FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13) TITLE OF THE INVENTION
"Process for preparation of Febuxostat polymorph"
Emcure Pharmaceuticals Limited, an Indian company, registered under the Indian Company's Act 1957 and
having its registered office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of Form G of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid (Febuxostat) wherein the crude solid is crystallized in alcohol, followed by treatment of the obtained solid with water to give form G.
BACKGROUND OF THE INVENTION
Febuxostat of formula (I), chemically known as 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, is indicated for use in the treatment of hyperuricemia and chronic gout (a disorder caused by deposition of urate crystals in joints and other tissues). The drug is a non-purine inhibitor of xanthine oxidase, and exerts the desired effect by lowering urate concentrations in the body; Febuxostat was approved in the United States by the Food and Drug Administration (FDA) on February 13, 2009 for the chronic management of hyperuricemia in patients with gout. It is available under the brand name Uloric (Takeda Pharma.).

Febuxostat (I)
Febuxostat (I) and the process for its preparation were first disclosed in US 5,614,520. The procedure for Febuxostat synthesis, as disclosed in US'520 comprises crystallization from ethanol as the final step.. However, the document does not describe any specific polymorphic form for the molecule under consideration.
US 7,361,676 discloses solid formulations containing a singular crystalline form A of Febuxostat.

US 6,225,474 describes five different crystalline forms of Febuxostat denoted as Form A, Form B, Form C, Form D and Form G along with details of their methods of preparation and X-ray diffraction patterns. According to the disclosure, while majority of these forms are obtained by Methanol/Water reprecipitation method, the crystal forms A, D and G are obtained by crystallizing Febuxostat in different compositions of methanol and water under varied temperature conditions. Solvent mediated polymorphic transition in methanol and water mixture gives Form C, while drying of Form G yields Form B.
In addition, US '474 further discloses an amorphous form denoted as Form E for Febuxostat and also mentions that forms A, C and G are useful since they retain their crystal forms during the long-term storage of their formulations.
After a careful study of the preparation methods for obtaining various polymorphs of Febuxostat as disclosed in prior art, followed by related experimentation, it was observed that since processes for all three important polymorphs A, C and G involved mixtures of methanol and water, obtaining the desired polymorph in pure form was largely dependent on solvent composition, effective reaction temperature, reaction time, stirring speed etc. Minor changes in these parameters, especially in the preparations on commercial scale, usually resulted in a crystal-mixture rather than a single desired polymorph. This mixture of polymorphs thus obtained, necessitated further purification processes, which involved a number of unit operations and incurred additional cost.
Thus, there still exists a need for a convenient and robust process for preparation of a single polymorph of Febuxostat which avoids use of solvent mixtures, extensive purification procedures and is capable of providing the desired crystal form as a single polymorph.
The present inventors, after extensive experimentation followed by stability and shelf-life studies, converged on Form G as desired polymorph for Febuxostat and have developed a robust, yet convenient process for preparing the same, wherein the aforementioned drawbacks from prior art methods are avoided and the required Febuxostat-G having desired polymorphic purity is obtained in good yield.

OBJECT OF THE INVENTION
An objective of the present invention is to provide Febuxostat-Form G by a cost-effective and industrially viable process wherein crude Febuxostat is sequentially treated with ethanol and water to yield the form G having desired polymorphic purity.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparation of Febuxostat-Form G having desired
polymorphic purity.
An aspect of the invention relates to a process for preparation of Febuxostat-Form G
comprising heating Febuxostat in alcohol at 65-70°C to obtain a clear solution, isolation of
solid by cooling and filtration, addition of water to the resultant solid and heating till
completion of formation of Form-G, followed by isolation to afford Form G
The objectives of the present invention will become more apparent from the following detailed
description.
DETAILED DESCRIPTION OF THE INVENTION
Polymorphism is defined as ability of a material to exist in more than one crystalline state and such states are called as polymorphs or polymorphic forms of the said material. It is now well established that different polymorphic forms of a compound exhibit significant differences in physical properties such as appearance and shape of crystals, strength as hardness or brittleness of the crystalline material, melting points etc. as well as varied stability profiles. Thus, polymorphs, due to their varied properties, influence operational parameters, preparation procedures, dissolution profiles and shelf-life stability of their respective pharmaceutical • formulations.
Hence, selection of a particular polymorph for an active pharmaceutical ingredient (API) exerts profound effect on the important attributes such as stability and bioavailability of the formulation.
Different polymorphic forms of Febuxostat have been reported in the prior art along with preparation procedures for the same. These strategies comprise of methanol/water reprecipitation method wherein the desired polymorph is said to be obtained by changing the composition and temperature parameters. Since process of crystallization is highly sensitive to solvent and temperature, it is clear that minor changes in these conditions, either deliberate or

inadvertent, would result in drastic changes in the resultant polymorphic composition and these effects would be more pronounced on industrial scale wherein large quantities of solvent volumes are involved. It was experimentally observed that application of prior art methods usually resulted in mixture of different polymorphs of Febuxostat and even if in some cases, reasonably pure polymorph was obtained, repeatability of the experimentation was very poor.
The present inventors, therefore, during their extensive experimentation towards developing a
robust and industrially applicable method for preparation of polymorphically pure Febuxostat,
focused on a method which involved sequential use of singular solvents, thus avoiding solvent
mixtures. Further, the method would result in a single polymorphic form in a highly consistent
manner, in laboratory experiments as well as on commercial scale.
Accordingly, the inventors studied different polymorphs of Febuxostat with respect to stability
as well as shelf life studies of their respective formulations and selected Form-G as the desired
polymorph.
Further, the synthetic strategy for obtaining the required polymorph was designed such that
crude Febuxostat was first crystallized from alcohol, followed by subsequent water treatment
which enabled polymorphic transition, as monitored by IR spectroscopy, converting the
mixture into Form G possessing desired polymorphic purity.
Desired polymorphic purity refers to Febuxostat sample wherein more than 99.5 % of
Febuxostat is present as Form-G
Avoiding solvent mixtures was advantageous since it significantly reduced the problems and
inconsistencies associated with changes in composition, resulting in desired polymorphic
material in good yield. It also improved the recovery of alcoholic solvents, which significantly
reduced the load of organic solvents in the effluent, thus making the process eco-friendly.
In an embodiment, crude Febuxostat was mixed with an alcoholic solvent, and heated till a clear solution was obtained. The mixture was gradually cooled and a seeding of Febuxostat- G was added to it. The stirring was continued, followed by cooling and filtration to yield a solid. The alcoholic solvent was selected from the group comprising of methanol, ethanol and isopropanol.

The obtained solid was mixed with water and heated along with stirring, simultaneously
monitoring the intermittent samples by IR spectroscopy for polymorphic composition of
Febuxostat.
After complete conversion, when the peaks for polymorphs other than G were no longer
observed in the IR spectrum, the reaction mass was cooled, filtered and air-dried till the
moisture content was between 2.5% to 4%.
The solid was characterized as follows.

Fig.l: XRD pattern of 2-[3-cyno-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid -Form G of the present invention

XRD : (Fig-1) 28 : 4.8, 6.23, 6.91, 8.04, 8.42, 8.95, 9.65, 10.70, 11.86, 12.86, 13.04, 13.86, 14.19, 14.71, 16.07, 16.34, 16.89, 17.7, 18.6, 19.10, 20.10, 20.86, 21.36, 22.60, 22.98, 23.49, 23.85, 24.03, 24.89, 25.26, 28.86, 26.19, 26.75, 27.14, 27.66, 28.00, 28.67, 28.93, 29.6, 29.78, 30.09, 30.99, 31.43, 32.26, 32.54, 33.54, 34.24, 35.08, 35.82, 36.55, 37.19, 38.19, 39.16, 40.38, 41.52, 41.81, 42.50, 42.66, 43.93, 45.11, 46.69 ±0.2 degrees.
EXAMPLES
Example 1: Preparation of 2-[3-cyno-4-(2-methylpropoxy) phenyl]-4-methyIthiazole-5-
carboxylic acid (Febuxostat)
Ethyl-2-[3-cyno-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate (200.5 g) was dissolved in ethyl alcohol (1000 ml) and the stirred solution was treated with aqueous solution of sodium hydroxide (25.6 g in 240 ml water) at 55 to 65oC. After completion of reaction as monitored by HPLC, the reaction mixture was cooled, along with stirring to obtain sodium 2-[3-cyno-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate as solid, which was filtered.
Water (2000 ml) and concentrated hydrochloride acid (35 ml) were added to the filtered solid and the stirred mixture was heated to 60 to 65°C. After completion of the reaction as monitored by HPLC, ethyl acetate (1400 ml) was added to the reaction mass, stirred and the layers were separated. The organic layer was separated, concentrated, followed by addition of water to the residue and heating. The resulting mixture was cooled and filtered to obtain crude 2-[3-cyno-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid.
Yield: 157.6 g (86%)
Example 2: Preparation of Febuxostat -Form G
Crude Febuxostat (140.2 g) was dissolved in ethanol (1120 ml) and heated till a clear solution was obtained. The mixture was cooled gradually, followed by addition of seeding of Febuxostat- G and stirred further, followed by cooling and filtration. The obtained solid was mixed with water (1400 ml) and heated till the formation of Form G was complete. The reaction mixture was cooled, filtered and the solid was air dried till the moisture content in the sample was between 2.5% to 4%. Yield: 120.6 g.

We claim:
1. A process for preparation of Febuxostat -Form G comprising heating Febuxostat in alcohol at 65-70°C till a clear solution is obtained, isolating form G, adding water to the resultant solid, heating and isolating Febuxostat -Form G.
2. The process as claimed in claim 1, wherein the alcohol is selected from methanol and ethanol.
3. The process as claimed in claim 1, wherein the isolation comprises cooling the reaction mixture, filtration and drying.
4. The process as claimed in claim 1, wherein polymorphic purity of the obtained Form-G is not less than 99.5%.