JP2006511614A - Polymorphic shape of nateglinide - Google Patents

Abstract

A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, U, V, Y, α, β, γ, δ, ε, σ, θ and Crystalline forms of nateglinide labeled Ω form, processes for its preparation, and processes for the preparation of other nateglinide crystalline forms are provided. Also provided are pharmaceutical formulations and administration methods thereof.

Description

構造式 Ｃ₁₉Ｈ₂₇ＮＯ₃
分子量 ３１７．４２
正確な質量 ３１７．１９９０９３
組成 Ｃ７１．８９％ Ｈ８．５７％ Ｎ４．４１％ Ｏ１５．１２％ The present invention relates to solid phase chemistry of nateglinide.
BACKGROUND OF THE INVENTION Nateglinide, known as (-)-N- (trans-4-isopropylcyclohexanecarbonyl) -D-phenylalanine, has the following structure and properties:

Structural formula C ₁₉ H ₂₇ NO ₃
Molecular weight 317.42
Exact mass 317.199093
Composition C71.89% H8.57% N4.41% O15.12%

  Nateglinide is commercialized as STARLIX formulated as an oral tablet with dosages of 60 mg and 120 mg for the treatment of type II diabetes. STARLIX can be used as a monotherapy or in combination with metaformin to stimulate the pancreas to secrete insulin. According to the manufacturer of STARLIX, nateglinide is a white powder that is freely soluble in methanol, ethanol and chloroform, soluble in ether, slightly soluble in acetonitrile and octanol, and virtually insoluble in water.

  Nateglinide can be crystallized from a mixture of water and methanol and further dried, as disclosed in US Pat. No. 4,816,484. The procedure of the '484 patent results in a hydrate labeled as Z form by the applicant (s) or methanolate labeled as E form by the applicant (s).

  The present invention relates to the solid state physical properties of nateglinide. These properties can be influenced by controlling the conditions under which nateglinide is obtained in solid form. For example, the physical properties of the solid state include the fluidity of the ground solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. If the powdered compound particles do not flow easily through each other, the formulation specialist must take it into account when developing tablet or capsule formulations, including colloidal silicon dioxide, The use of glidants such as talc, starch and tribasic calcium phosphate may be necessary.

  Another important solid state property of a pharmaceutical compound is its dissolution rate in an aqueous fluid. The rate of dissolution of the active ingredient in the patient's gastric fluid may have therapeutic consequences because it imposes an upper limit on the rate at which the orally administered active ingredient can reach the patient's bloodstream. Dissolution rate is also a consideration in formulating syrups, elixirs, and other liquid chemicals as well. The solid state form of a compound can also affect its behavior on compression and its storage stability.

  These practical physical properties are affected by the conformation and orientation of the molecules within the unit cell that define the specific polymorphic shape of a substance. A polymorphic shape can generate different thermal behavior than that of an amorphous material or another polymorphic shape. Thermal behavior is measured in the laboratory by techniques such as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) to distinguish some polymorphic shapes from other polymorphic shapes. Can be used. Certain polymorphic forms can also produce quite different spectral properties that can be detected by powder X-ray crystallography, solid state C NMR spectroscopy and infrared spectroscopy.

Nateglinide exists in various crystalline forms. US Pat. Nos. 5,463,116 and 5,488,150 disclose two crystal forms of nateglinide called Form B and Form H and their preparation process. These patents are hereby incorporated by reference with respect to their disclosure of shape. Both shapes are characterized by melting point, X-ray powder diffraction (“XRPD”) pattern, IR spectrum in KBr and DSC thermography. According to these patents, type B has a melting point of 129-130 ° C, while type H has a melting point of 136-142 ° C. H-type crystals are strong in these patents by XRPD with peaks at 8.1, 13.1, 19.6 and 19.9 ± 2 degrees 2θ, and between 15 and 17 ± 0.2 degrees 2θ Characterized by reflection. B-type crystals are reported to lack these peaks and have a weak reflection between 15 and 17 ± 0.2 degrees 2θ. H-type crystals have been reported as having IR spectra with characteristic absorption at about 1714, 1649, 1542, and 1214 cm ⁻¹ . These absorptions have been reported to be lacking in the spectrum of B-type crystals.

  According to US Pat. No. 5,463,116, type B crystals are unstable and can change during milling, as demonstrated by DSC. B-type DSC thermography shows a sharp endothermic peak at 131.4 ° C. before grinding, while the H-type shows a sharp endothermic peak at 140.3 ° C. After milling, Type B DSC thermography shows a second endothermic peak at 138.2 ° C., suggesting a solid-solid transformation during milling.

  According to US Pat. No. 5,463,116, the temperature during crystallization and filtration determines whether the crystalline form is B-type or H-type. Temperatures above 10 ° C., more preferably temperatures above 15 ° C., lead to H-type formation, while temperatures below 10 ° C. lead to B-type formation.

Another crystalline form of nateglinide, called S-type, has been disclosed in two Chinese papers. That is, ACTAPharm. Sinica 2001, 36 (7), 532-34 and Yaowu Fenxi Zazhi, 2001, 21 (5) 342-44. S type, a melting point of 172.0 ° C., accompanied by a peak in 3283cm ^-1 (different from 3257cm ^-1 and 3306cm ^-1 for each B-type and H-type) Fourier transformation IR, and 3.78 ± 0.2 degrees The XRPD pattern with a strong peak at 2θ is reported to be distinguishable from the B and H forms.

  US Pat. No. 5,463,116 (“the '116 patent”) lists methanolate, ethanolate, isopropanolate and acetonitrylate solvates of nateglinide. According to the '116 patent, amorphous nateglinide can be obtained by drying hydrates and solvates. Hydrates can be crystallized by dissolving B-form crystals in a 1.5: 1 mixture of ethanol and water, followed by crystallization as disclosed in Example B-3 of the '116 patent. It is.

  The applicant himself obtained the hydrate of nateglinide labeled as Z form. However, repeating Example B-3 of the '116 patent or Comparative Example A3 also results in the Z form, similar to the crystal procedure of the' 484 patent. The Z form is obtained when only water is present, whereas the B form methanolate or ethanolate is obtained when both methanol or ethanol and water are present.

  Japanese PCT publication WO 02/34713, in its summary, comprises the steps of drying wet crystals of nateglinide solvate at a low temperature until the solvent disappears and then subjecting them to a crystalline transition. Process for preparing B-form nateglinide crystals free of any H-form crystals ". According to the applicant's translation of WO published in Example 1, “Nateglinide Form H (24.5 kg) was added to ethanol (3602) and stirred at room temperature until dissolved. ) Was cooled to 5 ° C. and allowed to grow sufficiently for 1 hour at 5 ° C. The deposited crystals were separated to obtain wet crystals (43.0 kg) which were stored in a shelf drying oven at 45 ° C. for 24 hours. Dried in water (water content about 1%) and then heated at 90 ° C. for 12 hours resulting in crystal transformation, at which time dry crystals (13.3 kg) were obtained, which were measured by DSC, A characteristic B-shaped peak was detected (mp. About 130 ° C.), but a characteristic H-shaped peak (mp. About 139 ° C.) was not detected, so the crystals obtained were only the B-type. It was concluded that the H form was essentially absent. "

According to the applicant's translation on page 3, line 2 of the WO publication;
“The resulting wet solvate crystals (BS: from the cooled solution) are dried until the solvent disappears. The temperature for this will depend on the type and quantity of the solvent, but usually 60 Below 50 ° C., preferably below 50 ° C. There is no lower limit to the temperature, but [drying] is usually carried out for economic reasons above 20 ° C. Drying is advantageously carried out under reduced pressure: industrially Under achievable vacuum, drying will be completed in a short time, and drying at low temperature can continue until the solvent is virtually gone, but it need not be completely cleaned, on the order of 5% by weight Even if there is a solvent up to, it disappears during the crystal transformation, so there is no problem at all.Dry crystals are heated to 60-110 ° C., preferably 70-100 ° C., to form B The crystal transformation is brought about. It is usually preferably carried out within 0.5 to 48 hours, most preferably 1 to 24 hours. "

Another PCT publication, WO 03/022251, discloses one crystalline form of nateglinide labeled “AL type”. This crystalline form has a melting point of 174-178 ° C., an XRPD pattern with peaks at 7.5, 15.5, 19.8 and 20.2 degrees 2θ, and 1711.5, 1646.5, 1538.7, Characterized as having an infrared spectrum with absorption bands in the regions of 1238.8, 1215.1 and 700.5 cm ⁻¹ . This crystalline form has been obtained in the examples from acetonitrile solutions under a specific temperature range.

A process for preparing nateglinide is disclosed in WO / 0232854.
The discovery of new polymorphic forms of pharmaceutically useful compounds provides a new opportunity to improve the performance characteristics of pharmaceutical products. It expands the repertoire of materials available to pharmacists in designing pharmaceutical dosage forms of drugs with, for example, target release profiles or other desired characteristics. A new polymorphic form of nateglinide has now been discovered.

SUMMARY OF THE INVENTION The present invention provides A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, U, V, Y, α (alpha), β ( It provides 26 crystalline forms of nateglinide called beta, γ (gamma), δ (delta), ε (epsilon), σ (sigma), θ (theta), and Ω (omega) forms.

Some of these crystalline forms are bonded solvents, ie, solvents (solvates) that form part of the crystal structure. These solvates with bound solvent include form A (xylene), form C (dimethylacetamide- "DMA"), form D (ethanol- "EtOH"), form E (ethanol and methanol- "MeOH"), F (n-propanol- "n-PrOH"), Form G (isopropyl alcohol- "IPA"), I (n-butanol- "n-BuOH"), J (N-methylpyrrolidone- " NMP "), K form (dimethylformamide-" DMF "), M form (carbon tetrachloride-" CTC "), N form (dichloroethane-" DCE "), O form (methanol), Q form (chloroform-" CHcl ") ₃ "), T-form (methanol), V-form (dimethoxyethane-" DME "), Y-form (chloroform; dichloromethane), beta-form (N-methylpyrrolidone), gamma-form (N-methylpyrrolidone) Dong) and δ form (acetone; acetonitrile- “MeCN”; nitromethane “NM”) and θ form (heptane). The Z form is a hydrate with water in the crystal structure. The Ω form is a solvate of both water and isopropyl alcohol.

  Other crystalline forms are anhydrous with no binding solvent, ie, less than about 2% as measured by loss on drying ("LOD"). These anhydrides include crystalline forms L, P, U, α, δ, and σ.

  XRPD patterns of these shapes substantially described are disclosed in FIGS. 1-27 and 63, and characteristic peaks are listed in Table I. The DSC thermography for the shape is disclosed in FIGS. 36-62, and the characteristic DSC peaks are listed in Table II. FTIR spectra and characteristic peaks in the anhydrous and hydrate form are also provided. LOD values from TGA analysis of some of these shapes are listed in Table III. The preparation of the various shapes by the crystallization procedure is listed in Table IV, while the preparation by sharma is listed in Tables V and VI, the data on solvent vapor absorption are listed in Table VII, and the preparation by solvent removal Data are listed in Table VIII and data for crystallization from solvent / antisolvent systems are listed in Tables IX-XI. Table 28 summarizes the thermal stability of various shapes.

  The present invention also provides pharmaceutical formulations of various crystalline forms and their administration.

DETAILED DESCRIPTION OF THE INVENTION In one aspect, the invention provides A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, U, V, Y, It offers 26 crystalline forms of nateglinide (“NTG”) called α, β, γ, δ, ε, σ, θ and Ω forms. These crystalline shapes are characterized by, among other things, their XRPD patterns, DSC thermography and TGA analysis. Also provided are processes for preparing other polymorphic shapes such as B, E, H, S, and Z shapes.

  Various crystalline shapes are characterized by their XRPD patterns that vary from polymorph to polymorph. The E form is rather similar to the Z form by XRRD, but some differences can also be observed. The peak at 3.7 is characteristic of the E form and is not observed with the Z form XRPD. Patterns within the range of 19-22 degrees 2 theta are also somewhat different between these two shapes. Table I lists the most characteristic peaks for the new crystalline shape. The XRPD pattern is illustrated in FIGS. 1-27 and 63.

ナテグリニドのさまざまな結晶性形状もそのＤＳＣサーモグラフィーにより特徴づけされる。表ＩＩは、ＤＳＣピークを列挙している（吸熱ピーク）。表ＩＩに列挙されたピークに加えて、さまざまな結晶性形状の数多くが約１６５℃での発熱とそれに続く恐らくはＳ型形状への再結晶化に起因する約１７４℃での吸熱ピークを示す。 Table I: XRPD characteristic peaks for crystalline form of nateglinide

Various crystalline forms of nateglinide are also characterized by its DSC thermography. Table II lists the DSC peaks (endothermic peaks). In addition to the peaks listed in Table II, many of the various crystalline shapes exhibit an endothermic peak at about 174 ° C. due to an exotherm at about 165 ° C. followed by recrystallization, presumably to an S-type shape.

さまざまな結晶性形状が同様に熱重量分析（ＴＧＡ）によっても分析される。ＴＧＡ測定は、Ａ、Ｄ、Ｅ、Ｆ、Ｇ、Ｉ、Ｊ、Ｋ、Ｍ、Ｎ、Ｏ、Ｑ、Ｔ、Ｕ、Ｖ、Ｙ、Ｚ、β、γ、δ、θ及びΩ形が多大な量の結合された溶媒を含有し、ナテグリニドの溶媒和された形状とみなすことができる、ということを示している。これらの溶媒和形状のいくつかのＸＲＰＤ分析は、それらのうちのいくつかが２４時間開放びん中に放置された場合に不安定であることを示している。以上で列挙した形状とは対照的に、Ｌ、Ｐ、Ｕ、α、δ及びσ形のＴＧＡプロフィールは有意な重量損失を全く示していない。ナテグリニドのこれらの多形性形状は、結合された溶媒を含まず、すなわち約２％ＬＯＤ未満である。表ＩＩＩは、ナテグリニドの溶媒和形状の調製に用いられる溶媒ならびにＴＧＡ分析に基づくＬＯＤ値を列挙している。 Table II: DSC peak of crystalline form of nateglinide

Various crystalline forms are similarly analyzed by thermogravimetric analysis (TGA). TGA measurement includes A, D, E, F, G, I, J, K, M, N, O, Q, T, U, V, Y, Z, β, γ, δ, θ and Ω types. It shows that it contains a significant amount of bound solvent and can be considered a solvated form of nateglinide. Several XRPD analyzes of these solvated forms indicate that some of them are unstable when left in an open bottle for 24 hours. In contrast to the shapes listed above, the L, P, U, α, δ, and σ TGA profiles do not show any significant weight loss. These polymorphic forms of nateglinide are free of bound solvent, i.e. less than about 2% LOD. Table III lists the solvents used to prepare the solvated form of nateglinide as well as LOD values based on TGA analysis.

  The ethanolate solvate of nateglinide disclosed herein has an ethanol content of about 10 to about 30 weight percent. The ethanol solvate of nateglinide ethanol solvate is represented by the structural formula NTG · 3/2 EtOH. Specifically, the solvate is D-formeglinide.

The nateglinide methanol solvate disclosed herein has a methanol content of about 2 to about 60 weight percent. In particular, nateglinide methanol solvate exists as nateglinide E, O and T form methanol solvates. Nateglinide methanol solvate is represented by structural formula NTG ^* 1/4 MeOH (O form) or structural formula NTG ^* 1/2 MeOH (E form). T-form nateglinide contains greater than about 20 weight percent methanol. The methanol content of the T form is about 20 weight percent to about 60 weight percent.

  The isopropyl solvate of nateglinide disclosed herein has an isopropyl alcohol content of about 12 weight percent to about 30 weight percent. Specifically, the isopropyl solvate of nateglinide exists as Form G nateglinide.

The hydrate of Z-form nateglinide is measured by either the Karl Fischer method or LOD, from about 10 to about 50%, more preferably from about 10% to about 40%, most preferably from about 15% to about 25%. Having a water content of The Ω form is a hydrate-solvate of isopropanol and contains about 50% LOD of water and isopropanol.
The heptane solvated form of nateglinide, the θ form, has about 7 to about 8 weight percent heptane and is represented by the structural formula NTG ^* 1/4 heptane.

Table III: Solvents used for the preparation of LOD values and nateglinide solvated forms by TGA

The anhydrous form and the hydrated Z form are also characterized by FTIR spectra. The Z form is characterized by FTIR spectra (FIG. 31) with peaks at about 699, 1542, 1645, 1697, 2848, 2864, 2929, 3279 and 3504 cm ⁻¹ . More characteristic peaks are observed at about 1645, 1697, 3279 and 3504 cm ⁻¹ . The characteristic FTIR peaks are for the anhydride and the L, U, P, α, δ and σ forms are disclosed in the table below.

  The various crystalline forms are transformed into another form as a result of drying one form, ie nateglinide A, B, D, E, F, G, H, I, J, K, L, M, Correlated to each other in that N, Q, S, T, V, Z, α, β, δ, γ, ε, θ and Ω forms can be produced. Drying is performed by heating the sample under atmospheric pressure or reduced pressure. In general, the preferred temperature is from about 40 ° C to about 80 ° C, more preferably under reduced pressure. Of these shapes, B-type, H-type, L-type, U-type and sigma-type are thermally stable and do not convert to another shape upon heating. Many of the above shapes convert to B-type when dry, ie, A, C, D, E, F, G, J, K, P, Q, T, Z, α, β, δ, θ, and Ω. Of these shapes, the α, δ, Y and O forms are somewhat stable and usually retain their crystal structure after heating unless heated to high temperatures. For example, Form δ is stable when heated to 60 ° C. overnight (at least about 8 hours), but heating Form δ at 120 ° C. and 1 atmosphere results in Form B. Thus, heating to temperatures above about 80 ° C. can cause transformations in these shapes. As used herein, the term “stable” means a polymorphic change of less than about 5 weight percent, more preferably less than about 2%, especially for the δ form.

  The conversion of some shapes to B shape transitions through another shape. For example, the conversion from Ω and E form to B form may proceed through the Z form.

  The G shape may represent a link between F, T shape on the one hand and B shape on the other hand. The T and F forms are converted to a mixture of B and G forms at the time of drying, so that the probability that the F and T forms are converted to the B form by passing through the G form is high.

  Of the shapes that convert to B shape, some will sometimes convert to other shapes when dry. The K form can be converted to the shape α or S, while the C form can be converted to the B or α form. The α form can be converted to the S form upon heating, but the presence of the B form seed in the α form sample results in the B form. Presumably the C and K forms first transform to the α form, and it is through the α form that they transform to the B or S form. The J form can be converted to the B form or the β form, but the conversion to the B form can pass through the β form. The J form used in preparing the β form is preferably obtained by crystallization from N-methylpyrrolidone. If the J form contains some seeds of the γ form, heating results in the γ form.

  The epsilon form of the acetonitrile solvate, when dried, results in form B. On the other hand, the epsilon form of the nitromethane solvate yields the H or P form when dried. When the P system is dried, the H form is obtained, so the conversion of the epsilon form to the H form is more likely to pass the P form.

  Another heat stable form of nateglinide is the L shape. The L form can be obtained by heating the M, N and D forms. In order to obtain the L form, these various shapes are preferably heated under reduced pressure within a temperature range of about 40 ° C. to about 80 ° C., more preferably at about 50 ° C. for about 3-10 hours. The γ form can also be prepared by heating the J form containing γ form seeds under similar conditions.

  Another heat stable form of nateglinide is the H form, which can be prepared by heating P, V and ε form nateglinide. The S form can be prepared by heating the alpha form and the K form, but the transition from the K form to the S form can pass through the alpha form.

The U form is another heat stable nateglinide form 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 room pressure can similarly cause a transition from one form to another. Form A is partially converted to Form B during storage for about a day at room temperature. Similarly, under the same conditions, the Q form is converted to the Y form (including chloroform), while the T form is converted to the E form.

  The α form is related to the F, G, I and δ forms in that they can be crystallized from the same solvents as their forms such as n-propanol, isopropyl alcohol, n-butanol and acetonitrile, respectively. However, the α form is crystallized under different conditions. See, for example, Table IV. The α form is often obtained with an extended crystallization stage (at least about 2-3 days). Although not bound by any theory, this phenomenon can point to the possibility of conversion of another crystalline form, such as that obtained from the same solvent, to the alpha form over time in the solvent. .

  The E and D forms are also related in that both forms can be crystallized from ethanol. However, these shapes crystallize under different conditions. See, for example, Table IV. Crystallization of Form B in ethanol is extended for at least about 5 days, more preferably for at least about 1 month. Without being bound by any theory, it may be possible that the initial D form crystallizes and then converts to the E form over time in a solvent.

  In order to prepare the S form, the wet sample obtained after crystallization must be dried. Crystallization from a solution of nateglinide in n-butanol and DMF results in a solvate that needs to be dried to obtain the S form. The wet samples are K, I and alpha forms of nateglinide.

  Some of these shapes first appear as gels, then during the filtration stage (eg epsilon form from nitromethane, and form A from xylene) or over time (eg M from carbon tetrachloride). And J form from N-methylpyrrolidone), transformed into crystals. In general, gels are unstable shapes that crystallize over time.

  Some of the crystalline forms can be obtained by grinding. As used herein, Kenwa means obtaining a solid from a mixture of nateglinide in a solvent without complete dissolution. One form of nateglinide is mixed in a particular solvent and stirred for a time sufficient to allow transformation to another crystalline form. After stirring, a suspension or paste is formed. At this time, solids can be separated from the suspension by techniques well known in the art such as filtration. To name one technique, the paste can be filtered to remove excess solvent. The result of this kneading procedure is various forms of nateglinide.

  A submerged delta form can result in a Z form after about 5 hours and an E form after about 8 hours, which can also indicate a transition from the Z form to the E form. . All three shapes can be heated to obtain the B shape.

  Some crystalline forms can be obtained by solvent removal. First, a solution of nateglinide in a suitable solvent is prepared. A clear solution can be obtained by heating the solvent. The solvent can 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 a high temperature within the above range. The solvent is preferably removed by evaporation, with evaporation under reduced pressure being particularly preferred. The resulting residue is then inspected. Suitable solvents include esters, ketones, amines, amides, alcohols and nitriles. Removal of acetonitrile, acetone, ethyl acetate and isopropyl alcohol as a solvent results in Form B nateglinide.

  Part of the crystalline shape is obtained by absorption of solvent vapor. Nateglinide is contacted with the vapor of a particular solvent, resulting in solvent absorption. As a result of the absorption of ethanol, the D form is obtained, the O form is obtained as a result of the absorption of methanol, and the Y form is obtained as a result of the absorption of DCM. Form H was stable in the presence of water and acetone vapors.

  Part of the crystalline form can be obtained by crystallization from a suitable solvent. The omega form is obtained by crystallization of nateglinide from a mixture of water and isopropanol. Preferably, the ratio of water to isopropanol is about 1/2 to about 1/5, more preferably 1/3 (vol / vo /).

  Z-form nateglinide is generally prepared by acidification of a solution of an alkali metal or alkaline earth metal salt of nateglinide in an aqueous solvent. A preferred solvent is water without a cosolvent. Preferred salts are sodium and potassium salts, with sodium salts being most preferred. Prior to acidification, the solution preferably has a pH above about 8, while after acidification, the pH is preferably from about 1 to about 5, most preferably from about 2 to about 5. Acidification results in the precipitation of nateglinide, which can be recovered by techniques well known in the art such as filtration.

  Forms B and U nateglinide can be prepared by crystallization from an organic solvent such as ethyl acetate or acetone. In the procedure for the preparation of Form B, crystallization is preferably induced by concentration of the solvent, whereas for Form U, it is induced by seeding into solution.

The B, H, U, Z, δ, θ and δ form nateglinides are related in that they can all be prepared from two solvent systems. The two solvent system used is a mixture of solvent and antisolvent. Examples of suitable anti-solvent, it is C ₅ -C ₁₂ saturated hydrocarbons, such as C ₅ -C ₁₂ aromatic hydrocarbons such as toluene and xylene, and like hexane and heptane. Examples of suitable solvents include C ₁ -C ₅ alcohols such as methanol, ethanol, isopropanol, n-butanol and n-propanol, lower ketones (C ₃ -C ₆ ) such as acetone, and ethyl acetate. Are lower esters (C ₃ -C ₆ ). After crystallization, the crystals can be recovered and dried by techniques well known in the art such as filtration and centrifugation. In order to dry, the temperature may be increased or the pressure may be decreased. In one embodiment, it is dried at about 40 ° C. to 60 ° C. at a pressure of less than about 50 mm Hg.

  When nateglinide is crystallized from a binary mixture, particularly in the absence of agitation, the crystalline product is often in Form B as illustrated in Table IX. A binary mixture is prepared by suspending nateglinide in an antisolvent and then adding the solvent to form a solution. Form B nateglinide can be obtained at different crystallization temperatures, such as about 0 ° C. and room temperature, especially in the absence of agitation.

  Crystallization from a binary mixture of the above solvent and anti-solvent may lead to other forms of nateglinide other than Form B. Crystallization from a toluene / methanol mixture can result in Form E nateglinide, which can be converted to Form B by heating. In addition, the heptane / ethyl acetate combination can sometimes lead to a mixture of Forms B and Z, especially with longer crystallization cycles (about 3 days or more), while toluene / ethyl acetate mixtures May result in a mixture of shapes. A mixture of Forms B and Z can be converted through heating to substantially contain Form B, since the Form Z converts to Form B through heating.

  In another embodiment, rather than first preparing the solution by suspending nateglinide in the antisolvent, the solution is prepared in the solvent and then combined with the antisolvent. This combination is performed in this embodiment in such a way that a solution is formed at the time of addition and any precipitated solid returns to the solution. Preferably, the antisolvent is heated in such a way that no immediate precipitation occurs at the time of mixing the solution and the antisolvent.

  The solvent / anti-solvent ratio can obtain different shapes depending on the crystallization conditions and the stirring time. Generally, the Z shape is about 2-4, the H shape is about 4 to about 7, the B shape is about 6 to about 8, the U shape is about 1 to about 2, the θ shape is about 1, the δ shape is about 1 to about 1. Crystallization from an ethyl acetate / heptane ratio of about 8, more preferably about 1 to about 2 (vol / vol).

  Among these, some shapes crystallize like other shapes, and are converted after being stirred in a solvent for a sufficient time. Stirring the resulting slurry from crystallization at a temperature of about −15 ° C. to about 10 ° C., preferably about 5 ° C., can result in the δ form. It seems that the δ shape is obtained as a result of stirring in the shapes of U shape, θ shape, H shape and B shape. Preferably, the agitation to obtain the δ form is performed for at least about 2-3 hours, more preferably for at least about 10 hours.

  Except for a solvent: antisolvent ratio of about 1, the formation of the θ form would be advantageous at lower crystallization and filtration temperatures of about −15 ° C. to about 10 ° C., preferably 5 ° C. As described above, the δ form is preferably obtained as a result of stirring the θ form in the specified temperature range.

The U form can be obtained by stirring with the B form or the H form in an organic solvent.
The U form can be obtained by stirring with the B form or the H form in an organic solvent. Stirring for about 1 hour is sufficient to obtain the U shape. However, additional agitation, such as about 5 hours or more, can result in a transition to the δ form. The U form can also be obtained by crystallization at a specified ratio, preferably from about -15 ° C to about 10 ° C and crystallization at a filtration temperature. The U form generally begins at a temperature of about 25 ° C. to about 35 ° C., then cools to a temperature of about 0 ° C. to about 10 ° C. in less than about 1 hour (but preferably about 5 ° C.), and then less than about 1 hour It has an advantageous effect when filtered through. A higher solvent to anti-solvent ratio can favor the U form as compared to the θ form.

  Form H can be obtained at both high and low crystallization temperatures, preferably under the specified solvent / antisolvent ratio. On the other hand, Form B has a tendency to crystallize at a temperature of at least about 15 ° C.

  The Z form generally crystallizes after about one day at a final 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 crystallization temperature for these shapes is preferably above 35 ° C, followed by cooling to about 20 ° C to about 25 ° C within a few hours, more preferably within about 1 hour. These conditions can lead to the Z form, which converts to the B form upon drying.

The σ form can also be obtained by stirring the B form crystals. Without being bound by any theory, it may be possible to obtain the σ form through the U form, i.e., the agitation results in a transition from the B form to the U form followed by the σ form. . In order to obtain the sigma form, crystallization and filtration for a long time, preferably at least about 10 hours, are preferred.
Table X shows no transition from Form B to other forms despite prolonged stirring in the antisolvent / solvent system due to the use of a high proportion of ethyl acetate. Preferably, a solvent to antisolvent ratio of 1: 1 is used to obtain other forms through B form agitation in the solvent / antisolvent mixture.

The result of the process can vary when the solid is precipitated after combining the solution and the anti-solvent. In this embodiment, unlike other embodiments that result in a solution after the combining step, the solution and anti-solvent are combined in a manner that results in precipitation. In order to cause substantial precipitation, the solution is preferably combined with a cold anti-solvent. More preferably, the anti-solvent is about 20 ° C. to about 40 ° C. cooler than the solution, especially when the ethyl acetate / heptane system is used. Most preferably, heptane has a temperature of about 0 ° C. to about 10 ° C. and ethyl acetate has a temperature of about 30 ° C. to about 40 ° C.
In this embodiment, the U form can be obtained over a wide range of solvent / antisolvent ratios and crystallization temperatures. For example, Table XI shows that the U form can be obtained with a solvent-antisolvent ratio of about 1 to about 6 and a final crystallization temperature of about 0 ° C. to about 30 ° C. While not being bound by any theory, the presence of other shapes, especially after the long crystallization stage, especially the δ and σ shapes, suggests the possibility of U-shaped transitions to these shapes. Pointed out. The presence of a mixture of Forms B and U after 1 hour can likewise be crystallized immediately from solution and then transitions to form U, which itself forms over time to form δ or σ. It points out the possibility of change.
The table below provides guidance on obtaining B, H, U, Z, δ, θ, and σ forms from a solvent: poor solvent system:

  Depending on the precipitation procedure, δ form nateglinide may contain from about 0.5 wt% to about 3 wt% residual heptane. Removing heptane without changing the crystal shape can be carried out in a fluid bed dryer at a temperature of about 60 to about 70 ° C., more preferably for at least about 3 hours. Residual heptane can also be removed under stirring at a temperature of at least about 40 ° C. under vacuum. Form δ is preferably polymorphically pure, less than about 5% (wt / wt), more preferably less than about 2% (wt / wt), and most preferably less than about 0.5% (wt / wt). Containing the H form.

The crystalline form δ is stable for at least about 3 months at a temperature of about 40 ° C. and a relative humidity of about 75%.
A review of the δ form in ethyl acetate can result in other polymorphic forms of nateglinide. Trituration of δ form nateglinide in ethyl acetate at a temperature of about 20 to about 30 ° C results in the U form, while at higher temperatures (about 40 ° C) such as about 50 ° C As a result.
The process of the present invention makes it possible to obtain δ and B forms with a purity of at least about 95%, more preferably at least about 98% (wt / wt) compared to other polymorphic forms. These shapes can be generated without specifically including the H-shape.

The starting materials used for the process of the present invention can be in any crystalline or amorphous form, including various solvates and hydrates. In the crystallization process, the crystalline form of the starting material usually does not affect the final result. In kneading, the final product may vary depending on the starting material. One skilled in the art will recognize the manipulation of starting materials within the skill of the art to obtain the desired shape with a review.
The process of the present invention can also be practiced as a final step in prior art processes for synthesizing nateglinide.

Numerous processes of the present invention involve crystallization from a specific solvent, that is, obtaining a solid material from a solution. One skilled in the art will recognize that crystallization conditions can be modified without affecting the resulting polymorphic shape. For example, when nateglinide is mixed in a solvent to form a solution, it may be necessary to warm the mixture to completely dissolve the starting material. If the mixture does not clear upon warming, the mixture can be diluted or filtered. To filter, the hot mixture can be passed through a clarifying material such as paper, glass fiber or other membrane material or celite. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration device to avoid premature crystallization.
Conditions can also be changed to induce precipitation. A preferred method for inducing precipitation is to reduce the solubility of the solvent. The solubility of the solvent can be reduced, for example, by cooling the solvent.

In one embodiment, an anti-solvent is added to the solution to reduce its solubility for a particular compound and thus result in precipitation. Another way to accelerate crystallization is by seeding the product crystals or scratching the internal surface of the crystallization vessel with a glass rod. In other cases, crystallization may occur spontaneously without any induction. The present invention encompasses both embodiments where crystallization of a particular shape of nateglinide occurs spontaneously or is induced / accelerated unless such induction is critical to obtaining a particular shape. It is.
Starting from crystals, powder aggregates and coarse powders with a new crystalline form of nateglinide, nateglinide of a defined particle size can be produced by known particle size reduction methods. The main work of conventional size reduction is grinding of the raw material and sorting by size of the ground material.

  A fluid energy mill or micronizer is a particularly preferred type of mill because of its ability to produce small size particles with a narrow particle size distribution. As will be appreciated by those skilled in the art, micronizers use collision kinetic energy between particles suspended in a fluid stream that moves rapidly to divide the particles. An air jet mill is the preferred fluid energy mill. Suspended particles are injected into the recirculated particle stream under pressure. The smaller particles are carried up the mill and are swept into a vent connected to a particle size classifier such as a cyclone. The raw material is first ground to about 150-850 μm, which can be done using conventional balls, rollers or hammer mills. One skilled in the art will recognize that some crystalline shapes may undergo a transition to another shape during particle size reduction.

  The pharmaceutical composition can be prepared as a drug to be administered orally, parenterally, rectally, transdermally, buccally or nasally. Suitable forms for oral administration include tablets, compressed or coated pills, dragees, packaging bags, hard or gelatin capsules, sublingual tablets, syrups and suspensions. Suitable forms for parenteral administration include aqueous or non-aqueous solutions or emulsions, while suitable dosage forms for rectal administration include suppositories with hydrophilic or hydrophobic vehicles. For topical administration, the present invention provides suitable transdermal delivery systems known in the art, and for intranasal delivery, suitable aerosol delivery systems known in the art are provided. Yes.

  The pharmaceutical preparation of the present invention includes A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, V, Y, α, β, γ, δ, ε. It contains a nateglinide shape selected from among, σ, θ, and Ω forms. The pharmaceutical composition may contain only a single form of nateglinide, or it may contain a mixture of various forms of nateglinide with or without an amorphous form. In addition to the active ingredient (s), the pharmaceutical composition of the invention may contain one or more excipients or ashvants. The choice of excipients and amount to be used can be readily determined by the pharmacist based on experience taking into account standard procedures and reference work in the field.

  Diluents increase the bulk of solid pharmaceutical compositions and can make pharmaceutical dosage forms containing compositions that are easy for patients and caregivers to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (eg Avicel®), microfine cellulose, lactose, starch, gelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrate, dextrin , Dextrose, dicalcium phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (eg Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol And talc.

Solid pharmaceutical compositions, such as tablets, compacted into a form may include excipients that have functions including helping to bind the active ingredient and other excipients after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomers (eg carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose (eg Klucel®) ), Hydroxypropyl methylcellulose (eg Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, povidone (eg Kollidon®, Plasdone®), gelatinized starch , Sodium alginate and starch.
The dissolution rate of a consolidated solid pharmaceutical composition in the patient's stomach can be accelerated by adding a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, sodium carboxymethylcellulose (for example, Ac-Di-Sol (registered trademark), primellose (registered trademark)), colloidal silicon dioxide, croscarmellose sodium, crospovidone (for example, Kollidon (registered) (Trademark), Polyplastone (registered trademark), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, gelatinized starch, sodium alginate, sodium glycolate starch (for example, Explotabe (registered trademark)) ) And starch.

  A glidant can be added to improve the flowability of the unconsolidated solid composition and improve the accuracy of weighing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tricalcium phosphate.

  When a dosage form such as a tablet is made by compaction of a powdered composition, the composition is subjected to pressure from a punch and mold. Some excipients and active ingredients have a tendency to adhere to the surface of punches and dyes, thus allowing the product to have indentations and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and facilitate the release of the product from the mold. 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, stearin Acids, talc and zinc stearate are included.

Flavoring and flavor enhancing agents make the dosage form more palatable to the patient. Common flavorings and flavor enhancers for pharmaceutical compositions that can be included in the compositions of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid. included.
Any pharmaceutically acceptable colorant can be used to color solid and liquid compositions to improve appearance and / or facilitate identification of the product and unit dosage levels by the patient.

In the liquid pharmaceutical composition of the present invention, nateglinide and any other solid excipient are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
Liquid pharmaceutical compositions can contain emulsifiers to disperse uniformly throughout the composition active ingredients or other excipients that cannot be dissolved in the liquid carrier. Emulsifiers that may be useful in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondras, pectin, methylcellulose, carbomer, cetostearyl alcohol and cetyl alcohol.

The liquid pharmaceutical composition of the present invention can also contain a thickening agent to improve the mouthfeel of the product and / or coat the inner surface of the gastrointestinal tract. Such agents include acacia, bentonite alginate, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone , Propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolic acid, starch tragacanth and xanthan gum.
Sweeteners such as sorbitol, saccharin, sodium saccharin, sucrose, aspartam, fructose, mannitol and invert sugar can be added to improve the taste.
Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid can be added at levels safe for consumption to improve storage stability. is there.

According to the present invention, the liquid composition may also include a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.
The choice of excipients and amount to be used can be readily determined by the pharmacist based on experience taking into account standard procedures and reference work in the field.
The solid composition of the present invention includes powders, granules, aggregates and compacted compositions. Dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular and intravenous), inhalation and ophthalmic administration. Although the most appropriate administration in any given case will depend on the nature and severity of the physical condition being treated, the most preferred route of the present invention is oral. Dosages are suitably presented in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art.

Dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, packaging bags, troches and lozenges as well as liquid syrups, suspensions and elixirs.
The dosage form of the present invention may be a capsule containing a composition, preferably a powdered or granulated solid composition of the present invention, preferably in either a hard or soft shell. The shell may be made of gelatin and may optionally contain plasticizers such as glycerin and sorbitol and opacifiers or colorants.
The active ingredients and excipients can be formulated into compositions and dosage forms according to methods known in the art.
A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredient and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powder to agglomerate 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 such as glidants and / or lubricants may be added prior to tableting.

  The tableting composition can be prepared conventionally by dry blending. For example, the compounded composition of the active ingredient and excipients can be compacted into a blob or sheet and then ground into a compacted granule. The compacted granules can then be compressed into a tablet form.

  As an alternative to dry granulation, the blended composition can 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 suitable 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 skilled in the art who challenge specific formulations of direct compression tableting.

The capsule filling of the present invention can include any of the above-described formulations and granulates described for tableting, but these are not subjected to a final tableting step.
STARLIX dosages and formulations can be used as a guide. The dosage used is about 30 to about 240 mg, more preferably about 60 to about 120 mg nateglinide. The pharmaceutical composition of the present invention, preferably in the form of a coated tablet, is administered about 10 minutes to about 1 hour before a meal, preferably about 15 minutes before each meal. If the meal is omitted, the dose is not taken. The pharmaceutical composition can also be used in combination with metaformin.

Meters and gauges:
X-ray powder diffraction X-ray diffraction was carried out on an X-ray powder diffractometer, Scintag (registered trademark), a variable angle meter, a Cu-tube, and a solid detector. Sample holder: Round standard aluminum sample holder with round zero background crystal plate.
The sample was placed on the sample holder and analyzed immediately as it was.
Scanning parameters: Range: 2-40 degrees 2θ, continuous scanning, speed: 3 degrees 1 minute.
DSC:
DSC821 ^e Mettler Toledo®, sample weight; 3-5 mg, acceleration rate: 10 ° C./min, number of holes in crucible;
TGA:
Mettier TG50® sample weight; 7-15 mg, heating rate; 10 ° C./min FTIR:
Perkin-Elmer®, Spectrum One FTIR spectrometer, range; 4000-400 cm ⁻¹ , scan number; 16, rotation; 4.0 cm ⁻¹ , DRIFT technology.

Examples Example 1-This example illustrates the preparation of various forms of nateglinide from one solution.
Nateglinide (5 g) was placed in an Erlenmeyer flask and heated to the specified temperature. The solvent was added in 1-ml portions until a clear solution was obtained (in some cases, the solvent was added in 5 ml portions). If a clear solution was not obtained after adding 150 ml of solvent, the hot mixture was filtered.
The clear solution was crystallized at room temperature. If crystallization did not occur or was poor, the solution was frozen at 3 ° C. The precipitate was removed by filtration (at 5 ° C. or RT depending on the temperature of crystallization), weighed and divided into two equal parts. A portion was dried to a constant weight (± 0.01 g) at 50 ° C. under reduced pressure (20-30 mmHg) for about 3-10 hours. Details are presented in Table IV.
Table IV. Data on crystallization of NTG from a single solvent

Legend. L / S-liquid / solid ratio; ^* Solvent added in 5 ml aliquots; T-starting temperature; Ww-weight of wet sample after filtration, Wd-weight of sample after drying at 80-90 ° C./20 mbar Solvent Abbreviations: MeOH-methanol EtOH-ethanol, n-PrOH-n-propanol, IPA-2-propanol, n-BuOH-n-butanol, EA-ethyl acetate, NM-nitromethane, DMF-N, N-dimethylformamide, DMA -N, N-dimethylacetamide, NMP-N-methylpyrrolidone, MeCN-acetonitrile, Ether-diethyl ether, DME-dimethoxyethane, DCM-dichloromethane, DCE-1,2-dichloroethane and CTC-carbon tetrachloride

Example 2 This example demonstrates the trituration of H-form and U-form nateglinide in various solvents.
Nateglinide (5 g) was placed in an Erlenmeyer flask. The solvent was added in 1 ml portions to prepare a stirrable mixture. The flask was stirred with a magnetic stirrer at room temperature. The solid was filtered at room temperature, weighed and divided into two equal parts. A portion was dried at 55 ° C. under a pressure of 20-30 mm / Hg until a constant weight was achieved (± 0.01 g).
Details are presented in Tables V and VI.

Table V-Data on NTG trituration in a single solvent

Table VI. Data on the study of NTG in a single solvent

Example 3 This example shows the absorption of solvent vapor by nateglinide.
Nateglinide (3.50 g) was added to a polypropylene can and weighed. The can was introduced into a larger polypropylene container containing the solvent and stored at room temperature. The can was removed from the container and weighed (W final). The contents of the can were divided into two portions. An aliquot was dried to a constant weight (± 0.01 g) at a temperature of 55 ° C. and a pressure of 20-30 mm Hg. Details are presented in Table VII.

Table VII. Data on solvent vapor absorption in H-form NTG

  Legend. Starting weight of can with Brutto-NTG; W final—final weight of can with NTG after exposure; Δ—excess weight

Example 4 This example illustrates the preparation of various forms of nateglinide by removing the solvent.
Nateglinide (5 g) was dissolved in the following solvent at about 55 ° C. over about 15 minutes until a clear solution was obtained. The solvent was removed to dryness by evaporation at about 55 ° C./20-30 mm Hg to give dry nateglinide.
Table VIII-Data on solvent removal

Example 5 This example illustrates the preparation of the Z form.
D-phenylalanine (PheOH, 7.73 g) was treated with 3.5% NaOH (185 mL, 3.5 eq) at room temperature to give a clear solution of the corresponding Na salt. A solution of pure trans-4-isopropylcyclohexanecarbonyl chloride (IPCHAC, 9.02 g, 1.01 eq) was added to the Phe-OH solution obtained above over 3 minutes with stirring at room temperature. The remainder of IPCHAC in the funnel was washed with toluene (1 ml) and added. The resulting mixture was stirred for 1 hour, treated with 10% HCl (32 ml) and the pH adjusted to 3 with stirring. The mixture was stirred for 1 hour and filtered. The solid was washed with water (200 ml) and thoroughly sucked to give 33.3 g of wet product which lost weight after drying at 78 ° C./2.2 mbar. Test 98.4%, purity> 99%, yield 86%

Example 6 This example shows the preparation of nateglinide by crystallization from a binary mixture (solvent / antisolvent).
In an Erlenmeyer flask, nateglinide (5 g) and a poor solvent (20 ml) were placed. The mixture was heated at about 55 ° C. for about 15 minutes, after which the solvent was added in 0.25 to 1 ml portions until a clear solution was obtained. The clear solution crystallized without stirring at room temperature.
If crystallization did not occur after 24 hours or was poor, the solution was frozen at 3-5 ° C. The precipitate was removed by filtration (at RT or 5 ° C. depending on the crystallization temperature) to give Form B. The wet material was dried at 50 ° C. under reduced pressure (20-30 mmHg) to obtain dry Form B.

Table IX. Data on crystallization of NTG from binary solvents

Legend:
L / S-liquid / solid ratio (liquid = solvent + antisolvent); f-sign RT → 3, crystallization started at room temperature, then the mixture was cooled to 3 ° C. to complete the precipitation It means that.

Example 7 Preparation of Delta Form (A) This example shows the preparation of nateglinide delta form by crystallization from an ethyl acetate-heptane solvent system.
Preparation of δ Form Nateglinide D-Phenylalanine (15.44 g) was added all at once with stirring (230 min ⁻¹ ) at 20 ° C. against a 3.5% NaOH solution (370 ml 3.5 eq). A clear solution formed immediately. To the reaction solution was added pure trans-4-isopropylcyclohexylcarboxychloride (18.03 g) for 5 minutes. A solid formed and the temperature rose to 32 ° C. The mixture was stirred for 1 hour at 20 ° C. under stirring. 15% H ₂ SO ₄ (56.1 g) was added to the reaction mixture all at once and the pH was adjusted to 1-2. The mixture was stirred for 1 hour at 20 ° C. and the solid product was removed by filtration to give a filtered mass—76 g wet product (65% moisture). The product was dissolved in EA (200 ml) and the aqueous phase was removed. The organic phase was concentrated under reduced pressure at 50 ° C. to give 104 g of a suspension containing 95 ml of EA. The solution was filtered and added to hot heptane (54 ° C., 250 ml) for 30 minutes. The initially formed solid was completely dissolved after the addition of 2/3 of the EA solution. The clear solution was cooled to 25 ° C., seeded in B-form and crystallized overnight with stirring at 215 rpm min ⁻¹ . The solid was removed by filtration and washed with heptane (30 ml). The filter cake was dried at 60 ° C./20 mbar to obtain 6.84 g of the δ-form. Yield 33%.

Preparation of δ Form Nateglinide D-Phenylalanine (20.00 g) was added all at once while stirring (230 min ⁻¹ ) against a 3.5% NaOH solution (370.12 g, 2.7 equivalents) heated to 35 ° C. Added. A clear solution formed immediately. To the hot reaction mixture was added pure trans-4-isopropylcyclohexylcarboxy chloride (23.3 g) all at once. A turbid solution formed and the temperature rose to 40 ° C. The mixture was stirred for 20 minutes at 40-43 ° C. under stirring. 85% H ₂ SO ₄ (11.94 g) was added to the reaction mixture all at once and the pH was adjusted to 1-2. The solid product was extracted with EA (140 ml). The hot organic extract was washed first with warm water (100 ml) and then with 40 ° C. brine (25 ml, 30.0 g) and dried over anhydrous magnesium sulfate (3.05 g) for 1.5 hours. The organic solution was filtered through a PTFE 0.45 μm filter and heated to 38 ° C., against which hot heptane (40 ° C., 125 ml) was added. The resulting clear solution was gradually cooled to 13 ° C. for 45 minutes to seed B-shaped NTG. Crystallization started. The mixture was then cooled to 5 ° C. for 17 minutes and stirred for 16 hours. The solid was removed by filtration and washed with a cold (5 ° C.) mixture of heptane-EA mixture (5; 1, total 180 ml) to give 36.49 g of wet product (wetness 42.5%). The wet product was dried at 60 ° C./13 mbar to give 20.38 g of product, Form δ, with a purity greater than 99.8%. Yield 55%.

Preparation of δ Form Nateglinide D-Phenylalanine (20.02 g) was all added once with stirring (150 min ⁻¹ ) to a 3.5% NaOH solution (410.5 g, 2.99 equivalents) heated to 39 ° C. Added to. A clear solution formed immediately. Pure trans-4-isopropylcyclohexylcarboxychloride (24.73 g) was added all at once to the reaction mixture. The mixture (clear solution) was stirred for 25 minutes at 44-45 ° C. with stirring. Ethyl acetate (140 ml) followed by a 85% solution of H ₂ SO ₄ (14.08 g) was added all at once to the reaction mixture to adjust the pH to 1-2. The hot organic layer was separated, washed twice with 30 ° C. water (100 ml) and filtered through a PTFE 0.45 μm filter. The clear solution (141 g) was heated to 46 ° C., to which hot heptane (46 ° C., 153 ml) was added with stirring at 150 min ⁻¹ . The clear solution was gradually cooled to 28 ° C. to seed the delta form. Crystallization occurred at 24 ° C. The mixture was stirred at 24 ° C. for 30 minutes, gradually cooled to 5 ° C. and stirred overnight at 5 ° C. The solid was removed by filtration and washed with cold (5 ° C.) heptane-EA mixture (6: 1, 30 ml total) to give 49.1 g of wet product in delta form (50% wetness). The wet product was dried for 24 hours at 23 ° C./20 mbar to give 24.65 g of product in delta form with a purity> 99.8%. Yield 65%.

(B) This example shows the preparation of crystallized δ form.
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 completely dissolved. The mixture was allowed to cool to 30 ° C. and seeded with δ form nateglinide (0.1 grams). The mixture was stirred for 30 minutes and then cooled to below 10 ° C. in 2 hours. The mixture was stirred overnight at 5-10 ° C. and then filtered in vacuo. The wet product was washed with an 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 wet and dry samples were in the δ form.

  Starting material: wet nateglinide (40% total wetness. 2 ml water, 10 ml ethyl acetate, 21 ml heptane). Wet crude nateglinide (83 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 seeded with δ form nateglinide (0.1 grams). The mixture was stirred for 30 minutes and then cooled to below 10 ° C. in 2 hours. The mixture was stirred overnight at 5-10 ° C. and then filtered in vacuo. The wet product was washed with an ethyl acetate heptane mixture (100 ml) (ratio 1: 3 v / v). The wet product was dried in a vacuum oven at 50 ° C. overnight. Both wet and dry samples were in the δ form.

(C) This example shows δ-type drying with a fluidized bed dryer.
Delta form nateglinide (10 grams) with about 3% heptane (wt / wt) was dried in a fluid bed dryer at 60 ° C. for 4 hours. After ethyl acetate was below the detection limit, the residual heptane was 1578 ppm. The polymorphic shape of the dried product is delta.
According to these procedures, a series of experiments were performed under various heptane / ethyl ratios, liquid / solidification, temperature and seeding. The results are summarized in Table X.

Table X. Data on crystallization of NTG in EA-heptane solvent system

  Temperature profile: crystallization temperature (h) → final temperature (h): L, t-L, trans-isomer

Example 8 This example shows the preparation of the form of nateglinide by precipitation that does not go into solution after combination.
Preparation of U-shaped nateglinide D-phenylalanine (20.02 g) was added all at once while stirring (230 rpm min ^-1 ) at 3.5C in a 3.5% NaOH solution (369.73 ml, 2.7 equivalents). Added. A clear solution formed immediately. To the hot reaction solution was added pure trans-4-isopropylcyclohexylcarboxychloride (23.9 g) for 1 minute. A solid formed and the temperature rose to 32 ° C. The mixture was stirred for 40 minutes at 20 ° C. under stirring. An 85% H ₂ SO ₄ solution (11.55 g) was added to the reaction mixture all at once and the pH was adjusted 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 over anhydrous sodium sulfate (10 g) for 1.5 hours and filtered. Excess EA was removed under reduced pressure, yielding 86 g of a 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 funnel heated to 35 ° C. Heptane (320 ml) was placed in the reactor and cooled to 5 ° C. to seed type B. The clear, hot EA solution was added to cold heptane for 5 minutes under stirring. Precipitation occurred immediately and a solid was obtained. The mixture was stirred for 2.5 hours at 5 ° C. The solids were removed by filtration and washed with a cold (5 ° C.) heptane-EA mixture (4.5; 1, total to 120 ml) to give 63.62 g of wet product (wetness 54%). Dry the filter cake (62.4 g) at 60 ° C./10 mbar to obtain 28.6 g of product containing ˜0.6% L, trans isomer (other impurities <0.1%) in U form. Got. Yield 77%.

Ｔ_EA−ＥＡ溶液の温度； Ｔ_AS（time）−貧溶媒の温度（露呈時間）→最終温度（露呈時間）：Ｌ，ｔ−Ｌ，トランス−異性体の量。 Table XI. Data on crystallization of NTG during the crystallization process (precipitation that does not migrate into solution after combination)

T _EA -EA solution temperature; T _AS (time) -poor solvent temperature (exposure time) → final temperature (exposure time): amount of L, t-L, trans-isomer.

Example 9- Heating of U-shaped nateglinide A sample of U-shaped nateglinide (~ 1 g) was introduced into a 6 gram vial and heated in a 100 ° C oil bath for 8.5 hours. The vial was extracted from the bath and the resulting sample showed a U shape by XRPD.
A sample of U-shaped nateglinide (˜0.5 g) was heated to 120 ° under atmospheric pressure for 1 hour. The resulting sample showed a U shape by XRPD.

Example 10- Heating of delta form nateglinide A sample of delta form nateglinide (~ 0.5 g) was heated at atmospheric pressure for 1 hour. The resulting sample showed Form B by XRPD.

Example 11- Preparation of the omega form Delta form nateglinide (5 grams) was dissolved in isopropanol (15 ml) at room temperature. The solution was allowed to cool to ~ 0 ° C. Water (6 ml) was added. A white solid suddenly precipitated. The solid was heated to 35 ° C. resulting in complete dissolution. The solution was cooled to ~ 7 ° C to precipitate the product. The product was filtered in vacuo. XRPD confirmed the presence of the omega form.

Example 12. Drying Omega Formed Wet Sample The product of Example 11 was dried in a vacuum oven at 50 ° C. overnight and analyzed by XRD. A mixture of omega and Z forms was obtained.

Example 13 This example illustrates the preparation of the U form by triturating the delta form in ethyl acetate.
Form 8 nateglinide (5 grams) was triturated in ethyl acetate (10 ml) at 25 ° C. for 2 hours. The wet material was filtered under vacuum and washed with ethyl acetate (10 ml). The wet product was dried overnight at 50 ° C. in a vacuum oven. The wet and dry product was U-shaped.

Example 14 This example shows the preparation of Form B by triturating the δ form in ethyl acetate.
Form 5 nateglinide (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 in vacuo and washed with ethyl acetate (10 ml). The wet product was dried overnight at 50 ° C. in a vacuum oven. The wet and dry product was obtained as Form B.

Example 15- Process for the preparation of Form B nateglinide Form B nateglinide can also be obtained by precipitation of Form G nateglinide from isopropanol and subsequent conversion from Form G to Form B. In this embodiment, one form of nateglinide, such as delta form nateglinide (about 3% LOD) is dissolved in the IPA / H ₂ O mixture within 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 per unit weight of nateglinide.
The solution obtained after dissolution is preferably cooled to a temperature of about 30 ° C. in order to seed the B-form crystals. The seeded solution is preferably allowed to stir at the seeding temperature for about 30 minutes to about 3 hours. The solution was then cooled to about 0 ° C. plus / minus 5 ° C., preferably for at least about 5 hours, and preferably stirred at 5 ° C. for at least about 30 minutes. Precipitated nateglinide crystals can be collected and dried under reduced pressure at a preferred temperature of about 70 to about 90 ° C. to obtain Form B nateglinide.
In this embodiment, prior to crystallization, the starting material can optionally be dissolved in an IPA or IPA / H ₂ O mixture (same solvent ratio as the crystallization mixture) and subsequently evaporated under reduced pressure. After evaporation, the IPA / H ₂ O mixture is replenished into the reactor to obtain a solution. Form B nateglinide is obtained after evaporation.
By using IPA, the methyl ester can be removed as an impurity in the final product as illustrated in FIG.

Example 15 (A)
Nateglinide (40 grams) was dissolved in IPA (240 ml) at 25 ° C. The solution was filtered to remove insoluble material. 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 Form B.

Example 15 (B)
Nateglinide (30 grams) was dissolved in IPA (150 ml) in the reactor. The solvent was evaporated under reduced pressure at a jacket temperature T _j = 50 ° C. A solution was obtained by feeding IPA (150 ml) to the reactor and replenished with water (150 ml) at T _j = 50 ° C. A clear solution was obtained, cooled to TR = 29.4 ° C., and seeded B-type crystals. The seeded solution was stirred for an additional 3 hours at TR = 29.4 ° C. and then cooled to TR = 0 ° C. for 10 hours. At 0 ° C., the resulting slurry was stirred for an additional 5 hours (overnight). The crystals were isolated and dried at 90 ° C. under reduced pressure. 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 replenished 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. B-type crystals were seeded into the solution at 28 ° C.
The solution seeded at 28 ° C. for another 2 hours was stirred and then cooled to 5 ° C. for 10 hours. The solution was stirred at 5 ° C. for an additional 4 hours (overnight). The product was isolated and dried at 90 ° C. under reduced pressure. 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 Form B nateglinide by trituration in water δ form nateglinide was triturated in 5 volumes of water at about 25 ° C. for about 7 hours. The crystals were isolated and dried at 90 ° C. under reduced pressure.
Example (A): Moistening of wet starting material 50 grams of moist δ form nateglinide (about 37% LOD) was triturated in 250 ml water at 25 ° C. After 4 hours of grinding, a sample of the slurry was taken and dried at 90 ° C. under reduced pressure. Wet crystals were tested by XRD and found to be δ type. Dry crystals were tested by XRD and found to be B type. After 7 hours of trituration, the product was isolated and dried at 90 ° C. under reduced pressure. Wet crystals were tested by XRD and found to be δ type. The dried crystals were tested by XRD and found to be B type.

Example (B): Drying of dried starting material 50 grams of dry δ form nateglinide was triturated in 250 ml of water at 25 ° C, after 4.5 hours of grinding, a sample of the slurry was taken at 90 ° C Dry under reduced pressure. Wet crystals were tested by XRD and found to be Z-shaped. Dry crystals were tested by XRD and found to be B type. After 7.5 hours of trituration, the product was isolated and dried at 90 ° C. under reduced pressure. The wet crystals were tested by XRD and found to be E type. The dried crystals were tested by XRD and found to be B type.

Example 17- Preparation of Form U nateglinide (A): Crystallization from acetone Form 8 nateglinide (50 grams) was dissolved in acetone (175 ml) at 42 ° C. The clear solution was cooled to 10 ° C. for seeding. After seeding with B-type crystals, the seeded solution was stirred for an additional 3 hours at a temperature of 10 ° C., cooled to 10-10 ° C. and stirred at −10 ° C. overnight. The crystals were isolated and dried at 90 ° C. The wet crystals were tested by XRD and found to be U-shaped. The dried crystals were tested and found to be U-shaped.

Example (B): Crystals from ethyl acetate Nateglinide (20 grams) was dissolved in ethyl acetate (560 ml) at 40 ° C. The solution was filtered to remove insoluble material. The clear solution was evaporated under reduced pressure and ethyl acetate (460 ml) was evaporated (solvent volume in the reactor was 5 volumes per unit weight of nateglinide). The solution was cooled to 20 ° C. to seed type B crystals. The seeded solution was stirred for an additional 30 minutes at 20 ° C., allowed to cool to 0 ° C. for 1.5 hours, and stirred for an additional 30 minutes at 0 ° C. The crystals were isolated and dried under reduced pressure at 30 ° C, 50 ° C and 90 ° C. Wet crystals were tested by XRD and found to be U-shaped. The dried crystals were tested by XRD and found to be U-shaped.

Example 18- Removal of residual solvent from delta form Delta form nateglinide (40 grams (1.5% heptane) was dried in a stirred reactor (7-10 rpm) at 60 ° C under 60 mm Hg vacuum. After 6 hours of drying, the residual solvent of the material was 613 ppm heptane, and the polymorph of the dried material remained in the delta form, like the starting material.

Example 19- Preparation of Form B Nateglinide from Ethyl Acetate Form δ nateglinide was dissolved in ethyl acetate at 25 ° C. The solvent is evaporated under reduced pressure until turbidity appears. The turbid solution was cooled to 0 ° C. plus / minus 5 ° C. for 1 hour and stirred for 1 hour. The product was isolated and dried at 50 ° C. under reduced pressure.

Example (A)
δ form nateglinide (12 grams) was dissolved in 165 ml of ethyl acetate at 25 ° C. The solvent was evaporated under reduced pressure 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 at 50 ° C. under reduced pressure. Both wet and dry crystals were tested by XRD and DSC and found to be Form B.

  Thus, although the invention has been described with reference to certain preferred embodiments and examples, those skilled in the art will recognize that the invention can be practiced without departing from the spirit and scope of the invention as disclosed in the specification. Modifications to the invention as described and illustrated herein can be recognized. The examples are set forth to aid in understanding the present invention, but are not intended to limit the scope in any way and should not be construed as such. . The examples do not include a detailed description of conventional methods. Such methods are well known to those skilled in the art and have been described in numerous publications. “Polymorphs in Pharmaceutical Solids, Drugs and Pharmaceutical Sciences”, Volume 95 can be used as a guide. All references mentioned in this document are hereby incorporated in their entirety.

FIG. 5 is an XRPD pattern for Form A nateglinide. FIG. 5 is an XRPD pattern for Form C nateglinide. FIG. 5 is an XRPD pattern for Form D nateglinide. FIG. 5 is an XRPD pattern for E-form nateglinide. FIG. 5 is an XRPD pattern for Form F nateglinide. FIG. 3 is an XRPD pattern for G-form nateglinide. FIG. 5 is an XRPD pattern for Form I nateglinide. FIG. 5 is an XRPD pattern for J-form nateglinide. FIG. 5 is an XRPD pattern for K-form nateglinide. FIG. 5 is an XRPD pattern for L-form nateglinide. FIG. 5 is an XRPD pattern for M-form nateglinide. FIG. 5 is an XRPD pattern for N-form nateglinide. FIG. 5 is an XRPD pattern for O-form nateglinide. FIG. 5 is an XRPD pattern for P-form nateglinide. FIG. 5 is an XRPD pattern for Q-form nateglinide. FIG. 5 is an XRPD pattern for T-form nateglinide. FIG. 5 is an XRPD pattern for U-shaped nateglinide. FIG. 4 is an XRPD pattern for V-form nateglinide. FIG. 5 is an XRPD pattern for Y-shaped nateglinide. FIG. 5 is an XRPD pattern for Z-form nateglinide. FIG. 5 is an XRPD pattern for α form nateglinide. FIG. 3 is an XRPD pattern for β-form nateglinide. FIG. 5 is an XRPD pattern for γ-form nateglinide. FIG. 5 is an XRPD pattern for δ form nateglinide. FIG. 5 is an XRPD pattern for ε-form nateglinide. FIG. 5 is an XRPD pattern for σ-form nateglinide. It is a XRPD pattern about the θ-type nateglinide. FIG. 4 is a thermal stability diagram showing shape transformation during drying, and is a summary of comparison between wet and dry shapes exemplified in various tables in the present invention. 2 is an FTIR spectrum of nateglinide shape L. FIG. 2 is an FTIR spectrum of nateglinide shape P. FIG. 2 is an FTIR spectrum of nateglinide shape U. 2 is an FTIR spectrum of nateglinide shape Z. It is an FTIR spectrum of nateglinide shape α. 2 is an FTIR spectrum of nateglinide shape δ. It is a FTIR spectrum of nateglinide shape σ. 2 is a DSC thermography of nateglinide A type. 2 is a DSC thermography of nateglinide D type. 2 is a DSC thermography of nateglinide E type. 2 is a DSC thermography of nateglinide F type. It is a DSC thermography of nateglinide G type. 2 is a DSC thermography of nateglinide type I. It is a DSC thermography of nateglinide J type. It is a DSC thermography of nateglinide K type. 2 is a DSC thermography of nateglinide L form. 2 is a DSC thermography of nateglinide M type. It is a DSC thermography of nateglinide N form. 2 is a DSC thermography of nateglinide O type. It is a DSC thermography of nateglinide P type. It is a DSC thermography of nateglinide Q type. 2 is a DSC thermography of nateglinide T type. It is a DSC thermography of nateglinide U type. 2 is a DSC thermography of nateglinide V type. It is DSC thermography of nateglinide Y form (chloroform solvate). It is a DSC thermography of nateglinide Y form (coloromethane solvate). It is a DSC thermography of nateglinide Z type. It is a DSC thermography of nateglinide α form. 2 is a DSC thermography of nateglinide β form. It is a DSC thermography of nateglinide γ form. It is a DSC thermography of nateglinide δ form. It is a DSC thermography of nateglinide ε form. It is a DSC thermography of nateglinide σ form. It is a DSC thermography of nateglinide θ form. It is a DSC thermography of nateglinide Ω type. FIG. 6 is a determination of the purity of Form B prepared according to Example 15. FIG.

Claims (205)

  In the preparation process of Form B crystalline nateglinide, from the group consisting of A, C, D, F, G, J, Q, T, α, β, δ, ε, θ and Ω forms to obtain B form nateglinide A process comprising heating a crystalline form of a selected nateglinide.   The process of claim 1 wherein nateglinide is in the alpha form.   The process of claim 1 wherein nateglinide is in the δ form. a) preparing a suspension of nateglinide in C ₅ to C ₁₂ hydrocarbons;
b) adding a solvent selected from the group consisting of alcohols, esters, ketones or mixtures thereof to the suspension to obtain a solution;
c) crystallizing Form B nateglinide from solution without stirring;
c) recovering Form B nateglinide;
A process for the preparation of Form B nateglinide comprising:   The process of claim 4 wherein the hydrocarbon is selected from the group consisting of heptane, hexane, toluene and xylene.   The process according to claim 4, wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, n-propanol, acetone and ethyl acetate.   The process according to claim 4, wherein the crystallization is carried out by seeding and cooling.   The process of claim 4, wherein Form B crystallizes at a crystallization temperature greater than about 15 ° C.   The process of claim 4 wherein the solvent / hydrocarbon combination is ethyl acetate / heptane or hexane. preparing a nateglinide solution in a mixture of hydrocarbon a) ethyl acetate and C ₅ -C _12;
b) crystallizing Form B nateglinide from the solution; and c) recovering Form B nateglinide;
Process for the preparation of Form B crystalline nateglinide comprising   The process according to claim 10, wherein the crystallization step is carried out without stirring.   The process of claim 10, wherein the crystallization is performed at a temperature greater than about 15 ° C.   A process for preparing Form B nateglinide comprising storing Form A nateglinide at an appropriate temperature for a time sufficient to obtain Form B nateglinide. a) preparing a nateglinide solution in a solvent selected from the group consisting of esters, ketones, amines, amides, alcohols, nitriles; and b) removing the solvent to obtain Form B nateglinide. A process for the preparation of Form B nateglinide comprising.   15. A process according to claim 14, wherein the solvent is selected from the group consisting of acetonitrile, acetone, ethyl acetate and isopropyl alcohol.   The process of claim 14, wherein the removing step includes evaporation of the solvent.   The process of claim 16, wherein the solvent is evaporated at a temperature from about 40 ° C. to about 70 ° C.   A process for the preparation of Form B nateglinide comprising the step of triturating Form nateglinide in ethyl acetate at a suitable temperature for a time sufficient to obtain Form B nateglinide.   The process of claim 18, wherein the temperature is at least about 40 ° C. a) preparing a nateglinide solution in ethyl acetate;
b) concentrating the solution to precipitate Form B nateglinide; and c) recovering Form B nateglinide;
Process for the preparation of Form B nateglinide comprising a) preparing a nateglinide solution in a mixture of water and isopropanol;
b) crystallizing form B nateglinide from the solution, and c) recovering form B nateglinide,
A process for the preparation of Form B nateglinide comprising: a) preparing a nateglinide solution in a mixture of isopropanol and water;
b) seeding Form B nateglinide into the solution at a temperature 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 solids from the slurry; and g) heating the solids to obtain Form B nateglinide;
A process for the preparation of Form B nateglinide comprising: XRPD patterns with peaks at 17.6, 17.9 and 19.6 ± 0.2 degrees 2θ, DSC thermography with endothermic peaks at about 131 and 138 ° C., and about 1741, 1726, 1621, 1600, 1538, 1211 One crystalline form of nateglinide characterized by data selected from the group consisting of FTIR spectra with a peak at 1191 cm ⁻¹ (L form).   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.   24. Preparation of Form B nateglinide according to claim 23, comprising heating nateglinide selected from the group consisting of D, M and N shapes for a time sufficient to obtain nateglinide according to claim 23. process.   24. A process for preparing nateglinide according to claim 23 comprising the step of storing form I nateglinide at a suitable temperature for a time sufficient to obtain nateglinide according to claim 23. XRPD patterns with peaks at 4.0, 4.6, 13.4, 13.9 and 19.1 ± 0.2 degrees 2θ; FTIR spectra with peaks at about 3309, 1748, 1589 cm ⁻¹ ; One crystalline form of nateglinide (P form) characterized by data selected from the group consisting of an endothermic peak at 128 ° C and an exothermic peak at about 113 ° C. a) triturating nateglinide in a solvent selected from the group consisting of acetone, nitromethane, and acetonitrile to obtain the crystalline form of claim 27, wherein nateglinide triturated in nitromethane is H And b) recovering the crystalline form of nateglinide, provided that it is not in form;
28. A process for preparing crystalline nateglinide according to claim 27, comprising:   28. A process for preparing nateglinide according to claim 27 comprising heating epsilon nateglinide at a suitable temperature for a sufficient time.   A process for the preparation of S-form nateglinide comprising heating a nateglinide selected from the group consisting of the K, I, and α forms for a time sufficient to obtain S-form nateglinide. a) preparing a nateglinide solution in n-butanol or dimethylformamide;
b) crystallizing nateglinide from said solution;
c) recovering nateglinide;
d) heating nateglinide to obtain S form;
A process for preparing S-form nateglinide comprising: a) preparing a nateglinide solution in a mixture of a solvent and an anti-solvent selected from the group consisting of esters, ketones, alcohols and mixtures thereof;
b) crystallizing U-shaped nateglinide from solution; and c) recovering U-shaped nateglinide;
A U-shaped SN preparation process comprising: The poor solvent is a hydrocarbon of from C ₅ to C _12, The process of claim 32.   34. The process of claim 33, wherein the antisolvent is heptane.   33. 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 the ratio of ethyl acetate to antisolvent is from about 2: 1 to about 1: 1 (volume / volume).   38. The process of claim 36, wherein the anti-solvent is about 20 ° C to about 40 ° C lower than ethyl acetate.   40. The process of claim 38, wherein the anti-solvent has a temperature from about 0C to about 10C, and ethyl acetate has a temperature from about 30C to about 40C.   The U shape is prepared by preparing a solution having a temperature above about 25 ° C. and then cooling to a temperature between about 0 ° C. and about 10 ° C. to crystallize the U shape and transition to another shape. 40. The process of claim 32, prepared by recovery. a) adding a nateglinide solution in ethyl acetate to a vessel holding heptane to spontaneously precipitate U-shaped nateglinide, wherein the heptane is cooler than the solution; and b) U-shaped nateglinide Recovering the stage,
A process for preparing U-shaped nateglinide, comprising:   A process for preparing U-shaped nateglinide comprising the step of triturating δ-shaped nateglinide in ethyl acetate at an appropriate temperature for a time sufficient to obtain U-shaped nateglinide.   43. The process of claim 42, wherein the temperature is from about 20C to about 30C. a) preparing a nateglinide solution in ethyl acetate or acetone;
b) seeding the crystalline form of nateglinide into the solution to crystallize U-shaped nateglinide; and c) recovering U-shaped nateglinide;
Process for the preparation of U-shaped nateglinide comprising   45. The process of claim 44, wherein Form B is seeded into the solution. XRPD pattern with peaks at 4.8, 5.1, 19.0, 19.4, 27.2, 28.9 and 31.2 ± 0.2 degrees 2θ, DSC thermography with endothermic peak at about 129 ° C And one crystalline form of nateglinide (α form) characterized by data selected from the group consisting of FTIR spectra with peaks at about 3283, 1711, 1646, 1420, 1238 cm ⁻¹ .   47. The crystalline form of claim 46, which is stable when heated to a temperature of about 60 ° C. for about 8 hours. a) triturating nateglinide in a solvent selected from the group consisting of methanol, n-butanol and ethanol to obtain a crystalline form according to claim 46, wherein the nateglinide hydrated is in the H form And b) recovering α form nateglinide,
47. A process for preparing crystalline nateglinide according to claim 46, comprising:   49. The process of claim 48, wherein the hydrated nateglinide is U-shaped. 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;
49. A process for preparing a crystalline form of nateglinide according to claim 46.   47. The preparation of crystalline nateglinide according to claim 46, comprising heating one form of nateglinide selected from the group consisting of form K and form C for a time sufficient to obtain the crystalline form. process.   A process for preparing α-form and H-form crystalline nateglinide comprising the step of triturating 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 process is hydrated nateglinide or crystalline shape U. XRPD patterns with peaks at 5.6, 14.5, 18.2, 18.9 and 19.5 ± 0.2 degrees 2θ; FTIR spectra with peaks at about 3306, 1729, 1704, 1275 cm ⁻¹ ; and One crystalline form of nateglinide (δ form) characterized by data selected from the group consisting of DSC thermography with endothermic peaks at about 100 and 130 ° C.   55. The crystalline form of claim 54, which is stable for at least about 3 months at a temperature of about 40 ° C. and a relative humidity of about 75%.   55. The crystalline form of claim 54, which is stable after at least about 8 hours at a temperature of about 60 ° C.   55. The crystalline form of claim 54, substantially free of H-form nateglinide.   55. Preparation of the crystalline form of nateglinide according to claim 54, comprising the step of stirring anhydrous nateglinide in an organic solvent for a sufficient time, wherein the organic solvent is other than ethyl acetate alone. process.   59. The process of claim 58, wherein the anhydrous nateglinide is selected from the group consisting of B-form, H-form, U-form, and θ-form.   59. The process of claim 58, wherein the agitation is performed at a temperature from about minus 15 [deg.] C to about 10 [deg.] C. Organic solvent is a mixture of hydrocarbons and ethyl acetate C ₅ -C _12, The process of claim 58.   62. The process of claim 61, wherein the hydrocarbon is heptane.   55. A process for preparing crystalline nateglinide according to claim 54, comprising stirring the U-shaped nateglinide in a mixture of ethyl acetate and heptane for a time sufficient to obtain nateglinide according to claim 54. a) triturating nateglinide in a solvent selected from the group consisting of dioxane, chloroform and tetrahydrofuran to obtain the crystalline form, wherein nateglinide triturated in chloroform is not in the H form. 55. The process for preparing a crystalline nateglinide form according to claim 54, comprising conditions and b) recovering the crystalline form.   65. The process of claim 64, wherein the hydrated nateglinide is U-shaped. a) preparing a solution of nateglinide in a mixture of ethyl acetate and heptane;
b) cooling the solution and precipitating solids, thus forming a mixture;
c) stirring the mixture for a time sufficient to obtain the crystalline form of claim 54; and d) filtering the mixture;
55. A process for preparing a crystalline form according to claim 54, comprising:   55. The process of preparing a crystalline form according to claim 54, comprising the step of removing residual solvent in a fluid bed dryer, substantially free of residual solvent.   68. The process of claim 67, wherein the crystalline form contains less than about 0.5 wt% residual solvent after the removal process.   68. A crystalline form prepared by the process of claim 67.   55. The process of preparing a crystalline form according to claim 54, comprising removing the solvent with stirring at a temperature of at least about 40 ° C. under vacuum and substantially free of residual solvent. XRPD pattern with peaks at about 5.5, 6.1, 6.7, 14.3 ± 0.2 degrees 2θ; DSC thermography with endothermic peak at about 127 ° C .; and at about 3303, 1705 and 1640 cm ⁻¹ One crystalline form of nateglinide (δ form) characterized by data selected from the group consisting of FTIR spectra with peaks.   72. The process for preparing a crystalline form according to claim 71, comprising stirring the B-form or U-form nateglinide in an organic solvent for a time sufficient to obtain the delta form nateglinide. Wherein the organic solvent is a mixture of aliphatic hydrocarbons to C ₁₂ ethyl acetate and C _5, according to claim 72 process.   74. The process of claim 73, wherein the hydrocarbon is heptane.   73. The process of claim 72, wherein the stirring is performed at a temperature from about minus 15 [deg.] C to about 10 [deg.] C.   XRPD patterns with peaks at 6.6, 7.5, 13.1, 16.5, 17.4, and 21.1 ± 0.2 degrees 2θ; and DSC thermography with endothermic peaks at about 66 and 130 ° C. One crystalline form of nateglinide (D form) characterized by data selected from the group consisting of   77. The process for preparing a crystalline form of nateglinide according to claim 76, comprising contacting nateglinide in solid state with ethanol vapor, wherein nateglinide absorbs the vapor.   78. The process of claim 77, wherein the contacted nateglinide is in the H form. a) preparing a solution of nateglinide in ethanol;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form;
77. A process for preparing crystalline nateglinide according to claim 76, comprising: a) triturating one crystalline form of nateglinide in ethanol to obtain the crystalline form of claim 1; and b) recovering the crystalline form of claim 76;
77. A process for the preparation of a crystalline form of nateglinide according to claim 76, wherein the nateglinide hydrated here is not a U-shaped nateglinide.   81. The process of claim 80, wherein the hydrated nateglinide is H-form nateglinide.   A process for preparing Form E crystalline nateglinide comprising storing T form nateglinide at a suitable temperature for a sufficient time. a) preparing a solution in a mixture of toluene and ethanol;
b) crystallizing Form E nateglinide from the solution; and c) recovering Form E nateglinide;
A process for the preparation of Form E crystalline nateglinide comprising:   A process for preparing E-form nateglinide comprising the step of triturating Z-form or delta-form nateglinide in water for a time sufficient to obtain E-form nateglinide.   Group consisting of XRPD patterns with peaks at 4.8, 5.3, 15.2, 18.9 and 19.6 ± 0.2 degrees 2θ and DSC thermography with endothermic peaks at about 53, 103 and 128 ° C. One crystalline form of nateglinide characterized by data selected from (form F). a) preparing a solution of nateglinide in n-propanol;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form;
86. A process for preparing a crystalline shape according to claim 85, comprising:   90. A process for preparing a crystalline form of nateglinide according to claim 86 comprising the step of triturating one crystalline form of nateglinide in n-propanol.   Data selected from the group consisting of XRPD patterns with peaks at 14.4, 15.3, 19.3 and 20.3 ± 0.2 degrees 2θ and DSC thermography with endothermic peaks at about 106 and 127 ° C. One crystalline form of nateglinide characterized by (G form). a) preparing a solution of nateglinide in isopropyl alcohol;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form;
90. A process for preparing a crystalline form according to claim 88, comprising: a) triturating one crystalline form of nateglinide in isopropyl alcohol to obtain the crystalline form of claim 88; and b) recovering the crystalline form of claim 88;
90. A process for preparing a crystalline form of nateglinide according to claim 88, comprising:   92. The process of claim 90, wherein the hydrated nateglinide is in the H form. a) preparing a nateglinide solution in a mixture of isopropanol and water;
b) seeding Form B nateglinide into solution at a temperature 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 nateglinide according to claim 88 from the slurry;
90. Nateglinide according to claim 88, comprising:   Characterized by data selected from the group consisting of XRPD patterns with peaks at 5.5, 7.4 and 16.8 ± 0.2 degrees 2θ, and DSC thermography with endothermic peaks at about 46 and 121 ° C. 1 crystalline form of nateglinide (form I).   94. The preparation of crystalline nateglinide according to claim 93, comprising the step of triturating one crystalline form of nateglinide in n-butanol, provided that the nateglinide triturated here is not U-shaped. process.   95. The process of claim 94, wherein the hydrated nateglinide is in the H form. a) preparing a solution of nateglinide in n-butanol;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form;
94. A process for preparing a crystalline shape according to claim 93, comprising:   Selected from the group consisting of XRPD patterns with peaks at 4.4, 5.2, 15.7 and 16.6 ± 0.2 degrees 2θ and DSC thermography with endothermic peaks at about 106, 126 and 137 ° C. One crystalline form of nateglinide (O form) characterized by the data obtained.   98. The crystalline form of claim 97, which is stable when heated to a temperature of about 60 [deg.] C. for about 8 hours.   98. The process for preparing a crystalline form according to claim 97, comprising contacting solid state nateglinide with methanol vapor to obtain a crystalline form, wherein nateglinide absorbs the vapor.   100. The process of claim 99, wherein the contacted nateglinide is in the H form.   Of nateglinide, characterized by an XRPD pattern with peaks at 7.2, 7.9, 8.3 and 10.7 ± 0.2 degrees 2θ and a DSC thermography with endothermic peaks at about 68, 106, and 130 ° C. One crystalline shape (T form). a) refining one crystalline form of nateglinide in methanol to obtain the crystalline form of claim 101, provided that the nateglinide hydrated is not U-shaped; and b) T Recovering nateglinide form,
102. A process for preparing a crystalline shape according to claim 101, comprising:   103. The process of claim 102, wherein the hydrated nateglinide is in the H form.   Crystalline nateglinide in the form of a methanol solvate represented by the structural formula NTG · 1/4 MeOH (wt / wt).   105. The crystalline nateglinide of claim 104, which is O-form nateglinide methanol solvate.   Crystalline nateglinide in the form of a methanol solvate characterized by containing more than about 20% by weight of methanol.   107. Crystalline nateglinide according to claim 106, which is a T-form nateglinide methanol solvate.   Crystalline nateglinide in the form of an ethanol solvate represented by NTG · 3/2 EtOH (wt / wt) in the structural formula.   109. The crystalline form of claim 108, which is a D-form nateglinide ethanol solvate.   Crystalline nateglinide monoipanolate.   111. Crystalline nateglinide according to claim 110, wherein the monoipanolate is Form G nateglinide.   Crystalline nateglinide in the form of n-butanol solvate.   113. Crystalline nateglinide according to claim 112, wherein the crystalline form is Form I n-butanol solvate.   Crystalline nateglinide in the form of n-propanol solvate.   115. Crystalline nateglinide according to claim 114, wherein the solvate contains from about 16% to about 24% n-propanol.   115. Crystalline nateglinide according to claim 114, wherein the solvate is Form F n-propanol solvate.   One crystalline form of nateglinide in the solid state (form C) with XRPD patterns with peaks at 5.2, 8.2 and 8.8 ± 0.2 degrees 2θ.   118. The crystalline shape of claim 117, having an XRPD pattern substantially as described in FIG. a) grinding one crystalline form of nateglinide in dimethylacetamide to obtain the crystalline form of claim 117; and b) recovering the crystalline form of claim 117;
118. A process for preparing crystalline nateglinide according to claim 117, comprising: a) preparing a nateglinide solution in dimethylacetamide;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form;
118. A process for preparing crystalline nateglinide according to claim 117, comprising:   XRPD pattern with peaks at 8.0, 11.2, 12.0, 15.9, 16.1, 17.7 and 28.1 ± 0.2 degrees 2θ, and endotherm at about 49, 105 and 168 ° C. One crystalline form of nateglinide in solid state (J form) characterized by data selected from the group consisting of DSC thermography with peaks. a) preparing a nateglinide solution in N-methylpyrrolidone;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form;
122. A process for preparing a crystalline shape according to claim 121, comprising: a) grinding one crystalline form of nateglinide in N-methylpyrrolidone to obtain the crystalline form of claim 121; and b) recovering the crystalline form of claim 121;
122. A process for preparing a crystalline shape according to claim 121, comprising:   In the group consisting of XRPD patterns with peaks at 9.5, 15.4, 17.1, and 21.1 ± 0.2 degrees 2θ, and DSC thermography with endothermic peaks at about 79, 105, 145 and 170 ° C. One crystalline form of nateglinide in the solid state characterized by data selected from (K form). a) preparing a nateglinide solution in DMF;
b) crystallizing the crystalline form from the solution and c) recovering the crystalline form;
129. A process for preparing a crystalline shape according to claim 124, comprising: a) grinding one crystalline form of nateglinide in DMF to obtain the crystalline form of claim 124; and b) recovering the crystalline form;
129. A process for preparing a crystalline shape according to claim 124, comprising:   Selected from the group consisting of XRPD patterns with peaks at 4.5, 5.8, 11.4 and 16.4 ± 0.2 degrees 2θ, and DSC thermography with endothermic peaks at about 81 and 139 ° C. One crystalline form of nateglinide characterized by data (V form). a) preparing a nateglinide solution in dimethylethane;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form;
128. A process for preparing a crystalline shape according to claim 127. a) grinding one crystalline form of nateglinide in dimethoxyethane to obtain the crystalline form according to claim 121, provided that the nateglinide hydrated is not U-shaped; and b) Recovering the crystalline form of claim 127;
128. A process for preparing a crystalline shape according to claim 127, comprising:   130. The process of claim 129, wherein the hydrated nateglinide is in the H form.   Data selected from the group consisting of XRPD patterns with peaks at 4.6, 9.4, 13.9 and 18.8 ± 0.2 degrees 2θ and DSC thermography with endothermic peaks at about 91 and 100 ° C. One crystalline form of nateglinide in the solid state characterized by (β form).   132. The process for preparing a crystalline form according to claim 131, comprising heating J-form crystalline nateglinide.   132. A process for preparing a crystalline form according to claim 131, comprising heating a solid obtained from trituration of Form H nateglinide in N-methylpyrrolidone.   4.4, 8.9, 18.4, 18.8 and 19.5 ± 0.2 degrees from the group consisting of XRPD patterns with peaks at 2θ and DSC thermography with endothermic peaks at about 93 and 136 ° C One crystalline form of nateglinide characterized by selected data (γ form).   135. Heating a solid obtained by triturating one crystalline form of nateglinide in N-methylpyrrolidone, provided that the nateglinide triturated is not in the H form. A process for preparing a crystalline form as described in 1.   138. The process of claim 135, wherein the crystallized form of hydrated nateglinide is U-shaped nateglinide.   4.2, 13.0, 13.6, 14.3, 16.2, 16.7 and 19.6 ± 0.2 degrees 2θ peaks and XRPD patterns and endothermic peaks at about 64, 108 and 129 ° C. One crystalline form of nateglinide (ε form) characterized by data selected from the group consisting of DSC thermography with a) preparing a nateglinide solution 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;
138. A process for preparing a crystalline shape according to claim 137.   138. The process of claim 138, wherein the solvent is nitromethane. a) grinding one crystalline form of nateglinide in nitromethane to obtain the crystalline form of claim 137, provided that the crystallized form is not U-shaped; And b) recovering the crystalline form of claim 137;
138. A process for preparing a crystalline shape according to claim 137, comprising:   145. The process of claim 140, wherein the hydrated crystalline form is H form.   One crystalline form of nateglinide, a dimethylacetamide solvate.   143. The crystalline form of claim 142, wherein the crystalline form is C-form nateglinide.   One crystalline form of nateglinide, which is an n-methylpyrrolidone solvate.   145. The crystalline form of claim 144, wherein the crystalline form is J-form nateglinide.   Crystalline form of nateglinide, a dimethylformamide solvate.   147. The crystalline form of claim 146, which is K-type nateglinide.   Α1 crystalline form of nateglinide, a dimethoxyethane solvate.   149. The crystalline form of claim 148, which is V-form nateglinide.   Crystalline form of nateglinide, an N-methylpyrrolidone solvate.   165. The crystalline form of claim 150, which is a gamma or beta form of nateglinide.   One crystalline form of nateglinide, 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.   153. The crystalline form of claim 152, wherein the crystalline form is epsilon nateglinide.   XRPD patterns with peaks at 6.6, 13.3, 13.9, 16.8, 27.2 and 28.0 ± 0.2 degrees 2θ and DSC thermography with endothermic peaks at about 70, 98 and 138 ° C. One crystalline form of nateglinide characterized by data selected from the group consisting of (form A). a) preparing a solution of nateglinide in xylene;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form;
165. The process of preparing a crystalline form according to claim 155, comprising:   XRPD patterns with peaks at 16.2, 16.4, 17.0, 17.8, 18.6, 19.4 and 19.6 ± 0.2 degrees 2θ and endothermic peaks at about 90, 102 and 128 ° C One crystalline form of nateglinide characterized by data selected from the group consisting of DSC thermography with (M form). a) preparing a solution of nateglinide in carbon tetrachloride;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form;
158. A process for preparing a crystalline form of nateglinide according to claim 157.   5.3, 5.5, 8.9, 9.9, 20.4 and XRPD patterns with peaks at 21.1 ± 0.2 degrees 2θ and peaks at about 77, 100, 130 and 137 ° C. One crystalline form of nateglinide characterized by data selected from the group consisting of DSC thermography (N form). a) preparing a solution of nateglinide in dichloroethane;
b) crystallizing the crystalline nateglinide from the solution; and c) recovering the crystalline nateglinide;
160. A process for preparing a crystalline shape according to claim 159, comprising:   Data selected from the group consisting of XRPD patterns with peaks at 5.1, 5.6, 16.2 and 19.8 ± 0.2 degrees 2θ and DSC thermography with endothermic peaks at about 102 and 126 ° C. One crystalline form of nateglinide characterized by (Q form). a) preparing a solution of nateglinide in chloroform;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline nateglinide;
164. A process for preparing a crystalline form of nateglinide according to claim 161. 169. Refining one crystalline form of nateglinide in chloroform, provided that the nateglinide honed here is not U-shaped; and b) recovering the crystalline form of claim 161 Stage,
164. The process of preparing a crystalline form according to claim 161, comprising:   166. The process of claim 163, wherein the hydrated nateglinide is in the H form. a) triturating one crystalline form of nateglinide in dichloroethane to obtain the crystalline form of claim 161; and b) recovering the crystalline form of claim 161;
164. The process of preparing a crystalline form according to claim 161, comprising:   One crystalline form of nateglinide, wherein the crystalline form (Y form) has an XRPD pattern with peaks at 6.1, 14.2, 15.1 and 18.7 ± 0.2 degrees 2θ.   166. The crystalline shape of claim 166, having an XRPD pattern substantially as depicted in FIG.   175. The crystalline form of nateglinide according to claim 166, which is stable upon heating to a temperature of about 60 ° C. for about 8 hours.   175. The crystalline form of a dichloromethane solvate of claim 166, comprising contacting the solid state nateglinide with a vapor of dichloromethane to obtain a crystalline form, wherein the contacted nateglinide absorbs the vapor. Preparation process. a) grinding one crystalline form of nateglinide in dichloromethane to obtain the crystalline form of claim 166; and b) recovering the crystalline form of claim 166;
175. A process for preparing a crystalline form of a dichloromethane solvate of claim 166, comprising:   171. The process of claim 170, wherein the hydrated nateglinide is in the H form. a) preparing a solution of nateglinide in dichloromethane;
b) crystallizing the crystalline form from the solution; and c) recovering the crystalline form;
175. A process for preparing a crystalline form of nateglinide according to claim 166, comprising:   166. Preparation of the crystalline form of the chloroform solvate of claim 166, comprising storing the Q-form crystalline nateglinide at a suitable temperature for a time sufficient to obtain the crystalline form of claim 166. process. a) preparing an alkali metal or alkaline earth metal salt solution of nateglinide in an aqueous solvent;
b) acidifying the solution to precipitate Z-form nateglinide; and c) recovering the crystalline form;
A process for the preparation of Z-form crystalline nateglinide comprising:   175. The process of claim 174, wherein the aqueous solvent is water without a cosolvent.   175. The process of claim 174, wherein the salt is a potassium or sodium salt. a) preparing a nateglinide solution in a mixture of ethyl acetate and C _{5 to} C ₁₂ hydrocarbons;
b) crystallizing the crystalline form of nateglinide from the solution; and c) recovering the crystalline form;
Process for the preparation of Z-form crystalline nateglinide comprising   178. The process of claim 177, wherein the hydrocarbon is heptane.   178. The process of claim 178, wherein the heptane to ethyl acetate ratio is about 2 to about 4 (v / v).   A process for the preparation of Z form nateglinide comprising the step of triturating delta form nateglinide in water for a time sufficient to obtain Z form.   XRPD patterns with peaks at 4.8, 7.8, 15.5, 17.7 ± 0.2 degrees 2θ; and endothermic peaks at about 70 ° C., 104 ° C., and 130 ° C. One crystalline form of nateglinide (θ form) characterized by data selected from the group consisting of DSC thermography with. a) preparing a solution of nateglinide in a mixture of solvents 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;
181. A process for preparing crystalline nateglinide according to claim 181, comprising:   183. The process of claim 182, wherein crystallization is performed at a temperature of about 0C to about 10C.   183. The process of claim 182, wherein the solvent is ethyl acetate.   Crystalline form of nateglinide, a solvate of xylene.   186. The crystalline form of claim 185, which is Form A nateglinide.   Crystalline form of nateglinide, a solvate of carbon tetrachloride.   188. The crystalline form of claim 187, which is M-form nateglinide.   Crystalline form of nateglinide, a solvate of dichloroethane.   189. The crystalline form of claim 189, which is N-type nateglinide.   Crystalline form of nateglinide, a solvate of chloroform.   191. The crystalline form of claim 191, which is Y-form nateglinide.   191. The crystalline form of claim 191, which is Q-form nateglinide.   Crystalline form of nateglinide, a solvate of dichloromethane.   195. The crystalline form of claim 194, which is a Y form nateglinide.   Crystalline form of nateglinide, a solvate of heptane.   196. The crystalline shape of claim 196, which is a θ-type nateglinide.   One crystallinity of nateglinide characterized by XRPD pattern with peaks at 4.5, 7.8, 15.5, 16.9, 17.8, 19.2, 19.7 ± 0.2 degrees 2θ Shape (Omega). 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;
199. A process for preparing crystalline nateglinide according to claim 198, comprising:   200. The process of claim 199, wherein the water to isopropanol ratio is from about 1/2 to about 1/5 (vol / vol).   199. A process for preparing Z-form nateglinide comprising heating the crystalline form of claim 198.   The crystalline form of nateglinide, the solvated form of isopropanol and water.   203. The crystalline form of claim 202, comprising about 50% water and isopropanol (LOD).   Crystalline 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 A pharmaceutical formulation for administration to a mammal comprising a shape and a pharmaceutically acceptable excipient.   205. A method of lowering blood sugar levels in a mammal comprising the step of administering the pharmaceutical formulation of claim 204 to the mammal.

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