WO2014057461A1 - Process for the preparation of crystalline form g of febuxostat - Google Patents

Process for the preparation of crystalline form g of febuxostat Download PDF

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Publication number
WO2014057461A1
WO2014057461A1 PCT/IB2013/059285 IB2013059285W WO2014057461A1 WO 2014057461 A1 WO2014057461 A1 WO 2014057461A1 IB 2013059285 W IB2013059285 W IB 2013059285W WO 2014057461 A1 WO2014057461 A1 WO 2014057461A1
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Prior art keywords
febuxostat
crystalline form
methanol
water
volume ratio
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PCT/IB2013/059285
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French (fr)
Inventor
Ashwini Kumar Kapoor
Asok Nath
Mohan Prasad
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Ranbaxy Laboratories Limited
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Publication of WO2014057461A1 publication Critical patent/WO2014057461A1/en

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    • 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

Definitions

  • Febuxostat is a xanthine oxidase inhibitor known from U.S. Patent No. 5,614,520. It is chemically 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, having the structure as represented by Formula I.
  • U.S. Patent No. 6,225,474 discloses processes for the preparation of the crystalline Form G of febuxostat using a mixed solvent of methanol and water having a volume ratio of methanol to water of 50:50, or by using a mixed solvent of 2-propanol and water having a volume ratio of 2-propanol to water of from about 90: 10 to 50:50.
  • PCT Publication No. WO 201 1/141933 discloses a process for the preparation of the crystalline Form G of febuxostat using acetone and water.
  • Japanese Publication No. JP 2003261548 discloses a process for the preparation of the crystalline Form G of febuxostat using a mixed solvent of methanol and water having a volume ratio of methanol to water of 70:30.
  • U.S. Patent No. 7,361,676 discloses milling for reducing the particle size of the crystalline Form A of febuxostat.
  • genotoxic impurities in a pharmaceutical product is considered to be a serious risk factor due to their potential to damage DNA at any level of exposure which may lead to, or contribute towards, tumor development.
  • ICH guidelines on the limit of genotoxic impurities in pharmaceutical products there is a need to control the genotoxic impurities to the lowest possible level in pharmaceutical products.
  • the particle size of an active pharmaceutical ingredient is also an important aspect that affects the bioavailability of the drugs.
  • drugs having poor aqueous solubility e.g., febuxostat
  • a general method for reducing the particle size of an active pharmaceutical ingredient involves carrying out micronization of the active pharmaceutical ingredient.
  • carrying out micronization of the active pharmaceutical ingredient sometimes results in agglomeration of the smaller particles to form larger particles, thereby reducing the solubility and bioavailability of the drug.
  • greater energy input is required for carrying out micronization, it sometimes also causes instability and discoloration of the drug substance. Reducing the particle size of the active
  • pharmaceutical ingredient by micronization also increases the cost of the manufacturing process due to an increase in the manufacturing time and the requirement of additional process controls.
  • the present invention provides an eco-friendly, cost-effective, and industrially advantageous process for the preparation of crystalline Form G of febuxostat.
  • the process of the present invention involves the use of a mixed solvent of methanol and water having a volume ratio of methanol to water from 5:95 to 45:55.
  • Crystalline form G of febuxostat obtained by the process of the present invention, is substantially free of genotoxic impurities, ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl- 1 ,3-thiazole-5- carboxylate (hereinafter referred to as "the febuxostat ethyl ester impurity"), 2- [3- carbamoyl-4-(2-methylpropoxy)phenyl]-4-methyl- 1 ,3-thiazole-5-carboxylic acid impurity, and residual solvents.
  • the process of the present invention provides crystalline Form G of febuxostat having a small particle size, without the need for carrying out micronization.
  • a first aspect of the present invention provides a process for the preparation of crystalline Form G of febuxostat in a mixed solvent of methanol and water having a volume ratio of methanol to water from 5:95 to 45:55.
  • Embodiments of the process may include one or more of the following features.
  • preparation of the crystalline Form G of febuxostat may be carried out at a temperature of about 50°C to about 70°C.
  • the crystalline Form G of febuxostat may be substantially free of the genotoxic impurities selected from 2-[3-cyano-4-hydroxyphenyl]-4-methylthiazole-5-carboxylic acid ethyl ester, 1 -bromo-2-methylpropane, ethyl-2-chloroacetoacetate, methyl methane sulfonate, ethyl methane sulfonate, acetoacetic acid ethyl ester, ethyl 2,2-dichloro-3- oxobutanoate, and n-butyl bromide.
  • the genotoxic impurities selected from 2-[3-cyano-4-hydroxyphenyl]-4-methylthiazole-5-carboxylic acid ethyl ester, 1 -bromo-2-methylpropane, ethyl-2-chloroacetoacetate, methyl methane sulfonate, ethy
  • the crystalline Form G of febuxostat may be substantially free of the febuxostat ethyl ester impurity, the 2-[3-carbamoyl-4-(2- methylpropoxy)phenyl]-4-methyl-l,3-thiazole-5-carboxylic acid impurity, and/or methanol.
  • the volume ratio of methanol to water may be about 37.5:62.5, about 35.3:64.7, or about 40:60.
  • the volume ratio of methanol to water may range from about 35:65 to about 40:60.
  • a second aspect of the present invention provides crystalline form G of febuxostat, wherein the particle size of 90% of the particles is less than 15 ⁇ .
  • Figure 1 X-ray powder diffraction (XRPD) pattern of crystalline Form G of febuxostat.
  • FIG. 2 Particle size distribution of crystalline Form G of febuxostat prepared by the process of the present invention.
  • Crystalline Form G of febuxostat refers to the crystalline Form G of febuxostat disclosed in U.S. Patent No. 6,225,474, the contents of which are incorporated herein by reference, in particular for data characterizing Form G of febuxostat such as the x-ray diffraction data and infrared spectroscopic absorption data disclosed therein.
  • substantially free of genotoxic impurities refers to the crystalline Form G of febuxostat obtained by the process of the present invention having less than 0.001% of genotoxic impurities.
  • the genotoxic impurities include 2-[3-cyano-4- hydroxyphenyl]-4-methylthiazole-5-carboxylic acid ethyl ester, l-bromo-2- methylpropane, ethyl-2-chloroacetoacetate, methyl methane sulfonate, ethyl methane sulfonate, acetoacetic acid ethyl ester, ethyl 2,2-dichloro-3-oxobutanoate, and n-butyl bromide.
  • the amount of the genotoxic impurities in crystalline Form G of febuxostat may be determined using high performance liquid chromatography (HPLC), gas
  • GC chromatography
  • LCMS liquid chromatography mass spectrometry
  • substantially free of the febuxostat ethyl ester impurity refers to the crystalline Form G of febuxostat obtained by the process of the present invention containing less than 0.15% of the febuxostat ethyl ester impurity.
  • substantially free of 2-[3-carbamoyl-4-(2-methylpropoxy)phenyl]-4- methyl-l,3-thiazole-5-carboxylic acid impurity refers to the crystalline Form G of febuxostat obtained by the process of the present invention containing less than 0.15% of the 2-[3-carbamoyl-4-(2-methylpropoxy)phenyl]-4-methyl- 1 ,3-thiazole-5- carboxylic acid impurity.
  • substantially free of residual solvents refers to the crystalline Form G of febuxostat obtained by the process of the present invention containing less than 0.2% of methanol, as determined by gas chromatography (GC).
  • Febuxostat to be used for the preparation of the crystalline Form G of the present invention, may be obtained by any of the processes known in the literature, such as by the process disclosed in U.S. Patent No. 5,614,520.
  • Febuxostat, to be used as starting material for the preparation of the crystalline Form G 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, or it may be isolated from the reaction mixture and then used for the preparation of crystalline Form G.
  • the preparation of the crystalline Form G of the present invention is carried out by dissolving febuxostat in a mixed solvent of methanol and water having a volume ratio of methanol to water from 5:95 to 45:55.
  • the reaction mixture is heated to about 50°C to about 70°C, filtered, and washed with methanol.
  • the combined filtrate is heated to about 50°C to about 70°C.
  • Deionized water is added slowly over a period of not more than 10 minutes.
  • the reaction mixture is stirred at about 45°C to about 65°C for about 1 hour, cooled to about 20°C to about 35°C for about 15 minutes to about 45 minutes, filtered, and washed with deionized water to obtain a wet solid. Deionized water is added.
  • the contents are stirred at about 20°C to about 35°C for about 15 minutes to about 45 minutes, filtered, washed with deionized water, and dried in an air oven at about 40°C to about 45°C to obtain the crystalline Form G of febuxostat of the present invention.
  • crystalline Form G of febuxostat is prepared by dissolving febuxostat in a mixed solvent of methanol and water having a volume ratio of methanol to water of 40:60.
  • crystalline Form G of febuxostat is prepared by dissolving febuxostat in a mixed solvent of methanol and water having a volume ratio of methanol to water of 37.5:62.5.
  • crystalline Form G of febuxostat is prepared by dissolving febuxostat in a mixed solvent of methanol and water having a volume ratio of methanol to water of 35.3:64.7.
  • the crystalline Form G of febuxostat obtained by the process of the present invention is substantially free of genotoxic impurities, febuxostat ethyl ester impurity, and 2-[3-carbamoyl-4-(2-methylpropoxy)phenyl]-4-methyl-l,3-thiazole-5-carboxylic acid impurity.
  • the crystalline Form G of febuxostat obtained by the process of the present invention is substantially free of methanol.
  • the crystalline Form G of febuxostat obtained by the process of the present invention has a particle size distribution wherein the size of 90% of the particles is less than 15 ⁇ .
  • XRPD X-ray Powder Diffraction Patterns
  • the particle size distribution was measured using a Malvern ® Mastersizer ® 2000 instrument equipped with Hydro 2000S(A), flow cell, Fourier lenses, and a multielement detector.
  • HPLC purity was determined using an Atlantis T3, 3 ⁇ column with a flow rate: 1.5 mL/minute; column oven temperature: 50°C; Detector: UV at 320 nm; Injection volume: 10 ⁇ ; Run time: 35 minutes; using orthophosphoric acid as the buffer, and acetonitrile as the diluent.
  • the gas chromatography was performed using a PerkinElmer ® , Clarus ® 500,
  • Agilent ® 7890A (or equivalent) equipped with a flame ionization detector.
  • the liquid chromatography-mass spectrometry was performed using an Applied Biosystems ® API 2000.
  • Example 1 Preparation of crystalline Form G using a mixed solvent of methanol and water having a volume ratio of methanol to water of 37.5:62.5
  • Febuxostat 100 g was added to a reaction vessel containing methanol (1000 mL). The reaction mixture was heated to about 60°C to about 65°C, filtered, and washed with methanol (200 mL). The combined filtrate was heated to about 60°C to about 65°C. Deionized water (2000 mL) was added over a period of not more than 10 minutes. The reaction mixture was stirred at about 50°C to about 60°C for about 1 hour, cooled to about 25°C to about 30°C for about 30 minutes, filtered, and washed with deionized water (200 mL) to obtain a wet solid. Deionized water (1000 mL) was added.
  • reaction mixture was stirred at about 25°C to about 30°C for about 30 minutes, filtered, washed with deionized water (2 x 200 mL), and dried at about 40°C to about 45°C in an air oven to obtain crystalline Form G of febuxostat.
  • Example 2 Preparation of crystalline Form G using a mixed solvent of methanol and water having a volume ratio of methanol to water of 40:60
  • Febuxostat 50 g was added to a reaction vessel containing methanol (500 mL). The reaction mixture was heated to about 60°C to about 65°C, filtered, and washed with methanol (100 mL). The combined filtrate was heated to about 60°C to about 65°C. Deionized water (900 mL) was added over a period of not more than 10 minutes. The reaction mixture was stirred at about 50°C to about 60°C for about 1 hour, cooled to about 25°C to about 30°C for about 30 minutes, filtered, and washed with deionized water (100 mL) to obtain a wet solid. Deionized water (500 mL) was added.
  • reaction mixture was stirred at about 25°C to about 30°C for about 30 minutes, filtered, washed with deionized water (2 x 100 mL), and dried at about 40°C to about 45°C in an air oven to obtain crystalline Form G of febuxostat.
  • Febuxostat 25 g was added to a reaction vessel containing methanol (250 mL). The reaction mixture was heated to about 60°C to about 65°C, filtered, and washed with methanol (50 mL). The combined filtrate was heated to about 60°C to about 65°C.
  • Deionized water (550 mL) was added over a period of not more than 10 minutes. The reaction mixture was stirred at about 50°C to about 60°C for about 1 hour, cooled to about 25°C to about 30°C for about 30 minutes, filtered, and washed with deionized water (50 mL) to obtain a wet solid. Deionized water (250 mL) was added. The reaction mixture was stirred at about 25°C to about 30°C for about 30 minutes, filtered, washed with deionized water (2 x 50 mL), and dried at about 40°C to about 45°C in an air oven to obtain crystalline Form G of febuxostat.

Abstract

Provided herein is a process for the preparation of crystalline Form G of febuxostat in which the crystalline Form G of febuxostat is formed from a mixed solvent of methanol and water having a volume ratio of methanol to water of from 5:95 to 45:55.

Description

PROCESS FOR THE PREPARATION OF CRYSTALLINE FORM G OF
FEBUXOSTAT
Field of the Invention
Provided herein is a process for the preparation of crystalline Form G of febuxostat.
Background of the Invention
Febuxostat is a xanthine oxidase inhibitor known from U.S. Patent No. 5,614,520. It is chemically 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, having the structure as represented by Formula I.
Figure imgf000002_0001
Formula I
U.S. Patent No. 6,225,474 discloses processes for the preparation of the crystalline Form G of febuxostat using a mixed solvent of methanol and water having a volume ratio of methanol to water of 50:50, or by using a mixed solvent of 2-propanol and water having a volume ratio of 2-propanol to water of from about 90: 10 to 50:50.
PCT Publication No. WO 201 1/141933 discloses a process for the preparation of the crystalline Form G of febuxostat using acetone and water.
Japanese Publication No. JP 2003261548 discloses a process for the preparation of the crystalline Form G of febuxostat using a mixed solvent of methanol and water having a volume ratio of methanol to water of 70:30.
U.S. Patent No. 7,361,676 discloses milling for reducing the particle size of the crystalline Form A of febuxostat.
As per the International Conference on Harmonisation (ICH) guidelines for residual solvents in the pharmaceutical products, in order to protect patients from the potential adverse effects due to the inherent toxicity associated with methanol (a Class 2 residual solvent), its amount needs to be limited in the pharmaceutical products.
Further, the presence of genotoxic impurities in a pharmaceutical product is considered to be a serious risk factor due to their potential to damage DNA at any level of exposure which may lead to, or contribute towards, tumor development. Thus, as per the ICH guidelines on the limit of genotoxic impurities in pharmaceutical products, there is a need to control the genotoxic impurities to the lowest possible level in pharmaceutical products.
The particle size of an active pharmaceutical ingredient is also an important aspect that affects the bioavailability of the drugs. For drugs having poor aqueous solubility, e.g., febuxostat, it is desirable that the active pharmaceutical ingredient should have small particle size. A general method for reducing the particle size of an active pharmaceutical ingredient involves carrying out micronization of the active pharmaceutical ingredient. However, carrying out micronization of the active pharmaceutical ingredient sometimes results in agglomeration of the smaller particles to form larger particles, thereby reducing the solubility and bioavailability of the drug. Additionally, since greater energy input is required for carrying out micronization, it sometimes also causes instability and discoloration of the drug substance. Reducing the particle size of the active
pharmaceutical ingredient by micronization also increases the cost of the manufacturing process due to an increase in the manufacturing time and the requirement of additional process controls.
Thus, there exists a need in the art for the development of an eco-friendly, cost- effective, and industrially advantageous process for the preparation of crystalline Form G of febuxostat that involves the use of a lesser amount of methanol as compared to the amount of water, controls the formation of genotoxic impurities, and avoids the need for reducing the particle size by carrying out micronization.
Summary of the Invention
The present invention provides an eco-friendly, cost-effective, and industrially advantageous process for the preparation of crystalline Form G of febuxostat. The process of the present invention involves the use of a mixed solvent of methanol and water having a volume ratio of methanol to water from 5:95 to 45:55. Crystalline form G of febuxostat, obtained by the process of the present invention, is substantially free of genotoxic impurities, ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl- 1 ,3-thiazole-5- carboxylate (hereinafter referred to as "the febuxostat ethyl ester impurity"), 2- [3- carbamoyl-4-(2-methylpropoxy)phenyl]-4-methyl- 1 ,3-thiazole-5-carboxylic acid impurity, and residual solvents. The process of the present invention provides crystalline Form G of febuxostat having a small particle size, without the need for carrying out micronization.
A first aspect of the present invention provides a process for the preparation of crystalline Form G of febuxostat in a mixed solvent of methanol and water having a volume ratio of methanol to water from 5:95 to 45:55.
Embodiments of the process may include one or more of the following features. For example, preparation of the crystalline Form G of febuxostat may be carried out at a temperature of about 50°C to about 70°C.
The crystalline Form G of febuxostat may be substantially free of the genotoxic impurities selected from 2-[3-cyano-4-hydroxyphenyl]-4-methylthiazole-5-carboxylic acid ethyl ester, 1 -bromo-2-methylpropane, ethyl-2-chloroacetoacetate, methyl methane sulfonate, ethyl methane sulfonate, acetoacetic acid ethyl ester, ethyl 2,2-dichloro-3- oxobutanoate, and n-butyl bromide. In particular, the crystalline Form G of febuxostat may be substantially free of the febuxostat ethyl ester impurity, the 2-[3-carbamoyl-4-(2- methylpropoxy)phenyl]-4-methyl-l,3-thiazole-5-carboxylic acid impurity, and/or methanol.
In the process, the volume ratio of methanol to water may be about 37.5:62.5, about 35.3:64.7, or about 40:60. The volume ratio of methanol to water may range from about 35:65 to about 40:60.
A second aspect of the present invention provides crystalline form G of febuxostat, wherein the particle size of 90% of the particles is less than 15 μιη.
Brief Description of Figures
Figure 1 : X-ray powder diffraction (XRPD) pattern of crystalline Form G of febuxostat.
Figure 2: Particle size distribution of crystalline Form G of febuxostat prepared by the process of the present invention. Detailed Description of the Invention
Various embodiments and variants of the present invention are described hereinafter.
Crystalline Form G of febuxostat refers to the crystalline Form G of febuxostat disclosed in U.S. Patent No. 6,225,474, the contents of which are incorporated herein by reference, in particular for data characterizing Form G of febuxostat such as the x-ray diffraction data and infrared spectroscopic absorption data disclosed therein.
The term "about", as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
The term "substantially free of genotoxic impurities", as used herein, refers to the crystalline Form G of febuxostat obtained by the process of the present invention having less than 0.001% of genotoxic impurities. The genotoxic impurities include 2-[3-cyano-4- hydroxyphenyl]-4-methylthiazole-5-carboxylic acid ethyl ester, l-bromo-2- methylpropane, ethyl-2-chloroacetoacetate, methyl methane sulfonate, ethyl methane sulfonate, acetoacetic acid ethyl ester, ethyl 2,2-dichloro-3-oxobutanoate, and n-butyl bromide. The amount of the genotoxic impurities in crystalline Form G of febuxostat may be determined using high performance liquid chromatography (HPLC), gas
chromatography (GC), or liquid chromatography mass spectrometry (LCMS).
The term "substantially free of the febuxostat ethyl ester impurity", as used herein, refers to the crystalline Form G of febuxostat obtained by the process of the present invention containing less than 0.15% of the febuxostat ethyl ester impurity.
The term "substantially free of 2-[3-carbamoyl-4-(2-methylpropoxy)phenyl]-4- methyl-l,3-thiazole-5-carboxylic acid impurity", as used herein, refers to the crystalline Form G of febuxostat obtained by the process of the present invention containing less than 0.15% of the 2-[3-carbamoyl-4-(2-methylpropoxy)phenyl]-4-methyl- 1 ,3-thiazole-5- carboxylic acid impurity.
The term "substantially free of residual solvents", as used herein, refers to the crystalline Form G of febuxostat obtained by the process of the present invention containing less than 0.2% of methanol, as determined by gas chromatography (GC).
Febuxostat, to be used for the preparation of the crystalline Form G of the present invention, may be obtained by any of the processes known in the literature, such as by the process disclosed in U.S. Patent No. 5,614,520. Febuxostat, to be used as starting material for the preparation of the crystalline Form G 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, or it may be isolated from the reaction mixture and then used for the preparation of crystalline Form G.
The preparation of the crystalline Form G of the present invention is carried out by dissolving febuxostat in a mixed solvent of methanol and water having a volume ratio of methanol to water from 5:95 to 45:55. The reaction mixture is heated to about 50°C to about 70°C, filtered, and washed with methanol. The combined filtrate is heated to about 50°C to about 70°C. Deionized water is added slowly over a period of not more than 10 minutes. The reaction mixture is stirred at about 45°C to about 65°C for about 1 hour, cooled to about 20°C to about 35°C for about 15 minutes to about 45 minutes, filtered, and washed with deionized water to obtain a wet solid. Deionized water is added. The contents are stirred at about 20°C to about 35°C for about 15 minutes to about 45 minutes, filtered, washed with deionized water, and dried in an air oven at about 40°C to about 45°C to obtain the crystalline Form G of febuxostat of the present invention.
In one embodiment of the present invention, crystalline Form G of febuxostat is prepared by dissolving febuxostat in a mixed solvent of methanol and water having a volume ratio of methanol to water of 40:60.
In another embodiment of the present invention, crystalline Form G of febuxostat is prepared by dissolving febuxostat in a mixed solvent of methanol and water having a volume ratio of methanol to water of 37.5:62.5.
In yet another embodiment of the present invention, crystalline Form G of febuxostat is prepared by dissolving febuxostat in a mixed solvent of methanol and water having a volume ratio of methanol to water of 35.3:64.7.
The crystalline Form G of febuxostat obtained by the process of the present invention is substantially free of genotoxic impurities, febuxostat ethyl ester impurity, and 2-[3-carbamoyl-4-(2-methylpropoxy)phenyl]-4-methyl-l,3-thiazole-5-carboxylic acid impurity.
The crystalline Form G of febuxostat obtained by the process of the present invention is substantially free of methanol. The crystalline Form G of febuxostat obtained by the process of the present invention has a particle size distribution wherein the size of 90% of the particles is less than 15 μιη.
In the foregoing section, embodiments are described by way of examples to illustrate the processes of the invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of the examples would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.
Methods
The X-ray Powder Diffraction Patterns (XRPD) were recorded using a
PANalytical® X'Pert PRO X-Ray Powder Diffractometer using 3 degree 2Θ to 40 degree 2Θ as scan range, 0.02 as step size, copper radiation, and an X'Celerator as a detector.
The particle size distribution was measured using a Malvern® Mastersizer® 2000 instrument equipped with Hydro 2000S(A), flow cell, Fourier lenses, and a multielement detector.
The HPLC purity was determined using an Atlantis T3, 3μιη column with a flow rate: 1.5 mL/minute; column oven temperature: 50°C; Detector: UV at 320 nm; Injection volume: 10 μί; Run time: 35 minutes; using orthophosphoric acid as the buffer, and acetonitrile as the diluent.
The gas chromatography was performed using a PerkinElmer®, Clarus® 500,
Agilent® 7890A (or equivalent) equipped with a flame ionization detector.
The liquid chromatography-mass spectrometry was performed using an Applied Biosystems® API 2000.
EXAMPLES
Example 1 : Preparation of crystalline Form G using a mixed solvent of methanol and water having a volume ratio of methanol to water of 37.5:62.5
Febuxostat (100 g) was added to a reaction vessel containing methanol (1000 mL). The reaction mixture was heated to about 60°C to about 65°C, filtered, and washed with methanol (200 mL). The combined filtrate was heated to about 60°C to about 65°C. Deionized water (2000 mL) was added over a period of not more than 10 minutes. The reaction mixture was stirred at about 50°C to about 60°C for about 1 hour, cooled to about 25°C to about 30°C for about 30 minutes, filtered, and washed with deionized water (200 mL) to obtain a wet solid. Deionized water (1000 mL) was added. The reaction mixture was stirred at about 25°C to about 30°C for about 30 minutes, filtered, washed with deionized water (2 x 200 mL), and dried at about 40°C to about 45°C in an air oven to obtain crystalline Form G of febuxostat.
Yield: 96.0%
Genotoxic impurities: Not detected
Febuxostat ethyl ester: Not detected
2-[3-carbamoyl-4-(2-methylpropoxy)phenyl]-4-methyl-l,3-thiazole-5-carboxylic acid: Not detected
Residual methanol: Not detected
X-ray Diffraction pattern and particle size distribution of crystalline Form G are provided in Figure 1 and Figure 2, respectively.
Example 2: Preparation of crystalline Form G using a mixed solvent of methanol and water having a volume ratio of methanol to water of 40:60
Febuxostat (50 g) was added to a reaction vessel containing methanol (500 mL). The reaction mixture was heated to about 60°C to about 65°C, filtered, and washed with methanol (100 mL). The combined filtrate was heated to about 60°C to about 65°C. Deionized water (900 mL) was added over a period of not more than 10 minutes. The reaction mixture was stirred at about 50°C to about 60°C for about 1 hour, cooled to about 25°C to about 30°C for about 30 minutes, filtered, and washed with deionized water (100 mL) to obtain a wet solid. Deionized water (500 mL) was added. The reaction mixture was stirred at about 25°C to about 30°C for about 30 minutes, filtered, washed with deionized water (2 x 100 mL), and dried at about 40°C to about 45°C in an air oven to obtain crystalline Form G of febuxostat.
Yield: 96.4% Example 3 : Preparation of crystalline Form G using a mixed solvent of methanol and water having a volume ratio of methanol to water of 35.3:64.7
Febuxostat (25 g) was added to a reaction vessel containing methanol (250 mL). The reaction mixture was heated to about 60°C to about 65°C, filtered, and washed with methanol (50 mL). The combined filtrate was heated to about 60°C to about 65°C.
Deionized water (550 mL) was added over a period of not more than 10 minutes. The reaction mixture was stirred at about 50°C to about 60°C for about 1 hour, cooled to about 25°C to about 30°C for about 30 minutes, filtered, and washed with deionized water (50 mL) to obtain a wet solid. Deionized water (250 mL) was added. The reaction mixture was stirred at about 25°C to about 30°C for about 30 minutes, filtered, washed with deionized water (2 x 50 mL), and dried at about 40°C to about 45°C in an air oven to obtain crystalline Form G of febuxostat.
Yield: 97.0%

Claims

We Claim:
1. A process for the preparation of crystalline Form G of febuxostat in a mixed solvent of methanol and water having a volume ratio of methanol to water from 5:95 to 45:55.
2. The process according to claim 1 , wherein the preparation of the crystalline Form G of febuxostat is carried out at a temperature of about 50°C to about 70°C.
3. The crystalline Form G of febuxostat of claim 1, substantially free of the genotoxic impurities selected from 2-[3-cyano-4-hydroxyphenyl]-4-methylthiazole-5-carboxylic acid ethyl ester, 1 -bromo-2-methylpropane, ethyl-2-chloroacetoacetate, methyl methane sulfonate, ethyl methane sulfonate, acetoacetic acid ethyl ester, ethyl 2,2-dichloro-3- oxobutanoate, and n-butyl bromide.
4. The crystalline Form G of febuxostat of claim 1 , substantially free of the febuxostat ethyl ester impurity.
5. The crystalline Form G of febuxostat of claim 1, substantially free of the 2-[3- carbamoyl-4-(2-methylpropoxy)phenyl]-4-methyl- 1 ,3-thiazole-5-carboxylic acid impurity.
6. The crystalline Form G of febuxostat of claim 1 , substantially free of methanol.
7. The crystalline Form G of febuxostat of claim 1 , wherein the particle size of 90% of the particles is less than 15 μιη.
8. The crystalline Form G of febuxostat of claim 1, wherein the volume ratio of methanol to water is about 37.5:62.5.
9. The crystalline Form G of febuxostat of claim 1, wherein the volume ratio of methanol to water is about 35.3:64.7.
10. The crystalline Form G of febuxostat of claim 1, wherein the volume ratio of methanol to water is about 40:60.
11. The crystalline Form G of febuxostat of claim 1, wherein the volume ratio of methanol to water is about 35:65 to about 40:60.
PCT/IB2013/059285 2012-10-11 2013-10-10 Process for the preparation of crystalline form g of febuxostat WO2014057461A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106397352A (en) * 2016-09-06 2017-02-15 浙江华海药业股份有限公司 Method for preparing febuxostat G crystal form
CN108033929A (en) * 2017-12-27 2018-05-15 青岛黄海制药有限责任公司 A kind of synthetic method of gout suppressant Febustat intermediate impurities and its application for synthesizing impurity
CN112390766A (en) * 2019-08-13 2021-02-23 浙江天宇药业股份有限公司 Preparation method of febuxostat crystal form A

Citations (5)

* Cited by examiner, † Cited by third party
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
JP2003261548A (en) 2002-03-07 2003-09-19 Teijin Ltd Method of producing polymorphic crystal of 2-(3-cyano-4- isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid
US7361676B2 (en) 2002-03-28 2008-04-22 Teijin Limited Solid preparation containing single crystal form
WO2011141933A2 (en) 2010-05-12 2011-11-17 Msn Laboratories Limited Process for preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid and its pharmaceutically acceptable salts

Patent Citations (5)

* Cited by examiner, † Cited by third party
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
JP2003261548A (en) 2002-03-07 2003-09-19 Teijin Ltd Method of producing polymorphic crystal of 2-(3-cyano-4- isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid
US7361676B2 (en) 2002-03-28 2008-04-22 Teijin Limited Solid preparation containing single crystal form
WO2011141933A2 (en) 2010-05-12 2011-11-17 Msn Laboratories Limited Process for preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid and its pharmaceutically acceptable salts

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106397352A (en) * 2016-09-06 2017-02-15 浙江华海药业股份有限公司 Method for preparing febuxostat G crystal form
CN108033929A (en) * 2017-12-27 2018-05-15 青岛黄海制药有限责任公司 A kind of synthetic method of gout suppressant Febustat intermediate impurities and its application for synthesizing impurity
CN112390766A (en) * 2019-08-13 2021-02-23 浙江天宇药业股份有限公司 Preparation method of febuxostat crystal form A
CN112390766B (en) * 2019-08-13 2022-09-06 浙江天宇药业股份有限公司 Preparation method of febuxostat crystal form A

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