FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
Title
STABLE PHARMACEUTICAL COMPOSITONS OF FEBUXOSTAT AND
METHOD OF PREPARATION THEREOF
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification particularly describes the invention and the manner in which it is to be performed:

Stable pharmaceutical compositions of Febuxostat & method of preparation thereof
FIELD OF THE INVENTION:
The present invention relates to a stable pharmaceutical composition comprising febuxostat and one or more of the component selected from acidic co-formers, polymers, and amino acids, 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 urate 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 includes Form A, B, C, D (methanolate), E, G (hydrate), as well as an amorphous form. The crystals B, C, D, E and G may interchange from one to the other. PCT Publication No. WO 1999/065885 also discloses that there may be interchange of the crystal forms B and D into a hydrous form, i.e., crystal G if the crystal forms B and D is exposed to moisture. Hence there is a need for stable crystalline form of febuxostat or to be stabilized in the composition. PCT Publication No. WO2012153313, WO2012172461 WO2013001441 dislcoses pharmaceutical composition along with febuxostat and its polymorph. However, various methods were tried for stabilization of febuxostat polymorph into composition.
Thus, there remains a need for stable pharmaceutical compositions, which can be employed for any polymorphic form and remains stable throughout the shelf life of composition.
BRIEF DESCRIPTION OF DRAWINGS
Fig 1 illustrates an overlay of the XRPD pattern of Febuxostat, placebo and tablet.
SUMMARY OF THE INVENTION:
In one aspect, the present invention provides a stable pharmaceutical composition comprising febuxostat.
In one aspect, the present invention provides a stable pharmaceutical composition comprising febuxostat and one or more of the component selected from acidic co-formers, polymers, and amino acids.
In one aspect, the present invention provides a stable pharmaceutical composition further comprises moisture adsorbent, preferably Syloid ® AL-l-FP, Syloid ® 244 FP and/ or mixtures thereof.

In an another aspect, the present invention provides a stable composition comprising febuxostat and acidic co-formers are selected from the group comprising of amoic 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, malonic acid, lactobionic acid, oxalic acid, orotic acid, sebacic acid, tartaric acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, pyruvic acid, lactic acid, citric acid, benzoic acid, o- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, p-toluenesulfonic 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, lauryl sulfuric acid, gluconic acid, hydroxynaphthoic acid and muconic acid and inorganic acid includes hydrochloride, sulphuric acid, hydrogen fluoride, hydrogen iodide, hydrogen bromide and phosphoric acid or mixture thereof.
In another aspect, the present invention provides a stable pharmaceutical composition comprising febuxostat and polymers are selected from the group comprising of carbomer, sodium carboxymethylcellulose, microcrystalline celluloses (MCC), microfine celluloses, dextrin, guar gum, hydoxypropylmethyl cellulose, hydroxypropyl cellulose, pregelatinized starch, starch, povidone, polyvinyl alcohol , polyvinyl acetate , polyethylene glycol (PEG), methyl cellulose (MC), hydroxy ethyl cellulose, cyclodextrin, pectin, galactomannan, Hydroxy propyl methyl cellulose phthalate (HPMCP), eudragitLlOO, eudragit El00, eudragit RL, eudragit RS, polyoxyethylene stearate, poloxamer 188, tweens, spans, pentaerythrityl tetraacetate, urethane, hydroxy alkyl xanthins or mixture thereof.

In one aspect, the present invention provides a stable composition comprising febuxostat and amino acids are selected from the group comprising of arginine, lysine, histidine, serine, valine or mixtures thereof.
In another aspect, the present invention provides a pharmaceutical composition comprising febuxostat prepared according to present invention.
In another aspect, the present invention provides a process of preparation of the pharmaceutical composition comprising febuxostat according to present invention, and one or more of the component is selected from acidic co-formers, polymers, and amino acids.
In another aspect, the present invention includes pharmaceutical composition by providing core comprising febuxostat and one or more of the component is selected from acidic co-formers, polymers, and amino acids.
In another aspect, the present invention includes pharmaceutical composition by providing core comprising febuxostat and one or more of the component is selected from acidic co-formers, polymers, and amino acids and one or more pharmaceutically acceptable excipients.
In yet another general aspect, the present invention provides for the use of febuxostat for chronic management of hyperuricemia in patients with gout.
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.
Febuxostat as described herein includes febuxostat, or its salts. Febuxostat or its salts includes isomers, racemates, enantiomers, hydrates, solvates, metabolites, polymorphs, complexes, cocrystals thereof. Polymorphs may be of crystalline or amorphous Form of Febuxostat.
In one aspect, the present invention provides a stable composition comprising febuxostat.
The term "stable" for purposes of the present invention relates to polymorphic stability and chemical stability. The term "polymorphic stability" refers to maintaining the polymorphic form of the drug both while manufacturing and during shelf life. The term "chemical stability" refers to maintaining the impurities and/or drug degradation products in an acceptable limit in the pharmaceutical composition during storage.
In one aspect, the present invention provides a stable composition comprising febuxostat and one or more of the component is selected from acidic co-formers, polymers, and amino acids.
In one aspect, the present invention provides a stable composition comprising febuxostat and two or more of the component is selected from acidic co-formers, polymers, and amino acids.

In an another aspect, the present invention provides a stable composition comprising febuxostat and acidic co-formers are selected from the group comprising of amoic 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, malonic acid, lactobionic acid, oxalic acid, orotic acid, sebacic acid, tartaric acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, pyruvic acid, lactic acid, citric acid, benzoic acid, o- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, p-toluenesulfonic 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, lauryl sulfuric acid, gluconic acid, hydroxynaphthoic acid and muconic acid and inorganic acid includes hydrochloride, sulphuric acid, hydrogen fluoride, hydrogen iodide, hydrogen bromide and phosphoric acid or mixture thereof.
In another aspect, the present invention provides a stable pharmaceutical composition comprising febuxostat and polymers are selected from the group comprising of carbomer, sodium carboxymethylcellulose, microcrystalline celluloses (MCC), microfine celluloses, dextrin, guar gum, hydoxypropylmethyl cellulose, hydroxypropyl cellulose, pregelatinized starch, starch, povidone, Polyvinyl alcohol, Polyvinyl acetate, polyethylene glycol (PEG), methyl cellulose (MC), hydroxy ethyl cellulose, cyclodextrin, pectin, galactomannan, Hydroxy?' propyl methyl cellulose phthalate (HPMCP), eudragitLlOO, eudragit E100, eudragit RL, eudragit RS, Polyoxyethylene stearate, poloxamer 188, tweens, spans, pentaerythrityl tetraacetate, urethane, hydroxy alkyl xanthins or mixture thereof.

In one aspect, the present invention provides a stable composition comprising febuxostat and amino acids include but not limited to arginine, lysine, histidine, serine, valine or mixtures thereof.
At least, febuxostat compositions of the present invention and one or more of the component is selected from acidic co-formers, polymers, and amino acids; as long as can be administered an effective amount of the active pharmaceutical ingredients, the amount of febuxostat for use in the compositions, particularly but are not limited to, 0.5 to 100 parts by weight of the composition. It may be 1 to 20 parts by weight, preferably 5 to 15 parts by weight, preferably 1 to 10 parts by weight.
In embodiment, a pharmaceutical composition may optionally comprise one or more additional therapeutic agents.
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 and osmotic dosage form.
The pharmaceutical compositions include a stable composition comprising febuxostat and one or more of the component is selected from acidic co-formers, polymers, and amino acids, and /or comprise one or more pharmaceutically acceptable excipient.

The pharmaceutical compositions may comprise one or more pharmaceutically acceptable excipients are selected from diluent, disintegrant, binder, lubricant, glidant, stabilizer, moisture adsorbent, organoleptic ingredients such as Coloring agents, sweetening agents, flavoring agents, and fragrance,and others known to the skilled person in the art.
In an embodiment, the present invention includes process of preparation of the pharmaceutical composition comprising febuxostat, and one or more of the component is selected from acidic co-formers, polymers, and amino acids, includes various optional pharmaceutical excipients. Febuxostat compositions of the present invention can be obtained by adding and/or mixing, granulating, drying, sizing, post-mixing and pressing into suitable dosage form.
The pharmaceutical compositions may be prepared using any one or more of techniques well known to the person having ordinary skill in the art of pharmaceutical technology such as, dry granulation method, direct compression method, slugging, and wet granulation method. Wet granulation may be aqueous or non-aqueous.
Further, it may be possible to prepare the granules, powders or fine granules, using a granulating liquid. The granulating liquids may include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, acetone, methyl ethyl ketone, dichloromethane and other hydroalcoholic solvents such as isopropyl alcohol-water mixture.
In another embodiment, one or more of the component selected from acidic co-formers, polymers, and amino acids may be optionally added to granulation liquid along with binder. Preferably amino acid may be optionally added to granulation liquid along with binder. Preferably amino acid such as arginine may be optionally added to granulation liquid along with binder such as polyvinylpyrolidone.

In another embodiment, the pharmaceutical composition of present invention can optionally be coated, if required. The pharmaceutical 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 immediate release oral solid composition. The pharmaceutical compositions of the present invention may be formulated into solid oral dosage forms such as tablets, hard gelatin or soft gelatin capsules or HPMC capsules, pills, granules, sachets, etc.
In an embodiment, Pharmaceutical compositions can be achieved by providing cores comprising febuxostat and one or more of the component selected from acidic co-formers, polymers, and amino acids.
In an embodiment, Pharmaceutical compositions can be achieved by providing cores comprising febuxostat and one or more of the component selected from acidic co-formers, polymers, and amino acids and one or more pharmaceutically acceptable excipients.
Febuxostat, and one or more of the component selected from acidic co-formers, polymers, and amino acids may be formulated into a single mixture or granule without formulating these components into separate granules or can be separated from each other by a boundary or the like, optionally with one or more pharmaceutically acceptable excipients.
Then, after the sieved product thus obtained, optionally may be added or mixed with pharmaceutical excipient, such as disintegrating agents, moisture adsorbent and lubricant, Coloring agents, sweetening agents, flavoring agents, and fragrance, pressing or tableting the powder that are commonly used in solid pharmaceutical dosage form preparations.

The pharmaceutical compositions of the present invention may be formulated into solid oral dosage forms such as tablets, capsules, pills, granules, sachets, etc. Febuxostat compositions of the present invention, in the form of tablet can be obtained by compression molding, for example using a rotary tableting machine or a single punch tableting machine.
In yet another embodiment, the present invention provides for the use of febuxostat for chronic management of hyperuricemia in patients with gout.
In an embodiment, salts of febuxostat include organic or inorganic salts such as hydrochloride, sodium and the like.
Polymorphs of Febuxostat or its salts include Form A, B, C, D, E, F, G, III, K amorphous and the like.
In an embodiment, a co-crystal includes a co-crystal of febuxostat and a co-former molecule, wherein the co-former molecule is organic acids of monocarboxylic as well as dicarboxylic acid.
A co-crystal includes a co-crystal of Febuxostat and a co-former molecule, wherein the co-former molecule is succinic acid, fumaric acid or stearic acid.
A co-crystal includes a co-crystal of Febuxostat and a co-former molecule, wherein the co-former molecule is Phthalimide.
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 powders, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, sorbitol, starch, or a mixture thereof.

The diluents comprise lactose, microcrystalline cellulose, calcium dihydrogen phosphate dihydrates, or a mixture thereof. A fillers or diluents may be added at granular stage and /or extragranular stage.
Examples of binders may include, but are not limited to, carbomer, sodium carboxymethylcellulose, microcrystalline celluloses (MCC), microfine celluloses, dextrin, lactose, glucose, guar gum, hydoxypropylmethyl cellulose, hydroxypropyl cellulose, pregelatinized starch, starch, povidone, or mixture thereof or other materials known to one of ordinary skill in the art. The ratio of febuxostat to binder may depend upon nature of binder and febuxostat. The ratio of febuxostat to binder may be 0.1:1 to 10:1.
Examples of stabilizers may include, but are not limited to, carbomer, sodium carboxymethylcellulose, microcrystalline celluloses (MCC), microfine celluloses, dextrin, lactose, glucose, guar gum, hydoxypropylmethyl cellulose, 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, polacrilin potassium, microcrystalline cellulose, or mixture thereof. A disintegrant may be added at granular stage and /or extragranular stage.
Some excipient materials can function as both a diluent and a binder, or 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, "diluent", "binder", and "disintegrant", 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 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 moisture adsorbent may include silicon dioxide selected from Syloid ® AL-l-FP, Syloid ® 244 FP and/ or mixtures thereof.
The moisture adsorbent may present in an amount from about 0.2% to 2% by weight based on total composition weight. The moisture adsorbent may be present in an amount from about 1% by weight based on total composition weight.
The moisture adsorbent may include silicon dioxide selected from Syloid ® AL-1 -FP, Syloid ® 244 FP and/ or mixtures thereof and may present in an amount from about 0.2% to 2% by weight based on total composition weight. The moisture adsorbent may include silicon dioxide selected from Syloid ® AL-l-FP, Syloid ® 244 FP and/ or mixtures thereof and may be present in an amount from about 1% by weight based on total composition weight.
The ratio of one or two or more of the component is selected from acidic co-formers, polymers, and amino acids to moisture adsorbent may present in a ratio of 10.0:0.5 to 5.0:0.1,preferably 7.0:2.0 to 3.0:0.3,most preferably 5.0:1.0 to 2.0:.0.3.
The coloring agents, for example, yellow ferric oxide, ferric oxide, food yellow No. 4 aluminum lake, Food Yellow No. 5 Aluminum Lake, Blue No. 1 aluminum

lake, Food Red No. 2 aluminum lake, Food Red No. 3 aluminum lake, it is possible to increase the food red 102 aluminum lake, etc., yellow ferric oxide, ferric oxide is preferred.
As a flavoring, fragrance, for example, orange oil, lemon oil, strawberry essence, vanilla essence, banana essence, orange micron, micron strawberry, vanilla micron, micron banana, peach micron, cider micron, micron menthol, 1-menthol, etc.
Examples of sweetening agents, for example, aspartame, stevia extract, licorice, saccharin, saccharin sodium, dipotassium glycyrrhizin, thaumatin, sucralose, dried invert sugar, dextrose, glucose, fructose, galactose, levulose, maltose, neotame, and the like.
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 dosage form i.e. tablet obtained may be optinally film-coated. Additional excipients for coating includes film-forming agents, solvents, plasticizers, antiadherents, opacifiers and optionally colorants, pigments, antifoam agents, and polishing agents.
Film-forming agents include, but are not limited to, cellulose derivatives such as soluble alkyl- or hydroalkyl-cellulose derivatives such as methylcelluloses, hydroxymethyl celluloses,hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethylethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, etc.; insoluble cellulose derivatives such as ethylcelluloses and the like, dextrins, starches and starch derivatives; polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic; xanthans; alginates; polyacrylic acids; polyvinyl alcohols; polyvinyl acetates;

polyvinylpyrrolidones; polymethacrylates and derivatives thereof (Eudragit products); chitosan and derivatives thereof; shellac and derivatives thereof; waxes and fat substances or mixtures thereof.
/
The coating can also be performed using any commercially available ready-to-coat preparations such as Opadry(R) AMB, Opadry(R) White, Opadry(R) Clear, Opadry(R) II, etc. Opadry(R) formulations generally comprise polymer, plasticizer, and, if desired, pigment in a dry concentrate. Opadry(R) products produce coatings on a variety of tablet cores and can be used in both aqueous and organic coating procedures.
Adjuvants used as exciepient to the coating process, including excipients such as plasticizers, opacifiers, antiadhesives and polishing agents.
Plasticizers include, but are not limited to, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols, propylene glycols, triacetin, triethyl citrate, and mixtures thereof.
An opacifier like titanium dioxide may also be present.
Antiadhesives are used in the film-coating process to avoid sticking effects during film formation and drying. An antiadhesive may be talc.
Examples of polishing agents include, but are not limited to, polyethylene glycols of various molecular weights or mixtures thereof, talc, surfactants such as glycerol monostearate and poloxamers, fatty alcohols such as stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol and waxes such as carnauba wax, candelilla wax and white wax.
The product prepared as per this invention will give a stabilized polymorphic form of API throughout the shelflife. The constant polymorph will ensure desired

properties of the drug substance in drug product. The changes in polymoprh are associated with changes in physico-chemical properties of the drug substance which can in turn affect the biological availability of the drug for desired action or can affect the purity of drug itself or another undesired affects are expected with change in polymorphic form of unstable API.
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.
Example 1:

s.
No. Ingredient Mg/tablet
1 Febuxostat 120.00
2 Lactose anhydrous (DCL 21) 412.00
3 Microcrystalline cellulose (Avicel PH 101) 125.00
Binder Solution
4 Hydroxy propyl cellulose 22.50
5 Methanol q.s.
Extra granular
6 Croscarmellose sodium 40.00
7 Syloid® AL-l-FP 15.00
8 Syloid ® 244 FP 7.50
9 Magnesium Stearate 7.50
Total Tablet weight 750.00
Coatin remixt g with opadry readymix coating es
Brief Procedure:
1. Lactose anhydrous (DCL-21), microcrystalline cellulose and Febuxostat was co-sifted through appropriate mesh. The Co sifted material was added into Fluidized Bed Processor.
2. Binder solution was prepared by dissolving hydroxy propyl cellulose in Methanol under stirring.

3. Granulation was performed by Top-spraying the binder solution of step 2 into Cosifted material of Stepl.
4. After the finishing of Top-spray process, granulated material was dried and screened through appropriate screen.
5. Croscarmellose sodium, microcrystalline cellulose, Silicon dioxide (Syloid ® AL-l-FP ) and Silicon dioxide (Syloid ® 244 FP) was blended.
6. The blend was mixed with magnesium stearate.
7. Core tablets were prepared using the lubricated blend and optionally coating was performed with opadry ready mix coating remixes.
Table 1: Polymorphic stability data of compositions of example 1

Stability conditions Initial 3 month 6 month
25°C/60% RH No No No
change change Change
30°C/75% RH No No No
change change Change
40°C/75% RH No No No
change change Change
Pharmaceutical composition prepared was found to be very stable polymorphically with no conversion over time to other polymorphs. The stability

of the sample was tested by subjecting the sample to stability conditions (25 ° C temperatures and 60%. relative humidity) for 6 months.
The polymorphic purity (Fig: 1, measured by XRPD) was monitored for 6 months and the sample was found to be polymorphically stable under stability conditions (25°C temperature and 60%. relative humidity).
Example 2:

s.
No. Material Mg/tablet
1 Febuxostat 120.00
2 Lactose anhydrous (DCL 21) 292.00
3 Microcrystalline cellulose (Avicel PH 101) 125.00
4 Arginine 120.00
Binder Solution
5 Hydroxypropylmethyl Cellulose (3 cps/ 5 cps) Polyvinyl Pyrrolidone/ Hydroxypropyl Cellulose 22.50
6 Methanol/ isopropyl alcohol /ethanol q.s.
Extra granular
7 Croscarmellose sodium 40.00
8 Silicon dioxide (Syloid ® AL-l-FP) 15.00
9 Silicon dioxide (Syloid ® 244-FP) 7.50
10 Magnesium Stearate 7.50
TOTAL (Core Tablet) 750.00
Total Tablet weight 750.00
Coating with opadry readymix
Brief Procedure:
1. Cosift Lactose anhydrous (DCL-21), microcrystalline cellulose and Febuxostat Arginine through appropriate mesh. Transfer the Cosifted material in Fluidized Bed Processor.
2. Binder solution is prepared by dissolving polyvinylpyrolidone/ hydroxypropylmethyl Cellulose (3 cps/ 5 cps) / hydroxypropyl Cellulose in isopropyl alcohol/ methanol/ ethanol.

3. Granulation is prepared by Top-spraying the binder solution of step 2 into Cosifted material of Step 1.
4. After the finishing of Top-spray process, granulated material is dried and screened through appropriate screen.
5. Croscarmellose sodium, microcrystalline cellulose, Silicon dioxide (Syloid ® AL-l-FP ) and Silicon dioxide (Syloid ® 244 FP) was blended.
6. The blend is mixed with magnesium stearate.
7. Core Tablets are prepared using the lubricated blend and optionally coating was performed with opadry ready mix coating remixes.
Example 3:

s.
No. Material Mg/tablet
1 Febuxostat 120.00
2 Lactose anhydrous (DCL 21) 292.00
3 Microcrystalline cellulose (Avicel PH101) 125.00
4 Arginine 120.00
Binder Solution
5 Polyvinylpyrrolidone 22.50
6 Isopropyl alcohol q.s.
Extra garnular
7 Croscarmellose sodium 40.00
8 Silicon dioxide (Syloid ® AL-l-FP) 15.00
9 Silicon dioxide (Syloid ® 244-FP) 7.50
10 Magnesium Stearate 7.50
TOTAL (Core Tablet) 750.00
Total Tablet weight 750.00
Coating

Brief Procedure:
1. Cosift Lactose anhydrous (DCL-21), microcrystalline cellulose and Febuxostat, Arginine through appropriate mesh. Transfer the Cosifted material in Fluidized Bed Processor.
2. Binder solution is prepared by dissolving polyvinylpyrrolidone in isopropyl alcohol.
3. Granulation is prepared by Top-spraying the binder solution of step 2 into Cosifted material of Step 1.
4. After the finishing of Top-spray process, granulated material is dried and screened through appropriate screen.
5. Croscarmellose sodium, microcrystalline cellulose, Silicon dioxide (Syloid ® AL-l-FP) and Silicon dioxide (Syloid ® 244 FP) was blended.
6. The blend is mixed with magnesium stearate.
7. Core Tablets are prepared using the lubricated blend and optionally coating was performed with opadry ready mix coating remixes.
Example 4:

s.
No. Material Mg/tablet
1 Febuxostat 120.00
2 Lactose anhydrous (DCL 21) 292.00
3 Microcrystalline cellulose (Avicel PH101) 125.00
Binder Solution
4 Polyvinylpyrrolidone 22.50
5 Isopropyl alcohol q.s.

6
Arginine 120.00
Extra granular
7 Croscarmellose sodium 40.00
8 Silicon dioxide (Syloid ® AL-l-FP) 15.00
9 Silicon dioxide (Syloid ® 244-FP) 7.50
10 Magnesium Stearate 7.50
TOTAL (Core Tablet) 750.00
Total Tablet weight 750.00
Coating with opadry readymix
Brief Procedure:
1. Cosift Lactose anhydrous (DCL-21), microcrystalline cellulose and Febuxostat through appropriate mesh. Transfer the Cosifted material in Fluidized Bed Processor.
2. Binder solution is prepared by dissolving polyvinylpyrolidone in isopropyl alcohol, followed by addition of arginine.
3. Granulation is prepared by Top-spraying the binder solution of step 2 into Cosifted material of Step 1.
4. After the finishing of Top-spray process, granulated material is dried and screened through appropriate screen.
5. Croscarmellose sodium, microcrystalline cellulose, Silicon dioxide (Syloid ® AL-l-FP) and Silicon dioxide (Syloid ® 244 FP) was blended.
6. The blend is mixed with magnesium stearate.
7. Core Tablets are prepared using the lubricated blend and optionally coating was performed with opadry ready mix coating remixes.

Example 5:

s.
No. Ingredient Mg/tablet
1 Febuxostat 120.00
2 Lactose anhydrous (DCL 21) 416.00
3 Microcrystalline cellulose (Avicel PH101) 125.00
4 Croscarmellose sodium 8.00
Binder Solution
5 Hydroxy propyl cellulose 22.50
6 Methanol q.s.
Extra granular
7 Croscarmellose sodium 08.00
8 Silicon dioxide (Syloid ® AL-l-FP) 15.00
9 Silicon dioxide (Syloid ® 244-FP) 7.50
10 Magnesium Stearate 7.50
Total Tablet weight 730.00
Coatin remix ig with opadry readymix coating es
Brief Procedure:
1. Lactose anhydrous (DCL-21), microcrystalline cellulose , Croscarmellose sodium and Febuxostat was co-sifted through appropriate mesh. The Co sifted material was added into Fluidized Bed Processor.
2. Binder solution was prepared by dissolving hydroxy propyl cellulose in Methanol under stirring.
3. Granulation was performed by Top-spraying the binder solution of step 2 into Cosifted material of Step 1.
4. After the finishing of Top-spray process, granulated material was dried and screened through appropriate screen.

5. Croscarmellose sodium, microcrystalline cellulose, Silicon dioxide (Syloid ® AL-l-FP) and Silicon dioxide (Syloid ® 244 FP) was blended.
6. The blend was mixed with magnesium stearate.
7. Core tablets were prepared using the lubricated blend and optionally coating was performed with opadry ready mix coating remixes.
Example 6:

s.
No. Ingredient Mg/tablet
1 Febuxostat 120.00
2 Lactose anhydrous (DCL 21) 366.00
3 Microcrystalline cellulose (Avicel PH 101) 125.00
4 Croscarmellose sodium 8.00
Binder Solution
5 Hydroxy propyl cellulose 22.50
6 Methanol q.s.
Extra granular
7 Croscarmellose sodium 08.00
8 Lactose anhydrous (DCL 21) 50.00
10 Silicon dioxide (Syloid ® AL-1FP) 15.00
11 Silicon dioxide (Syloid ® AL-244 FP) 7.50
12 Magnesium Stearate 7.50
Total Tablet weight 730.00
Coating with opadry readymix coating remixes
Brief Procedure:
1. Lactose anhydrous (DCL-21), microcrystalline cellulose , Croscarmellose sodium and Febuxostat was co-sifted through appropriate mesh. The Co sifted material was added into Fluidized Bed Processor.

2. Binder solution was prepared by dissolving hydroxy propyl cellulose in Methanol under stirring.
3. Granulation was performed by Top-spraying the binder solution of step 2 into Cosifted material of Step 1.
4. After the finishing of Top-spray process, granulated material was dried and screened through appropriate screen.
5. Croscarmellose sodium, microcrystalline cellulose, Lactose anhydrous (DCL-21), Silicon dioxide (Syloid ® AL-l-FP) and Silicon dioxide (Syloid ® 244 FP) was blended.
6. The blend was mixed with magnesium stearate.
7. Core tablets were prepared using the lubricated blend and optionally coating was performed with opadry ready mix coating remixes. '

We Claim:
1. A stable pharmaceutical composition comprising febuxostat and one or
more of the component selected from acidic co-formers, polymers, and
amino acids.
2. A stable pharmaceutical composition comprising febuxostat according to
claim 1 .wherein the acidic co-formers are selected from the group
comprising of amoic 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, malonic acid, lactobionic acid,
oxalic acid, orotic acid, sebacic acid, tartaric acid, hexanoic acid,
heptanoic acid, cyclopentanepropionic acid, pyruvic acid, lactic acid, citric
acid, benzoic acid, o- (4-hydroxybenzoyl) benzoic acid, cinnamic acid,
mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-
ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic
acid, p-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, p-
toluenesulfonic 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, lauryl sulfuric acid, gluconic acid,
hydroxynaphthoic acid and muconic acid and inorganic acid includes
hydrochloride, sulphuric acid, hydrogen fluoride, hydrogen iodide,
hydrogen bromide and phosphoric acid or mixture thereof.
3. A stable pharmaceutical composition comprising febuxostat according to
claim 1, wherein the polymers are selected from the group comprising of
carbomer, sodium carboxymethylcellulose, microcrystalline celluloses
(MCC), microfine celluloses, dextrin, guar gum, hydoxypropylmethyl

cellulose, hydroxypropyl cellulose, pregelatinized starch, starch, povidone, polyvinyl alcohol , polyvinyl acetate , polyethylene glycol (PEG), methyl cellulose (MC), hydroxy ethyl cellulose, cyclodextrin, pectin, galactomannan, Hydroxy propyl methyl cellulose phthalate (HPMCP), eudragitLlOO, eudragit El00, eudragit RL, eudragit RS, polyoxyethylene stearate, poloxamer 188, tweens, spans, pentaerythrityl tetraacetate, urethane, hydroxy alkyl xanthins or mixture thereof.
4. A stable pharmaceutical composition comprising febuxostat according to claim 1, wherein the amino acids selected from the group comprising of arginine, lysine, histidine, serine, valine or mixtures thereof.
5. A stable pharmaceutical composition comprising febuxostat according to claim 1, further comprises one or more pharmaceutically acceptable excipients.
6. A stable pharmaceutical composition comprising febuxostat according to claim 5,wherein one or more pharmaceutically acceptable excipient is selected from diluent, disintegrant, binder, lubricant, glidant, stabilizer, moisture adsorbent, organoleptic ingredients such as Coloring agents, sweetening agents, flavoring agents, and fragrance.
7. A stable pharmaceutical composition comprising febuxostat according to claim 6, wherein moisture adsorbent includes silicon dioxide.
8. A stable pharmaceutical composition comprising febuxostat according to claim 7, wherein silicon dioxide selected from Syloid ® AL-I-FP, Syloid ® AL-244FP and/ or mixtures thereof.

9. A stable pharmaceutical composition comprising febuxostat according to claim 6, wherein moisture adsorbent present in an amount from about 0.2% to 2%, preferably 1% by weight based on total composition weight.

We Claim:
1. A stable pharmaceutical composition comprising febuxostat and one or
more of the component selected from acidic co-formers, polymers, and
amino acids.
2. A stable pharmaceutical composition comprising febuxostat according to
claim 1 ,wherein the acidic co-formers are selected from the group
comprising of amoic 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, malonic acid, lactobionic acid,
oxalic acid, orotic acid, sebacic acid, tartaric acid, hexanoic acid,
heptanoic acid, cyclopentanepropionic acid, pyruvic acid, lactic acid, citric
acid, benzoic acid, o- (4-hydroxybenzoyl) benzoic acid, cinnamic acid,
mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-
ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic
acid, p-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, p-
toluenesulfonic 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, lauryl sulfuric acid, gluconic acid,
hydroxynaphthoic acid and muconic acid and inorganic acid includes
hydrochloride, sulphuric acid, hydrogen fluoride, hydrogen iodide,
hydrogen bromide and phosphoric acid or mixture thereof.
3. A stable pharmaceutical composition comprising febuxostat according to
claim 1, wherein the polymers are selected from the group comprising of
carbomer, sodium carboxymethylcellulose, microcrystalline celluloses
(MCC), microfine celluloses, dextrin, guar gum, hydoxypropylmethyl

cellulose, hydroxypropyl cellulose, pregelatinized starch, starch, povidone, polyvinyl alcohol , polyvinyl acetate , polyethylene glycol (PEG), methyl cellulose (MC), hydroxy ethyl cellulose, cyclodextrin, pectin, galactomannan, Hydroxy propyl methyl cellulose phthalate (HPMCP), eudragitLlOO, eudragit El00, eudragit RL, eudragit RS, polyoxyethylene stearate, poloxamer 188, tweens, spans, pentaerythrityl tetraacetate, urethane, hydroxy alkyl xanthins or mixture thereof.
4. A stable pharmaceutical composition comprising febuxostat according to claim 1, wherein the amino acids selected from the group comprising of arginine, lysine, histidine, serine, valine or mixtures thereof.
5. A stable pharmaceutical composition comprising febuxostat according to claim 1, further comprises one or more pharmaceutical^ acceptable excipients.
6. A stable pharmaceutical composition comprising febuxostat according to claim 5,wherein one or more pharmaceutically acceptable excipient is selected from diluent, disintegrant, binder, lubricant, glidant, stabilizer, moisture adsorbent, organoleptic ingredients such as Coloring agents, sweetening agents, flavoring agents, and fragrance.
7. A stable pharmaceutical composition comprising febuxostat according to claim 6, wherein moisture adsorbent includes silicon dioxide.
8. A stable pharmaceutical composition comprising febuxostat according to claim 7, wherein silicon dioxide selected from Syloid ® AL-I-FP, Syloid ® AL-244FP and/ or mixtures thereof.

9. A stable pharmaceutical composition comprising febuxostat according to claim 6, wherein moisture adsorbent present in an amount from about 0.2% to 2%, preferably 1% by weight based on total composition weight.