Field of the Invention:

The present invention relates to a novel crystalline form of anti-hyperuricemia drug, i.e. 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid represented by the structure formula-1 and its process for preparation.

Background of the Invention:

2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid is an inhibitor of xanthine oxidase that is indicated for use in the treatment of hyperuricemia and gout.

2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid was approved by the European Medicines and the U.S. Food and Drug Administration. 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid is marketed by Takeda Pharmaceuticals with the brand names Adenuric (EU) and Uloric (US).

Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal lattice". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Polymorphism may influence pharmaceutically relevant properties of the solid such as bio-availability, bio-equivalence, drug product stability, dissolution properties. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential scanning calorimetry (DSC) and Infrared spectrometry (IR).

Solvent medium and mode of crystallization play very important role in obtaining one polymorphic form over the other.

2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid can exist in different polymorphic forms, which may differ from each other in terms of stability, physical properties, spectral data and method of preparation.

2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid and its process were first disclosed in US 5614520.

US 6225474 was disclosed crystalline form-A, form-B, form-C, form-D, form-G and amoiphous form of 2-[3-cyano-4-(2-methylpropoxy)phenyI]-4-methylthiazole-5-carboxylic acid.

WO 2008067773 was disclosed crystalline form-H, form-I and form-J of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, which are obtained from nitrile solvents such as acetonitrile, propionitrile under different reaction conditions.

WO2010144685 was disclosed crystalline form-F1, form-F2, form-F3, form-F4, form-F5, form-F6, form-F7, form-F8, form-F9, form-F10, form-F11, form-F12, form-F13 and Form-F14 of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid.

Summary of the Invention:

The first aspect of the present invention relates to an ethylene glycol solvate of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1.

The second aspect of the present invention provides a process for preparation of ethylene glycol solvate of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1.

Brief description of the Figures:

Figure-1: Illustrates the powder X-ray diffractogram of ethylene glycol solvate of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1. Figure-2: Illustrates the Infrared spectrum of ethylene glycol solvate of 2-[3-cyano-4- (2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1. Detailed description of the Invention:

The first aspect of the present invention relates to an ethylene glycol solvate of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1.

The ethylene glycol solvate of compound of formula-1 of the present invention is obtained as crystalline solid.

The crystalline solid (herein after designated as crystalline form-S) of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1, which is characterized by its powder XRD having peaks at about 7.29, 17.19, 19.76, 22.03, 26.96 and 28.69 ± 0.2 degrees theta and substantially as shown in figure-1.

The crystalline form-S of compound of formula-1 is further characterized by powder XRD having peaks at about 9.82, 20.76, 22.33, 22.64, 24.13, 24.82, 25.35 and 25.63 ± 0.2 degrees two-theta and substantially as shown in figure-1.

The second aspect of the present invention provides a process for preparation of crystalline ethylene glycol solvate of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1, comprising of:

a) Dissolving the 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5- carboxylic acid compound of formula-1 in ethylene glycol by heating,

b) cooling the reaction mixture to 25-35°C and stirring the reaction mixture,

c) filtering the solid and then drying to get crystalline ethylene glycol solvate of compound of formula-1.

The 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1 which is used as a starting material for the preparation of crystalline ethylene glycol solvate of compound of formula-1 can be prepared as per the process disclosed in US 5614520 and heterocycles, 1998, 47 (2), pg. 863. The starting material can also be prepared from any prior known processes. The starting material can be taken as either wet or dried material.

The crystalline ethylene glycol solvate of the present invention can be used as a medicament for the treatment of hyperuricemia and gout.

The crystalline ethylene glycol solvate of the present invention can be further micronized or milled to get the desired particle size. Techniques that may be used for particle size reduction include, without limitation, ball, roller, hammer mills and jet mills.

PXRD analysis of crystalline ethylene glycol solvate of 2-[3-cyano-4-(2-methyl propoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1 was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not construed as limitation of the scope of the invention.

Examples:

Example-1: Process for the preparation of ethylene glycol solvate of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyItliiazole-5-carboxylicacid

A mixture of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1 (10 g) and ethylene glycol (300 ml) was heated to 160-165°C and then stirred for 45 minutes. The reaction mixture was cooled to 25-35°C and then stirred for 24 hours. Filtered the solid, washed with ethylene glycol and then dried to get title compound.

Yield: 14 grams; MR: 140-145°C; Ethylene glycol content: 35000 ppm PXRD and IR of the obtained 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid ethylene glycol solvate are represented in figure-1 and figure-2 respectively.
We Claim:

1. 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid ethylene glycol solvate.

2. According to claim 1, Ethylene glycol solvate of 2-[3-cyano-4-(2-methyl propoxy)phenyl]-4-methylthiazole-5-carboxylic acid is obtained as crystalline solid.

3. A crystalline ethylene glycol solvate of 2-[3-cyano-4-(2-methyl propoxy)phenyl]-4-methylthiazole-5-carboxylic acid, which is characterized by its powder X-ray diffractogram having peaks at about 7.29, 17.19, 19.76, 22.03, 26.96 and 28.69 ± 0.2 degrees two-theta and substantially as shown in figure-1.

4. A crystalline ethylene glycol solvate of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid according to claim 3, which is further characterized by its powder X-ray diffractogram having peaks at about 9.82, 20.76, 22.33, 22.64, 24.13, 24.82, 25.35 and 25.63 ± 0.2 degrees two-theta and substantially as shown in figure-1.

5. A process for the preparation of crystalline ethylene glycol solvate of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, comprising of:

a) Dissolving the 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1 in ethylene glycol by heating,

b) cooling the reaction mixture to 25-35°C and stirring the reaction mixture,

c) filtering the solid and then drying to get crystalline ethylene glycol solvate of compound of formula-1.

6. Use of crystalline ethylene glycol solvate of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid in the preparation of pharmaceutical composition for the treatment of hyperuricemia and gout.