WO2011080651A2

WO2011080651A2 - Polymorphic forms of febuxostat

Info

Publication number: WO2011080651A2
Application number: PCT/IB2010/055897
Authority: WO
Inventors: Ram Thaimattam; Pranab Kishore Dash; Raghvendra Prasad; Subhash Dhar
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2009-12-31
Filing date: 2010-12-16
Publication date: 2011-07-07
Also published as: WO2011080651A3

Abstract

The present invention provides crystalline forms of febuxostat, processes for their preparation, pharmaceutical compositions comprising them and their use for chronic management of hyperuricemia in patients with gout.

Description

POLYMORPHIC FORMS OF FEBUXOSTAT

Field of the Invention

The present invention provides crystalline forms of febuxostat, processes for their preparation, pharmaceutical compositions comprising them and their use for the chronic management of hyperuricemia in patients with gout.

Background of the Invention

Febuxostat is a non-purine xanthine oxidase inhibitor known from U.S. Patent No. 5,614,520. It is chemically described as 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4- methylthiazole-5-carboxylic acid, and has a structure as represented by Formula I.

FORMULA I

Febuxostat is marketed in the United States under the brand name Uloric for the chronic management of hyperuricemia in patients with gout.

Crystalline Forms A, B, C, D, G, H, I, J, K and Form I and Form II of febuxostat are disclosed in U.S. Patent No. 6,225,474; WO 2008/067773; and Chinese Patent Nos. 101139325, 101085761 and 101386605. The processes described in the above references involve the preparation of crystalline forms of febuxostat using a mixture of methanol, ethanol or propanol with water, acetonitrile, acetone, ethyl acetate or 1,4-dioxane solvents.

Summary of the Invention

In one general aspect, the present invention provides for crystalline Form Rl of febuxostat, which includes X-ray diffraction peaks at d-spacing of about 15.11, 10.07, 7.56, 7.19 and 6.04 A.

Embodiments of this aspect may include one or more of the following features. For example, the crystalline Form of Rl may further include X-ray diffraction peaks at d- spacing of about 7.37 A, 5.04 A, 3.75 A, 3.53 A and 3.07 A. The crystalline Form of Rl may include an X-ray diffraction pattern as depicted in Figure 1. In addition, the crystalline Form Rl of febuxostat may include a DSC having endotherms at about 189.05°C, 201.50°C and 209.38°C, a DSC as depicted in Figure 7, and/or a TGA as depicted in Figure 9.

In another general aspect, the present invention provides for crystalline Form R2 of febuxostat, which includes X-ray diffraction peaks at d-spacing 12.31, 6.15, 5.46, 3.77 and 3.37 A.

Embodiments of this aspect may include one or more of the following features. For example, the crystalline Form R2 may further include X-ray diffraction peaks at d- spacing of about 4.10 A, 4.05 A, 3.94 A, 3.90 A and 3.10 A. The crystalline Form R2 may include an X-ray diffraction pattern as depicted in Figure 2.

In another general aspect, the present invention provides for crystalline Form R3 of febuxostat, which includes X-ray diffraction peaks at d-spacing of about 11.45, 7.63, 3.57, 3.54 and 3.43 A.

Embodiments of this aspect may include one or more of the following features. For example, the crystalline Form R3 may further include X-ray diffraction peaks at d- spacing of about 9.87 A, 6.90 A, 4.92 A, 4.85 A and 3.81 A. The crystalline Form R3 of febuxostat may also include an X-ray diffraction pattern as depicted in Figure 3.

In another general aspect, the present invention provides for crystalline Form R4 of febuxostat, which includes X-ray diffraction peaks at d-spacing of about 15.96, 14.60, 7.97, 7.78 and 3.52 A.

Embodiments of this aspect may include one or more of following features. For example, the crystalline Form R4 may further include X-ray diffraction peaks at d-spacing of about 7.29 A, 5.31 A, 5.21 A, 3.45 A and 3.39 A. The crystalline Form R4 of febuxostat may also include an X-ray diffraction pattern as depicted in Figure 4. Further, the crystalline Form R4 of febuxostat may include endotherms at about 92.23°C, 199.71°C and 209.22°C, a DSC as depicted in Figure 8, and/or a TGA as depicted in Figure 10.

In another general aspect, the present invention provides for crystalline Form R5 of febuxostat, which includes X-ray diffraction peaks at d-spacing of about 11.96, 5.98, 5.01 and 3.34 A.

Embodiments of this aspect may include one or more of the following features. For example, the crystalline Form R5 may further include X-ray diffraction peaks at d- spacing of about 7.94 A, 5.29 A, 3.99 A and 3.42 A. The crystalline Form R5 of febuxostat may include an X-ray diffraction pattern as depicted in Figure 5.

In another general aspect, the present invention provides for a process for the preparation of crystalline Form Rl of febuxostat. The process includes the steps of:

i) contacting febuxostat with a chlorinated solvent;

ii) optionally adding an anti-solvent; and

iii) isolating crystalline Form Rl.

Embodiments of this aspect may include one or more of the following features. For example, the febuxostat to be used as starting material for the preparation of crystalline Form Rl is obtained as a solution directly from a reaction in which it is formed and is used as such without isolation.

The chlorinated solvent may be dichloromethane or chloroform. The febuxostat is contacted with the chlorinated solvent at a temperature of about 15°C to the reflux temperature of the solvent. The crystallization is carried out by cooling the reaction mixture containing the febuxostat in the chlorinated solvent to about -10°C to about 25°C. The crystallization may also be carried out by adding an anti-solvent selected from hydrocarbons, alkyl acetates, or mixtures thereof, to the solution of the febuxostat in the chlorinated solvent. The hydrocarbon solvent is selected from hexane, cyclohexane, benzene, toluene, heptanes or octane. A seed crystal of crystalline Form Rl may also be added to the solution of the febuxostat in the chlorinated solvent.

In another general aspect, the present invention provides for a process for the preparation of crystalline Form R2 of febuxostat. The process includes contacting febuxostat with a sulphoxide solvent.

Embodiments of this aspect may include one or more of the following features. For example, the febuxostat to be used as starting material for the preparation of crystalline Form R2 is obtained as a solution directly from a reaction in which it is formed and is used as such without isolation. The sulphoxide solvent is selected from dimethyl sulphoxide or diethyl sulphoxide. The febuxostat is contacted with the sulphoxide solvent at a temperature of about 40°C to about 80°C. The crystallization is carried out by cooling the reaction mixture containing the febuxostat in the sulphoxide solvent to about -10°C to about 35°C.

In another general aspect, the present invention provides for a process for the preparation of crystalline Form R3 of febuxostat. The process includes contacting febuxostat with an amide solvent.

Embodiments of this aspect may include one or more of the following features. For example, the febuxostat to be used as starting material for the preparation of crystalline Form R3 is obtained as a solution directly from a reaction in which it is formed and is used as such without isolation. The amide solvent may be selected from N, N- dimethylformamide or N, N-dimethylacetamide. The febuxostat may be contacted with the amide solvent at a temperature of about 40°C to about 80°C. The crystallization is carried out by cooling the reaction mixture containing the febuxostat in the amide solvent to about 15°C to about 35°C.

In another general aspect, the present invention provides for a process for the preparation of crystalline Form R4 of febuxostat. The process includes the steps of:

i) contacting febuxostat with a ketone or ether solvent;

ii) optionally adding an anti-solvent; and

iii) isolating crystalline Form R4.

Embodiments of this aspect may include one or more of the following features. For example, the febuxostat to be used as starting material for the preparation of crystalline Form R4 is obtained as a solution directly from a reaction in which it is formed and is used as such without isolation.

The ketone solvent is selected from acetone, dimethyl ketone, ethyl methyl ketone or methyl iso-butyl ketone. The ether solvent is selected from diethyl ether, ethyl methyl ether, di-isopropyl ether, tetrahydrofuran or 1,4-dioxane. The febuxostat is contacted with the ketone or the ether solvent at a temperature of about 15°C to about 35°C.

The crystallization may be carried out by adding an anti- solvent selected from hydrocarbons, alkyl acetates, or mixtures thereof, to the solution of febuxostat in a ketone or ether. The hydrocarbon solvent is selected from hexane, cyclohexane, benzene, toluene, heptanes or octane.

In another general aspect, the present invention provides for a process for the preparation of crystalline Form R5 of febuxostat. The process includes the steps of:

i) contacting febuxostat with a carboxylic acid solvent;

ii) optionally adding an anti-solvent; and

iii) isolating crystalline Form R5.

Embodiments of this aspect may include one or more of the following features. For example, the febuxostat to be used as starting material for the preparation of crystalline Form R5 is obtained as a solution directly from a reaction in which it is formed and is used as such without isolation.

The carboxylic acid solvent is selected from formic acid, acetic acid or propionic acid. The febuxostat is contacted with carboxylic acid solvent at about 25°C to about 80°C. The crystallization may be carried out by cooling the reaction mixture containing the febuxostat in the carboxylic acid solvent to a temperature of about 15°C to about 35°C. The crystallization may also be carried out by adding an anti-solvent selected from hydrocarbons, alkyl acetates, or mixtures thereof, to a reaction mixture containing febuxostat in a carboxylic acid solvent.

The hydrocarbon solvent is selected from hexane, cyclohexane, benzene, toluene, heptanes or octane.

In another general aspect, the present invention provides for a pharmaceutical composition that includes one or more of crystalline Form Rl, R2, R3, R4 or R5 of febuxostat and one or more pharmaceutically acceptable carriers, diluents or excipients.

In a final general aspect, the present invention provides for a method of treating hyperuricemia. The method includes administering a pharmaceutical composition that includes one or more of crystalline Form Rl, R2, R3, R4 or R5 of febuxostat and one or more pharmaceutically acceptable carriers, diluents, or excipients. Brief Description of the Figures

Figure 1: X-ray diffraction (XRD) spectrum of crystalline Form Rl

Figure 2: X-ray diffraction spectrum of crystalline Form R2

Figure 3: X-ray diffraction spectrum of crystalline Form R3

Figure 4: X-ray diffraction spectrum of crystalline Form R4

Figure 5: X-ray diffraction spectrum of crystalline Form R5

Figure 6: Differential Scanning Thermogram (DSC) of crystalline Form Rl

Figure 7: Differential Scanning Thermogram of crystalline Form R4

Figure 8: Thermogravimetric Analysis (TGA) of crystalline Form Rl

Figure 9: Thermogravimetric Analysis of crystalline Form R4

Detailed Description of the Invention

Crystalline Form Rl of febuxostat may be characterized by XRD peaks at about 5.84 (d-spacing at 15.11 A), 8.77 (10.07 A), 11.70 (7.56 A), 12.29 (7.19 A) and 14.64 (6.04 A) + 0.2° 2Θ. It may be further characterized by XRD peaks at about 11.99 (7.37 A), 17.58 (5.04 A), 23.71 (3.75 A), 25.20 (3.53 A) and 29.07 (3.07 A) + 0.2° 2Θ. Crystalline Form Rl of febuxostat may also be characterized by XRD pattern as depicted in Figure 1.

Table 1 below summarizes the d-spacing in A and the corresponding 2Θ values.

Crystalline Form Rl may also be characterized by a DSC having endotherms at about 189.05°C, 201.50°C and 209.38°C. Crystalline Form Rl may also be characterized by the DSC as depicted in Figure 7 or the TGA as depicted in Figure 9.

Table 1: XRD Peaks of Crystalline Form Rl

Crystalline Form R2 of febuxostat may be characterized by XRD peaks at about 7.17 (12.31 A), 14.38 (6.15 A), 16.21 (5.46 A), 23.59 (3.77 A) and 26.44 (3.37 A) + 0.2° 2Θ. It may be further characterized by XRD peaks at about 21.64 (4.10 A), 21.89 (4.05 A), 22.56 (3.94 A), 22.77 (3.90 A) and 28.74 (3.10 A) + 0.2° 2Θ. Crystalline Form R2 of febuxostat may also be characterized by the XRD pattern as depicted in Figure 2. Table 2 below summarizes the d-spacing in A and the corresponding 2Θ values. Table 2: XRD Peaks of Crystalline Form R2

Position (°2Θ) d-spacing (A) Relative Intensity ( )

7.17 12.31 100.00

8.25 10.72 0.99

10.66 8.30 3.27

11.23 7.88 1.22

11.73 7.54 2.48

12.06 7.34 1.14

13.89 6.38 5.95

14.38 6.15 26.64

14.88 5.95 0.80

15.35 5.77 2.59

16.21 5.46 38.08

16.98 5.22 3.20

17.27 5.13 3.45

17.70 5.01 0.68

18.82 4.71 1.59

19.45 4.56 3.55

21.09 4.21 3.81

21.64 4.10 5.44

21.89 4.05 4.01

22.20 4.00 3.47

22.56 3.94 5.81

22.77 3.90 6.45

22.99 3.87 1.86

23.59 3.77 21.02

24.40 3.65 2.16

24.81 3.59 5.42

25.64 3.47 1.34

26.44 3.37 20.45

27.66 3.22 1.58

28.31 3.15 2.66

28.74 3.10 3.97

28.97 3.08 2.64

29.60 3.02 1.67

29.85 2.99 1.58

30.85 2.90 1.13

31.71 2.82 1.56

32.23 2.78 0.93

32.78 2.73 1.54

33.50 2.68 1.22

34.23 2.62 1.05

35.06 2.56 1.14

36.06 2.49 1.12

36.48 2.46 2.79

37.51 2.40 1.14

38.18 2.36 1.15

39.66 2.27 1.72 Crystalline Form R3 of febuxostat may be characterized by XRD peaks at about 7.72 (11.45 A), 11.59 (7.63 A), 24.88 (3.57 A), 25.10 (3.54 A) and 25.90 (3.43 A) + 0.2° 2Θ. It may be further characterized by XRD peaks at about 8.95 (9.87 A), 12.81 (6.90 A), 17.99 (4.92 A), 18.27 (4.85 A) and 23.31 (3.81 A) + 0.2° 2Θ. Crystalline Form R3 of febuxostat may also be characterized by the XRD pattern as depicted in Figure 3. Table 3 below summarizes the d- spacing in A and the corresponding 2Θ values. Table 3: XRD Peaks of Crystalline Form R3

Position (°2Θ) d-spacing (A) Relative Intensity ( )

3.85 22.95 6.59

4.81 18.37 0.81

7.49 11.80 17.17

7.72 11.45 65.89

8.45 9.87 5.41

9.90 8.93 5.73

11.59 7.63 100.00

12.81 6.90 14.05

13.20 6.71 2.21

13.63 6.50 1.79

14.57 6.08 3.63

14.97 5.92 3.56

15.24 5.81 3.27

15.50 5.72 2.61

15.82 5.60 10.01

16.10 5.50 3.07

16.68 5.32 4.31

16.93 5.23 3.36

17.60 5.04 7.23

17.99 4.92 22.31

18.27 4.85 23.02

19.45 4.56 7.87

20.07 4.42 9.08

20.46 4.34 7.45

20.90 4.25 3.32

21.56 4.12 3.61

22.38 3.97 10.49

22.64 3.93 7.33

23.31 3.81 15.66

23.60 3.77 7.48

23.89 3.72 5.67

24.31 3.66 5.84

24.88 3.57 57.92

25.10 3.54 42.96

25.90 3.43 39.28 Position (°2Θ) d-spacing (A) Relative Intensity ( )

26.51 3.36 11.73

27.16 3.28 9.61

27.41 3.25 9.49

27.70 3.22 9.29

28.26 3.16 4.37

29.34 3.04 6.35

29.85 2.99 8.08

30.13 2.97 7.98

31.06 2.88 5.59

31.52 2.84 4.89

32.62 2.75 3.99

33.31 2.69 5.92

34.38 2.61 3.76

35.92 2.50 4.45

36.40 2.47 4.25

36.65 2.45 4.51

37.89 2.37 4.45

38.66 2.33 4.20

Crystalline Form R4 of febuxostat may be characterized by XRD peaks at about 5.53 (15.96 A), 6.05 (14.60 A), 11.09 (7.97 A), 11.36 (7.78 A) and 25.25 (3.52 A) and + 0.2° 2Θ. It may be further characterized by XRD peaks at about 12.14 (7.29 A), 16.67 (5.31 A), 16.99 (5.21 A), 25.78 (3.45 A) and 26.24 (3.39 A) + 0.2° 2Θ. Crystalline Form R4 of febuxostat may also be characterized by the XRD pattern as depicted in Figure 4.

Table 4 below summarizes the d-spacing in A and the corresponding 2Θ values.

Crystalline Form R4 may also be characterized by a DSC having endotherms at about 92.23°C, 199.71°C and 209.22°C. Crystalline Form R4 may also be characterized by the DSC as depicted in Figure 8 or the TGA as depicted in Figure 10.

Table 4: XRD Peaks of Crystalline Form R4

Position (°2Θ) d-spacing (A) Relative Intensity ( )

3.70 23.91 15.46

4.90 18.04 12.36

5.53 15.96 91.05

6.05 14.60 91.75

7.38 11.98 6.36

7.85 11.26 0.89

8.63 10.25 3.59

9.20 9.61 1.72

9.66 9.16 1.28

10.17 8.70 3.29

11.09 7.97 100.00

11.36 7.78 94.44

12.14 7.29 34.23

12.57 7.04 14.04

12.86 6.89 14.49

15.32 6.65 5.35

14.07 6.30 5.85

14.73 6.02 4.36

15.88 5.58 9.90

16.67 5.31 56.82

16.99 5.21 22.75

17.71 5.01 14.91

18.24 4.86 9.14

19.67 4.51 10.13

20.81 4.27 17.18

21.56 4.12 5.27

22.81 3.90 13.39

23.46 3.79 5.97

24.48 3.64 6.44

25.25 3.52 68.96

25.78 3.45 21.21

26.24 3.39 24.04

26.61 3.35 19.32

27.63 3.23 13.32

29.80 3.00 4.53

30.59 2.92 4.13

32.20 2.78 2.28

33.70 2.66 1.42

35.93 2.50 2.11

37.29 2.41 1.31 Crystalline Form R5 of febuxostat may be characterized by XRD peaks at about 7.38 (11.96 A), 14.79 (5.98 A), 17.68 (5.01 A) and 26.64 (3.34 A) + 0.2° 2Θ. It may be further characterized by the XRD peaks at about 11.14 (7.94 A), 16.73 (5.29 A), 22.24 (3.99 A) and 25.99 (3.42 A) + 0.2° 2Θ. Crystalline Form R5 of febuxostat may also be characterized by XRD pattern as depicted in Figure 5. Table 5 below summarizes the d- spacing in A and the corresponding 2Θ values. Table 5: XRD Peaks of Crystalline Form R5

Position (°2Θ) d-spacing (A) Relative Intensity ( )

4.84 18.24 0.30

6.66 13.27 0.16

7.38 11.96 100.00

8.82 10.03 2.12

11.14 7.94 3.83

11.86 7.46 2.63

13.90 6.37 0.35

14.79 5.98 10.94

15.32 5.78 0.20

16.73 5.29 5.47

17.07 5.19 0.24

17.68 5.01 6.22

18.34 4.84 0.70

18.83 4.71 0.59

19.60 4.53 1.37

20.31 4.37 0.33

22.24 3.99 4.45

22.84 3.89 0.39

23.42 3.80 1.77

23.71 3.75 0.54

24.43 3.64 0.60

24.66 3.61 1.01

25.62 3.48 1.08

25.99 3.42 3.82

26.64 3.34 17.16

27.42 3.25 1.12

28.34 3.15 0.39

28.79 3.10 0.37

29.41 3.04 1.01

29.81 3.00 1.99

30.53 2.93 0.30

31.03 2.88 0.27

31.43 2.85 0.79

31.96 2.80 0.27

32.42 2.76 0.79 32.67 2.74 0.49

33.34 2.69 0.30

34.01 2.64 1.35

35.54 2.53 1.69

35.79 2.51 6.20

36.10 2.49 4.19

36.74 2.45 0.49

37.04 2.43 0.51

37.50 2.40 0.96

37.97 2.37 0.42

38.29 2.35 0.56

39.09 2.30 0.40

Febuxostat, to be used for the preparation of crystalline forms 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. 5,614520, U.S. Publication 2009/0203919 or U.S. Patent 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.

The term "contacting" may include dissolving, slurrying, stirring, or a combination thereof.

Febuxostat may be contacted with a solvent at a temperature of about 15°C to the reflux temperature of the solvent. The solvent may be C₃-C₁₀ alcohols, carboxylic acids, chlorinated hydrocarbons, ketones, amides, sulphoxides, ethers, 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 . Crystallization may be carried out by cooling the reaction mixture containing febuxostat in a solvent to a temperature of about -10°C to about 10°C. Crystallization may also be carried out by allowing the reaction mixture containing febuxostat to stand at a temperature of about 15°C to about 40°C for about 1 hour to about 2 weeks.

Crystallization may also be carried out by adding an anti- solvent to a solution of febuxostat in a solvent.

The anti-solvent may be selected from hydrocarbons, alkyl acetates, or mixtures thereof. Examples of hydrocarbons may include hexane, cyclohexane, benzene, toluene, heptane or octane. Examples of alkyl acetates may include ethyl acetate, propyl acetate, or butyl acetate.

In some embodiments, the crystalline form(s) of the present invention may be prepared by dissolving febuxostat in a solvent and cooling the solution to a temperature of about -10°C to about 10°C. In other embodiments, the crystalline form(s) of the present invention may be prepared by dissolving febuxostat in a solvent and allowing the solution to stand at a temperature of about 15°C to about 40°C for about 1 hour to about 2 weeks.

In other embodiments, the crystalline form(s) of the present invention may be prepared by adding an anti-solvent to a solution of febuxostat in a solvent and optionally cooling the reaction mixture to a temperature of about 0°C to about 10°C.

In other embodiments, the crystalline form(s) of the present invention may be prepared by suspending febuxostat in a solvent and cooling the solution to a temperature of about -10°C to about 10°C. In other embodiments, the crystalline form(s) of the present invention may be prepared by suspending febuxostat in a solvent and allowing the solution to stand at a temperature of about 15°C to about 40°C for about 1 hour to about 2 weeks. In other embodiments, the crystalline form(s) of the present invention may be prepared by adding an anti-solvent to a suspension of febuxostat in a solvent. A seed crystal may also be added for obtaining the crystalline form(s) of febuxostat of the present invention. The seed crystal may be prepared by the methods described herein for the preparation of the crystalline form(s) of the present invention.

Isolation may be accomplished by concentration, precipitation, cooling, filtration or centrifugation followed by drying. Any suitable method of drying may be employed, such as, drying under reduced pressure, vacuum tray drying, air drying, or a combination thereof. The crystalline form(s) may be dried 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 4 hours.

In one embodiment, the present invention provides a process for the preparation of crystalline Form Rl by dissolving febuxostat in a chlorinated hydrocarbon solvent at a temperature of about 25 °C to about 60°C and cooling to a temperature of about -10°C to about 10°C. For example, crystalline Form Rl may be prepared by dissolving febuxostat in a chlorinated hydrocarbon solvent at a temperature of about 40°C and cooling to a temperature of about 0°C to about 5°C. The chlorinated solvent may be selected from dichloromethane or chloroform, preferably, dichloromethane.

In another embodiment, the present invention provides a process for the preparation of crystalline Form Rl by dissolving febuxostat in a chlorinated hydrocarbon at a temperature of 25 °C to about 60°C and allowing the solution to stand at a temperature of about 20°C to about 25°C for complete evaporation. For example, crystalline Form Rl may be prepared by dissolving febuxostat in a chlorinated hydrocarbon solvent at a temperature of about 40°C and allowing the solution to stand at a temperature of about 20°C to about 25°C for complete evaporation. The chlorinated solvent may be selected from dichloromethane or chloroform, preferably, dichloromethane.

In another embodiment, the present invention provides a process for the preparation of crystalline Form Rl by dissolving febuxostat in a chlorinated hydrocarbon at a temperature of 25°C to about 60°C and adding an anti-solvent to the solution. For example, crystalline Form Rl may be prepared by dissolving febuxostat in a chlorinated hydrocarbon solvent at a temperature of about 40°C and adding an anti-solvent to the solution. Crystalline Form Rl may also be prepared by dissolving febuxostat in a chlorinated hydrocarbon solvent at a temperature of about 40°C, adding an anti-solvent and cooling the reaction mixture to a temperature of about 5°C. Crystalline Form Rl may also be prepared by seeding. The chlorinated solvent may be selected from

dichloromethane or chloroform, preferably, dichloromethane. The anti-solvent may be selected from hydrocarbons, alkyl acetates, or mixtures thereof. For example, hydrocarbons, such as, hexane, cyclohexane, benzene, toluene, heptane or octane may be used as anti-solvent. For example, the anti-solvent may be heptane. In another embodiment, the present invention provides a process for the preparation of crystalline Form Rl by stirring a suspension of febuxostat in a chlorinated solvent at about 25 °C to about 60°C for about 3 hours to about 10 hours. For example, crystalline Form Rl may be prepared by stirring a suspension of febuxostat in a chlorinated solvent at about 40°C for about 6 hours. The chlorinated solvent may be selected from dichloromethane or chloroform, preferably, dichloromethane.

In another embodiment, the present invention provides a process for the preparation of crystalline Form R2 by dissolving febuxostat in a sulphoxide solvent at a temperature of about 40°C to about 80°C and allowing the solution to stand at a temperature of about 15°C to about 35°C for about 30 minutes to about 5 hours. For example, crystalline Form R2 may be prepared by dissolving febuxostat in a sulphoxide solvent at a temperature of about 65 °C and allowing the solution to stand at a temperature of about 15°C to about 35°C for about 3 hours. The sulphoxide solvent may be selected from dimethyl sulfoxide or diethyl sulphoxide, preferably, dimethyl sulfoxide.

In another embodiment, the present invention provides a process for the preparation of crystalline Form R2 by dissolving febuxostat in a sulphoxide solvent at a temperature of about 40°C to about 80°C and cooling in an ice bath for about 1 hour. For example, crystalline Form R2 may be prepared by dissolving febuxostat in the sulphoxide solvent at a temperature of about 65 °C and cooling in an ice bath for about 15 minutes. The sulphoxide solvent may be selected from dimethyl sulfoxide or diethyl sulphoxide, preferably, dimethyl sulfoxide.

In another embodiment, the present invention provides a process for the preparation of crystalline Form R2 by dissolving febuxostat in sulphoxide solvent at a temperature of about 40°C to about 80°C and allowing the solution to stand at a temperature of about 15°C to about 35°C for about 12 hours to about 36 hours. For example, crystalline Form R2 may be prepared by dissolving febuxostat in a sulphoxide solvent at a temperature of about 65 °C and allowing the solution to stand at a temperature of about 15°C to about 35°C for about 24 hours. The sulphoxide solvent may be selected from dimethyl sulfoxide or diethyl sulphoxide, preferably, dimethyl sulfoxide.

In another embodiment, the present invention provides a process for the preparation of crystalline Form R3 by dissolving febuxostat in an amide solvent at a temperature of about 40°C to about 80°C and allowing the solution to stand at a temperature of about 15°C to about 35°C for about 12 hours to about 36 hours. For example, crystalline Form R3 may be prepared by dissolving febuxostat in an amide solvent at a temperature of about 65 °C and allowing the solution to stand at a temperature of about 15°C to about 35°C for about 24 hours. The amide solvent may be selected from N, N-dimethylformamide or N, N-dimethylacetamide, preferably, N, N- dimethylf ormamide .

In another embodiment, the present invention provides a process for the

preparation of crystalline Form R3 by dissolving febuxostat in an amide solvent at a temperature of about 40°C to about 80°C and allowing the solution to stand at a temperature of about 15°C to about 35°C for about 1 week. For example, crystalline Form R3 may be prepared by dissolving febuxostat in an amide solvent at a temperature of about 65°C and allowing the solution to stand at a temperature of about 15°C to about 35°C for about 1 week. The amide solvent may be selected from N, N-dimethylformamide or N, N- dimethylacetamide, preferably, N, N-dimethylformamide.

In another embodiment, the present invention provides a process for the

preparation of crystalline Form R4 by adding a solution of febuxostat in a ketone or ether solvent to an anti-solvent at a temperature of about 15°C to about 35°C. The ketone may be selected from, such as acetone, dimethyl ketone, ethyl methyl ketone or methyl iso- butyl ketone, preferably, methyl iso-butyl ketone. The ether may be selected from diethyl ether, ethyl methyl ether, di-isopropyl ether, tetrahydrofuran or 1,4-dioxane. The anti- solvent may be selected from hydrocarbons, alkyl acetates or mixtures thereof. For example, hydrocarbons, such as hexane, cyclohexane, benzene, toluene, heptane or octane may be used as anti-solvent. More preferably, the anti-solvent may be cyclohexane.

In a preferred embodiment, crystalline Form R4 may be prepared by adding a solution of febuxostat in methyl iso-butyl ketone to cyclohexane. For example, crystalline Form R4 may be prepared by adding a solution of febuxostat in tetrahydrofuran to cyclohexane.

In another embodiment, the present invention provides a process for the

preparation of crystalline Form R5 by dissolving febuxostat in a carboxylic acid at a temperature of about 40°C to about 80°C and allowing the solution to stand at about 15°C to about 35°C for about 30 minutes to about 5 hours. For example, crystalline Form R5 may be prepared by dissolving febuxostat in a carboxylic acid at a temperature of about 65°C and allowing the solution to stand at about 15°C to about 35°C for about 3 hours. The carboxylic acid may be selected from formic acid, acetic acid or propionic acid, preferably, acetic acid.

In another embodiment, the present invention provides a process for the preparation of crystalline Form R5 by adding a solution of febuxostat in a carboxylic acid to an anti-solvent at a temperature of about 15°C to about 35°C and allowing the solution to stand for about 12 hours to about 24 hours. The carboxylic acid may be selected from formic acid, acetic acid or propionic acid. For example, acetic acid may be used. The anti-solvent may be selected from hydrocarbons, alkyl acetates, or mixtures thereof.

Hydrocarbons, such as hexane, cyclohexane, benzene, toluene, heptane or octane may be used as anti-solvent. For example, the anti-solvent may be heptane.

In another embodiment, the present invention provides a process for the preparation of crystalline Form R5 by adding a solution of febuxostat, prepared by dissolving febuxostat in a carboxylic acid solvent at a temperature of about 40°C to about 80°C, to an anti-solvent at a temperature of about 15°C to about 35°C and allowing the solution to stand for about 12 hours to about 24 hours. For example, crystalline Form R5 may be prepared by adding a solution of febuxostat, prepared by dissolving febuxostat in a carboxylic acid solvent at a temperature of about 65°C, to an anti-solvent at a temperature of about 15°C to about 35°C and allowing the solution to stand for about 12 hours to about 24 hours. The carboxylic acid may be selected from formic acid, acetic acid or propionic acid. Preferably, acetic acid may be used. The anti-solvent may be selected from hydrocarbons, alkyl acetates, or mixtures thereof. Hydrocarbons, such as hexane, cyclohexane, benzene, toluene, heptane or octane may be used as anti- solvent. For example, the anti-solvent may be cyclohexane.

In another embodiment, the present invention provides a process for the preparation of crystalline Form R5 by stirring a suspension of febuxostat in a carboxylic acid solvent at about 40°C to about 80°C for about 3 hours to about 12 hours. For example, crystalline Form R5 may be prepared by stirring a suspension of febuxostat in a carboxylic acid solvent at about 60°C for about 8 hours. The carboxylic acid may be selected from formic acid, acetic acid or propionic acid. For example, acetic acid may be used.

The crystalline forms of febuxostat of the present invention may be converted into amorphous form of febuxostat by evaporation of the solvent, spray drying, freeze-drying or lyophilization.

Solvates, pseudomorphs and hydrates of crystalline forms of the present invention are also included within the scope of the present invention. In experiments where the yield is more than the input material, it may be a solvate form, which is also included within the scope of the present invention.

The crystalline forms 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. Accordingly, in a further aspect, there are provided pharmaceutical compositions that include the crystalline forms of febuxostat of the present invention, and one or more pharmaceutically acceptable carriers, diluents or excipients, and optionally, other therapeutic ingredients. The crystalline forms of febuxostat of the present invention may conventionally be formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed, for example, peroral or parental.

In the foregoing section, embodiments are described by way of examples to illustrate the processes of 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 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° 2Θ as range.

The DSC and TGA were recorded using Mettler Toledo DSC 82 le and

TA instrument- Q 500, respectively. EXAMPLES

Example 1: Preparation of Crystalline Form Rl of Febuxostat

Febuxostat (1 g) was dissolved in dichloromethane (38 mL) at a temperature of about 40°C. The solution was cooled to about 0°C to about 5°C, filtered and dried in a vacuum tray dryer at a temperature of about 45 °C for 4 hours to obtain crystalline Form Rl of febuxostat (0.9 g).

Example 2: Preparation of Crystalline Form Rl of Febuxostat

Febuxostat (1 g) was dissolved in dichloromethane (60 mL) at a temperature of about 40°C. The solution was allowed to stand at about 25 °C until the complete evaporation of the solvent takes place and dried in a vacuum tray dryer at a temperature of about 45°C for 4 hours to obtain crystalline Form Rl of febuxostat (0.9 g).

Example 3: Preparation of Crystalline Form Rl of Febuxostat

Febuxostat (1 g) was dissolved in dichloromethane (40 mL) at a temperature of about 40°C. Heptane (100 mL) maintained at room temperature was added to the above solution. The reaction mixture was filtered and dried in a vacuum tray dryer at a temperature of about 45°C for 4 hours to obtain crystalline Form Rl of febuxostat (0.86 g)-

Example 4: Preparation of Crystalline Form Rl of Febuxostat

The suspension of febuxostat (1 g) in dichloromethane (15 mL) was stirred at a temperature of about 40°C for 6 hours. The reaction mixture was filtered and dried in air for 24 hours to obtain crystalline Form Rl of febuxostat (0.80 g).

Example 5: Preparation of Crystalline Form R2 of Febuxostat

Febuxostat (0.7 g) was dissolved in dimethyl sulphoxide (12 mL) at a temperature of about 65 °C. The solution was allowed to stand at about 25 °C for 3 hours, filtered and dried in a vacuum tray dryer at a temperature of about 45 °C for 4 hours to obtain crystalline Form R2 of febuxostat (0.6 g).

Example 6: Preparation of Crystalline Form R2 of Febuxostat

Febuxostat (1 g) was dissolved in dimethyl sulphoxide (3 mL) at a temperature of about 65 °C. The solution was cooled in an ice bath, dried under suction on a filter paper followed by drying in a vacuum tray dryer at a temperature of about 45 °C for 4 hours to obtain crystalline Form R2 of febuxostat ((0.6 g).

Example 7: Preparation of Crystalline Form R2 of Febuxostat

Febuxostat (1 g) was dissolved in dimethyl sulphoxide (17 mL) at a temperature of about 65°C. The solution was allowed to stand at a temperature of about 25°C for 24 hours, filtered and dried in a vacuum tray dryer at a temperature of about 45 °C for 4 hours to obtain crystalline Form R2 of febuxostat (0.75 g).

Example 8: Preparation of Crystalline Form R3 of Febuxostat

Febuxostat (0.7 g) was dissolved in N, N-dimethylformamide (10 mL) at a temperature of about 65°C. The solution was allowed to stand at about 25°C for 24 hours, dried under suction on a filter paper followed by drying in a vacuum tray dryer at a temperature of about 45°C for 4 hours to obtain crystalline Form R3 of febuxostat (0.5 g).

Example 9: Preparation of Crystalline Form R3 of Febuxostat

Febuxostat (1 g) was dissolved in N, N-dimethylformamide (10 mL) at a temperature of about 65°C. The solution was allowed to stand at about 25°C for 1 week. The material was dried in a vacuum tray dryer at a temperature of about 45°C for 4 hours to obtain crystalline Form R3 of febuxostat (1.1 g).

Example 10: Preparation of Crystalline Form R4 of Febuxostat

A solution of febuxostat (1 g) in methyl iso-butyl ketone (15 mL) was added to cyclohexane (100 mL) at a temperature of about 25 °C. The reaction mixture was filtered and dried in a vacuum tray dryer at a temperature of about 45 °C for 4 hours to obtain crystalline Form R4 of febuxostat (0.97 g).

Example 11: Preparation of Crystalline Form R5 of Febuxostat

Febuxostat (1 g) was dissolved in acetic acid (25 mL) at a temperature of about 65 °C. The solution was allowed to stand at about 25 °C for 24 hours, filtered and dried in a vacuum tray dryer at a temperature of about 45°C for about 4 hours to obtain crystalline Form R5 of febuxostat (1.1 g). Example 12: Preparation of Crystalline Form R5 of Febuxostat

A solution of febuxostat (1 g) in acetic acid (25 mL) was added to heptane (100 mL) at a temperature of about 25°C. The solution was allowed to stand for 24 hours, filtered and dried in a vacuum tray dryer at a temperature of about 45 °C for 4 hours to obtain crystalline Form R5 of febuxostat (0.95 g).

Example 13: Preparation of Crystalline Form R5 of Febuxostat

Febuxostat (1 g) was dissolved in acetic acid (25 mL) at a temperature of about 65°C. The above solution was added to cyclohexane (100 mL) at about 25°C. The solution was allowed to stand at about 25 °C for 24 hours, filtered and dried in a vacuum tray dryer at a temperature of about 45 °C for 4 hours to obtain crystalline Form R5 of febuxostat (0.95 g).

Example 14: Preparation of Crystalline Form R5 of Febuxostat

A suspension of febuxostat (1 g) in acetic acid (15 mL) was stirred at about 60°C for 8 hours. The reaction mixture was filtered and dried in air for 48 hours to obtain crystalline Form R5 of febuxostat (0.9 g).

Example 15: Preparation of Crystalline Form Rl of Febuxostat

Febuxostat (7 g) was dissolved in dichloromethane (280 mL) at a temperature of about 40°C. Heptane (400 mL) maintained at room temperature was added to the above solution in 30 minutes. The reaction mixture was cooled to a temperature of about 5°C and stirred for 45 minutes. The reaction mixture was filtered and dried at a temperature of about 55°C in a vacuum tray dryer for 5 hours to obtain crystalline Form Rl of febuxostat (6.2 g).

Example 16: Preparation of Crystalline Form Rl of Febuxostat

Febuxostat (1 g) was dissolved in dichloromethane (45 mL) at a temperature of about 40°C. 10 mg of seed crystal of febuxostat (prepared as per Example-16) was added. The reaction mixture was cooled to room temperature followed by cooling in an ice bath for 15 minutes to obtain crystalline Form Rl of febuxostat (0.7 g). Example 17: Preparation of Crystalline Form R4 of Febuxostat

A solution of febuxostat (1 g) in tetrahydrofuran (20 mL) was added to cyclohexane (75 mL) at a temperature of about 25°C. The reaction mixture was filtered and dried in a vacuum tray dryer at a temperature of about 45 °C for 4 hours to obtain crystalline Form R4 of febuxostat (0.7 g).

Claims

We Claim:

1. Crystalline Form Rl of febuxostat comprising X-ray diffraction peaks at d-spacing of about 15.11, 10.07, 7.56, 7.19 and 6.04 A.

2. Crystalline Form of Rl of claim 1 further comprising X-ray diffraction peaks at d- spacing of about 7.37 A, 5.04 A, 3.75 A, 3.53 A and 3.07 A.

3. Crystalline Form of Rl comprising an X-ray diffraction pattern as depicted in Figure 1.

4. Crystalline Form Rl of febuxostat comprising a DSC having endotherms at about 189.05°C, 201.50°C and 209.38°C.

5. Crystalline Form Rl of febuxostat comprising a DSC as depicted in Figure 7.

6. Crystalline Form Rl of febuxostat comprising a TGA as depicted in Figure 9.

7. Crystalline Form R2 of febuxostat comprising a X-ray diffraction peaks at d- spacing 12.31, 6.15, 5.46, 3.77 and 3.37 A.

8. Crystalline Form R2 of claim 7 further comprising an X-ray diffraction peaks at d- spacing of about 4.10 A, 4.05 A, 3.94 A, 3.90 A and 3.10 A.

9. Crystalline Form R2 of febuxostat comprising an X-ray diffraction pattern as depicted in Figure 2.

10. Crystalline Form R3 of febuxostat comprising an X-ray diffraction peaks at d- spacing of about 11.45, 7.63, 3.57, 3.54 and 3.43 A.

11. Crystalline Form R3 of claim 10 further comprising an X-ray diffraction peaks at d-spacing of about 9.87 A, 6.90 A, 4.92 A, 4.85 A and 3.81 A.

12. Crystalline Form R3 of febuxostat comprising an X-ray diffraction pattern as depicted in Figure 3.

13. Crystalline Form R4 of febuxostat comprising an X-ray diffraction peaks at d- spacing of about 15.96, 14.60, 7.97, 7.78 and 3.52 A.

14. Crystalline Form R4 of claim 13 further comprising an X-ray diffraction peaks at d-spacing of about 7.29 A, 5.31 A, 5.21 A, 3.45 A and 3.39 A.

15. Crystalline Form R4 of febuxostat comprising an X-ray diffraction pattern as depicted in Figure 4.

16. Crystalline Form R4 of febuxostat comprising endotherms at about 92.23°C, 199.71°C and 209.22°C.

17. Crystalline Form R4 of febuxostat comprising a DSC as depicted in Figure 8.

18. Crystalline Form R4 of febuxostat comprising a TGA as depicted in Figure 10.

19. Crystalline Form R5 of febuxostat comprising X-ray diffraction peaks at d-spacing of about 11.96, 5.98, 5.01 and 3.34 A.

20. Crystalline Form R5 of claim 19 further comprising X-ray diffraction peaks at d- spacing of about 7.94 A, 5.29 A, 3.99 A and 3.42 A.

21. Crystalline Form R5 of febuxostat comprising an X-ray diffraction pattern as depicted in Figure 5.

22. A process for the preparation of crystalline Form Rl of febuxostat comprising the steps of:

i) contacting febuxostat with a chlorinated solvent;

ii) optionally adding an anti-solvent; and

iii) isolating crystalline Form Rl.

23. The process according to claim 22, wherein the febuxostat to be used as starting material for the preparation of crystalline Form Rl is obtained as a solution directly from a reaction in which it is formed and is used as such without isolation.

24. The process according to claim 22, wherein the chlorinated solvent comprises dichloromethane or chloroform.

25. The process according to claim 22, wherein the febuxostat is contacted with the chlorinated solvent at a temperature of about 15°C to the reflux temperature of the solvent.

26. The process according to claim 22, wherein crystallization is carried out by cooling the reaction mixture containing the febuxostat in the chlorinated solvent to about -10°C to about 25°C.

27. The process according to claim 22, wherein crystallization is carried out by adding an anti-solvent selected from hydrocarbons, alkyl acetates, or mixtures thereof, to the solution of the febuxostat in the chlorinated solvent.

28. The process according to claim 27, wherein the hydrocarbon solvent is selected from hexane, cyclohexane, benzene, toluene, heptanes or octane.

29. The process according to claim 22, wherein a seed crystal of crystalline Form Rl is added to the solution of the febuxostat in the chlorinated solvent.

30. A process for the preparation of crystalline Form R2 of febuxostat comprising contacting febuxostat with a sulphoxide solvent.

31. The process according to claim 30, wherein the febuxostat to be used as starting material for the preparation of crystalline Form R2 is obtained as a solution directly from a reaction in which it is formed and is used as such without isolation.

32. The process according to claim 30, wherein the sulphoxide solvent is selected from dimethyl sulphoxide or diethyl sulphoxide.

33. The process according to claim 30, wherein the febuxostat is contacted with the sulphoxide solvent at a temperature of about 40°C to about 80°C.

34. The process according to claim 30, wherein crystallization is carried out by cooling the reaction mixture containing the febuxostat in the sulphoxide solvent to about -10°C to about 35°C.

35. A process for the preparation of crystalline Form R3 of febuxostat comprising contacting febuxostat with an amide solvent.

36. The process according to claim 35, wherein the febuxostat to be used as starting material for the preparation of crystalline Form R3 is obtained as a solution directly from a reaction in which it is formed and is used as such without isolation.

37. The process according to claim 35, wherein the amide solvent is selected from N, N-dimethylformamide or N, N-dimethylacetamide.

38. The process according to claim 35, wherein the febuxostat is contacted with the amide solvent at a temperature of about 40°C to about 80°C.

39. The process according to claim 35, wherein crystallization is carried out by cooling the reaction mixture containing the febuxostat in the amide solvent to about 15°C to about 35°C.

40. A process for the preparation of crystalline Form R4 of febuxostat comprising the steps of:

i) contacting febuxostat with a ketone or ether solvent;

ii) optionally adding an anti-solvent; and

iii) isolating crystalline Form R4.

41. The process according to claim 40, wherein the febuxostat to be used as starting material for the preparation of crystalline Form R4 is obtained as a solution directly from a reaction in which it is formed and is used as such without isolation.

42. The process according to claim 40, wherein the ketone solvent is selected from acetone, dimethyl ketone, ethyl methyl ketone or methyl iso-butyl ketone.

43. The process according to claim 40, wherein the ether solvent is selected from diethyl ether, ethyl methyl ether, di-isopropyl ether, tetrahydrofuran or 1,4-dioxane.

44. The process according to claim 40, wherein the febuxostat is contacted with the ketone or the ether solvent at a temperature of about 15°C to about 35°C.

45. The process according to claim 40, wherein crystallization is carried out by adding an anti-solvent selected from hydrocarbons, alkyl acetates, or mixtures thereof, to the solution of febuxostat in a ketone or ether.

46. The process according to claim 45, wherein the hydrocarbon solvent is selected from hexane, cyclohexane, benzene, toluene, heptanes or octane.

47. A process for the preparation of crystalline Form R5 of febuxostat comprising the steps of:

i) contacting febuxostat with a carboxylic acid solvent;

ii) optionally adding an anti-solvent; and

iii) isolating crystalline Form R5.

48. The process according to claim 47, wherein the febuxostat to be used as starting material for the preparation of crystalline Form R5 is obtained as a solution directly from a reaction in which it is formed and is used as such without isolation.

49. The process according to claim 47, wherein the carboxylic acid solvent is selected from formic acid, acetic acid or propionic acid.

50. The process according to claim 47, wherein the febuxostat is contacted with carboxylic acid solvent at about 25 °C to about 80°C.

51. The process according to claim 47, wherein crystallization is carried out by cooling the reaction mixture containing the febuxostat in the carboxylic acid solvent to a temperature of about 15°C to about 35°C.

52. The process according to claim 47, wherein crystallization is carried out by adding an anti-solvent selected from hydrocarbons, alkyl acetates, or mixtures thereof, to a reaction mixture containing febuxostat in a carboxylic acid solvent.

53. The process according to claim 52, wherein the hydrocarbon solvent is selected from hexane, cyclohexane, benzene, toluene, heptanes or octane.

54. A pharmaceutical composition comprising crystalline Form Rl, R2, R3, R4 or R5 of febuxostat and one or more pharmaceutically acceptable carriers, diluents or excipients.

55. A method of treating hyperuricemia, the method comprising administering a pharmaceutical composition comprising a crystalline Form Rl, R2, R3, R4 or R5 of febuxostat and one or more pharmaceutically acceptable carriers, diluents, or excipients.