FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents [Amendment] Rules, 2006
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
Novel Polymorphs Of 2-[3-Cyano-4-(2-Methylpropoxy)Phenyl]-4-Methyl-5-Thiazole Carboxylic Acid And Processes For Preparing The Same
2. APPLICANT
NAME : Frichem Private Limited
NATIONALITY : Indian
ADDRESS : 12, Concord, Bullock Road, Band Stand, Bandra West, Mumbai -400 050, India
3. PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the Invention
The present invention relates to novel crystalline polymorphs of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazole carboxylic acid and the processes for their preparation. This invention also relates to new processes for the production of known crystalline polymorphs of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazole carboxylic acid.
Background of the Invention
2-[3-Cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazole carboxylic acid is marketed under the brand name Uloric®(US), a xanthine oxidase inhibitor indicated for the chronic management of hyperuricemia in patients with gout, which is available as tablet in strengths of 40 mg and 80 mg once daily. 2-[3-Cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazole carboxylic acid, which is generically known as Febuxostat and represented by formula (I), was first disclosed in US patent 5,614,520 (US '520).

In addition to this, US '520 patent also discloses a process for preparation of claimed compound thereof, as well as its therapeutic use for treating gout or hyperuricemia or disease associated with a production of interleukin. However, US '520 does not describe anything on polymorphism.
US patent 6,225,474 provides different polymorphs of Febuxostat and methods of producing the same, which comprises crystallizing the febuxostat under the conditions defined by specific temperature and composition of a mixed solvent of methanol and water. These polymorphs, including methanol solvate & hydrate, are recognized as A, B, C, D & G. This patent also discloses the amorphous form of Febuxostat and its process of preparation. This

patent further expresses conversion of one polymorph to other polymorph by drying under reduced pressure with heating. According to the disclosure of this patent, polymorph A (anhydrous) is metastable, polymorph D (methanol solvate) converts to polymorph G (hydrate having moisture content of 2.5-2.7%) first and then converts to polymorph B (anhydrous) on drying under reduced pressure with heating. Form B can also be converted to form G under normal humidity conditions by absorbing water. The experimental operation suggests that stability varies with each polymorph which may interconvert to other and thus exerting an influence on the results of the long-term storage stability. Each of the polymorphs and methods for producing the same has drawbacks, in that the desired polymorph can not be obtained with high stability.
Further CN 1,970,547, CN 101,139,325, CN 101, 386, 605, CN 101,648,926 and CN 101,412,700 disclose several polymorphs of Febuxostat isolated from cyanide solvents like acetonitrile, propionitrile; ethanol and ethyl acetate; mixed solvent system of dioxane and n-hexane, petroleum ether & cyclohexane; and acetone respectively.
Control of the crystallization behavior of these polymorphous crystals is important, because physical properties such as the solubility, the melting point, and the solid density are different among these polymorphs. Solubility is also an important factor because the relative thermodynamic stability of polymorphs and the direction of the transformation between them are determined by the solubility of polymorphs. Furthermore, the super saturation of each polymorph, which is different even in the same solution, is also based on the solubility of each polymorph.
Consequently there is an outstanding demand to provide novel polymorph of Febuxostat which would have desirable properties, such as ease of handling, ease of processing, storage stability and ease of purification. New polymorphic forms enlarges the selection of materials and facilitate in formulation optimization, and for at least these reasons, there is a need for additional polymorphs of Febuxostat. There is further presented a process which is able to produce highly pure known polymorph of febuxostat in an efficient way on a commercial scale.

Objects and Summary of the Invention
It is an object of the present invention to provide novel polymorphs of febuxostat to resolve the problems associated with prior arts and processes for preparing the same.
It is another object of the present invention to provide stable polymorphs of febuxostat.
It is another object of the present invention to provide stable polymorphs resulting into stable composition of febuxostat.
It is still another object of the present invention to provide process to synthesize known polymorph of febuxostat under specific range of eminent parameters for crystallization.
It is yet another object of the invention to employ ecofriendly solvents in low quantity and thereby to make the process economical.
The above and other objects of the present invention are attained according to the following preferred embodiments of the present invention. However the scope of the invention is not restricted to the particular embodiments discussed herein after.
In accordance with one embodiment of the invention, there is provided, a crystalline polymorph of febuxostat, hereinafter referred as crystal III, characterized by data selected from the powder XRD pattern with peaks at 5.85, 8.06, 11.64, 12.83, 17.03, 20.59 ± 0.2 20 values.
In accordance with another embodiment of the invention, there is provided a crystalline polymorph of febuxostat, herein after referred as crystal IV, characterized by data selected from the powder XRD pattern with peaks at 5.85, 6.74, 8.13,9.34, 11.01, 11.72, 13.57, 14.25, 15.73, 16.26, 16.65, 17.41, 18.33, 25.85, 26.73 ± 0.2 2θ values.
In accordance with still another embodiment of the invention, there is provided a process for preparing novel crystalline forms III & IV of febuxostat as depicted in the previous aspects.

In accordance with yet another embodiment of the invention there is provided a process for preparing known crystalline form A of febuxostat under specific range of eminent parameters.
Brief Description of the Drawings
Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures wherein:
Figure 1 is a graph showing a PXRD pattern of the crystal III of the present invention.
Figure 2 is a graph showing a PXRD pattern of the crystal IV of the present invention.
Figure 3 is a graph showing an FTIR absorption curve of the crystal III of the present
invention.
Figure 4 is a graph showing an FTIR absorption curve of the crystal IV of the present
invention.
Figure 5 is a graph showing a PXRD pattern of the crystal form A of febuxostat.
Detailed Description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
Accordingly, the present invention provides novel polymorphs and methods of producing the same. Each polymorph of the present invention exhibits characteristic X-ray powder diffraction (XRD) patterns with a specific 20 value, a characteristic absorption pattern in infrared (IR) spectroscopic analysis, a different melting point and density.
Thus, according to first aspect, the present invention provides a polymorph of febuxostat, crystal III, which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 20 of about 5.85, 8.06, 11.64, 12.83, 17.03, 20.59 and a characteristic

absorption pattern in infrared (IR) which can be distinguished from that of other polymorphs, at about 1292 and 1691 cm"1.
Further with respect to another aspect, the present invention also provides another novel polymorph of Febuxostat, crystal IV, which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ of about 5.85, 6.74, 8.13, 9.34, 11.01, 11.72, 13.57, 14.25, 15.73, 16.26, 16.65, 17.41, 18.33, 25.85, 26.73; and characteristic absorptions pattern in IR, which can be distinguished from the other polymorphs, at about 1288 and 1693 cm-1.
These polymorphs are important, because of their improved characteristics like solubility, dissolution rate, higher crystallinity, the melting point, low hygroscopicity, flowability, advantageous processing and handling characteristics such as compressibility, and bulk density, which results into enhancement in the bioavailability. In addition to these, the novel polymorphs are stable in such a way that it is easy to make composition of the said polymorphs with one or more pharmaceutically acceptable excipients.
In accordance with the third aspect there is provided a process to prepare novel polymorph form III of the febuxostat where Crystalline form III can be prepared by crystallizing febuxostat from carboxylic acid ester solvents.
The crystallization typically comprises dissolving febuxostat in a solvent selected from solvent of carboxylic acid ester class comprising of methyl acetate, ethyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof. Dissolution of febuxostat in a solvent is made at room temperature to reflux of solvent. Optionally, the solution obtained above may be filtered to remove any insoluble particles by techniques known in the art. Reaction mixture is cooled or maintained to precipitate out the crystals where the cooling is done to a temperature of about 40°C to about 0°C, and the maintaining is typically done at a temperature of about room temperature, for a time period of about 1-24 hours. The obtained crystalline form III is further recovered by filtering, followed by drying.
In continuation with the third aspect, the present invention is provided with process for preparation of crystalline form IV comprising crystallizing febuxostat from a mixture

comprising methyl isobutyl ketone (MIBK) and hexane. The crystallization, typically done at about room temperature, comprises dissolving febuxostat in methyl isobutyl ketone and then adding hexane to obtain said crystalline form. Dissolution of febuxostat is carried out at room temperature to reflux of methyl isobutyl ketone. The reaction mixture is cooled or maintained. After crystallization, crystals are collected and dried where the drying is carried out at a temperature range from 25°C to 80°C under reduced pressure or atmospheric pressure.
Febuxostat that is employed for crystallization according to third aspect of the invention is either acquired from a reaction mixture containing febuxostat that is obtained in the course of its manufacture or febuxostat in isolated form.
In fourth aspect, the present invention provides a process for preparing crystalline form A of febuxostat under the eminent parameter of crystallization, which includes the following steps:
a) providing a solution of febuxostat in a suitable solvent or mixture of solvents;
b) isolating crystalline form A of febuxostat.
Suitable solvents used in step a) are selected from, water, alcohols, ketones, polar aprotic solvents, and mixtures thereof.
Suitable solvents used in step a) include but are not limited to: water; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, and the like; ketones such as acetone, butanone; 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone and the like; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide. acetamide, propanamide terahydrofuran and the like; and mixtures thereof.
The dissolution temperatures may be in the range of 20°C to 150°C depending on the solvent used for dissolution. The solution may be treated with materials such as carbon, hyflow or any other suitable material to remove colour or to improve clarity of the solution.
Step b) involves isolation of crystalline form A of febuxostat by removal of solvent where the removal of solvent is carried out, optionally under reduced pressure, at temperatures in the range of about 20°C to 200°C.

Alternatively, isolation may be effected by adding a suitable anti-solvent to the solution obtained in step a), or optionally after concentrating the solution obtained in step a). Suitable anti-solvents that may be used are selected from ethers, aliphatic or alicyclic hydrocarbons, aromatic hydrocarbons, esters and mixtures thereof.
Alternatively, isolation may be effected by adding a suitable anti-solvent to the solution obtained in step a), or optionally after concentrating the solution obtained in step a). Suitable anti-solvents that may be used include but are not limited to: ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, 2-methoxyethanol, 2-ethoxyethanol, anisole and the like; aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, n-pentane, cyclohexane, methylcyclohexane, nitromethane and the like; aromatic hydrocarbons such as toluene, xylenes; chlorobenzene; tetraline; and the like; esters like ethyl acetate, methyl acetate and the like and mixtures thereof.
The crystalline form A of febuxostat obtained by the process of the present invention is pure where the term "pure" refers to substantially free from any other polymorphic forms cited in the literature.
Febuxostat employed for preparation of crystalline form A of the present invention is acquired from either a reaction mixture containing febuxostat that is obtained in the due course of its manufacture or febuxostat in isolated form.
Best mode for carrying out the Invention
The production of the crystalline febuxostat by the new processes of this invention is now illustrated with reference to the following Examples, to which this invention is not limited. Example 1 is illustrative example of carrying out the process for preparation of crystalline form III. Example 2 is an illustrative example of carrying out the process for preparation of crystalline form IV. Example 3 to 8 are an illustrative example of process according to forth aspect of the invention, i.e., process for preparing crystalline form A of febuxostat.

Example 1
Febuxostat (5.0 g) was dissolved in ethyl acetate (75 ml) and refluxed, with stirring to dissolve the solid completely. This solution was allowed to cool to room temperature to get precipitates. The obtained solid was filtered and dried at 40°C under reduced pressure to get 3.0 g white crystal of form III.
Example 2
Febuxostat (5.0 g) was dissolved in methyl isobutyl ketone (MIBK) (125 ml) and refluxed, with stirring, to dissolve the solid completely. The temperature of the solution was dropped down to 50-55°C followed by addition of hexane (62.4 ml) and then after reaction, solution was allowed to cool to room temperature to get precipitates. The obtained solid was filtered and dried at 40°C under reduced pressure to get 1.8 g white crystal of form IV.
Example 3
Febuxostat (1.5 g) was dissolved in acetone (15.0 ml) and refluxed, with stirring, to dissolve the solid completely. The temperature of the solution was dropped to room temperature, followed by filtration and drying at 40°C under reduced pressure to get white crystal (0.6 g) of pure form A.
Example 4
Febuxostat (5 g) was dissolved in isopropyl alcohol (75 ml) and refluxed, with continuous stirring, to dissolve the solid completely. The temperature of the solution was reduced to room temperature and the compound thus obtained was filtered and dried at 75-80°C under vacuum to get crystalline pure form A.
Example 5
Febuxostat (10 g) was dissolved in tetrahydrofuran (20 ml) and refluxed, with continuous stirring, to dissolve the solid completely. The temperature of the solution was reduced to room temperature and the compound thus obtained was filtered and dried at 75-80°C under vacuum to get crystalline pure form A.

Example 6
Febuxostat (5 g) was dissolved in tetrahydrofuran (20 ml) and refluxed, with continuous stirring, to dissolve the solid completely. Then hexane was added to the solution and cooled to room temperature. The compound thus obtained was filtered and dried at 75-80°C under vacuum to get crystalline pure form A.
Example 7
Febuxostat (5 g) was dissolved in n-butenol (50 ml) and refluxed, with continuous stirring, to dissolve the solid completely. The temperature of the solution was reduced to room temperature and the compound thus obtained was filtered and dried at 75-80°C under vacuum to get crystalline pure form A.
Example 8
Febuxostat (5 g) was dissolved in n-propmol (50 ml) and refluxed. with continuous stirring, to dissolve the solid completely. The temperature of the solution was reduced to room temperature and the compound thus obtained was filtered and dried at 75-80°C under vacuum to get crystalline pure form A.
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope of this invention.

We Claim:
1. A crystalline form III of febuxostat, characterized by an X-ray powder
diffraction pattern having peaks at about 5.85, 8.06, 11.64, 12.83, 17.03, 20.59 ± 0.2 2θ
values.
2. The crystalline form III of febuxostat as claimed in claim 1, further characterized by FTIR spectrum having peaks at about 1292 and 1691 cm-1.
3. A crystalline form IV of febuxostat, characterized by an X-ray powder diffraction pattern having peaks at about 5.85, 6.74, 8.13, 9.34, 11.01, 11.72, 13.57, 14.25, 15.73, 16.26, 16.65, 17.41, 18.33, 25.85, 26.73 ± 0.2 2θ values.
4. The crystalline form IV of febuxostat as claimed in claim 3, further characterized by FTIR spectrum having peaks at about 1288 and 1693 cm" .
5. A process for preparing crystalline form III as claimed in claim 1, by crystallizing febuxostat from carboxylic acid ester solvents.
6. The process as claimed in claim 5, wherein the carboxylic acid ester solvents are selected from the group comprising of methyl acetate, ethyl acetate, n-butyl acetate, isobutyl acetate, or mixtures thereof.
7. A process for preparing crystalline form IV as claimed in claim 3, comprising dissolving febuxostat in methyl isobutyl ketone and then adding hexane to obtain a solid.
8. The process as claimed in claim 7, further comprising drying the solid at a temperature in the range from 25°C to 80°C under reduced pressure or atmospheric pressure.
9. A process for preparing crystalline form A, wherein the process comprises:

(a) providing a solution of febuxostat in a suitable solvent or mixture of solvents; and
(b) isolating crystalline form A of febuxostat.

10. The process as claimed in claim 9, wherein the solvent or mixture of solvents is selected from the group consisting of water, alcohols, ketones, polar aprotic solvents, and mixtures thereof.
11. The process as claimed in claim 9, wherein the solution is provided by dissolution of febuxostat in a solvent at a temperature range of 20°C to 150°C.
12. The process as claimed in claim 9, wherein isolation is carried out by removal of solvent by known technique in the art or adding anti-solvent.
13. The process as claimed in claim 12, wherein the anti-solvent used for isolation is selected from the group consisting of ethers, aliphatic or alicyclic hydrocarbons, aromatic hydrocarbons, esters and mixtures thereof.