FIELD OF INVENTION

The invention relates to the pharmaceutical field. Specifically it relates to process for preparing solid oral pharmaceutical composition comprising febuxostat and one or more pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS

Febuxostat is a xanthine oxidase inhibitor indicated for the chronic management of hyperuricemia in patients with gout and is not recommended for the treatment of asymptomatic hyperuricemia.

Febuxostat is described chemically as 2-[3-cyano-4-(2-methylpropoxy) phenyl] -4-methylthiazole-5-carboxylic acid. The empirical formula is C16H16N2O3S and its molecular weight is 316.38. Febuxostat is a non-hygroscopic, white crystalline powder that is freely soluble in dimethylformamide; soluble in dimethylsulfoxide; sparingly soluble in ethanol; slightly soluble in methanol and acetonitrile; and practically insoluble in water. The melting range of febuxostat is 205°C to 208°C.

Febuxostat was introduced into the U.S. under the brand name of Uloric (febuxostat 40mg and 80mg) is available for oral administration as tablet formulation. Each tablet contains febuxostat, and lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium croscarmellose, silicon dioxide and magnesium stearate, as inactive ingredients. Uloric® tablets are coated with Opadry II, green.

Chinese Patent No. 101671315 discloses febuxostat tablet formulation wherein said tablet formulation is prepared by non-aqueous granulation process using 30% ethanol as granulating aid.

Chinese Patent Application No. 101759656 discloses febuxostat tablet formulation wherein said tablet formulation is prepared by direct compression method.

Chinese Patent Application No. 1275126 discloses febuxostat crystalline form A, B, C, D, G and its amorphous form and process for preparing the same.

Chinese Patent No 1970547 discloses febuxostat crystalline form H, I, J, and process for preparing the same.

Chinese Patent Application No. 101817801 discloses febuxostat crystalline for K and process for preparing the same.

PCT Application No. WO 2013/001441 discloses dry process for preparing solid oral pharmaceutical composition comprising febuxostat to avoid polymorphic conversion due to aqueous granulation process. Said patent application in examples disclose direct compression and dry granulation process for preparing stable oral tablet composition comprising febuxostat, wherein aqueous based film coating is applied to the tablet.

Different polymorphs of the same drug has different solubility and stability profiles, thus the polymorphic conversion during tablet manufacturing process or during long term storage adversely affects the dissolution and shelf life of product. Therefore it is extremely important that the finished dosage form should retain the same polymorphic form used during manufacturing process to ensure uniform dissolution and stability during the shelf life of product, thereby ensuring consistent performance of said dosage form.

In the above prior arts dry process i.e. direct compression or dry granulation has been used to prepare febuxostat solid oral tablet formulation to avoid febuxostat polymorphic form conversion to different polymorphic form. However none of them discusses or solves the eminent problem of polymorphic form conversion due to the use of aqueous based film coating process.

The inventors of this invention have found that even if dry process is used for preparing febuxostat tablet formulation, when said tablets are film-coated using aqueous based film coating dispersion/suspension showed febuxostat polymorphic form conversion during stability study.

Surprisingly, the inventors of this invention have found that febuxostat tablets prepared by using dry process and film-coated using organic solvent, specifically dichloromethane or dichloromethane and isopropyl alcohol based film coating dispersion/ suspension showed no febuxostat polymorphic form conversion.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to process for preparing solid oral pharmaceutical composition comprising febuxostat and one or more pharmaceutically acceptable excipients.

More specifically it relates to oral film-coated tablet comprising febuxostat and one or more pharmaceutically acceptable excipients prepared by employing dry process, wherein the tablets are film-coated using dichloromethane or dichloromethane and isopropyl alcohol based film coating dispersion/ suspension to maintain febuxostat in its original polymorphic form.

An objective of the invention is to prepare oral film-coated tablet comprising febuxostat and one or more pharmaceutically acceptable excipients, wherein the tablets are prepared by employing dry granulation process and said tablets are film-coated using dichloromethane or dichloromethane and isopropyl alcohol based film coating dispersion/ suspension to maintain febuxostat in its original polymorphic form.

Another objective of the invention, is to prepare oral film-coated tablet comprising febuxostat and one or more pharmaceutically acceptable excipients, wherein the tablets are prepared by employing direct compression process and said tablets are film-coated using dichloromethane or dichloromethane and isopropyl alcohol based film coating dispersion/suspension to maintain febuxostat in its original polymorphic form.

Yet another objective of the invention, is to prepare tablet comprising febuxostat and one or more pharmaceutically acceptable excipients, having comparable in-vitro dissolution profile with that of the marketed Uloric tablets, wherein the tablets are prepared by employing a dry process and said tablets are film-coated using dichloromethane or dichloromethane and isopropyl alcohol based film coating dispersion/suspension to maintain febuxostat in its original polymorphic form.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1: illustrates an overlay of XRPD pattern of crystalline febuxostat active ingredient, placebo and tablets from Exhibit A (Initial and 3 Month at 40°C/75%RH).

Figure 2: illustrates an overlay of XRPD pattern of crystalline febuxostat active ingredient, placebo and tablets from Exhibit B (Initial and 1 Month at 40°C/75%RH).

Figure 3: illustrates an overlay of XRPD pattern of crystalline febuxostat active ingredient, placebo and tablets from Exhibit D (Initial and 1 Month at 40°C/75%RH).

Figure 4: illustrates an overlay of XRPD pattern of crystalline febuxostat active ingredient, placebo and tablets from Exhibit E (Initial and 1 Month at 40°C/75%RH).

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to process for preparing solid oral pharmaceutical composition comprising febuxostat and one or more pharmaceutically acceptable excipients.

As discussed in the background of the invention, dry process i.e. direct compression or dry granulation has been used to prepare febuxostat solid oral tablet to avoid polymorphic conversion to different polymorphic form. However none of them discusses or solves the eminent problem of polymorphic form conversion to different polymorphic form due to the use of aqueous based film coating process. The inventors of this invention have found that even if dry process is used to prepare febuxostat tablet formulation, when said tablets are film-coated using aqueous based film coating dispersion/suspension showed polymorphic form conversion during stability study. Surprisingly, the inventors of this invention have found that febuxostat tablets prepared by using dry process, when film-coated using dichloromethane or dichloromethane and isopropyl alcohol based film coating dispersion/ suspension, showed no febuxostat polymorphic form conversion to different polymorphic form during stability.

Specifically it relates to oral film-coated tablet comprising febuxostat and one or more pharmaceutically acceptable excipients prepared by employing dry process, wherein the tablets are film-coated using dichloromethane or dichloromethane and isopropyl alcohol based film coating dispersion/suspension to maintain febuxostat in its original polymorphic form.

More specifically, the embodiments of the invention relates to:

A film-coated tablet comprising febuxostat and one or more pharmaceutically acceptable excipients, prepared by dry granulation process, wherein said tablets are film coated using dichloromethane as coating solvent.

A film-coated tablet comprising febuxostat and one or more pharmaceutically acceptable excipients, prepared by dry granulation process, wherein said tablets are film coated using dichloromethane and isopropyl alcohol as coating solvent.

A film-coated tablet comprising febuxostat and one or more pharmaceutically acceptable excipients, prepared by direct compression process, wherein said tablets are film coated using dichloromethane as coating solvent.

A film-coated tablet comprising febuxostat and one or more pharmaceutically acceptable excipients, prepared by direct compression process, wherein said tablets are film coated using dichloromethane and isopropyl alcohol as coating solvent.

In context of the invention, terms like "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for febuxostat or its pharmaceutically acceptable salts or esters or derivatives thereof.

According to the invention, febuxostat may be present in an amorphous or crystalline form. As used herein, the term, "febuxostat" is intended to include the active agent itself, as well as its pharmaceutically acceptable salts or derivatives or polymorphs thereof.

As used herein, the term, "pharmaceutical composition" is intended to include solid oral composition in the form of granules, mini-tablets, tablets, coated tablets and the like.

As used herein, the term, "stable" as used in connection with "tablet dosage form" relates to physicochemical and polymorphically stability of tablet dosage form.

As used herein, the term, "dry process" as used in connection with "process for preparing tablet" intended to include direct compression or dry granulation process.

As used herein, the term, "direct compression" as relates to the process by which tablets are compressed directly from the powder blend of active ingredient and suitable pharmaceutically acceptable excipients.

As used herein, the term, "dry granulation" as relates to the process of granulating the powder blend of active ingredients and suitable pharmaceutically acceptable excipients without the use of granulating solvent/liquid.

In context of the invention, terms "dry granulation" or "compaction" or "slugging" or "chilsonation" may be used interchangeably and synonymously.

There are two dry granulation methods used in the pharma industry: (1) Slugging: in which powder blend is compacted in to large tablets known as a 'slug' using large flat faced punches using a heavy-duty tabletting press, or (2) Roll compaction or chilsonation: in which powder blend is compacted in to 'sheet' or 'flakes' using a roller then broken or milled using a suitable milling technique to produce granules of desired size, which can be further processed in to tablets.

Film coating is the process whereby a tablet is surrounded by a thin layer of polymeric material to improve visual appearance, to mask taste, odor or color of active ingredient and also to protect the active ingredient form light, moisture and environmental gases. Tablet film coating is performed by two types; one is aqueous film coating using water as a solvent and non aqueous film coating using organic solvents. The basic components of a film coating system are film forming polymer, plasticizer and solvent; optionally contains colorant, anti-tackifying agents etc. Mainly three types of coating equipments are commonly used in pharma industry, which are: (1) standard coating pan, (2) perforated coating pan, and (3) fluidized bed (air suspension) coater.

According to an embodiment of the invention, febuxostat having the polymorphic form designated as crystalline form K is used to prepare tablet formulation using dry granulation process, wherein said polymorphic form K has X-ray powder diffraction (XRPD) characteristic peaks (29) values of 5.832 ± 0.2, 8.003 ± 0.2, 11.632 ± 0.2, 12.798 ± 0.2, 14.418 ± 0.2, 16.913 ± 0.2, 17.496 ± 0.2, 18.242 ±0.2, 18.533 ±0.2.

According to an embodiment of the invention, tablet contains from about 8 to 30% by weight of febuxostat and one or more pharmaceutically acceptable excipients.

According to an embodiment of the invention, dry granulation process for preparing film-coated tablet comprising febuxostat and one or more pharmaceutically acceptable excipients essentially comprises the step of:

a) sifting febuxostat, diluent(s), disintegrant(s) and/or superdisintegrants(s), dry binder, and lubricant(s) and/or glidant(s) through Quadro-co-mill/mechanical fitted with suitable screen;

b) mixing febuxostat, intragranular part of diluent(s), disintegrant(s) and/or superdisintegrants(s), dry binder, and lubricant(s) and/or glidant(s) to get a uniform blend;

c) compacting the blend of step (b) using roller compactor or tablet press using slugging tool to get sheet or small flat pellets or flakes of material;

d) milling and/or screening the sheet or small flat pellets or flakes of step (c) through suitable shear mill to get granules of suitable size;

e) mixing the granules obtained in step (d) with extragranular part of diluent(s), disintegrant(s) and/or superdisintegrants(s), dry binder if remaining to get a uniform blend;

f) lubricating the blend of step (e) with lubricant(s) and/or glidant(s);

g) compressing the blend of step (f) into tablets, and;

h) film-coating the tablets obtained in the step (g) using dichloromethane or dichloromethane and isopropyl alcohol solvent based film coating dispersion/suspension.

According to an embodiment of the invention, direct compression process for preparing film-coated tablet formulation comprising febuxostat and one or more pharmaceutically acceptable excipients essentially comprises the step of:

a) sifting febuxostat, diluent(s), disintegrant(s) and/or superdisintegrants(s), dry binder, and lubricant(s) and/or glidant(s) through suitable size sieve;

b) blending febuxostat, with diluent(s), disintegrant(s) and/or superdisintegrants(s), dry binder, optionally with lubricant(s) and/or glidant(s), to get a uniform blend;

c) lubricating the blend of step (b) with lubricant(s) and/or glidant(s);

d) compressing the blend of step (c) into tablets, and;

e) film-coating the tablets obtained in the step (d) using dichloromethane or dichloromethane and isopropyl alcohol solvent based film coating dispersion/suspension.

According to an embodiment of the invention, film-coated tablet contains from about 8 to 30% by weight of febuxostat and one or more pharmaceutically acceptable excipients selected from a group comprising of diluents, binders, disintegrants, super-disintegrants, surfactants, wetting agents, glidants and/ or lubricants, film-formers, plasticizers, colorants, and opacifiers.

Suitable diluents according to the invention include, but are not limited to, mannitol, xylitol, sorbitol, lactose, anhydrous lactose, sucrose, cellulose, microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, starch, calcium trisilicate, magnesium trisilicate, cellulose acetate, dextrose, or combinations thereof.

Suitable dry binders according to the invention include, but are not limited to povidone, copovidone, pregelatinized starch, polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), starch, hydroxyethyl cellulose (HEC), ethyl cellulose (EC), chitosan, guar gum, methyl cellulose (MC), carbomer, acacia, sodium alginate, calcium alginate or combinations thereof.

Suitable disintegrants according to the invention include, but are not limited to starch, microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, polacrilin potassium or combinations thereof.

Suitable superdisintegrants according to the invention include, but are not limited to crospovidone, croscarmellose sodium, and sodium starch glycolate, low-substituted hydroxypropyl cellulose (L-HPC), pregelatinised starch or combinations thereof.

Suitable glidants and/or lubricants according to the invention include, but are not limited to, silicon dioxide, colloidal silicon dioxide, talc, magnesium stearate, sodium stearyl fumarate, calcium stearate, sodium dodecyl sulfate or combinations thereof.

Suitable surfactants or wetting agents according to the invention include, but are not limited to, anionic surfactants such as potassium laurate, triethanolamine stearate, sodium lauryl sulfate, cationic surfactants include quaternary ammonium compounds, benzalkonium chloride, cetyltrimethylammonium bromide; nonionic surfactants include glycerol monostearate, cetyl alcohol, cetostearyl alcohol, and. polyoxyethylene glycol sorbitan alkyl esters (polysorbate), sorbitan alkyl esters (span), poloxamer or combinations thereof.

According to the invention, film coating excipients may be selected from a group comprising of film-formers, plasticizers, anti-tacking agents, colorants, opacifiers etc.

Suitable film forming polymers according to the invention include, but are not limited to, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), methyl cellulose (MC) and ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methacrylic acid copolymer, cellulose acetate phthalate, cellulose phthalate, hydroxypropyl methylcellulose phthalate (HPMCP), Polyvinyl acetate phthalate, and natural gums and resins such as zein, gelatin, shellac and acacia or combinations thereof.

Suitable plasticizers according to the invention include, but are not limited to, castor oil, polyethylene glycol, propylene glycol, glycerin, triacetin, polysorbates, phthalate esters, dibutyl sebacate, citrate esters, and monoglycerides or combinations thereof.

Suitable opacifiers according to the invention include, but are not limited to, titanium dioxide, zinc oxide and talc or combinations thereof.

Suitable anti-tackifying agents according to the invention include, but are not limited to, talc, kaolin, and magnesium stearate or combinations thereof.

Suitable coloring agents according to the invention include, but are not limited to, FDA approved dyes and lakes such as sunset yellow, tartrazine, erythrosine, iron oxide yellow, and natural colors such as carmine or combinations thereof.

Suitable solvents for preparing film coating dispersion/ suspension according to the invention include dichloromethane (DCM) or mixture of isopropyl alcohol (IPA) and dichloromethane (DCM).

According to the invention ready-to-use film coating systems such as Opadry ™, Instacoat™ may also be used for film coating of tablets.

The embodiments of the invention are described in the following examples, but the examples are illustrative and do not limit the scope of this invention.

EXAMPLE 1 (Exhibit A)

Febuxostat tablets 80 mg prepared using dry granulation method and film-coated using isopropyl alcohol and dichloromethane solvent based film coating dispersion/suspension.

Unit Composition:

Brief manufacturing process:

1. Sift febuxostat and silicon dioxide together through Quadro-co-mill fitted with suitable size screen.

2. Sift anhydrous lactose, croscarmellose sodium and hydroxypropyl cellulose through Quadro-co-mill fitted with suitable size screen.

3. Blend the material of step (1) and step (2) in bin blender for suitable time.

4. Sift required quantity of mixture of sodium dodecyl sulfate (6%) + magnesium stearate (94%) through Quadro-co-mill fitted with suitable size screen.

5. Blend the material of step (3) and step (4) in bin blender for suitable time

6. Compact the material of step (5) using roller compactor to get flakes.

7. Sift or pass the flakes of step (6) through Quadro-co-mill fitted with suitable size screen.

8. Sift crospovidone, microcrystalline cellulose, colloidal silicon dioxide, sodium lauryl sulfate and talc through Quadro-co-mill fitted with suitable size screen.

9. Blend the material of step (7) and sifted material of step (8) in bin blender for suitable time.

10. Sift magnesium stearate through Quadro-co-mill fitted with suitable size screen.

11. Blend the material of step (9) and sifted magnesium Stearate of step (10) in bin blender for suitable time

12. Compress the blend of step (11) using rotary tablet compression machine fitted with appropriate dies and punches.

13. Disperse ready-to-use film coating systems in isopropyl alcohol and dichloromethane solvent mixture under continuous stirring till homogenous dispersion is not obtained.

14. Coat the compressed tablets of step (12) using coating dispersion of step (13) to get suitable weight build up.

EXAMPLE 2 (Exhibit B)

Febuxostat tablets 80 mg prepared using dry granulation method and film-coated using dichloromethane solvent based film coating dispersion/suspension.

Unit Composition:

Brief manufacturing process:

1. Sift febuxostat and silicon dioxide together through Quadro-co-mill fitted with suitable size screen.

2. Sift anhydrous lactose, croscarmellose sodium and hydroxypropyl cellulose through Quadro-co-mill fitted with suitable size screen.

3. Blend the material of step (1) and step (2) in bin blender for suitable time.

4. Sift required quantity of mixture of sodium dodecyl sulfate (6%) + magnesium stearate (94%) through Quadro-co-mill fitted with suitable size screen.

5. Blend the material of step (3) and step (4) in bin blender for suitable time

6. Compact the material of step (5) using roller compactor to get flakes.

7. Sift or pass the flakes of step (6) through Quadro-co-mill fitted with suitable size screen.

8. Sift crospovidone, microcrystalline cellulose, colloidal silicon dioxide, sodium lauryl sulfate and talc through Quadro-co-mill fitted with suitable size screen.

9. Blend the material of step (7) and sifted material of step (8) in bin blender for suitable time.

10. Sift magnesium stearate through Quadro-co-mill fitted with suitable size screen.

11. Blend the material of step (9) and sifted magnesium Stearate of step (10) in bin blender for suitable time

12. Compress the blend of step (11) using rotary tablet compression machine fitted with appropriate dies and punches.

13. Disperse ready-to-use film coating systems in dichloromethane under continuous stirring till homogenous dispersion is not obtained.

14. Coat the compressed tablets of step (12) using coating dispersion of step (13) : to get suitable weight build up.

EXAMPLE 3 (Exhibit C)

Febuxostat tablets 80 mg prepared using direct compression method and film-coated using dichloromethane solvent based film coating dispersion/suspension.

Unit Composition:

Brief manufacturing process:

1. Sift febuxostat, anhydrous lactose, silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, crospovidone, microcrystalline cellulose, colloidal silicon dioxide, sodium lauryl sulfate and talc together through Quadro-co-mill fitted with suitable size screen.

2. Sift required quantity of mixture of sodium dodecyl sulfate (6%) + magnesium stearate (94%) through Quadro-co-mill fitted with suitable size screen.

3. Sift magnesium stearate through Quadro-co-mill fitted with suitable size screen.

4. Blend the material of step (1) with sifted material of step (2) and step (3) in bin blender for suitable time

5. Compress the blend of step (4) using rotary tablet compression machine fitted with appropriate dies and punches.

6. Disperse ready-to-use film coating systems in dichloromethane solvent under continuous stirring till homogenous dispersion is not obtained.

7. Coat the compressed tablets of step (5) using coating dispersion of step (6) to get suitable weight build up.

COMPARATIVE EXAMPLE1

(Exhibit D)

Febuxostat tablets 80 mg prepared using dry granulation method and film-coated using isopropyl alcohol solvent based film coating dispersion/suspension. Unit Composition:

Brief manufacturing process:

1. Sift febuxostat and silicon dioxide together through Quadro-co-mill fitted with suitable size screen.

2. Sift anhydrous lactose, croscarmellose sodium and hydroxypropyl cellulose through Quadro-co-mill fitted with suitable size screen.

3. Blend the material of step (1) and step (2) in bin blender for suitable time.

4. Sift required quantity of mixture of sodium dodecyl sulfate (6%) + magnesium stearate (94%) through Quadro-co-mill fitted with suitable size screen.

5. Blend the material of step (3) and step (4) in bin blender for suitable time

6. Compact the material of step (5) using roller compactor to get flakes.

7. Sift or pass the flakes of step (6) through Quadro-co-mill fitted with suitable size screen.

8. Sift crospovidone, microcrystalline cellulose, colloidal silicon dioxide, sodium lauryl sulfate and talc through Quadro-co-mill fitted with suitable size screen.

9. Blend the material of step (7) and sifted material of step (8) in bin blender for suitable time.

10. Sift magnesium stearate through Quadro-co-mill fitted with suitable size screen.

11. Blend the material of step (9) and sifted magnesium Stearate of step (10) in bin blender for suitable time

12. Compress the blend of step (11) using rotary tablet compression machine fitted with appropriate dies and punches.

13. Disperse ready-to-use film coating systems in isopropyl alcohol under continuous stirring till homogenous dispersion is not obtained.

14. Coat the compressed tablets of step (12) using coating dispersion of step (13) to get suitable weight build up.

COMPARATIVE EXAMPLE 2 (Exhibit E)

Febuxostat tablets 80 mg prepared using dry granulation method and film-coated using aqueous based film coating dispersion/suspension. Unit Composition:

Brief manufacturing process:

1. Sift febuxostat and silicon dioxide together through Quadro-co-mill fitted with suitable size screen.

2. Sift anhydrous lactose, croscarmellose sodium and hydroxypropyl cellulose through Quadro-co-mill fitted with suitable size screen.

3. Blend the material of step (1) and step (2) in bin blender for suitable time.

4. Sift required quantity of mixture of sodium dodecyl sulfate (6%) + magnesium stearate (94%) through Quadro-co-mill fitted with suitable size screen.

5. Blend the material of step (3) and step (4) in bin blender for suitable time

6. Compact the material of step (5) using roller compactor to get flakes.

7. Sift or pass the flakes of step (6) through Quadro-co-mill fitted with suitable size screen.

8. Sift crospovidone, macrocrystalline cellulose, colloidal silicon dioxide, sodium lauryl sulfate and talc through Quadro-co-mill fitted with suitable size screen.

9. Blend the material of step (7) and sifted material of step (8) in bin blender for suitable time.

10. Sift magnesium stearate through Quadro-co-mill fitted with suitable size screen.

11. Blend the material of step (9) and sifted magnesium Stearate of step (10) in bin blender for suitable time

12. Compress the blend of step (11) using rotary tablet compression machine fitted with appropriate dies and punches.

13. Disperse ready-to-use film coating systems in purified water under continuous stirring till homogenous dispersion is not obtained.

14. Coat the compressed tablets of step (12) using coating dispersion of step (13) to get suitable weight build up.

Dissolution Testing:

In-vitro dissolution test was performed for febuxostat 80mg film-coated tablets prepared according to Example 1 and 3 and marketed Uloric® 80mg tablets using 900 ml of pH 6.8 Phosphate buffer at 37°C, using USP apparatus II, at 75 rpm and the resultant data is compiled in Table -1.

Above dissolution data shows that the febuxostat tablets prepared according to Example 1 and 3 has comparative similar in-vitro dissolution profile as that of marketed Uloric® tablets.

X-ray powder diffraction (XRPD) Analysis:

XRPD analysis of febuxostat API, placebo, and febuxostat film-coated tablets of Example 1 and 2 and febuxostat film-coated tablets prepared according to Comparative Example 1 and 2 was performed.

Results of XRPD analysis confirmed that the characteristic 26 value peaks present in febuxostat API remain unchanged at the end of 3 months at accelerated stability study at 40°C/75%RH in febuxostat film-coated tablet prepared according to Example 1 and at the end of 1 month at accelerated stability study at 40°C/75%RH in febuxostat film-coated tablet prepared according to Example 2.

However, most of the characteristic peaks were found to be absent and new peaks were found present in XRPD of febuxostat film-coated tablets prepared according to Comparative Example 1 and 2 at the end of 1 month at accelerated stability study at 40°C/75%RH, thereby indicating the change in the polymorphic form of febuxostat on accelerated stability conditions.

Thus from the above discussion it is clear that not only dry process of tablet manufacturing, but also the use of dichloromethane or dichloromethane and isopropyl alcohol as a solvent for film coating is necessary to maintain febuxostat in its original polymorphic form during shelf life of febuxostat film-coated tablets. Thus the use of IPA or aqueous solvent based film coating of febuxostat tablets should be avoided.

Stability Data:

Febuxostat film-coated tablets prepared according to Example 1 where packed in HDPE bottles and were subjected to accelerated stability study at 40°C/75%RH and the resultant data is compiled in Table -2.

Table -2

Tablets prepared according to Example 1 were physically stable with respect to size, shape, weight, color, texture etc during accelerated stability study. Above accelerated stability data and XRPD analysis of tablets showed that the febuxostat film-coated tablets prepared according to Example 1 were physico chemically and polymorphically stable at the end of 3 months at 40°C/ 75% RH.

WE CLAIM:

1. A film-coated tablet comprising febuxostat and one or more pharmaceutically acceptable excipients, prepared by dry granulation process, wherein said tablets are film coated using dichloromethane as coating solvent.

2. A film-coated tablet comprising febuxostat and one or more pharmaceutically acceptable excipients, prepared by dry granulation process, wherein said tablets are film coated using dichloromethane and isopropyl alcohol as coating solvent.

3. A film-coated tablet comprising febuxostat and one or more pharmaceutically acceptable excipients, prepared by direct compression process, wherein said tablets are film coated using dichloromethane as coating solvent.

4. A film-coated tablet comprising febuxostat and one or more pharmaceutically acceptable excipients, prepared by direct compression process, wherein said tablets are film coated using dichloromethane and isopropyl alcohol as coating solvent.

5. The film-coated tablet according to claims 1-4, comprising about 8 to 30% by weight of febuxostat.

6. The film-coated tablet according to claims 1-4, wherein one or more pharmaceutically excipients are selected from a group comprising diluents, binders, disintegrants, super-disintegrants, surfactants, wetting agents, glidants or lubricants and combinations thereof.

7. The film-coated tablet according to claims 1-4, wherein the film coating composition comprises a film-former, plasticizer, anti-tacking agent, colorant, opacifiers and solvent is selected either from dichloromethane or combination of dichloromethane and isopropyl alcohol.

8. A film-coated tablet comprising febuxostat, having the following unit composition:

9. A film-coated tablet comprising febuxostat, having the following unit composition:

10. A film-coated tablet comprising febuxostat, as herein described and exemplified.