FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention: -Process for preparation of febuxostat and crystalline form
thereof
2. Applicant(s)
(a) NAME: CAD1LA HEALTHCARE LIMITED.
(b) NATIONALITY: INDIAN
(c) ADDRESS: CADILA HEALTHCARE LTD; PLOT NO. 26-29 & 31, DABHASA-UMARAYA ROAD, VILL. DABHASA-391440, TAL. PADRA, DIST. VADODARA, GUJARAT, INDIA
3. PREAMBLE TO THE DESCRIPTION:
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 an improved process for the preparation of febuxostat and its crystalline form. In particular, the present invention provides an improved process for the preparation of crystalline Form-A of febuxostat. The present invention also relates to crystalline Form-A of Febuxostat having particle size D (90) less than about 12 µm.
BACKGROUND AND PRIOR ART
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
The common name of "2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid" is Febuxostat(1), mainly is used for the treatment of hyperuricemia.

U.S. Patent No. 5,614,520 discloses the process for the preparation of 2-arylthiazole derivative or pharmaceutically acceptable salt thereof, including febuxostat for treating diseases selected from consisting of gout or hyperuricemia and diseases associated with a production of interleukin.
Heterocycles Vol. 47, No. 2 (1998) p 857 discloses the process for the preparation of febuxostat (I) by using 4-isobutoxy-l,3-benzenedicarbonitrile.

The process parameters provided in Heterocycles discloses introduction of cyano group to 4-nitrobenzonitrile and converting it to 4-a!koxy-l,3-benzenedicarbonitrile in a one pot process. Further the obtained 4-alkoxy-1,3-benzenedicarbonitrile can be converted to febuxostat (1) as shown in reaction scheme-2.

Scheme-2
U.S. Patent 6,225,474 B1 discloses the presence of five crystal polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, crystals A, B, C, D, and G and an amorphous form and a method for producing them. The method for producing crystal polymorphs described here involves the production of each crystal polymorph by adding a predetermined mixed solvent of methanol and water to 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, dissolving the resultant mixture by heating with stirring, cooling the mixture by the addition of water to obtain the predetermined methanol and water composition and temperature, then collecting crystals by filtration, and drying the crystals.
U.S. Patent 7,361,676 B2 discloses crystal Fom-A with particle size from about 3 µm to 50 µm are better for preparation of pharmaceutical compositions such as tablets. More particular, the particle size having average diameter from about 12.9 to 26.2 are more suitable for pharmaceutical composition based on the disintegration time for the tablets.
International (PCT) Publication WO 2007/0148787 A1 discloses a process for selective production of crystal A of Febuxostat which comprises dissolving Febuxostat in methanol or a

methanol/water mixed solvent (having a methanol/water volume ratio of 90/10 or above), adding water to the resulting solution to adjust the methanol/water ratio to 7/3, and adding a specified amount of seed crystals to the solution during the addition of water at a specified stage.
The present invention has also found that crystalline form A with reduced particle size are suitable for preparation of pharmaceutical compositions like tablets and are having better bioavailability and stability with respect to particle size reported in the prior art. An object of the invention is, therefore, to provide improved process for the preparation of crystalline Form-A of febuxostat (1) with reduced particle size. An object of the invention is, also to provide crystalline Form-A of febuxostat (1) having higher purity.
SUMMARY OF INVENTION
In accordance with the invention it has been surprisingly found that certain particle size distribution have a beneficial effect on the content uniformity of solid pharmaceutical compositions of Febuxostat (1) in particular crystalline Form-A. Milling, as well as other methods can be used to alter the particle size distribution (hereinafter "PSD") of Febuxostat in order to provide greater uniformity of content of the drug product.
In first aspect, there is provided an improved process for the preparation of crystalline Form-A of Febuxostat (1),

the process comprising:
(a) combining Febuxostat with suitable organic solvent to form the reaction mixture;
(b) heating the reaction mixture at boiling point of solvent;
(c) removing the organic solvent to obtain residue:
(d) treating the residue with suitable anti-solvent: and
(e) isolating crystalline Form-A of Febuxostat (1).

In an aspect the present invention provides Febuxostat crystalline Form-A with PSD D(90) less than 12 µm and D(50) less than 7 µm, comprising milling Febuxostat crystalline Form-A to reduce the particle size.
In second aspect, there is provided an improved process for the preparation of crystalline Form-A of Febuxostat (1), the process comprising:
(a) providing solution of Febuxostat in suitable organic solvent to form the reaction mixture;
(b) heating the reaction mixture at boiling point of solvent;
(c) optionally, partially removing suitable organic solvent;
(d) cooling the reaction mixture;
(e) optionally seeding with crystalline Form-A; and
(f) isolating crystalline Form-A of Febuxostat (1).
In third aspect, there is provided an improved process for the preparation of crystalline Form-A of Febuxostat (I) with particle size D(90) less than 12 urn and D(50) less than 7 urn, the process comprising:
(a) combining Febuxostat with suitable organic solvent to form the reaction mixture;
(b) heating the reaction mixture:
(c) removing the organic solvent to obtain residue;
(d) treating the residue with suitable anti-solvent;
(e) isolating crystalline Form-A of Febuxostat (1): and
(f) milling to obtain crystalline Form-A with particle size D(90) less than 12 µm and D(50) less than 7 µn.
According to one of the aspect, there is provided Febuxostat crystalline Form-A having PSD D(90) < 12µm and D(50) < 7 µm.
According to one of the aspect, Febuxostat crystalline Form-A used for the preparation of pharmaceutical compositions is characterized by atleast one of an x-ray powder diffraction spectrum having peaks expressed as at about 7.1°, 12.7° and 19.5° (20) and differential scanning calorimetry analysis having one cndothermic peaks in the range of 208-211°C.

In an aspect, the present application provides a compound Febuxostat crystalline Form-A having a HPLC purity of greater than about 95%. In particular it may be greater than about 97%. More particularly, it may be greater than about 99%, as determined using high performance liquid chromatography (HPLC).
An aspect of the present invention provides compositions comprising Febuxostat crystalline Form-A substantially free of one or more of its corresponding impurities as measured by HPLC.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG1: X-ray diffraction pattern of crystalline Febuxostat Form-A.
FIG.2: Differential Scanning Calorimetry of crystalline Febuxostat Form-A.
FIG.3: Infrared spectrum of crystalline Febuxostat Form-A.
DETAILED DESCRIPTION OF THE INVENTION
As used here in the term "isolation" includes filtration, filtration under vacuum, centrifugation, decanlation and the like. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
Optionally, the solution, prior to any solids formation, can be filtered to remove any undissolved solids, solid impurities and the like prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used.
As used herein, the terms "solution" includes formation of solution of febuxostat obtained by formation of Febuxostat in the reaction mixture, addition of Febuxostat in suitable organic solvent and/or generation of Febuxostat during the reaction. The solution may be a heterogeneous mixture where complete dissolution does not occur. Also, heating the suspension or slurry can result in a homogenous mixture where complete or partial dissolution occurs at an elevated temperature or ambient temperature.
The term "heating" used herein means, heating the reaction mixture either heterogeneous or homogeneous at a temperature from about 35°C to boiling point of solvent. In particularly, it may

be from about 35°C to about S20°C. The term "ambient temperature'1 used herein means, slurrying the reaction mixture either heterogeneous or homogeneous at a temperature from about 10°C to about 35°C of solvent.
The term "PSD" means particle size distribution.
Febuxostat crystalline Form-A, however is readily soluble in water. Such better dissolution behavior minimizes concerns related to gastrointestinal absorption and bioavailability. Hence. increasing solubility is not a motivating factor for comminution of febuxostat crystalline Form-A.
Jn such cases where drug substances already posses high solubility, particle size reduction may be inadvisable and even deleterious. Increasing surface area by comminution can increase degradation rates of the active substance. Febuxostat may also undergo unwanted polymorphic transformation during comminution. As a result, comminution may affect the efficacy and safety of a drug substance.
In spite of the fact that comminution is unnecessary to increase the solubility of readily-soluble febuxostat Form-A, it was unexpectedly found that reduction of particle size, via comminution, improved content uniformity of the tablet as well as particle size D(90) less than 12 µm and D(50) less than 7 µm shows better bioavailability.
A method for comminution is determined based on the characteristics of the material, such as initial particle size and desired particle size, as well as melting point, brittleness. hardness, and moisture content. Milling has been determined to be suitable to alter the PSD of Febuxostat crystalline Form-A in order to provide uniformity of content of the drug product.
Many analytical tools are available to determine PSD. In the early development stage, the analysis of PSD was performed through microscopic and sieve analysis. Laser diffraction was chosen as the final analytical method for measuring the PSD. Because the large particles were of major concern, the important characteristic of the PSD were the D(90), which is the size, in microns, below which 90% of the particles by volume are found, and the D(50). which is the size, in microns, below which 50% of the particle by volume are found.

"Blend uniformity," as used herein, refers to the homogeneity of granulate including Febuxostat crystalline Form-A particles before tablet formulation, and can represent either one sample or the average of more than one sample.
"Content uniformity," as used herein, refers to the homogeneity of the Febuxostat crystalline Form-A content among dosage forms, e.g. tablets, after formulation.
''Particle," as used herein, refers to an aggregated physical unit of the febuxostat crystalline Form-A, i.e. a piece or grain of the febuxostat crystalline Form-A,
"Relative standard deviation," or "RSD," as used herein, refers to a measurement of how precise each measurement of blend uniformity or content uniformity is. i.e.. how much each individual unit deviates from the group.
In one general aspect, there is provided an improved process for the preparation of crystalline Form-A of Febuxostat (1),

the process comprising:
(a) combining Febuxostat with one or move of suitable organic solvent to form the reaction mixture:
(b) heating the reaction mixture;
(c) removing the organic solvent to obtain residue;
(d) treating the residue with suitable anti-solvent; and
(e) isolating crystalline Form-A of Febuxostat (I).
In general, the suitable organic solvent comprises one or more of C1-4 alcohol. C3-8 ketones, C2-6 ester, amides, sulfoxide, nitriles, and the like. In particular, the suitable solvent may be one or more of methanol, ethanol, isopropanol, butanol, acetone, methylethyl ketone, methyl

isobutylketone, ethyl acetate, n-butyl acetate, isopropyl acetate, dimethylformamide. dimethylacetamide, dimethyl sulfoxide, acetonitrile, N-methylpyrrolidone and water, or a mixture thereof in suitable combination. In particular, it may be ethyl acetate.
The anti-solvent used comprises one or more of hexane, heptane, cyclohexane, diethylether, diisopropytether or mixture thereof. In particular, cyclohexane or n-heptane may be used.
According to further embodiments, febuxostat was heated in ethyl acetate to dissolve at about 75°C to 80°C followed by removal of solvent. The solvent may be removed by distillation atmospherically at 75°C to 80°C followed by under vacuum at less than 600 mm/Hg pressure below 45°C. The residue obtained are treated with cyclohexane below 45°C and stirred for 1 hour. The product was filtered, washed with cyclohexane and suck dried to give febuxostat crystalline Form-A.
According to further embodiments, febuxostat was dissolved in ethyl acetate at about 75°C to 80°C followed by removal of solvent. The solvent may be removed by distillation atmospherically at 75°C to 80°C followed by under vacuum at less than 600 mm/Hg pressure below 45°C. The residue obtained are treated with n-heptane below 45°C arid stirred for I hour. The product was filtered, washed with n-heptane and suck dried to give febuxostat crystalline Form-A.
In an embodiment, the present invention provides febuxostat crystalline Form-A with PSD D(90) less than 12 urn and D(50) less than 7 urn. comprising milling febuxostat crystalline Form-A to reduce the particle size.
In an embodiment, the present invention provides febuxostat crystalline Form-A with PSD D(90) less than 12 µm and D(50) less than 7 urn.
In another general aspect, there is provided an improved process for the preparation of crystalline Form-A of febuxostat (1), the process comprising:
(a) providing solution of febuxostat in one or more of suitable organic solvent to form the reaction mixture:
(b) heating the reaction mixture;
(c) optionally, partially removing suitable organic solvent;
(d) cooling the reaction mixture;

(e) optionally seeding with crystalline Form-A; and
(f) isolating crystalline Form-A of febuxostat (1).
The solution of febuxostat in one or more of suitable organic solvent may be obtained to form the reaction mixture by formation of febuxostat during the reaction or addition of febuxostat solid or suspension in one or more of suitable solvent to obtain a heterogeneous mixture.
The suitable organic solvent comprises one or more of C1-4 alcohol. C3-6 ketones, C2-6 ester, amides, sulfoxide, nitriles and the like. In particular, the suitable solvent may be one or more of methanol, ethanol, isopropanol, butanol, acetone, methylethyl ketone, methyl isobutylketone, ethyl acetate, n-butyl acetate, isopropyl acetate, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile. N-methylpyrrolidone and water, or a mixture thereof in suitable combination. In particular, it may be ethyl acetate.
In general, the solution of febuxostat in ethyl acetate is heated to reflux temperature of solvent. In particular, it may be heated from about 50°C to about 90°C to obtain the clear solution. The reaction mixture is distilled atmospherically for partial removal of solvent. The reaction mixture is cooled to about 50°C whereupon, it may optionally be seeded with 1% crystalline Form-A. The reaction mixture is further cooled gradually to obtain crystalline Form-A.
In another general aspect, there is provided an improved process for the preparation of crystalline Form-A of febuxostat (1) with particle size D(90) less than 12 µm and D(50) less than 7 µm. the process comprising:
(a) combining febuxostat with one or more of suitable organic solvent to form the reaction mixture:
(b) heating the reaction mixture;
(c) removing the organic solvent to obtain residue:
(d) treating the residue with suitable anti-solvent;
(e) isolating crystalline Form-A of febuxostat (1); and
(f) milling to obtain crystalline Form-A with particle size D(90) less than 12 µm and D(50) less than 7 urn.
The suitable organic solvent comprises one or more of C1-4 alcohol. C3-6 ketones, C2-6 ester, amides, sulfoxide, nitriles and the like. In particular, the suitable organic solvent comprises one or more of methanol, ethanol, isopropanol. butanol, acetone, methylethyl ketone, methyl

isobutylketone, ethyl acetate, n-butyl acetate, isopropy] acetate, dimerhylformamide, dimelhylacetamide, dimethylsulfoxide, acetonitrile, N-methylpyrrolidone and water, or a mixture thereof in suitable combination. In particular, it may be ethyl acetate.
According to the present invention, anti-solvent used comprises of hexane, heptane, cyclohexane. diethylether, diisopropylether or mixture thereof.
According to the present invention, febuxostat is dissolved in ethyl acetate at about 75°C to 80°C followed by removal of solvent. The solvent may be removed by distillation atmospherically at 75°C to 80°C followed by under vacuum at less than 600 min/Hg pressure below 45°C. The residue obtained are treated with cyclohexane below 45oC and stirred for 1 hour. The product was filtered, washed with cyclohexane and suck dried to give febuxostat crystalline Form-A. The isolated Febuxostat crystalline Form-A is having PSD D(90) > 200 urn and D(50) > 15 µm when measured by Malvern Laser Diffraction, using the Mastersizer instrument.
According to the present invention, febuxostat is dissolved in ethyl acetate at about 75°C to 80°C followed by removal of solvent. The solvent may be removed by distillation atmospherically at 75DC to 80°C followed by under vacuum at less than 600 mm/Hg pressure below 45°C. The residue obtained are treated with n-heptane below 45°C and stirred for 1 hour. The product was filtered, washed with n-heptane and suck dried to give febuxostat crystalline Form-A. The isolated febuxostat crystalline Form-A is having PSD D(90) > 200 µm and D(50) > 15 µm when measured by Malvern Laser Diffraction, using the Mastersizer instrument as shown in Table-2.

Table 2
Pulverizer D(90) D(50)
As such before sieving 225.67 µm 16.16 µm
Sieving from 40 mesh 85.86µm 12.06 µm
Sieving from 60 mesh 48.61 µm 9.08 µm
Jet-Mill Ist time 24.68 µm 5.83 µm
Jet-Mill 2nd time 27.46 µm 4.52 µm
Jet-Mill 3rd time 22.25 µm 7.20 µm
Table 3 discloses the PSD of crystalline Form-A of febuxostat for the same batch when measured by image analysis measuring instruments after Jet-Mill 3rd time.

Table 3
Particle Size D(90) D(50)
Slide # 1 6.5 µm 11.5 µm
Slide #2 5.3 µm 11.5 µm
Slide # 3 5.8 µm 14.4 µm
Slide #4 6.0 µm 12.1 µm
Slide #5 5.9 µm 13.2 µm
Mean 5.9 µm 12.5 µm
Table 4 discloses the PSD of crystalline Form-A of febuxostat prepared as per example 7 when measured by image analysis measuring instruments after Jet-Mill 3rd time.

Particle Size* D(90) D(50)
Slide # 1 11.9 µm 5.0 µm
Slide #2 10.6 µm 4.6 µm
Slide # 3 11.5µm 5.5 µm
Mean 11.3 µm 5.0 µm

Particle Size** D(90) D(50)
Slide # 1 8.2 µm 4.0µm
Slide # 2 9.9 µm
5.4 µm
Slide #3 9.6µm 5.0µm
Mean 9.2 µm 4.8µm
* Parti ** Particle S cle Size after Jet-mil lit ize after sieving from 60 mesh
It is also the scope of the present invention to pulverize the solution of crystalline Form-A of febuxostat to obtain PSD D(90) < 12 µmm and D(50) < 7 µm when measured by Malvern Laser Diffraction, using the Mastersizer instrument or when measured by image analysis measuring instruments. In general, the solution of crystalline febuxostat Form-A may be prepared in suitable organic solvent comprises one or more of methanol, ethanol, isopropanol. butanol, acetone, methylethyl ketone, methyl isobutylketone, ethyl acetate, n-butyl acetate, isopropyl acetate, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile. N-methylpyrrolidone and water, or a mixture thereof in suitable combination. In particular, it may be ethyl acetate.

According to present invention, crystalline Febuxostat Form-A may be further milled to obtain PSD D(90) < 10 urn and D(50) < 7 µm when measured by Malvern Laser Diffraction, using the Mastersizer instrument or when measured by image analysis measuring instruments. According to one of the embodiment, crystalline Form-A of febuxostat used for the preparation of pharmaceutical compositions is characterized by atleast one of an x-ray powder diffraction pattern with characteristic peaks expressed at about 7.1°, 12.7° and ! 9.5° (29).
According to still another of embodiment, crystalline Form-A of febuxostat is characterized by differential scanning calorimetry analysis having one endothemic peak in the range of 208-2! I°C.
In an embodiment, the present application provides a compound febuxostat crystalline Form-A having a HPLC purity of greater than about 95%. In particular, it may be greater than about 97%. More particularly, it may be greater than about 99%. as determined using high performance liquid chromatography (HPLC).
An embodiment of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form-A of febuxostat having purity greater than 99% by HPC and one or more of pharmaceutically acceptable carriers, excipients, or diluents.
An embodiment of the present invention provides pharmaceutical compositions comprising therapeutically effective amount of crystalline Form-A of febuxostat having particle size distribution D(90) < 12 µm and D(50) < 7 urn alongwith
Powder X-ray Diffraction, and IR can be characterized crystalline Form-A of febuxostat as follows:
(i) Characterization by Powder X-ray Diffraction
The X-ray powder diffraction spectrum was measured under the following experimental
conditions:
Instrument : X-Ray Diffractometer. D/Max-2200/PC Make: Rigaku, Japan.
X- Ray : Cu/40kv/40mA
Diverging : 1
Scattering Slit 1°
Receiving Slit 0.15 mm

Monochromator RS : 0.8 mm
Counter : Scintillation Counter
Scan Mode Continuous
Scan Speed : 3.000°/Min
Sampling Width : 0.020
Scan Axes : Two Theta / Theta
Scan Range : 2.000° to 40.000°
Theta Offset : 0.000°
The 1R spectrum was measured by the KBr method.
In an embodiment, scheme-3 illustrates the process outline for present invention.


The invention also encompasses a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form-A of febuxostat with particle size distribution D(90) < 12µm and D(50) < 7 urn and one or more pharmaceutically acceptable carriers, excipients, or diluents.
As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" includes tablets, pills. powders: liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
Pharmaceutical compositions containing the crystalline Febuxostat Form-A with PSD D(90) < 12 urn and D(50) < 7 urn of the invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants. Various modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
Any excipient commonly known and used widely in the art can be used in the pharmaceutical composition.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification.
EXAMPLE 1:
Preparation of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (7):
1.0 Kg 4-hydroxyebenzonitrile. 0.95 Kg thioacetamide and 10 L isopropanolic hydrochloric acid were heated at 50°C for 16 hours. After the complelion of the reaction by TLC, the reaction mixture was cooled and filtered. The wet-cake was washed with 1 L of isopropanol and dried. 2.5 Kg of wet-cake. 1.51 Kg of ethyl-2-chloroaceloacetate and 10 L water were heated at 75°C for 1 hour. After the completion of the reaction by TLC, the reaction mixture was cooled and stirred for 30 min. The reaction mixture was filtered and the product was dried at 65°C to 70°C for 12 hours to obtain 72.4% yield ethyl 2-(4-hydroxyphenyl)-4-methylthiazoie-5-carboxy(ate.
EXAMPLE 2:

Preparation of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (5):
1.0 Kg ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate. 0.59 Kg hexamethyle-netetramine and 5 L triflouro acetic acid were heated at 80°C for 30 hours followed by cooling to 65°C. The reaction mixture was distilled under vacuum below 70°C and cooled to 40°C. A mixture of 10 L water and 2 L methanol was added and reaction mixture was stirred for 1 hour. The reaction mixture was filtered and washed with water. 2.20 Kg wet-cake was slurried in 3 L water and filtered. The wet-cake dried at 65°C to 70°C for 12 hours to obtain 90% yield ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazo!e-5-carboxylate.
EXAMPLE 3:
Preparation of ethyl 2-(3-formvl-4-isobutoxvphenyl)-4-methvlthiazole-5-carboxylate (4):
1.0 Kg ethyl 2-(3-formyl-4-hydroxyphenyl)-4-inethylthiazole-5-c.arboxylate, 0.59 Kg potassium carbonate, 1.41 Kg isobutyl bromide and 5 L dimethyl sulfoxide were heated at 80°C for 2 hours. After the completion of the reaction by TLC the reaction mixture was cooled and 3.5 L water was added. The reaction mixture stirred for 30 min. The product was filtered and washed with water. The wet-cake was dried at 65°C to 70°C for 12 hours to obtain 84% yield of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate.
EXAMPLE 4:
Preparation of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxvlate (3):
1.0 Kg ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazoIe-5-carboxylate, 3.67 Kg formic acid, 0.245 Kg hydroxylamine hydrochloride and 0.35 Kg sodium formate were heated at 100°C for 3 hours. After completion of the reaction as monitored by TLC. the reaction mixture was cooled and treated with 3 L water and stirred for 2 hours. The reaction mixture was filtered and washed with water. 1.90 Kg wet-cake was partitioned with 15 L ethyl acetate and 3 L water at 55°C and stirred to separate the layer at 55°C. The separated organic layer was treated with 0.1 Kg activated carbon, heated to 55°C and filtered. The wet-cake was washed with ethyl acetate. The filtrate was distilled under atmosphere at 75°C partially. The reaction mixture was cooled and stirred for 3 hours. The reaction mixture was filtered and washed with ethyl acetate to obtain 1.0 Kg ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate. The product was dried

at 65°C to 70°C for 12 hours to obtain 73% yield of 2-(3-cyano-4-isobutoxyphertyl)-4-methylthiazole-5-carboxylate.
EXAMPLE S:
Preparation of sodium 2-(3-cvano-4-isobutoxyphenyl)-4-niethylthiazole-5-carboxylate (2):
i.O Kg 2-(3-cyano-4-isobutoxypheny!)-4-methyIthiazole-5-carboxyiate. 0.128 Kg sodium hydroxide. 1 L water and 5 L isopropanol were heated at 75°C for 30 minutes. After the completion of the reaction by TLC, the reaction mixture was cooled and stirred for further 2 hours. The reaction mixture was filtered and washed with chilled isopropanol. The product was dried at 65°C to 70°C for 8 hours to obtain 79 % yield of sodium 2-(3-cyano-4-isobutoxyphenyl)-4-methy!thiazole-5-carboxylate.
EXAMPLE 6:
Preparation of Febuxostat Form-A:
100 g of sodium 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate and 1000 mL water and 2500 mL ethyl acetate were stirred at room temperature for 10 minutes. 70 mL (2.0%) conc, hydrochloric acid solution in 830 mL water was added to the reaction mixture. The reaction mixture was heated to 45°C and layers were separated. The separated organic layer was washed with 500 mL water. The separated organic layer was charcoalized at 45°C and filtered. The wet-cake was washed with 3 L hot ethyl acetate. The combined filtrate was distilled under atmosphere below 80°C to remove approx. ]600 mL ethyl acetate. The reaction mixture was cooled to 50°C and seeded with 1% Febuxostat Form-A. The reaction mixture was gradually cooled and filtered at 5°C. The wet-cake was washed with child ethyl acetate. The wet-cake was dried at 40°C to 45°C for 4 hours followed by drying at 50°C to 55°C for 8 hours to obtain 84% yield Febuxostat crystalline Form-A. The crystalline Febuxostat is characterized is X-ray diffraction pattern as shown in FIG. 1. Differential Scanning Calorimetry as shown in FIG.2 and Infrared spectrum as shown in FIG.3.
The crystalline Febuxostat Form-A was jet-milled followed by sieving from 60 mesh to obtain PSD D(90) < 12 µm and D(50) < 7µm.

EXAMPLE 7:
Preparation of Febuxostat Form-A:
250 g of 2-(3-cyano-4-isobutoxypheny])-4-methylthiazole-5-carboxy]ic acid and 6250 mL ethyl acetate were stirred at room temperature for 10 minutes. The reaction mixture was heated at 80°C to obtain clear solution. The reaction mixture was distilled atmospherically to remove 3250 mL ethyl acetate. The reaction mixture was cooled to 45°C and remaining ethyl acetate was distilled under vacuum to obtain residue. The residue was treated with 1750 mL cyclohexane and stirred for 1 hour. The product was isolated by filtration followed by washing wet-cake with cyclohexane. The wet-cake was dried at 40°C to 45oC for 4 hours followed by drying at 50°C to 55°C for 8 hours to obtain Febuxostat crystalline Form-A. The crystalline Febuxostat is characterized is X-ray diffraction pattern as shown in FIG. 1, Differential Scanning Calorimetry as shown in FIG.2 and Infrared spectrum as shown in FIG.3.The crystalline Febuxostat Form-A was jet-milled followed by sieving from 60 mesh to obtain PSD D(90) < 12 µm and D(50) < 7 µm.
EXAMPLE 8:
Preparation of Febuxostat Form-A:
250 g of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid and 6250 mL ethyl acetate were stirred at room temperature for 10 minutes. The reaction mixture was heated at 80°C to obtain clear solution. The reaction mixture was distilled atmospherically to remove 3250 mL ethyl acetate. The reaction mixture was cooled to 45°C and remaining ethyl acetate was distilled under vacuum to obtain residue. The residue was treated with 1500 ml.. hexane and stirred for I hour. The product was isolated by filtration followed by washing wet-cake with hexane. The wet-cake was dried at 40°C to 45°C for 4 hours followed by drying at 50°C to 55°C for 8 hours to obtain Febuxostat crystalline Form-A. The crystalline Febuxostat is characterized is X-ray diffraction pattern as shown in FIG.I, Differentia! Scanning Calorimetry as shown in FIG.2 and Infrared spectrum as shown in FIG.3. The crystalline Febuxostat Form-A was jet-milled followed by sieving from 60 mesh to obtain PSD D(90) < 12µm and D(50) < 7µm.

EXAMPLE 9:
Impurity Profile Determination of Febuxostat or Febuxostat Technical:
HPLC
Kromasil LC2010C HPLC svstem equipped with a UV-
Column & Packing:
VIS detector or equivalent
Eluent A: Buffer
Eluent B: Acetonitrile
Gradient of Eluent: Time (min) Eluent A (%) Eluent B (%)
0.01 55 45
35 20 80
50 20 80
51 55 45 60 55 45
Stop time: 60 min
Flow: 1.3 mL/minute
Detector: 318 nm
Injection Volume: 10µm
Diluent: Premixed Buffer and Acetonitrile in the volume ratio of 50:50
Column temperature: 30°C
Sample Solution Preparation:
Weigh accurately and transfer about 25 mg of sample of Febuxostat or Febuxostat (technical) into
a 50 mL volumetric flask. Add 5 mL tetrahydrofuran. sonicate to dissolve and make up the
volume with diluent. Make fresh two preparations at the time of injection.
Preparation of Buffer:
Transfer 1 mL of orthophosphoric acid in 1000 mL volumetric flask containing about 500 mL
water and make up the volume with water. Filter through 0.2 urn membrane filter paper.
Method
Inject sample solutions containing the chromatogram upto the end of gradient.
Determine the area of each impurity using suitable integrator.
Calculations: Any impurity in a sample is calculated as follows:
Area impurity in sample
% Impurity in sample = X 100
Σ Areas of all peaks RRT of the substances

Impurity RT RRT
FB-Acid amide 3.42 032
FB-Diacid 4.47 0.42
FB-Oxime 21.94 2.07
FB-Ethylester 26.33 2.48
FB-[sopropylester 30.22 2.85
The limit of quantification in the HPLC method is 0.01% for unknown impurities and 0.015% for known impurities.

We claim:
1. An improved process for the preparation of crystalline Form-A of febuxostat (1),

the process comprising:
(a) combining febuxostat with one or more of suitable organic solvent to form the reaction mixture;
(b) heating the reaction mixture;
(c) removing the organic solvent to obtain residue;
(d) treating the residue with suitable anti-solvent; and
(e) isolating crystalline Form-A of febuxostat (I).
2. An improved process for the preparation of crystalline Form-A of febuxostat (J), the process
comprising:
(a) providing solution of febuxostat in one or more of suitable organic solvent to form the reaction mixture;
(b) heating the reaction mixture;
(c) optionally, partially removing suitable organic solvent;
(d) cooling the reaction mixture:
(e) optionally seeding with crystalline Form-A; and
(f) isolating crystalline Form-A of febuxostat (1).
3. An improved process for the preparation of crystalline Form-A of febuxostat (1) with particle
size D(90) less than 12 um and D(50) less than 7 urn, the process comprising:
(a) combining febuxostat with one or more of suitable organic solvent to form the reaction mixture;
(b) heating the reaction mixture;
(c) removing the organic solvent to obtain residue:
(d) treating the residue with suitable anti-solvent:
(e) isolating crystalline Form-A of febuxostat (1): and
(f) milling to obtain crystalline Form-A with particle size distribution D(90) less than 12 µm and D(50) less than 7 µm.

4. The process according any preceding claims, wherein suitable organic solvent comprises one or more of C1-4 alcohols like methanol, ethanol, isopropanol, butanol, C3-8 ketones like acetone, methylethyl ketone, methyl isobulylketone, C2-6 esters like ethyl acetate, n-butyl acetate, isopropyl acetate, amides like dimethylformamide, dimethyiacetamide. sulfoxide like dimethylsulfoxide, nitriles like acetonitrile, N-methylpyrrolidone and water, or a mixture thereof in suitable combination.
5. The process according to any preceding claims, wherein suitable anti-solvent comprises of hexane, heptane, cyclohexane, diethylether. diisopropylether or mixture thereof.
6. The process according any preceding claims, wherein crystalline Form-A of febuxostat is isolated by filtration, filtration under vacuum, centrifugation, decantation and the like.
7. The process according to any preceding claims, wherein milling comprises jet-milling, multi-milling, ball-milling, grinding, cryo-grinding, pulverizing and the like.
8. A process to pulverize the solution of crystalline Form-A of febuxostat to obtain particle size distribution D(90) < 12 µm and D(50) < 7 µm when measured by Malvern Laser Diffraction, using the Mastersizer instrument or when measured by image analysis measuring instruments.
9. A pharmaceutical composition comprising a therapeutically effective amount of crystalline Form-A of febuxostat with particle size distribution D{90) < 12 µm and D(50) < 7µm and one or more pharmaceutically acceptable carriers, excipients, or diluents.
10. A pharmaceutical composition comprising a therapeutically effective amount of crystalline Form-A of febuxostat having purity greater than 99% by HPLC prepared by process according to any preceding claims and one or more of pharmaceutically acceptable carriers, excipients, or diluents.