other times, crystallization may
occur
spontaneously without any inducement. The present invention encompasses both
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embodiments where crystallization of a particular form of nateglinide occurs
spontaneously or is induced/accelerated, unless if such inducement is critical
for obtaining
a particular form.
Nateglinide of defined particle size may be produced by known methods of
particle
size reduction starting with crystals, powder aggregates and course powder of
the new
crystalline forms of nateglinide. The principal operations of conventional
size reduction
are milling of a feedstock material and sorting of the milled material by
size.
A fluid energy mill, or micronizer, is an especially preferred type of mill
for its
ability to produce particles of small size in a narrow size distribution. As
those skilled in
1o the art are aware, micronizers use the kinetic energy of collision between
particles
suspended in a rapidly moving fluid stream to cleave the particles. An air jet
mill is a
preferred fluid energy mill. The suspended particles are injected under
pressure into a
recirculating particle stream. Smaller particles are carried aloft inside the
mill and swept
into a vent connected to a particle size classifier such as a cyclone. The
feedstock should
15 first be milled to about 150 to X50 ~m which may be done using a
conventional ball,
roller, or hammer mill. One of skill in the art would appreciate that some
crystalline forms
may undergo a transition to another form during particle size reduction.
Pharmaceutical compositions may be prepared as medicaments to be administered
orally, parenterally, rectally, transdermally, bucally, or nasally. Suitable
forms for oral
20 administration include tablets, compressed or coated pills, dragees,
sachets, hard or gelatin
capsules, sub-lingual tablets, syrups and suspensions. Suitable forms of
parenteral
administration include an aqueous or non-aqueous solution or emulsion, while
for rectal
administration suitable forms for administration include suppositories with
hydrophilic or
hydrophobic vehicle. For topical administration the invention provides
suitable
25 transdermal delivery systems known in the art, and for nasal delivery there
are provided
suitable aerosol delivery systems known in the art.
Pharmaceutical formulationss of the present invention contain a nateglinide
Form
selected from A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, V, Y, a, [3, y, 8,
s, ~, 6 and S2.
The pharmaceutical composition may contain only a single form of nateglinide,
or a
3o mixture of various forms of nateglinide, with or without amorphous form. In
addition to
the active ingredient(s), the pharmaceutical compositions of the present
invention may
contain one or more eXCipients or adjuvants. Selection of excipients and the
amounts to
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use may be readily determined by the formulation scientist based upon
experience and
consideration of standard procedures and reference works in the field.
Diluents increase the bulk of a solid pharmaceutical composition, and rnay
make a
pharmaceutical dosage form containing the composition easier for the patient
and care
giver to handle. Diluents for solid compositions include, for example,
microcrystalline
cellulose (e.g. Avicel~), microfme cellulose, lactose, starch, pregelitinized
starch, calcium
carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic
calcium phosphate
dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium
oxide,
maltodextrin, mannitol, polymethacrylates (e.g. Eudragit~), potassium
chloride, powdered
cellulose, sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions that are compacted into a dosage form, such
as
a tablet, may include excipients whose functions include helping to bind the
active
ingredient and other excipients together after compression. Binders for solid
pharmaceutical compositions include acacia, alginic acid, carbomer (e.g.
carbopol),
carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum,
hydrogenated
vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel~),
hydroxypropyl methyl cellulose (e.g. Methocel~), liquid glucose, magnesium
aluminum
silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g.
Kollidon~,
Plasdone~), pregelatinized starch, sodium alginate and starch.
2o The dissolution rate of a compacted solid pharmaceutical composition in the
patient's stomach rnay be increased by the addition of a disintegrant to the
composition.
Disintegrants include alginic acid, carboxymethylcellulose calcium,
carboxymethylcellulose sodium (e.g. Ac-Di-Sol~, Primellose~, colloidal silicon
dioxide,
croscarmellose sodium, crospovidone (e.g. Kollidon~, Polyplasdone~), guar gum,
magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose,
polacrilin
potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium
starch
glycolate (e.g. Explotab~) and starch.
Glidants can be added to improve the flowability of a non-compacted solid
composition and to improve the accuracy of dosing. Excipients that may
function as
3o glidants include colloidal silicon dixoide, magnesium trisilicate, powdered
cellulose,
starch, talc and tribasic calcium phosphate.
When a dosage form such as a tablet is made by the cornpaction of a powdered
composition, the composition is subjected to pressure from a punch and dye.
Some
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excipients and active ingredients have a tendency to adhere to the surfaces of
the punch
and dye, which can cause the product to have pitting and other surface
irregularities. A
lubricant can be added to the composition to reduce adhesion and ease the
release of the
product from the dye. Lubricants include magnesium stearate, calcium stearate,
glyceryl
monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated
vegetable
oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate,
sodium
stearyl fumarate, stearic acid, talc and zinc stearate.
Flavoring agents and flavor enhancers make the dosage form more palatable to
the
patient. Common flavoring agents and flavor enhancers for pharmaceutical
products that
may be included in the composition of the present invention include maltol,
vanillin, ethyl
vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
Solid and liquid compositions may also be dyed using any pharmaceutically
acceptable colorant to improve their appearance and/or facilitate patient
identification of
the product and unit dosage level.
In liquid pharmaceutical compositions of the present invention, nateglinide
and any
other solid excipients are dissolved or suspended in a liquid carrier such as
water,
vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
Liquid pharmaceutical compositions may contain emulsifying agents to disperse
uniformly throughout the composition an active ingredient or other excipient
that is not
soluble in the liquid carrier. Emulsifying agents that may be useful in liquid
compositions
of the present invention include, for example, gelatin, egg yolk, casein,
cholesterol, acacia,
tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol
and cetyl
alcohol.
Liquid pharmaceutical compositions of the present invention may also contain a
viscosity enhancing agent to improve the mouth-feel of the product andlor coat
the lining
of the gastrointestinal tract. Such agents include acacia, alginic acid
bentonite, carbomer,
carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl
cellulose,
ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl
cellulose,
hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone,
propylene
carbonate, propylene glycol alginate, sodium alginate, sodium starch
glycolate, starch
tragacanth and xanthan gum.
Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose,
aspartame, fructose, mannitol and invert sugar may be added to improve the
taste.
24
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Preservatives and chelating agents such as alcohol, sodium benzoate, butylated
hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid
may be
added at levels safe for ingestion to improve storage stability.
According to the present invention, a liquid composition may also contain a
buffer
such as guconic acid, lactic acid, citric acid or acetic acid, sodium
guconate, sodium
lactate, sodium citrate or sodium acetate.
Selection of excipients and the amounts used may be readily determined by the
formulation scientist based upon experience and consideration of standard
procedures and
reference works in the field.
to The solid compositions of the present invention include powders,
granulates,
aggregates and compacted compositions. The dosages include dosages suitable
for oral,
buccal, rectal, parenteral (including subcutaneous, intramuscular, and
intravenous),
inhalant and ophthalmic administration. Although the most suitable
administration in any
given case will depend on the nature and severity of the condition being
treated, the most
15 preferred route of the present invention is oral. The dosages may be
conveniently
presented in unit dosage form and prepared by any of the methods well-known in
the
pharmaceutical arts.
Dosage forms include solid dosage forms like tablets, powders, capsules,
suppositories, sachets, troches and losenges, as well as liquid syrups,
suspensions and
20 elixirs.
The dosage form of the present invention may be a capsule containing the
composition, preferably a powdered or granulated solid composition of the
invention,
within either a hard or soft shell. The shell may be made from gelatin and
optionally
contain a plasticizer such as glycerin and sorbitol, and an opacifying agent
or colorant.
25 The active ingredient and excipients may be formulated into compositions
and
dosage forms according to methods known in the art.
A composition for tableting or capsule filling may be prepared by wet
granulation.
In wet granulation, some or all of the active ingredients and excipients in
powder form are
blended and then further mixed in the presence of a liquid, typically water,
that causes the
3o powders to clump into granules. The granulate is screened and/or milled,
dried and then
screened and/or milled to the desired particle size. The granulate may then be
tableted, or
other excipients may be added prior to tableting, such as a glidant and/or a
lubricant.
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A tableting composition may be prepared conventionally by dry blending. For
example, the blended composition of the actives and excipients may be
compacted into a
slug or a sheet and then comminuted into compacted granules. The compacted
granules
may subsequently be compressed into a tablet.
As an alternative to dry granulation, a blended composition may be compressed
directly into a compacted dosage form using direct compression techniques.
Direct
compression produces a more uniform tablet without granules. Excipients that
are
particularly well suited for direct compression tableting include
microcrystalline cellulose,
spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The
proper use of
these and other excipients in direct compression tableting is known to those
in the art with
experience and skill in particular formulation challenges of direct
compression tableting.
A capsule filling of the present invention may comprise any of the
aforementioned
blends and granulates that were described with reference to tableting,
however, they are
not subjected to a final tableting step.
The dosage and formulation of STARLIX may be used as a guidance. The dosage
used is preferably from about 30 to about 240 mg of nateglinide, more
preferably from
about 60 to about 120 mg of nateglinide. The pharmaceutical compositions of
the present
invention, preferably in the form of a coated tablet, are administered from
about 10
minutes to about 1 hours prior to a meal, more preferably about 15 minutes
before each
2o meal. The dose is not taken if the meal is skipped. The pharmaceutical
compositions may
also be used in combination with metaformin.
Instruments
X-Ray Powder Diffraction:
X-Ray diffraction was performed on X-Ray powder diffractometer,
Scintag°, variable
goniometer, Cu-tube, solid state detector. Sample holder: A round standard
aluminum
sample holder with round zero background quartz plate.
The sample was put on the sample holder and immediately analyzed as is.
Scanning parameters: Range: 2-40 deg 28, Continuos Scan, Rate: 3deg./min.
3o DSC:
DSC~2le Mettler Toledo°, Sample weight: 3-Smg, Heating rate:
10°C/min, Number of
holes in the crucible: 3
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TGA:
Mettler TG50~, Sample weight: 7-l5mg, Heating rate: 10°Clmin
FTIR:
s Perkin -Elmer~, Spectrum One FTIR spectrometer, Range: 4000-400cm-1, no. of
scans:
16, resolution: 4.Ocm-1, DRIFT technique.
EXAMPLES
to Example 1- This example illustrates preparation of various forms of
nate~linide from a
solution
Nateglinide (5 g) was placed into an erlenmeyer flask and heated to the
specified
temperature. The solvent was added in 1-ml portions (in some cases, the
solvent was
added in 5-ml portions) until a clear solution was obtained. If a clear
solution was not
15 obtained after addition of 150 ml of the solvent, the hot mixture was
filtered.
The clear solution was left to crystallize at room temperature. If
crystallization did
not happen or was poor, the solution was refrigerated at 3°C. The
precipitate was filtered
off (at RT or at 5°C depending on the temperature of the
crystallization), weighed and
divided into 2 equal parts. One part was dried at 50°C under reduced
pressure (20-30
2o mmHg) to constant weight 00.01 g) for about 3-10 hours. Details are
presented in Table
IV.
Table IV. Data on crystallization of NTG from a single solvent
SolventLIS, T, Time Time Form Form
ml/g C RT, 3C, Wet Dry
h h
Xylene 30 70 25 A AB
DMA 1 55 25 C
EtOH 1 55 25 D L
EtOH 2* 54 6 42 D B
MeOH 1 55 24 E B
EtOH 3 55 1 m 18 d E B
n-PrOH 1 57 25 144 F G+B
n-PrOH 2 55 10 cc a
d
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n-PrOH 2 55 3 5 d a a
IPA 1.2 57 25 48 G B
IPA 3 55 1 m 20 a a
NMP 1.4 57 73 J B+(3
DMF 1.6 56 24 52 K S
CTC 30 65 25 M L
DCE 2.2 55 23 47 N L
CHC13 1 54 73 193 Q Q
DME 1.4 56 96 V H
n-BuOH 4 55 1 m 20 a S
n-BuOH 1.4 57 25 144 I S
Acetone2 20 144 20 H
NM 30 70 24 s P
MeCN 8 55 3 20 E s+B
MeCN 19 5 8 d a a
S
MeCN 19 55 7 d 5 a a
DCM 2* 54 47 Y Y
EA 9 55 22 a a
EA 9 55 lOd Sd a a
EA 15 55 9 d a a
EA 15 55 8d Sd a a
LegefZd. L/S - liquid/solid ratio: * - the solvent was added in 5-ml portions;
T - starting
temperature; Ww - weight of wet sample after filtration, Wd - weight of the
sample after
drying at 80-90°C/20 mbar.
Solvent abbreviations: MeOH- methanol, EtOH - ethanol, n-PrOH - n-propanol,
IPA- 2-
propanol, n-BuOH- n-butanol, EA - ethyl acetate, NM - nitromethane, DMF - N,N-
dimethylformamide, DMA - N,N-dimethylacetamide, NMP - N-methylpyrrolidone,
MeCN - acetonitrile, Ether - diethyl ether, DME - dimethoxyethane, DCM -
dichloromethane, DCE - 1,2-dichloroethane and CTC -carbon tetrachloride.
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Example 2- This example illustrates trituration of nateg~linide Form H and U
in various
solvents
Nateglinide (5 g) was placed into an Erlenmeyer flask. Solvent was added in 1-
ml
portions to prepare a stirrable mixture. The flask was stirred with a magnetic
stirrer at
room temperature. A solid was filtered off at room temperature, weighted, and
divided
into 2 equal parts. One part was dried at 55°C under 20-30 mm/Hg
pressure to constant
weight 00.01 g).
Details are presented in Tables V and VI.
Table V. Data on trituration of NTG with a single solvent
Start SolvenL/S Time,Form Form
Form t ml/g h wet dry
H MeOH 1.2 24 T G+B
H EtOH 1.2 24 D B
H IPA 1.2 24 G ~ G+B
H n- 1.2 23 F B
PrOH
H n- 1.4 24 I
BuOH
H MeCN 4.8 25 P H+P
H NM 4 26 s H+P
H NMP 0.8 24 J (3
H DMF 1.2 25 K
H DMA 1.2 26 C B
H DME 1.4 24 V H
H Dioxa2.2 24 s s
ne
H THF 0.8 ~
23
H DCM 1.8 25 Y Y
H CHC131 25 Q Q+B
H ~ 1.8 24 Q+H Q+H
DCE
Table VI. Data on trituration of NTG with a single solvent
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Start SolvenL/S Time,Form Form
Form t mUg h wet dry
U AcOH 1.8 24 H+S H+S
U MeOH 1.2 24 a a
U EtOH 1.6 24 B+a B+a
U IPA 1.8 24 G+S G+S
U n- 1.4 25 F B
PrOH
U n- 1.6 26 a a
BuOH
U NM 5 24 P P
U NMP 1 25 J+y
U DMF 1 23 K a
U DMA 1.2 24 C a
U Aceto2 24 P P
ne
U MEK 2.4 23 H+a H+S
U MIPK 3 24 H+a H
U MIBK 3.6 24 H+a H+S
U DME 1.8 24 H+a H+S
U Dioxa2 23 g B
ne
U THF 0.8 23 g 8+B
U DCM 1.6 24 Y+S Y+S
U CHC131.2 25 g g
U DCE 3.8 26 Q Q
Example 3- This Example illustrates Absorption of solvent va ors by
nate~linide
Nateglinide (3.50 g) was added to a polypropylene can and weighed. The can was
introduced into a bigger polypropylene container containing a solvent, and
stored at room
CA 02492644 2005-O1-17
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temperature. The can was removed from the container and weighed (Wfinal). The
can
content was divided into 2 portions. One portion was dried at a temperature of
55 °C and a
pressure of 20-30 imnHg to constant weight 00.01 g). Details are presented in
Table VII.
Table VII. Data on absorption of solvent vapors with NTG Form H
NTG Brutto,SolveTime,WBn D Form Form
W,
g g nt d al wet dry
3.50 15.77 EtOH 4 16.290.5D B
2
3.50 15.94 MeOH 4 16.120.1O O
8
3.50 15.78 Aceto4 15.860.0H H
ne 8
3.49 51.86 DCM 4 51.900.0Y
4
3.50 15.27 Water4 15.290.0H H
2
Legehd. Brutto - starting weight of the can with NTG; Wfinal - final weight of
the can
with NTG after the exposure; D - overweight
Example 4- This example illustrates preparation of various forms of
nate~linide by
solvent removal.
1o Nateglinide (5g) was dissolved in the following solvents at about 55 C in
over
about 15 minutes until a clear solution was obtained. The solvent was removed
to dryness
by evaporation at about 55 C/20-30 mmHg to give dry nateglinide.
Table VIII- Data on solvent removal
SolventForm,
dry
MeCN B
AcetoneB
EA B
Example 5- This example illustrates preparation of Form Z.
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D-Phenylalanine (PheOH, 7.73 g) was treated with 3.5% NaOH (185 ml, 3.5
equivalents), at room temperature to afford a clear solution of the
corresponding Na-salt.
A solution of neat trans-4-isopropylcyclohexanecarboxyl chloride (IPCHAC, 9.02
g, 1.01
equivalent) was added to the solution of Phe-OH obtained above, over 3
minutes, while
stirring at room temperature. The rest of the IPCHAC in the funnel was washed
with
toluene (1 ml) and added. The resulting mixture was stirred for 1 hour, and
was treated
with 10% HCl (32 ml) to adjust the pH to 3, while stirring. The mixture was
stirred for 1
hour, and filtered. The solid was washed with water (200 ml) and sucked well
to afford
33.3 g of the moist product, which lost weight after drying at 78°C/2.2
mbar. Assay
98.4%, purity >99%, yield 86%.
Example 6- This example illustrates preparation of nate~linide by
crystallization from
binary mixtures (solvent/anti-solvent).
Nateglinide (Sg) and an anti-solvent (20 ml) were placed into an Erlenmayer
flask.
The mixture was heated at about 55°C over about 15 minutes, followed by
addition of
solvent in 0.25-1 ml portions until a clear solution was obtained. The clear
solution was
left to crystallize without stirring at room temperature.
If crystallization did not happen or was poor after 24 hours, the solution was
refrigerated at 3-5°C. The precipitate was filtered off (at RT or at
5°C depending on the
temperature of crystallization) to give Form B. The wet material was dried at
50°C under
2o reduced pressure (20-30 mmHg) to give dry Form B.
Table IX. Data on crystallization of NTG from binary solvents
Solvents Ratio,L/S, T~,yst.,TimeWw, Wd,Form Form
v/v ml/g Cf , g g wet dry
h
Toluene- 40:1 4.1 RT-~3 23/237.843.56B B
EtOH
Toluene- 40:1 4.1 3 22/236.823.72E B
MeOH
Toluene-IPA27:1 4.15 RT~3 22/247.833.28 B
Toluene-EA4.2:1 4.95 RT 26 7.274.0 B+H
Toluene-n-20:1 4.2 3 18/253.341.76B B
BuOH
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Toluene-n-27:1 4.15 3 24/715.182.64B B
PrOH
Xylene-EA2:1 6 3 23/729.403.60B B
Heptane-EA1:1.3 9.2 RT 94 3.622.26B+Z B
Heptane-EA1:1.3 9.2 RT 25 4.362.24B B
Hexane-EA1:1.2 8.8 RT 94 5.052.46B B
Hexane-EA1:1.2 8.8 RT 25 2.722.32B B
Toluene- 5.7:1 4.7 3 22/725.562.88B B
acetone
Legehd:
L/S- liquid/solid ratio (liquid= solvent+anti-solvent); f - symbol RT33 means
that
crystallization was started at room temperature then the mixture was cooled to
3°C to
complete precipitation.
Example 7- Preparation of Form delta
(A) This example illustrates preparation of nate~linide Form delta by
crystallization
from an ethyl acetate-heptane solvents s s
Preparation of nate~linide form ~
io D-Phenylalanine (15.44 g) was added all at once to a 3.5% NaOH solution
(370 ml, 3.5
equivalents), at 20°C, under stirring, 230 mini 1. A clear solution was
immediately formed.
A neat traps-4-isopropylcyclohexylcarboxychloride (18.03 g) was added for 5
minutes to
the reaction solution. A solid was formed and the temperature rose to
32°C. The mixture
was stirred for 1 hour at 20°C, under stirring. A 15% H2S04 (56.1 g)
was added all at
once to the reaction mixture to adjust the pH to 1-2. The mixture was stirred
for 1 h at
20°C and the solid product was filtered off to afford cake- 76 g of a
wet product (moisture
65%). The product was dissolved in EA (200 ml), and the aqueous phase was
removed.
The organic phase was concentrated at 50°C under reduced pressure to
afford 104 g of a
turbid solution, containing 95 ml of EA. The solution was filtered and added
for 30
2o minutes to hot heptane (54°C, 250 ml). The initially formed solid
completely dissolved
after addition of 2/3 of the EA solution. The clear solution was allowed to
cool to 25°,
seeded with B-form, and left for crystallization overnight, under stirring at
215 revolutions
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miri 1. The solid was filtered off and washed with heptane (30 ml). The cake
was dried at
60°C120 mbar to afford 6.84 g of the d-form. Yield 33%.
Preparation of nateglinide Form 8
D-Phenylalanine (20.00 g) was added all at once to a 3.5% NaOH solution
(370.12 g, 2.7
equivalents), heated to 35°C, under stirring, 200 miri 1. A clear
solution was immediately
formed. A neat trans-4-isopropylcyclohexylcarboxychloride (23.3 g) was, added
all at
once to the hot reaction mixture for 1 minute. A turbid solution was formed
and the
temperature rose to 40°C. The mixture was stirred for 20 minutes at 40-
43°C under
stirring. An 85% solution of HZS04 (11.94 g) was added all at once to the RM
to adjust
1o pH 1-2. The solid product was extracted with EA (140 ml). The hot organic
extract was
washed with warm water (100 ml), followed by brine (25 ml, 30.0 g) at
40°C, and dried
with anhydrous magnesium sulfate (3.05 g) over 1.5 hours. The organic solution
was
filtered through a PTFE 0.45 p.m filter, heated to 38°C and to which
was added hot
heptane (40°C, 125 ml). The resulting clear solution was gradually
cooled for 45 minutes
to 13°C and seeded with NTG in B-form. The crystallization started. The
mixture was
then cooled for 17 min to 5°C and stirred for 16 h. The solid was
filtered off and washed
with a cold (5°C) mixture of heptane-EA mixture (5:1, total 180 ml) to
afford 36.49 g of a
wet product (wetness 42.5%). The wet product was dried at 60°C/13 mbar
to afford 20.38
g of the product, Form 8, with a purity >99.8%. Yield 55%.
Preparation of nateglinide form S
D-Phenylalanine (20.02 g) was added all at once to a 3.5% NaOH solution (total
410.5 g,
2.99 equivalents), heated to 39°C, under stirring 150 miri 1. A clear
solution was
immediately formed. A neat trans-4-isopropylcyclohexylcarboxychloride (24.73
g) was
added all at once to the hot reaction mixture. The mixture (clear solution)
was stirred for
25 minutes at 44-45°C, under stirring. Ethyl acetate (140 ml), followed
by an 85%
solution of HzS04 (14.08 g) were added all at once to the reaction mixture to
adjust the pH
to 1-2. The hot organic layer was separated, washed twice with water (100 ml)
at 30°C,
and filtered through a PTFE 0.45 p.m filter. The clear solution (141 g) was
heated to 46°C
and to which was added hot heptane (46°C, 153 ml), under stirring at 1
SO miri 1. The
3o clear solution was gradually cooled to 28°C and seeded with Form
delta. The
crystallization occurred at 24°C. The mixture was stirred for 30
minutes at 24°C,
gradually cooled to S°G and stirred overnight at 5°C. The solid
was filtered off and
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washed with a cold (5°C) heptane-EA mixture (6:1, total 30 ml) to
afford 49.1 g of a wet
product in form delta (wetness 50%). The wet product was dried for 24 h at
23°C/20 mbar
to afford 24.65 g of the product in a form delta with a purity >99.8%. Yield
65%.
(B) This example illustrates thepreparation of form ~ crystallization
Crude nateglinide (50 grams) was dissolved in ethyl acetate (200 ml) and water
(2.5 ml) at
45°C. Hot heptane (260 ml) at 50°C was added. The mixture was
still fully dissolved.
The mixture was cooled to 30°C and seeded with nateglinide Form 8 (0.1
grams). The
mixture was stirred for 30 minutes and then cooled to less than 10°C in
2 hours. The
mixture was stirred at 5-10°C overnight and then filtered with vacuum.
The wet product
to was washed with ethyl acetate (100 ml) heptane mixture (ratio 1:3 v/v). The
wet product
was dried in a vacuum oven at 50°C overnight. Both the wet and dry
samples were Form
s.
Starting material: Wet nateglinide (40% total wetness. 2 ml water, 10 ml ethyl
acetate, 21
ml of heptane). Wet crude nateglinide (~3 grams) and dry nateglinide (50
grams) were
dissolved in ethyl acetate (190 ml) at 45°C. Hot heptane (239 ml) at
50°C was added.
The solution was cooled to 30°C and a seeded with nateglinide (0.1
grams) Form 8. The
mixture was stirred for 30 minutes and then cooled to less than 10°C in
2 hours. The
mixture was stirred at 5-10°C overnight and then filtered with vacuum.
The wet product
was washed with ethyl acetate-heptane mixture (100 ml) (ratio 1:3 v/v). The
wet product
2o was dried in a vacuum oven at 50°C overnight. Both the wet and dry
samples were Form
s.
(C) This example illustrates the dryin~ of form 8 by fluidized bed dryer
Nateglinide Form delta (10 grams), with about 3 % heptane (wt/wt), was dried
in a
fluidized bed drier for 4 hours at 60°C. Residual heptane was 1578 ppm
af. Ethyl acetate
is under detection limit. Polymorphic form of the dry product is delta.
According to these procedures, a series of experiments were carried out under
various heptane/ethyl ratios, liquidlsolid ratios, temperature and seeding.
The results are
summarized in Table X:
3o Table X. Data on crystallization of NTG in EA-Heptane solvents system
Seed Anti- Ratio L/S, TemperatureYield, Form Form
ml/g %
solventv/v profile wet dry
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None Hexane 2.7:1 11 40(1)20(16) 58' Z B+Z
None Heptane4:1 16 40(1)20(16) 64 Z B
None Heptane5:1 11 40(1)20(16) 74 H H
None Heptane4.7:1 11 40(1)20(16) 68 H H
None Heptane7.5: 11 40(1)20(16) 48 B B
None Heptane5:1 8 40(1)20(16) 72 H
None Heptane6:1 10 60(0.1)20(16)76 B B
None Heptane7.1:1 11 20(16) 78 H H
B Heptane5.1:1 14 5(1.5)5(1) 77 H H
B Heptane2.5:1 16 5(2)-j5(1) 74 H H
B Heptanel:l 7.5 165(16) 51
B Heptanel:l 7 30(1)5(16) 58
B Heptane1:1 7.6 13(1)-5(16) 59
B Heptane1:1 7.4 13(1)-35(16)55 8 b
B Heptane2:1 9 30(0.5)-X5(1)76 H+U
5(1)-j5(16) 8
B Heptane1.5:1 7.5 32(0.5)5 71 U
5(1) U
5(1)5(16) 8
None Heptane2:1 10 31(0.5)-35(4.5)67 8
None Heptane1:1 9(0.5)5(1) 8 B
5(1)-5(16) g
Heptane1:1 7.8 9(0.5)5(16) 46 ~ g
B Heptane1.1:1 6.1 25(0.5)5(16)63
Heptane1:1 7 19(0.5)-5(16)54 8 S
B Heptane1:1 7.6 13 (0.5)5 52 8 8
(16)
b Heptane1:1 6.1 30(0.5)5(16)55 8 b
Temperature profile: crystallization temperature (h)-j~nal temperature (h);
L,t-
amount of L,trans-isomer.
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Example 8 This example illustrates preparation of forms of nate lig ~iude by
precipitation
without ~oin~ to solution after combining
Preparation of Nate~linide form U
D-Phenylalanine (20.02 g) was added all at once to a 3.5% NaOH solution
(369.73 g, 2.7
equivalents), at 20°C, under stirring, 200 revolutions miri ~. A clear
solution was
immediately formed. A neat trans-4-isopropylcyclohexylcarboxychloride (23.9 g)
was
added all at once to the hot reaction solution for 1 minute. A solid was
formed and the
temperature rose to 32°C. The mixture was stirred for 40 minutes at
20°C, under stirring.
An 85% solution of HZS04 (11.55 g) was added all at once to the reaction
mixture to
1o adjust the pH to 1-2. The solid product was extracted with EA (150 ml) at
55°C for 55
minutes. The hot organic extract was washed with warm water (100 ml), followed
by
brine (40°C, 50 ml), dried with anhydrous sodium sulfate (10 g) over
1.5 h, and filtered.
The excess of EA was removed under reduced pressure to afford 86 g of the
solution,
containing ~54 g (60 ml) of EA. The EA solution was finally filtered through a
PTFE
15 0.45 wm filter into a clean dropping funnel heated to 35°C. Heptane
(320 ml) was placed
into the reactor; cooled to 5°C, and seeded with B-form. The clear hot
EA-solution was
added for 5 minutes to the cold heptane, under stirring. Precipitation
immediately
happened to afford a solid. The mixture was stirred for 2.5 hours at
5°C. The solid was
filtered off and washed with a cold (5°C) mixture of heptane-EA mixture
(4.5:1, total
20 120 ml) to afford 63.62 g of a wet product (wetness 54%). The cake (62.4 g)
was dried
at 60°C/10 mbar to afford 28.6 g of the product, containing ~0.6% of
L,trans-isomer (other
impurities <0.1%) in the U-form. Yield 77%.
Table XI. Data on crystallization of NTG during the crystallization process
(precipitation without going into solution after combining)
Seed Anti- RatioL/S, TEA, TAS(time),YielL,t,Form Form
solventv/v ml/g C C(h) d, % wet dry
B Heptane3.7:117 25 55(25) 33 0.058
None Heptane5.4:112 40 5(2.5) 77 0.7 U U
None Heptane0.77:19.7 45 45325(1) 71 0.01B+U
25(1)25(22) 2 U U
None Heptane0.8:19.7 45 45-j25(21)72 0.03a a
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TEA - temperature of the EA solution; TAS(time) - temperature of anti-solvent
(exposure
time)-~final temperature (exposure time); L,t- amount of L,trans-isomer.
Example 9- Heating of nate~linide Form U
Sample of nateglinide form U (Nl g) was introduced into a 6-gram vial and
heated over
8.5 h in a 100°C oil bath. The vial were extracted from the bath. The
resulted sample
showed Form U by XRPD.
Sample of nateglinide form U (N0.5 g) was heated to 120°C for lh in an
atmospheric
pressure. The resulted sample showed Form U by XRPD.
Example 10- heating of nateglinide Form 8
Sample ofnateglinide form & (~0.5 g) was heated to 120°C for lh in an
atmospheric
pressure. The resulted sample showed Form B by XRPD.
Example 11- Preparation of Form Omega
Nateglinide Form delta (5 grams) was dissolved in isopropanol (15 ml) at room
is temperature. The solution was cooled to ~ 0°C. Water (6 ml) was
added. A white solid
precipitated suddenly. The solid was heated to 35 °C, resulting in
complete dissolution.
The solution was cooled to ~7°C and the product precipitated. The
product was filtered
with vacuum. XRPD confirmed the presence of Form omega.
Example 12- Dryin~ of a wet sample of Form Omega
2o The product of example 11 was dried at 50°C in a vacuum oven
overnight, and analyzed
by XRD. A mixture of Form omega and Form Z was obtained.
Example 13- This example illustrates the preparation of Form U by trituratin~
form 8 in
Ethyl-Acetate
Nateglinide Form ~ (5 grams) was triturated in ethyl acetate (10 ml) at 25
°C for 2 hours.
25 The wet material was filtered with vacuum and washed with ethyl acetate (10
ml). The
wet product was dried at 50°C in a vacuum oven overnight. The wet and
dry products
were Form U.
Example 14- This example illustrates the preparation of form B by trituratin~
Form 8 in
ethyl-acetate
30 Nateglinide Form 8 (5 grams) was triturated in ethyl acetate (10 ml) at
50°C for 1 hour.
The mixture was cooled to 20°C and triturated for 1 hour. The wet
material was filtered
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with vacuum and washed with ethyl acetate (lOml). The wet product was dried at
50°C in
a vacuum oven overnight. The wet and dry products were obtained as Form B.
Example 15- Process for the Preparation of Nate~linide Form B
Nateglinide Form B may also be obtained by precipitation of nateglinide Form
G,
from isopropanol followed by conversion of Form G to Form B. In this
embodiment, a
form of nateglinide, such as nateglinide Form ~ (about 3% LOD) is dissolved in
a mixture
of IPA/H20 at a preferred temperature range of about 40 to about 50 °
C. Preferably, the
IPA concentration in the solvent mixture is in the range of about 50% to about
70% (v/v),
and the volume of the solvent mixture is about 5 to about 20 volumes/unit
weight of
nateglinide.
The solution obtained after dissolution is preferably cooled to a temperature
of
about 30°C for seeding with crystals of Form B. The seeded solution is
preferably stirred
at the seeding temperature for about 30 minutes to about 3 hours. The solution
is
preferably then cooled to about 0 °C plus/minus 5 °C for at
preferably least about 5 hours,
and preferably stirred at 5 °C for at least about 30 minutes. The
precipitated nateglinide
crystals may be recovered and dried under reduced pressure at a preferred
temperature of
about 70 to about 90°C to obtain nateglinide Form B.
In this embodiment, before crystallization, the starting material may
optionally be
dissolved in IPA or in a IPA/H2O mixture (in the same solvent ratio as the
crystallization
2o mixture), followed by evaporation under reduced pressure. After the
evaporation,
IPAlH2O mixture is fed into the reactor to obtain a solution. Nateglinide Form
B is
obtained after the evaporation.
The use of IPA allows for the elimination of methyl esters as impurities in
the final
product as illustrated in Figure 64.
Example 15 (Al_
Nateglinide (40 grams) was dissolved in IPA (240 ml) at 25 °C. The
solution was filtered
to remove insoluble materials. The clear solution was heated to 50°C
and stirred for 5
hours. After stirring, the solvent was evaporated under reduced pressure. The
residue was
tested by XRD and found to be B type.
3o Example 1 S Bl
Nateglinide (30 grams) was dissolved in IPA (150 ml) in a reactor. The solvent
was
evaporated under reduced pressure at a jacket temperature Tj=50°C. A
solution was
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obtained by feeding the reactor with IPA (150 ml) and water (150 ml) were fed
at
Tj=50°C. The clear solution obtained, was cooled to TR=29.4°C,
and seeded by B type
crystals. The seeded solution was stirred at TR=29.4°C for additional 3
hours, and
afterwards cooled to TR=0°C for 10 hours. At 0°C, the resulting
slurry was stirred for
additional 5 hours (over-night). The crystals were isolated and dried under
reduced
pressure at 90 °C. The wet crystals were tested by XRD and found to be
G type. The
dried crystals were tested by XRD and found to be B type.
Example 15 (C)
Nateglinide (20 grams) was dissolved in IPA (200 ml) in a round bottom flask
and the
to solvent was evaporated under reduced pressure at a temperature of 50
°C. IPA (200 ml)
and water (200 ml) were fed into the round bottom flask to obtain a clear
solution. The
solution was transferred to a reactor and cooled to a temperature of TR=28
°C. At 28 °C,
the solution was seeded with type B crystals.
The seeded solution was stirred at 28°C for an additional 2 hours, and
afterwards cooled
15 to 5 ° C for 10 hours. At 5 ° C, the solution was stirred for
an additional 4 hours (over-
night). The product was isolated and dried under reduced pressure at 90
° C. The wet
crystals were tested by XRD and found to be G type. The dried crystals were
tested by
XRD and found to be B type.
Example 16 Process for the Preparation of Nate~linide Form B by Trituration in
Water
2o Nateglinide Form S was triturated in 5 volumes water at about 25 °C
for about 7 hours.
The crystals were isolated and dried under reduced pressure at 90
°C
Example (A): Trituration of wet starting material
50 gr Nateglinide form 8 wet (about 37% LOD) was triturated in 250 ml water at
25 °C.
After 4 hrs trituration, the slurry was sampled and dried under reduced
pressure at 90°C.
25 The wet crystals were tested by XRD and found to be ~ type. The dry
crystals were tested
by XRD and found to be B type. After 7 hours of trituration, the product was
isolated and
dried under reduced pressure at 90°C. The wet crystals were tested by
XRD and found to
be 8 type. The dry crystals were tested by XRD and found to be B type.
Example (B): Trituration of dry starting material
30 50 gr Nateglinide form 8 dry was triturated in 250 ml water at 25
°C. After 4.5 hrs
trituration, the slurry was sampled and dried under reduced pressure at
90°C. The wet
crystals were tested by XRD and found to be Z type. The dry crystals were
tested by XRD
CA 02492644 2005-O1-17
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and found to be B type. After 7.5 hours of trituration, the product was
isolated and dried
under reduced pressure at 90 ° C. The wet crystals were tested by XRD
and found to be E
type. The dry crystals were tested by XRD and found to be B type.
Example 17- Preparation of Nate~linide form U
Example (A): Crystallization from Acetone
Nateglinide (50 grams) Form S was dissolved in acetone (175 ml) at
42°C. The clear
solution was cooled to 10 ° C for seeding. After seeding with type B
crystals, the seeded
solution was stirred for an additional 3 hours at a temperature of 10°C
and cooled to -
10°C for 10 hours, and stirred at -10°C over night. The crystals
were isolated and dried at
l0 90 ° C. The wet crystals were tested by XRD and found to be U type.
The dry crystals were
tested and found to be U type.
Example (B): Crystallization from Ethyl Acetate
Nateglinide (20 grams) were dissolved in ethyl acetate (560 ml) at
40°C. The solution
was filtered to remove insoluble matter. The clear solution was evaporated
under reduced
15 pressure, and Ethyl Acetate (460 ml) was evaporated (the solvent volume in
the reactor
was 5 volumeslunit weight Nateglinide). The solution was cooled to 20°C
and seeded
with type B crystals. The seeded solution was stirred at 20 °C for an
additional 30
minutes, cooled to 0°C for 1.5 hours, and stirred at 0°C for an
additional 30 minutes. The
crystals were isolated and dried under reduced pressure at 30°C,
50°C, 90°C. The wet
2o crystals were tested by XRD and found to be U type. The dry crystals were
tested by
XRD and found to be U type.
Example 18- Removal of residual solvent from Form delta
Nateglinide (40 grams) Form delta (1.5% heptane) was dried in a stirred
reactor (7-10
rpm) under 60 mmHg vacuum and at 60 ° C. After 6 hours of drying, the
residual solvent
25 of the material was 613 ppm of heptane. The polymorph of the dried material
remained
delta form, as the starting material.
Example 19- Preparation of nate~linide Form B from ethyl acetate
Nateglinide form 8 is dissolved in ethyl acetate at 25 °C. The solvent
is evaporated under
reduced pressure, until turbidity appears. The turbid solution is cooled to
0°C plus/minus
30 5 °C for 1 hour and stirred for 1 hour. The product was isolated and
dried under reduced
pressure at 50°C.
Example (A)
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Nateglinide (12 grams) Form 8 was dissolved in 165 ml of ethyl acetate at 25
°C.
The solvent was evaporated under reduced pressure at 25 °C, until
turbidity appeared. At
the end of evaporation, the volume in the reactor was 90-95 ml. The mixture
was cooled
from 25 °C to 5 °C for 1 hour and stirred at 5 °C for 1
hour. The product was isolated and
s dried under reduced pressure at 50°C. Both the wet and the dry
crystals were tested by
~~RD and DSC and found to be B type.
Having thus described the invention with reference to particular preferred
embodiments and illustrative examples, those in the art may appreciate
modifications to
the invention as described and illustrated that do not depart from the spirit
and scope of the
1o invention as disclosed in the specification. The Examples are set forth to
aid in
understanding the invention but are not intended to, and should not be
construed to, limit
its scope in any way. The examples do not include detailed descriptions of
conventional
methods. Such methods are well known to those of ordinary skill in the art and
are
described in numerous publications. Polymorphism in Pharmaceutical Solids,
Drugs and
15 the Pharmaceutical Sciences, Volume 95 may be used as a guidance. All
references
mentioned herein are incorporated in their entirety.
25
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