CA2492644A1 - Polymorphic forms of nateglinide - Google Patents

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 arid methods of administration.

Description

POLYMORPHIC FORMS OF NATEGLINIDE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. provisional applications Serial Nos.
60/396,904 filed July 18, 2002; 60/413,622, filed September 25, 2002;
60/414,199, filed September 26, 2002; 60/423,750, filed November 5, 2002; 60/432,093, filed December 10, 2002; 60/432,962, filed December 12, 2002; 60/442,109, filed January 23, 2003;
60/449,791, filed February 24, 2003; 60/479,016, filed June 16, 2003, and 10/
, filed July 3, 2003 (attorney docket No. 1662/60606, the contents of all of which are to incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to the solid state chemistry of nateglinide.

Nateglinide, known as (-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-Phenylalanine, has the following structure and characteristics:
(CH3)2CH~~".. H
I

C
I I
O
Formula C 19H27N03 Molecular Weight 317.42 Exact Mass 317.199093 Composition C 71.89% H 8.57% N 4.41% O 15.12%
2o Nateglinide is marketed as STARLIX, which is prescribed as oral tablets having a dosage of 60mg and 120mg for the treatment of type II diabetes. STARLIX may be used as monotherapy or in combination with metaformin to stimulate the pancreas to secrete insulin. According to the maker of STARLIX, nateglinide is a white powder that is freely soluble in methanol, ethanol, and chloroform, soluble in ether, sparingly soluble in acetonitrile and octanol, and practically insoluble in water.
Nateglinide may be crystallized out of a mixture of water and methanol, and further dried, as disclosed in U.S. Pat. No. 4,816,484. The procedure of the '484 patent results in a hydrate labeled by the present Applicants) as Form Z, or in a methanolate lablelled by the Applicants) as Form E. Drying of the wet sample results in Form B
The present invention relates to the solid state physical properties of nateglinide.
These properties may be influenced by controlling the conditions under which nateglinide is obtained in solid Form. Solid state physical properties include, for example, the io flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
15 Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient may reach the patient's bloodstream.
The rate of dissolution is also a consideration in formulating syrups, elixirs and other 20 liquid medicaments. The solid state Form of a compound may also affect its behavior on compaction and its storage stability:
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic Form of a substance. The polymorphic Form may give rise to thermal behavior different from that of 25 the amorphous material or another polymorphic Form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and may be used to distinguish some polymorphic forms from others. A particular polymorphic Form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, 3o solid state C NMR spectrometry and infrared spectrometry.
Nateglinide exists in various crystalline forms. U.S. Pat. Nos. 5,463,116 and 5,488,150 disclose two crystal forms ofnateglinide, designated B-type and H-type, and processes for their preparation. These patents are incorporated herein by reference for their disclosure of the forms. Both forms are characterized by melting point, X-Ray Powder Diffraction ("XRPD") pattern, IR spectrum in KBr and DSC thermogram.
According to these patents, B-type has a melting point of 129-130 °C
while H-type has a melting point of 136-142°C. The H-type crystals are characterized in these patents by an XRPD pattern with peaks at 8.1, 13.1, 19.6 and 19.9 X0.2 degrees 28, and a strong reflection between 15 and 17 X0.2 degrees 20. The B-type crystal is reported to lack these peaks and have a weak reflection between 15 and 17 X0.2 degrees 28. H-type crystals are reported to have an IR spectrum with characteristic absorptions at about 1714, 1649, 1542 and 1214crri I. These absorptions are reported to be missing in the spectrum of B-type 1o crystals.
According to U.S. Pat. No. 5,463,116, B-type crystals are unstable and susceptible to change during grinding as demonstrated by DSC. The DSC thermogram of B-type shows a sharp endotherm at 131.4°C before grinding while that of H-type shows a sharp endotherm at 140.3°C. After grinding, the DSC thermogram of B-type shows a second 15 endotherm at 138.2°C, suggesting a solid-solid transformation during grinding.
According to U.S. Pat. No. 5,463,116, the temperature during crystallization and filtration determines whether the crystal Form is B-type or H-type.
Temperatures above 10°C, more preferably above 15°C, lead to formation of H-type, while those below 10°C
lead to formation of B-type.
20 Another crystalline form of nateglinide designated Type-S is disclosed in two Chinese articles: ACTA Pharm. Sinica 2001, 36(7), 532-34 and Yaowu Fenxi Zazhi, 2001, 21 (5), 342-44. Form S is reported to be distinguisheable from Forms B and H
by a melting point of 172.0°C, a Fourier Transform IR with a peak at 3283crri 1 (as supposed to 3257cni' and 3306crri 1 for Forms B and H respectively) and an XRPD pattern with a 25 strong peak at 3.78 X0.2 degrees 20.
U.S. Pat. No. 5,463,116 ("the '116 patent") lists the methanolate, ethanolate, isopropanolate and acetonitrilate solvates of nateglinide. According to the '116 patent, amorphous nateglinide may be obtained by drying the hydrate and the solvates.
The hydrate may be crystallized by dissolving B-type crystals in a 1.5:1 mixture of ethanol and 3o water, followed by crystallization, as disclosed in Example B-3 of the '116 patent.
The present Applicants obtained a hydrate of nateglinide which the Applicants labeled as Form Z. However, repeating of Example B-3 or comparative Example A3 of the '116 patent also results in Form Z, as well as the crystallization procedure of the '484 patent. Form Z is obtained when only water is present, but Form E methanolate or ethanolate when both methanol or ethanol and water are present.
WO 02134713, a PCT publication in Japanese, provides in its abstract: "A
process for preparing B form nateglinide crystals containing substantially no H-form crystals, which comprises the step of drying wet crystals of a nateglinide solvate at a low temperature until the solvent disappears and then causing them to undergo a crystal transition." According to the Applicant's translation of Example 1 of the WO
publication:
"Nateglinide H-form crystals (24.5 kg) were added to ethanol (360 L) and stirred to dissolution at room temperature. After dissolution was confirmed (the mixture) was cooled to 5 °C and allowed to mature at 5 °C for one hour. The deposited crystals were separated and damp crystals (43.0 kg) obtained. These were dried at 45 °C in a rack drier for 24 hours (water content ca. 1 %) and then heated for 12 hours at 90 ° C to bring about a crystal transformation, when dry crystals (13.3 kg) were obtained. When these crystals were measured by DSC, the characteristic B-form peak was detected (mp ca.
130°C) but the characteristic H-form peak (mp ca. 139°C) was not detected. Hence the crystals obtained were of the B-form only and the H-form was concluded to be essentially absent."
According to the Applicants' translation of Page 3, Line 2 of the WO
publication:
"The moist solvate crystals obtained (BS: from the cooled solution) are dried till the 2o solvent disappears. The temperature for this will differ depending on the type and duantity~
of solvent, but usually lies below 60°C and preferably below 50°C. Although there is no lower limit to the temperature, [the drying] is usually carried out at 20°C or more for economic reasons. Drying is favorably carried out at usual reduced pressure;
at industrially attainable reduced pressures the drying will be complete in a short time.
Though the drying at low temperature can be continued to virtual disappearance of the solvent it is not necessary to clear it completely. Even if solvent to the extent of 5% by weight is present this is no problem because it will disappear during the crystal transformation. By heating the dried crystals at 60-110°C, preferably 70-100°C, a crystal transformation into the B-form is brought about. Though the crystal transformation is 3o usually favorably carried out in 0.5 to 4~ hours, a period of 1-24 hours is most favored."
Another PCT publication, WO 03/022251 discloses a crystalline form of nateglinide labeled "AL-type". The crystalline form is characterized as having a melting point of 174-178 ° C, an XRPD pattern with peaks at 7.5, 15.5, 19.8 and 20.2 degrees 2A, and an infra red spectrum with absorption bands in the region 1711.5, 1646.5, 1538.7, 1238.8, 1215.1 and 700.5 cm 1. The crystalline form is obtained in the examples from a solution of acetonitrile under a specific temperature range.
Processes for preparation of nateglinide are disclosed in WO/0232854.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. New polymorphic forms of nateglinide have now been discovered.
SUMMARY OF THE INVENTION
The present invention provides for 26 crystalline forms of nateglinide, denominated Forms A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, U, V, Y, a (alpha), (3 (beta), y (gamma), S (delta), s (epsilon), 6 (sigma), 8 (theta) and S2 (omega).
Some of these crystalline forms have bound solvents, that is solvents that are part of the crystalline structure (solvates). These solvates having bound solvent include Form A (xylene), C (dimethylacetamide- "DMA"), D (ethanol- "EtOH"), E (ethanol and methanol-"MeOH"), F (n-propanol- "n-PrOH"), G (isopropyl alcohol- "IPA"), I (n-2o butanol- "n-BuOH"), J (N-methylpyrrolidone- "NMI'"), K (dimethylformamide-"DMF"), M (carbon tetrachloride- "CTC"), N (dichlaroethane-"DCE"), O (methanol), Q
(chloroform- "CHC13"), T (methanol), V (dimethoxyethane- "DME"), Y
(chloroform;
dichloromethane), (3 (N-methyl pyrolidone), 'y (N-methylpyrolidone) and s (acetone;
acetonitrile- "MeCN"; nitromethane-"NM") and 8 (heptane). Form Z is a hydrate, having water in the crystalline structure. Form S2 is a solvate of both water and isopropyl alcohol.
Other crystalline forms do not have bound solvents, i. e., less than about 2%
as measured by loss on drying ("LOD"), and are anhydrates. These anhydrates include crystalline Forms L, P, U, a, S and ~.
3o The XRPD pattern of these forms as substantially depicted is disclosed in Figures 1-27 and 63, with the characteristic peaks listed in Table I. The DSC
thermograms for the forms is disclosed in Figures 36 to 62, and the characteristic DSC peaks are listed in Table II. The FTIR spectrum of the anhydrite and hydrate Forms and their characteristic peaks are also provided. The LOD values from the TGA analysis of some of these Forms is listed in Table III. Preparation of the various Forms by crystallization procedure is listed in Table IV, while preparation by trituration is listed in Tables V and VI, data on absorption of solvent vapors is listed in Table VII, data on preparation by solvent removal is listed in Table VIII and data on crystallization from a solventlanti-solvent system is listed in Tables IX-XI. Figure 28 summarizes the thermal stability of the various forms.
The present invention also provides for pharmaceutical formulations of the various crystalline forms and their administration.
to BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is an XRPD pattern for nateglinide Form A.
Figure 2 is an XRPD pattern for nateglinide Form C.
Figure 3 is an XRPD pattern for nateglinide Form D.
Figure 4 is an XRPD pattern for nateglinide Form E.
i5 Figure 5 is an XRPD pattern for nateglinide Form F.
Figure 6 is an XRPD pattern for nateglinide Form G.
Figure 7 is an XRPD pattern for nateglinide Form I.
Figure 8 is an XRPD pattern for nateglinide Form J.
Figure 9 is an XRPD pattern for nateglinide Form K.
2o Figure 10 is an XRPD pattern for nateglinide Form L.
Figure 11 is an XRPD pattern for nateglinide Form M.
Figure 12 is an XRPD pattern for nateglinide Form N.
Figure 13 is an XRPD pattern for nateglinide Form O.
Figure 14 is an XRPD pattern for nateglinide Form P.
25 Figure 15 is an XRPD pattern for nateglinide Form Q.
Figure 16 is an XRPD pattern for nateglinide Form T.
Figure 17 is an XRPD pattern for nateglinide Form U.
Figure 18 is an XRPD pattern for nateglinide Form V.
Figure 19 is an XRPD pattern for nateglinide Form Y.
30 Figure 20 is an XRPD pattern for nateglinide Form Z.
Figure 21 is an XRPD pattern for nateglinide Form a.
Figure 22 is an XRPD pattern for nateglinide Form (3.

Figure 23 is an XRPD pattern for nateglinide Form y.
Figure 24 is an XRPD pattern for nateglinide Form ~.
Figure 25 is an XRPD pattern for nateglinide Form s.
Figure 26 is an XRPD pattern of nateglinide Form a.
Figure 27 is an XRPD pattern of nateglinide Form 8.
Figure 28 is a thermal stability chart showing transformation of the forms during drying, and is a summary of a comparison between the wet and the dry forms illustrated in various tables in the present invention.
Figure 29 is an FTIR spectrum of nateglinide Form L.
Figure 30 is an FTIR spectrum of nateglinide Form P.
Figure 31 is an FTIR spectrum of nateglinide Form U.
Figure 32 is an FTIR spectrum of nateglinide Form Z.
Figure 33 is an FTIR spectrum of nateglinide Form a.
Figure 34 is an FTIR spectrum of nateglinide Form 8.
Figure 35 is an FTIR spectrum of nateglinide Form ~.
Figure 36 is a DSC thermogram of nateglinide Form A.
Figure 37 is a DSC thermogram of nateglinide Form D.
Figure 38 is a DSC thermogram of nateglinide Form E.
Figure 39 is a DSC thermogram of nateglinide Form F.
2o Figure 40 is a DSC thermogram of nateglinide Form G.
Figure 41 is a DSC thermogram of nateglinide Form I.
Figure 42 is a DSC thermogram of nateglinide Form J.
Figure 43 is a DSC thermogram of nateglinide Form I~.
Figure 44 is a DSC thermogram of nateglinide Form L.
Figure 45 is a DSC thermogram of nateglinide Form M.
Figure 46 is a DSC thermogram of nateglinide Form N.
Figure 47 is a DSC thermogram of nateglinide Form O.
Figure 48 is a DSC thermogram of nateglinide Form P.
Figure 49 is a DSC thermogram of nateglinide Form Q.
3o Figure 50 is a DSC thermogram of nateglinide Form T.
Figure 51 is a DSC thermogram of nateglinide Form U.
Figure 52 is a DSC thermogram of nateglinide Form V.

Figure 53 is a DSC thermogram of nateglinide Form Y (chloroform solvate).
Figure 54 is a DSC thermogram of nateglinide Form Y (dichloromethane solvate).
Figure 55 is a DSC thremogram of nateglinide Form Z.
Figure 56 is a DSC thermograrn of nateglinide Form a.
Figure 57 is a DSC thermogram of nateglinide Form (3.
Figure 58 is a DSC thermogram of nateglinide Form y.
Figure 59 is a DSC thermogram of nateglinide Form 8.
Figure 60 is a DSC thermogram of nateglinide Form s.
Figure 61 is a DSC thermogram of nateglinide Form a.
l0 Figure 62 is a DSC thermogram of nateglinide Form 8.
Figure 63 is a XRPD pattern of nateglinide Form s~.
Figure 64 is a determination of purity of Form B prepared by Example 15.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides for 26 crystalline forms of nateglinide 15 ("NTG"), denominated Form A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, U, V, Y, a, (3, y, 8, s, 6, 8 and SI. These crystalline forms are characterized by their XRPD
pattern, DSC
thermogram and TGA analysis, among others. Also provided are processes for preparation of other polymorphic forms such as Form B, E, H, S and Z.
The various crystalline forms are characterized by their XRPD pattern, which 2o differs from one polymorph to another. Form E is rather similar by XRPD to Form Z, although some differences may be observed. The peak at 3.7 is characteristic of Form E
and is not observed in the XRPD of Form Z. The pattern in the range of 19-22 degrees two theta is also somewhat different between these two forms. Table I lists the most characteristic peaks for the new crystalline forms. The XRPD patterns are illustrated in 25 figures 1-27 and 63.
Table I: XRPD characteristic peaks for the nateglinide crystalline forms Crystal FormCharacteristic XRD peaks- Within about t 0.2 degrees two theta A 6.6, 13.3, 13.9, 16.8, 27.2, 28.0 (Fig. 1) C 5.2, 8.2,8.8 (Fig. 2) D 6.6, 7.5, 13.1, 16.5, 17.4, 21.1 (Fig. 3) E 3.7, 4.6, 14.9, 15.6, 16.1 (Fig. 4) F 4.8, 5.3, 15.2, 18.9, 19.6 (Fig. 5) G 14.4, 15.3, 19.3, 20.3 (Fig. 6) I 5.5, 7.4, 16.8 (Fig. 7) J 8.0, 11.2, 12.0, 15.9, 16.1, 17.7, 28.1 (Fig.
8) I~ 9.5, 15.4, 17.1, 21.2 (Fig. 9) L 17.6, 17.9, 19.6 (Fig. 10) M 16.2, 16.4, 17.0, 17.8, 18.6, 19.4, 19.6 (Fig.l l) N 5.3, 5.5, 8.9, 9.9, 20.4, 21.1 (Fig. 12) O 4.4, 5.2, 15.7, 16.6 (Fig. 13) P 4.0, 4.6, 13.4, 13.9, 19.1 (Fig. 14) Q 5.1, 5.6, 16.2, 19.8 (Fig. 15) T 7.2, 7.9, 8.3, 10.7 (Fig. 16) U 4.7, 7.4, 13.8, 17.0 (Fig. 17) V 4.5, 5.8, 11.4, 16.4 (Fig. 18) Y 6.1, 14.2, 15.1, 18.7 (Fig. 19) Z 4.7, 5.3, 13.5, 13.9, 15.1, 15.7, 16.1, 18.7, 19.5, 21.5 (Fig. 20) 4.8, 5.1, 19.0, 19.4, 27.7, 28.9, 31.2 (Fig.
21) (3 4.6, 9.4, 13.9, 18.8 (Fig. 22) y 4.4, 8.9, 18.4, 18.8, 19.5 (Fig. 23) 5.6, 14.5, 18.2, 18.9, 19.5 (Fig. 24) s 4.2, 13.0, 13.6, 14.3, 16.2, 16.7, 19.6 (Fig.
25) A 4.8, 7.8, 15.5, 17.7 (Fig. 26) a 5.5, 6.1, 6.7, 14.3 (Fig. 27) S2 4.5, 7.8, 15.5, 16.9, 17.8, 19.2, 19.7 (Figure 63) The various crystalline forms of nateglinide are also characterized by their DSC
therrnograms. Table II lists the DSC peaks (endotherms). In addition to the peaks listed in Table II, many of the various crystalline forms show an exotherm at about 165°C
followed by an endotherm at about 174°C, probably due to recrystallization into S-Type Form.
Table II: DSC peaks of the nateglinide crystalline forms Crystal Form ~ DSC Peaks (°C) A (Fig 36) 70 98 138 -D (Fig 37) 66 130 E (Fig. 38) 75 86 104 129 F (Fig 39) 53 103 128 G (Fig 40) 106 127 - -I (Fig 41) 46 121 - -J (Fig 42) 49 105 168 -K (Fig 43) 79 105 145 170 L (Fig 44) 131 138 -M (Fig 45) 90 102 128 -N (Fig 46) 77 100 130 137 O (Fig 47) 106 126 137 -P (Fig 48) 106 113 (exotherm)128 -Q (Fig 49) 102 126 - -T (Fig 50) 68 106 130 -U (Fig 51) 128 138 - -V (Fig 52) 81 139 - -Y dichloromethane 122 130 - -solvate (Fig 54) Z (Fig. 53) 90 95 a (Fig 56) 129 - - -(3 (Fig 57) 91 100 - -y (Fig 58) 93 136 - -8 (Fig 59) 100 107 (exotherm)130 -E (Fig 60) 64 108 129 -6 (Fig 61) - - - 127 B (Fig 62) 70 104 115 130 (exo) The various crystalline forms are also analyzed by Thermal Gravimetric Analysis (TGA). TGA measurements show that Forms A, D, E, F, G, I, J, K, M, N, O, Q, T, U, V, Y, Z, (3, y, s, A and S~ contain significant amounts of bound solvents and may be considered as solvated forms of nateglinide. The XRPD analysis of some of these solvated forms show that some of them are unstable when left in an open bottle for 24 hours. In contrast to the above listed forms, TGA profiles of forms L, P, U, a, 8 and 6 show no significant weight loss. These polymorphic forms ofnateglinide are free of bound solvents, i. e., less than about 2% LOD. Table III lists the solvents used for the preparation for nateglinide solvated forms, as well as LOD values based on TGA
analysis.
The ethanol solvate of nateglinide disclosed herein has an ethanol content of from about 10% to about 30% by weight. The ethanol solvate of nateglinide ethanol solvate is 1o represented by formula NTG~3/2 EtOH. Specifically, the solvate is nateglinide Form D.
The methanol solvates of nateglinide disclosed herein have a methanol content of from about 2 to about 60% by weight. Specifically, nateglinide methanol solvate exists as nateglinide Form E, Form O and Form T methanol solvate. Nateglinide methanol solvate is represented by the formula NTG* 1/4 MeOH (Form O) or by the formula NTG*

15 MeOH (form E). Nateglinide Form T contains more than about 20% methanol by weight.
The methanol content of Form T is from about 20% to about 60% by weight.
The isopropyl solvate of nateglinide disclosed herein has an isopropyl alcohol content of from about 12% to about 30% by weight. Specifically, isopropyl solvate of nateglinide exists as nategli'nide Form G.
2o A hydrate of nateglinide, Form Z, has a water content of about 10 to about 50%, more preferably about 10% to about 40%, and most preferably from about 15% to about 25%, measured either by the Karl Fischer method or LOD. Form S~, is a hydrate-solvate of isopropanol and contains about SO% LOD water and isopropanol.
The heptane solvated form of nateglinide, Form 8, has about 7 to about ~%
heptane 25 by weight, and is represented by the formula NTG~ 1/4Heptane.
Table III: LOD values by TGA and solvents used for the preparation of nateglinide solvated forms Crystal Form Solvent LOD by TGA Comments (weight %) Storage at RT for 24h is A Xylene g0 results in a partial conversion to Form B

C DMA >5 D Ethanol 25 E MeOH 4 F n-PrOH 16-24 G Isopropyl Alcohol22-28 20 Storage at RT for 24h I n-BnOH results in a conversion to Form L

XRD pattern slightly up to 100C.

J N-Methyl Pyrolidone changed after storage at RT

sharp weight loss at for overnight K Dimethyl formamide34 M Carbon tetra 2 chloride N Dichloroethane 8 O MeOH 2 Storage at RT for 24h results in a conversion to Q Chloroform 10 Form Y, which contains chloroform.

>20 Storage at RT for 24h T MeOH results in a conversion to Form E

V Dimethoxyethane 8-16 A sharp weight loss step of 7-8% is observed at 70C

Y Dichloromethane/2-8 Chloroform Beta N-Methyl Pyrolidone No significant weight loss Gamma N-Methyl Pyrolidone- up to 90C

Sharp weight loss at 90C

Acetone/

Nitromethane/ Above 4 Epsilon Acetonitrile Theta Heptane 7.4%

Omega IPA and Water 50%

The anhydrate forms and the hydrated Form Z, are also characterized by their FTIR spectrum. Form Z is characterized by a FT1R spectrum (Figure 31) with peaks at about 699, 1542, 1645, 1697, 2848, 2864, 2929, 3279 and 3504 cm 1. The more characteristic peaks are observed at about 1645, 1697, 3279 and 3504 cni 1.
Characteristic FTIR peaks are for the anhydrates, specifically Forms L, U, P, a, 8 and a are disclosed in the following table.
nateglinide form Characteristic FTIR Peaks Form Alfa: 3283, 1711, 1646, 1420, 1238 cm (Fig.
32) Form L: 1741, 1726, 1621, 1600, 1538, 1211, 1191 cm (Fig. 28) Form U: 3350, 1711, 1646, 1291 cm (Fig. 30) Form 8: 3306, 1729, 1704, 1275 cm 1 (Fig. 34) Form a~ 3303, 1705, 1640 cm ' (Fig. 35) Form P: ~ 3309, 1748, 1589 ciri 1 (Fig. 29) The various crystalline forms are related to each other in that drying of one form i0 may result in a transformation to another form, namely nateglinide Forms A, B, D, E, F, G, H, I, J, K, L, M, N, Q, S, T, V, Z, a, (3, b, y, s, 0 and S2. The drying is carned out by heating a sample under ambient or reduced pressure. Generally, a preferred temperature is from about 40°C to about 80°C, more preferably under reduced pressure. Of these forms, Forms B, H, L, U and sigma are thermally stable, and do not convert to another form upon heating. Many of the above forms convert to Form B upon drying, namely Forms A, C, D, E, F, G, J, K, P, Q, T, Z, a, (3, b, 0 and S2. Of these forms, Form a, 6, Y
and O are somewhat stable, and usually retain their crystalline structure after heating, unless heated to a high temperature. For example, Form 8 is stable when heated to 60°C overnight (at least about 8 hours), but heating of Form b at 120°C and 1 atmosphere results in Form B.
zo Thus, heating at a temperature above about 80°C may cause a transformation in these forms. The term "stable" as used herein refers to a polymorphic change of less than about 5% by weight, more preferably less than about 2%, particularly for Form 8.
The conversion of some of the forms to Form B goes through another form. For example, the conversion of Form S2 and E to Form B may go through Form ~.
Form G may represent a link between Forms F, T on the one hand, and Form B on the other hand. Forms T and F, upon drying, convert to a mixture of Form B and G, which makes is probable that Forms F and T convert to Fonn B by going through Form G.
Of the forms that convert to Form B, some of them sometimes under drying convert to other forms. Form K may convert to Forms a or S, while Form C may convert 1o to Form B or a. Form a may convert to Form S upon heating, but the presence of seeds of Form B in the sample of Form a results in Form B. Probably Forms C and K
transform to Form a first, and that it is through Form a that they transform to Form B or S. Form J
may convert to Form B or (3, though its conversion to Form B may go through Form (3.
The Form J used in preparing Form (3 is preferably obtained by crystallization from N-15 methylpyrrolidone. When Form J contains some seeds of Form y, heating results in Form Y.
The acetonitrile solvate of Form Epsilon, when dried, results in Form B. While the nitromethane solvates of Form Epsilon when dried result in Forms H or P. When Form P
is dried, Form H is obtained, which makes it probable that conversion of Form Epsilon to 20 Form H goes through Form P.
Another thermally stable Form of nateglinide is Form L. Form L may be obtained by heating Forms M, N and D. To obtain Form L, these various forms are preferably heated for about 3-10 hours at a preferred temperature range of from about 40°C to about 80°C, more preferably about 50°C under reduced pressure. Form y may also be prepared 25 by heating Form J containing seeds of Form y under similar conditions.
Another thermally stable form of nateglinide is Form H which may be prepared by heating nateglinide Forms P, V and s. Form S may be prepared by heating Forms a and K, though the transition of Form K to Form S may go through Form a.
Form U is another thermally stable Form of nateglinide, and does not undergo a 3o transition after being heated at about 100°C for at least about 8.5 hours.
Storage at room temperature and pressure may also cause a transition of one form to another. Form A partially converts to Form B during storage at room temperature for about a day. Form I converts to Form L under the same conditions. Also under the same conditions, Form Q converts to Form Y (containing chloroform), while Form T
converts to Form E.
Form a is related to Forms F, G, I and s in that it may be crystallized out of the same solvent as those forms, n-propanol, isopropyl alcohol, n-butanol and acetonitrile, respectively. Form a however is crystallized under different conditions, see e.g., Table N. Form a is often obtained with prolonged crystallization step (at least about 2-3 days).
Not being bound by any theory, this phenomenon may point to a possible conversion of another crystalline form, such as those obtained from the same solvent, to Form a overtime in the solvent.
Forms E and D are also related in that both of the forms may be crystallized out of ethanol; but these forms crystallize under different conditions, see e.g., Table IV. The crystallization of Form E in ethanol is prolonged, for at least about 5 days, more preferably at least about 1 month. Not being bound by any theory, it might be possible that initially Form D crystallizes out, followed by a conversion to Form E overtime in the solvent.
To prepare Form S, the wet sample obtained after crystallization has to be dried Crystallization from a solution of nateglinide in n-butanol and DMF results in a solvate, which needs to be dried to obtain Form S. The wet samples are nateglinide Forms K, I
and alpha.
Some of the forms may first appear as a gel, and then transform into crystals during the filtration step (e.g. form epsilon from nitromethane, and form A
from xylene) or overtime (e.g. Form M from carbon tetrachloride and Form J from N-methylpyrrolidone).
Generally, gels are unstable forms which crystallize over time.
Some of the crystalline forms may be obtained by trituration. As used herein, trituration refers to obtaining a solid from a mixture of nateglinide in a solvent without complete dissolution. A form of nateglinide is mixed in a particular solvent and agitated for a suf~'icient time to allow for transformation to another crystalline form. After agitation, a suspension or a paste forms. A solid may then be separated from the suspension by techniques well known in the art, such as filtration. The paste may be 3o filtered, to name one technique, to remove excess solvent. The result of this trituration procedure is various forms of nateglinide.

The trituration of Form delta in water may result in Form Z after about 5 hours, and Form E after about 8 hours, which may also point to a transition of Form Z
to Form E.
All three forms may be heated to obtain Form B.
Some of the crystalline forms may be obtained by solvent removal. First a solution of nateglinide in a suitable solvent is prepared. The solvent may be heated to obtain a clear solution. The solvent may be heated from about 40°C to about 70°C, with about 55°C being preferred. The solvent is then removed to obtain a residue, preferably at elevated temperature within the said range. The solvent is preferably removed by evaporation, with evaporation under reduced pressure being particularly preferred. The to resulting residue is then examined. Suitable solvents include esters, ketones, amines, amides, alcohols and nitriles. Removal of acetonitrile, acetone, ethyl acetate and iso-propyl alcohol as solvents results in nateglinide Form B.
Some of the crystalline forms are obtained by absorption of solvent vapors.
Nateglinide is contacted with vapors of a particular solvent, resulting in absorption of the solvent. Absorption of ethanol results in Form D, methanol in Form O, and DCM
in Form Y. Form H was stable in the presence of vapors of water and acetone.
Some of the crystalline forms may be obtained by crystallization from a suitable solvent. Form omega is obtained by crystallization of nateglinide out of a mixture of water and isopropanol. Preferably, the ratio of the water to isopropanol is from about 1/2 2o to about 1/5, more preferably 1/3 (vol/vol).
Nateglinide Form Z is generally prepared by acidification of a solution of an alkali metal or alkaline earth metal salt of nateglinide in an aqueous solvent.
Preferred solvent is water free of a co-solvent. Preferred salts are sodium and potassium salts, with the sodium salt being most preferred. Before acidification, the solution preferably has a pH of above about 8, while after acidification, the pH is preferable from about 1 to about 5, most preferably from about 2 to about 5. Acidification results in precipitation of nateglinide, which may be recovered by techniques well known in the art, such as filtration.
Nateglinide Forms B and U may be prepared by crystallization from an organic solvent such as ethyl acetate or acetone. In the procedure for the preparation of form B, 3o crystallization is preferably induced by concentration of the solvent, while for Form U, by seeding of the solution.
Nateglinide Forms B, H, U, Z, 8, 8 and 6 are related in that all of them may be prepared from a two solvent system. The two solvent system used is a mixture of a solvent and an anti-solvent. Example of suitable antisolvents are CS to C12 aromatic hydrocarbons such as toluene and xylene, and CS to C12 saturated hydrocarbons such as hexane and heptane. Examples of suitable solvents are C1 to CS alcohols such as methanol, ethanol, isopropanol, n-butanol and n-propanol, lower ketones (C3 to C6) such as acetone and lower esters ( C3 to C6) such as ethyl acetate. After crystallization, the crystals are recovered by techniques well known in the art, such as filtration and centrifugation, and may be dried. To dry, the temperature may be increased or the pressure reduced. In one embodiment, the crystals are dried at about 40°C to 60°C, at a pressure of less than about 50 mmHg.
When nateglinide is crystallized out of a binary mixture, particularly in the absence of stirnng, the crystalline product is often Form B, as illustrated in Table IX. The binary mixture is prepared by suspending nateglinide in the anti-solvent, and then adding the solvent to form a solution. Nateglinide Form B may be obtained at different crystallization temperatures, such as at room temperature and at about 0°C, particularly in the absence of stirring.
Crystallization from a binary mixture of the above solvents and anti-solvents may lead to other forms of nateglinide other than Form B. Crystallization out of a toluene/methanol mixture may result in nateglinide Form E, which may be converted to Form B by heating. Additionally, a heptane/ethyl acetate combination may sometimes lead to a mixture of Forms B and Z, especially with longer period of crystallization (over about 3 days), while a toluene/ethyl acetate mixture may result in a mixture of Form B and H. A mixture of Form B and Z may be converted to one containing substantially Form B
through heating, since Form Z converts to Form B through heating.
In another embodiments, rather than preparing a solution by first suspending nateglinide in the anti-solvent, a solution is prepared in the solvent, followed by combining with the anti-solvent. The combining is carried out in this embodiment in such a way where upon additon a solution is formed, and any precipitated solids go back into solution. Preferrably, the anti-solvent is heated so that upon mixing of the solution and the anti-solvent, immediate precipitation does not take place.
3o The different forms may be obtained depending on the solvent/anti-solvent ratio, crystallization conditions and the time of stirring. Generally, Form Z is crystallized from an ethyl acetate/heptane ratio of about 2 to 4, form H a ratio of about 4 to about 7, Form B
a ratio of about 6 to about 8, Form U a ratio of about 1 to about ~, Farm 8 a ratio of about 1 and Form 8 a ratio of about 1 to about 8, more preferably from about 1 to about 2 (vol/vol).
Of these, some forms may crystallize as other forms, and convert after being stirred for a sufficient time in the solvents. Stirnng the resulting slurry from crystallization at a temperature of from about -15°C to about 10°C, preferably about 5 °C, may result in Form S. Form 8 seems to result from stirring of forms such as Form U, Form 8, Form H and even Form B. Preferably the stirring to obtain Form ~ is carried out for at least about 2-3 hours, more preferably for at least about 10 hours.
Other than a solvent:antisolvent ratio of about 1, formation of Form 8 seems to be 1o favored at lower crystallization and filtering temperatures, from about -15°C to about 10°C
preferably 5°C. As previously noted, stirring of Form 8, preferably at the specified temperature range, results in Form b.
Form U may be obtained by stirnng with Form B or H in an organic solvent.
Stirring for about 1 hour is sufficient to obtain Form U. However, additional stirring, such 15 as above about 5 hours, may result in a transition to Form S. Form U may also be obtained by crystallization, preferably at the specified ratio, more preferably at a crystallization and filtering temperature of about -15°C to about 10° C. Form U is generally favored when starting with a temperature of from about 25°C to about 35°C, followed by cooling in less than about 1 hour to a temperature of from about 0°C to about 10°C, with about 5°C being 2o preferred, followed by filtering in less than about 1 hour. Higher solvent to anti-solvent ratio may favor form U over 0.
Form H may be obtained under both low and high crystallization temperatures, preferably under the specified solvent/anti-solvent ratio. Form B, on the other hand, tends to crystallize at a temperature of at least about 15 °C.
25 Forms Z generally crystallizes after about a day at a final cxystallization temperature of at least about 15 °C, more preferably from about 15 °C to about 30°C, and rnostpreferably from about 20°C to about 25°C. The initial crystallization temperature for these forms is preferably above 35 °C, followed by cooling in a few hours, more preferably about 1 hour, to about 20°C to about 25 °C. These conditions may lead to Form 30 Z, which converts to Form B by drying.
Form ~ may also be obtained by stirring of crystals of Form B. Not being bound by any theory, it may be possible that Form a is obtained through Form U, that is stirring results in a transition of Form B to Form U followed to Form a. Prolonged crystallization and filtration is preferred for obtaining Form 6, i.e., preferably at least about 10 hours.
Table X does not show a transition of Form B to other forms despite prolonged stirring in the anti-solvent/solvent system due to use of a high ratio of ethyl acetate.
Preferably about a 1:1 ratio of solvent to anti-solvent is used for obtaining other forms through stirring of Form B in a solvent/antisolvent mixture.
The results of the processes may vary when precipitating a solid after combining the solution and the anti-solvent. In this embodiment, the solution is combined with the anti-solvent in such a way to result in precipitation, in contrast with the other embodiments l0 that result in a solution after the combining step. To cause substantial precipitation, preferably, the solution is combined with a cold anti-solvent. More preferably, the antisolvent is from about 20°C to about 40°C colder than the solution, particularly when an ethyl acetate/heptane system is used. Most preferably, the heptane has a temperature of from about 0 ° C to about 10 ° C and the ethyl acetate a temperature of from about 30 ° C to 15 about 40 ° C.
In this embodiment, Form U may be obtained within a wide range of solvent/anti-solvent ratios and crystallization temperatures. For example, table XI shows that Form U
may be obtained from a solvent to anti-solvent ratio of frpm about 1 to about 6, and final crystallization temperatures from about 0°C to about 30°C. Not being bound by any 2o theory, the presence of other forms, particularly Form 8 and Q, especially after long crystallization step, points to possible a transition of Form U to these forms. The presence of a mixture of Form B and U after 1 hour also points to the possibility that Form B might be immediately crystallized out of the solution, followed by a transition to Form U, which itself may change overtime to Forms 8 or 6.
25 The following table provides guidance on obtaining Forms B, H, U, Z, ~, 8 and a from a solvent:anti-solvent system:
V/V ratio Filtration Crystal temp.

(EA/l3eptane)(about) form (about) obtained i :1 15 C - 3 No stirring B

preferably 15 C - 30 Immediately after B
C crystallization 1: I With stirring preferably Stirring for at least about 21h 1:1 1 S C - PrecipitationImmediately after B
30 C crystallization preferably without 20-25 C going into solutionStirring for at U
least about lh after combining 1:1 -15C -10 Immediately after C crystallization D,y~s preferably a -~

Stirring at about g 1.5:1 -15C -10 C

preferably Immediately after U
5C crystallization Stirring at about g 2:1 - 8:1 -15C - 10 Immediately after H (95%
C crystallization preferably yield) Stirring for about 1-5h U

Stirring for at least about Sh 2:1 - 8:1 15 C - Wet crude p preferably material Z ~ B

2:1 - 8:1 15 C - Dry crude H

preferably material Depending on the preparation procedure, nateglinide Form ~ may contain from about 0.5% to about 3 % of residual heptane by weight. The removal of heptane without changing the crystal form may be carried out in a fluidized bed drier, preferably at a temperature of from about 60 to about 70°C, more preferably for at least about 3 hours.
The residual Heptane may be also removed under stirnng, preferably at a temperature of at least about 40°C under vacuum. The 8 Form is preferably polymorphically pure and contains less than about 5% Form H (wtlwt), more preferably less than about 2%
(wt/wt), and most preferably less than about 0.5% (wt/wt).
10, Crystalline Form 8 is stable at a temperature of about 40°C and a relative humidity of about 75% for at least about 3 months.

Trituration of Form 8 in ethyl acetate may result in other polymorphic forms of nateglinide. Triturating nateglinide Form 8 at a temperature of from about 20 to about 30°C in ethyl acetate results in Form U, while triturating at higher temperatures (above 40°C), such as at about 50°C, results in Form B.
The processes of the present invention allow for obtaining Forms b and B with a purity of at least about 95%, more preferably at least about 98% wt/wt compared to other polymorphic forms. These forms may be produced particularly free of the H
Form.
The starting material used for the processes of the present invention may be any crystalline or amorphous form of nateglinide, including various solvates and hydrates.
to With crystallization processes, the crystalline form of the starting material does not usually affect the final result. With trituration, the final product may very depending on the starting material. One of skill in the art would appreciate the manipulation of the starting material within skill in the art to obtain a desirable form with trituration.
The processes of the present invention may also be practiced as the last step of 15 prior art processes that synthesize nateglinide.
Many processes of the present invention involve crystallization out of a particular solvent, i.e., obtaining a solid material from a solution. One skilled in the art would appreciate that the conditions concerning crystallization may be modified without affecting the form of the polymorph obtained. For example, when mixing nateglinide in a 2o solvent to form a solution, warming of the mixture may be necessary to completely dissolve the starting material. If warming does not clarify the mixture, the mixture may be diluted or filtered. To filter, the hot mixture may be passed through paper, glass fiber or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration 25 apparatus may need to be preheated to avoid premature crystallization.
The conditions may also be changed to induce precipitation. A preferred way of inducing precipitation is to reduce the solubility of the solvent. The solubility of the solvent may be reduced, for example, by cooling the solvent.
In one embodiment, an anti-solvent is added to a solution to decrease its solubility 30 for a particular compound, thus resulting in precipitation. Another way of accelerating crystallization is by seeding with a crystal of the product or scratching the inner surface of the crystallization vessel with a glass rod. Other times, crystallization may occur spontaneously without any inducement. The present invention encompasses both embodiments where crystallization of a particular form of nateglinide occurs spontaneously or is induced/accelerated, unless if such inducement is critical for obtaining a particular form.
Nateglinide of defined particle size may be produced by known methods of particle size reduction starting with crystals, powder aggregates and course powder of the new crystalline forms of nateglinide. The principal operations of conventional size reduction are milling of a feedstock material and sorting of the milled material by size.
A fluid energy mill, or micronizer, is an especially preferred type of mill for its ability to produce particles of small size in a narrow size distribution. As those skilled in 1o the art are aware, micronizers use the kinetic energy of collision between particles suspended in a rapidly moving fluid stream to cleave the particles. An air jet mill is a preferred fluid energy mill. The suspended particles are injected under pressure into a recirculating particle stream. Smaller particles are carried aloft inside the mill and swept into a vent connected to a particle size classifier such as a cyclone. The feedstock should 15 first be milled to about 150 to X50 ~m which may be done using a conventional ball, roller, or hammer mill. One of skill in the art would appreciate that some crystalline forms may undergo a transition to another form during particle size reduction.
Pharmaceutical compositions may be prepared as medicaments to be administered orally, parenterally, rectally, transdermally, bucally, or nasally. Suitable forms for oral 20 administration include tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, sub-lingual tablets, syrups and suspensions. Suitable forms of parenteral administration include an aqueous or non-aqueous solution or emulsion, while for rectal administration suitable forms for administration include suppositories with hydrophilic or hydrophobic vehicle. For topical administration the invention provides suitable 25 transdermal delivery systems known in the art, and for nasal delivery there are provided suitable aerosol delivery systems known in the art.
Pharmaceutical formulationss of the present invention contain a nateglinide Form selected from A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, V, Y, a, [3, y, 8, s, ~, 6 and S2.
The pharmaceutical composition may contain only a single form of nateglinide, or a 3o mixture of various forms of nateglinide, with or without amorphous form. In addition to the active ingredient(s), the pharmaceutical compositions of the present invention may contain one or more eXCipients or adjuvants. Selection of excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
Diluents increase the bulk of a solid pharmaceutical composition, and rnay make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel~), microfme cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit~), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g.
carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel~), hydroxypropyl methyl cellulose (e.g. Methocel~), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g.
Kollidon~, Plasdone~), pregelatinized starch, sodium alginate and starch.
2o The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach rnay be increased by the addition of a disintegrant to the composition.
Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol~, Primellose~, colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon~, Polyplasdone~), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab~) and starch.
Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as 3o glidants include colloidal silicon dixoide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
When a dosage form such as a tablet is made by the cornpaction of a powdered composition, the composition is subjected to pressure from a punch and dye.
Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A
lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
In liquid pharmaceutical compositions of the present invention, nateglinide and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product andlor coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
According to the present invention, a liquid composition may also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.
Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
to The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most 15 preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and losenges, as well as liquid syrups, suspensions and 20 elixirs.
The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
25 The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.
A composition for tableting or capsule filling may be prepared by wet granulation.
In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the 3o powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.

A tableting composition may be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
The dosage and formulation of STARLIX may be used as a guidance. The dosage used is preferably from about 30 to about 240 mg of nateglinide, more preferably from about 60 to about 120 mg of nateglinide. The pharmaceutical compositions of the present invention, preferably in the form of a coated tablet, are administered from about 10 minutes to about 1 hours prior to a meal, more preferably about 15 minutes before each 2o meal. The dose is not taken if the meal is skipped. The pharmaceutical compositions may also be used in combination with metaformin.
Instruments X-Ray Powder Diffraction:
X-Ray diffraction was performed on X-Ray powder diffractometer, Scintag°, variable goniometer, Cu-tube, solid state detector. Sample holder: A round standard aluminum sample holder with round zero background quartz plate.
The sample was put on the sample holder and immediately analyzed as is.
Scanning parameters: Range: 2-40 deg 28, Continuos Scan, Rate: 3deg./min.
3o DSC:
DSC~2le Mettler Toledo°, Sample weight: 3-Smg, Heating rate:
10°C/min, Number of holes in the crucible: 3 TGA:
Mettler TG50~, Sample weight: 7-l5mg, Heating rate: 10°Clmin FTIR:
s Perkin -Elmer~, Spectrum One FTIR spectrometer, Range: 4000-400cm-1, no. of scans:
16, resolution: 4.Ocm-1, DRIFT technique.
EXAMPLES
to Example 1- This example illustrates preparation of various forms of nate~linide from a solution Nateglinide (5 g) was placed into an erlenmeyer flask and heated to the specified temperature. The solvent was added in 1-ml portions (in some cases, the solvent was added in 5-ml portions) until a clear solution was obtained. If a clear solution was not 15 obtained after addition of 150 ml of the solvent, the hot mixture was filtered.
The clear solution was left to crystallize at room temperature. If crystallization did not happen or was poor, the solution was refrigerated at 3°C. The precipitate was filtered off (at RT or at 5°C depending on the temperature of the crystallization), weighed and divided into 2 equal parts. One part was dried at 50°C under reduced pressure (20-30 2o mmHg) to constant weight 00.01 g) for about 3-10 hours. Details are presented in Table IV.
Table IV. Data on crystallization of NTG from a single solvent SolventLIS, T, Time Time Form Form ml/g C RT, 3C, Wet Dry h h Xylene 30 70 25 A AB

EtOH 1 55 25 D L

EtOH 2* 54 6 42 D B

MeOH 1 55 24 E B

EtOH 3 55 1 m 18 d E B

n-PrOH 1 57 25 144 F G+B

n-PrOH 2 55 10 cc a d n-PrOH 2 55 3 5 d a a IPA 1.2 57 25 48 G B

IPA 3 55 1 m 20 a a NMP 1.4 57 73 J B+(3 DMF 1.6 56 24 52 K S

DCE 2.2 55 23 47 N L

DME 1.4 56 96 V H

n-BuOH 4 55 1 m 20 a S

n-BuOH 1.4 57 25 144 I S

Acetone2 20 144 20 H

NM 30 70 24 s P

MeCN 8 55 3 20 E s+B

MeCN 19 5 8 d a a S

MeCN 19 55 7 d 5 a a DCM 2* 54 47 Y Y

EA 9 55 22 a a EA 9 55 lOd Sd a a EA 15 55 9 d a a EA 15 55 8d Sd a a LegefZd. L/S - liquid/solid ratio: * - the solvent was added in 5-ml portions;
T - starting temperature; Ww - weight of wet sample after filtration, Wd - weight of the sample after drying at 80-90°C/20 mbar.
Solvent abbreviations: MeOH- methanol, EtOH - ethanol, n-PrOH - n-propanol, 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 nateg~linide Form H and U
in various solvents Nateglinide (5 g) was placed into an Erlenmeyer flask. Solvent was added in 1-ml portions to prepare a stirrable mixture. The flask was stirred with a magnetic stirrer at room temperature. A solid was filtered off at room temperature, weighted, and divided into 2 equal parts. One part was dried at 55°C under 20-30 mm/Hg pressure to constant weight 00.01 g).
Details are presented in Tables V and VI.
Table V. Data on trituration of NTG with a single solvent Start SolvenL/S Time,Form Form Form t ml/g h wet dry H MeOH 1.2 24 T G+B

H EtOH 1.2 24 D B

H IPA 1.2 24 G ~ G+B

H n- 1.2 23 F B
PrOH

H n- 1.4 24 I
BuOH

H MeCN 4.8 25 P H+P

H NM 4 26 s H+P

H NMP 0.8 24 J (3 H DMF 1.2 25 K

H DMA 1.2 26 C B

H DME 1.4 24 V H

H Dioxa2.2 24 s s ne H THF 0.8 ~

H DCM 1.8 25 Y Y

H CHC131 25 Q Q+B

H ~ 1.8 24 Q+H Q+H
DCE

Table VI. Data on trituration of NTG with a single solvent Start SolvenL/S Time,Form Form Form t mUg h wet dry U AcOH 1.8 24 H+S H+S

U MeOH 1.2 24 a a U EtOH 1.6 24 B+a B+a U IPA 1.8 24 G+S G+S

U n- 1.4 25 F B
PrOH

U n- 1.6 26 a a BuOH

U NMP 1 25 J+y U DMF 1 23 K a U DMA 1.2 24 C a U Aceto2 24 P P
ne U MEK 2.4 23 H+a H+S

U MIPK 3 24 H+a H

U MIBK 3.6 24 H+a H+S

U DME 1.8 24 H+a H+S

U Dioxa2 23 g B
ne U THF 0.8 23 g 8+B

U DCM 1.6 24 Y+S Y+S

U CHC131.2 25 g g U DCE 3.8 26 Q Q

Example 3- This Example illustrates Absorption of solvent va ors by nate~linide Nateglinide (3.50 g) was added to a polypropylene can and weighed. The can was introduced into a bigger polypropylene container containing a solvent, and stored at room temperature. The can was removed from the container and weighed (Wfinal). The can content was divided into 2 portions. One portion was dried at a temperature of 55 °C and a pressure of 20-30 imnHg to constant weight 00.01 g). Details are presented in Table VII.
Table VII. Data on absorption of solvent vapors with NTG Form H
NTG Brutto,SolveTime,WBn D Form Form W, g g nt d al wet dry 3.50 15.77 EtOH 4 16.290.5D B

3.50 15.94 MeOH 4 16.120.1O O

3.50 15.78 Aceto4 15.860.0H H

ne 8 3.49 51.86 DCM 4 51.900.0Y

3.50 15.27 Water4 15.290.0H H

Legehd. Brutto - starting weight of the can with NTG; Wfinal - final weight of the can with NTG after the exposure; D - overweight Example 4- This example illustrates preparation of various forms of nate~linide by solvent removal.
1o Nateglinide (5g) was dissolved in the following solvents at about 55 C in over about 15 minutes until a clear solution was obtained. The solvent was removed to dryness by evaporation at about 55 C/20-30 mmHg to give dry nateglinide.
Table VIII- Data on solvent removal SolventForm, dry MeCN B

AcetoneB

EA B

Example 5- This example illustrates preparation of Form Z.

D-Phenylalanine (PheOH, 7.73 g) was treated with 3.5% NaOH (185 ml, 3.5 equivalents), at room temperature to afford a clear solution of the corresponding Na-salt.
A solution of neat trans-4-isopropylcyclohexanecarboxyl chloride (IPCHAC, 9.02 g, 1.01 equivalent) was added to the solution of Phe-OH obtained above, over 3 minutes, while stirring at room temperature. The rest of the IPCHAC in the funnel was washed with toluene (1 ml) and added. The resulting mixture was stirred for 1 hour, and was treated with 10% HCl (32 ml) to adjust the pH to 3, while stirring. The mixture was stirred for 1 hour, and filtered. The solid was washed with water (200 ml) and sucked well to afford 33.3 g of the moist product, which lost weight after drying at 78°C/2.2 mbar. Assay 98.4%, purity >99%, yield 86%.
Example 6- This example illustrates preparation of nate~linide by crystallization from binary mixtures (solvent/anti-solvent).
Nateglinide (Sg) and an anti-solvent (20 ml) were placed into an Erlenmayer flask.
The mixture was heated at about 55°C over about 15 minutes, followed by addition of solvent in 0.25-1 ml portions until a clear solution was obtained. The clear solution was left to crystallize without stirring at room temperature.
If crystallization did not happen or was poor after 24 hours, the solution was refrigerated at 3-5°C. The precipitate was filtered off (at RT or at 5°C depending on the temperature of crystallization) to give Form B. The wet material was dried at 50°C under 2o reduced pressure (20-30 mmHg) to give dry Form B.
Table IX. Data on crystallization of NTG from binary solvents Solvents Ratio,L/S, T~,yst.,TimeWw, Wd,Form Form v/v ml/g Cf , g g wet dry h Toluene- 40:1 4.1 RT-~3 23/237.843.56B B

EtOH

Toluene- 40:1 4.1 3 22/236.823.72E B

MeOH

Toluene-IPA27:1 4.15 RT~3 22/247.833.28 B

Toluene-EA4.2:1 4.95 RT 26 7.274.0 B+H

Toluene-n-20:1 4.2 3 18/253.341.76B B

BuOH

Toluene-n-27:1 4.15 3 24/715.182.64B B
PrOH

Xylene-EA2:1 6 3 23/729.403.60B B

Heptane-EA1:1.3 9.2 RT 94 3.622.26B+Z B

Heptane-EA1:1.3 9.2 RT 25 4.362.24B B

Hexane-EA1:1.2 8.8 RT 94 5.052.46B B

Hexane-EA1:1.2 8.8 RT 25 2.722.32B B

Toluene- 5.7:1 4.7 3 22/725.562.88B B
acetone Legehd:
L/S- liquid/solid ratio (liquid= solvent+anti-solvent); f - symbol RT33 means that crystallization was started at room temperature then the mixture was cooled to 3°C to complete precipitation.
Example 7- Preparation of Form delta (A) This example illustrates preparation of nate~linide Form delta by crystallization from an ethyl acetate-heptane solvents s s Preparation of nate~linide form ~
io D-Phenylalanine (15.44 g) was added all at once to a 3.5% NaOH solution (370 ml, 3.5 equivalents), at 20°C, under stirring, 230 mini 1. A clear solution was immediately formed.
A neat traps-4-isopropylcyclohexylcarboxychloride (18.03 g) was added for 5 minutes to the reaction solution. A solid was formed and the temperature rose to 32°C. The mixture was stirred for 1 hour at 20°C, under stirring. A 15% H2S04 (56.1 g) was added all at once to the reaction mixture to adjust the pH to 1-2. The mixture was stirred for 1 h at 20°C and the solid product was filtered off to afford cake- 76 g of a wet product (moisture 65%). The product was dissolved in EA (200 ml), and the aqueous phase was removed.
The organic phase was concentrated at 50°C under reduced pressure to afford 104 g of a turbid solution, containing 95 ml of EA. The solution was filtered and added for 30 2o minutes to hot heptane (54°C, 250 ml). The initially formed solid completely dissolved after addition of 2/3 of the EA solution. The clear solution was allowed to cool to 25°, seeded with B-form, and left for crystallization overnight, under stirring at 215 revolutions miri 1. The solid was filtered off and washed with heptane (30 ml). The cake was dried at 60°C120 mbar to afford 6.84 g of the d-form. Yield 33%.
Preparation of nateglinide Form 8 D-Phenylalanine (20.00 g) was added all at once to a 3.5% NaOH solution (370.12 g, 2.7 equivalents), heated to 35°C, under stirring, 200 miri 1. A clear solution was immediately formed. A neat trans-4-isopropylcyclohexylcarboxychloride (23.3 g) was, added all at once to the hot reaction mixture for 1 minute. A turbid solution was formed and the temperature rose to 40°C. The mixture was stirred for 20 minutes at 40-43°C under stirring. An 85% solution of HZS04 (11.94 g) was added all at once to the RM
to adjust 1o pH 1-2. The solid product was extracted with EA (140 ml). The hot organic extract was washed with warm water (100 ml), followed by brine (25 ml, 30.0 g) at 40°C, and dried with anhydrous magnesium sulfate (3.05 g) over 1.5 hours. The organic solution was filtered through a PTFE 0.45 p.m filter, heated to 38°C and to which was added hot heptane (40°C, 125 ml). The resulting clear solution was gradually cooled for 45 minutes to 13°C and seeded with NTG in B-form. The crystallization started. The mixture was then cooled for 17 min to 5°C and stirred for 16 h. The solid was filtered off and washed with a cold (5°C) mixture of heptane-EA mixture (5:1, total 180 ml) to afford 36.49 g of a wet product (wetness 42.5%). The wet product was dried at 60°C/13 mbar to afford 20.38 g of the product, Form 8, with a purity >99.8%. Yield 55%.
Preparation of nateglinide form S
D-Phenylalanine (20.02 g) was added all at once to a 3.5% NaOH solution (total 410.5 g, 2.99 equivalents), heated to 39°C, under stirring 150 miri 1. A clear solution was immediately formed. A neat trans-4-isopropylcyclohexylcarboxychloride (24.73 g) was added all at once to the hot reaction mixture. The mixture (clear solution) was stirred for 25 minutes at 44-45°C, under stirring. Ethyl acetate (140 ml), followed by an 85%
solution of HzS04 (14.08 g) were added all at once to the reaction mixture to adjust the pH
to 1-2. The hot organic layer was separated, washed twice with water (100 ml) at 30°C, and filtered through a PTFE 0.45 p.m filter. The clear solution (141 g) was heated to 46°C
and to which was added hot heptane (46°C, 153 ml), under stirring at 1 SO miri 1. The 3o clear solution was gradually cooled to 28°C and seeded with Form delta. The crystallization occurred at 24°C. The mixture was stirred for 30 minutes at 24°C, gradually cooled to S°G and stirred overnight at 5°C. The solid was filtered off and washed with a cold (5°C) heptane-EA mixture (6:1, total 30 ml) to afford 49.1 g of a wet product in form delta (wetness 50%). The wet product was dried for 24 h at 23°C/20 mbar to afford 24.65 g of the product in a form delta with a purity >99.8%. Yield 65%.
(B) This example illustrates thepreparation of form ~ crystallization Crude nateglinide (50 grams) was dissolved in ethyl acetate (200 ml) and water (2.5 ml) at 45°C. Hot heptane (260 ml) at 50°C was added. The mixture was still fully dissolved.
The mixture was cooled to 30°C and seeded with nateglinide Form 8 (0.1 grams). The mixture was stirred for 30 minutes and then cooled to less than 10°C in 2 hours. The mixture was stirred at 5-10°C overnight and then filtered with vacuum.
The wet product to was washed with ethyl acetate (100 ml) heptane mixture (ratio 1:3 v/v). The wet product was dried in a vacuum oven at 50°C overnight. Both the wet and dry samples were Form s.
Starting material: Wet nateglinide (40% total wetness. 2 ml water, 10 ml ethyl acetate, 21 ml of heptane). Wet crude nateglinide (~3 grams) and dry nateglinide (50 grams) were dissolved in ethyl acetate (190 ml) at 45°C. Hot heptane (239 ml) at 50°C was added.
The solution was cooled to 30°C and a seeded with nateglinide (0.1 grams) Form 8. The mixture was stirred for 30 minutes and then cooled to less than 10°C in 2 hours. The mixture was stirred at 5-10°C overnight and then filtered with vacuum.
The wet product was washed with ethyl acetate-heptane mixture (100 ml) (ratio 1:3 v/v). The wet product 2o was dried in a vacuum oven at 50°C overnight. Both the wet and dry samples were Form s.
(C) This example illustrates the dryin~ of form 8 by fluidized bed dryer Nateglinide Form delta (10 grams), with about 3 % heptane (wt/wt), was dried in a fluidized bed drier for 4 hours at 60°C. Residual heptane was 1578 ppm af. Ethyl acetate is under detection limit. Polymorphic form of the dry product is delta.
According to these procedures, a series of experiments were carried out under various heptane/ethyl ratios, liquidlsolid ratios, temperature and seeding.
The results are summarized in Table X:
3o Table X. Data on crystallization of NTG in EA-Heptane solvents system Seed Anti- Ratio L/S, TemperatureYield, Form Form ml/g %

solventv/v profile wet dry None Hexane 2.7:1 11 40(1)20(16) 58' Z B+Z

None Heptane4:1 16 40(1)20(16) 64 Z B

None Heptane5:1 11 40(1)20(16) 74 H H

None Heptane4.7:1 11 40(1)20(16) 68 H H

None Heptane7.5: 11 40(1)20(16) 48 B B

None Heptane5:1 8 40(1)20(16) 72 H

None Heptane6:1 10 60(0.1)20(16)76 B B

None Heptane7.1:1 11 20(16) 78 H H

B Heptane5.1:1 14 5(1.5)5(1) 77 H H

B Heptane2.5:1 16 5(2)-j5(1) 74 H H

B Heptanel:l 7.5 165(16) 51 B Heptanel:l 7 30(1)5(16) 58 B Heptane1:1 7.6 13(1)-5(16) 59 B Heptane1:1 7.4 13(1)-35(16)55 8 b B Heptane2:1 9 30(0.5)-X5(1)76 H+U
5(1)-j5(16) 8 B Heptane1.5:1 7.5 32(0.5)5 71 U
5(1) U
5(1)5(16) 8 None Heptane2:1 10 31(0.5)-35(4.5)67 8 None Heptane1:1 9(0.5)5(1) 8 B
5(1)-5(16) g Heptane1:1 7.8 9(0.5)5(16) 46 ~ g B Heptane1.1:1 6.1 25(0.5)5(16)63 Heptane1:1 7 19(0.5)-5(16)54 8 S

B Heptane1:1 7.6 13 (0.5)5 52 8 8 (16) b Heptane1:1 6.1 30(0.5)5(16)55 8 b Temperature profile: crystallization temperature (h)-j~nal temperature (h);
L,t-amount of L,trans-isomer.

Example 8 This example illustrates preparation of forms of nate lig ~iude by precipitation without ~oin~ to solution after combining Preparation of Nate~linide form U
D-Phenylalanine (20.02 g) was added all at once to a 3.5% NaOH solution (369.73 g, 2.7 equivalents), at 20°C, under stirring, 200 revolutions miri ~. A clear solution was immediately formed. A neat trans-4-isopropylcyclohexylcarboxychloride (23.9 g) was added all at once to the hot reaction solution for 1 minute. A solid was formed and the temperature rose to 32°C. The mixture was stirred for 40 minutes at 20°C, under stirring.
An 85% solution of HZS04 (11.55 g) was added all at once to the reaction mixture to 1o adjust the pH to 1-2. The solid product was extracted with EA (150 ml) at 55°C for 55 minutes. The hot organic extract was washed with warm water (100 ml), followed by brine (40°C, 50 ml), dried with anhydrous sodium sulfate (10 g) over 1.5 h, and filtered.
The excess of EA was removed under reduced pressure to afford 86 g of the solution, containing ~54 g (60 ml) of EA. The EA solution was finally filtered through a PTFE
15 0.45 wm filter into a clean dropping funnel heated to 35°C. Heptane (320 ml) was placed into the reactor; cooled to 5°C, and seeded with B-form. The clear hot EA-solution was added for 5 minutes to the cold heptane, under stirring. Precipitation immediately happened to afford a solid. The mixture was stirred for 2.5 hours at 5°C. The solid was filtered off and washed with a cold (5°C) mixture of heptane-EA mixture (4.5:1, total 20 120 ml) to afford 63.62 g of a wet product (wetness 54%). The cake (62.4 g) was dried at 60°C/10 mbar to afford 28.6 g of the product, containing ~0.6% of L,trans-isomer (other impurities <0.1%) in the U-form. Yield 77%.
Table XI. Data on crystallization of NTG during the crystallization process (precipitation without going into solution after combining) Seed Anti- RatioL/S, TEA, TAS(time),YielL,t,Form Form solventv/v ml/g C C(h) d, % wet dry B Heptane3.7:117 25 55(25) 33 0.058 None Heptane5.4:112 40 5(2.5) 77 0.7 U U

None Heptane0.77:19.7 45 45325(1) 71 0.01B+U
25(1)25(22) 2 U U

None Heptane0.8:19.7 45 45-j25(21)72 0.03a a TEA - temperature of the EA solution; TAS(time) - temperature of anti-solvent (exposure time)-~final temperature (exposure time); L,t- amount of L,trans-isomer.
Example 9- Heating of nate~linide Form U
Sample of nateglinide form U (Nl g) was introduced into a 6-gram vial and heated over 8.5 h in a 100°C oil bath. The vial were extracted from the bath. The resulted sample showed Form U by XRPD.
Sample of nateglinide form U (N0.5 g) was heated to 120°C for lh in an atmospheric pressure. The resulted sample showed Form U by XRPD.
Example 10- heating of nateglinide Form 8 Sample ofnateglinide form & (~0.5 g) was heated to 120°C for lh in an atmospheric pressure. The resulted sample showed Form B by XRPD.
Example 11- Preparation of Form Omega Nateglinide Form delta (5 grams) was dissolved in isopropanol (15 ml) at room is temperature. The solution was cooled to ~ 0°C. Water (6 ml) was added. A white solid precipitated suddenly. The solid was heated to 35 °C, resulting in complete dissolution.
The solution was cooled to ~7°C and the product precipitated. The product was filtered with vacuum. XRPD confirmed the presence of Form omega.
Example 12- Dryin~ of a wet sample of Form Omega 2o The product of example 11 was dried at 50°C in a vacuum oven overnight, and analyzed by XRD. A mixture of Form omega and Form Z was obtained.
Example 13- This example illustrates the preparation of Form U by trituratin~
form 8 in Ethyl-Acetate Nateglinide Form ~ (5 grams) was triturated in ethyl acetate (10 ml) at 25 °C for 2 hours.
25 The wet material was filtered with vacuum and washed with ethyl acetate (10 ml). The wet product was dried at 50°C in a vacuum oven overnight. The wet and dry products were Form U.
Example 14- This example illustrates the preparation of form B by trituratin~
Form 8 in ethyl-acetate 30 Nateglinide Form 8 (5 grams) was triturated in ethyl acetate (10 ml) at 50°C for 1 hour.
The mixture was cooled to 20°C and triturated for 1 hour. The wet material was filtered with vacuum and washed with ethyl acetate (lOml). The wet product was dried at 50°C in a vacuum oven overnight. The wet and dry products were obtained as Form B.
Example 15- Process for the Preparation of Nate~linide Form B
Nateglinide Form B may also be obtained by precipitation of nateglinide Form G, from isopropanol followed by conversion of Form G to Form B. In this embodiment, a form of nateglinide, such as nateglinide Form ~ (about 3% LOD) is dissolved in a mixture of IPA/H20 at a preferred temperature range of about 40 to about 50 °
C. Preferably, the IPA concentration in the solvent mixture is in the range of about 50% to about 70% (v/v), and the volume of the solvent mixture is about 5 to about 20 volumes/unit weight of nateglinide.
The solution obtained after dissolution is preferably cooled to a temperature of about 30°C for seeding with crystals of Form B. The seeded solution is preferably stirred at the seeding temperature for about 30 minutes to about 3 hours. The solution is preferably then cooled to about 0 °C plus/minus 5 °C for at preferably least about 5 hours, and preferably stirred at 5 °C for at least about 30 minutes. The precipitated nateglinide crystals may be recovered and dried under reduced pressure at a preferred temperature of about 70 to about 90°C to obtain nateglinide Form B.
In this embodiment, before crystallization, the starting material may optionally be dissolved in IPA or in a IPA/H2O mixture (in the same solvent ratio as the crystallization 2o mixture), followed by evaporation under reduced pressure. After the evaporation, IPAlH2O mixture is fed into the reactor to obtain a solution. Nateglinide Form B is obtained after the evaporation.
The use of IPA allows for the elimination of methyl esters as impurities in the final product as illustrated in Figure 64.
Example 15 (Al_ Nateglinide (40 grams) was dissolved in IPA (240 ml) at 25 °C. The solution was filtered to remove insoluble materials. The clear solution was heated to 50°C
and stirred for 5 hours. After stirring, the solvent was evaporated under reduced pressure. The residue was tested by XRD and found to be B type.
3o Example 1 S Bl Nateglinide (30 grams) was dissolved in IPA (150 ml) in a reactor. The solvent was evaporated under reduced pressure at a jacket temperature Tj=50°C. A
solution was obtained by feeding the reactor with IPA (150 ml) and water (150 ml) were fed at Tj=50°C. The clear solution obtained, was cooled to TR=29.4°C, and seeded by B type crystals. The seeded solution was stirred at TR=29.4°C for additional 3 hours, and afterwards cooled to TR=0°C for 10 hours. At 0°C, the resulting slurry was stirred for additional 5 hours (over-night). The crystals were isolated and dried under reduced pressure at 90 °C. The wet crystals were tested by XRD and found to be G type. The dried crystals were tested by XRD and found to be B type.
Example 15 (C) Nateglinide (20 grams) was dissolved in IPA (200 ml) in a round bottom flask and the to solvent was evaporated under reduced pressure at a temperature of 50 °C. IPA (200 ml) and water (200 ml) were fed into the round bottom flask to obtain a clear solution. The solution was transferred to a reactor and cooled to a temperature of TR=28 °C. At 28 °C, the solution was seeded with type B crystals.
The seeded solution was stirred at 28°C for an additional 2 hours, and afterwards cooled 15 to 5 ° C for 10 hours. At 5 ° C, the solution was stirred for an additional 4 hours (over-night). The product was isolated and dried under reduced pressure at 90 ° C. The wet crystals were tested by XRD and found to be G type. The dried crystals were tested by XRD and found to be B type.
Example 16 Process for the Preparation of Nate~linide Form B by Trituration in Water 2o Nateglinide Form S was triturated in 5 volumes water at about 25 °C
for about 7 hours.
The crystals were isolated and dried under reduced pressure at 90 °C
Example (A): Trituration of wet starting material 50 gr Nateglinide form 8 wet (about 37% LOD) was triturated in 250 ml water at 25 °C.
After 4 hrs trituration, the slurry was sampled and dried under reduced pressure at 90°C.
25 The wet crystals were tested by XRD and found to be ~ type. The dry crystals were tested by XRD and found to be B type. After 7 hours of trituration, the product was isolated and dried under reduced pressure at 90°C. The wet crystals were tested by XRD and found to be 8 type. The dry crystals were tested by XRD and found to be B type.
Example (B): Trituration of dry starting material 30 50 gr Nateglinide form 8 dry was triturated in 250 ml water at 25 °C. After 4.5 hrs trituration, the slurry was sampled and dried under reduced pressure at 90°C. The wet crystals were tested by XRD and found to be Z type. The dry crystals were tested by XRD

and found to be B type. After 7.5 hours of trituration, the product was isolated and dried under reduced pressure at 90 ° C. The wet crystals were tested by XRD
and found to be E
type. The dry crystals were tested by XRD and found to be B type.
Example 17- Preparation of Nate~linide form U
Example (A): Crystallization from Acetone Nateglinide (50 grams) Form S was dissolved in acetone (175 ml) at 42°C. The clear solution was cooled to 10 ° C for seeding. After seeding with type B
crystals, the seeded solution was stirred for an additional 3 hours at a temperature of 10°C
and cooled to -10°C for 10 hours, and stirred at -10°C over night. The crystals were isolated and dried at l0 90 ° C. The wet crystals were tested by XRD and found to be U type.
The dry crystals were tested and found to be U type.
Example (B): Crystallization from Ethyl Acetate Nateglinide (20 grams) were dissolved in ethyl acetate (560 ml) at 40°C. The solution was filtered to remove insoluble matter. The clear solution was evaporated under reduced 15 pressure, and Ethyl Acetate (460 ml) was evaporated (the solvent volume in the reactor was 5 volumeslunit weight Nateglinide). The solution was cooled to 20°C
and seeded with type B crystals. The seeded solution was stirred at 20 °C for an additional 30 minutes, cooled to 0°C for 1.5 hours, and stirred at 0°C for an additional 30 minutes. The crystals were isolated and dried under reduced pressure at 30°C, 50°C, 90°C. The wet 2o crystals were tested by XRD and found to be U type. The dry crystals were tested by XRD and found to be U type.
Example 18- Removal of residual solvent from Form delta Nateglinide (40 grams) Form delta (1.5% heptane) was dried in a stirred reactor (7-10 rpm) under 60 mmHg vacuum and at 60 ° C. After 6 hours of drying, the residual solvent 25 of the material was 613 ppm of heptane. The polymorph of the dried material remained delta form, as the starting material.
Example 19- Preparation of nate~linide Form B from ethyl acetate Nateglinide form 8 is dissolved in ethyl acetate at 25 °C. The solvent is evaporated under reduced pressure, until turbidity appears. The turbid solution is cooled to 0°C plus/minus 30 5 °C for 1 hour and stirred for 1 hour. The product was isolated and dried under reduced pressure at 50°C.
Example (A) Nateglinide (12 grams) Form 8 was dissolved in 165 ml of ethyl acetate at 25 °C.
The solvent was evaporated under reduced pressure at 25 °C, until turbidity appeared. At the end of evaporation, the volume in the reactor was 90-95 ml. The mixture was cooled from 25 °C to 5 °C for 1 hour and stirred at 5 °C for 1 hour. The product was isolated and s dried under reduced pressure at 50°C. Both the wet and the dry crystals were tested by ~~RD and DSC and found to be B type.
Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art may appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the 1o invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications. Polymorphism in Pharmaceutical Solids, Drugs and 15 the Pharmaceutical Sciences, Volume 95 may be used as a guidance. All references mentioned herein are incorporated in their entirety.

Claims (205)

What is claimed is:

1. A process for preparing crystalline nateglinide Form B comprising heating a crystalline form of nateglinide selected from the group consisting of Form A, C, D, F, G, J, Q, T, .alpha., .beta., .delta., .epsilon., .theta. and .OMEGA. to obtain nateglinide Form B.

2. The process of claim 1, wherein the nateglinide is Form .alpha..

3. The process of claim 1, wherein the nateglinide is Form .delta..

4. A process for preparing nateglinide Form B comprising the steps of:
a) preparing a suspension of nateglinide in a C5 to a C12 hydrocarbon;
b) adding a solvent selected from the group consisting of an alcohol, an ester, a ketone or mixtures thereof to the suspension to obtain a solution;
c) crystallizing nateglinide Form B from the solution in the absence of stirring; and c) recovering the nateglinide Form B.

5. The process of claim 4, wherein the hydrocarbon is selected from the group consisting of heptane, hexane, toluene and xylene.

6. The process of claim 4, wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, n-propanol, acetone and ethyl acetate.

7. The process of claim 4, wherein crystallizing is carried out by seeding and cooling.

8. The process of claim 4, wherein Form B crystallizes at a crystallization temperature of higher than about 15°C.

9. The process of claim 4, wherein the solvent/hydrocarbon combination is ethyl acetate/heptane or hexane.

10. A process for preparing crystalline nateglinide Form B comprising the steps of:
a) preparing a solution of nateglinide in a mixture of ethyl acetate and a C5 to a C12 hydrocarbon;
b) crystallizing nateglinide Form B from the solution; and c) recovering the nateglinide Form B.

11. The process of claim 10, wherein the crystallizing step is carried out in the absence of stirring.

12. The process of claim 10, wherein crystallization is carried out at a temperature of higher than about 15°C.

13. A process for preparing nateglinide Form B comprising the step of storing nateglinide Form A at a suitable temperature for a sufficient amount of time to obtain nateglinide Form B.

14. A process for preparing nateglinide Form B comprising the steps of:
a) preparing a solution of nateglinide in a solvent selected from the group consisting of an ester, ketone, amine, amide, alcohol, nitrile; and b) removing the solvent to obtain nateglinide Form B.

15. The process of claim 14, wherein the solvent is selected from the group consisting of acetonitrile, acetone, ethyl acetate and iso-propyl alcohol.

16. The process of claim 14, wherein removing involves evaporation of the solvent.

17. The process of claim 16, wherein the solvent is evaporated at a temperature of from about 40°C to about 70°C.

18. A process for preparing nateglinide Form B comprising the step of triturating nateglinide Form .delta. in ethyl acetate at a suitable temperature for a sufficient amount of time to obtain nateglinide Form B.

19. The process of claim 18, wherein the temperature is at least about 40°C.

20. A process for preparing nateglinide Form B comprising the steps of:
a) preparing a solution of nateglinide in ethyl acetate;
b) concentrating the solution to precipitate nateglinide Form B; and c) recovering the nateglinide Form B.

21. A process for preparing nateglinide Form B comprising the steps of:
a) preparing a solution of nateglinide in a mixture of water and isopropanol;
b) crystallizing nateglinide Form B from the solution; and c) recovering the nateglinide Form B.

22. A process for preparing nateglinide Form B comprising the steps of:
a) preparing a solution of nateglinide in a mixture of isopropanol and water;
b) seeding the solution with nateglinide Form B at a temperature of from about 25°C
to about 35°C;
c) stirring the solution;
d) cooling the solution to a temperature of about minus 5°C to about 5°C to obtain a slurry;
e) stirring the slurry;

f) recovering a solid from the slurry; and g) heating the solid to obtain nateglinide Form B.

23. 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°C and an FTIR
spectrum with peaks at about 1741, 1726, 1621, 1600, 1538, 1211, 1191 cm-1.

24. The crystalline form of claim 23, wherein the crystalline form is stable when heated at a temperature of about 100°C for at least about 8 hours.

25. A process for preparing nateglinide of claim 23 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 23.

26. A process for preparing nateglinide of claim 23 comprising the step of storing nateglinide Form I at a suitable temperature for a sufficient time to obtain the nateglinide of claim 23.

27. 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-1;
and a DSC
thermogram with endotherms at about 106 and 128°C and an exotherm at about 113°C.

28. A process for preparing the crystalline nateglinide of claim 27 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 27, with the proviso that the nateglinide triturated in nitromethane is not Form H; and b) recovering the crystalline form of nateglinide.

29. A process for preparing nateglinide of claim 27 comprising the step of heating nateglinide Form epsilon for a sufficient amount of time at a suitable temperature.

30. A process for preparing nateglinide Form S comprising the step of heating a nateglinide selected from the group consisting of Form K, I and .alpha. for a sufficient amount of time to obtain nateglinide Form S.

31. A process for preparing nateglinide Form S comprising the steps of:
a) preparing a solution of nateglinide in n-butanol or di-methyl formamide;
b) crystallizing nateglinide from the solution;

c) recovering the nateglinide; and d) heating the nateglinide to obtain Form S.

32. A process for preparing nateglinide Form U comprising the steps of:
a) preparing a solution of nateglinide in a mixture of a solvent selected from the group consisting of an ester, ketone, alcohol and mixtures thereof, and an anti-solvent;
b) crystallizing nateglinide Form U from the solution; and c) recovering the nateglinide Form U.

33. The process of claim 32, wherein the anti-solvent is a C5 to a C12 hydrocarbon.

34. The process of claim 33, wherein the anti-solvent is heptane.

35. The process of claim 32, wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, n-propanol, acetone and ethyl acetate.

36. The process of claim 35, wherein the solvent is ethyl acetate.

37. The process of claim 36, wherein ethyl acetate to anti-solvent ratio is from about 2:1 to about 1:1 (vol/vol).

38. The process of claim 36, wherein the anti-solvent is from about 20°C to about 40°C
colder than the ethyl acetate.

39. The process of claim 38 wherein the anti-solvent has a temperature of from about 0°C
to about 10°C and the ethyl acetate a temperature of from about 30°C to about 40°C.

40. The process of claim 32, wherein Form U is prepared by preparing a solution having a temperature of at least about 25°C, followed by cooling to a temperature of from about 0°C to about 10°C to crystallize Form U, and recovery of Form U
before its transition to another form.

41. A process for preparing nateglinide Form U comprising the steps of:
a) adding a solution of nateglinide in ethyl acetate to a container holding heptane to spontaneously precipitate nateglinide Form U, wherein the heptane is colder than the solution; and b) recovering the nateglinide Form U.

42. A process for preparing nateglinide Form U comprising the step of triturating nateglinide Form .delta. in ethyl acetate at a suitable temperature for a sufficient amount of time to obtain nateglinide Form U.

43. The process of claim 42, wherein the temperature is from about 20°C
to about 30°C.

44. A process for preparing nateglinide Form U comprising the steps of:

a) preparing a solution of nateglinide in ethyl acetate or acetone;
b) seeding the solution with a crystalline form of nateglinide to crystallize nateglinide Form U; and c) recovering the nateglinide Form U.

45. The process of claim 44, wherein the solution is seeded with Form B.

46. 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°C; and an FTIR
spectrum with peaks at about 3283, 1711, 1646, 1420, 1238 cm-1.

47. The crystalline form of claim 46, wherein the crystalline form is stable when heated to a temperature of about 60°C for about 8 hours.

48. A process for preparing crystalline nateglinide of claim 46 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 46, with the proviso that the nateglinide triturated is not Form H; and b) recovering the nateglinide Form .alpha..

49. The process of claim 48, wherein the nateglinide triturated is Form U.

50. A process for preparing crystalline form of nateglinide of claim 46 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 46.

51. A process for preparing crystalline nateglinide of claim 46 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.

52. 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.

53. The process of claim 52, wherein the nateglinide triturated is crystalline Form U.

54. A crystalline form of nateglinide nateglinide (Form .delta.) characterized by data selected from the group consisting of: an XRPD pattern with peaks at 5.6, 14.5, 18.2, 18.9 and 19.5 ~0.2 degrees 2.theta.; an FTIR spectrum with peaks at about 3306, 1729, 1704, 1275 cm-1; and a DSC thermogram with endotherms at about 100 and 130°C.

55. The crystalline form of claim 54, wherein the crystalline form is stable at a temperature of about 40°C and a relative humidity of about 75% for at least about 3 months.

56. The crystalline form of claim 54, wherein the crystalline form is stable at a temperature of about 60°C after at least about 8 hours.

57. The crystalline form of claim 54, wherein the crystalline form is substantially free of nateglinide Form H.

58. A process for preparing the crystalline form of nateglinide of claim 54 comprising the step of stirring a nateglinide anhydrate for a sufficient time in an organic solvent, with the proviso that the organic solvent is a solvent other than only ethyl acetate.

59. The process of claim 58, wherein the nateglinide anhydrate is selected from the group consisting of Form B, Form H, Form U and Form .theta..

60. The process of claim 58, wherein stirring is carried out at a temperature of from about minus 15°C to about 10°C.

61. The process of claim 58, wherein the organic solvent is a mixture of a C5 to a C12 hydrocarbon and ethyl acetate.

62. The process of claim 61, wherein the hydrocarbon is heptane.

63. A process for preparing crystalline nateglinide of claim 54 comprising the step of stirring nateglinide Form U in a mixture of ethyl acetate and heptane for a sufficient time to obtain nataglinide of claim 54.

64. A process for preparing the crystalline nateglinide form of claim 54 comprising the steps of:
a) triturating a nateglinide in a solvent selected from the group consisting of dioxane, chloroform and tetrahydrofuran to obtain the crystalline form, with the proviso that the nateglinide triturated in chloroform is not Form H; and b) recovering the crystalline form.

65. The process of claim 64, wherein the nateglinide triturated is Form U.

66. A process for preparing the crystalline form of claim 54 comprising the steps of:

a) preparing a solution of nateglinide in a mixture of ethyl acetate and heptane;
b) cooling the solution to precipitate a solid, thereby forming a mixture;
c) striring the mixture for a sufficient time to obtain the crystalline form of claim 54;
and d) filtering the mixture.

67. A process for preparing the crystalline form of claim 54 substantially free of residual solvent comprising the step of removing the residual solvent with a fluidized bed dryer.

68. The process of claim 67, wherein the crystalline form contains less than about 0.5% by weight of residual solvent after the removal process.

69. The crystalline form prepared by the process of claim 67.

70. A process for preparing the crystalline form of claim 54 substantially fee of residual solvent comprising the step of removing the solvent under stirring at a temperature of at least about 40°C under vacuum.

71. A crystalline form of nateglinide (Form .sigma.) characterized by data selected from the group consisting of: an XRPD pattern with peaks at about 5.5, 6.1, 6.7, 14.3 ~0.2 degrees 2.theta.; DSC thermogram with an endotherm at about 127°C; and an FTIR
spectrum with peaks at about 3303, 1705 and 1640 cm-1.

72. A process for preparing the crystalline form of claim 71 comprising the step of stirring nateglinide Form B or Form U in an organic solvent for a sufficient time to obtain nateglinide Form .sigma..

73. The process of claim 72, wherein the organic solvent is a mixture of ethyl acetate and a C5 to a C12 aliphatic hydrocarbon.

74. The process of claim 73, wherein the hydrocarbon is heptane.

75. The process of claim 72, wherein the stirring is carried out at a temperature of about minus 15°C to about 10°C.

76. A crystalline form of nateglinide (Form D) characterized by data selected from the group consisting of an XRPD pattern with peaks at 6.6, 7.5, 13.1, 16.5, 17.4 and 21.1 ~0.2 degrees 2.theta.; and a DSC thermogram with endotherms at about 66 and 130°C.

77. A process for preparing the crystalline form of nateglinide of claim 76, comprising the step of contacting a nateglinide in the solid state with vapors of ethanol, wherein the nateglinide absorbs the vapors.

78. The process of claim 77, wherein the nateglinide contacted is Form H.

79. A process for preparing the crystalline nateglinide of claim 76 comprising the steps of:
a) preparing a solution of nateglinide in ethanol;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form.

80. A process for preparing the crystalline form of nateglinide of claim 76 comprising the steps of:
a) triturating a crystalline form of nateglinide in ethanol to obtain the crystalline form of claim 1; and b) recovering the crystalline form of claim 76, with the proviso that the nateglinide triturated is not nateglinide Form U.

81. The process of claim 80, wherein the nateglinide triturated is nateglinide Form H.

82. A process for preparing crystalline nateglinide Form E comprising the step of storing nateglinide Form T for a sufficient time under a suitable temperature.

83. A process for preparing crystalline nateglinide Form E comprising the steps of:
a) preparing a solution in a mixture of toluene and methanol;
b) crystallizing nateglinide Form E from the solution; and c) recovering the nateglinide Form E.

84. A process for preparing nateglinide Form E comprising the step of triturating nateglinide Form Z or delta in water for a sufficient amount of time to obtain nateglinide Form E.

85. A crystalline form of nateglinide (Form F) characterized by data selected from the group consisting of an XRPD pattern with peaks at 4.8, 5.3, 15.2, 18.9 and 19.6 ~0.2 degrees 2.theta.; and a DSC thermogram with endotherms at about 53, 103 and 128°C.

86. A process for preparing the crystalline form of claim 85 comprising the steps of:
a) preparing a solution of nateglinide in n-propanol;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form.

87. A process for preparing crystalline form of nateglinide of claim 86 comprising the step of triturating a crystalline form of nateglinide in n-propanol.

88. A crystalline form of nateglinide (Form G) characterized by data selected from the group consisting of an XRPD pattern with peaks at 14.4, 15.3, 19.3 and 20.3 ~0.2 degrees 2.theta. and a DSC thermogram with endotherms at about 106 and 127°C.

89. A process for preparing the crystalline form of claim 88 comprising the steps of:

a) preparing a solution of nateglinide in iso-propyl alcohol;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form.

90. A process for preparing the crystalline form of claim 88 comprising the steps of:
a) triturating a crystalline form of nateglinide in iso-propyl alcohol to obtain the crystalline form of claim 88; and b) recovering the crystalline form of claim 88.

91. The process of claim 90, wherein the nateglinide triturated is Form H.

92. A process for preparing nateglinide of claim 88 comprising the steps of:
a) preparing a solution of nateglinide in a mixture of isopropanol and water;
b) seeding the solution with nateglinide Form B at a temperature of from about 25°C
to about 35°C;
c) stirring the solution;
d) cooling the solution to a temperature of about minus 5°C to about 5°C to obtain a slurry;
e) stirring the slurry; and f) recovering the nateglinide of claim 88 from the slurry.

93. A crystalline form of nateglinide (Form I) characterized by data selected from the group consisting of an XRPD pattern with peaks at 5.5, 7.4 and 16.8 ~0.2 degrees 2.theta.; and a DSC thermogram with endotherms at about 46 and 121°C.

94. A process for preparing the crystalline nateglinide of claim 93 comprising the step of triturating a crystalline form of nateglinide in n-butanol, with the proviso that the nateglinide triturated is not Form U.

95. The process of claim 94, wherein the nateglinide triturated is Form H.

96. A process for preparing the crystalline form of claim 93 comprising the steps of:
a) preparing a solution of nateglinide in n-butanol;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form.

97. A crystalline form of nateglinide (Form O) characterized by data selected from the group consisting of: an XRPD pattern with peaks at 4.4, 5.2, 15.7 and 16.6 ~0.2 degrees 2.theta. and a DSC thermogram with endotherms at about 106, 126 and 137°C.

98. The crystalline form of claim 97, wherein the crystalline form is stable when heated to a temperature of about 60°C for about 8 hours.

99. A process for preparing the crystalline form of claim 97 comprising the step of contacting a nateglinide in the solid state with vapors of methanol to obtain the crystalline form, wherein the nateglinide absorbs the vapors.

100. The process of claim 99, wherein the nateglinide contacted is Form H.

101. A crystalline form of nateglinide (Form T) characterized by an XRPD
pattern with peaks at 7.2, 7.9, 8.3 and 10.7 ~0.2 degrees 2.theta. and a DSC thermogram with endotherms at about 68, 106 and 130°C.

102. A process for preparing the crystalline form of claim 101 comprising the steps of:
a) triturating a crystalline form of nateglinide in methanol to obtain the crystalline form of claim 101, with the proviso that the nateglinide triturated is not Form U; and b) recovering the nateglinide Form T.

103. The process of claim 102, wherein the nateglinide triturated is Form H.

104. A crystalline nateglinide in the form of a methanol solvate represented by the formula NTG.cndot.1/4 MeOH (wt/wt).

105. The crystalline nateglinide of claim 104, wherein the crystalline form is nateglinide Form O methanol solvate.

106. A crystalline nateglinide in the form of a methanol solvate characterized by containing more than about 20% methanol by weight.

107. The crystalline nateglinide of claim 106 wherein the nateglinide is nateglinide Form T
methanol solvate.

108. A crystalline nateglinide in the form of an ethanol solvate represented by the formula NTG.cndot.3/2 EtOH (wt/wt).

109. The crystalline form of claim 108 wherein the crystalline form is nateglinide Form D
ethanol solvate.

110. A crystalline nateglinide monoipanolate.

111. The crystalline nateglinide of claim 110 wherein the monoipanolate is nateglinide Form G.

112. A crystalline nateglinide in the form of n-butanol solvate.

113. The crystalline nateglinide of claim 112, wherein the crystalline form is Form I n-butanol solvate.

114. A crystalline nateglinide in the form of an n-propanol solvate.

115. The crystalline nateglinide of claim 114, wherein the solvate contains about 16% to about 24% n-propanol.

116. The crystalline nateglinide of claim 114, wherein the solvate is Form F n-propanol solvate.

117. A crystalline form of nateglinide (Form C) in the solid state having an XRPD pattern with peaks at 5.2, 8.2 and 8.8 ~0.2 degrees 2.theta..

118. The crystalline form of claim 117, wherein the crystalline form has an XRPD pattern as substantially depicted in Figure 2.

119. A process for preparing the crystalline nateglinide of claim 117 comprising the steps of:
a) triturating a crystalline form of nateglinide in dimethylacetamide to obtain the crystalline form of claim 117; and b) recovering the crystalline form of claim 117.

120. A process for preparing the crystalline nateglinide of claim 117 comprising the steps of:
a) preparing a solution of nateglinide in dimethylacetamide;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form.

121. A crystalline form of nateglinide (Form J) in the solid state characterized by data selected from the group consisting of an XRPD pattern with peaks at 8.0, 11.2, 12.0, 15.9, 16.1, 17.7 and 28.1 ~0.2 degrees 2.theta.; and a DSC thermogram with endotherms at about 49, 105 and 168 °C.

122. A process for preparing the crystalline form of claim 121 comprising the steps of:
a) preparing a solution of nateglinide in N-methyl pyrolidone;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form.

123. A process for preparing the crystalline form of claim 121 comprising the steps of:
a) triturating a crystalline form of nateglinide in N-methyl pyrolidone to obtain the crystalline form of claim 121; and b) recovering the crystalline form of claim 121.

124. A crystalline form of nateglinide (Form K) in the solid state characterized by data selected from the group consisting of an XRPD pattern with peaks at 9.5, 15.4, 17.1 and 21.2 ~0.2 degrees 2.theta.; and a DSC thermogram with endotherms at about 79, 105, 145 and 170°C.

125. A process for preparing the crystalline form of claim 124 comprising the steps of:
a) preparing a solution of nateglinide in DMF;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form.

126. A process for preparing the crystalline form of claim 124 comprising the steps of:
a) triturating a crystalline form of nateglinide in DMF to obtain the crystalline form of claim 124; and b) recovering the crystalline form.

127. A crystalline form of nateglinide (Form V) characterized by data selected from the group consisting of: an XRPD pattern with peaks at 4.5, 5.8, 11.4 and 16.4 ~0.2 degrees 2.theta. and a DSC thermogram with endotherms at about 81 and 139°C.

128. A process for preparing the crystalline form of claim 127 comprising the steps of:
a) preparing a solution of nateglinide in dimethylethane;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form.

129. A process for preparing the crystalline form of claim 127 comprising the steps of:
a) triturating a crystalline form of nateglinide in dimethoxy ethane to obtain the crystalline form of claim 127, with the proviso that the nateglinide triturated is not Form U; and b) recovering the crystalline form of claim 127.

130. The process of claim 129, wherein the nateglinide triturated is Form H.

131. A crystalline form of nateglinide in solid state (Form .beta.) characterized by data selected from the group consisting of an XRPD pattern with peaks at 4.6, 9.4, 13.9 and 18.8 ~0.2 degrees 2.theta.; and a DSC thermogram with endotherms at about 91 and 100°C.

132. A process for preparing the crystalline form of claim 131 comprising the step of heating crystalline nateglinide Form J.

133. A process for preparing crystalline form of claim 131 comprising the step of heating a solid obtained from trituration of nateglinide Form H in N-methyl pyrolidone.

134. A crystalline form of nateglinide (Form .gamma.) characterized by data selected from the group consisiting of an XRPD pattern with peaks at 4.4, 8.9, 18.4, 18.8 and 19.5 ~0.2 degrees 2.theta.; and a DSC thermogram with endotherms at about 93 and 136°C.

135. A process for preparing the crystalline form of claim 134, comprising the step of heating a solid obtained from trituration of a crystalline form of nateglinide in N-methyl pyrolidone, with the proviso that the nateglinide triturated is not Form H.

136. The process of claim 135, wherein the crystalline form of nateglinide triturated is nateglinide Form U.

137. A crystalline form of nateglinide (Form .epsilon.) characterized by data selected from the group consisting of: an XRPD pattern with peaks at 4.2, 13.0, 13.6, 14.3, 16.2, 16.7 and 19.6 ~0.2 degrees 2.theta.; and a DSC thermogram with endotherms at about 64, 108 and 129°C.

138. A process for preparing the crystalline form of claim 137 comprising the steps of:
a) preparing a solution of nateglinide in a solvent selected from the group consisting of acetone, acetonitrile and nitromethane;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form.

139. The process of claim 138, wherein the solvent is nitromethane.

140. A process for preparing the crystalline form of claim 137 comprising the steps of:
a) triturating a crystalline form of nateglinide in nitromethane to obtain the crystalline form of claim 137, with the proviso that the crystalline form triturated is not Form U; and b) recovering the crystalline form of claim 137.

141. The process of claim 140, wherein the crystalline form triturated is Form H.

142. A crystalline form of nateglinide, wherein the crystalline form is a dimethyl acetamide solvate.

143. The crystalline form of claim 142, wherein the crystalline form is nateglinide Form C.

144. A crystalline form of nateglinide, wherein the crystalline form is an n-methylpyrolidone solvate.

145. The crystalline form of claim 144, wherein the crystalline form is nateglinide Form J.

146. A crystalline form of nateglinide, wherein the crystalline form is a dimethyl formamide solvate.

147. The crystalline form of claim 146, wherein the crystalline form is nateglinide Form K.

148. A crystalline form of nateglinide, wherein the crystalline form is a dimethoxy ethane solvate.

149. The crystalline form of claim 148, wherein the crystalline form is nateglinide Form V.

150. A crystalline form of nateglinide, wherein the crystalline form is an N-methyl pyrolidone solvate.

151. The crystalline form of claim 150, wherein the crystalline form is nateglinide Form gamma or beta.

152. A crystalline form of nateglinide, wherein the crystalline form is a solvate of a solvent selected from the group consisting of acetone, acetonitrile and nitromethane.

153. The crystalline form of claim 152, wherein the solvent is acetone or nitromethane.

154. The crystalline form of claim 152, wherein the crystalline form is nateglinide Form Epsilon.

155. A crystalline form of nateglinide (Form A) characterized by data selected from the group consisting of an XRPD pattern with peaks at 6.6, 13.3, 13.9, 16.8, 27.2 and 28.0 ~0.2 degrees 2.theta.; and a DSC thermogram with endotherms at about 70, 98 and 138°C.

156. A process for preparing the crystalline form of claim 155 comprising the steps of:
a) preparing a solution of nateglinide in xylene;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form.

157. A crystalline form of nateglinide (Form M) characterized by data selected from the group consisting of an XRPD pattern with peaks at 16.2, 16.4, 17.0, 17.8, 18.6, 19.4 and 19.6 ~0.2 degrees 2.theta.; and a DSC thermogram with endotherms at about 90, 102 and 128 °C.

158. A process for preparing the crystalline form of nateglinide of claim 157 comprising the steps of:
a) preparing a solution of nateglinide in carbon tetrachloride;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form.

159. A crystalline form of nateglinide (Form N) characterized by data selected from the group consisting of: an XRPD pattern with peaks at 5.3, 5.5, 8.9, 9.9, 20.4 and 21.1 ~0.2 degrees 2.theta.; and a DSC thermogram with endotherms at about 77, 100, 130 and 137 °C.

160. A process for preparing the crystalline Form of claim 159 comprising the steps of:

a) preparing a solution of nateglinide in dichloroethane;
b) crystallizing the crystalline nateglinide from the solution; and c) recovering the crystalline nateglinide.

161. A crystalline form of nateglinide (Form Q) characterized by data selected from the group consisting of an XRPD pattern with peaks at 5.1, 5.6, 16.2 and 19.8 ~0.2 degrees 2.theta.; and a DSC thermogram with endotherms at about 102 and 126°C.

162. A process for preparing the crystalline form of nateglinide of claim 161 comprising the steps of:
a) preparing a solution of nateglinide in chloroform;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form of nateglinide.

163. A process for preparing the crystalline form of claim 161 comprising the steps of:
a) triturating a crystalline form of nateglinide in chloroform, with the proviso that the nateglinide triturated is not Form U; and b) recovering the crystalline form of claim 161.

164. The process of claim 163, wherein the nateglinide triturated is Form H.

165. A process for preparing a crystalline form of claim 161 comprising the steps of:
a) triturating a crystalline form of nateglinide in dichloroethane to obtain the crystalline form of claim 161; and b) recovering the crystalline form of claim 161.

166. A crystalline form of nateglinide, wherein the crystalline form (Form Y) has an XRPD
pattern with peaks at 6.1, 14.2, 15.1 and 18.7 ~0.2 degrees 2.theta..

167. The crystalline form of claim 166, wherein the crystalline form has an XRPD pattern as substantially depicted in Figure 166.

168. The crystalline form of nateglinide of claim 166, wherein the crystalline form is stable when heated to a temperature of about 60°C for about 8 hours.

169. A process for preparing dichloromethane solvate of the crystalline form of claim 166 comprising the steps of contacting nateglinide in the solid state with vapors of di-chloro methane to obtain the crystalline form, wherein the nateglinide contacted absorbs the vapors.

170. A process for preparing dichloromethane solvate of the crystalline form of claim 166 comprising the steps of:

a) triturating a crystalline form of nateglinide in dichloromethane to obtain the crystalline form of claim 166; and b) recovering the crystalline form of claim 166.

171. The process of claim 170, wherein the nateglinide triturated is Form H.

172. A process for preparing the crystalline form of nateglinide of claim 166 comprising the steps of:
a) preparing a solution of nateglinide in dichloromethane;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form.

173. A process for preparing chloroform solvate of crystalline form of claim comprising the step of storing crystalline nateglinide Form Q for a sufficient time at a suitable temperature to obtain the crystalline form of claim 166.

174. A process for preparing nateglinide crystalline Form Z comprising the steps of:
a) preparing a solution of an alkali metal or an alkaline earth metal salt of nateglinide in an aqueous solvent;
b) acidifying the solution to precipitate nateglinide Form Z; and c) recovering the crystalline form.

175. The process of claim 174, wherein the aqueous solvent is water free of a co-solvent.

176. The process of claim 174, wherein the salt is that of potassium or sodium.

177. A process for preparing nateglinide crystalline Form Z comprising the steps of:
a) preparing a solution of nateglinide in a mixture of ethyl acetate and a C5 to a C12 hydrocarbon;
b) crystallizing the crystalline form of nateglinide from the solution; and c) recovering the crystalline form.

178. The process of claim 177, wherein the hydrocarbon is heptane.

179. The process of claim 178, wherein the heptane to ethyl acetate ratio is from about 2 to about 4 (v/v).

180. A process for preparing nateglinide Form Z comprising the step of triturating nateglinide Form delta in water for a sufficient amount of time to obtain Form Z.

181. A crystalline form of nateglinide (Form .theta.) characterized by data selected from the group consisting of an XRPD pattern with peaks at 4.8, 7.8, 15.5, 17.7 ~0.2 degrees 2.theta.;

and a DSC thermogram with endotherms at about 70°C, 104°C, and 130°C, and an exotherm at about 115°C.

182. A process for preparing crystalline nateglinide of claim 181 comprising the steps of:
a) preparing a solution of nateglinide in a mixture of a solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone and ethyl acetate, and heptane;
b) crystallizing the crystalline form of nateglinide; and c) recovering the crystalline form of nateglinide.

183. The process of claim 182, wherein crystallizing is carried out at a temperature of from about 0°C to about 10°C

184. The process of claim 182, wherein the solvent is ethyl acetate.

185. A crystalline form of nateglinide, wherein the crystalline form is a solvate of xylene.

186. The crystalline form of claim 185, wherein the crystalline form is nateglinide Form A.

187. A crystalline form on nateglinide, wherein the crystalline form is a solvate of carbon tetrachloride.

188. The crystalline form of claim 187, wherein the crystalline form is nateglinide Form M.

189. A crystalline form on nateglinide, wherein the crystalline form is a solvate of dichloroethane.

190. The crystalline form of claim 189, wherein the crystalline form is nateglinide Form N.

191. A crystalline form of nateglinide, wherein the crystalline form is a solvate of chloroform.

192. The crystalline form of claim 191, wherein the crystalline form is nateglinide Form Y.

193. The crystalline form of claim 191, wherein the crystalline form is nateglinide Form Q.

194. A crystalline form of nateglinide, wherein the crystalline form is a solvate of dichloromethane.

195. The crystalline form of claim 194, wherein the crystalline form is nateglinide Form Y.

196. A crystalline form of nateglinide, wherein the crystalline form is a solvate of heptane.

197. The crystalline form of claim 196, wherein the crystalline form is nateglinide Form .theta..

198. A crystalline form (omega) of nateglinide characterized by an XRPD
pattern with peaks at 4.5, 7.8, 15.5, 16.9, 17.8, 19.2, 19.7 ~0.2 degrees 2.theta..

199. A process of preparing the crystalline nateglinide of claim 198, comprising the steps of:

a) preparing a solution of nateglinide in a mixture of water and isopropanol;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline nateglinide.

200. The process of claim 199, wherein the water to isopropanol ratio is from about 1/2 to about 1/5 (vol/vol).

201. A process for preparing nateglinide Form Z comprising the step of heating the crystalline form of claim 198.

202. A crystalline form of nateglinide, wherein the crystalline form is a solvated form of isopropanol and water.

203. The crystalline form of claim 202, wherein the crystalline form contains about 50%
water and isopropanol (LOD).

204. A pharmaceutical formulation for administration to a mammal comprising a crystalline form of nateglinide selected from the group consisting of A, C, D, F, G, I, J, K, M , N, O, Q and T, V, Y, gamma, epsilon, theta, omega and a pharmaceutically acceptable excipient.

205. A method of lowering the blood level sugar of a mammal comprising administering the pharmaceutical formulation of claim 204 to the mammal.