WO2011107911A1 - Polymorph of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid - Google Patents
Polymorph of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid Download PDFInfo
- Publication number
- WO2011107911A1 WO2011107911A1 PCT/IB2011/050785 IB2011050785W WO2011107911A1 WO 2011107911 A1 WO2011107911 A1 WO 2011107911A1 IB 2011050785 W IB2011050785 W IB 2011050785W WO 2011107911 A1 WO2011107911 A1 WO 2011107911A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- febuxostat
- crystalline form
- ketone
- reaction mixture
- process according
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
Definitions
- the present invention provides for crystalline Form R of 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, and process for its preparation.
- the present invention also includes a pharmaceutical composition, which includes Form R and its use in the chronic management of hyperuricemia in patients with gout.
- 2-[3-Cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid is a non-purine xanthine oxidase inhibitor having the structure as represented by Formula I.
- U.S. Patent No. 6,225,474 discloses crystalline Forms A, B, C, D and G of febuxostat prepared using a mixture of methanol, ethanol or propanol with water.
- WO 2008/067773 discloses crystalline Forms H, I and J of febuxostat prepared using acetonitrile.
- CN 101139325, CN 101085761, CN 101386605 and CN 101412700 disclose crystalline forms of febuxostat prepared using ethanol, ethyl acetate, acetone or 1,4- dioxane.
- the present invention provides for crystalline Form R of febuxostat, which includes X-ray diffraction peaks at d-spacing of about 15.62, 15.23, 11.08, 6.93 and 3.43 A
- Embodiments of this aspect may include one or more of the following features.
- the crystalline Form may further include X-ray diffraction peaks at d-spacing of about 7.61, 7.04, 5.25, 4.32 and 3.40 A.
- the present invention provides for crystalline Form R of febuxostat characterized by X-ray diffraction pattern as depicted in Figure- 1.
- the present invention provides for Crystalline Form R of febuxostat characterized by DSC as depicted in Figure-2.
- the present invention provides for Crystalline Form R of febuxostat characterized by TGA as depicted in Figure-3.
- the present invention provides for Crystalline Form R of febuxostat characterized by IR spectrum as depicted in Figure 4.
- the present invention provides for a process for the preparation of crystalline Form R of febuxostat.
- the process includes:
- Embodiments of this aspect may include one or more of the following features.
- the ketone is acetone, dimethyl ketone, ethyl methyl ketone or methyl iso- butyl ketone.
- the ketone may be ethyl methyl ketone.
- the febuxostat may be contacted with the solvent at room temperature.
- the reaction mixture may be heated to about 40°C to the reflux temperature of the solvent.
- the reaction mixture may be stirred for about 5 minutes to about 30 minutes.
- the reaction mixture may also be further cooled to about 5°C to about 25 °C.
- the reaction mixture may also be further dried under reduced pressure at a temperature of about 35°C to about 60°C.
- the present invention provides for a pharmaceutical composition, which includes crystalline Form R of febuxostat and one or more
- the present invention also provides for the use of crystalline Form R of febuxostat in the manufacture of a medicament for use in chronic management of hyperuricemia in patients with gout.
- Figure- 1 X-ray diffraction pattern (XRD) of crystalline Form R
- Crystalline Form R of the present invention may be characterized by primary XRD 2 ⁇ peaks at about 5.65 (d-spacing at 15.62 A), 5.80 (15.23 A), 7.97 (11.08 A), 12.76 (6.93 A) and 25.92 (3.43 A) + 0.2° 2 ⁇ . It may be further characterized by XRD peaks at about 11.62 (7.61 A), 12.56 (7.04 A), 16.88 (5.25 A), 20.54 (4.32 A) and 26.19 (3.40 A) + 0.2° 2 ⁇ . Crystalline Form R may also be characterized by an endothermic maximum at 201 + 2°C observed during thermal analysis using DSC.
- the febuxostat used for the preparation of the crystalline Form R of the present invention may be obtained by any of the methods known in the literature such as those described in U.S. Patent No. 5,614,520; U.S. Publication 2009/0203919; and U.S. Patent No. 7,541,475, which are incorporated herein by reference.
- Febuxostat, to be used as starting material for the preparation of crystalline forms of the present invention may be obtained as a solution directly from a reaction in which it is formed and used as such without isolation.
- contacting may include dissolving, slurrying, stirring or a combination thereof.
- room temperature includes temperature in the range of about 15°C to about 35°C.
- the solvent may be selected from the group comprising of C 3 -C 10 alcohols, carboxylic acids, chlorinated hydrocarbons, ketones, amides, sulphoxides, ethers, alkyl acetates, water or mixtures thereof.
- C 3 -C 10 alcohols may include 1-propanol, 1-butanol or 2- butanol.
- carboxylic acids may include formic acid, acetic acid or propionic acid.
- chlorinated hydrocarbons may include dichloromethane or chloroform.
- ketones may include acetone, dimethyl ketone, ethyl methyl ketone or methyl iso-butyl ketone.
- Examples of ethers may include diethyl ether, ethyl methyl ether, di- isopropyl ether, tetrahydrofuran or 1,4-dioxane.
- Examples of amides may include N, N- dimethylformamide or N, N-dimethylacetamide.
- Examples of sulphoxides may include dimethyl sulfoxide or diethyl sulphoxide.
- Examples of cyclic ethers may include tetrahydrofuran.
- alkyl acetates may include methyl acetate, ethyl acetate, propyl acetate or butyl acetate.
- the reaction mixture may be stirred for a period of about 1 minute to about 15 minutes followed by heating to a temperature of about 40°C to the reflux temperature of the solvent and further stirring for about 2 minutes to about 30 minutes. It may be cooled to a temperature of about 5°C to about 25°C, preferably, to about 15°C to about 20°C, over a period of about 10 minutes to about 2 hours, preferably, over a period of about 30 minutes. It may be further stirred for about 30 minutes to about 5 hours, preferably, for about 2 hours, and dried. Any suitable method of drying may be employed, such as, drying under reduced pressure, vacuum tray drying, air drying, or a combination thereof. Drying may be carried out at a temperature of about 20°C to about 60°C, preferably, at about 45°C, for a period of about 1 hour to about 8 hours, preferably, for about 5 hours.
- crystalline Form R of the present invention is prepared by contacting febuxostat with a ketone solvent at a temperature of about 15°C to about 35°C.
- the reaction mixture is stirred for about 1 minute to about 15 minutes, and the reaction mixture is heated to a temperature of about 40°C to the reflux temperature of the solvent. This is stirred for about 5 minutes to about 30 minutes. This is then cooled to a temperature of about 5°C to about 25°C in a period of about 10 minutes to about 2 hours, and then for about 30 minutes to about 5 hours; followed by drying.
- the ketone solvent may be acetone, dimethyl ketone, ethyl methyl ketone or methyl iso-butyl ketone.
- crystalline Form R of the present invention is prepared by contacting febuxostat with ethyl iso-butyl ketone at room temperature, stirring the reaction mixture for about 1 minute to about 15 minutes. The reaction mixture is then heated to a temperature of about 40°C to the reflux temperature of the solvent, and stirred for about 5 minutes to about 30 minutes. This is then cooled to a temperature of about 15°C to about 20°C over a period of 30 minutes. Finally, the reaction mixture is stirred for about 2 hours and then dried under reduced pressure at a temperature of about 45 °C for about 5 hours.
- Crystalline Form R of the present invention is a highly pure, easy to filter, free- flowing solid.
- crystalline Form R has a particle size of less than 100 ⁇ .
- Crystalline Form R of the present invention is free of residual solvents, is stable towards polymorphic conversion and shows little or no variation in dissolution profile.
- free of residual solvents refers to crystalline Form R of febuxostat containing less than 5000 ppm, preferably, less than 1000 ppm and more preferably, less than 500 ppm of residual solvents.
- the crystalline Form R of febuxostat of the present invention may be converted into an amorphous form of febuxostat by evaporation of the solvent, spray drying, freeze - drying or lyophilization. Solvates, pseudomorphs and hydrates of crystalline Form R of the present invention are also included within the scope of the present invention.
- the crystalline Form R of febuxostat of the present invention may be administered as part of a pharmaceutical composition for the chronic management of hyperuricemia in patients with gout. Any suitable route of administration may be employed for example peroral or parental.
- the present invention also provides for a pharmaceutical composition which includes crystalline Form R of febuxostat, one or more pharmaceutically acceptable carriers, diluents or excipients and optionally other therapeutic ingredients.
- the excipients may be vegetable oils, oily esters, glycerin esters, alcohols, physiological saline, glycols, animal fat and oil, cellulose derivatives, polyvinyl pyrrolidone, dextrin, lactose, mannitol, sorbitol or starch.
- vegetable oils may include corn oil, cotton seed oil, coconut oil, almond oil, peanut oil or olive oil.
- oily esters may include glyceride oils or mineral oils.
- Examples of glycerin esters may include tricaprylin or triacetin.
- Examples of alcohols may include methanol, ethanol or propanol.
- Examples of glycols may include propylene glycol or polyethylene glycol.
- Examples of cellulose derivatives may include crystalline cellulose, hydroxypropyl cellulose,
- the diluents may be calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate.
- the crystalline Form R of febuxostat of the present invention may be formulated into capsules, hard capsules, tablets, granules, powder, suspension, solutions and syrups, injections, suppositories and external preparations.
- Embodiments of the present invention are described by way of example to illustrate the process of invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.
- the X-ray diffraction patterns were recorded using Panalytical Expert PRO with Xcelerator as detector, 3-40 as scan range, 0.02 as step size and 3-40° 2 ⁇ as range.
- DSC and TGA were recorded using Mettler Toledo DSC 82 le and Perkin Elmer TGA 7 instruments, respectively.
- Febuxostat (3 g) was added to a round-bottomed flask containing ethyl methyl ketone (21 mL) at room temperature. The reaction mixture was stirred for about 3 minutes, followed by heating to about 50°C to about 55°C. The reaction mixture was stirred for about 5 minutes, cooled to about 15°C to about 20°C over a period of about 30 minutes, stirred for about 2 hours, filtered, washed with ethyl methyl ketone (3 mL) and dried under reduced pressure at a temperature of about 45 °C for about 5 hours to obtain crystalline Form R of febuxostat.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2792036A CA2792036A1 (en) | 2010-03-04 | 2011-02-24 | Polymorph of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid |
AU2011222462A AU2011222462A1 (en) | 2010-03-04 | 2011-02-24 | Polymorph of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid |
EP11711672.3A EP2542540A1 (en) | 2010-03-04 | 2011-02-24 | Polymorph of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid |
Applications Claiming Priority (2)
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IN488DE2010 | 2010-03-04 | ||
IN488/DEL/2010 | 2010-03-04 |
Publications (1)
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WO2011107911A1 true WO2011107911A1 (en) | 2011-09-09 |
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PCT/IB2011/050785 WO2011107911A1 (en) | 2010-03-04 | 2011-02-24 | Polymorph of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid |
Country Status (4)
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EP (1) | EP2542540A1 (en) |
AU (1) | AU2011222462A1 (en) |
CA (1) | CA2792036A1 (en) |
WO (1) | WO2011107911A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013076738A2 (en) | 2011-11-15 | 2013-05-30 | Mylan Laboratories Ltd | Process for the preparation of febuxostat polymorphs |
EP2619191A2 (en) | 2010-09-24 | 2013-07-31 | Hetero Research Foundation | Novel polymorphs of febuxostat |
EP2718272A2 (en) | 2011-06-06 | 2014-04-16 | Hetero Research Foundation | Process for febuxostat |
WO2016091230A1 (en) | 2014-12-12 | 2016-06-16 | Zentiva, K.S. | Formulations containing a solid solution of febuxostat |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5614520A (en) | 1990-11-30 | 1997-03-25 | Teijin Limited | 2-arylthiazole derivatives and pharmaceutical composition thereof |
US6225474B1 (en) | 1998-06-19 | 2001-05-01 | Teijin Limited | Polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid and method of producing the same |
CN101085761A (en) | 2007-06-29 | 2007-12-12 | 上海华拓医药科技发展股份有限公司 | Febuxotat microcrystal and compositions thereof |
CN101139325A (en) | 2006-09-07 | 2008-03-12 | 上海医药工业研究院 | 2-(3-cyano-4-isobuoxy phenyl)4-methyl-5-thiazole aminic acid crystal and preparation method thereof |
WO2008067773A1 (en) | 2006-12-07 | 2008-06-12 | Chongqing Pharmaceutical Research Institute Co., Ltd. | New crystal types of febuxostat and their preparation methods |
CN101386605A (en) | 2008-10-23 | 2009-03-18 | 中国科学院上海药物研究所 | Febustat novel crystal and preparation method thereof |
CN101412700A (en) | 2007-10-19 | 2009-04-22 | 上海医药工业研究院 | Crystal form and preparation of febuxostat |
US7541475B2 (en) | 2003-07-30 | 2009-06-02 | Abbott Laboratories | Substituted thiazoles |
US20090203919A1 (en) | 2006-06-23 | 2009-08-13 | Mitsutaka Kitamura | Method for producing crystal polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid |
-
2011
- 2011-02-24 EP EP11711672.3A patent/EP2542540A1/en not_active Withdrawn
- 2011-02-24 CA CA2792036A patent/CA2792036A1/en not_active Abandoned
- 2011-02-24 WO PCT/IB2011/050785 patent/WO2011107911A1/en active Application Filing
- 2011-02-24 AU AU2011222462A patent/AU2011222462A1/en not_active Abandoned
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5614520A (en) | 1990-11-30 | 1997-03-25 | Teijin Limited | 2-arylthiazole derivatives and pharmaceutical composition thereof |
US6225474B1 (en) | 1998-06-19 | 2001-05-01 | Teijin Limited | Polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid and method of producing the same |
US7541475B2 (en) | 2003-07-30 | 2009-06-02 | Abbott Laboratories | Substituted thiazoles |
US20090203919A1 (en) | 2006-06-23 | 2009-08-13 | Mitsutaka Kitamura | Method for producing crystal polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid |
CN101139325A (en) | 2006-09-07 | 2008-03-12 | 上海医药工业研究院 | 2-(3-cyano-4-isobuoxy phenyl)4-methyl-5-thiazole aminic acid crystal and preparation method thereof |
WO2008067773A1 (en) | 2006-12-07 | 2008-06-12 | Chongqing Pharmaceutical Research Institute Co., Ltd. | New crystal types of febuxostat and their preparation methods |
CN101085761A (en) | 2007-06-29 | 2007-12-12 | 上海华拓医药科技发展股份有限公司 | Febuxotat microcrystal and compositions thereof |
CN101412700A (en) | 2007-10-19 | 2009-04-22 | 上海医药工业研究院 | Crystal form and preparation of febuxostat |
CN101386605A (en) | 2008-10-23 | 2009-03-18 | 中国科学院上海药物研究所 | Febustat novel crystal and preparation method thereof |
Non-Patent Citations (3)
Title |
---|
CAIRA M R: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS", TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP001156954, ISSN: 0340-1022, ISBN: 978-3-540-36760-4, DOI: DOI:10.1007/3-540-69178-2_5 * |
HASEGAWA T: "A FACILE ONE-POT SYNTHESIS OF 4-ALKOXY-1,3-BENZENEDICARBONITRILE", HETEROCYCLES, ELSEVIER SCIENCE PUBLISHERS B.V. AMSTERDAM, NL, vol. 47, no. 2, 1 January 1998 (1998-01-01), pages 857 - 864, XP001056564, ISSN: 0385-5414 * |
See also references of EP2542540A1 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2619191A2 (en) | 2010-09-24 | 2013-07-31 | Hetero Research Foundation | Novel polymorphs of febuxostat |
EP2718272A2 (en) | 2011-06-06 | 2014-04-16 | Hetero Research Foundation | Process for febuxostat |
WO2013076738A2 (en) | 2011-11-15 | 2013-05-30 | Mylan Laboratories Ltd | Process for the preparation of febuxostat polymorphs |
CN104114545A (en) * | 2011-11-15 | 2014-10-22 | 迈兰实验室有限公司 | Process for the preparation of febuxostat polymorphs |
JP2014533297A (en) * | 2011-11-15 | 2014-12-11 | マイラン ラボラトリーズ リミテッドMylan Laboratories Limited | Process for the preparation of polymorphs of febuxostat |
WO2016091230A1 (en) | 2014-12-12 | 2016-06-16 | Zentiva, K.S. | Formulations containing a solid solution of febuxostat |
Also Published As
Publication number | Publication date |
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AU2011222462A1 (en) | 2012-09-27 |
EP2542540A1 (en) | 2013-01-09 |
CA2792036A1 (en) | 2011-09-09 |
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