Pharmaceutical Co-crystals of Febuxostat
FIELD OF THE INVENTION:
The present invention relates to pharmaceutical co-crystals of Febuxostat, Pharmaceutical composition thereof, processes for their preparation and their use for the chronic management of hyperuricemia in patients with gout.
BACKGROUND OF THE INVENTION:
Febuxostat is a non-purine xanthine oxidase inhibitor disclosed in U.S. Patent No. 5,614,520. It is chemically described as 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid having the structure as represented by Formula I. as below:
Febuxostat is marketed in the United States under the brand name Uloric® for the chronic management of hyperuricemia in patients with gout. Gout is a disorder caused by the deposition of monosodium utrate crystals in joints and tissues as result of extracellular urate super saturation. However, hyperuricemia is the most important risk factor for the development of gout and occurs as result of increased uric acid production.
PCT Publication No. WO 1999/065885 discloses crystalline forms of Febuxostat include Form A, B, C, D (methanolate), E, G (hydrate), as well as an amorphous form.
PCT Publication No. WO 2004/078163 A1 discloses generally the list of various co-former and active pharmaceutically acceptable ingredients including Febuxostat.

PCT Publication No. WO 2012/098501 describes Febuxostat co-crystal with urea, nicotinamide and caffeine. However, isolation of co-crystal takes more time and it is not a commercially feasible process. The yield of Febuxostat co-crystal with urea, nicotinamide and caffeine is less.
"Crystal Growth & Design (2013), 13(7), P3188-3196" describes Febuxostat co-crystal with urea, nicotinamide, saccharin, acetamide and p-aminobenzoic acid (PABA). CN 103044353 B describes Febuxostat co-crystal with isonicotinic acid.
Still, there remains need for co-crystal of Febuxostat which can be used in pharmaceutical composition.
SUMMARY OF THE INVENTION:
In one aspect, the present invention provides a co-crystal of the compound 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of formula (I) and a co-former molecule
Wherein the co-former molecule is an organic acids of one or more carboxylic groups.
In one aspect, the present invention provides a co-crystal of the compound 2-[3-cyano-4-(2-
methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of formula (I) and a co-former
molecule

Wherein the co-former molecule is selected from Pamoic acid, Palmitic acid, Glycolic acid, Salicylic acid, 4-Amino Salicylic acid, Decanoic (capric) acid, Gentisic acid, Glutaric acid, Vanillic acid, Succinic acid, Malonic acid, Fumaric acid, Stearic acid, L-Tartaric acid, L-malic acid, Malic acid, Adipic acid, Lactobionic acid, Oxalic acid, Orotic acid, Sebacic acid, Tartaric acid, Serine, Valine, Hexanoic acid, Heptanoic acid, Cyclopentanepropionic acid, Pyruvic acid, Lactic acid, Citric acid, Benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, Cinnamic acid, Madelic acid, , Ethanesulfonic acid, , 2-Hydroxyethanesulfonic acid, , p-Chlorobenzenesulfonic acid, Camphorsulfonic acid, 4-Methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, Glucoheptonic acid, 4,4'-Methylenebis(3-hydroxy-2-ene-l-carboxylic acid), 3-Phenylpropionic acid, Trimethylacetic acid, tertiary Butylacetic acid, Gluconic acid, Hydroxynaphthoic acid and Muconic acid.
Another aspect of the present invention is to provides a co-crystal of the compound 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of formula (I) and a co-former molecule
wherein the co-former molecule is succinic acid, fumaric acid or stearic acid.

Another aspect of the present invention is to provides a co-crystal of the compound 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of formula (I) (Compound of Formula I) and a co-former molecule
wherein the co-former molecule is Phthalimide.
In a further aspect, the present invention provides method of preparing a co-crystal of the compound of formula (I).
In a further aspect, the present invention provides method of preparing a co-crystal of the compound of formula (I) comprising the step of mixing a solution of the compound of formula (I) in a free form with the appropriate co-former molecule in a inert solvent.
In a further aspect, the present invention provides method of preparing Stearic acid, Fumaric acid, Succinic acid and Phthalimide co-crystal of the compound of formula (I).
In a further aspect, the present invention includes a pharmaceutical composition. The pharmaceutical composition includes a co-crystal of the compound of formula (I). The co-crystal includes co crystals of Febuxostat with Stearic acid, Fumaric acid, Succinic acid and Phthalimide.
In another aspect, the present invention provides a pharmaceutical composition comprising a co-crystal of the compound of formula (I) prepared according to present invention.

In yet another general aspect, the present invention provides for the use of co- crystals of the compound of formula (I) for chronic management of hyperuricemia in patients with gout.
Brief Description of the Figures
Figure 1: X-ray diffraction pattern (XRD) of Febuxostat-Stearic acid co-crystal. Figure 2: Differential Scanning Thermogram (DSC) of Febuxostat- Stearic acid co-crystal. Figure 3: Infrared (IR) of Febuxostat- Stearic acid co-crystal. Figure 4: X-ray diffraction pattern of Febuxostat-Fumaric acid co-crystal. Figure 5: Differential Scanning Thermogram of Febuxostat- Fumaric acid co- crystal. Figure 6: IR of Febuxostat- Fumaric acid co-crystal. Figure 7: X-ray diffraction pattern of Febuxostat-Succinic acid co-crystal. Figure 8: Differential Scanning Thermogram of Febuxostat- Succinic acid co-crystal. Figure 9: IR of Febuxostat- Succinic acid co-crystal. Figure 10: X-ray diffraction pattern of Febuxostat-Phthalimide co-crystal. Figure 11: Differential Scanning Thermogram of Febuxostat- Phthalimide co-crystal. Figure 12: IR of Febuxostat- Phthalimide co-crystal.
Figure 13: X-ray diffraction pattern overlay of Febuxostat, Stearic acid, and Febuxostat- Stearic acid co-crystal.
Figure 14: X-ray diffraction pattern overlay of Febuxostat, Fumaric acid, and Febuxostat-Fumaric acid co-crystal.
Figure 15: X-ray diffraction pattern overlay of Febuxostat, Succinic acid, and Febuxostat-Succinic acid co-crystal.
Figure 16: X-ray diffraction pattern overlay of Febuxostat, Phthalimide, and Febuxostat-Phthalimide co-crystal.
Figure 17: DSC overlay of Febuxostat, Stearic acid, and Febuxostat- Stearic acid co-crystal. Figure 18: DSC overlay of Febuxostat, Fumaric acid, and Febuxostat-fumaric acid co-crystal. Figure 19: DSC overlay of Febuxostat, Succinic acid, and Febuxostat- Succinic acid co-crystal. Figure 20: DSC overlay of Febuxostat, Phthalimide, and Febuxostat- Phthalimide co-crystal. Figure 21: IR overlay of Febuxostat, Stearic acid, and Febuxostat- Stearic acid co-crystal. Figure 22: IR overlay of Febuxostat, Fumaric acid, and Febuxostat-Fumaric acid co-crystal.

Figure 23: IR overlay of Febuxostat, Succinic acid, and Febuxostat- Succinic acid co-crystal. Figure 24: IR overlay of Febuxostat, Phthalimide, and Febuxostat- Phthalimide co-crystal.
DETAILED DESCRIPTION:
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The term "contacting" may include dissolving, slurring, stirring or a combination thereof.
The term "ambient temperature", as used herein, refers to a temperature in the range of about 19°C to about 35°C.
In one aspect, the present invention provides a co-crystal of the compound 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of formula (I) and a co-former molecule
Wherein the co-former molecule is an organic acids of one or more carboxylic groups.

In one aspect, the present invention provides a co-crystal of the compound 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of formula (I) and a co-former molecule
Wherein the co-former molecule is selected from Pamoic acid, Palmitic acid, Glycolic acid, Salicylic acid, 4-Amino Salicylic acid, Decanoic (capric) acid, Gentisic acid, Glutaric acid, Vanillic acid, Succinic acid, Malonic acid, Fumaric acid, Stearic acid, L-Tartaric acid, L-malic acid, Malic acid, Adipic acid, Lactobionic acid, Oxalic acid, Orotic acid, Sebacic acid, Tartaric acid, Serine, Valine, Hexanoic acid, Heptanoic acid, Cyclopentanepropionic acid, Pyruvic acid, Lactic acid, Citric acid, Benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, Cinnamic acid, Madelic acid, , Ethanesulfonic acid, , 2-Hydroxyethanesulfonic acid, , p-Chlorobenzenesulfonic acid, Camphorsulfonic acid, 4-Methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, Glucoheptonic acid, 4,4'-Methylenebis(3-hydroxy-2-ene-l-carboxylic acid), 3-Phenylpropionic acid, Trimethylacetic acid, tertiary Butylacetic acid, Gluconic acid, Hydroxynaphthoic acid and Muconic acid.
Another aspect of the present invention is to provides a co-crystal of the compound 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of formula (I) and a co-former molecule

Wherein the co-former molecule is Succinic acid, Fumaric acid or Stearic acid.
Another aspect of the present invention is to provides a co-crystal of the compound 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of formula (I) and a co-former molecule
wherein the co-former molecule is Phthalimide.
In one embodiment, the present invention provides a co-crystal of the compound 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylic acid of formula (I) and a co-former molecule selected form Aspirin, Metformin, Allopurinol, Probenecid, Saltans such as Olmesartan, NSAID is selected from the group consisting of: Ibuprofen, Acetaminophen, Amoxiprin, Benorilate, Choline, Magnesium Salicylate, Diflunisal, Fisalamine, Methyl Salicylate, Magnesium Salicylate, Salicyl Salicylate, Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Ketorolac, Nabumetone, Sulindac, Tolmetin, Carprofen, Fenbufen, Fenoprofen, Flurbiprofen, Ketoprofen, Loxoprofen, Naproxen, Tiaprofenic acid, Mefenamic acid, Meclofenamic acid, Tolfenamic acid, Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone, Piroxicam, Lomoxicam, Lornoxicam, Meloxicam, Tenoxicam, Celecoxib, Etoricoxib, Lumiracoxib, Parecoxib, Nimesulide, Licofelone, Indomethacin, a COX-2 inhibitor and pharmaceutically acceptable salts thereof and mixtures thereof.
In embodiments, Co-former molecule includes organic acids of one or more carboxylic acid. An organic acid of one or more carboxylic groups includes monocarboxylic, dicarboxylic, tricarboxylic or an acid having more than three carboxylic groups. An organic acids of one or more carboxylic acid includes Pamoic acid, Palmitic acid, Glycolic acid, Salicylic acid, 4-Amino Salicylic acid, Decanoic (capric) acid, Gentisic acid, Glutaric acid, Vanillic acid, Succinic acid, Malonic acid, Fumaric acid, Stearic acid, L-Tartaric acid, L-malic acid, Malic acid, Adipic acid,

Lactobionic acid, Oxalic acid, Orotic acid, Sebacic acid, Tartaric acid, Serine, Valine, Hexanoic acid, Heptanoic acid, Cyclopentanepropionic acid, Pyruvic acid, Lactic acid, Citric acid, Benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, Cinnamic acid, Madelic acid,, Ethanesulfonic acid,, 2-Hydroxyethanesulfonic acid, , p-Chlorobenzenesulfonic acid, Camphorsulfonic acid, 4-Methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, Glucoheptonic acid, 4,4'-Methylenebis(3-hydroxy-2-ene-l-carboxylic acid), 3-Phenylpropionic acid, Trimethylacetic acid, tertiary Butylacetic acid, Gluconic acid, Hydroxynaphthoic acid and Muconic acid.
In another embodiment of invention, organic acid of one or more carboxylic groups also includes Methanesulfonic acid, 1,2-ethanedisulfonic acid, Benzenesulfonic acid, 2- Naphthalenesulfonic acid, p-Toluenesulfonic acid and Lauryl sulfuric acid.
In another embodiment, the present invention provides a co-crystal of the compound 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylic acid of formula (I) and a co-former molecule includes aminoacid is selected from but not limited to arginine, lysine, histidine, benzamide, pyridone, aminopyridine, piperazine, Immidazole.
Further embodiment of invention provides a co-crystal of the compound 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of formula (I) and a co-former molecule includes succinic acid, fumaric acid and stearic acid.
Further embodiment of invention provides a co-crystal of the compound 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of formula (I) and a co-former molecule includes Phthalimide.
In yet another embodiments of this invention, said co-crystal of the compound of formula (I) may be in a crystalline form.
The ratio of Febuxostat to co-crystal former may be stoichiometric or non-stoichiometric according to the present invention. For example, 1:1, 1.5:1, 1:1.5, 2:1,1:2, 3:1, 1:3, 4:1 and 1:4 ratios of Febuxostat: co-crystal former are acceptable.

In yet another embodiment of this invention, said co-crystal of the compound of formula (I) is in a crystalline form having an XRPD pattern and Differential Scanning calorimetry substantially as shown in any of the appended Figures. According to the present invention there is provided a co-crystal of Febuxostat wherein said co-crystal can be characterized by an X-ray powder diffraction pattern with specific peaks at about 2-theta (or d-spacing) and Differential Scanning calorimetry as shown in Table 1.
Table 1: Primary Reflections distinguishing novel Forms from pure Febuxostat free form or pure co-former solid forms

Febuxostat and DSC of Co- XRPD angle (°2θ) (±0.2) d-spacing (A) (±0.05)
Co-former crystal form (measured at 1.5418A) (measured at 1.5418A)
Febuxostat Endothermic 5.67,5.82,7.99,11.63,12.57, 15.54, 15.15, 11.05, 7.59, 7.03, 6.92,
208-210°C. 12.77, 20.54 and 25.90. 4.31 and 3.43.
Stearic acid 58.82°C (DSC) 2.0,2.28,4.55,6.8, 11.49,18.68, 42.73, 38.69, 19.39, 12.98, 7.69,4.74,
20.40,21.21,21.40,21.65,23.92, 4.34, 4.18, 4.14,4.09, 3.71, 3.53, 3.32,
25.17,26.75,27.68,29.35,30.5, 3.22, 3.04, 2.92, 2.82, 2.48, 2.36 and
31.68, 36.13, 38.06 and 39.24 2.29.
Febuxostat- Endothermic 2.3, 7.26 and 12.89. 38.29, 12.16 and 6.86.
stearic acid 56.71°C
Fumaric acid 294°C (DSC) 17.15, 18.57, 19.26,22.79,24.67, 5.16,4.77,4.6,3.89,3.6,3.55,3.46,
25.0,25.71,26.76,27.72,28.25, 3.32, 3.21, 3.15, 3.09, 3.03, 2.91, 2.85,
28.78,29.4,30.67,31.28,32.33, 2.76, 2.71, 2.66, 2.53, 2.5, 2.37, 2.36,
32.98,33.54,35.36,35.85,37.83, 37.93, 38.4, 38.64, 39.13 and 39.8 2.34, 2.32, 2.3 and 2.26
Febuxostat- Endothermic 6.59, 10.78,13.34, 15.52, 17.37, 13.39, 8.19, 6.63, 5.7, 5.10,4.06, 3.93,
fumaric acid 196.39°C. and 21.86, 22.57,24.48, 24.52, 25.12, 3.63, 3.62, 3.54, 3.3, 3.27, 3.12 and
203.32°C. 26.94, 27.2, 28.54 and 28.84. 3.09.
Succinic acid 188°C(DSC) 15.99, 18.04, 18.88, 19.32, 19.99, 5.53,4.91,4.69,4.59,4.43,4.05,4.04,
21.88,21.96,23.5,25.45,25.72, 3.78, 3.49, 3.46, 3.41, 3.35, 3.29, 3.14,
26.06, 26.57, 27.07, 28.33, 31.46, 2.84, 2.76, 2.63, 2.55, 2.45, 2.36 and
32.4, 34.04, 35.15, 36.61, 37.94 and 38.35 2.34.
Febuxostat- Endothermic 6.71, 10.96, 13.48, 15.67, 17.51, 13.15,8.06,6.56,5.64,5.05,4.44,

succinic acid
176.04°C. and 191.07°C 19.94, 22.03, 24.63 and 25.26. 4.03, 3.61 and 3.52.
Phthalimide 234°C(DSC) 3.86,6.96,7.74, 13.91, 15.33, 22.84,12.67,11.4,6.36,5.77,5.7,
15.51, 16.41, 19.38,23.19,23.35, 5.39, 4.57, 3.83, 3.8, 3.77, 3.64, 3.63,
23.55, 24.43, 24.5, 25.78, 26.01, 3.45, 3.42, 3.39, 3.31, 3.28, 3.24, 3.17,
26.26, 26.85, 27.08, 27.43, 28.04, 3.13, 3.0,2.95, 2.85,2.7, 2.69,2.56,
28.43, 29.73, 30.19, 31.31, 33.08,
33.17,34.89,36.53,37.07,37.17, 37.31, 39.35 and 39.44 2.45,2.42,2.41,2.4,2.29 and 2.28
Febuxostat- Endothermic 4.83,7.24,7.75, 11.81, 12.86, 18.25, 12.19, 11.39,7.48,6.87,6.35,
phthalimide 178.91°C. and 13.92, 15.52, 16.4, 23.35, 25.89 and 5.7, 5.39, 3.80, 3.43 and 3.29.
184.21°C. 27.07.
According to another aspect of the present invention, there is provided a co-crystal of Febuxostat wherein said co-crystal can be characterized by an X-ray powder diffraction pattern with specific peaks (in addition to those in Table 1) at about 2-theta (or d- spacing) as shown in Table 2
Table 2; Secondary Reflections distinguishing novel forms from pure Febuxostat free form or pure co-former solid forms

Febuxostat and XRPD angle (°2θ) (±0.2) d-spacing (A) (±0.05)
Co-former (measured at 1.5418A) (measured at 1.5418A)
Febuxostat 11.36, 12.91, 16.87, 17.48, 18.18, 18.51, 7.78, 6.84, 5.25, 5.06, 4.87, 4.78, 4.22 and
21.01 and 23.86. 3.72.
Febuxostat- 6.68,6.87, 19.64 and 23.81. 13.21, 12.85,4.51 and 3.73.
Stearic acid
Febuxostat- 9.81, 16.73, 18.7, 19.64,20.15,20.58, 9.0, 5.29, 4.73, 4.51, 4.4, 4.31, 3.79, 3.47,
Fumaric acid 23.44,25.59,29.17, 31.12 and 34.02. 3.05, 2.87 and 2.63.
Febuxostat- 9.97, 16.87, 18.84, 20.29, 2073, 22.68, 8.85, 5.24, 4.7, 4.37, 4.28, 3.91, 3.76, 3.28,
Succinic acid 23.61, 27.10, 27.35, 28.66, 28.98 and 31.35. 3.25, 3.11, 3.07 and 2.85.
Febuxostat- 6.66,6.89, 16.0, 16.54, 17.54, 19.38, 19.61, 13.25, 12.8, 5.53, 5.35, 5.05,4.57,4.52,
Phthalimide 23.03, 23.77, 24.49, 24.82, 25.21, 26.27, 3.85, 3.73, 3.63, 3.58, 3.52, 3.38, 3.33, 3.18,
26.72, 27.98, 28.38 and 29.74. 3.14 and 3.0.

In another embodiment of this invention, said co-crystal of the compound of formula (I) is in a crystalline form having Infra red spectra substantially as shown in any of the appended Figures. According to the present invention there is provided a co-crystal of Febuxostat wherein said co-crystal is characterized by shifting functional groups as shown in Table 3.
Table 3: Infra red spectra distinguishing novel forms from pure Febuxostat free form or pure co-former solid forms

Febuxostat and Co-former COOH (C=0, Stretch) cm-1 O-H stretch cm-1
Febuxostat 1690.66 2964.20
Febuxostat-Stearic acid 1680.24 2960.10
Febuxostat-Fumaric acid 1701.34 2950.14
Febuxostat-Succinic acid 1701.41 2949.42
Febuxostat-Phthalimide 1677.88 2964.34
The FT-IR stretching frequencies are at 1690.6 cm-1 (COOH C=0 stretch) and 2964.2 cm-1 (O-H. stretch). On the basis of the changes in these IR values, the formation of novel co-crystal form is shifted in C=0 shift frequency of 5-20 cm-1 and O-H shift frequency 2-15 cm-1, FT-IR frequencies as shown in Table-3.
In a further aspect, the present invention provides method of preparing a co-crystal of the compound of formula (I).
In a further aspect, the present invention provides method of preparing Stearic acid, Fumaric acid, Succinic acid and Phthalimide co-crystal of the compound of formula (I).
Yet another embodiments of this invention provides method of preparing a co-crystal of the compound of formula (I) comprising the step of contacting a solution of the compound of formula (I) in a free form with the appropriate coformer molecule in a inert solvent.
Febuxostat can be contacted with the co-former molecule optionally in a solvent. Solvents includes any solvents but are not limited to alcohols like methanol, ethanol, isopropanol, butanol

and the like; ketones like acetone, methyl isopropyl ketone, methyl isobutyl ketone, methyl ethyl ketone and the like; aliphatic ethers like diethyl ether, di-tert-butyl ether, diisopropyl ether, methyl-tert-butyl ether and the like; cyclic ethers like tetrahydrofuran, dioxane and the like; aliphatic esters like methyl acetate, ethyl acetate and the like; hydrocarbons like toluene, heptane, hexane and the like; chlorinated solvent like chloroform, dichloromethane and the like; nitriles like acetonitrile; polar aprotic solvent like dimethyl formamide; dimethyl sulphoxide; water or mixture thereof. The Febuxostat may be contacted with the co-crystal former in acetone as solvent. The Febuxostat may also be contacted with the co-crystal former without solvent.
The Febuxostat may be contacted with the co-crystal former at ambient temperature to reflux temperature of solvent.
The reaction mixture containing Febuxostat and the co-crystal former in solvent may be maintained at a temperature of about -15°C. to about 95°C, preferably -5°C. to about 75°C. and more preferably 0°C. to about 55°C. For Hot melt technique, temperature may be about 35°C. to about 200°C, preferably about 45°C. to about 150°C. and more preferably about 50°C. to 120°C.
In an embodiment, Crystallization conditions may be applied to the Febuxostat and co-former molecule. This may be require changing a property of the solution, such as pH or temperature and may require concentration of the solute, usually by removal of the solvent, typically by drying the solution. Solvent removal results in the concentration of both Febuxostat and co-former molecule increasing over time so as to facilitate crystallization. For example, evaporation, cooling, co-sublimation, or the addition of an antisolvent may be used to crystallize co-crystals.
Co-crystallization of Febuxostat is possible by techniques like holtmelt, solvent drop co-mixing, co-heating, co-grinding, co-vibration of Febuxostat and co-crystal former. And all these techniques can be employed in case of Febuxostat co-crystal formation.
The crystallization methods include, but are not limited to, melt recrystallization, grinding, milling, standing, co-crystal formation from solution by evaporation, thermally driven

crystallization from solution, co-crystal formation from solution by addition of anti-solvent, co-crystal formation from solution by vapor- diffusion, co-crystal formation from solution by drown-out, co-crystal formation from solution by any combination of the above mentioned techniques, co-crystal formation by co-sublimation, co-crystal formation by sublimation using a Knudsen cell apparatus, co- crystal formation by standing the desired components of the co-crystal in the presence of solvent vapor, co-crystal formation by slurry conversion of the desired components of the co-crystal in a solvent or mixtures of solvents, or co-crystal formation by any combination of the above techniques in the presence of additives, nucleates, crystallization enhancers, precipitants, chemical stabilizers, or anti-oxidants.
The Febuxostat co-crystal can be isolated by using any techniques such as decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product, and optionally the solid can be washed with a solvent. In embodiments, tlje cocrystal of Febuxostat can be isolated by evaporating solvents.
In embodiments, Febuxostat co-crystal after isolation can be dried at suitable temperature, and atmospheric or reduced pressure, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying temperatures and times will be sufficient to achieve desired product purity.
The Febuxostat co-crystal can be prepared, for example, by a process comprising co-milling
or milling the two solids together. The use of a granulating liquid may improve co-crystal
formation.
The co-crystals of Febuxostat may be purified by crystallization from a solvent selected from the group of alcohols, ketones, water, carboxylic acids, chlorinated hydrocarbons, amides, sulphoxides, ethers, ester or mixtures thereof.
Febuxostat to be used for the preparation of Febuxostat co-crystals of the present invention may be obtained by any of the methods known in the literature. Febuxostat to be used as starting

material for the preparation of Febuxostat co-crystals of the present invention may be obtained as a solution directly from a reaction in which it is formed and used as such without isolation.
In another embodiment, the difference in pKa value of the co-crystal former and the API may be less than 2. In other embodiments, the difference in pKa values of the co-crystal former and API maybe less than 3.
In a further aspect, the present invention includes a pharmaceutical composition. The pharmaceutical composition includes a co-crystal of the compound of formula (I). In a preferred aspect, the co-crystal includes co crystals of Febuxostat with Stearic acid, Fumaric acid, Succinic acid and Phthalimide.
In another aspect, the present invention provides a pharmaceutical composition comprising a co-crystal of the compound of formula (I) prepared according to present invention.
In a further aspect, the present invention includes a stable pharmaceutical composition. The stable pharmaceutical composition includes a co-crystal of the compound of formula (I). The co-crystal includes co crystals of Febuxostat with Stearic acid, Fumaric acid, Succinic acid and Phthalimide.
In embodiments, Pharmaceutical composition may be stable. A composition may comprise one or more additional therapeutic agents.
The pharmaceutical compositions further comprise pharmaceutically acceptable excipient.
The pharmaceutical compositions may be formulated as: solid oral dosage forms, such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze-dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt

preparations, and modified release compositions may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate-controlling substances to form matrix or reservoir systems, or combinations of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry process, wet process, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated powder coated, enteric coated, or modified release coated. The most preferred composition of present invention is oral solid composition.
The pharmaceutical compositions may comprise one or more pharmaceutical^ acceptable excipients but not limited to diluent, disintegrant, binder, lubricant, glidant, stabilizer, organoleptic ingredients such as coloring agent, flavoring agent, sweetener, film formers, plasticizers, viscosity enhancers, preservatives, antioxidants and others known to the skilled person in the art.
Examples of fillers or diluents may include, but are not limited to, corn starch, anhydrous lactose, lactose monohydrate, white sugar, sugar compressible, sugar confectioners, sucrose, glucose, maltose, calcium carbonate, calcium dihydrogen phosphate dihydrates, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, rnanniiol, sorbitol, starch, or a mixture thereof. The diluents comprise lactose, microcrystalline cellulose, calcium dihydrogen phosphate dihydrates, or a mixture thereof.
Examples of binders may include, but are not limited to, carbomer, sodium carboxymetbylcellulose, microcrystalline celluloses (MCC), microfine celluloses, dextrin, lactose, glucose, guar gum, hypromellose, hydroxypropyl cellulose, pregelatinized starch, starch, povidone, or mixture thereof or other materials known to one of ordinary skill in the art.
Examples of disintegrants include, but are not limited to, starch, sodium starch glycolate, croscarmellose sodium, crospovidone, alginic acid, low-substituted hydroxy propyl cellulose, carboxymethyl cellulose sodium, microcrystalline cellulose, calcium carbonate, sodium carbonate, alginic acids, agar, guar gum, or mixture thereof.

Some excipient materials can function as both a diluent and a binder, or a filler and a disintegrant, and some materials may exist that can fulfill all three roles. There is no intention to limit the invention to methods only using three distinct excipient materials, "diluents", " binder", and "disintegrants", but rather the invention is directed to materials fulfilling these functions. For example, the material that is "at least one diluent" also might be the same as the material fulfilling the role of "at least one tablet binder" as long as the material is present in sufficient amount to fulfill both functions.
Examples of lubricants may include, but are not limited to, stearic acid, polyethylene glycol, magnesium stearate, calcium stearate, talc, zinc stearate, hydrogenated castor oil, silica, colloidal silica, cornstarch, calcium silicate, magnesium silicate, silicon hydrogel, or mixture thereof.
Examples of glidants may include, but are not limited to, colloidal silicon dioxide, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel, or mixture thereof.
The coloring agents and flavoring agents may include approved colors and flavors for oral use.
The sweetener may include aspartame, saccharin sodium, acesulfame potassium, dried invert sugar, dextrose, glucose, fructose, galactose, ievulose, maltose, neotame, sucralose, or mixture thereof.
The granulating liquids may include, but are not limited to, water, ethanol, isopropyl alcohol, acetone, dichloromethane and other hydroalcoholic solvents such as isopropyl alcohol-water mixture.
In another embodiment, the composition of present invention can optionally be film-coated.
The pharmaceutical compositions of the present invention can be prepared by dry process or wet process.

In yet another general aspect, the present invention provides for the use of co- crystals of a co-crystal of the compound of formula (I) for chronic management of hyperuricemia in patients with gout.
The processes described in the present invention were demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
EXAMPLES:
Example-1: Preparation of Febuxostat-stearic acid co-crystal:
Febuxostat (1.0 gm, 0.003 lmol) and acetone (10 ml) were charged into a round bottom flask at room temperature and stirred to get a mixture. Stearic acid (0.88 gm, 0.003 lmol) was charged to the mixture at room temperature and stirred for 10-15minutes. The reaction mass was heated up to 50°C. and stirred at 50±5°C. for 9 hours. The solution was cooled and kept for overnight at ambient temperature. The solvent was evaporated from the reaction mass and separated solid was dried at 50±5°C. for 7 hours to obtain the title compound. Yield: 1.7 gm. Detailed characterization of the Febuxostat-stearic acid co-crystal is listed in Table 1, 2 and 3. Fig. 1,2,3, 13, 17 and 21
Example-2: Preparation of Febuxostat-fumaric acid co-crystal:
Febuxostat (2.0 gm, 0.0063mol) and acetone (20 ml) were charged into a round bottom flask at room temperature and stirred to get a mixture. Fumaric acid (0.36 gm, 0.003lmol) was charged to the mixture at room temperature and stirred stirred for 10-15minutes. The reaction mass was heated up to 50°C. and stirred at 50±5°C. for 9 hours. The solution was cooled and kept for overnight at ambient temperature. The solvent was evaporated from the reaction mass and separated solid was dried at 50±5°C. for 7 hours to obtain the title compound. Yield: 2.3 gm. Detailed characterization of the Febuxostat- fumaric acid co-crystal is listed in Table 1, 2 and 3 Fig. 4,5,6, 14, 18 and 22

Example-3; Preparation of Febuxostat-succinic acid co-crystal;
Febuxostat (2.0 gm, 0.0063mol) and Acetone (10 ml) were charged into a round bottom flask at room temperature and stirred to get a mixture. Succinic acid (0.37 gm, 0.003lmol) was charged to the mixture at room temperature and stirred for 10-15minutes. The reaction mass was heated up to 50°C. and stirred at 50±5°C. for 9 hours. The solution was cooled and kept for overnight at ambient temperature. The solvent was evaporated from the reaction mass and separated solid was dried at 50±5°C. for 7 hours to obtain the title compound. Yield: 2.3 gm. Detailed characterization of the Febuxostat- succinic acid co-crystal is listed in Table 1,2 and 3 Fig. 7,8,9,, 15, 19 and 23
Example-4; Preparation of Febuxostat-phthalimide co-crystal;
Febuxostat (1.0 gm, 0.003 lmol) and Acetone (15 ml) were charged into a round bottom flask at room temperature and stirred to get a mixture. Phthalimide (0.46 gm, 0.003 lmol) was charged to the mixture at room temperature and stirred for 10-15minutes. The reaction mass was heated up to 50°C. and stirred at 50±5°C. for 9 hours. The solution was cooled and kept for overnight at ambient temperature. The solvent was evaporated from the reaction mass and separated solid was dried at 50±5°C. for 7 hours to obtain the title compound. Yield: 1.4 gm. Detailed characterization of the Febuxostat- phthalimide co-crystal is listed in Table 1, 2 and 3 Fig. 10, 11, 12, 16,20 and 24

We Claim:
1. A co-crystal of the compound 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of formula (I) and a co-former molecule, wherein co-former molecule is an organic acids of one or more carboxylic groups.
2. A co-crystal of the compound 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of formula (I) and a co-former molecule, wherein the co-former molecule is succinic acid, fumaric acid or stearic acid or Phthalimide.
3.A method of preparing a co-crystal of the compound of formula (I) comprising the step of mixing a solution of the compound of formula (I) in a free form with the appropriate co-former molecule in a inert solvent.
4. The method of preparing according to claim 3, wherein the inert solvent includes a group comprising of lower aliphatic alcohols such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butanol, isobutanol; aromatic hydrocarbon such as toluene, xylene; chlorinated solvents such as dichloromethane: esters such as ethyl acetate, ethers, diethyl ether, tetrahydrofuran;dipolar aprotic solvents such as dimethylformamide, cyclohexane ; ketones such as acetone; cyclic or acyclic alkanes such as hexane, heptane, methylcyclohexane.
5. The process as claimed in claim 3, wherein the inert solvent is acetone.
6. A pharmaceutical composition comprising a co-crystal of the compound of formula (I) and pharmaceutical acceptable excipient.
7. A pharmaceutical composition comprising a co-crystal of the compound of formula (I)
prepared according to claim 3.