DESC:FIELD OF INVENTION

The present invention relates to oral photostable pharmaceutical compositions of axitinib, or crystalline forms and the process for preparation thereof.

BACKGROUND OF THE INVENTION

Axitinib is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma after the failure of one prior systemic therapy, which is chemically represented as N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide and its chemical structure is as follows

Axitinib is a white to light-yellow powder with a pKa of 4.8. The solubility of axitinib in aqueous media over the range pH 1.1 to pH 7.8 is in excess of 0.2 µg/mL. Axitinib is marketed with the brand name Inlyta in US by Pfizer Labs. INLYTA is supplied as red, film-coated tablets containing either 1 mg or 5 mg of axitinib together with microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, and Opadry® II red 32K15441 as inactive ingredients. The Opadry II red 32K15441 film coating contains lactose monohydrate, HPMC 2910/Hypromellose 15cP, titanium dioxide, triacetin (glycerol triacetate), and red iron oxide.

Axitinib, as well as pharmaceutically acceptable salts, thereof are described in US Patent No. 6,534,524. The Dosage forms of axitinib are described in U.S. Publication No. 2004-0224988.

Polymorphic forms and pharmaceutical compositions of axitinib are described in U.S.Publication Nos. 2006-0094763, 2008-0274192 and 2014-0248347 and in U.S Patent No. 8,791,140.
U.S Publication No. 2006-0094763 is related to invention of crystalline forms of axitinib or pharmaceutically acceptable salts thereof, wherein the crystalline forms are selected from the group consisting of polymorph Form I, Form II, Form III, Form IV, Form VI, Form VII, and Form VIII. Further US ‘763 Publication discloses the axitinib polymorphs or solid forms comprising two or more such polymorphs as described in the invention may be formulated into pharmaceutical compositions suitable for mammalian medical use.

U.S Publication No. 2008-0274192 relates to amorphous axitinib or pharmaceutically acceptable salts or solvates thereof. Further US ‘192 Publication discloses pharmaceutical composition comprising axitinib or pharmaceutically acceptable salt or solvate thereof, wherein at least a portion of said compound is amorphous.

U.S Patent No. 8,791,140 is related to invention of crystalline forms of axitinib or pharmaceutically acceptable salts thereof, wherein the crystalline forms are selected from group consisting of polymorph Form XXV, Form XVI, Form VIII, Form XLI, Form IX, Form XII and Form XV. US ‘140 Patent further describes that crystalline Form XXV is anhydrous crystalline and is more thermodynamically stable, with improved photostability, has more regular crystalline shape, does not have a tendency to form agglomerates and has better bulk flow properties which are important for better tablet processing and manufacturing when compared to Form IV. Further US ‘140 Patent describes that crystalline Form XLI is anhydrous crystalline and is most thermodynamically stable form, with improved photostability, and has more regular crystalline shape, does not have a tendency to form agglomerates, has a better bulk flow properties which are important for better tablet processing and manufacturing when compared with Form IV. Further US ‘140 Patent in Example-6 discloses the comparison of photostability of Form XLI and Form XXV over Form IV when exposed to artificial light equivalent to the International Conference on Harmonization (ICH) Guidelines for Photostability Testing of New Drug Substances, Option 1 exposure, that Form XXV has 100% potency, Form XLI has 89% potency and Form IV has 34% potency. US ‘140 Patent in Example-7 further discloses the filtration time comparison of Form XXV, Form XLI over Form IV, which Form XLI has 0.1hr, Form XXV has 4.0hr and Form IV has 25.9 hr. US ‘140 patent therefore discloses that Form XLI is less photostable compared to Form XXV, and where Form XXV has more filtration time.
US Publication No. 2014-0248347 relates to the pharmaceutical composition comprising a core and a coating, the core comprising axitinib or pharmaceutically acceptable salts thereof and excipients, and the coating comprising metal oxide i.e. iron oxide. US ‘347 Publication further discloses the composition comprising Form XXV, Form XLI and Form IV of axitinib, wherein the film coating composition comprises iron oxide. Further US ‘347 Application in Example-7 discloses that Cis-isomer of axitinib and asymmetric dimer of axitinib are the major photodegradants in Form XLI tablet compositions. Further the Example-5 of US’347 disclose that 2+2 dimer as the major photodegradant in Form IV tablet composition.

In view of above disadvantages with the formation of photodegradation impurities in the compositions comprising axitinib Form-XLI and Form IV, there further still exists a need to develop the oral photostable pharmaceutical compositions of axitinib or crystalline forms thereof comprising novel crystalline forms of axitinib.

SUMMARY OF INVENTION

Some embodiments relate to an oral pharmaceutical composition comprising crystalline axitinib wherein oral composition is optionally coated, which coating is devoid of any metal oxides.

Further embodiments relates to an oral pharmaceutical composition described above, wherein the coating further comprises a filler, a polymer, a plasticizer, or an opacifier, or combinations thereof.

Additional embodiments relate to any of the embodiments of an oral pharmaceutical composition described above, wherein the coating further comprises a colorant.

Further embodiments relate to any of the embodiments of an oral pharmaceutical composition described above, wherein the coating is selected from the group consisting of Opadry red II 32K550010.

Additional embodiments relate to an oral pharmaceutical composition described above, wherein the composition is an uncoated tablet.

Some embodiments relate to an oral pharmaceutical composition described above, wherein the composition is a film coated tablet.

Additional embodiments relate to an oral pharmaceutical composition described above, wherein the coating comprises about 4 weight percent of the composition.

Further embodiments relate to an oral pharmaceutical composition of axitinib comprising crystalline axitinib, wherein the coating comprises about 2 weight percent to about 20 weight percent of Aluminum Lake, based on the total weight of the coating.

More embodiments of invention relates to an oral pharmaceutical composition of axitinib comprising crystalline axitinib and:
a. about 80 weight percent to about 98 weight percent of at least one filler;
b. about 2 weight percent to about 5 weight percent of a disintegrant;
c. about 0.25 weight percent to about 5 weight percent of a lubricant; and
d. about 1 weight percent to about 8 weight percent of the coating, based on the total weight of the pharmaceutical composition.

Further embodiments of invention relates to an oral pharmaceutical composition of axitinib comprising crystalline axitinib and
a. 20 weight percent to about 98 weight percent microcrystalline cellulose;
b. about 10 weight percent to about 85 weight percent lactose monohydrate;
c. about 2 weight percent to about 5 weight percent croscarmellose sodium;
d. about 0.25 weight percent to about 5 weight percent magnesium stearate; and
e. about 1 weight percent to about 8 weight percent of the coating, based on the total weight of the pharmaceutical composition.

Some embodiments relate to an oral pharmaceutical composition comprising crystalline axitinib and excipients, wherein the pharmaceutical composition is devoid of the following compounds
Formula I

(2+2 dimer)
Formula II

(asymmetric dimer)
and

Formula III

cis-isomer

Some embodiments relate to an oral pharmaceutical composition comprising crystalline axitinib, wherein photodegradation of axitinib or a pharmaceutically acceptable salt thereof, is less than about 1% as measured by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guideline, Q1B Photostability Testing of New Drug Substances and Products, published on November 1996.

Embodiments relate to the an oral pharmaceutical composition comprising crystalline axitinib Form SAB-I characterized by X-ray powder diffraction pattern comprising at least five characteristic 2?° peaks selected from 7.6, 8.1, 15.6, 16.4 and 17.6 ±0.2 2?° and excipients, wherein oral composition is optionally coated, which coating is devoid of any metal oxides.

Further embodiments relate to an oral pharmaceutical composition of axitinib comprising crystalline axitinib Form SAB-I characterized by DSC isotherm comprising two endothermic peaks ranging between-
a. Peak -1- Between 213 to 217°C.
b. Peak -2- Between 219 to 224°C.

Some embodiments relate to an oral pharmaceutical composition comprising crystalline axitinib Form SAB-I characterized by X-ray powder diffraction pattern comprising at least five characteristic 2?° peaks selected from 7.6, 8.1, 15.6, 16.4 and 17.6 ±0.2 2?° and excipients, wherein photodegradation of axitinib or a pharmaceutically acceptable salt thereof, is less than about 1% as measured by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guideline, Q1B photostability Testing of New Drug Substances and Products, published on November 1996.

Additional embodiments relate to an oral pharmaceutical composition comprising crystalline axitinib monohydrate Form SAB-II characterized by X-ray powder diffraction pattern comprising at least five characteristic 2?° peaks selected from 7.5, 8.0, 14.2, 14.7, 15.7, 18.1, 20.1, 24.4, 29.8 and 32.0 ±0.2 2?° and excipients, wherein oral composition is optionally coated, which coating is devoid of any metal oxides.

Further embodiments relate to an oral pharmaceutical composition of axitinib comprising crystalline axitinib Form SAB-II characterized by DSC isotherm comprising three endothermic peaks ranging between-
a. Peak -1- Between 48 to 86°C
b. Peak -2- Between 213 to 217°C
c. Peak -2- Between 219 to 224°C.

Additional embodiments relate to an oral pharmaceutical composition comprising crystalline axitinib Form SAB-III characterized by X-ray powder diffraction pattern comprising at least four characteristic 2?° peaks selected from 10.1, 10.4, 15.3, 18.3, 18.7, 19.7and 24.6 ±0.2 2?° and excipients, wherein oral composition is optionally coated, which coating is devoid of any metal oxides.

Further embodiments relate to an oral pharmaceutical composition of axitinib comprising crystalline axitinib Form SAB-III characterized by DSC isotherm comprising three endothermic peaks ranging between-
a. Peak -1- Between 53 to 73°C
b. Peak -2- Between 214 to 218°C
c. Peak -2- Between 222 to 225°C.

Some embodiments relate to a method of treating abnormal cell growth in a subject comprising administering to the subject an amount of any of the embodiments of an oral pharmaceutical composition of crystalline axitinib that is effective in treating abnormal cell growth.

More embodiments relate to the method of treating abnormal cell growth, wherein the abnormal cell growth is cancer.

Additional embodiments relate to the method of treating cancer, wherein the cancer is selected from the group consisting of liver cancer, melanoma, mesothelioma, non-small cell lung cancer, prostate cancer, renal cell carcinoma, soft tissue sarcomas and solid tumors.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows an annotated powder X-ray diffraction pattern of crystalline axitinib Form SAB-I in drug product according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, an “active pharmaceutical ingredient” or “API” is the biologically active substance in a pharmaceutical composition, formulation, drug product or unit dosage form. Specifically, axitinib is the active pharmaceutical ingredient in the pharmaceutical composition or drug product of the present invention.

As used herein, a “drug product” refers to a formulated active pharmaceutical ingredient. For example, a drug product may refer to a tablet or capsule that contains an active pharmaceutical ingredient and excipients. Specifically, a drug product is a pharmaceutical composition of the present invention. The terms “drug product” and “pharmaceutical composition” may be used interchangeably.

In an embodiment, the present invention relates an oral photostable pharmaceutical composition comprising crystalline axitinib or a pharmaceutical salt thereof. In another embodiment, the present invention relates to an oral photostable pharmaceutical composition comprising crystalline axitinib and excipients, or a pharmaceutical salt thereof.

In another embodiments the invention relate to an oral pharmaceutical composition comprising crystalline axitinib wherein oral composition is optionally coated, which coating is devoid of any metal oxides.

In another embodiment, the present invention relates to an oral photostable pharmaceutical composition comprising a core and a coating, the core comprising axitinib or a pharmaceutically acceptable salt thereof and excipients, and the coating is devoid of any metal oxides.

The pharmaceutical composition of the present invention includes a core and a coating. The core includes axitinib or a pharmaceutically acceptable salt thereof and excipients. The pharmaceutically acceptable core excipients may include fillers, disintegrants and lubricants.

Suitable fillers or diluents are known in the art. For example, suitable fillers include, but are not limited to, lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), starch, dextrin, glucose, silicic acid, sucrose, Sorbitol, Sodium Saccharin, Acesulfame potassium, Xylitol, Aspartame, Mannitol, polyvinyl pyrrolidone, low molecular weight hydroxypropyl cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, low molecular weight hydroxypropyl methylcellulose, low molecular weight carboxymethyl cellulose, ethyl cellulose, a suitable inorganic calcium salt such as dicalcium phosphate, alginates, gelatin, polyethylene oxide, acacia, magnesium aluminum silicate, and polymethacrylates, or a combination thereof. In one embodiment, fillers include agents selected from the group consisting of microcrystalline cellulose and lactose anhydrous, or a combination thereof. The filler comprises from about 80 weight percent to about 98 weight percent of the composition, based upon total weight of the composition.

Suitable disintegrants are also known in the art. Suitable disintegrants include, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate, or a combination thereof. In one embodiment, the disintegrant includes croscarmellose sodium. The disintegrant comprises from about 2 weight percent to about 5 weight percent of the composition, based upon total weight of the composition.

Suitable lubricants are also known in the art. Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate, or combinations thereof. In one embodiment, the lubricant includes magnesium stearate. The lubricant comprises from about 0.25 weight percent to about 5 weight percent of the composition by weight, based upon total weight of the composition.

A suitable coating or coating excipient of the present invention includes Aluminum Lake. In an embodiment, Aluminum Lake is present in an amount of about 2 weight percent to about 20 weight percent, based on the total weight of the coating.
In an embodiment, the coating or coating excipients may further include polymers, plasticizers, opacifiers, diluents or fillers, and colorants.

In an embodiment, the coating of the present invention is an aqueous coating. The coating or aqueous coating of the present invention comprises a polymer, a plasticizer, an opacifier, a pharmaceutically acceptable diluent or filler and optionally a colorant.

Suitable polymers are known in the art. Suitable polymers include, but are not limited to, cellulosics such as hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, methylcellulose, and sodium carboxymethylcellulose. Further examples of polymers include vinyls such as polyvinyl pyrrolidone. In an embodiment, the polymer is hydroxypropyl methylcellulose. The polymer comprises from about 25 weight percent to about 30 weight percent of the coating by weight, based upon total weight of the coating composition.

Suitable plasticizers are known in the art. Suitable plasticizers include, but are not limited to, polyhydric alcohols such as glycerol and polyethylene glycols and acetate esters such as glycerol triacetate or glyceryl triacetate, which are known as triacetin, and triethyl citrate. In an embodiment, the plasticizer is triacetin. The plasticizer comprises from about 5 weight percent to about 10 weight percent of the coating by weight, based upon total weight of the coating composition.

Suitable opacifiers are known in the art. In an embodiment the opacifier is calcium carbonate. The opacifier comprises from about 4 weight percent to about 25 weight percent of the coating by weight, based upon total weight of the coating composition.

Suitable fillers or diluents are known in the art. For example, suitable fillers include, but are not limited to, lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), lactilol, starch, dextrin, glucose, silicic acid, sucrose, Sorbitol, Sodium Saccharin, Acesulfame potassium, Xylitol, Aspartame, Mannitol, polyvinyl pyrrolidone, low molecular weight hydroxypropyl cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, low molecular weight hydroxypropyl methylcellulose, low molecular weight carboxymethyl cellulose, ethylcellulose, a suitable inorganic calcium salt such as dicalcium phosphate, alginates, gelatin, polyethylene oxide, acacia, magnesium aluminum silicate, and polymethacrylates, or a combination thereof. In one embodiment, the filler is lactose monohydrate. The filler comprises about 40 weight percent of the coating by weight, based upon total weight of the coating composition.

Optionally, the compositions of the present invention may include a colorant or a glidant. Such colorants are available from a number of commercial vendors and are well known to those skilled in the art. In an embodiment, the colorant is Aluminum Lake. Suitable glidants are known in the art. Suitable glidants include, but are not limited to, silicon dioxide, talc and cornstarch.

In certain embodiments, the coating for a film coated tablet includes a film coating system that contains filler, a polymer, a plasticizer, an opacifier and Aluminum Lake. A suitable film coating system is the Opadry® II 32K550010.

The composition of the Opadry® II 32K550010 are shown in the Table-1 below
Table-1
Opadry® II 32K550010 Composition
Component Function Opadry® II 32K550010
(Aluminum Lake w/w %)
Hypromellose Polymer 28
Lactose monohydrate Filler 40
Calcium carbonate Opacifier 21.61
Triacetin Plasticizer 8
FD&C Red #40/allura Red AC Aluminum Lake Colorant 2.39
FD&C yellow #6/sunset yellow FCF Aluminum Lake
FD&C blue #2/indigo carmine Aluminum Lake

The coating or coating excipients of the present invention comprise from about 1 weight percent to about 8 weight percent of the composition, based upon total weight of the composition. The coating or coating excipients of the present invention comprise from about 1 weight percent to about 9 weight percent of the composition, based upon total weight of the composition. In an embodiment, the coating of the present invention comprises from about 2 weight percent to about 5 weight percent of the composition, based upon total weight of the composition. In an embodiment, the coating of the present invention comprises from about 4 weight percent of the composition, based upon total weight of the composition.

More embodiments of invention relates to an oral pharmaceutical composition of axitinib comprising crystalline axitinib and:
a. about 80 weight percent to about 98 weight percent of at least one filler;
b. about 2 weight percent to about 5 weight percent of a disintegrant;
c. about 0.25 weight percent to about 5 weight percent of a lubricant; and
d. about 1 weight percent to about 8 weight percent of the coating, based on the total weight of the pharmaceutical composition.

Further embodiments of invention relates to an oral pharmaceutical composition of axitinib comprising crystalline axitinib and
a. 20 weight percent to about 98 weight percent microcrystalline cellulose;
b. about 10 weight percent to about 85 weight percent lactose monohydrate;
c. about 2 weight percent to about 5 weight percent croscarmellose sodium;
d. about 0.25 weight percent to about 5 weight percent magnesium stearate; and
e. about 1 weight percent to about 8 weight percent of the coating, based on the total weight of the pharmaceutical composition.

In an embodiment, the composition of axitinib Form SAB-I 1mg red film coated tablets is shown in Table-2 as below.
Table-2
Composition of Axitinib 1mg Form SAB-I in red film coated tablets.
Component Function mg/tablet
Axitinib Form SAB-I API 1
Microcrystalline cellulose Filler 63.25
Lactose anhydrous Filler 32
Croscarmellose sodium Disintegrant 3
Magnesium stearate Lubricant 0.75
Core tablet weight 100
Opadry® II 32K550010 Coating 4
Purified water Solvent q.s
Coated tablet weight 104
1The exact amount of axitinib to be weighted will be adjusted for potency. The amount of microcrystalline cellulose will be adjusted accordingly.
2The composition is provided in Table 1 above.
3Evaporated during processing and does not appear in the final product.

In the embodiments of the compositions of the present invention, it will be appreciated that the exact amount of axitinib to be weighted will be adjusted for potency. The potency of axitinib, in a free base form or a pharmaceutical salt thereof, will be determined in order to calculate the exact weight of axitinib, in a free base form or a pharmaceutical salt thereof, which is required to reach the desired mg of the free base form of axitinib, in the composition.

In an embodiment, the composition of axitinib Form SAB-I 5mg red film coated tablets is shown in Table-3 as below.
Table-3
Composition of Axitinib 5mg Form SAB-I in red film coated tablets.
Component Function mg/tablet
Axitinib Form SAB-I1 API 5
Microcrystalline cellulose Filler 59.25
Lactose anhydrous Filler 32
Croscarmellose sodium Disintegrant 3
Magnesium stearate Lubricant 0.75
Core tablet weight 100
Opadry® II 32K5500102 Coating 4
Purified water3 Solvent q.s
Coated tablet weight 104
1The exact amount of axitinib to be weighted will be adjusted for potency. The amount of microcrystalline cellulose will be adjusted accordingly.
2The composition is provided in Table 1 above.
3Evaporated during processing and does not appear in the final product.

The pharmaceutical composition or solid formulation of the present invention may be manufactured by a conventional dry granulation, direct compression, wet granulation, drug layering or liquid-filled manufacturing process using equipment commonly available in the pharmaceutical industry.

In an embodiment, the pharmaceutical composition or solid formulation of the present invention may be manufactured by a conventional direct compression manufacturing process that includes blending, blend lubrication, compression, and aqueous based film coating using equipment commonly available in the pharmaceutical industry.

In an embodiment, the pharmaceutical composition of the present invention may be manufactured using the process as described below.
Blending:-
Step 1: - Sift axitinib and microcrystalline cellulose together through mesh # 40
Step 2:- Sift lactose anhydrous and croscarmellose sodium together through mesh # 40.
Step 3:- Optionally sift the contents of step 1 and step 2 (axitinib, microcrystalline cellulose, lactose anhydrous and croscarmellose sodium) through mesh # 40.
Step 4:- Charge the contents of step 3 (axitinib, microcrystalline cellulose, croscarmellose sodium and anhydrous lactose) into a suitable blender and blend for 15 minutes.
Step 5:- Sift magnesium stearate through mesh # 60.
Step 6:- Add material of blending step 4 and sifted material of step 5 and blend for 5 minutes in a suitable blender.
Preparation of core tablet:-
Step 7:- Compress the lubricated blend of Step 6 on a tablet press and compress into core tablets.
Preparation of film coated tablet:-
Step 8:- Add purified water to a vessel. While mixing the contents with a propeller mixer, add the Opadry red II 32K550010 and mix until the solids are completely dissolved.
Step 9:- Charge a suitable pan load of tablet cores from Step 7 into a suitable pan coater.
Step 10:- With the coating pan rotating at an appropriate speed, apply the coating suspension from Step 8 until the appropriate level of coating (4% w/w build up) is achieved.
Alternatively, the active pharmaceutical ingredient and excipients of the present invention may be filled into hard-shell capsules, also referred to as the dry-filled capsules.

The pharmaceutical compositions of the present invention may be formulated into a unit dosage form. Such formulations are well known to one of ordinary skill in the art.

In an embodiment, the present invention provides a pharmaceutical composition comprising a solid unit dosage form as a tablet. In some embodiments, a unit dosage form contains 1 mg, 3 mg, 5 mg, 7 mg or 10 mg of axitinib. In some embodiments, a unit dosage form contains 1 mg, 5 mg, or 10 mg of axitinib. In some embodiments, a unit dosage form contains 1 mg or 5 mg of axitinib. In some embodiments, satisfactory results are obtained when axitinib, or a pharmaceutically acceptable salt thereof, is administered at a daily dosage from about 1 mg to about 25 mg, optionally given in divided doses two times a day. The total daily dosage is projected to be from about 1 mg to about 10 mg two times a day, preferably from about 5 to about 10 mg two times a day. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.

An embodiment relates to methods of treating abnormal cell growth in a subject comprising administering to the subject an amount of a pharmaceutical composition according to the present invention. In an embodiment, the abnormal cell growth is cancer. In another embodiment, the cancer is liver cancer, melanoma, mesothelioma, non-small cell lung cancer, prostate cancer, renal cell carcinoma, soft tissue sarcomas and solid tumors.

The pharmaceutical composition of the present invention provides protection of axitinib from degradation, including photodegradation and oxidative degradation.

The pharmaceutical composition of the present invention provides protection of axitinib from degradation throughout prolonged storage. Prolonged storage may be at least 9 months, at least 12 months, at least 24 months or at least 36 months. In an embodiment, prolonged storage may be at least 36 months.

Some embodiments relate to an oral pharmaceutical composition comprising crystalline axitinib and excipients, wherein the pharmaceutical composition is devoid of the following Compounds
Formula I

(2+2 dimer)
Formula II

(asymmetric dimer)
and

Formula III

cis-isomer

The compound of formula I may be referred to as the 2+2 dimer, the compound of formula II may be referred as asymmetric dimer and compound of formula III may be referred as cis-isomer.

In some embodiments, the pharmaceutical compositions of present invention include oxidative degradants. The oxidative degradants include the compound of Formula IV, which may be referred as the sulfoxide derivate.

Formula-IV

(sulfoxide derivative)

The 2+2 dimer, asymmetric dimer and cis-isomer as the photodegradants are not present in an oral pharmaceutical composition comprising crystalline axitinib Form SAB-I, Form SAB-II and Form SAB-III. The sulfoxide derivative is the oxidative degradant present in an oral pharmaceutical comprising crystalline axitinib Form SAB-I, Form-SAB II and Form SAB-III.
Some embodiments relate to an oral pharmaceutical composition comprising crystalline Axitinib Form SAB-I characterized by X-ray powder diffraction pattern comprising at least five characteristic 2?° peaks selected from 7.6, 8.1, 15.6, 16.4 and 17.6 ±0.2 2?° and excipients, wherein the pharmaceutical composition is devoid of the following compounds
Formula I

(2+2 dimer)
Formula II

(asymmetric dimer)
and

Formula III

cis-isomer

Some embodiments relate to an oral pharmaceutical composition comprising crystalline axitinib, wherein photodegradation of axitinib or a pharmaceutically acceptable salt thereof, is less than about 1% as measured by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guideline, Q1B photostability Testing of New Drug Substances and Products, published on November 1996.

Some embodiments relate to an oral pharmaceutical composition comprising crystalline axitinib Form SAB-I characterized by X-ray powder diffraction pattern comprising at least five characteristic 2?° peaks selected from 7.6, 8.1, 15.6, 16.4 and 17.6 ±0.2 2?° and excipients, wherein photodegradation of axitinib or a pharmaceutically acceptable salt thereof, is less than about 1% as measured by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guideline, Q1B Photostability Testing of New Drug Substances and Products, published on November 1996.

HPLC are the techniques that may be used to detect the photodegradants and oxidative degradants. An example of a suitable HPLC assay is gradient elution reversed-phase liquid chromatography, which may be used to separate axitinib from degradation products and formulation excipients. Comparison of the peak area response and retention time of axitinib for a sample and the standard provides a quantitative assay and identification test for axitinib. Degradation products of the present invention are identified by their retention time relative to axitinib and quantitated by area percent.

The assay may be conducted with equipment, methodology and reagents well known in the art. For example, the assay may utilize a suitable liquid chromatograph. The suitable liquid chromatograph may include a pump, constant flow delivery, an ultraviolet (UV) detector, an injector or autosampler, and/or a column heater. The suitable liquid chromatograph may include a UV detector capable of operating at between about 205 nm and about 400 nm, an injector or autosampler capable of making about 1 to about 100 microliter injections, and/or a column heater capable of maintaining temperature of 25° C. The suitable liquid chromatograph may also include an integrator/data acquisition system. The assay may utilize a HPLC column. A suitable column is a Reliant 250mm x 4.6 mm C18, 5 µ or equivalent.

The pharmaceutical composition of the present invention contains an axitinib or a pharmaceutically acceptable salt thereof. Each crystalline form of axitinib, as formulated in the pharmaceutical composition or drug product of the present invention, can be characterized by one or more of the following: powder X-ray diffraction pattern (i.e., X-ray diffraction peaks at various diffraction angles (2?), aqueous solubility, light stability under ICH high intensity light conditions, and physical and chemical storage stability.

Crystalline axitinib polymorphic Form SAB-I of axitinib within the drug product or pharmaceutical composition of the present invention were each characterized by the positions of peaks in their powder X-ray diffraction patterns. The detection of characteristic powder X-ray diffraction peaks of axitinib within the drug product or pharmaceutical composition of the present invention enables unique identification of polymorphic Forms SAB-I of axitinib in the drug product or pharmaceutical composition.

The powder X-ray diffraction patterns of the axitinib pharmaceutical compositions were generated using a Bruker D-8 Advance diffractometer using copper radiation (Copper K2 a wavelength: 1.54056 Å).

Crystalline axitinib Form SAB-I in drug product, which was prepared as provided in Example 8, was characterized by the PXRD pattern shown in FIG. 1. The PXRD pattern expressed in terms of the degree 2? and relative intensities is shown in Table 4 below.
Crystalline axitinib Form SAB-I in drug product, which was prepared as provided in Example-2, was characterized by the PXRD pattern as shown in Fig-1. The PXRD pattern expressed in terms of the degree 2? and relative intensities are show in Table- 4 below
Table-4

Angle
(2?) Relative Intensity
7.6 2.7
8.1 5.9
15.6 9.6
16.4 3.2
17.6 8.9

Further embodiments relate to an oral pharmaceutical composition of axitinib comprising crystalline axitinib Form SAB-I characterized by DSC isotherm comprising two endothermic peaks ranging between-
a. Peak -1- Between 213 to 217°C.
b. Peak -2- Between 219 to 224°C.

Additional embodiments relate to an oral pharmaceutical composition comprising crystalline axitinib monohydrate Form SAB-II characterized by X-ray powder diffraction pattern comprising at least five characteristic 2?° peaks selected from 7.5, 8.0, 14.2, 14.7, 15.7, 18.1, 20.1, 24.4, 29.8 and 32.0 ±0.2 2?° and excipients, wherein oral composition is optionally coated, which coating is devoid of any metal oxides.

Further embodiments relate to an oral pharmaceutical composition of axitinib comprising crystalline axitinib Form SAB-II characterized by DSC isotherm comprising three endothermic peaks ranging between-
a. Peak -1- Between 48 to 86°C
b. Peak -2- Between 213 to 217°C
c. Peak -2- Between 219 to 224°C.

Additional embodiments relate to an oral pharmaceutical composition comprising crystalline axitinib Form SAB-III characterized by X-ray powder diffraction pattern comprising at least four characteristic 2?° peaks selected from 10.1, 10.4, 15.3, 18.3, 18.7, 19.7and 24.6 ±0.2 2?° and excipients, wherein oral composition is optionally coated, which coating is devoid of any metal oxides.

Further embodiments relate to an oral pharmaceutical composition of axitinib comprising crystalline axitinib Form SAB-III characterized by DSC isotherm comprising three endothermic peaks ranging between-
a. Peak -1- Between 53 to 73°C
b. Peak -2- Between 214 to 218°C
c. Peak -2- Between 222 to 22

EXAMPLES

The following examples are provided to illustrate the present invention. It should be understood, however, that the invention is not limited to the specific conditions or details described in the examples below.
Example-1
Preparation of the axitinib 1mg Form SAB-I Opadry red II 32K550010 film coated tablets
The composition of axitinib 1mg crystalline Form SAB-I film coated tablets is disclosed in Table-2 depicted above.

Process for preparation of film coated tablets of 1mg:-
Blending:-
Step 1: - Sift axitinib and microcrystalline cellulose together through mesh # 40
Step 2:- Sift lactose anhydrous and croscarmellose sodium together through mesh # 40.
Step 3:- Optionally sift the contents of step 1 and step 2 (axitinib, microcrystalline cellulose, lactose anhydrous and croscarmellose sodium) through mesh # 40.
Step 4:- Charge the contents of step 3 (axitinib, microcrystalline cellulose, croscarmellose sodium and anhydrous lactose) into a suitable blender and blend for 15 minutes.
Step 5:- Sift magnesium stearate through mesh # 60.
Step 6:- Add material of blending step 4 and sifted material of step 5 and blend for 5 minutes in a suitable blender.
Preparation of core tablet:-
Step 7:- Compress the lubricated blend of Step 6 on a tablet press and compress into core tablets.
Preparation of film coated tablet:-
Step 8:- Add purified water to a vessel. While mixing the contents with a propeller mixer, add the Opadry red II 32K550010 and mix until the solids are completely dissolved.
Step 9:- Charge a suitable pan load of tablet cores from Step 7 into a suitable pan coater.
Step 10:- With the coating pan rotating at an appropriate speed, apply the coating suspension from Step 8 until the appropriate level of coating (4% w/w build up) is achieved.

Example-2
Preparation of the axitinib 5mg Form SAB-I Opadry red II 32K550010 film coated tablets
The composition of axitinib 5mg crystalline Form SAB-I film coated tablets is shown in Table-3 depicted above.
The film coated tablets of example-2 are prepared by the process as described in example-1.
Crystalline axitinib Form SAB-I in drug product, which was prepared as provided in Example-2, was characterized by the PXRD pattern as shown in Fig-1. The PXRD pattern expressed in terms of the degree 2? and relative intensities are show in Table-4 above.
,CLAIMS:CLAIMS

1. An oral pharmaceutical composition comprising crystalline axitinib Form SAB-I characterized by X-ray powder diffraction pattern comprising at least five characteristic 2?° peaks selected from 7.6, 8.1, 15.6, 16.4 and 17.6 ±0.2 2?° and excipients, wherein solid oral composition is optionally coated, which coating is devoid of any metal oxide.

2. An oral pharmaceutical composition according to claim 2, wherein the solid oral composition is an uncoated tablet.

3. An oral pharmaceutical composition according to claim 2, wherein the oral composition is a coated tablet.

4. An oral pharmaceutical composition according to claim 3, wherein the pharmaceutical composition comprises crystalline axitinib Form SAB-I and:
a. about 80 weight percent to about 98 weight percent of at least one filler;
b. about 2 weight percent to about 5 weight percent of a disintegrant;
c. about 0.25 weight percent to about 5 weight percent of a lubricant; and
d. about 1 weight percent to about 8 weight percent of the coating, based on the total weight of the pharmaceutical composition.

5. An oral pharmaceutical composition according to claim 4, wherein coating comprises a polymer, filler, a plasticizer, or an opacifier, colorants or combinations thereof.

6. An oral pharmaceutical composition according to claim 5, wherein coating comprises hypromellose, lactose monohydrate, triacetin and calcium carbonate and Aluminum Lake.

7. An oral pharmaceutical composition according to claim 1, wherein photodegradation of crystalline axitinib Form SAB-I is less than about 1% as measured by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guideline, Q1B Photostability Testing of New Drug Substances and Products, published on November 1996.

8. An oral pharmaceutical composition according to claim 1, wherein the composition is devoid of the following compounds
Formula I

(2+2 dimer)
Formula II

(asymmetric dimer)
and
Formula III

cis-isomer

9. An oral pharmaceutical composition comprising crystalline axitinib Form SAB-I characterized by DSC isotherm comprising two endothermic peaks ranging between-
a. Peak -1- Between 213 to 217°C.
b. Peak -2- Between 219 to 224°C.

10. An oral pharmaceutical composition comprising crystalline axitinib Form SAB-I characterized by X-ray powder diffraction pattern comprising at least two characteristic 2?° peaks selected from 7.6, 8.1, 15.6, 16.4 and 17.6 ±0.2 2?° and excipients, wherein solid oral composition is optionally coated, which coating is devoid of any metal oxide.