CA2792036A1 - 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
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- 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
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- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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Abstract
The present invention provides crystalline Form R of 2-[3-cyano-4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, process for its preparation, pharmaceutical composition comprising it and its use for the chronic management of hyperuricemia in patients with gout.
Description
POLYMORPH OF 2-[3-CYANO-4-(2-METHYLPROPOXY)PHENYL]-4-Field of the Invention 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.
Background of the Invention
Background of the Invention
2-[3-Cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid (febuxostat) is a non-purine xanthine oxidase inhibitor having the structure as represented by Formula I.
x CO-H, Formula I
Febuxostat is disclosed in U.S. Patent No. 5,614,520 and is marketed in the United States under the brand name Uloric for the chronic management of hyperuricemia in patients with gout. Crystalline forms of febuxostat are disclosed in U.S.
Patent No.
6,225,474; WO 2008/067773; CN 101139325; CN 101085761; CN 101386605; and CN
101412700.
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.
x CO-H, Formula I
Febuxostat is disclosed in U.S. Patent No. 5,614,520 and is marketed in the United States under the brand name Uloric for the chronic management of hyperuricemia in patients with gout. Crystalline forms of febuxostat are disclosed in U.S.
Patent No.
6,225,474; WO 2008/067773; CN 101139325; CN 101085761; CN 101386605; and CN
101412700.
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.
3 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.
Summary of the Invention In one general aspect, 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.
For example, 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.
In another general aspect, the present invention provides for crystalline Form R of febuxostat characterized by X-ray diffraction pattern as depicted in Figure-1.
In another general aspect, the present invention provides for Crystalline Form R of febuxostat characterized by DSC as depicted in Figure-2.
In another general aspect, the present invention provides for Crystalline Form R of febuxostat characterized by TGA as depicted in Figure-3.
In another general aspect, the present invention provides for Crystalline Form R of febuxostat characterized by IR spectrum as depicted in Figure 4.
In another general aspect, the present invention provides for a process for the preparation of crystalline Form R of febuxostat. The process includes:
i) contacting febuxostat with a ketone to form a reaction mixture; and ii) isolating crystalline Form R.
Embodiments of this aspect may include one or more of the following features.
For example, 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.
In yet another general aspect, the present invention provides for a pharmaceutical composition, which includes crystalline Form R of febuxostat and one or more pharmaceutically acceptable carriers, diluents or excipients.
In another general aspect, 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.
Brief Description of the Figures Figure-1: X-ray diffraction pattern (XRD) of crystalline Form R
Figure-2: Differential Scanning Calorimetry (DSC) of crystalline Form R
Figure-3: Thermogravimetric Analysis (TGA) of crystalline Form R
Figure-4: Infra-red spectrum (IR) of crystalline Form R
Detailed Description of the Invention Crystalline Form R of the present invention may be characterized by primary XRD
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 20. 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 20. Crystalline Form R may also be characterized by an endothermic maximum at 20 2 C observed during thermal analysis using DSC. It may be characterized by XRD
pattern, DSC, TGA and IR as depicted in Figures 1, 2, 3 and 4, respectively.
Table-1 provides XRD peaks of crystalline Form R.
CN 101139325, CN 101085761, CN 101386605 and CN 101412700 disclose crystalline forms of febuxostat prepared using ethanol, ethyl acetate, acetone or 1,4-dioxane.
Summary of the Invention In one general aspect, 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.
For example, 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.
In another general aspect, the present invention provides for crystalline Form R of febuxostat characterized by X-ray diffraction pattern as depicted in Figure-1.
In another general aspect, the present invention provides for Crystalline Form R of febuxostat characterized by DSC as depicted in Figure-2.
In another general aspect, the present invention provides for Crystalline Form R of febuxostat characterized by TGA as depicted in Figure-3.
In another general aspect, the present invention provides for Crystalline Form R of febuxostat characterized by IR spectrum as depicted in Figure 4.
In another general aspect, the present invention provides for a process for the preparation of crystalline Form R of febuxostat. The process includes:
i) contacting febuxostat with a ketone to form a reaction mixture; and ii) isolating crystalline Form R.
Embodiments of this aspect may include one or more of the following features.
For example, 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.
In yet another general aspect, the present invention provides for a pharmaceutical composition, which includes crystalline Form R of febuxostat and one or more pharmaceutically acceptable carriers, diluents or excipients.
In another general aspect, 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.
Brief Description of the Figures Figure-1: X-ray diffraction pattern (XRD) of crystalline Form R
Figure-2: Differential Scanning Calorimetry (DSC) of crystalline Form R
Figure-3: Thermogravimetric Analysis (TGA) of crystalline Form R
Figure-4: Infra-red spectrum (IR) of crystalline Form R
Detailed Description of the Invention Crystalline Form R of the present invention may be characterized by primary XRD
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 20. 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 20. Crystalline Form R may also be characterized by an endothermic maximum at 20 2 C observed during thermal analysis using DSC. It may be characterized by XRD
pattern, DSC, TGA and IR as depicted in Figures 1, 2, 3 and 4, respectively.
Table-1 provides XRD peaks of crystalline Form R.
4 Table-1: X-Ray Diffraction Peaks of Crystalline Form R
Position ( 20) d-spacing (A) Relative Intensity (%)
Position ( 20) d-spacing (A) Relative Intensity (%)
5.65 15.62 28.29 5.80 15.23 70.59 7.97 11.08 100.00 11.62 7.61 18.87 12.56 7.04 8.63 12.76 6.93 36.73 12.94 6.84 3.81 14.40 6.15 1.38 15.53 5.71 2.08 16.16 5.49 1.10 16.88 5.25 7.59 17.46 5.08 5.48 18.19 4.88 5.66 18.49 4.80 6.63 20.54 4.32 12.74 21.01 4.23 3.82 22.34 3.98 1.15 23.38 3.81 2.65 23.86 3.73 6.53 24.40 3.65 3.74 24.63 3.62 2.99 25.92 3.43 19.38 26.19 3.40 10.36 26.76 3.33 1.22 27.50 3.24 1.09 28.09 3.18 1.09 28.57 3.12 1.79 28.92 3.09 3.66 30.10 2.97 1.68 31.36 2.85 1.93 32.67 2.74 0.98 33.49 2.68 0.78 34.48 2.60 1.92 35.68 2.52 1.11 36.12 2.49 0.95 36.72 2.45 1.14 37.85 2.38 1.09 38.69 2.33 1.20 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.
5 The term "contacting" may include dissolving, slurrying, stirring or a combination thereof.
The term "about", as used herein, includes variations in the range of 10% in the temperature and time period.
The term "room temperature", as used herein, includes temperature in the range of about 15 C to about 35 C.
Febuxostat may be contacted with a solvent at about room temperature. The solvent may be selected from the group comprising of C3-C10 alcohols, carboxylic acids, chlorinated hydrocarbons, ketones, amides, sulphoxides, ethers, alkyl acetates, water or mixtures thereof. Examples of C3-C10 alcohols may include 1-propanol, 1-butanol or 2-butanol. Examples of carboxylic acids may include formic acid, acetic acid or propionic acid. Examples of chlorinated hydrocarbons may include dichloromethane or chloroform.
Examples of 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. Examples of 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,
5 The term "contacting" may include dissolving, slurrying, stirring or a combination thereof.
The term "about", as used herein, includes variations in the range of 10% in the temperature and time period.
The term "room temperature", as used herein, includes temperature in the range of about 15 C to about 35 C.
Febuxostat may be contacted with a solvent at about room temperature. The solvent may be selected from the group comprising of C3-C10 alcohols, carboxylic acids, chlorinated hydrocarbons, ketones, amides, sulphoxides, ethers, alkyl acetates, water or mixtures thereof. Examples of C3-C10 alcohols may include 1-propanol, 1-butanol or 2-butanol. Examples of carboxylic acids may include formic acid, acetic acid or propionic acid. Examples of chlorinated hydrocarbons may include dichloromethane or chloroform.
Examples of 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. Examples of 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,
6 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.
In a particular embodiment, 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.
In another embodiment, 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 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-20 flowing solid. Preferably, crystalline Form R has a particle size of less than 100 m.
Variations in dissolution profiles may arise due to larger particle size.
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.
The term "free of residual solvents", as used herein, 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.
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.
In a particular embodiment, 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.
In another embodiment, 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 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-20 flowing solid. Preferably, crystalline Form R has a particle size of less than 100 m.
Variations in dissolution profiles may arise due to larger particle size.
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.
The term "free of residual solvents", as used herein, 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.
7 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. Examples of vegetable oils may include corn oil, cotton seed oil, coconut oil, almond oil, peanut oil or olive oil. Examples of 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, hydroxypropylmethyl cellulose or methyl 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.
Methods 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 20 as range.
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. Examples of vegetable oils may include corn oil, cotton seed oil, coconut oil, almond oil, peanut oil or olive oil. Examples of 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, hydroxypropylmethyl cellulose or methyl 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.
Methods 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 20 as range.
8 DSC and TGA were recorded using Mettler Toledo DSC 821e and Perkin Elmer TGA 7 instruments, respectively.
IR spectrum was recorded using Perkin Elmer Spectrum one FT-IR spectrometer.
Example: Preparation of Crystalline Form R of Febuxostat 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 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.
Yield: 2.4 g
IR spectrum was recorded using Perkin Elmer Spectrum one FT-IR spectrometer.
Example: Preparation of Crystalline Form R of Febuxostat 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 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.
Yield: 2.4 g
Claims (16)
1. Crystalline Form R of febuxostat comprising X-ray diffraction peaks at d-spacing of about 15.62, 15.23, 11.08, 6.93 and 3.43 .ANG.
2. The crystalline Form R according to claim 1 further comprising X-ray diffraction peaks at d-spacing of about 7.61, 7.04, 5.25, 4.32 and 3.40 .ANG..
3. Crystalline Form R of febuxostat characterized by X-ray diffraction pattern as depicted in Figure-1.
4. Crystalline Form R of febuxostat as defined in claim 1 characterized by DSC
as depicted in Figure-2.
as depicted in Figure-2.
5. Crystalline Form R of febuxostat as defined in claim 1 characterized by TGA
as depicted in Figure-3.
as depicted in Figure-3.
6. Crystalline Form R of febuxostat as defined in claim 1 characterized by IR
spectrum as depicted in Figure-4.
spectrum as depicted in Figure-4.
7. A process for the preparation of crystalline Form R of febuxostat comprising:
i) contacting febuxostat with a ketone to form a reaction mixture; and ii) isolating crystalline Form R.
i) contacting febuxostat with a ketone to form a reaction mixture; and ii) isolating crystalline Form R.
8. The process according to claim 7, wherein the ketone consists of acetone, dimethyl ketone, ethyl methyl ketone or methyl iso-butyl ketone.
9. The process according to claim 8, wherein the ketone consists of ethyl methyl ketone.
10. The process according to claim 7, wherein the febuxostat is contacted with the solvent at room temperature.
11. The process according to claim 7, wherein the reaction mixture is heated to about 40°C to the reflux temperature of the solvent.
12. The process according to claim 7, wherein the reaction mixture is stirred for about minutes to about 30 minutes.
13. The process according to claim 7, wherein the reaction mixture is further cooled to about 5°C to about 25°C.
14. The process according to claim 7, wherein the reaction mixture is further dried under reduced pressure at a temperature of about 35°C to about 60°C.
15. A pharmaceutical composition comprising crystalline Form R of febuxostat as defined in claim 1 and one or more pharmaceutically acceptable carriers, diluents or excipients.
16. Use of crystalline Form R of febuxostat defined in claim 1, in the manufacture of a medicament for use in chronic management of hyperuricemia in patients with gout.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN488/DEL/2010 | 2010-03-04 | ||
| IN488DE2010 | 2010-03-04 | ||
| 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 |
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| Publication Number | Publication Date |
|---|---|
| CA2792036A1 true CA2792036A1 (en) | 2011-09-09 |
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| CA2792036A Abandoned CA2792036A1 (en) | 2010-03-04 | 2011-02-24 | Polymorph of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP2542540A1 (en) |
| AU (1) | AU2011222462A1 (en) |
| CA (1) | CA2792036A1 (en) |
| WO (1) | WO2011107911A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012038971A2 (en) | 2010-09-24 | 2012-03-29 | Hetero Research Foundation | Novel polymorphs of febuxostat |
| US20140112992A1 (en) | 2011-06-06 | 2014-04-24 | Hetero Research Foundation | Process for febuxostat |
| AU2012342011A1 (en) | 2011-11-15 | 2014-06-05 | Mylan Laboratories Ltd | Process for the preparation of Febuxostat polymorphs |
| CZ27857U1 (en) | 2014-12-12 | 2015-02-23 | Zentiva, K.S. | Formulation containing febuxostat solid solution |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100221041B1 (en) | 1990-11-30 | 1999-09-15 | 야스이 쇼사꾸 | 2-arylthiazole derivatives and pharmaceutical compositions thereof |
| IL134594A (en) | 1998-06-19 | 2004-12-15 | Teijin Ltd | Polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid and methods of producing the same |
| US7541475B2 (en) | 2003-07-30 | 2009-06-02 | Abbott Laboratories | Substituted thiazoles |
| CA2656264C (en) | 2006-06-23 | 2014-07-08 | Teijin Pharma Limited | Method for producing crystal polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid |
| CN101139325B (en) | 2006-09-07 | 2010-05-12 | 上海医药工业研究院 | 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid crystal form and preparation method thereof |
| CN1970547B (en) | 2006-12-07 | 2011-04-06 | 重庆医药工业研究院有限责任公司 | Novel febuxostat crystal form and its preparation method |
| CN100546985C (en) | 2007-06-29 | 2009-10-07 | 上海华拓医药科技发展股份有限公司 | Febuxotat microcrystal and composition thereof |
| CN101412700B (en) | 2007-10-19 | 2011-06-08 | 上海医药工业研究院 | Crystal form and preparation of febuxostat |
| CN101386605B (en) | 2008-10-23 | 2010-09-08 | 中国科学院上海药物研究所 | Novel crystal of febuxostat and preparation method thereof |
-
2011
- 2011-02-24 AU AU2011222462A patent/AU2011222462A1/en not_active Abandoned
- 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 EP EP11711672.3A patent/EP2542540A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| AU2011222462A1 (en) | 2012-09-27 |
| WO2011107911A1 (en) | 2011-09-09 |
| EP2542540A1 (en) | 2013-01-09 |
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