EP1467964A1 - Polymorphe formen von nateglinid - Google Patents

Polymorphe formen von nateglinid

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Publication number
EP1467964A1
EP1467964A1 EP03765665A EP03765665A EP1467964A1 EP 1467964 A1 EP1467964 A1 EP 1467964A1 EP 03765665 A EP03765665 A EP 03765665A EP 03765665 A EP03765665 A EP 03765665A EP 1467964 A1 EP1467964 A1 EP 1467964A1
Authority
EP
European Patent Office
Prior art keywords
nateglinide
crystalline form
crystalline
preparing
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03765665A
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English (en)
French (fr)
Inventor
Ronit Yahalomi
Evgeny Shapiro
Ben-Zion Dolitzky
Yigael Gozlan
Boaz Gome
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceutical Industries Ltd
Original Assignee
Teva Pharmaceutical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/614,266 external-priority patent/US6861553B2/en
Application filed by Teva Pharmaceutical Industries Ltd filed Critical Teva Pharmaceutical Industries Ltd
Publication of EP1467964A1 publication Critical patent/EP1467964A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to the solid state chemistry of nateglinide.
  • Nateglinide known as (-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D- Phenylalanine, has the following structure and characteristics:
  • STARLIX Molecular Weight 317.42 Exact Mass 317.199093 Composition C 71.89% H 8.57% N 4.41% O 15.12% Nateglinide is marketed as STARLIX, which is prescribed as oral tablets having a dosage of 60mg and 120mg for the treatment of type II diabetes. STARLLX may be used as monotherapy or in combination with metaformin to stimulate the pancreas to secrete insulin.
  • nateglinide is a white powder that is freely soluble in methanol, ethanol, and chloroform, soluble in ether, sparingly soluble in acetonitrile and octanol, and practically insoluble in water.
  • Nateglinide may be crystallized out of a mixture of water and methanol, and further dried, as disclosed in U.S. Pat. No. 4,816,484.
  • the procedure of the '484 patent results in a hydrate labeled by the present Applicant(s) as Form Z, or in a methanolate lablelled by the Applicant(s) as Form E. Drying of the wet sample results in Form B.
  • the present invention relates to the solid state physical properties of nateglinide. These properties may be influenced by controlling the conditions under which nateglinide is obtained in solid Form.
  • Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate. Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid.
  • the rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient may reach the patient's bloodstream.
  • the rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments.
  • the solid state Form of a compound may also affect its behavior on compaction and its storage stability:
  • the polymorphic Form may give rise to thermal behavior different from that of the amorphous material or another polymorphic Form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and may be used to distinguish some polymorphic forms from others.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • a particular polymorphic Form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state C NMR spectrometry and infrared spectrometry.
  • the H-type crystals are characterized in these patents by an XRPD pattern with peaks at 8.1, 13.1, 19.6 and 19.9 ⁇ 0.2 degrees 2 ⁇ , and a strong reflection between 15 and 17 ⁇ 0.2 degrees 20.
  • the B-type crystal is reported to lack these peaks and have a weak reflection between 15 and 17 ⁇ 0.2 degrees 2 ⁇ .
  • H-type crystals are reported to have an BR. spectrum with characteristic absorptions at about 1714, 1649, 1542 and 1214cm "1 . These absorptions are reported to be missing in the spectrum of B-type crystals.
  • B-type crystals are unstable and susceptible to change during grinding as demonstrated by DSC.
  • the DSC thermogram of B-type shows a sharp endotherm at 131.4° C before grinding while that of H-type shows a sharp endotherm at 140.3°C.
  • the DSC thermogram of B-type shows a second endotherm at 138.2°C, suggesting a solid-solid transformation during grinding.
  • the temperature during crystallization and filtration determines whether the crystal Form is B-type or H-type. Temperatures above 10°C, more preferably above 15°C, lead to formation of H-type, while those below 10°C lead to formation of B-type.
  • Another crystalline form of nateglinide designated Type-S is disclosed in two
  • Form S is reported to be distinguisheable from Forms B and H by a melting point of 172.0 °C, a Fourier Transform IR with a peak at 3283cm “1 (as supposed to 3257cm “1 and 3306cm “1 for Forms B and H respectively) and an XRPD pattern with a strong peak at 3.78 ⁇ 0.2 degrees 2 ⁇ .
  • U.S. Pat. No. 5,463,116 (“the '116 patent”) lists the methanolate, ethanolate, isopropanolate and acetonitrilate solvates of nateglinide.
  • amorphous nateglinide may be obtained by drying the hydrate and the solvates.
  • the hydrate may be crystallized by dissolving B-type crystals in a 1.5 : 1 mixture of ethanol and water, followed by crystallization, as disclosed in Example B-3 of the ' 116 patent.
  • Example Z a hydrate of nateglinide which the Applicants labeled as Form Z.
  • repeating of Example B-3 or comparative Example A3 of the '116 patent also results in Form Z, as well as the crystallization procedure of the '484 patent.
  • Form Z is obtained when only water is present, but Form E methanolate or ethanolate when both methanol or ethanol and water are present.
  • WO 02/34713 a PCT publication in Japanese, provides in its abstract: "A process for preparing B form nateglinide crystals containing substantially no H-form crystals, which comprises the step of drying wet crystals of a nateglinide solvate at a low temperature until the solvent disappears and then causing them to undergo a crystal transition.”
  • Example 1 of the WO publication “Nateglinide H-form crystals (24.5 kg) were added to ethanol (360 L) and stirred to dissolution at room temperature. After dissolution was confirmed (the mixture) was cooled to 5 °C and allowed to mature at 5 °C for one hour. The deposited crystals were separated and damp crystals (43.0 kg) obtained.
  • the temperature for this will differ depending on the type and quantity of solvent, but usually lies below 60°C and preferably below 50°C. Although there is no lower limit to the temperature, [the drying] is usually carried out at 20 °C or more for economic reasons. Drying is favorably carried out at usual reduced pressure; at industrially attainable reduced pressures the drying will be complete in a short time. Though the drying at low temperature can be continued to virtual disappearance of the solvent it is not necessary to clear it completely. Even if solvent to the extent of 5% by weight is present this is no problem because it will disappear during the crystal transformation. By heating the dried crystals at 60-110°C, preferably 70-100°C, a crystal transformation into the B-form is brought about.
  • WO 03/022251 discloses a crystalline form of nateglinide labeled "AL-type".
  • the crystalline form is characterized as having a melting point of 174-178 °C, an XRPD pattern with peaks at 7.5, 15.5, 19.8 and 20.2 degrees 2 ⁇ , and an infra red spectrum with absorption bands in the region 1711.5, 1646.5, 1538.7, 1238.8, 1215.1 and 700.5 cm “1 .
  • the crystalline form is obtained in the examples from a solution of acetonitrile under a specific temperature range. Processes for preparation of nateglinide are disclosed in WO/0232854.
  • the present invention provides for 26 crystalline forms of nateglinide, denominated Forms A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, U, V, Y, ⁇ (alpha), ⁇ (beta), ⁇ (gamma), ⁇ (delta), ⁇ (epsilon), ⁇ (sigma), ⁇ (theta) and ⁇ (omega).
  • solvates Some of these crystalline forms have bound solvents, that is solvents that are part of the crystalline structure (solvates).
  • These solvates having bound solvent include Form A (xylene), C (dimethylacetamide- "DMA”), D (ethanol- “EtOH”), E (ethanol and methanol-"MeOH”), F (n-propanol- "n-PrOH”), G (isopropyl alcohol- "IPA”), I (n- butanol- "n-BuOH”), J (N-methylpyrrolidone- "NMP”), K (dimethylformamide- "DMF”), M (carbon tetrachloride- "CTC”), N (dichloroethane-"DCE”), O (methanol), Q (chloroform- "CHC1 3 "), T (methanol), V (dimethoxyethane- "DME”), Y (chloroform; dichloromethane), ⁇ (N-methyl pyrolidon
  • Figure 1 is an XRPD pattern for nateglinide Form A.
  • Figure 2 is an XRPD pattern for nateglinide Form C.
  • Figure 3 is an XRPD pattern for nateglinide Form D.
  • Figure 4 is an XRPD pattern for nateglinide Form E.
  • Figure 5 is an XRPD pattern for nateglinide Form F.
  • Figure 6 is an XRPD pattern for nateglinide Form G.
  • Figure 7 is an XRPD pattern for nateglinide Form I.
  • Figure 8 is an XRPD pattern for nateglinide Form J.
  • Figure 9 is an XRPD pattern for nateglinide Form K.
  • Figure 10 is an XRPD pattern for nateglinide Form L.
  • Figure 11 is an XRPD pattern for nateglinide Form M.
  • Figure 12 is an XRPD pattern for nateglinide Form N.
  • Figure 13 is an XRPD pattern for nateglinide Form O.
  • Figure 14 is an XRPD pattern for nateglinide Form P.
  • Figure 15 is an XRPD pattern for nateglinide Form Q.
  • Figure 16 is an XRPD pattern for nateglinide Form T.
  • Figure 17 is an XRPD pattern for nateglinide Form U.
  • Figure 18 is an XRPD pattern for nateglinide Form V.
  • Figure 19 is an XRPD pattern for nateglinide Form Y.
  • Figure 20 is an XRPD pattern for nateglinide Form Z.
  • Figure 21 is an XRPD pattern for nateglinide Form .
  • Figure 22 is an XRPD pattern for nateglinide Form ⁇ .
  • Figure 23 is an XRPD pattern for nateglinide Form ⁇ .
  • Figure 24 is an XRPD pattern for nateglinide Form ⁇ .
  • Figure 25 is an XRPD pattern for nateglinide Form ⁇ .
  • Figure 26 is an XRPD pattern of nateglinide Form ⁇ .
  • Figure 27 is an XRPD pattern of nateglinide Form ⁇ .
  • Figure 28 is a thermal stability chart showing transformation of the forms during drying, and is a summary of a comparison between the wet and the dry forms illustrated in various tables in the present invention.
  • Figure 29 is an FTIR spectrum of nateglinide Form L.
  • Figure 30 is an FTIR spectrum of nateglinide Form P.
  • Figure 31 is an FTIR spectrum of nateglinide Form U.
  • Figure 32 is an FTIR spectrum of nateglinide Form Z.
  • Figure 33 is an FTIR spectrum of nateglinide Form ⁇ .
  • Figure 34 is an FTIR spectrum of nateglinide Form ⁇ .
  • Figure 35 is an FTIR spectrum of nateglinide Form ⁇ .
  • Figure 36 is a DSC thermogram of nateglinide Form A.
  • Figure 37 is a DSC thermogram of nateglinide Form D.
  • Figure 38 is a DSC thermogram of nateglinide Form E.
  • Figure 39 is a DSC thermogram of nateglinide Form F.
  • Figure 40 is a DSC thermogram of nateglinide Form G.
  • Figure 41 is a DSC thermogram of nateglinide Form I.
  • Figure 42 is a DSC thermogram of nateglinide Form J.
  • Figure 43 is a DSC thermogram of nateglinide Form K.
  • Figure 44 is a DSC thermogram of nateglinide Form L.
  • Figure 45 is a DSC thermogram of nateglinide Form M.
  • Figure 46 is a DSC thermogram of nateglinide Form N.
  • Figure 47 is a DSC thermogram of nateglinide Form O.
  • Figure 48 is a DSC thermogram of nateglinide Form P.
  • Figure 49 is a DSC thermogram of nateglinide Form Q.
  • Figure 50 is a DSC thermogram of nateglinide Form T.
  • Figure 51 is a DSC thermogram of nateglinide Form U.
  • Figure 52 is a DSC thermogram of nateglinide Form V.
  • Figure 53 is a DSC thermogram of nateglinide Form Y (chloroform solvate).
  • Figure 54 is a DSC thermogram of nateglinide Form Y (dichloromethane solvate).
  • Figure 55 is a DSC thremogram of nateglinide Form Z.
  • Figure 56 is a DSC thermogram of nateglinide Form ⁇ .
  • Figure 57 is a DSC thermogram of nateglinide Form ⁇ .
  • Figure 58 is a DSC thermogram of nateglinide Form ⁇ .
  • Figure 59 is a DSC thermogram of nateglinide Form ⁇ .
  • Figure 60 is a DSC thermogram of nateglinide Form ⁇ .
  • Figure 61 is a DSC thermogram of nateglinide Form ⁇ .
  • Figure 62 is a DSC thermogram of nateglinide Form ⁇ .
  • Figure 63 is a XRPD pattern of nateglinide Form ⁇ .
  • Figure 64 is a determination of purity of Form B prepared by Example 15.
  • the present invention provides for 26 crystalline forms of nateglinide ("NTG"), denominated Form A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, U, V, Y, ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ and ⁇ .
  • NTG nateglinide
  • These crystalline forms are characterized by their XRPD pattern, DSC thermogram and TGA analysis, among others.
  • processes for preparation of other polymorphic forms such as Form B, E, H, S and Z.
  • the various crystalline forms are characterized by their XRPD pattern, which differs from one polymorph to another.
  • Form E is rather similar by XRPD to Form Z, although some differences may be observed.
  • the peak at 3.7 is characteristic of Form E and is not observed in the XRPD of Form Z.
  • the pattern in the range of 19-22 degrees two theta is also somewhat different between these two forms. Table I lists the most characteristic peaks for the new crystalline forms.
  • the XRPD patterns are illustrated in figures 1-27 and 63.
  • nateglinide The various crystalline forms of nateglinide are also characterized by their DSC thermograms. Table II lists the DSC peaks (endotherms). In addition to the peaks listed in Table II, many of the various crystalline forms show an exotherm at about 165°C followed by an endotherm at about 174°C, probably due to recrystallization into S-Type Form. Table II: DSC peaks of the nateglinide crystalline forms
  • TGA Thermal Gravimetric Analysis
  • nateglinide is free of bound solvents, i.e., less than about 2% LOD.
  • Table III lists the solvents used for the preparation for nateglinide solvated forms, as well as LOD values based on TGA analysis.
  • the ethanol solvate of nateglinide disclosed herein has an ethanol content of from about 10% to about 30% by weight.
  • the ethanol solvate of nateglinide ethanol solvate is represented by formula NTG-3/2 EtOH. Specifically, the solvate is nateglinide Form D.
  • the methanol solvates of nateglinide disclosed herein have a methanol content of from about 2 to about 60% by weight.
  • nateglinide methanol solvate exists as nateglinide Form E, Form O and Form T methanol solvate.
  • Nateglinide methanol solvate is represented by the formula NTG* 1/4 MeOH (Form O) or by the formula NTG* 1/2 MeOH (form E).
  • Nateglinide Form T contains more than about 20% methanol by weight. The methanol content of Form T is from about 20% to about 60% by weight.
  • the isopropyl solvate of nateglinide disclosed herein has an isopropyl alcohol content of from about 12% to about 30% by weight.
  • isopropyl solvate of nateglinide exists as nateglinide Form G.
  • a hydrate of nateglinide, Form Z has a water content of about 10 to about 50%, more preferably about 10% to about 40%, and most preferably from about 15% to about 25%, measured either by the Karl Fischer method or LOD.
  • Form ⁇ is a hydrate-solvate of isopropanol and contains about 50% LOD water and isopropanol.
  • the heptane solvated form of nateglinide, Form ⁇ has about 7 to about 8% heptane by weight, and is represented by the formula NTG* l/4Heptane.
  • Table III LOD values by TGA and solvents used for the preparation of nateglinide solvated forms
  • the anhydrate forms and the hydrated Form Z are also characterized by their FTIR spectrum.
  • Form Z is characterized by a FTIR spectrum ( Figure 31) with peaks at about 699, 1542, 1645, 1697, 2848, 2864, 2929, 3279 and 3504 cm “1 . The more characteristic peaks are observed at about 1645, 1697, 3279 and 3504 cm “1 .
  • Characteristic FTIR peaks are for the anhydrates, specifically Forms L, U, P, ⁇ , ⁇ and ⁇ are disclosed in the following table.
  • the various crystalline forms are related to each other in that drying of one form may result in a transformation to another form, namely nateglinide Forms A, B, D, E, F,
  • the drying is carried out by heating a sample under ambient or reduced pressure.
  • a preferred temperature is from about 40°C to about 80°C, more preferably under reduced pressure.
  • Forms B, H, L, U and sigma are thermally stable, and do not convert to another form upon heating. Many of the above forms convert to Form B upon drying, namely Forms A, C, D,
  • Form ⁇ , ⁇ , Y and O are somewhat stable, and usually retain their crystalline structure after heating, unless heated to a high temperature.
  • Form ⁇ is stable when heated to 60°C overnight (at least about 8 hours), but heating of Form ⁇ at 120°C and 1 atmosphere results in Form B.
  • heating at a temperature above about 80°C may cause a transformation in these forms.
  • stable refers to a polymo ⁇ hic change of less than about 5% by weight, more preferably less than about 2%, particularly for Form ⁇ .
  • Form B goes through another form.
  • the conversion of Form ⁇ and E to Form B may go through Form Z.
  • Form G may represent a link between Forms F, T on the one hand, and Form B on the other hand.
  • Forms T and F upon drying, convert to a mixture of Form B and G, which makes is probable that Forms F and T convert to Form B by going through Form G.
  • Form K may convert to Forms ⁇ or S
  • Form C may convert to Form B or cc.
  • Form ⁇ may convert to Form S upon heating, but the presence of seeds of Form B in the sample of Form a results in Form B.
  • Forms C and K transform to Form ⁇ first, and that it is through Form that they transform to Form B or S.
  • Form J may convert to Form B or ⁇ , though its conversion to Form B may go through Form ⁇ .
  • the Form J used in preparing Form ⁇ is preferably obtained by crystallization from N- methylpyrrohdone. When Form J contains some seeds of Form ⁇ , heating results in Form y-
  • Form L Another thermally stable Form of nateglinide is Form L.
  • Form L may be obtained by heating Forms M, N and D. To obtain Form L, these various forms are preferably heated for about 3-10 hours at a preferred temperature range of from about 40°C to about 80°C, more preferably about 50°C under reduced pressure.
  • Form ⁇ may also be prepared by heating Form J containing seeds of Form ⁇ under similar conditions.
  • Form H Another thermally stable form of nateglinide is Form H which may be prepared by heating nateglinide Forms P, V and ⁇ .
  • Form S may be prepared by heating Forms ⁇ and K, though the transition of Form K to Form S may go through Form ⁇ .
  • Form U is another thermally stable Form of nateglinide, and does not undergo a transition after being heated at about 100°C for at least about 8.5 hours.
  • Form A partially converts to Form B during storage at room temperature for about a day.
  • Form I converts to Form L under the same conditions.
  • Form Q converts to Form Y (containing chloroform), while Form T converts to Form E.
  • Form ⁇ is related to Forms F, G, I and ⁇ in that it may be crystallized out of the same solvent as those forms, n-propanol, isopropyl alcohol, n-butanol and acetonitrile, respectively.
  • Form ⁇ however is crystallized under different conditions, see e.g., Table JN.
  • Form ⁇ is often obtained with prolonged crystallization step (at least about 2-3 days). Not being bound by any theory, this phenomenon may point to a possible conversion of another crystalline form, such as those obtained from the same solvent, to Form ⁇ overtime in the solvent.
  • Forms E and D are also related in that both of the forms may be crystallized out of ethanol; but these forms crystallize under different conditions, see e.g., Table JN.
  • the crystallization of Form E in ethanol is prolonged, for at least about 5 days, more preferably at least about 1 month. Not being bound by any theory, it might be possible that initially Form D crystallizes out, followed by a conversion to Form E overtime in the solvent.
  • Form S the wet sample obtained after crystallization has to be dried. Crystallization from a solution of nateglinide in n-butanol and DMF results in a solvate, which needs to be dried to obtain Form S.
  • the wet samples are nateglinide Forms K, I and alpha. Some of the forms may first appear as a gel, and then transform into crystals during the filtration step (e.g. form epsilon from nitromethane, and form A from xylene) or overtime (e.g. Form M from carbon tetrachloride and Form J from N-methylpyrrolidone). Generally, gels are unstable forms which crystallize over time.
  • trituration refers to obtaining a solid from a mixture of nateglinide in a solvent without complete dissolution.
  • a form of nateglinide is mixed in a particular solvent and agitated for a sufficient time to allow for transformation to another crystalline form. After agitation, a suspension or a paste forms.
  • a solid may then be separated from the suspension by techniques well known in the art, such as filtration.
  • the paste may be filtered, to name one technique, to remove excess solvent.
  • the result of this trituration procedure is various forms of nateglinide.
  • the trituration of Form delta in water may result in Form Z after about 5 hours, and Form E after about 8 hours, which may also point to a transition of Form Z to Form E. All three forms may be heated to obtain Form B.
  • Some of the crystalline forms may be obtained by solvent removal.
  • First a solution of nateglinide in a suitable solvent is prepared.
  • the solvent may be heated to obtain a clear solution.
  • the solvent may be heated from about 40 °C to about 70 °C, with about 55°C being preferred.
  • the solvent is then removed to obtain a residue, preferably at elevated temperature within the said range.
  • the solvent is preferably removed by evaporation, with evaporation under reduced pressure being particularly preferred.
  • the resulting residue is then examined.
  • Suitable solvents include esters, ketones, amines, amides, alcohols and nitriles. Removal of acetonitrile, acetone, ethyl acetate and isopropyl alcohol as solvents results in nateglinide Form B.
  • Form omega is obtained by crystallization of nateglinide out of a mixture of water and isopropanol.
  • the ratio of the water to isopropanol is from about 1/2 to about 1/5, more preferably 1/3 (vol/vol).
  • Nateglinide Form Z is generally prepared by acidification of a solution of an alkali metal or alkaline earth metal salt of nateglinide in an aqueous solvent.
  • Preferred solvent is water free of a co-solvent.
  • Preferred salts are sodium and potassium salts, with the sodium salt being most preferred.
  • the solution preferably has a pH of above about 8, while after acidification, the pH is preferable from about 1 to about 5, most preferably from about 2 to about 5. Acidification results in precipitation of nateglinide, which may be recovered by techniques well known in the art, such as filtration.
  • Nateglinide Forms B and U may be prepared by crystallization from an organic solvent such as ethyl acetate or acetone.
  • crystallization is preferably induced by concentration of the solvent, while for Form U, by seeding of the solution.
  • Nateglinide Forms B, H, U, Z, ⁇ , ⁇ and ⁇ are related in that all of them may be prepared from a two solvent system.
  • the two solvent system used is a mixture of a solvent and an anti-solvent.
  • suitable antisolvents are C 5 to C 12 aromatic hydrocarbons such as toluene and xylene, and C 5 to C 12 saturated hydrocarbons such as hexane and heptane.
  • suitable solvents are to C 5 alcohols such as methanol, ethanol, isopropanol, n-butanol and n-propanol, lower ketones (C 3 to C 6 ) such as acetone and lower esters ( C 3 to C 6 ) such as ethyl acetate.
  • C 5 alcohols such as methanol, ethanol, isopropanol, n-butanol and n-propanol
  • lower ketones C 3 to C 6
  • acetone C 3 to C 6
  • lower esters C 3 to C 6
  • the crystals are recovered by techniques well known in the art, such as filtration and centrifugation, and may be dried. To dry, the temperature may be increased or the pressure reduced. In one embodiment, the crystals are dried at about 40 °C to 60 °C, at a pressure of less than about 50 mmHg.
  • Crystallization from a binary mixture of the above solvents and anti-solvents may lead to other forms of nateglinide other than Form B. Crystallization out of a toluene/methanol mixture may result in nateglinide Form E, which may be converted to Form B by heating. Additionally, a heptane/ethyl acetate combination may sometimes lead to a mixture of Forms B and Z, especially with longer period of crystallization (over about 3 days), while a toluene/ethyl acetate mixture may result in a mixture of Form B and H. A mixture of Form B and Z may be converted to one containing substantially Form B through heating, since Form Z converts to Form B through heating.
  • a solution is prepared in the solvent, followed by combining with the anti-solvent.
  • the combining is carried out in this embodiment in such a way where upon additon a solution is formed, and any precipitated solids go back into solution.
  • the anti-solvent is heated so that upon mixing of the solution and the anti-solvent, immediate precipitation does not take place.
  • the different forms may be obtained depending on the solvent/anti-solvent ratio, crystallization conditions and the time of stirring.
  • Form Z is crystallized from an ethyl acetate/heptane ratio of about 2 to 4, form H a ratio of about 4 to about 7, Form B a ratio of about 6 to about 8, Form U a ratio of about 1 to about 2, Form ⁇ a ratio of about 1 and Form ⁇ a ratio of about 1 to about 8, more preferably from about 1 to about 2 (vol vol).
  • some forms may crystallize as other forms, and convert after being stirred for a sufficient time in the solvents.
  • Stirring the resulting slurry from crystallization at a temperature of from about -15°C to about 10°C, preferably about 5 °C, may result in Form ⁇ .
  • Form ⁇ seems to result from stirring of forms such as Form U, Form ⁇ , Form H and even Form B.
  • the stirring to obtain Form ⁇ is carried out for at least about 2-3 hours, more preferably for at least about 10 hours.
  • Form ⁇ seems to be favored at lower crystallization and filtering temperatures, from about -15°C to about 10°C preferably 5°C.
  • stirring of Form ⁇ preferably at the specified temperature range, results in Form ⁇ .
  • Form U may be obtained by stirring with Form B or H in an organic solvent. Stirring for about 1 hour is sufficient to obtain Form U. However, additional stirring, such as above about 5 hours, may result in a transition to Form ⁇ .
  • Form U may also be obtained by crystallization, preferably at the specified ratio, more preferably at a crystallization and filtering temperature of about -15°C to about 10° C. Form U is generally favored when starting with a temperature of from about 25°C to about 35°C, followed by cooling in less than about 1 hour to a temperature of from about 0°C to about 10°C, with about 5°C being preferred, followed by filtering in less than about 1 hour. Higher solvent to anti-solvent ratio may favor form U over ⁇ .
  • Form H may be obtained under both low and high crystallization temperatures, preferably under the specified solvent/anti-solvent ratio.
  • Form B tends to crystallize at a temperature of at least about 15 °C.
  • Forms Z generally crystallizes after about a 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 forms is preferably above 35 °C, followed by cooling in a few hours, more preferably about 1 hour, to about 20°C to about 25 °C. These conditions may lead to Form Z, which converts to Form B by drying.
  • Form ⁇ may also be obtained by stirring of crystals of Form B. Not being bound by any theory, it may be possible that Form ⁇ is obtained through Form U, that is stirring results in a transition of Form B to Form U followed to Form ⁇ . Prolonged crystallization and filtration is preferred for obtaining Form ⁇ , i.e., preferably at least about 10 hours.
  • Table X does not show a transition of Form B to other forms despite prolonged stirring in the anti-solvent/solvent system due to use of a high ratio of ethyl acetate. Preferably about a 1 : 1 ratio of solvent to anti-solvent is used for obtaining other forms through stirring of Form B in a solvent/antisolvent mixture.
  • the results of the processes may vary when precipitating a solid after combining the solution and the anti-solvent, hi this embodiment, the solution is combined with the anti-solvent in such a way to result in precipitation, in contrast with the other embodiments that result in a solution after the combining step.
  • the solution is combined with a cold anti-solvent. More preferably, the antisolvent is from about 20 °C to about 40 °C colder than the solution, particularly when an ethyl acetate/heptane system is used. Most preferably, the heptane has a temperature of from about 0°C to about 10 °C and the ethyl acetate a temperature of from about 30 °C to about 40 °C.
  • Form U may be obtained within a wide range of solvent/antisolvent ratios and crystallization temperatures.
  • table XI shows that Form U may be obtained from a solvent to anti-solvent ratio of from about 1 to about 6, and final crystallization temperatures from about 0°C to about 30°C.
  • the presence of other forms, particularly Form ⁇ and ⁇ , especially after long crystallization step, points to possible a transition of Form U to these forms.
  • the presence of a mixture of Form B and U after 1 hour also points to the possibility that Form B might be immediately crystallized out of the solution, followed by a transition to Form U, which itself may change overtime to Forms ⁇ or ⁇ .
  • the following table provides guidance on obtaining Forms B, H, U, Z, ⁇ , ⁇ and ⁇ from a solvent: anti-solvent system:
  • nateglinide Form ⁇ may contain from about 0.5% to about 3% of residual heptane by weight.
  • the removal of heptane without changing the crystal form may be carried out in a fluidized bed drier, preferably at a temperature of from about 60 to about 70°C, more preferably for at least about 3 hours.
  • the residual Heptane may be also removed under stirring, preferably at a temperature of at least about 40 °C under vacuum.
  • the ⁇ Form is preferably polymo ⁇ hically pure and contains less than about 5% Form H (wt/wt), more preferably less than about 2% (wt/wt), and most preferably less than about 0.5% (wt/wt).
  • Crystalline Form ⁇ is stable at a temperature of about 40 °C and a relative humidity of about 75% for at least about 3 months. Trituration of Form ⁇ in ethyl acetate may result in other polymo ⁇ hic forms of nateglinide. Triturating nateglinide Form ⁇ at a temperature of from about 20 to about 30°C in ethyl acetate results in Form U, while triturating at higher temperatures (above 40°C), such as at about 50°C, results in Form B.
  • the processes of the present invention allow for obtaining Forms ⁇ and B with a purity of at least about 95%, more preferably at least about 98% wt/wt compared to other polymo ⁇ hic forms. These forms may be produced particularly free of the H Form.
  • the starting material used for the processes of the present invention may be any crystalline or amo ⁇ hous form of nateglinide, including various solvates and hydrates. With crystallization processes, the crystalline form of the starting material does not usually affect the final result. With trituration, the final product may very depending on the starting material. One of skill in the art would appreciate the manipulation of the starting material within skill in the art to obtain a desirable form with trituration.
  • the processes of the present invention may also be practiced as the last step of prior art processes that synthesize nateglinide.
  • Many processes of the present invention involve crystallization out of a particular solvent, i.e., obtaining a solid material from a solution.
  • a particular solvent i.e., obtaining a solid material from a solution.
  • the conditions concerning crystallization may be modified without affecting the form of the polymo ⁇ h obtained.
  • warming of the mixture may be necessary to completely dissolve the starting material. If warming does not clarify the mixture, the mixture may be diluted or filtered. To filter, the hot mixture may be passed through paper, glass fiber or other membrane material, or a clarifying agent such as celite.
  • the filtration apparatus may need to be preheated to avoid premature crystallization.
  • the conditions may also be changed to induce precipitation.
  • a preferred way of inducing precipitation is to reduce the solubility of the solvent.
  • the solubility of the solvent may be reduced, for example, by cooling the solvent.
  • an anti-solvent is added to a solution to decrease its solubility for a particular compound, thus resulting in precipitation.
  • Another way of accelerating crystallization is by seeding with a crystal of the product or scratching the inner surface of the crystallization vessel with a glass rod. Other times, crystallization may occur spontaneously without any inducement.
  • the present invention encompasses both embodiments where crystallization of a particular form of nateglinide occurs spontaneously or is induced/accelerated, unless if such inducement is critical for obtaining a particular form.
  • Nateglinide of defined particle size may be produced by known methods of particle size reduction starting with crystals, powder aggregates and course powder of the new crystalline forms of nateglinide.
  • the principal operations of conventional size reduction are milling of a feedstock material and sorting of the milled material by size.
  • a fluid energy mill is an especially preferred type of mill for its ability to produce particles of small size in a narrow size distribution.
  • micronizers use the kinetic energy of collision between particles suspended in a rapidly moving fluid stream to cleave the particles.
  • An air jet mill is a preferred fluid energy mill.
  • the suspended particles are injected under pressure into a recirculating particle stream. Smaller particles are carried aloft inside the mill and swept into a vent connected to a particle size classifier such as a cyclone.
  • the feedstock should first be milled to about 150 to 850 ⁇ m which may be done using a conventional ball, roller, or hammer mill.
  • a conventional ball, roller, or hammer mill One of skill in the art would appreciate that some crystalline forms may undergo a transition to another form during particle size reduction.
  • compositions may be prepared as medicaments to be administered orally, parenterally, rectally, transdermally, bucally, or nasally.
  • suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, sub-lingual tablets, syrups and suspensions.
  • Suitable forms of parenteral administration include an aqueous or non-aqueous solution or emulsion, while for rectal administration suitable forms for administration include suppositories with hydrophilic or hydrophobic vehicle.
  • the invention provides suitable transdermal dehvery systems known in the art, and for nasal delivery there are provided suitable aerosol delivery systems known in the art.
  • compositions of the present invention contain a nateglinide Form selected from A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, V, Y, ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ and ⁇ .
  • the pharmaceutical composition may contain only a single form of nateglinide, or a mixture of various forms of nateglinide, with or without amo ⁇ hous form.
  • the pharmaceutical compositions of the present invention may contain one or more excipients or adjuvants. Selection of excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle.
  • Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), rnicrofine cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit ® ), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
  • microcrystalline cellulose e.g. Avicel®
  • rnicrofine cellulose lactose
  • starch pregelitinized starch
  • calcium carbonate calcium sulfate
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel ® ), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol ® , Primellose ® ), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g.
  • Kollidon ® Polyplasdone ®
  • guar gum magnesium aluminum silicate
  • methyl cellulose microcrystalline cellulose
  • polacrilin potassium powdered cellulose
  • pregelatinized starch sodium alginate
  • sodium starch glycolate e.g. Explotab ®
  • Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dixoide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
  • a dosage form such as a tablet
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
  • Common flavoring agents and flavor enhancers for pharmaceutical products include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
  • Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • nateglinide and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
  • Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
  • Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
  • Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
  • a liquid composition may also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.
  • a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.
  • the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
  • the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
  • Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and losenges, as well as liquid syrups, suspensions and elixirs.
  • the dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
  • the shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • the active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.
  • a composition for tableting or capsule filling may be prepared by wet granulation.
  • wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules.
  • the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
  • the granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
  • a tableting composition may be prepared conventionally by dry blending.
  • the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
  • a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
  • a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
  • the dosage and formulation of STARLIX may be used as a guidance.
  • the dosage used is preferably from about 30 to about 240 mg of nateglinide, more preferably from about 60 to about 120 mg of nateglinide.
  • the pharmaceutical compositions of the present invention preferably in the form of a coated tablet, are administered from about 10 minutes to about 1 hours prior to a meal, more preferably about 15 minutes before each meal. The dose is not taken if the meal is skipped.
  • the pharmaceutical compositions may also be used in combination with metaformin.
  • X-Ray Powder Diffraction X-Ray diffraction was performed on X-Ray powder diffractometer, Scintag ® , variable goniometer, Cu-tube, solid state detector.
  • Sample holder A round standard aluminum sample holder with round zero background quartz plate.
  • the sample was put on the sample holder and immediately analyzed as is.
  • Example 1- This example illustrates preparation of various forms of nateglinide from a solution
  • Nateglinide (5 g) was placed into an erlenmeyer flask and heated to the specified temperature. The solvent was added in 1-ml portions (in some cases, the solvent was added in 5-ml portions) until a clear solution was obtained. If a clear solution was not obtained after addition of 150 ml of the solvent, the hot mixture was filtered.
  • Nateglinide (5 g) was placed into an Erlenmeyer flask. Solvent was added in 1-ml portions to prepare a stirrable mixture. The flask was stirred with a magnetic stirrer at room temperature. A solid was filtered off at room temperature, weighted, and divided into 2 equal parts. One part was dried at 55°C under 20-30 mm Hg pressure to constant weight ( ⁇ 0.01 g).
  • Example 3- This Example illustrates Abso ⁇ tion of solvent vapors bv nateglinide.
  • Nateglinide (3.50 g) was added to a polypropylene can and weighed.
  • the can was introduced into a bigger polypropylene container containing a solvent, and stored at room temperature.
  • the can was removed from the container and weighed (Wfinal).
  • the can content was divided into 2 portions. One portion was dried at a temperature of 55 °C and a pressure of 20-30 mmHg to constant weight ( ⁇ 0.01 g). Details are presented in Table VII. Table VII. Data on absorption of solvent vapors with NTG Form H
  • Example 4- This example illustrates preparation of various forms of nateglinide by solvent removal.
  • Example 5- This example illustrates preparation of Form Z.
  • D-Phenylalanine PheOH, 7.73 g
  • IPCHAC trans-4-isopropylcyclohexanecarboxyl chloride
  • Example 6- This example illustrates preparation of nateglinide by crystallization from binary mixtures (solvent/anti-solvent).
  • Nateglinide (5g) and an anti-solvent (20 ml) were placed into an Erlenmayer flask. The mixture was heated at about 55 °C over about 15 minutes, followed by addition of solvent in 0.25-1 ml portions until a clear solution was obtained. The clear solution was left to crystallize without stirring at room temperature.
  • Form B If crystallization did not happen or was poor after 24 hours, the solution was refrigerated at 3-5°C. The precipitate was filtered off (at RT or at 5°C depending on the temperature of crystallization) to give Form B. The wet material was dried at 50°C under reduced pressure (20-30 mmHg) to give dry Form B.
  • the hot organic extract was washed with warm water (100 ml), followed by brine (25 ml, 30.0 g) at 40°C, and dried with anhydrous magnesium sulfate (3.05 g) over 1.5 hours.
  • the organic solution was filtered through a PTFE 0.45 ⁇ m filter, heated to 38°C and to which was added hot heptane (40°C, 125 ml).
  • the resulting clear solution was gradually cooled for 45 minutes to 13°C and seeded with NTG in B-form. The crystallization started. The mixture was then cooled for 17 min to 5°C and stirred for 16 h.
  • the hot organic layer was separated, washed twice with water (100 ml) at 30°C, and filtered through a PTFE 0.45 ⁇ m filter.
  • the clear solution (141 g) was heated to 46°C and to which was added hot heptane (46°C, 153 ml), under stirring at 150 min "1 .
  • the clear solution was gradually cooled to 28°C and seeded with Form delta. The crystallization occurred at 24°C.
  • the mixture was stirred for 30 minutes at 24°C, gradually cooled to 5°C and stirred overnight at 5°C.
  • the wet product was washed with ethyl acetate (100 ml) heptane mixture (ratio 1 :3 v/v). The wet product was dried in a vacuum oven at 50°C overnight. Both the wet and dry samples were Form ⁇ .
  • the wet product was washed with ethyl acetate-heptane mixture (100 ml) (ratio 1:3 v/v). The wet product was dried in a vacuum oven at 50°C overnight. Both the wet and dry samples were Form ⁇ .
  • Example 8 This example illustrates preparation of forms of nateglinide bv precipitation without going to solution after combining Preparation of Nateglinide form U
  • the hot organic extract was washed with warm water (100 ml), followed by brine (40°C, 50 ml), dried with anhydrous sodium sulfate (10 g) over 1.5 h, and filtered.
  • the excess of EA was removed under reduced pressure to afford 86 g of the solution, containing ⁇ 54 g (60 ml) of EA.
  • the EA solution was finally filtered through a PTFE 0.45 ⁇ m filter into a clean dropping funnel heated to 35°C.
  • Heptane (320 ml) was placed into the reactor,' cooled to 5°C, and seeded with B-form. The clear hot EA-solution was added for 5 minutes to the cold heptane, under stirring.
  • T EA temperature of the EA solution
  • TAs( ime) temperature of anti-solvent (exposure time)- final temperature (exposure time)
  • Example 9 Heating of nateglinide Form U Sample of nateglinide form U ( ⁇ 1 g) was introduced into a 6-gram vial and heated over
  • Nateglinide Form delta (5 grams) was dissolved in isopropanol (15 ml) at room temperature. The solution was cooled to - 0°C. Water (6 ml) was added. A white solid precipitated suddenly. The solid was heated to 35 °C, resulting in complete dissolution.
  • Example 12- Drying of a wet sample of Form Omega
  • the product of example 11 was dried at 50° C in a vacuum oven overnight, and analyzed by XRD. A mixture of Form omega and Form Z was obtained.
  • Example 13- This example illustrates the preparation of Form U bv triturating form ⁇ in
  • Nateglinide Form ⁇ (5 grams) was triturated in ethyl acetate (10 ml) at 25 °C for 2 hours. The wet material was filtered with vacuum and washed with ethyl acetate (10 ml). The wet product was dried at 50 °C in a vacuum oven overnight. The wet and dry products were Form U.
  • Example 14- This example illustrates the preparation of form B bv triturating Form ⁇ in ethyl-acetate Nateglinide Form ⁇ (5 grams) was triturated in ethyl acetate (10 ml) at 50 °C for 1 hour.
  • Nateglinide Form B may also be obtained by precipitation of nateglinide Form G, from isopropanol followed by conversion of Form G to Form B.
  • a form of nateglinide such as nateglinide Form ⁇ (about 3% LOD) is dissolved in a mixture of IPA/H 2 0 at a preferred temperature range of about 40 to about 50°C.
  • the IPA concentration in the solvent mixture is in the range of about 50% to about 70% (v/v), and the volume of the solvent mixture is about 5 to about 20 volumes/unit weight of nateglinide.
  • the solution obtained after dissolution is preferably cooled to a temperature of about 30°C for seeding with crystals of Form B.
  • the seeded solution is preferably stirred at the seeding temperature for about 30 minutes to about 3 hours.
  • the solution is preferably then cooled to about 0°C plus/minus 5°C for at preferably least about 5 hours, and preferably stirred at 5 °C for at least about 30 minutes.
  • the precipitated nateglinide crystals may be recovered and dried under reduced pressure at a preferred temperature of about 70 to about 90 °C to obtain nateglinide Form B.
  • the starting material may optionally be dissolved in IPA or in a IPA/H 2 0 mixture (in the same solvent ratio as the crystallization mixture), followed by evaporation under reduced pressure. After the evaporation, rPA H 2 0 mixture is fed into the reactor to obtain a solution. Nateglinide Form B is obtained after the evaporation.
  • Example 16 Process for the Preparation of Nateglinide Form B by Trituration in Water Nateglinide Form ⁇ was triturated in 5 volumes water at about 25 °C for about 7 hours. The crystals were isolated and dried under reduced pressure at 90 °C
  • Nateglinide (50 grams) Form ⁇ was dissolved in acetone (175 ml) at 42 °C. The clear solution was cooled to 10 °C for seeding. After seeding with type B crystals, the seeded solution was stirred for an additional 3 hours at a temperature of 10°C and cooled to - 10°C for 10 hours, and stirred at -10°C over night. The crystals were isolated and dried at 90 °C. The wet crystals were tested by XRD and found to be U type. The dry crystals were tested and found to be U type.
  • Example (A) Nateglinide (12 grams) Form ⁇ was dissolved in 165 ml of ethyl acetate at 25 °C. The solvent was evaporated under reduced pressure at 25 °C, until turbidity appeared. At the end of evaporation, the volume in the reactor was 90-95 ml. The mixture was cooled from 25 °C to 5 °C for 1 hour and stirred at 5 °C for 1 hour. The product was isolated and dried under reduced pressure at 50 °C. Both the wet and the dry crystals were tested by XRD and DSC and found to be B type.

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HU227073B1 (hu) * 2003-07-10 2010-06-28 Richter Gedeon Nyrt Eljárás királisan tiszta N-(transz-4-izopropil-ciklohexilkarbonil)-D-fenil-alanin (nateglinid) és kristálymódosulatainak elõállítására, valamint a G-kristálymódosulata
WO2005110972A1 (en) * 2004-05-07 2005-11-24 Teva Pharmaceutical Industries Ltd. Polymorphic forms of nateglinide
US7563930B2 (en) * 2005-11-22 2009-07-21 Teva Pharmaceutical Industries Ltd Crystal forms of Cinacalcet HCI and processes for their preparation
TWI665190B (zh) 2013-11-15 2019-07-11 阿克比治療有限公司 ｛［５－（３－氯苯基）－３－羥基吡啶－２－羰基］胺基｝乙酸之固體型式，其組合物及用途
CN109369443A (zh) * 2018-11-05 2019-02-22 扬子江药业集团江苏海慈生物药业有限公司 一种新的那格列奈h晶型的制备方法

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WO2004009532A1 (en) 2004-01-29

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