U.S. patent application number 12/150062 was filed with the patent office on 2008-12-25 for polymorphic forms of nateglinide.
Invention is credited to Ben-Zion Dolitzky, Boaz Gome, Igal Gozlan, Evgeny Shapiro, Shlomit Wizel, Ronit Yahalomi.
Application Number | 20080319075 12/150062 |
Document ID | / |
Family ID | 32966935 |
Filed Date | 2008-12-25 |
United States Patent
Application |
20080319075 |
Kind Code |
A1 |
Yahalomi; Ronit ; et
al. |
December 25, 2008 |
Polymorphic forms of nateglinide
Abstract
Provides are crystalline forms of nateglinide, labeled Forms A,
C, D, F, G, I, J, K, L, M, N, O, P, Q, T, U, V, Y, .alpha., .beta.,
.gamma., .delta., .epsilon., .sigma., .theta. and .OMEGA.,
processes for their preparation and processes for preparation of
other crystalline forms of nateglinide. Also provided are their
pharmaceutical formulations and methods of administration.
Inventors: |
Yahalomi; Ronit; (Kiryat
Bialik, IL) ; Shapiro; Evgeny; (Haifa, IL) ;
Dolitzky; Ben-Zion; (Petach Tiqva, IL) ; Gozlan;
Igal; (Haifa, IL) ; Gome; Boaz;
(Rishon-Lezion, IL) ; Wizel; Shlomit; (Petah
Tiqva, IL) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
32966935 |
Appl. No.: |
12/150062 |
Filed: |
April 23, 2008 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10622905 |
Jul 18, 2003 |
7420084 |
|
|
12150062 |
|
|
|
|
Current U.S.
Class: |
514/563 ;
562/450 |
Current CPC
Class: |
C07C 233/63 20130101;
A61K 31/198 20130101; C07C 231/24 20130101; C07B 2200/13 20130101;
A61K 31/16 20130101; C07C 231/02 20130101; C07C 2601/14 20170501;
C07C 51/60 20130101; C07C 51/60 20130101; C07C 231/24 20130101;
C07C 231/02 20130101; C07C 61/08 20130101; C07C 233/63 20130101;
C07C 233/63 20130101 |
Class at
Publication: |
514/563 ;
562/450 |
International
Class: |
A61K 31/195 20060101
A61K031/195; C07C 229/36 20060101 C07C229/36 |
Claims
1. A crystalline form of nateglinide (Form L) characterized by data
selected from the group consisting of: an XRPD pattern with peaks
at 17.6, 17.9 and 19.6.+-.0.2 degrees 2.theta., a DSC thermogram
with endotherms at about 131 and 138.degree. C. and an FTIR
spectrum with peaks at about 1741, 1726, 1621, 1600, 1538, 1211,
1191 cm.sup.-1.
2. The crystalline form of claim 1, wherein the crystalline form is
characterized by an XRPD pattern with peaks at 17.6, 17.9 and
19.6.+-.0.2 degrees 2.theta..
3. The crystalline form of claim 2, wherein the crystalline form
has an XRPD pattern as substantially depicted in FIG. 10.
4. The crystalline form of claim 1, wherein the crystalline form is
stable when heated at a temperature of about 100.degree. C. for at
least about 8 hours.
5. A process for preparing nateglinide of claim 1 comprising the
step of heating a nateglinide selected from the group consisting of
Form D, M and N for a sufficient amount of time to obtain the
nateglinide of claim 1.
6. A process for preparing nateglinide of claim 1 comprising the
step of storing nateglinide Form I at a suitable temperature for a
sufficient time to obtain the nateglinide of claim 1.
7. A crystalline form of nateglinide (Form P) characterized by data
selected from the group consisting of: an XRPD pattern with peaks
at 4.0, 4.6, 13.4, 13.9 and 19.1.+-.0.2 degrees 2.theta.; an FTIR
spectrum with peaks at about 3309, 1748, 1589 cm.sup.-1; and a DSC
thermogram with endotherms at about 106 and 128.degree. C. and an
exotherm at about 113.degree. C.
8. The crystalline form of claim 7, wherein the crystalline form is
characterized by an XRPD pattern with peaks at 4.0, 4.6, 13.4, 13.9
and 19.1.+-.0.2 degrees 2.theta..
9. The crystalline form of claim 8, wherein the crystalline form
has an XRPD pattern as substantially depicted in FIG. 14.
10. A process for preparing the crystalline nateglinide of claim 7
comprising the steps of: a) triturating nateglinide in a solvent
selected from the group consisting of acetone, nitromethane and
acetonitrile to obtain the crystalline form of claim 7, with the
proviso that the nateglinide triturated in nitromethane is not Form
H; and b) recovering the crystalline form of nateglinide.
11. The process of claim 10, wherein the nateglinide triturated is
Form H and the solvent is acetonitrile.
12. The process of claim 10, wherein the nateglinide triturated is
Form U and the solvent is acetone or nitromethane.
13. A process for preparing nateglinide of claim 7 comprising the
step of heating nateglinide Form epsilon for a sufficient amount of
time at a suitable temperature.
14. A crystalline form of nateglinide (Form .alpha.) characterized
by data selected from the group consisting of: an XRPD pattern with
peaks at 4.8, 5.1, 19.0, 19.4, 27.2, 28.9 and 31.2.+-.0.2 degrees
2.theta.; a DSC thermogram with an endotherm at about 129.degree.
C.; and an FTIR spectrum with peaks at about 3283, 1711, 1646,
1420, 1238 cm.sup.-1.
15. The crystalline form of nateglinide of claim 14, wherein the
crystalline form is characterized by an XRPD pattern with peaks at
4.8, 5.1, 19.0, 19.4, 27.2, 28.9 and 31.2.+-.0.2 degrees
2.theta..
16. The crystalline form of claim 15, wherein the crystalline form
has an XRPD pattern as substantially depicted in FIG. 21.
17. The crystalline form of claim 14, wherein the crystalline form
is stable when heated to a temperature of about 60.degree. C. for
about 8 hours.
18. A process for preparing crystalline nateglinide of claim 14
comprising the steps of: a) triturating nateglinide in a solvent
selected from the group consisting of methanol, n-butanol and
ethanol to obtain the crystalline form of claim 14, with the
proviso that the nateglinide triturated is not Form H; and b)
recovering the nateglinide Form .alpha..
19. The process of claim 18, wherein the nateglinide triturated is
Form U.
20. A process for preparing crystalline form of nateglinide of
claim 14 comprising the steps of: a) preparing a solution of
nateglinide in a solvent selected from the group consisting of
n-propanol, n-butanol, isopropyl alcohol and acetonitrile; b)
crystallizing the crystalline form from the solution; and c)
recovering the crystalline form of claim 14.
21. A process for preparing crystalline nateglinide of claim 14
comprising the step of heating a form of nateglinide selected from
the group consisting of Form K and Form C for a sufficient time to
obtain the crystalline form.
22. A process for preparing a mixture of crystalline nateglinide
Form .alpha. and Form H comprising the step of triturating a
nateglinide in a solvent selected from the group consisting of
methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl
ketone and dimethyl ethane.
23. The process of claim 22, wherein the nateglinide triturated is
crystalline Form U.
24. A pharmaceutical formulation comprising a crystalline form
selected from the group consisting of nateglinide Form L, P, alpha,
and a pharmaceutically acceptable excipient.
25. A method for lowering blood sugar level in a mammal comprising
administering the pharmaceutical formulation of claim 24 to the
mammal.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. patent
application Ser. No. 10/622,905, filed Jul. 18, 2003, claims the
benefit of U.S. provisional application Ser. Nos. 60/396,904 filed
Jul. 18, 2002; 60/413,622, filed Sep. 25, 2002; 60/414,199, filed
Sep. 26, 2002; 60/423,750, filed Nov. 5, 2002; 60/432,093, filed
Dec. 10, 2002; 60/432,962, filed Dec. 12, 2002; 60/442,109, filed
Jan. 23, 2003; 60/449,791, filed Feb. 24, 2003; and 60/479,016,
filed Jun. 16, 2003, the contents of all of which are incorporated
herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to the solid state chemistry
of nateglinide.
BACKGROUND OF THE INVENTION
[0003] Nateglinide, known as
(-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-Phenylalanine, has
the following structure and characteristics:
TABLE-US-00001 ##STR00001## Formula C.sub.19H.sub.27NO.sub.3
Molecular Weight 317.42 Exact Mass 317.199093 Composition C 71.89%
H 8.57% N 4.41% O 15.12%
[0004] Nateglinide is marketed as STARLIX, which is prescribed as
oral tablets having a dosage of 60 mg and 120 mg 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 soluble in methanol, ethanol, and chloroform,
soluble in ether, sparingly soluble in acetonitrile and octanol,
and practically insoluble in water.
[0005] 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 Applicant(s) as Form Z, or in a methanolate
labeled by the Applicant(s) as Form E. Drying of the wet sample
results in Form B.
[0006] 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 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.
[0007] 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 liquid
medicaments. The solid state Form of a compound may also affect its
behavior on compaction and its storage stability.
[0008] 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 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,
solid state C NMR spectrometry and infrared spectrometry.
[0009] Nateglinide exists in various crystalline forms. U.S. Pat.
Nos. 5,463,116 and 5,488,150 disclose two crystal forms of
nateglinide, designated B-type and H-type, and processes for their
preparation. These patents are incorporated herein by reference for
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.degree. C. while H-type has a
melting point of 136-142.degree. 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.+-.0.2 degrees 2.theta., and a strong
reflection between 15 and 17.+-.0.2 degrees 2.theta.. The B-type
crystal is reported to lack these peaks and have a weak reflection
between 15 and 17.+-.0.2 degrees 2.theta.. H-type crystals are
reported to have an IR spectrum with characteristic absorptions at
about 1714, 1649, 1542 and 1214 cm.sup.-1. These absorptions are
reported to be missing in the spectrum of B-type crystals.
[0010] 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.degree. C. before grinding while that of H-type shows a sharp
endotherm at 140.3.degree. C. After grinding, the DSC thermogram of
B-type shows a second endotherm at 138.2.degree. C., suggesting a
solid-solid transformation during grinding.
[0011] 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 EC, more preferably
above 15.degree. C., lead to formation of H-type, while those below
10.degree. C. lead to formation of B-type.
[0012] 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 distinguishable from Forms B and H by a melting
point of 172.0.degree. C., a Fourier Transform IR with a peak at
3283 cm.sup.-1 (as supposed to 3257 cm.sup.-1 and 3306 cm.sup.-1
for Forms B and H respectively) and an XRPD pattern with a strong
peak at 3.78.+-.0.2 degrees 2.theta..
[0013] 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 water, followed by crystallization, as
disclosed in Example B-3 of the '116 patent.
[0014] 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 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.
[0015] WO 02/34713, 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.degree. C. and allowed to mature at
5.degree. C. for one hour. The deposited crystals were separated
and damp crystals (43.0 kg) obtained. These were dried at
45.degree. C. in a rack drier for 24 hours (water content ca. 1%)
and then heated for 12 hours at 90.degree. 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 EC) but the characteristic H-form
peak (mp ca. 139.degree. C.) was not detected. Hence the crystals
obtained were of the B-form only and the H-form was concluded to be
essentially absent."
[0016] 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 solvent disappears.
The temperature for this will differ depending on the type and
quantity of solvent, but usually lies below 60.degree. C. and
preferably below 50.degree. C. Although there is no lower limit to
the temperature, [the drying] is usually carried out at 20.degree.
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.degree. C., preferably
70-100.degree. C., a crystal transformation into the B-form is
brought about. Though the crystal transformation is usually
favorably carried out in 0.5 to 48 hours, a period of 1-24 hours is
most favored."
[0017] Another PCT publication, WO 03/022251 discloses a
crystalline form of nateglinide labeled "AL-type". The crystalline
form is characterized as having a melting point of 174-178.degree.
C., an XRPD pattern with peaks at 7.5, 15.5, 19.8 and 20.2 degrees
2.theta., 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.sup.-1.
The crystalline form is obtained in the examples from a solution of
acetonitrile under a specific temperature range.
[0018] Processes for preparation of nateglinide are disclosed in
WO/0232854.
[0019] 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
[0020] 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, .alpha.(alpha), .beta. (beta), .gamma. (gamma),
.delta. (delta), .epsilon. (epsilon), .sigma. (sigma), .theta.
(theta) and .OMEGA. (omega).
[0021] 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-butanol--"n-BuOH"), J
(N-methylpyrrolidone--"NMP"), K (dimethylformamide--"DMF"), M
(carbon tetrachloride--"CTC"), N (dichloroethane--"DCE"), O
(methanol), Q (chloroform--"CHCl.sub.3"), T (methanol), V
(dimethoxyethane--"DME"), Y (chloroform; dichloromethane), .beta.
(N-methylpyrolidone), .gamma. (N-methylpyrolidone) and .epsilon.
(acetone; acetonitrile--"MeCN"; nitromethane--"NM") and .theta.
(heptane). Form Z is a hydrate, having water in the crystalline
structure. Form .OMEGA. is a solvate of both water and isopropyl
alcohol.
[0022] 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,
.alpha., .delta. and .sigma..
[0023] The XRPD pattern of these forms as substantially depicted is
disclosed in FIGS. 1-27 and 63, with the characteristic peaks
listed in Table I. The DSC thermograms for the forms is disclosed
in FIGS. 36 to 62, and the characteristic DSC peaks are listed in
Table II. The FTIR spectrum of the anhydrate 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 solvent/anti-solvent
system is listed in Tables IX-XI. FIG. 28 summarizes the thermal
stability of the various forms.
[0024] The present invention also provides for pharmaceutical
formulations of the various crystalline forms and their
administration.
BRIEF DESCRIPTION OF THE FIGURES
[0025] FIG. 1 is an XRPD pattern for nateglinide Form A.
[0026] FIG. 2 is an XRPD pattern for nateglinide Form C.
[0027] FIG. 3 is an XRPD pattern for nateglinide Form D.
[0028] FIG. 4 is an XRPD pattern for nateglinide Form E.
[0029] FIG. 5 is an XRPD pattern for nateglinide Form F.
[0030] FIG. 6 is an XRPD pattern for nateglinide Form G.
[0031] FIG. 7 is an XRPD pattern for nateglinide Form I.
[0032] FIG. 8 is an XRPD pattern for nateglinide Form J.
[0033] FIG. 9 is an XRPD pattern for nateglinide Form K.
[0034] FIG. 10 is an XRPD pattern for nateglinide Form L.
[0035] FIG. 11 is an XRPD pattern for nateglinide Form M.
[0036] FIG. 12 is an XRPD pattern for nateglinide Form N.
[0037] FIG. 13 is an XRPD pattern for nateglinide Form O.
[0038] FIG. 14 is an XRPD pattern for nateglinide Form P.
[0039] FIG. 15 is an XRPD pattern for nateglinide Form Q.
[0040] FIG. 16 is an XRPD pattern for nateglinide Form T.
[0041] FIG. 17 is an XRPD pattern for nateglinide Form U.
[0042] FIG. 18 is an XRPD pattern for nateglinide Form V.
[0043] FIG. 19 is an XRPD pattern for nateglinide Form Y.
[0044] FIG. 20 is an XRPD pattern for nateglinide Form Z.
[0045] FIG. 21 is an XRPD pattern for nateglinide Form .alpha..
[0046] FIG. 22 is an XRPD pattern for nateglinide Form .beta..
[0047] FIG. 23 is an XRPD pattern for nateglinide Form .gamma..
[0048] FIG. 24 is an XRPD pattern for nateglinide Form .delta..
[0049] FIG. 25 is an XRPD pattern for nateglinide Form
.epsilon..
[0050] FIG. 26 is an XRPD pattern of nateglinide Form .sigma..
[0051] FIG. 27 is an XRPD pattern of nateglinide Form .theta..
[0052] FIG. 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.
[0053] FIG. 29 is an FTIR spectrum of nateglinide Form L.
[0054] FIG. 30 is an FTIR spectrum of nateglinide Form P.
[0055] FIG. 31 is an FTIR spectrum of nateglinide Form U.
[0056] FIG. 32 is an FTIR spectrum of nateglinide Form Z.
[0057] FIG. 33 is an FTIR spectrum of nateglinide Form .alpha..
[0058] FIG. 34 is an FTIR spectrum of nateglinide Form .delta..
[0059] FIG. 35 is an FTIR spectrum of nateglinide Form .sigma..
[0060] FIG. 36 is a DSC thermogram of nateglinide Form A.
[0061] FIG. 37 is a DSC thermogram of nateglinide Form D.
[0062] FIG. 38 is a DSC thermogram of nateglinide Form E.
[0063] FIG. 39 is a DSC thermogram of nateglinide Form F.
[0064] FIG. 40 is a DSC thermogram of nateglinide Form G.
[0065] FIG. 41 is a DSC thermogram of nateglinide Form I.
[0066] FIG. 42 is a DSC thermogram of nateglinide Form J.
[0067] FIG. 43 is a DSC thermogram of nateglinide Form K.
[0068] FIG. 44 is a DSC thermogram of nateglinide Form L.
[0069] FIG. 45 is a DSC thermogram of nateglinide Form M.
[0070] FIG. 46 is a DSC thermogram of nateglinide Form N.
[0071] FIG. 47 is a DSC thermogram of nateglinide Form O.
[0072] FIG. 48 is a DSC thermogram of nateglinide Form P.
[0073] FIG. 49 is a DSC thermogram of nateglinide Form Q.
[0074] FIG. 50 is a DSC thermogram of nateglinide Form T.
[0075] FIG. 51 is a DSC thermogram of nateglinide Form U.
[0076] FIG. 52 is a DSC thermogram of nateglinide Form V.
[0077] FIG. 53 is a DSC thermogram of nateglinide Form Y
(chloroform solvate).
[0078] FIG. 54 is a DSC thermogram of nateglinide Form Y
(dichloromethane solvate).
[0079] FIG. 55 is a DSC thermogram of nateglinide Form Z.
[0080] FIG. 56 is a DSC thermogram of nateglinide Form .alpha..
[0081] FIG. 57 is a DSC thermogram of nateglinide Form .beta..
[0082] FIG. 58 is a DSC thermogram of nateglinide Form .delta..
[0083] FIG. 59 is a DSC thermogram of nateglinide Form
.epsilon..
[0084] FIG. 60 is a DSC thermogram of nateglinide Form .gamma..
[0085] FIG. 61 is a DSC thermogram of nateglinide Form .sigma..
[0086] FIG. 62 is a DSC thermogram of nateglinide Form 2.
[0087] FIG. 63 is a XRPD pattern of nateglinide Form .OMEGA..
[0088] FIG. 64 is a determination of purity of Form B prepared by
Example 15.
DETAILED DESCRIPTION OF THE INVENTION
[0089] In one aspect, the present invention provides for 26
crystalline forms of nateglinide ("NTG"), denominated Form A, C, D,
F, G, I, J, K, L, M, N, O, P, Q, T, U, V, Y, .alpha., .beta.,
.gamma., .delta., .epsilon., .sigma., .theta. and .OMEGA.. 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.
[0090] The various crystalline forms are characterized by their
XRPD pattern, which 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 FIGS. 1-27
and 63.
TABLE-US-00002 TABLE I XRPD characteristic peaks for the
nateglinide crystalline forms Characteristic XRD peaks- Within
about .+-.0.2 degrees Crystal Form 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) 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) K 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. 11)
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) .alpha. 4.8, 5.1, 19.0, 19.4, 27.7, 28.9, 31.2
(FIG. 21) .beta. 4.6, 9.4, 13.9, 18.8 (FIG. 22) .gamma. 4.4, 8.9,
18.4, 18.8, 19.5 (FIG. 23) .delta. 5.6, 14.5, 18.2, 18.9, 19.5
(FIG. 24) .epsilon. 4.2, 13.0, 13.6, 14.3, 16.2, 16.7, 19.6 (FIG.
25) .theta. 4.8, 7.8, 15.5, 17.7 (FIG. 27) .sigma. 5.5, 6.1, 6.7,
14.3 (FIG. 26) .OMEGA. 4.5, 7.8, 15.5, 16.9, 17.8, 19.2, 19.7 (FIG.
63)
[0091] The various crystalline forms of nateglinide are also
characterized by their DSC thermograms. 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.degree. C. followed by an endotherm at about 174.degree. C.,
probably due to recrystallization into S-Type Form.
TABLE-US-00003 TABLE II DSC peaks of the nateglinide crystalline
forms Crystal Form DSC Peaks (EC) 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. 55) 90 95 .alpha. (FIG. 56) 129 -- -- -- .beta.
(FIG. 57) 91 100 -- -- .gamma. (FIG. 60) 93 136 -- -- .delta. (FIG.
58) 100 107 (exotherm) 130 -- .epsilon. (FIG. 59) 64 108 129 --
.sigma. (FIG. 61) -- -- -- 127 .theta. (FIG. 62) 70 104 115 130
(exo)
[0092] 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, Y, Z, .beta., .gamma.,
.epsilon., .theta. and .OMEGA. 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,
.alpha., .delta. and .sigma. show no significant weight loss. These
polymorphic forms of nateglinide 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.
[0093] 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 represented by
formula NTG3/2 EtOH. Specifically, the solvate is nateglinide Form
D.
[0094] 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 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.
[0095] 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
nateglinide Form G.
[0096] 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 .OMEGA., is a hydrate-solvate of
isopropanol and contains about 50% LOD water and isopropanol.
[0097] The heptane solvated form of nateglinide, Form .theta., has
about 7 to about 8% heptane by weight, and is represented by the
formula NTG1/4Heptane.
TABLE-US-00004 TABLE III LOD values by TGA and solvents used for
the preparation of nateglinide solvated forms Crystal LOD by TGA
Form Solvent (weight %) Comments A Xylene 80 Storage at RT for 24 h
is results in a partial conversion to Form B C DMA >5 D Ethanol
25 E MeOH 4 F n-PrOH 16-24 G Isopropyl 22-28 Alcohol I n-BuOH 20
Storage at RT for 24 h results in a conversion to Form L J N-Methyl
2-3 XRD pattern slightly Pyrolidone up to 100.degree. C. changed
after storage sharp weight at RTfor overnight loss at 100.degree.
C. K Dimethyl 34 formamide M Carbon tetra 2 chloride N
Dichloroethane 8 O MeOH 2 Q Chloroform 10 Storage at RT for 24 h
results in a conversion to Form Y, which contains chloroform. T
MeOH >20 Storage at RT for 24 h results in a conversion to Form
E V Dimethoxyethane 8-16 A sharp weight loss step of 7-8% is
observed at 70.degree. C. Y Dichloromethane/ 2-8 Chloroform Beta
N-Methyl Pyrolidone Gamma N-Methyl -- No significant weight loss
Pyrolidone up to 90.degree. C. Sharp weight loss at 90.degree.
Epsilon Acetone/ Above 4 Nitromethane/ Acetonitrile Theta Heptane
7.4% Omega IPA and Water 50%
[0098] The anhydrate forms and the hydrated Form Z, are also
characterized by their FTIR spectrum. Form Z is characterized by a
FTIR spectrum (FIG. 32) with peaks at about 699, 1542, 1645, 1697,
2848, 2864, 2929, 3279 and 3504 cm.sup.-1. The more characteristic
peaks are observed at about 1645, 1697, 3279 and 3504 cm.sup.-1.
Characteristic FTIR peaks are for the anhydrates, specifically
Forms L, U, P, .alpha., .delta. and .sigma. are disclosed in the
following table.
TABLE-US-00005 nateglinide form Characteristic FTIR Peaks Form
Alfa: 3283, 1711, 1646, 1420, 1238 cm.sup.-1 (FIG. 33) Form L:
1741, 1726, 1621, 1600, 1538, 1211, 1191 cm.sup.-1 (FIG. 29) Form
U: 3350, 1711, 1646, 1291 cm.sup.-1 (FIG. 31) Form .delta.: 3306,
1729, 1704, 1275 cm.sup.-1 (FIG. 34) Form .sigma. 3303, 1705, 1640
cm.sup.-1 (FIG. 35) Form P: 3309, 1748, 1589 cm.sup.-1 (FIG.
30)
[0099] The various crystalline forms are related to each other in
that drying of one form 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, .alpha., .beta., .delta., .gamma., .epsilon.,
.theta. and .OMEGA.. The drying is carried out by heating a sample
under ambient or reduced pressure. Generally, a preferred
temperature is from about 40.degree. C. to about 80.degree. 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, .alpha.,
.beta., .delta., .theta. and .OMEGA.. Of these forms, Form .alpha.,
.delta., Y and O are somewhat stable, and usually retain their
crystalline structure after heating, unless heated to a high
temperature. For example, Form .delta. is stable when heated to
60.degree. C. overnight (at least about 8 hours), but heating of
Form .delta. at 120.degree. C. and 1 atmosphere results in Form B.
Thus, heating at a temperature above about 80.degree. C. may cause
a transformation in these 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
.delta..
[0100] The conversion of some of the forms to Form B goes through
another form. For example, the conversion of Form .OMEGA. and E to
Form B may go through Form Z.
[0101] 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 Form B by going through Form G.
[0102] Of the forms that convert to Form B, some of them sometimes
under drying convert to other forms. Form K may convert to Forms
.alpha. or S, while Form C may convert to Form B or .alpha.. Form
.alpha. may convert to Form S upon heating, but the presence of
seeds of Form B in the sample of Form .alpha. results in Form B.
Probably Forms C and K transform to Form .alpha. first, and that it
is through Form .alpha. that they transform to Form B or S. Form J
may convert to Form B or .beta., though its conversion to Form B
may go through Form .beta.. The Form J used in preparing Form
.beta. is preferably obtained by crystallization from
N-methylpyrrolidone. When Form J contains some seeds of Form
.gamma., heating results in Form .gamma..
[0103] 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 Form H goes through Form P.
[0104] 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.degree. C. to about 80
EC, more preferably about 50.degree. C. under reduced pressure.
Form .gamma. may also be prepared by heating Form J containing
seeds of Form .gamma. under similar conditions.
[0105] Another thermally stable form of nateglinide is Form H which
may be prepared by heating nateglinide Forms P, V and .epsilon..
Form S may be prepared by heating Forms .alpha. and K, though the
transition of Form K to Form S may go through Form .alpha..
[0106] Form U is another thermally stable Form of nateglinide, and
does not undergo a transition after being heated at about
100.degree. C. for at least about 8.5 hours.
[0107] 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 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.
[0108] Form .alpha. is related to Forms F, G, I and .epsilon. in
that it may be crystallized out of the same solvent as those forms,
n-propanol, isopropyl alcohol, n-butanol and acetonitrile,
respectively. Form .alpha. however is crystallized under different
conditions, see e.g., Table IV. Form .alpha. 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 .alpha. overtime in the solvent.
[0109] 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.
[0110] 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.
[0111] 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.
[0112] 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 sufficient 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 filtered, to name one technique, to remove excess solvent. The
result of this trituration procedure is various forms of
nateglinide.
[0113] 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.
[0114] 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.degree. C. to about 70.degree.
C., with about 55.degree. 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 resulting residue is then examined.
Suitable solvents include esters, ketones, amines, amides, alcohols
and nitrites. Removal of acetonitrile, acetone, ethyl acetate and
iso-propyl alcohol as solvents results in nateglinide Form B.
[0115] 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.
[0116] 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 to about 1/5, more preferably 1/3 (vol/vol).
[0117] 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.
[0118] 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, crystallization is
preferably induced by concentration of the solvent, while for Form
U, by seeding of the solution.
[0119] Nateglinide Forms B, H, U, Z, .delta., .theta. and .PHI. 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 solvent and
an anti-solvent. Example of suitable antisolvents are C.sub.5 to
C.sub.12 aromatic hydrocarbons such as toluene and xylene, and
C.sub.5 to C.sub.12 saturated hydrocarbons such as hexane and
heptane. Examples of suitable solvents are C.sub.1 to C.sub.5
alcohols such as methanol, ethanol, isopropanol, n-butanol and
n-propanol, lower ketones (C.sub.3 to C.sub.6) such as acetone and
lower esters (C.sub.3 to C.sub.6) 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.degree. C. to 60.degree. C., at a pressure of less than about 50
mmHg.
[0120] When nateglinide is crystallized out of a binary mixture,
particularly in the absence of stirring, 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.degree. C., particularly in the absence
of stirring.
[0121] 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.
[0122] 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 addition 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.
[0123] 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 2, Form .theta. a ratio of about 1 and Form
.delta. a ratio of about 1 to about 8, more preferably from about 1
to about 2 (vol/vol).
[0124] Of these, some forms may crystallize as other forms, and
convert after being stirred for a sufficient time in the solvents.
Stirring the resulting slurry from crystallization at a temperature
of from about -15.degree. C. to about 10.degree. C., preferably
about 5.degree. C., may result in Form .delta.. Form .delta. seems
to result from stirring of forms such as Form U, Form .theta., Form
H and even Form B. Preferably the stirring to obtain Form .delta.
is carried out for at least about 2-3 hours, more preferably for at
least about 10 hours.
[0125] Other than a solvent:antisolvent ratio of about 1, formation
of Form .theta. seems to be favored at lower crystallization and
filtering temperatures, from about -15.degree. C. to about
10.degree. C. preferably 5.degree. C. As previously noted, stirring
of Form .theta., preferably at the specified temperature range,
results in Form .delta..
[0126] Form U may be obtained by stirring with Form B or H in an
organic solvent. Stirring for about 1 hour is sufficient to obtain
Form U. However, additional stirring, such as above about 5 hours,
may result in a transition to Form .delta.. Form U may also be
obtained by crystallization, preferably at the specified ratio,
more preferably at a crystallization and filtering temperature of
about -15.degree. C. to about 10.degree. C. Form U is generally
favored when starting with a temperature of from about 25.degree.
C. to about 35.degree. C., followed by cooling in less than about 1
hour to a temperature of from about 0.degree. C. to about
10.degree. C., with about 5.degree. C. being preferred, followed by
filtering in less than about 1 hour. Higher solvent to anti-solvent
ratio may favor form U over .theta..
[0127] 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.degree. C.
[0128] Forms Z generally crystallizes after about a day at a final
crystallization temperature of at least about 15.degree. C., more
preferably from about 15.degree. C. to about 30.degree. C., and
most preferably from about 20.degree. C. to about 25.degree. C. The
initial crystallization temperature for these forms is preferably
above 35.degree. C., followed by cooling in a few hours, more
preferably about 1 hour, to about 20.degree. C. to about 25.degree.
C. These conditions may lead to Form Z, which converts to Form B by
drying.
[0129] Form .sigma. may also be obtained by stirring of crystals of
Form B. Not being bound by any theory, it may be possible that Form
.sigma. is obtained through Form U, that is stirring results in a
transition of Form B to Form U followed to Form .sigma.. Prolonged
crystallization and filtration is preferred for obtaining Form
.sigma., i.e., preferably at least about 10 hours.
[0130] 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.
[0131] 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 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.degree. C. to about 40.degree. 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.degree. C. to about 10.degree. C. and the ethyl acetate a
temperature of from about 30 EC to about 40.degree. C.
[0132] 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 from about 1 to
about 6, and final crystallization temperatures from about
0.degree. C. to about 30.degree. C. Not being bound by any theory,
the presence of other forms, particularly Form .delta. and .PHI.,
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 .delta. or .PHI..
[0133] The following table provides guidance on obtaining Forms B,
H, U, Z, .delta., .theta. and .PHI. from a solvent:anti-solvent
system:
TABLE-US-00006 V/V ratio Crystal (EA/Heptane) Filtration temp. form
(about) (about) obtained 1:1 15.degree. C.-30.degree. C. No
stirring B preferably 20-25.degree. C. 1:1 15.degree. C.-30.degree.
C. With stirring Immediately after crystallization B preferably
20-25.degree. C. Stirring for at least about 21 h .sigma. 1:1
15.degree. C.-30.degree. C. Precipitation Immediately after
crystallization B preferably 20-25.degree. C. without going
Stirring for at least about 1 h U into solution after combining 1:1
-15.degree. C.-10.degree. C. Immediately after crystallization
Drying preferably 5.degree. C. .theta. .fwdarw. B Stirring at about
5.degree. C. .delta. 1.5:1 -15.degree. C.-10.degree. C. Immediately
after crystallization U preferably 5.degree. C. Stirring at about
5.degree. C. .delta. 2:1-8:1 -15.degree. C.-10.degree. C.
Immediately after crystallization H (95% yield) preferably
5.degree. C. Stirring for about 1-5 h U Stirring for at least about
5 h .delta. 2:1-8:1 15.degree. C.-30.degree. C. Wet crude Drying
preferably 20-25.degree. C. material Z .fwdarw. B 2:1-8:1
15.degree. C.-30.degree. C. Dry crude H preferably 20-25.degree. C.
material
[0134] Depending on the preparation procedure, nateglinide Form
.delta. 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.degree. C., more
preferably for at least about 3 hours. The residual Heptane may be
also removed under stirring, preferably at a temperature of at
least about 40 EC under vacuum. The .delta. Form is preferably
polymorphically pure and contains less than about 5% Form H
(wt/wt), more preferably less than about 2% (wt/wt), and most
preferably less than about 0.5% (wt/wt).
[0135] Crystalline Form .delta. is stable at a temperature of about
40 EC and a relative humidity of about 75% for at least about 3
months.
[0136] Trituration of Form .delta. in ethyl acetate may result in
other polymorphic forms of nateglinide. Triturating nateglinide
Form .delta. at a temperature of from about 20 to about 30.degree.
C. in ethyl acetate results in Form U, while triturating at higher
temperatures (above 40.degree. C.), such as at about 50.degree. C.,
results in Form B.
[0137] The processes of the present invention allow for obtaining
Forms .delta. 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.
[0138] 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. 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.
[0139] The processes of the present invention may also be practiced
as the last step of prior art processes that synthesize
nateglinide.
[0140] 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 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 apparatus may need to be preheated to avoid premature
crystallization.
[0141] 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.
[0142] In one embodiment, an anti-solvent is added to a solution to
decrease its solubility 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 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.
[0143] 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.
[0144] 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 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 first be milled
to about 150 to 850 .mu.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.
[0145] Pharmaceutical compositions may be prepared as medicaments
to be administered orally, parenterally, rectally, transdermally,
bucally, or nasally. Suitable forms for oral 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 transdermal delivery systems known in
the art, and for nasal delivery there are provided suitable aerosol
delivery systems known in the art.
[0146] Pharmaceutical formulations 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, .alpha., .beta., .gamma., .delta., .epsilon.,
.sigma., .theta. and .OMEGA.. The pharmaceutical composition may
contain only a single form of nateglinide, or a 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 use may be readily
determined by the formulation scientist based upon experience and
consideration of standard procedures and reference works in the
field.
[0147] Diluents increase the bulk of a solid pharmaceutical
composition, and may 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.RTM.), microfine cellulose,
lactose, starch, pregelatinized 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.RTM.), potassium chloride,
powdered cellulose, sodium chloride, sorbitol and talc.
[0148] 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.RTM.),
hydroxypropyl methyl cellulose (e.g. Methocel.RTM.), liquid
glucose, magnesium aluminum silicate, maltodextrin,
methylcellulose, polymethacrylates, povidone (e.g. Kollidon.RTM.,
Plasdone.RTM.), pregelatinized starch, sodium alginate and
starch.
[0149] The dissolution rate of a compacted solid pharmaceutical
composition in the patient's stomach may be increased by the
addition of a disintegrant to the composition. Disintegrants
include alginic acid, carboxymethylcellulose calcium,
carboxymethylcellulose sodium (e.g. Ac-Di-Sol.RTM.,
Primellose.RTM.), colloidal silicon dioxide, croscarmellose sodium,
crospovidone (e.g. Kollidon.RTM., Polyplasdone.RTM.), guar gum,
magnesium aluminum silicate, methyl cellulose, microcrystalline
cellulose, polacrilin potassium, powdered cellulose, pregelatinized
starch, sodium alginate, sodium starch glycolate (e.g.
Explotab.RTM.) and starch.
[0150] 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 glidants include colloidal
silicon dioxide, magnesium trisilicate, powdered cellulose, starch,
talc and tribasic calcium phosphate.
[0151] When a dosage form such as a tablet is made by the
compaction of a powdered composition, the composition is subjected
to pressure from a punch and dye. Some 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.
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] Liquid pharmaceutical compositions of the present invention
may also contain a viscosity enhancing agent to improve the
mouth-feel of the product and/or 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.
[0157] Sweetening agents such as sorbitol, saccharin, sodium
saccharin, sucrose, aspartame, fructose, mannitol and invert sugar
may be added to improve the taste.
[0158] 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.
[0159] According to the present invention, a liquid composition may
also contain a buffer such as gluconic acid, lactic acid, citric
acid or acetic acid, sodium gluconate, sodium lactate, sodium
citrate or sodium acetate.
[0160] 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.
[0161] 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
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.
[0162] Dosage forms include solid dosage forms like tablets,
powders, capsules, suppositories, sachets, troches and losenges, as
well as liquid syrups, suspensions and elixirs.
[0163] 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.
[0164] The active ingredient and excipients may be formulated into
compositions and dosage forms according to methods known in the
art.
[0165] 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 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.
[0166] 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.
[0167] 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.
[0168] 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.
[0169] 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 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:
[0170] X-Ray diffraction was performed on X-Ray powder
diffractometer, Scintag.RTM., 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 2.theta., Continuos Scan, Rate: 3
deg./min.
DSC:
[0171] DSC821.sup.e Mettler Toledo.RTM., Sample weight: 3-5 mg,
Heating rate: 10.degree. C./min, Number of holes in the crucible:
3
TGA:
[0172] Mettler TG50.RTM., Sample weight: 7-15 mg, Heating rate:
10.degree. C./min
FTIR:
[0173] Perkin-Elmer.RTM., Spectrum One FTIR spectrometer, Range:
4000-400 cm-1, no. of scans: 16, resolution: 4.0 cm-1, DRIFT
technique.
EXAMPLES
Example 1
This Example Illustrates Preparation of Various Forms of
Nateglinide from a Solution
[0174] 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
obtained after addition of 150 ml of the solvent, the hot mixture
was filtered.
[0175] The clear solution was left to crystallize at room
temperature. If crystallization did not happen or was poor, the
solution was refrigerated at 3.degree. C. The precipitate was
filtered off (at RT or at 5.degree. C. depending on the temperature
of the crystallization), weighed and divided into 2 equal parts.
One part was dried at 50.degree. C. under reduced pressure (20-30
mmHg) to constant weight (.+-.0.01 g) for about 3-10 hours. Details
are presented in Table IV.
TABLE-US-00007 TABLE IV Data on crystallization of NTG from a
single solvent L/S, T, Time Time Form Form Solvent ml/g .degree. C.
RT, h 3.degree. C., h Wet Dry Xylene 30 70 25 -- A A>>B DMA 1
55 25 -- C .alpha. 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 d -- .alpha. .alpha. n-PrOH 2 55 3 5 d .alpha.
.alpha. IPA 1.2 57 25 48 G B IPA 3 55 1 m 20 .alpha. .alpha. NMP
1.4 57 73 -- J B + .beta. DMF 1.6 56 24 52 K S CTC 30 65 25 -- M L
DCE 2.2 55 23 47 N L CHCl.sub.3 1 54 73 193 Q Q DME 1.4 56 96 -- V
H n-BuOH 4 55 1 m 20 .alpha. S n-BuOH 1.4 57 25 144 I S Acetone 2
20 144 20 .epsilon. H NM 30 70 24 -- .epsilon. P MeCN 8 55 3 20
.epsilon. .epsilon. + B MeCN 19 55 8 d -- .alpha. .alpha. MeCN 19
55 7 d 5 .alpha. .alpha. DCM 2* 54 47 -- Y Y EA 9 55 22 -- .alpha.
.alpha. EA 9 55 10 d 5 d .alpha. .alpha. EA 15 55 9 d -- .alpha.
.alpha. EA 15 55 8 d 5 d .alpha. .alpha. Legend. 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.degree. 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.
Example 2
This Example Illustrates Trituration of Nateglinide Form H and U in
Various Solvents
[0176] 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.degree. C. under 20-30
mm/Hg pressure to constant weight (.+-.0.01 g).
[0177] Details are presented in Tables V and VI.
TABLE-US-00008 TABLE V Data on trituration of NTG with a single
solvent Start L/S Form Form Form Solvent ml/g Time, 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
.epsilon. H + P H NMP 0.8 24 J .beta. H DMF 1.2 25 K H DMA 1.2 26 C
B H DME 1.4 24 V H H Dioxane 2.2 24 .delta. .delta. H THF 0.8 23
.delta. .delta. H DCM 1.8 25 Y Y H CHCl.sub.3 1 25 Q Q + B H DCE
1.8 24 Q + H Q + H
TABLE-US-00009 TABLE VI Data on trituration of NTG with a single
solvent Start L/S Form Form Form Solvent ml/g Time, h wet dry U
AcOH 1.8 24 H + S H + S U MeOH 1.2 24 .alpha. .alpha. U EtOH 1.6 24
B + .alpha. B + .alpha. U IPA 1.8 24 G + S G + S U n- 1.4 25 F B
PrOH U n- 1.6 26 .alpha. .alpha. BuOH U NM 5 24 P P U NMP 1 25 J +
.gamma. .gamma. U DMF 1 23 K .alpha. U DMA 1.2 24 C .alpha. U
Acetone 2 24 P P U MEK 2.4 23 H + .alpha. H + S U MIPK 3 24 H +
.alpha. H U MIBK 3.6 24 H + .alpha. H + S U DME 1.8 24 H + .alpha.
H + S U Dioxane 2 23 .delta. B U THF 0.8 23 .delta. .delta. + B U
DCM 1.6 24 Y + S Y + S U CHCl.sub.3 1.2 25 .delta. .delta. U DCE
3.8 26 Q Q
Example 3
This Example Illustrates Absorption of Solvent Vapors by
Nateglinide
[0178] 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 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.degree. C. and a pressure of 20-30 mmHg to
constant weight (.+-.0.01 g). Details are presented in Table
VII.
TABLE-US-00010 TABLE VII Data on absorption of solvent vapors with
NTG Form H Form Form NTG W, g Brutto, g Solvent Time, d Wfinal
.DELTA. wet dry 3.50 15.77 EtOH 4 16.29 0.52 D B 3.50 15.94 MeOH 4
16.12 0.18 O O 3.50 15.78 Acetone 4 15.86 0.08 H H 3.49 51.86 DCM 4
51.90 0.04 Y -- 3.50 15.27 Water 4 15.29 0.02 H H Legend. Brutto -
starting weight of the can with NTG; Wfinal - final weight of the
can with NTG after the exposure; .DELTA. - overweight
Example 4
This Example Illustrates Preparation of Various Forms of
Nateglinide be Solvent Removal
[0179] Nateglinide (5 g) 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-US-00011 TABLE VIII Data on solvent removal Solvent Form, dry
MeCN B Acetone B EA B
Example 5
This Example Illustrates Preparation of Form Z
[0180] 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.degree. C./2.2 mbar. Assay
98.4%, purity >99%, yield 86%.
Example 6
This Example Illustrates Preparation of Nateglinide by
Crystallization from Binary Mixtures (Solvent/Anti-Solvent)
[0181] Nateglinide (5 g) and an anti-solvent (20 ml) were placed
into an Erlenmayer flask. The mixture was heated at about
55.degree. 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.
[0182] If crystallization did not happen or was poor after 24
hours, the solution was refrigerated at 3-5.degree. C. The
precipitate was filtered off (at RT or at 5.degree. C. depending on
the temperature of crystallization) to give Form B. The wet
material was dried at 50.degree. C. under reduced pressure (20-30
mmHg) to give dry Form B.
TABLE-US-00012 TABLE IX Data on crystallization of NTG from binary
solvents Ratio, L/S, Form Form Solvents v/v ml/g T.sub.cryst.,
.degree. C..sup.f Time, h Ww, g Wd, g wet dry Toluene- 40:1 4.1
RT.fwdarw.3 23/23 7.84 3.56 B B EtOH Toluene- 40:1 4.1 3 22/23 6.82
3.72 E B MeOH Toluene-IPA 27:1 4.15 RT.fwdarw.3 22/24 7.83 3.28 --
B Toluene-EA 4.2:1 4.95 RT 26 7.27 4.0 -- B + H Toluene-n- 20:1 4.2
3 18/25 3.34 1.76 B B BuOH Toluene-n- 27:1 4.15 3 24/71 5.18 2.64 B
B PrOH Xylene-EA 2:1 6 3 23/72 9.40 3.60 B B Heptane-EA 1:1.3 9.2
RT 94 3.62 2.26 B + Z B Heptane-EA 1:1.3 9.2 RT 25 4.36 2.24 B B
Hexane-EA 1:1.2 8.8 RT 94 5.05 2.46 B B Hexane-EA 1:1.2 8.8 RT 25
2.72 2.32 B B Toluene- 5.7:1 4.7 3 22/72 5.56 2.88 B B acetone
Legend: L/S- liquid/solid ratio (liquid = solvent + anti-solvent);
.sup.fsymbol RT.fwdarw.3 means that crystallization was started at
room temperature then the mixture was cooled to 3.degree. C. to
complete precipitation.
Example 7
Preparation of Form Delta
[0183] (A) This Example Illustrates Preparation of Nateglinide Form
Delta by Crystallization from an Ethyl Acetate-Heptane Solvents
System:
Preparation of Nateglinide Form .delta.
[0184] D-Phenylalanine (15.44 g) was added all at once to a 3.5%
NaOH solution (370 ml, 3.5 equivalents), at 20.degree. C., under
stirring, 230 min.sup.-1. A clear solution was immediately formed.
A neat trans-4-isopropylcyclohexylcarboxychloride (18.03 g) was
added for 5 minutes to the reaction solution. A solid was formed
and the temperature rose to 32.degree. C. The mixture was stirred
for 1 hour at 20.degree. C., under stirring. A 15% H.sub.2SO.sub.4
(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.degree. 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.degree. 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 minutes to hot heptane (54.degree. 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.degree., seeded with B-form, and left for
crystallization overnight, under stirring at 215 revolutions
min.sup.-1. The solid was filtered off and washed with heptane (30
ml). The cake was dried at 60.degree. C./20 mbar to afford 6.84 g
of the .delta.-form. Yield 33%.
Preparation of Nateglinide Form .delta.
[0185] 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.degree. C.,
under stirring, 200 min.sup.-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.degree.
C. The mixture was stirred for 20 minutes at 40-43.degree. C. under
stirring. An 85% solution of H.sub.2SO.sub.4 (11.94 g) was added
all at once to the RM to adjust 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.degree. C., and dried with anhydrous magnesium sulfate (3.05 g)
over 1.5 hours. The organic solution was filtered through a PTFE
0.45 .mu.m filter, heated to 38.degree. C. and to which was added
hot heptane (40.degree. C., 125 ml). The resulting clear solution
was gradually cooled for 45 minutes to 13.degree. C. and seeded
with NTG in B-form. The crystallization started. The mixture was
then cooled for 17 min to 5.degree. C. and stirred for 16 h. The
solid was filtered off and washed with a cold (5.degree. 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.degree. C./13 mbar to afford 20.38 g of the product, Form
.delta., with a purity >99.8%. Yield 55%.
Preparation of Nateglinide Form .delta.
[0186] 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.degree. C., under stirring 150 min.sup.-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.degree. C., under stirring.
Ethyl acetate (140 ml), followed by an 85% solution of
H.sub.2SO.sub.4 (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.degree. C., and
filtered through a PTFE 0.45 .mu.m filter. The clear solution (141
g) was heated to 46.degree. C. and to which was added hot heptane
(46.degree. C., 153 ml), under stirring at 150 min.sup.-1. The
clear solution was gradually cooled to 28.degree. C. and seeded
with Form delta. The crystallization occurred at 24.degree. C. The
mixture was stirred for 30 minutes at 24.degree. C., gradually
cooled to 5.degree. C. and stirred overnight at 5.degree. C. The
solid was filtered off and washed with a cold (5.degree. 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.degree. C./20 mbar to afford 24.65 g of the product in a
form delta with a purity >99.8%. Yield 65%.
[0187] (B) This Example Illustrates the Preparation of Form .delta.
Crystallization
[0188] Crude nateglinide (50 grams) was dissolved in ethyl acetate
(200 ml) and water (2.5 ml) at 45.degree. C. Hot heptane (260 ml)
at 50.degree. C. was added. The mixture was still fully dissolved.
The mixture was cooled to 30.degree. C. and seeded with nateglinide
Form .delta. (0.1 grams). The mixture was stirred for 30 minutes
and then cooled to less than 10.degree. C. in 2 hours. The mixture
was stirred at 5-10.degree. C. overnight and then filtered with
vacuum. The wet product 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.degree. C. overnight. Both the wet and dry
samples were Form .delta..
[0189] Starting material: Wet nateglinide (40% total wetness. 2 ml
water, 10 ml ethyl acetate, 21 ml of heptane). Wet crude
nateglinide (83 grams) and dry nateglinide (50 grams) were
dissolved in ethyl acetate (190 ml) at 45.degree. C. Hot heptane
(239 ml) at 50.degree. C. was added. The solution was cooled to
30.degree. C. and a seeded with nateglinide (0.1 grams) Form
.delta.. The mixture was stirred for 30 minutes and then cooled to
less than 10.degree. C. in 2 hours. The mixture was stirred at
5-10.degree. 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 was dried in a vacuum oven at
50.degree. C. overnight. Both the wet and dry samples were Form
.delta..
[0190] (C) This Example Illustrates the Drying of Form .delta. by
Fluidized Bed Dryer
[0191] Nateglinide Form delta (10 grams), with about 3% heptane
(wt/wt), was dried in a fluidized bed drier for 4 hours at
60.degree. C. Residual heptane was 1578 ppm af. Ethyl acetate is
under detection limit. Polymorphic form of the dry product is
delta.
[0192] According to these procedures, a series of experiments were
carried out under various heptane/ethyl ratios, liquid/solid
ratios, temperature and seeding. The results are summarized in
Table X:
TABLE-US-00013 TABLE X Data on crystallization of NTG in EA-Heptane
solvents system Ratio Temperature Form Form Seed Anti-solvent v/v
L/S, ml/g profile Yield, % wet dry None Hexane 2.7:1 11
40(1).fwdarw.20(16) 58 Z B + Z None Heptane 4:1 16
40(1).fwdarw.20(16) 64 Z B None Heptane 5:1 11 40(1).fwdarw.20(16)
74 H H None Heptane 4.7:1 11 40(1).fwdarw.20(16) 68 H H None
Heptane 7.5: 11 40(1).fwdarw.20(16) 48 B B None Heptane 5:1 8
40(1).fwdarw.20(16) 72 -- H None Heptane 6:1 10
60(0.1).fwdarw.20(16) 76 B B None Heptane 7.1:1 11 20(16) 78 H H B
Heptane 5.1:1 14 5(1.5).fwdarw.5(1) 77 H H B Heptane 2.5:1 16
5(2).fwdarw.5(1) 74 H H B Heptane 1:1 7.5 16.fwdarw.5(16) 51
.delta. .delta. B Heptane 1:1 7 30(1).fwdarw.5(16) 58 .delta.
.delta. B Heptane 1:1 7.6 13(1).fwdarw.5(16) 59 .delta. .delta. B
Heptane 1:1 7.4 13(1).fwdarw.5(16) 55 .delta. .delta. B Heptane 2:1
9 30(0.5).fwdarw.5(1) 76 H + U -- 5(1).fwdarw.5(16) .delta. .delta.
B Heptane 1.5:1 7.5 32(0.5).fwdarw.5 71 U -- 5(1) U --
5(1).fwdarw.5(16) .delta. .delta. None Heptane 2:1 10
31(0.5).fwdarw.5(4.5) 67 .delta. .delta. None Heptane 1:1 --
9(0.5).fwdarw.5(1) -- .theta. B 5(1).fwdarw.5(16) .delta. .delta.
.delta. Heptane 1:1 7.8 9(0.5).fwdarw.5(16) 46 .delta. .delta. B
Heptane 1.1:1 6.1 25(0.5).fwdarw.5(16) 63 .delta. .delta. .delta.
Heptane 1:1 7 19(0.5).fwdarw.5(16) 54 .delta. .delta. B Heptane 1:1
7.6 13 (0.5).fwdarw.5 (16) 52 .delta. .delta. .delta. Heptane 1:1
6.1 30(0.5).fwdarw.5(16) 55 .delta. .delta. Temperature profile:
crystallization temperature (h).fwdarw.final temperature (h); L, t
- amount of L, trans-isomer.
Example 8 this Example Illustrates Preparation of Forms of
Nateglinide by Precipitation Without Going to Solution after
Combining
Preparation of Nateglinide Form U
[0193] D-Phenylalanine (20.02 g) was added all at once to a 3.5%
NaOH solution (369.73 g, 2.7 equivalents), at 20.degree. C., under
stirring, 200 revolutions min.sup.-1. 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.degree. C. The mixture was
stirred for 40 minutes at 20.degree. C., under stirring. An 85%
solution of H.sub.2SO.sub.4 (11.55 g) was added all at once to the
reaction mixture to adjust the pH to 1-2. The solid product was
extracted with EA (150 ml) at 55.degree. C. for 55 minutes. The hot
organic extract was washed with warm water (100 ml), followed by
brine (40.degree. 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
.about.54 g (60 ml) of EA. The EA solution was finally filtered
through a PTFE 0.45 .mu.m filter into a clean dropping funnel
heated to 35.degree. C. Heptane (320 ml) was placed into the
reactor, cooled to 5.degree. 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.degree. C. The solid was
filtered off and washed with a cold (5.degree. C.) mixture of
heptane-EA mixture (4.5:1, total 120 ml) to afford 63.62 g of a wet
product (wetness 54%). The cake (62.4 g) was dried at 60.degree.
C./10 mbar to afford 28.6 g of the product, containing .about.0.6%
of L, trans-isomer (other impurities <0.1%) in the U-form. Yield
77%.
TABLE-US-00014 TABLE XI Data on crystallization of NTG during the
crystallization process (precipitation without going into solution
after combining) Anti- Ratio L/S, T.sub.EA, T.sub.AS(time), Form
Form Seed solvent v/v ml/g .degree. C. .degree. C.(h) Yield, % L,
t, % wet dry B Heptane 3.7:1 17 25 55(25) 33 0.05 .delta. .delta.
None Heptane 5.4:1 12 40 5(2.5) 77 0.7 U U None Heptane 0.77:1 9.7
45 45.fwdarw.25(1) 71 0.01 B + U 25(1).fwdarw.25(22) 2 U U None
Heptane 0.8:1 9.7 45 45.fwdarw.25(21) 72 0.03 .sigma. .sigma.
T.sub.EA - temperature of the EA solution; T.sub.AS(time) -
temperature of anti-solvent (exposure time).fwdarw.final
temperature (exposure time); L, t - amount of L, trans-isomer.
Example 9
Heating of Nateglinide Form U
[0194] Sample of nateglinide form U (.about.1 g) was introduced
into a 6-gram vial and heated over 8.5 h in a 100.degree. C. oil
bath. The vial were extracted from the bath. The resulted sample
showed Form U by XRPD.
[0195] Sample of nateglinide form U (.about.0.5 g) was heated to
120.degree. C. for 1 h in an atmospheric pressure. The resulted
sample showed Form U by XRPD.
Example 10
Heating of Nateglinide Form .delta.
[0196] Sample of nateglinide form .delta. (.about.0.5 g) was heated
to 120.degree. C. for 1 h in an atmospheric pressure. The resulted
sample showed Form B by XRPD.
Example 11
Preparation of Form Omega
[0197] Nateglinide Form delta (5 grams) was dissolved in
isopropanol (15 ml) at room temperature. The solution was cooled to
.about.0.degree. C. Water (6 ml) was added. A white solid
precipitated suddenly. The solid was heated to 35.degree. C.,
resulting in complete dissolution. The solution was cooled to
.about.7.degree. C. and the product precipitated. The product was
filtered with vacuum. XRPD confirmed the presence of Form
omega.
Example 12
Drying of a Wet Sample of Form Omega
[0198] The product of example 11 was dried at 50.degree. 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 Triturating
Form .delta. in Ethyl-Acetate
[0199] Nateglinide Form .delta. (5 grams) was triturated in ethyl
acetate (10 ml) at 25.degree. C. for 2 hours. The wet material was
filtered with vacuum and washed with ethyl acetate (10 ml). The wet
product was dried at 50.degree. 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 Triturating
Form .delta. in Ethyl-Acetate
[0200] Nateglinide Form .delta. (5 grams) was triturated in ethyl
acetate (10 ml) at 50.degree. C. for 1 hour. The mixture was cooled
to 20.degree. C. and triturated for 1 hour. The wet material was
filtered with vacuum and washed with ethyl acetate (10 ml). The wet
product was dried at 50.degree. C. in a vacuum oven overnight. The
wet and dry products were obtained as Form B.
Example 15
Process for the Preparation of Nateglinide Form B
[0201] 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 .delta. (about 3% LOD) is dissolved in a mixture
of IPA/H.sub.2O at a preferred temperature range of about 40 to
about 50.degree. 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.
[0202] The solution obtained after dissolution is preferably cooled
to a temperature of about 30.degree. 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.degree. C. plus/minus 5.degree.
C. for at preferably least about 5 hours, and preferably stirred at
5.degree. 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.degree.
C. to obtain nateglinide Form B.
[0203] In this embodiment, before crystallization, the starting
material may optionally be dissolved in IPA or in a IPA/H.sub.2O
mixture (in the same solvent ratio as the crystallization mixture),
followed by evaporation under reduced pressure. After the
evaporation, IPA/H.sub.2O mixture is fed into the reactor to obtain
a solution. Nateglinide Form B is obtained after the
evaporation.
[0204] The use of IPA allows for the elimination of methyl esters
as impurities in the final product as illustrated in FIG. 64.
Example 15 (A)
[0205] Nateglinide (40 grams) was dissolved in IPA (240 ml) at
25.degree. C. The solution was filtered to remove insoluble
materials. The clear solution was heated to 50.degree. 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.
Example 15 (B)
[0206] 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.degree. C. A solution was obtained by
feeding the reactor with IPA (150 ml) and water (150 ml) were fed
at Tj=50.degree. C. The clear solution obtained, was cooled to
TR=29.4.degree. C., and seeded by B type crystals. The seeded
solution was stirred at TR=29.4.degree. C. for additional 3 hours,
and afterwards cooled to TR=0.degree. C. for 10 hours. At 0.degree.
C., the resulting slurry was stirred for additional 5 hours
(over-night). The crystals were isolated and dried under reduced
pressure at 90.degree. 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)
[0207] Nateglinide (20 grams) was dissolved in IPA (200 ml) in a
round bottom flask and the solvent was evaporated under reduced
pressure at a temperature of 50.degree. 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.degree. C. At 28.degree. C., the solution was
seeded with type B crystals.
[0208] The seeded solution was stirred at 28.degree. C. for an
additional 2 hours, and afterwards cooled to 5.degree. C. for 10
hours. At 5.degree. C., the solution was stirred for an additional
4 hours (over-night). The product was isolated and dried under
reduced pressure at 90.degree. 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 Nateglinide Form B by Trituration in
Water
[0209] Nateglinide Form .delta. was triturated in 5 volumes water
at about 25.degree. C. for about 7 hours. The crystals were
isolated and dried under reduced pressure at 90.degree. C.
Example (A)
Trituration of Wet Starting Material
[0210] 50 gr Nateglinide form .delta. wet (about 37% LOD) was
triturated in 250 ml water at 25.degree. C. After 4 hrs
trituration, the slurry was sampled and dried under reduced
pressure at 90.degree. C. The wet crystals were tested by XRD and
found to be .delta. 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.degree. C. The wet
crystals were tested by XRD and found to be .delta. type. The dry
crystals were tested by XRD and found to be B type.
Example (B)
Trituration of Dry Starting Material
[0211] 50 gr Nateglinide form .delta. dry was triturated in 250 ml
water at 25.degree. C. After 4.5 hrs trituration, the slurry was
sampled and dried under reduced pressure at 90.degree. C. The wet
crystals were tested by XRD and found to be Z type. The dry
crystals were tested by XRD and found to be B type. After 7.5 hours
of trituration, the product was isolated and dried under reduced
pressure at 90.degree. 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 Nateglinide Form U
Example (A)
Crystallization from Acetone
[0212] Nateglinide (50 grams) Form .delta. was dissolved in acetone
(175 ml) at 42.degree. C. The clear solution was cooled to
10.degree. C. for seeding. After seeding with type B crystals, the
seeded solution was stirred for an additional 3 hours at a
temperature of 10.degree. C. and cooled to -10.degree. C. for 10
hours, and stirred at -10.degree. C. over night. The crystals were
isolated and dried at 90.degree. 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
[0213] Nateglinide (20 grams) were dissolved in ethyl acetate (560
ml) at 40.degree. C. The solution was filtered to remove insoluble
matter. The clear solution was evaporated under reduced pressure,
and Ethyl Acetate (460 ml) was evaporated (the solvent volume in
the reactor was 5 volumes/unit weight Nateglinide). The solution
was cooled to 20.degree. C. and seeded with type B crystals. The
seeded solution was stirred at 20.degree. C. for an additional 30
minutes, cooled to 0.degree. C. for 1.5 hours, and stirred at
0.degree. C. for an additional 30 minutes. The crystals were
isolated and dried under reduced pressure at 30.degree. C.,
50.degree. C., 90.degree. C. The wet 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
[0214] Nateglinide (40 grams) Form delta (1.5% heptane) was dried
in a stirred reactor (7-10 rpm) under 60 mmHg vacuum and at
60.degree. C. After 6 hours of drying, the residual solvent 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 Nateglinide Form B from Ethyl Acetate
[0215] Nateglinide form .delta. is dissolved in ethyl acetate at
25.degree. C. The solvent is evaporated under reduced pressure,
until turbidity appears. The turbid solution is cooled to 0.degree.
C. plus/minus 5.degree. C. for 1 hour and stirred for 1 hour. The
product was isolated and dried under reduced pressure at 50.degree.
C.
Example (A)
[0216] Nateglinide (12 grams) Form .delta. was dissolved in 165 ml
of ethyl acetate at 25.degree. C. The solvent was evaporated under
reduced pressure at 25.degree. C., until turbidity appeared. At the
end of evaporation, the volume in the reactor was 90-95 ml. The
mixture was cooled from 25.degree. C. to 5.degree. C. for 1 hour
and stirred at 5.degree. C. for 1 hour. The product was isolated
and dried under reduced pressure at 50.degree. C. Both the wet and
the dry crystals were tested by XRD and DSC and found to be B
type.
[0217] 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 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 the
Pharmaceutical Sciences, Volume 95 may be used as a guidance. All
references mentioned herein are incorporated in their entirety.
* * * * *