Title of Invention

"A PROCESS FOR PREPARING NATEGLINIDE"

Abstract The present invention relates to a process for preparing nateglinide Form U comprising the steps of: (a) preparing a solution of nateglinide in a solvent selected from the group consisting of an ester, ketone, alcohol and mixtures thereof, at a temperature from about -15°C to about 50°C; (b) crystallizing hateglinide Form U from the solution; and (c) recovering the nateglinide Form U.
Full Text 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 incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to the sohd state chemistry of nateglinide.
BACKGROUND OF THE INVENTION
Nateglinide, known as (-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-Phenylalanine, has the following structure and characteristics:
(Formula Removed)
Fonnula C19H27NO3
Molecular Weight 317.42
Exact Mass 317.199093
Composition C 71.89% H 8.57% N4.41% O 15.12%
Nateglinide is marketed as STARLIX, which is prescribed as oral tablets having a
dosage of 60mg and 120mg for the treatment of type n diabetes. STARLIX may be used
as monotherapy or in combinafion with metaformin to stimulate the pancreas to secrete
insulin. According to the maker of STARLIX, nateglinide is a white powder that is freely
soluble ia methanol, ethanol, and chloroform, soluble in ether, sparingly soluble in acetonitrile and octanol, and practically insoluble in water.
Nateglinide maybe crystallized out of a mixture of water and methanol, and fiirther 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 Apphcant(s) as Form Z, or in a methanolate lablelled by the Applicant(s) as Form E. Drying of the wet sample results in Form B.
The present invention relates to the sohd state physical properties of nateglinide. These properties may be influenced by controlling the conditions under which nateglinide is obtained in solid Form, Solid state physical properties include, for example, the flowability of the milled sohd. Flowabihty 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 accoimt 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.
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 ther^eutic consequences since it imposes an upper limit on the rate at which an oraUy-administered active ingredient may readi the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state Form of a compoimd 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 the amorphous material or another polymorphic Form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thennogravimetric 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, sohd 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 of nateglinide, designated B-type and H-type, and processes for their preparation. These patents are incorporated herein by reference for
their disclosure of the forms. Both forms are characterized by melting point, X-Ray Powder Diffraction ("XRPD") pattern, IR spectrum in KBr and DSC thermogram. According to these patents, B-type has a melting point of 129-130°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 ±0.2 degrees 26, and a strong reflection between 15 and 17 ±0.2 degrees 20. The B-type crystal is reported to lack these peaks and have a weak reflection between 15 and 17 ±0.2 degrees 20. H-type crystals are reported to have an IR spectrum with characteristic absorptions at about 1714,1649,1542 and 1214cm', These absorptions are reported to be missing in the spectrum of B-type 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 endothenn 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 endothetm at 138.2°C, suggesting a solid-solid transformation during grinding.
According to U.S. Pat. No. 5,463,116, the temperature dxjring 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.
Another crystalline form of nateglinide designated Type-S is disclosed in two Chinese articles: ACTAPharm. 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 3283cm-1 (as supposed to 3257cm' and 3306cm-1 for Forms B and H respectively) and an XRPD pattern with a strong peak at 3.78 ±0.2 degrees 29.
U.S. Pat. No. 5,463,116 ("the '116 patenf') lists the methanolate, ethanolate, isopropanoiate and acetonitrilate solvates of nateglinide. According to the ' 116 patent, amorphous nateghnide may be obtained by drying the hydrate and the solvates. The hydrate may be crystallized by dissolving B-type crystals in a 1.5:1 mixture of ethanol and water, followed by crystallization, as disclosed in Example B-3 of the '116 patent
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 02/34713, a PCT publication in Japanese, provides in its abstract: "A process for preparing B form nateglinide crystals containing substantially no H-form crystals, which comprises the step of drying wet crystals of a nateglinide solvate at a low temperature imtil the solvent disappears and then causing them to imdergo 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-fonn 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 solvent disappears. Hie temperature for this will differ depending on the type and quantity 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-fonn is brought about. Though the crystal transformation is usually favorably carried out in 0.5 to 48 hours, a period of 1-24 hours is most favored."
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 26, and an inJBra red spectrum with absorption bands in the region 1711.5,1646.5, 1538.7, 1238.8,1215.1 and 700.5 cm'\ The crystalline form is obtained in the examples from a solution of acetonitrile under a specific temperature range.
Processes for prqjaration of nateglinide are disclosed in WO/0232854. The discovery of new polymorphic forms of a pharmaceutically useful compoimd provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation sciantist has available for designing, for example, a phannaceutical 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), ß (beta),  (gamma), δ (delta),  (epsilon), σ (sigma),  (theta) and Ω (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 (dhnethylacetamide- "DMA"), D (ethanol- "EtOH"), E (ethanol and methanol-"MeOH"), F (n-propanol- "n-PrOH"), G (isopropyl alcohol- "IFA"), I (n-butanol- "n-BuOH"), J (N-methylpyrroUdone- "NMP"), K (dimethylformamide- "DMF"), M (carbon tetrachloride- "CTC"), N (dichloroethane-"DCE"), O (methanol), Q (chloroform- "CHCI3"), T (methanol), V (dimethoxyethane- "DME"), Y (chloroform; dichloromethane), ß (N-methyl pyrohdone),  (N-methylpyroUdone) and  (acetone; acetonitrile- "MeCN"; nitromethane-"NM") and 9 (heptane). Form Z is a hydrate, having water in the crystalline structure. Form Q 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, 5 and a.
The XRPD pattern of these forms as substantially depicted is disclosed in. Figures 1-27 and 63, wifbi the characteristic peaks Usted 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 anhydrate and hydrate Forms and their characteristic peaks are also provided. The LOD values from the TGA analysis of some of these Forms is listed in Table IE. Preparation of the various Forms by crystallization procedure is listed in Table IV, while preparation by trituiation is Hsted 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 VHI and data on crystallization from a solvent/anti-solvent system is listed in Tables K-XI. Figure 28 summarizes the thermal stability of the various forms.
The present invention also provides for pharmaceutical formulations of the various crystaUine forms and their adminisfration. BRIEF DESCRIPTIQN Of THE FIGURES Figure 1 is an XKPD pattern for nateglinide Form A. Figure 2 is an XRPD pattern for nateglinide Form C. Figure 3 is an XRPD patteHn for nateglinide Form D. Figure 4 is an XRPD pattern for nateglinide Form E. 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. Figure 10 is an XRPD pattern for nategUnide 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. 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 nateglmide Form V. Figure 19 is an XRPD pattern for nateghnide Form Y. Figure 20 is an XRPD pattern for nateglinide Form Z. Figure 21 is an XRPD pattern for nateglinide Form α. Figure 22 is an XRPD pattern for nateglinide Form ß.
Figure 23 is an XRPD pattern for nateglinide Form .
Figure 24 is an XRPD pattern for nateglinide Form δ.
Figure 25 is an XRPD pattern for nateglinide Form .
Figure 26 is an XRPD pattern of nateglinide Form σ.
Figure 27 is an XRPD pattern of nateglinide Form .
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 Foim α.
Figure 34 is an FTIR spectrum of nateglinide Form δ
Figure 35 is an FTIR spectrum of nateglinide Form σ.
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.
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 K.
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 thermogfam of nateglinide Form O.
Figure 48 is a DSC thermogram of nateglinide Form P.
Figure 49 is a DSC thermogram of nateglinide Form Q.
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 nategUnide Form Y (dichloromethane solvate).
Figure 55 is a DSC thremogram of nateglinide Form Z.
Figure 56 is a DSC thermogram of nateglinide Form α.
Figure 57 is a DSC thermogram of nateglinide Form ß.
Figure 58 is a DSC thermogram of nateglinide Form .
Figure 59 is a DSC thermogram of nateglinide Form δ.
Figure 60 is a DSC thermogram of nateglinide Form .
Figure 61 is a DSC thermogram of nateglinide Form a.
Figure 62 is a DSC thermogram of nateglinide Form 6.
Figure 63 is a XRPD pattern of nateglinide Form Ω.
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 ("NTG"), denominated Form A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, U, V, Y, a, p, y, 6, s, 0-, 6 and Q. 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 differs from one polymorph to another. Form E is rather similar by XRPD to Form Z, although some differences may be observed. ITie 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 figures 1-27 and 63. Table I: XRPD characteristic peaks for the nateglinide crystalline forms
(Table Removed)
The various crystalline forms of nateglinide are also characterized by their DSC thermograms. Table 11 lists the DSC peaks (endotherais). In addition to the peaks listed in Table H, 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 H: DSC peaks of the sateglinide crystalline forms

(Table Removed)

The various crysttalime 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, ß, , ,  and Ω. contain significant amounts of bovmd solvents and may be considered as solvated forms of nateglimde. 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, 5 and σ show no significant weight loss. These polymorphic forms of nateglinide are firee of bound solvents, i.e., less than about 2% LOD. Table HI 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 represented by formida NTG-3/2 EtOH. Specifically, the solvate is nategliiude Form D.
The methanol solvates of nateglinide disclosed herem 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 fonmula NTG* 1/4 MeOH (Form O) or by the formula NTG* 1/2 MeOH (form E). Nateglinide Form T contains more than about 20% methanol by weight. The methanol content of Form T is from about 20% to about 60% by weight.
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 nateglimde Foim G.
A hydrate of nateglimde. 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 Ci, is a hydrate-solvate of isopropanol and contains about 50% LOD water and isopropanol.
The heptane solvated form of nateglinide, Form G, has about 7 to about 8% heptane by weight, and is represented by the formula NTG• l/4Heptane. Table III: LOD values by TGA and solvents used for the preparation of nateglinide solvated forms

(Table Removed)

The anhydrate forms and the hydrated Fonn Z, are also characterized by their FTIR spectrum. Form Z is characterized by a FTIR spectrum (Figure 31) with peaks at about 699, 1542, 1645,1697,2848, 2864, 2929, 3279 and 3504 cm'. The more characteristic peaks are observed at about 1645,1697,3279 and 3504 cm -1 Characteristic FTIR peaks are for the anhydrates, specifically Forms L, U, P, α, δ and σ are disclosed in the following table.
(Table Removed)

The various crystalline forms are related to each other in that drying of one form may result in a transformation to another form, namely nateglinide Forms A, B, D, E, F, G, H, I, J, K, L, M, N, Q, S, T, V, Z, α, ß, δ, , ,  and Ω. The drying is carried 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, α, ß, δ,  and Ω. Of these forms. Form a, 5, Y and 0 are somewhat stable, and usually retain their crystalline structure after heating, unless heated to a high temperature. For example. Form δ is stable v^en heated to 60°C overnight (at least about 8 hours), but heating of Form 5 at 120°C and 1 atmosphere results in Form B. 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 6.
The conversion of some of the forms to Form B goes through another form. For example, the conversion of Form Ω and E to Form B may go through Form Z.
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 Foijns F and T convert to Form B by going through Form G.
Of the forms that convert to Form B, some of them sometimes imder drying convert to other forms. Form K may convert to Forms a or S, while Form C may convert 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 ß, though its conversion to Form B may go through Form ß. The Form J used in preparing Form ß is preferably obtained by crystallization from N-methylpyrrolidone. When Form J contains some seeds of Form y, heating results in Form
-
The acetonitrile solvate of Form Epsilon, when dried, results in Form B. While the nitromethane solvates of Form Epsilon when dried result in Forms H or P. When Form P is dried. Form H is obtained, which makes it probable that conversion of Form Epsilon to Form H goes through Form P.
Anotha- thermally stable Form of nateglinide is Form L. Form L maybe 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 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 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 diuing 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 E 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 imder different conditions, see e.g., Table IV. Form α 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 convereion 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 Fomi 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 filfration 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 fomas 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 sufficient time to allow for transformation to another crystalline form. After agitation, a suspension or a paste forms. A solid may then be separated from the suspension by techniques well known in the art, such as filtration. The paste may be filtered, to name one technique, to remove excess solvent. The result of this trituration procedure is various forms of nateglinide.
The trituration of Form delta in water may result ia 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 solveat may be heated from about 40°C to about 70°C, with about 55°C beiag preferred. The solvent is then removed to obtain a residue, preferably at elevated temperature within the said range. The solvent is preferably removed by evaporation, with evaporation under reduced pressure being particularly preferred. The resulting residue is then examined. Suitable solvents include esters, ketones, amines, amides, alcohols and 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 ethtool 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 isopropanoi. Preferably, the ratio of the water to isopropanol is from about 1/2 to about 1/5, more preferably 1/3 (vol/vol).
Nateglinide Form Z is generally prepared by acidification of a solution of an alkah metal or alkalme earth metpl 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 acidifipation, 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, crj^tallization is preferably induced by concenfration of the solvent, while for Form U, by seeding of the solution.
Nateglinide Forms B, H, U, Z, 6, 8 and a are related in that all of them may be prepared from a two solvent system. The two solvent system used is a mixtore of a
solvent and an anti-solvait. Example of suitable antisolvents are C5 to Cn aromatic hydrocarbons such as toluene and xylene, and C5 to C12 saturated hydrocarbons such as hexane and heptane. Examples of suitable solvents are C1 to C5 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 enabodunent, the crystals are dried at about 40 °C to 60°C, at a pressure of less than about 50 mm Hg.
When nateglinide is crystallized out of a binary mixture, particularly in the absence of stirring, the crystalline product is often Form B, as illustrated in Table IX. The binary mixture is prepared by suspoiding 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.
hi 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.
The different forms may be obtained depending on the solvent/anti-solvent ratio, crystallization conditions and the time of stirring. Generally, Form Z is crystallized from an ethyl acetate/heptane ratio of about 2 to 4, form H a ratio of about 4 to about 7, Form B a ratio of about 6 to about 8, Form U a ratio of about 1 to about 2, Form 6 a ratio of about
1 and Form 5 a ratio of about 1 to about 8, more preferably from about 1 to about 2 (vol/vol).
Of these, some fortas may crystallize as other forms, and convert after being stirred for a sufficient time in the solvents. Stirring the resulting slurry from crystalUzation at a temperature of from about -15°C to about 10°C, preferably about 5 °C, may result in Form 5. Form 8 seems to result from stirring of forms such as Form U, Form 6, Form H and even Form B. Preferably the stirring to obtain Form 8 is carried out for at least about 2-3 hours, more preferably for at least about 10 hours.
Other than a solvenf.antisolvent ratio of about 1, formation of Form 6 seems to be favored at lower crystallization and filtering temperatures, from about -15°C to about 10°C preferably 5°C. As previously noted, stirring of Form 6, preferably at the specified temperature range, results in Form 8.
Form U may be obtained by stirring with Form B or H in an organic solvent. Stirring for about 1 hour is sufficient to obtain Form U. However, additional sticring, such as above about 5 hours, may result in a transition to Form 8. Form U may also be obtained by crystallization, preferably at the specified ratio, more preferably at a crystaUization 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 temparature of from about 0°C to about 10°C, with about 5°C being preferred, followed by filtering in less than about 1 hour. Higher solvent to anti-solvent ratio may favor form U over G.
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.
Forms Z generally crystallizes after about a day at a fmal crystallization temperature of at least about 15 °C, more preferably from about 15 °C to about 30°C, and most preferably from about 20°C to about 25 °C. The initial crystaUization 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 Z, which converts to Form B by drying.
Form σ may also be obtained by stirring of crystals of Form B. Not being boimd by any theory, it may be possible that Form c is obtained through Form U, that is stirring
results in a transition of Forpi B to Form U followed to Form cr. Prolonged crystallization and filtration is preferred for obtaining Form a, 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 Foim 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, ha this embodioient, the solution is combined with the anti-solvent in such a way to result in precipitation, m contrast vvdth the other embodiments that result in a solution after the combining step. To cause substantial precipitation, preferably, the solution is combined with a cold anti-solvent. More preferably, the antisolvent is from about 20°C to about 40 °C colder than the solution, particularly when an ethyl acetate/heptane system is used. Most preferably, the heptane has a temperstfure of from about 0°C to about 10°C and the ethyl acetate a temperature of from about 30°C to 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 solveaat to anti-solvent ratio of from about 1 to about 6, and final crystallization temperatures from about 0°C to about 30°C. Not being bound by any theory, the presence of other forms, particularly Form 5 and a, especially after long crystallization step, points to possible a fransition 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 Fonn U, which itself may change overtime to Forms 8 or a.
The following table provides guidance on obtaining Forms B, H, U, Z, 6, 6 and o from a solvent:auti-solvent system:
(Table Removed)

Depending on the preparation procedure, nateglinide Form 5 may contain from about 0.5% to about 3% of residual hqptane 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 renwved under stirring, preferably at a temperature of at least about 40 °C under vacuum. The 5 Form is preferably polymorphically pure and contains less than about 5% Form H (wt/wt), more preferably less than about 2% (wt/wt), and most preferably less than about 0.5% (wt/wt).
Crystalline Form 5 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 5 in ethyl acetate may result in other polymorphic forms of nateglinide. Triturating nateglinide Form 8 at a temperature of firom 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 5 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 matedal used for the processes of the present invention may be any crystalline or amorphous form of nateglinide, including various solvates and hydrates. With crystallization processes, the crystalline form of the starting material does not usually affect the fmal result. With trituration, the final product may very depending on the starting material. One of skill in the art would ^preciate the manipulation of the starting material within skill in the art to obtain a desnable form with trituration.
The processes of the present invention may also be practiced as the last step of prior art processes that synthesize nateglinide.
Many processes of the present invention involve crystallization out of a particular solvent, i.e., obtaining a solM material from a solution. One skilled in the art would appreciate that the conditions concerning crystalHzation may be modified without affecting the form of the polymorph obtained. For example, when mixing nateglinide in a solvent to form a solution, warming of the mixture may be necessary to completely dissolve the starting material. If warming does not clarify the mixture, the mixture may be diluted or filtered. To filter, the hot mixture may be passed through paper, glass fiber or other mmbrane material, or a clarifying agent such as celite. Depending upon the equipment used and the conoaitration and temperature of the solution, the filtration apparatus may need to be prdieated 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
for a particular compoun4 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 csrystals, 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 the art are aware, micronizers use the kiaetic energy of collision between particles suspended in a rapidly moving fluid stream to cleave the particles. An air jet mill is a preferred fluid energy mill. The suspended particles are injected under pressure into a recirculating particle stream. Smaller particles are carried aloft inside the mill and swept into a vent connected to a particle size classifier such as a cyclone. The feedstock should first be milled to about 150 to 850 nm which may be done using a conventional ball, roller, or hammer mill. One of skill in the art would appredate 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, paienterally, rectally, transdermally, bucally, or nasally. Suitable forms for oral administration include tablets, con^ressed or coated pills, dragees, sachets, hard or gelatin capsules, sub-linguzil tablets, syrups and suspensions. Suitable forms of parenteral administration include an aqueous or non-aqueous solution or emulsion, while for rectal administration suitable foiias for administration include suppositories with hydrophiHc or hydrophobic vehicle. For topical administration the invention provides suitable transdermal deUvery systems known in the art, and for nasal dehvery there are provided suitable aerosol delivery systems known in the art.
Pharmaceutical foimulationss of the present invention contain a nateglinide Form selected firom A, C, D, F, G, I, J, K, L, M, N, 0, P, Q, T, V, Y, α, ß, , δ. , σ,  and Ω. The phamiaceutical composition may contain only a single form of nateglinide, or a mixture of various forms of nateglmide, 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 deteixcdiied 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 may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions iaclude, for example, microcrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesixim oxide, maltodextrin, marmitol, 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 recipients 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), carboxymethylcelluiose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), hquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch.
The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a dismtegrant to the composition. Disintegrants include alginic acid, carboxymethylcelluiose calcium, carboxymethylcelluiose sodium (e.g. Ac-Di-Sol®, Primellose*^, colloidal sihcon 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, sodiimi 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 glidants include colloidal silicon dixoide, magnesium trisilicate, powdared cellulose, starch, talc and tribasic calcium phosphate.
When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some
excipients and active ingredienls 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 magnesimn stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fiimarate, 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, fiimaric acid, ethyl mailtol, and tartaric acid.
Sohd and Uquid 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 hquid pharmaceutical conqjositions 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 usefiil in hquid 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 and/or coat the lining of the gastiointestind tract. Such agents include acacia, alginic acid bentonite, cabomer, 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 ethylenedimnine 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 gucomc acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.
Selection of excipients and the amounts used maybe readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenterd (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 conditicm being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and losanges, as well as liquid syrups, suspensions and elixirs.
The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated soUd composition of the invention, within either a hard or soft shell. The diell may be made from gelatin and optionally contain aplasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
The active ingredient and excipients maybe formulated into compositions and dosage forms according to methods known in the art.
A composition for tabletuig 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 fiirttier mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tableted, or other excipients may be addqd 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 conmunuted 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, dicalcitim 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 dose and formulation of STARLIX may be used as a guidance. The dosage used is preferably from about 30 to about 240 mg of nateghnide, more preferably from about 60 to about 120 mg of nateglinide. Tlie pharmaceutical compositions of the present invention, preferably in tiie form of a coated tablet, are administered from about 10 minutes to about 1 hours prior to a meal, more preferably about 15 mmutes before each meal. The dose is not taken if the meal is skipped. The pharmaceutical compositions may also be used in combination with metaformin.
Instruments
X-Rav Powder Diffractiop:
X-Ray diffraction was petformed 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 20, Continuos Scan, Rate: 3deg./min.
DSC:
DSC821e Mettler Toledo®, Sample weight: 3-5mg, Heating rate: 10°C/min, Number of
holes in the cmcible: 3
TGA:
Mettler TG50®, Sample weight: 7-15mg, Heating rate: 10°C/min
ETIR:
Perkin -Elmer®, Spectrum Otie FTIR spectrometer, Range: 4000-400cm-l, no. of scans: 16, resolution: 4.0cm-l, DRIFT technique.
EXAMPLES
Example 1- This example illustrates preparation of various forms of nateglinide from a solution
Nateglinide (5 g) was placed into an erlemneyer flask and heated to the specified temperature. The solvent wa$ added in 1-ml portions (in some cases, the solvent was added in 5-ml portions) until a clear solution was obtained. If a clear solution was not obtained after addition of 150 ml of the solvent, the hot mixture was filtered
The clear solution was left to crystallize at room temperature. If crystallizaticHi did not happen or was poor, the solution was refiigerated 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 mmHg) to constant weight (±0.01 g) for about 3-10 hoxu-s. Details are presented in Table IV. Table IV. Data on crystaUizalion of NTG from a single solvent
(Table Removed)

Legend. L/S - liquid/solid ratio: * - the solvent was added in 5-nil 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, EPA- 2-propanol, n-BuOH- n-butanol, EA - ethyl acetate, NM - nitromethane, DMF - N,N-dimethylformamide, DlVIA-N,N-dimethylacetamide, NMP - N-methylpyrroIidone, MeCN - acetonitrile. Ether - diethyl ether, DME - dimethoxyethane, DCM -dichloromethane, DCE - 1,2-dichloroefliane and CTC -carbon tetrachloride.

Example 2- This example illustrates trituration of nateglinide Form H and U in various solvents
Nateglinide (5 g) was placed into an Erleiuneyer 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 (±0.01 g).
Details are presented in Tables V and VI. Table V. Data on tritaratioii of NTG with a single solvent
(Table Removed)
Table VI. Data on trituration of NTG with a single solvent
(Table Removed)
Example 3- This Example illustrates Absorption of solvent vapors by nateglinide.
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 mmHg to constant weight (±0.01 g). Details are presented in Table VII. Table Vn. Data on absorption of solvent vapors with NTG Form H
(Table Removed)

Legend. Brutto - starting weight of the can with NTG; Wfinal - final weight of the can with NTG after the exposure; A - overweight
Example 4- This example illustrates preparation of various forms of nateglinide bv solvent removal.
Nateglinide (5g) was dissolved in the followmg 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
(Table Removed)
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 noixture 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 ill\istrates preparation of nateglinide bv crystallization from binary mixtures rsolvent/aQti-solvent).
Nateglinide (5g) and an anti-solvent (20 ml) were placed into an Erlenmayar 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 crystalHze 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 reduced pressure (20-30 mrtiHg) to give dry Forai B.
Table IX. Data on crystallization of NTG from binary solvents
(Table Removed)

Legend:
L/S- liquid/solid ratio (liquid= solvent+anti-solvent); / - symbol RT-^3 means that crystallization was started at room temperature then the mixture was cooled to 3°C to complete precipitation.
Example 7- Preparation of yorm delta
(A) This example illustrates preparation of nateglinide Form delta by crystallization from an ethvl acetate-heptane solvents System: Preparation of nateglinide form 5
D-Phenyialanine (15.44 g) was added all at once to a 3.5% NaOH solution (370 ml, 3.5 equivalents), at 20°C, imder stirring, 230 min-1. A clear solution was immediately formed. A neat trans-4-isopropylcycl diexylcarboxychloride (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% H2SO4 (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 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
min-1. The solid was filtered oif and washed with heptane (30 ml). The cake was dried at 60°C/20 mbar to afford 6.84 g of the 5-form. Yield 33%. Preparation of nateglinide Form 5
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 min'\ A clear solution was umnediately 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 H2SO4 (11.94 g) was added all at once to the RM to adjust pH 1-2. The solid product was extracted with EA (140 ml). The hot organic extract was washed with warm water (100 ml), followed by brine (25 ml, 30.0 g) at 40°C, and dried with anhydrous magnesium sulfate (3.05 g) over 1.5 hours. The orgaiic solution was filtered through a PTFE 0.45 µm 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 afiford 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 6, with a purity >99.8%. Yield 55%. Preparation of nateglinde form δ
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 min-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 H2SO4 (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 µm 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 150 min-1. The clear solution was gradually cooled to 28°C and seeded with Form delta. The crystalli2a.tion occurred at 24°C. The mixture was stirred for 30 mmutes at 24°C, gradually cooled to 5°C 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 (wetn^s 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 the preparation of form S 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 folly dissolved. The mixture was cooled to 30°C and seeded with nateglinide Form 5 (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 was washed with ethyl acetate (100 ml) heptane mixture (ratio 1:3 v/v). The wet product was dried in a vacuinn oven at 50°C overnight. Both the wet and dry samples were Form 6.
Starting material: Wet nateglinide (40% total wetness. 2 ml water, 10 ml ethyl acetate, 21 ml of heptane). Wet crude nategHnide (83 grams) and dry nateghnide (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 was dried in a vacuum oven at 50°C ovanight. Both the wet and dry samples were Form 8.
(C) This example illustrates the drying of form 8 by fluidized bed drver
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, liquid/solid ratios, temperature and seeding. The results are summarized in Table X:
Table X. Data on crystalliazation of NTG in EA-Heptane solvents system
(Table Removed)
Temperature profile: crystallization temperature (h)→ final temperature (h); L,t-amount of L,trans-isomer.
Example 8 This example illustrates preparation of forms of nateeliaide by precipitation without going to solution after combining Preparation of Nateglinide 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 min'. 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 miautes at 20°C, imder stirring. An 85% solution of H2SO4 (11.55 g) was added all at once to the reaction mixture to adjust the pH to 1-2. The solid product was extracted with EA (150 ml) at 55°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 0.45 µm filter into a clean dropping fiinnel 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, imder stirring. Precipitation immediately happened to afford a solid. The mixture was stirred for 2.5 hours at 5°C. The soUd was filtered off and washed with a cold (5°C) mixture of heptane-EA mixture (4.5:1, total -120 ml) to afford 63.62 g of a wet product (wetness 54%). The cake (62.4 g) was dried at 60°C/10 mbar to afford 28.6 g of the product, containing -0.6% of L,trans-isomer (other impurities Table XI. Data on crystallization of NTG during the crystallization process (precipitation without going into solution after combining)
(Table Removed)
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 natealimde Form U
Sample of nateghnide form U (~1 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 (-0.5 g) was heated to 120°C for Ih in an atmospheric
pressure. The resulted sample showed Form U by XRPD.
Example 10- heating of natjeglinide Form 5
Sample of nateghnide form 6 (~0.5 g) was heated to 120°C for Ih 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
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, resultiag ia 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- Drying of a wet sample of Form Omega
The product of example 11 was dried at 50°C in a vacuum oven overnight, and analyzed
by XRD. A mixture of Fonn omega and Form Z was obtained.
Example 13- This example illustrates the preparation of Form U by trituratiag form 5 in
Ethvl-Acetate
Nateglinide Form 5 (5 grams) was triturated in ethyl acetate (10 ml) at 25 °C for 2 hours.
The wet material was filtered with vacuum and washed with ethyl acetate (10 ml). The
wet product was dried at 50°C in a vacuimi oven overnight. The wet and dry products
were Form U.
Example 14- This example illustrates the preparation of form B by triturating Form 6 in
ethvl-acetate
Nateglinide Form 5 (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 (lOmI). 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 Nateglinide Form B
Nateghnide Form B may also be obtained by precipitation of nategliaide Form G, from isopropanol followed by conversion of Form G to Form B. In this embodimait, a form of nateglinide, such as nateglinide Form 6 (about 3% LOD) is dissolved in a mixture of IPA/H2O at a preferred temperature range of about 40 to about 50 ° C. Preferably, the JPA concentration in the soiveant 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 prefared 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 mixture), followed by evaporation under reduced pressure. After flie evaporation, IPA/H2O 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 fmal product as illustrated in Figure 64.
Example 15 (A) 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.
Example 15 (B) Nateglinide (30 grams) was dissolved in IPA (150 ml) in a reactor. The solvent was evaporated imder 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 solvent was evaporated under reduced pressure at a temperature of 50 °C- IPA (200 ml) and water (200 ml) were fed into the roimd 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 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 imder reduced pressxire 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 Nateglinide Form B by Trituration in Water Nateglinide Form 6 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 S 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. The wet crystals were tested by XRD and fovind to be 5 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 5 type. The dry crystals were tested by XRD and found to be B type.
Example (B): Trituration of dry starting material 50 gr Nateglinide form 6 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 Nateglinide form U
Example (A): Crystallization from Acetone Nateglinide (50 grams) Form 8 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, tive 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 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 undw reduced pressure, and Ethyl Acetate (460 ml) was evaporated (the solvent volume in the reactor was 5 volumes/imit 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 crystals were tested by XRD and found to be U type. The dry crystals were tested by XRD and foimd to be U type.
Example 18- Removal of reside solvent from Form delta
Nateglinide (40 grams) Form delta (1.5% heptane) was dried in a stirred reactor (7-10 rpm) under 60 mmHg vacuxma suid at 60°C. After 6 hours of drying, the residual solvent of the material was 613 ppm of heptane. The polymorph of the dried material remained delta form, as the starting material.
Example 19- Preparation of nateglinide Form B from ethyl acetate Nateglinide form 6 is dissolved in ethyl acetate at 25 °C. The solvaat is evaporated under reduced pressure, until turbidity appears. The turbid solution is cooled to 0°C plus/minus 5 °C for 1 hour and stirred for 1 hour. The product was isolated and dried under reduced pressiue at 50° C.
Example (A)
Nateglinide (12 grams) Form 5 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 dried under reduced pressure at 50°C. Both the wet and the dry crystals were tested by XRD 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 fit)m the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in anyway. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications. Polymorphism in Pharmaceutical Solids, Drugs and the Pharmaceutical Sciences, Volume 95 may be used as a guidance. All references mentioned herein are incorporated in their entirety.






WE CLAIM:
1. A process for preparing nateglinide Form U comprising the steps
of:
(a) preparing a solution of nateglinide in a solvent selected from the group consisting of an ester, ketone, alcohol and mixtures thereof, at a temperature from -15°C to 50°C;
(b) crystallizing nateglinide Form U from the solution; and
(c) recovering the nateglinide Form U.

2. The process as claimed claim 1, wherein the solution of step (a) further comprises an anti-solvent, wherein the anti-solvent is a C5 to a C12 hydrocarbon.
3. The process as claimed in claim 2, wherein the anti-solvent is heptane.
4. The process as claimed in claim 1, wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, n-propanol, acetone and ethyl acetate.
5. The process as claimed in claim 4, wherein the solvent is ethyl acetate.
6. The process as claimed in claim 5, wherein the ethyl acetate to anti-solvent ratio is from 2:1 to 1:1 (vol/vol).
7. The process as claimed in claim 5, wherein the anti-solvent is from 20°C to 40°C colder than the ethyl acetate.
8. The process as claimed in claim 7, wherein the anti-solvent has a temperature of from 0°C to 10°C and the ethyl acetate a temperature of rrom 30°C to 40°C.
9. The process as claimed in claim 2, wherein the solution is prepared at a ternperature of at least 25°C, and the solution is then cooled to a temperature of from 0°C to 10°C to crystallize Form U, and Form U is recovered before its transition to another form.
10. The process as claimed in claim 1, further comprising, after step (a), adding the solution to a container holding heptane to spontaneously precipitate the nateglinide Form U, wherein the solvent is ethyl acetate and the heptane is colder than the solution.
11. The process as claimed in claim 1, wherein the solvent is ethyl acetate or acetone, and step (b) comprises seeding the solution with a crystalline form of nateglinide to crystallize nateglinide Form U.
12. The process as claimed in claim 11, wherein the solution is seeded with Form B.

Documents:

317-delnp-2005-abstract.pdf

317-delnp-2005-assignment.pdf

317-delnp-2005-claims.pdf

317-delnp-2005-complete specification (as file).pdf

317-delnp-2005-complete specification (granted).pdf

317-delnp-2005-correspondence-others.pdf

317-delnp-2005-correspondence-po.pdf

317-delnp-2005-description (complete).pdf

317-delnp-2005-drawings.pdf

317-delnp-2005-form-1.pdf

317-delnp-2005-form-18.pdf

317-delnp-2005-form-2.pdf

317-delnp-2005-form-3.pdf

317-delnp-2005-form-5.pdf

317-delnp-2005-gpa.pdf

317-delnp-2005-pct-101.pdf

317-delnp-2005-pct-210.pdf

317-delnp-2005-pct-220.pdf

317-delnp-2005-pct-304.pdf

317-delnp-2005-pct-306.pdf

317-delnp-2005-pct-308.pdf

317-delnp-2005-pct-318.pdf

317-delnp-2005-pct-409.pdf

317-delnp-2005-pct-416.pdf

317-delnp-2005-petition-137.pdf

317-delnp-2005-petition-138.pdf


Patent Number 246660
Indian Patent Application Number 317/DELNP/2005
PG Journal Number 10/2011
Publication Date 11-Mar-2011
Grant Date 09-Mar-2011
Date of Filing 27-Jan-2005
Name of Patentee TEVA PHARMACEUTICAL INDUSTRIES LTD
Applicant Address 5 BASEL STREET, P.O.BOX 3190, PETAH TIQVA 49131, ISRAEL.
Inventors:
# Inventor's Name Inventor's Address
1 RONIT YAHALOMI ZINGER 6, KIRYAT BIALIK 27037, ISRAEL.
2 EVGENY SHAPIRO 18/1 GUT LEVIN ST., HAIFA 32922, ISRAEL.
3 BEN-ZION DOLITZKY LOHAME HAGHETTO 32, PETACH TIQVA 49651, ISRAEL.
4 IGAL GOZLAN 27/2 GUT LEVIN ST., HAIFA 32922, ISRAEL.
5 BOAZ GOME TYOMKIN 14/14, RISHON-LEZION 75257, ISRAEL.
6 SHLOMIT WIZEL YEHUDA HANASSI 2, PETAH TIKVA 49742, ISRAEL.
PCT International Classification Number C07C 231/24
PCT International Application Number PCT/US2003/022375
PCT International Filing date 2003-07-18
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/413,622 2002-09-25 U.S.A.
2 60/414,199 2002-09-26 U.S.A.
3 60/432,962 2002-12-12 U.S.A.
4 10/614,266 2003-07-03 U.S.A.
5 60/396,904 2002-07-18 U.S.A.