FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
"PROCESS FOR PREPARATION OF POLYMORPHIC FORM II OF FEBUXOSTAT"
AJANTA PHARMA LTD.
A company incorporated under the laws of India having their office at
98, Ajanta house, Charkop, Kandivali (West)
Mumbai - 400067, Maharashtra, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION
The present invention relates to a reliable and industrial applicable process for the preparation of crystalline Form II of 2-[3-Cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic, commonly known as Febuxostat.
BACKGROUND OF THE INVENTION
Febuxostat is a common name for 2-(3-cyano-4-isobutyIoxyphenyI)-4-methyIthiazole-5-carboxylic acid, a compound having the following formula;

Febuxostat belongs to the class of Xanthine Oxidase (XO) inhibitor and is particularly used for the chronic management of hyperuricemia in patients with gout. Febuxostat is available in the market under tradename Uloric®, as a film coated tablet in 40mg and 80mg strengths.
Febuxostat can exist in different polymorphic forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
U.S. Patent No. 6,225,474 discloses crystalline form A, B, C, D, G and amorphous form of febuxostat.
PCT Publication Nos. WO 2008/067773, WO 2008/067773 & WO 2010/144685 discloses crystalline forms H, I, J, X, Y, Z and Fl to F14 of febuxostat.

Polymorphic form K, L, Q, M, N, P, R, S & T are disclosed respectively in Publication Nos. CN 101386605, CN 101759656, CN 101648926, CN 101824007, WO 2011/134101, CN 101824006, WO 2011/107911 & CN 101928260.
Chinese Publication No. CN 101812035 discloses polymorphic Form II of febuxostat characterized by XRPD peaks at 4.78, 6.82, 8.30, 9.58, 11.74,13.74 14.60, 15.92,16.68, 17.56, 21.26, 23.64, 24.80, 25.20, 25.78, 26.08, 26.66, 28.66 & 31.64 ± 0.2 (2θ). As disclosed in the published document, Form II of febuxostat was prepared by dissolving crude febuxostat in aqueous sodium hydroxide and ethanol mixture and then precipitating Form II of febuxostat by adding aqueous hydrochloric acid to above solution. However, this process is tedious and requires pH adjustment of febuxostat solution to precipitate Form II.
The present invention provides a simple, reproducible, industrially viable and economical process in which no pH adjustment is required for isolation of Form II of febuxostat.
SUMMARY OF THE INVENTION
In one general aspect there is provided a process for the preparation of crystalline Form II of febuxostat characterized by X-ray powder diffraction pattern having peaks expressed as 2θ at about 4.8, 6.9, 11.8, 16.0, 24.9, 25.2, 25.8 and 26.2+0.2 degrees. The process includes providing a solution of febuxostat in one or more suitable organic solvents to obtain febuxostat solution; precipitating Form II of febuxostat from the solution by addition of water followed by removal of solvents.
In another aspect there is provided process for the preparation of polymorphic Form II of febuxostat characterized by X-ray powder diffraction pattern having peaks expressed as 2θ at about 4.8, 6.9,11.8,16.0,24.9,25.2,25.8 and 26.2+0.2 degrees comprising the steps of:
(a) suspending febuxostat in a suitable organic solvent,
(b) dissolving febuxostat by heating the suspension and optionally adding water,
(c) crystallizing febuxostat by adding water to the solution obtained in step b) and cooling it,

(d) removing the solvent to isolate the obtained crystals.
The solvents may be removed by, for example, simple filtration, filtration under vacuum, decantation, centrifugation, distillation, and distillation under vacuum.
The process may include further drying of the product obtained. The process may include further forming of finished dosage form of the obtained crystals.
The process according to the present invention, despite of being easy, is a reliable process for the preparation of Form II of Febuxostat suitable for industrial scale, and a relative high yield can be achieved using simple techniques.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. I is an X-ray powder diffraction pattern of crystalline febuxostat Form II.
FIG. 2 is an FTIR spectrum of febuxostat Form II.
FIG. 3 is a DSC thermogram of crystalline febuxostat Form II.
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the present invention, there is provided novel a process for the preparation of the crystalline Form II of febuxostat, by providing solution of febuxostat in one or more suitable solvents to obtain febuxostat solution; and crystallizing Form II of febuxostat by adding water to the solution followed by the removal of solvents.
More specifically, there is provided a process for the preparation of polymorphic Form II of febuxostat characterized by X-ray powder diffraction pattern having peaks expressed as 2θ at about 4.8, 6.9,11.8,16.0,24.9,25.2, 25.8 and 26.2+0.2 degrees comprising the steps of:

(a) suspending febuxostat in a suitable organic solvent,
(b) dissolving febuxostat by heating the suspension and optionally adding water,
(c) crystallizing febuxostat by adding water to the solution obtained in step b) and cooling it,
(d) removing the solvent to isolate the obtained crystals.
In general, the solution of febuxostat may be obtained by dissolving any known form of febuxostat in a suitable solvent. The solution may be obtained by heating the suspension of febuxostat in a solvent or in some cases heating the suspension followed by addition of water. The resultant solution may be clarified to remove foreign particulate matter or treated with charcoal to remove coloring and other related impurities. The solution so obtained may be concentrated to reduce the amount of solvent.
Alternatively, such a solution may be obtained directly from a reaction in which febuxostat is formed.
In one of the embodiment, the suitable organic solvent as in step a) is selected from acetone, ethyl acetate, acetonitrile, tetrahydrofuran and dimethylformamide. Preferably, the solvent is acetone.
In another embodiment, the suspension of step a) is heated at about 30°C to about 120°C to get clear solution. Preferably, the suspension is heated at about 50°C to about 70°C. More preferably, the suspension is heated at 55°C to about 60°C. In case, clear solution is not achieved by heating only, water is added to the suspension with continuous heating to get clear solution.
After addition of water as in step c), reaction mixture is cooled at about 0 to 20° C. More preferably at about 15 to 20° C.
Febuxostat crystalline Form II may be isolated in step (d) by removing the solvents. As used herein, the term "removing the solvent" may include filtration, filtration under vacuum, centrifugation, and decantation to isolate product. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the

product may be dried in a hot air oven, tray drier, dried under vacuum and/or in a Fluid Bed Drier.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising crystalline Form II of febuxostat and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
The crystalline Form II may preferable be formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.
The invention will now be further described by the following examples, which are illustrative rather than limiting.
Example 1: Preparation of Febuxostat crude
Mixture of Ethyl-2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (5.0 g, 0.0145 mol), tetrahydrofuran (10 ml) and methanol (10 ml) was stirred for 10 to 15 min at 25-30°C. Aqueous sodium hydroxide solution (0.70 g, 0.0174 mol) dissolved in water (10 ml) was added to above mixture at 25-30°C. Resulting reaction mixture was stirred for 5 to 6 h at 25-30°C, after completion of reaction solvent was evaporated up to half volume. The residue was dissolved by addition of acetone (25 ml) and acidified to pH 2-3 by addition of aqueous IN HCL solution at 25°C to 30°C. Solid product precipitated was stirred at 15-20°C for 1 hour. Product was separated by filtration, washed with 50% aq. acetone (5ml) and water (4x5 ml) and dried at 60-65°C to get dry Febuxostat crude 3.7 g (Purity >99.0%).
Example 2: Preparation of febuxostat crystalline Form II using acetone/water mixture
Febuxostat crude (5.0 g) was charged in acetone (50 ml) and resulting suspension was slowly heated up to 55-60°C to get clear solution and stirred for 40-45 min. Water (50 ml) was added slowly at 55-60°C within 1 hour to reprecipitate the solid and stirring was continued for 40 -45 min. The mixture was cooled to 15-20°C and stirred for 1 hour. Precipitated crystals of febuxostat were collected by filtration, washed with water (2 x 10

ml), 50% aq. acetone (5 ml),) and dried at 60-65°C to get polymorphic Form II of febuxostat (4.4 g) with water content less than 3%.
Example 3: Preparation of febuxostat crystalline Form II using acetonitrile/water mixture
Febuxostat crude (5.0 g) was charged in Acetonitrile (25 ml) and resulting suspension was slowly heated up to 55-60°C. Water (5 ml) was added slowly at 55-60°C to get clear solution and stirred for 30 min. Water (20 ml) was added slowly to clear solution within 1 hour at 55-60°C and stirred for 30 min. The mixture was cool to 15-20°C and stirred for 1 hour. Precipitated crystals were collected by filtration, washed with 50% aq. Acetonitrile (5 ml), water (3x5 ml) and dried at 60-65°C to get polymorphic Form II of febuxostat (4.0 g) with water content less than 3 %.
Example 4: Preparation of febuxostat crystalline Form II using ethyl acetate/water mixture
Febuxostat crude (5.0 g) was charged in ethyl acetate (25 ml) and resulting suspension was slowly heated up to 55-60°C. Water (5 ml) was added slowly at 55-60°C to get clear bilayer solution and stirred for 30 min. Water (20 ml) was added slowly to clear solution within 1 hour at 55-60°C and stirred for 30 min. The resulting mixture was cooled to 15-20°C and stirred for 1 hour. The resulting crystals were collected by filtration, washed with 50% aq. ethyacteate (5 ml), water (3x5 ml) and dried at 60-65°C to get polymorphic Form II of febuxostat (4.7 g) with water content less than 3%,
Example 5: Preparation of febuxostat crystalline Form II
Febuxostat crude (5.0 g) was charged in Tetrahydrorurane (25 ml) and resulting suspension was slowly heated up to 55-60°C, Water (5 ml) was added slowly at 55-60°C to get clear solution and stirred for 30 min. Water (20 ml) was added slowly to clear solution within 1 hour at 55-60°C and stirred for 30 min. The resulting mixture was cooled to 15-20°C and stirred for 1 hour. The resulting crystals were collected by filtration, washed with 50% aq. Tetrahydrofuran (5 ml), water (3x5 ml) and dried at 60-65°C to get polymorphic Form II of febuxostat (4.0 g) with water content less than 3%.

Example 6: Preparation of febuxostat crystalline Form II
Febuxostat crude (5.0 g) was charged in dimethylformamide (25 ml) and resulting suspension slowly heated up to 55-60°C. Water (5 ml) was added slowly at 55-60°C to get clear solution and stirred for 30 min. Water (20 ml) was added slowly to clear solution within 1 hour at 55-60°C and stirred for 30 min. The resulting mixture was cooled to 15-20°C and stirred for 1 hour. The resulting crystals were collected by filtration, washed with 50% aq. dimethylformamide (5 ml), water (3x5 ml) and dried at 60-65°C to get polymorphic Form II of febuxostat (4.0 g) with water content less than 3%.

We claim:
1. A process for the preparation of polymorphic Form II of febuxostat characterized by
X-ray powder diffraction pattern having peaks expressed as 20 at about 4.8,6.9,11.8,
16.0, 24.9, 25.2, 25.8 and 26.2+0.2 degrees comprising the steps of:
a) suspending febuxostat in a suitable organic solvent,
b) dissolving febuxostat by heating the suspension and optionally adding water,
c) crystallizing febuxostat by adding water to the solution obtained in step b) and cooling it,
d) removing the solvent to isolate the obtained crystals.

2. A process according to claim 1, wherein the solvent selected in step a) is acetone.
3. A process according to claim 2, wherein febuxostat is dissolved in acetone by heating.
4. A process according to claim 1, wherein the solvent selected in step a) is selected from ethyl acetate, acetonitrile, tetrahydrofuran and dimethylformamide.
5. A process according to claim 4, wherein febuxostat is dissolved by heating the suspension and adding water.
6. A process for the preparation of polymorphic Form Ilof febuxostat characterized by X-ray powder diffraction pattern having peaks expressed as 20 at about 4.8, 6.9,11.8, 16.0,24.9,25.2,25.8 and 26.2+0.2 degrees comprising the steps of:

a) suspending febuxostat in acetone,
b) dissolving febuxostat by heating the suspension,
c) crystallizing febuxostat Form II by adding water to the solution obtained in step b) and cooling it,
d) isolating the obtained crystals.