DESC:FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions comprising Factor Xa inhibitors. Present invention particularly relates to pharmaceutical composition comprising apixaban or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The present invention also relates to a process for the preparation of pharmaceutical composition comprising apixaban or a pharmaceutically acceptable salt thereof and the use of the pharmaceutical compositions for the treatment and/or prevention of thromboembolic disorders.

BACKGROUND OF THE INVENTION
The prevention and treatment of blood clot formation, expansion, and/or migration in the blood and blood vessels of individuals having certain clinical history normally requires the use of anticoagulants. For the clinical management of the conditions such as venous thrombosis, pulmonary embolism, prosthetic (replacement or mechanical) heart valves, irregular heartbeat, and those who have suffered a heart attack, anticoagulants are frequently prescribed which act as blood thinner and decrease the clotting ability of the blood. Vitamin K antagonists (VKAs) e.g. warfarin, unfractionated heparin (UFH), and low molecular weight heparin (LMWH) have been commonly prescribed anticoagulants. Newer agents such as fondaparinux and enoxaparin sodium have been developed as more effective anticoagulants and reported to have substantially low risk for heparin-induced thrombocytopenia compared with LMWH or UFH.

While anticoagulants are effective in treating and reducing the risk of thromboembolic conditions, they are associated with significant limitations that may lead to the risk for related, and potentially serious or fatal, bleeding events affecting their clinical use and acceptability. These conventional anticoagulants like UFH, LMWH, and new agents like fondaparinux are administered parenterally, which is inconvenient and expensive with respect to the long-term use, and require a health care professional for its administration. Though Vitamin K antagonists are available for oral administration, they usually have a narrow therapeutic window and unpredictable therapeutic effect. Many research studies are conducted to develop newer, more effective anticoagulants that can be administered orally. One approach has been to develop small molecule direct factor Xa inhibitors which targets to inhibit single enzymes, unlike the traditional anticoagulants (UFH, LMWH, and VKAs) that target multiple enzymes in the coagulation cascade. Therefore, Factor Xa inhibitors are found to be a class of compounds more efficacious for the treatment of thromboembolic disorders. In this class of compounds, first agent developed was Rivaroxaban (Xarelto® by Janssen Pharms) and approved by USFDA in 2011 for oral administration.

Apixaban is a selective direct inhibitor of factor Xa that participates in the blood coagulation system, without requiring antithrombin III - unlike other conventional agents. It is developed by Bristol Myers Squibb and approved by the U.S. FDA for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, for the prophylaxis and treatment of deep vein thrombosis and pulmonary embolism in cases of hip or knee replacement.

The synthesis of apixaban was first described in WO 2003/026652. WO 2006/078331 relates to a process or apparatus for transforming a first polymorph into a second polymorph of the same chemical material, and discloses the H2-2 form in a needle-shaped dehydrate. It further discloses the H2-2 form to be less stable than the granular, non-solvate N-1 form. This international patent application does not relate to pharmaceutical compositions or method of making it. US 2016/143894 describes processes for the preparation of crystalline Form N-1 of apixaban having a mean particle size equal to or greater than 100 µm. WO 2010/147978 describes controlled release apixaban formulations that are mainly provided as osmotic-controlled release oral delivery systems (OROS-formulation) such formulations are known to be complex, involve time consuming processes and require high cost equipment, such as a laser for drilling the holes into the dosage form. WO 2013/174498 discloses modified release apixaban compositions containing crystalline apixaban with a particle size distribution preferably with D50 value of 5 to 500 µm. WO 2014/052678 describes liquid formulations of apixaban.

US 2013/0045245 and US 2016/0243101 further disclose compositions comprising crystalline apixaban wherein the drug particles have a maximum size cutoff and a D90 of the active equal to or less than about 89 µm. According to the disclosure of the above application, it was found that in a tablet composition, apixaban particles having a D90 less than 89 µm lead to consistent in-vivo dissolution and consistent exposure of the active in humans. It is also disclosed that tablets made using larger particles had lower exposures and/or dissolution compared to tablets made using the same process but with particle size of D90 of 50 µm. Therefore the invention of US 2013/0045245 is particularly restricted to the use of smaller sized apixaban particles, specifically having a D90 equal to or less than about 89 µm.

Hence, it was an object of the present invention to provide oral dosage forms of apixaban using the larger sized particles. In particular, it was an object of the present invention to provide apixaban oral dosage forms using a larger particle size than disclosed in the prior art. Inventors of this invention have surprisingly found, in contrast to that the teaching of the prior art, the desired dissolution and bioavailability profiles can be achieved using apixaban with a larger particle size. It was another object of the present invention to provide simple, less time consuming and cost-effective processes for the preparation of the pharmaceutical compositions.

SUMMARY OF THE INVENTION
The present invention provides pharmaceutical compositions for oral administration comprising a therapeutically effective amount of a selective factor Xa inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present invention is directed to pharmaceutical compositions comprising apixaban or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the apixaban particles have a D90 more than 89 µm.
Accordingly, the present invention particularly provides pharmaceutical compositions comprising apixaban particles having a D90 more than 89 µm as measured by any suitable technique known in the prior art and a pharmaceutically acceptable diluent or carrier. Suitable techniques known in the prior art for particle size determination that can be used in this invention include, but are not limited to microscopy, sieving, sedimentation and/or laser light scattering methods.

In one of the aspect of the present invention, the particle size of the apixaban is determined by using Malvern light scattering.

Another aspect of the present invention provides a process for manufacturing a solid oral dosage form of a pharmaceutical composition comprising the steps of: i) blending apixaban or a pharmaceutically acceptable salt, enantiomer, polymorph, ester or derivative thereof with at least one pharmaceutically acceptable carrier to form a blend; wherein apixaban particles have a D90 more than 89 µm, ii) granulating the blend to form a granulate, iii) adding one or more extragranular excipients, and iv) compressing the blend into solid oral dosage form and optionally coating the dosage form with a film coating.

In another aspect of the present invention, the pharmaceutical composition is prepared by a dry granulation process.

In yet another aspect of the present invention, the pharmaceutical composition is prepared by wet granulation.

Yet another aspect of the present invention provides a pharmaceutical composition comprising apixaban particles having a D90 more than 89 µm, which releases at least 85 wt % of apixaban within 30 minutes.

Another aspect of the present invention comprises the use of at least one surfactant as a pharmaceutical carrier in an amount of from about 0.1% to about 5% by weight.

Another aspect of the present invention provides a method of treating or preventing thromboembolic disorders, comprising administering to a subject in need thereof, a therapeutically effective amount of apixaban or a pharmaceutically acceptable salt, enantiomer, polymorph, ester or derivative thereof and a pharmaceutically acceptable carrier, wherein apixaban particles have a D90 more than 89 µm.

In another aspect of the present invention, it provides an easy and commercially viable process for manufacturing pharmaceutical composition of apixaban or a pharmaceutically acceptable salt, enantiomer, polymorph, ester or derivative thereof, characterized by apixaban particles having a D90 more than 89 µm.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an immediate release pharmaceutical composition comprising Factor Xa inhibitors. The present invention provides pharmaceutical composition(s) comprising apixaban having a larger particle size than disclosed in the prior art.

The term “apixaban” herein comprises various forms such as crystalline, amorphous, hydrates, anhydrates, solvates, pharmaceutical acceptable salts, enantiomers, polymorphs, esters, or derivatives thereof.

Apixaban may be obtained directly via the synthesis described in U.S. Pat. No. 6,967,208 and/or US2006/0069258 (based on U.S. application Ser. No. 11/235,510 filed Sep. 26, 2005) or any other known process.

In an aspect of the present invention, apixaban in crystalline form is used. Various crystalline forms of apixaban known in the prior art are within the scope of this invention, including but not limiting to, Form N-1, Form H2-2, Form M and others.

As used herein, the term “immediate release” means that at least 70 wt % of a compound initially present in the dosage form is released within one hour or less following introduction to a use environment. A “use environment” as used herein, can either mean various in- vivo fluids, such as the GI tract, or the in- vitro environment of a test solution, such as phosphate buffered saline.

The invention provides pharmaceutical compositions comprising apixaban particles having a D90 more than 89 µm and a pharmaceutically acceptable diluent or carrier. The ranges of particle size preferred for use in the present invention is D90 more than 89 µm, more preferably D90 is at least about 100 µm, even more preferably D90 is at least about 110 µm. In an aspect of the present invention, the D90 is between about 89 µm to about 250 µm. The particle size distribution of apixaban particles as described in the specification is characterized by D90 values. “D90” is defined as 90% of the volume of particles having a diameter less than a specified diameter.
Use of apixaban particles having particle size distribution more than that disclosed in the prior arts, particularly D90 more than 89 µm is a typical feature of this invention. As specified above in the background, patent application US 2013/0045245 is restricted to the use of smaller sized apixaban particles, specifically having D90 equal to or less than about 89 µm in order to achieve consistent dissolution. The compositions of the present invention use apixaban particles having the size higher than that disclosed in above application, but it still achieves consistent desired dissolution profile.
The particle size distribution stipulated herein refers to the particle sizes determined by using any known suitable techniques such as microscopy, sieving, sedimentation and/or laser light scattering techniques.
The term "particles" refers to individual drug substance particles. The particles may exist as single particles or as agglomerations, however, if the size of the primary apixaban particles comprising the agglomerate are more than 89 µm individually, then the agglomerate itself is considered to meet the particle size requirements as described in this specification.
The present invention provides solid oral pharmaceutical compositions comprising apixaban with a D90 more than 89 µm. Solid oral pharmaceutical compositions of the present invention include, but are not limited to, tablets, pellets, granules, powders, capsules, microcapsules, microspheres, spheroids, pellets filled in capsules, tablets in capsules, multilayer tablets, bilayer tablets, trilayer tablets, or premixed powders filled in capsules. In a preferred embodiment of the present invention, the solid oral dosage form is a tablet.

This invention further provides a pharmaceutical composition comprising the use of at least one surfactant or wetting agent. The term “wetting agent” or “surfactant”, as used herein, refers to a surface active agent or a mixture of agents that lower the interfacial tension between a solid & a liquid or two liquids. In pharmaceutical formulations, surfactants aid in wetting of a hydrophobic drug in a solid formulation to ensure efficient dissolution of the drug. The surfactant may be natural or synthetic in origin. Further, it may be non-ionic, anionic, cationic or amphoteric in nature. Representative examples of surfactants that can be used in the present invention include, but are not limited to, cremophors, polyethylene glycols, poloxamers, polysorbates, sodium lauryl sulphate, tragacanth, and/or mixtures thereof.

In an embodiment of the present invention, the surfactant used is sodium lauryl sulfate. In another embodiment of the present invention, the surfactant is a poloxamer. In yet another embodiment of the present invention, the surfactant is a mixture of sodium lauryl sulfate and a poloxamer in an appropriate amount. The present invention comprises the use of one or more surfactants from about 0.1% to 5% by weight. In an embodiment of the present invention, surfactants used in the compositions range from about 2% to 4%. In an embodiment of the present invention, the formulations exhibit and in vitro dissolution profile such that the amount of the drug equivalent to 85 wt% dissolves within 30 minutes.

To study the dissolution criterion, the suitable dissolution test is selected and it is carried out in an aqueous media non-buffered or buffered to a pH range (1 to 7.6) found in the gastrointestinal tract and controlled at 370C (± 100C). Various dosage forms, such as tablets and capsules, can be studied for dissolution profile, in a standard prescribed manner. When the dosage form is a tablet, typically paddles rotating at 50-75 rpm are used to test the dissolution rate of the tablets. The amount of dissolved apixaban can be determined using suitable analytical techniques such as UV or HPLC.

Since in-vivo-in-vitro relationships are established, the dissolution (in-vitro) test, in addition to its application as a quality control technique, can more preferably be used to predict the biological (in-vivo) performance of the tablet.

In one embodiment of the present invention, the dissolution test is performed in 900 mL of dissolution medium at 370 C., using USP Apparatus 2 (paddles) at a rotation speed of 75 rpm. Samples are removed after 5, 10, 15, 20, 30, 45, and 60 minutes from test initiation and analyzed for apixaban. 0.1 N HCl or 0.05 M sodium phosphate at a pH 6.8 containing 0.05% sodium lauryl sulphate (SLS) solution has been used as dissolution medium.

The formulations of the present invention lead to consistent in-vitro dissolution profiles. This is one of the advantages of the present invention.

The invention further provides processes for preparing pharmaceutical compositions of the present invention.

In one embodiment of the present invention, the pharmaceutical compositions are prepared by a dry granulation process comprising the steps of blending apixaban particles of a predetermined size with one or more excipients, granulating the blend using a dry granulation process, adding one or more extragranular excipients, compressing the blend into tablets and optionally film coating the tablet.

In another embodiment of the present invention, the pharmaceutical compositions are prepared by a dry granulation process comprises the steps of blending the apixaban particles of a predetermined size with one or more excipients, adding a binder, disintegrant, and other fillers, and carrying out dry granulation by compacting the blend to ribbons of density in the range of 1.0 to 1.2 g/cc and then sizing the compacted ribbons using a roller compactor.

In further embodiment of the present invention, the pharmaceutical compositions are prepared by a wet granulation process comprising the steps of blending apixaban particles of a predetermined size with one or more excipients, adding a binder, disintegrant, and other fillers, and carrying out wet granulation using a solution comprising the binder in a suitable solvent, followed by sizing the granules by passing them through a mill such as a screen mill. The granules are then dried using a convection oven or a fluid-bed dryer, and optionally sized by passing them through a mill such as a screen mill. A suitable disintegrant is then added as an extragranular material and mixed. The blend is then compressed into tablets. Optionally, a film coating is applied to the tablets.

Various pharmaceutically acceptable carriers or excipients are used in the compositions of the present invention, including fillers or diluents, binders, disintegrants, lubricants, glidants, and colorants.

“Fillers or diluents” may be selected from the group comprising carbohydrates, confectioners sugar, compressible sugars, dextrose, dextrates, dextrin, fructose, lactitol, xylitol, sorbitol, microcrystalline cellulose, mannitol, lactose, sucrose, maltose, starch, calcium carbonate, calcium sulfate, calcium hydrogen phosphate, or combinations thereof. Fillers or diluents may be used in the range of 10-90% w/w of the total weight of the oral pharmaceutical composition.

“Binders” may be selected from the group comprising potato starch, wheat starch, corn starch, microcrystalline cellulose, cellulose, including hydroxy propyl cellulose, hydroxy propyl methylcellulose, povidone, hydroxy ethyl cellulose, sodium carboxy methyl cellulose, natural gums including acacia, alginic acid, guar gum, liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth; or combinations thereof. Binders may be used in the range of 1-15% w/w of the total weight of the oral pharmaceutical composition.

“Disintegrants” may be selected from the group comprising alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, sodium alginate, sodium starch glycolate, starches or combinations thereof. Disintegrants may be used in the range of 1-20% w/w of the total weight of the oral pharmaceutical composition.
“Lubricants” may be selected from the group comprising aluminium stearate, zinc stearate, calcium stearate, magnesium stearate, polyethylene glycol, mineral oil, talc, hydrogenated vegetable oil, stearic acid, magnesium aluminum silicate, sodium stearyl fumarate, glyceryl behenate, sodium benzoate or mixtures thereof. Lubricants may be used in the range of 0.1 - 5 % w/w of the total weight of the oral pharmaceutical composition.

“Glidants” may be selected from the group comprising silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel or mixtures thereof. Glidants may be used in the range of 0.01 – 4% w/w of the total weight of the oral pharmaceutical composition.

“Colorants” may be selected from the group comprising iron oxide yellow, iron oxide red, titanium dioxide or mixtures thereof. Colorants may be used in the range of 0.01 – 1.5% w/w of the total weight of the oral pharmaceutical composition.

The pharmaceutical compositions of the present invention may have one or more coatings such as film coatings and/or sugar coatings. The coating may comprise from about 1 - 4.5% w/w of the total weight of the pharmaceutical composition. “Coating agents” which are useful in the coating process, may be selected from the group comprising water soluble polymers including, polyvinylpyrrolidone or water soluble cellulose including, hydroxy propyl methyl cellulose or hydroxy propyl cellulose. Coating agents may be selected from the group comprising soluble agents such as polysorbate 80, polysaccharides such as, acacia, corn, sucrose, gelatin, shellac, cellulose acetate phthalate, lipids, synthetic resins, acrylic polymers, opadry, polyvinyl alcohol, copolymers of vinyl pyrrolidone, vinyl acetate or combinations thereof. These may be applied from aqueous or non- aqueous systems or combinations of aqueous and non-aqueous system as appropriate.

“Additives” may be selected along with film formers to obtain satisfactory films. These additives may be selected from the group comprising plasticizers such as dibutyl phthalate, triethyl citrate, polyethylene glycol, or the like; antitacking agents such as, talc, stearic acid, magnesium stearate, colloidal silicon dioxide or the like; fillers such as talc or precipitated calcium carbonate; polishing agents such as beeswax, carnauba wax or synthetic chlorinated wax; opacifying agents such as titanium dioxide; or colorants, etc. Antitacking agents may be used in the range of 0.1 - 15% w/w of the total weight of the oral pharmaceutical composition.

“Solvents” may be any pharmaceutically acceptable, non-toxic agent or a mixture of agents in the form of a liquid, which is used for dissolving another solid or liquid, or as a dispersing or granulating media. Solvents employed in the present invention may be aqueous, alcoholic, hydroalcoholic or organic in nature with varying polarity. Representative examples of solvents employed include acetone, dichloromethane, ethyl alcohol, isopropyl alcohol, water, and mixtures thereof.

The amount of apixaban contained in a tablet, capsule, or other dosage form containing a composition of this invention will contain therapeutically effective amount of apixaban.
“Therapeutically effective amount” refers to amount of the active agent, which halts or reduces the progress of the condition being treated or which otherwise partly, cures or acts palliatively on the condition. A person skilled in the art can easily determine such an amount by routine experimentation and with an undue burden.

Therapeutically effective amount of apixaban in the respect of this invention is usually between 2.5 and 5 mg, usually administered orally twice a day, although amounts outside this range and different frequencies of administration are feasible for use in therapy under prescribed medical conditions. The pharmaceutical compositions of the present invention are useful, inter alia, in the prevention and/or treatment of thromboembolic disorders, for example, deep vein thrombosis, acute coronary syndrome, stroke, and pulmonary embolism.

The present invention should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Other features and embodiments of the invention will become apparent from the following examples, which are given for illustration of the invention rather than for limiting its intended scope.

EXAMPLES
Example 1

Ingredients mg/ tablet
Intra-granular
Apixaban 2.5
Lactose 49.5
Microcrystalline cellulose 39.5
Croscarmellose sodium 3.0
Magnesium stearate 0.5
Extra - granular
Poloxamer 2.0
Croscarmellose sodium 2.5
Magnesium stearate 0.5
Film coating
Opadry pink II --
Opadry yellow II 3.5

Brief manufacturing procedure:
1. Co-sift apixaban, lactose, microcrystalline cellulose, croscarmellose sodium through 40 # ASTM S.S. sieve.
2. Mix the step-1 blend in suitable blender for 25 minutes.
3. Sift magnesium stearate through 60# ASTM S.S. sieve and add to step 2 blend and lubricate the blend for 5 minutes.
4. Load the step-3 blend on roller compactor and compact the material of step-3 on roller compactor to get desired compacted flakes and milled through oscillating granulator.
5. Load the milled material on the vibratory sifter. Collect the undersize of #25 mesh (710 µm) S.S. sieve and oversize of #60 mesh (250 µm) S.S. sieve.
6. Pass the undersize of #60 mesh material of step-5 again through roller compactor to get compacted flakes.
7. Repeat steps 4 to 6 until the granules (# 25 mesh) and fines (# 60 mesh) attain ratio of 60 ± 5.0%: 40 ± 5.0%.
8. Load granules and fines, in suitable blender and mix for 10 minutes.
9. Sift croscarmellose sodium and poloxamer through 40# ASTM S.S. seive and load to step 8 blend and mix for 10 minutes.
10. Sift magnesium stearate through 60# ASTM S.S. seive and add to step 9 blend and lubricate the blend for 5 minutes.
11. Compress the tablet with step-10 blend using 6.0 mm round shaped bevel concave punches on a compression machine with suitable parameter.
Coating solution preparation:
12. Add and disperse quantity of opadry yellow under continuous stirring in purified water and stir for 45 minutes to get 10% w/w dispersion.
13. Load the tablets of step-11 into perforated coating pan and coat the tablet with an inlet air temperature 55 ± 5oC till 3.5% w/w ± 0.25% weight build up is attained.
14. Dry the tablet of step-10 for 60 minutes at inlet air temperature 55 ± 5oC with intermittent jogging.

Example 2

Ingredients mg/ tablet
Intra-granular
Apixaban 5.0
Lactose 99.0
Microcrystalline cellulose 79.0
Croscarmellose sodium 6.0
Magnesium stearate 1.0
Extra - granular
Poloxamer 4.0
Croscarmellose sodium 5.0
Magnesium stearate 1.0
Film coating
Opadry pink II 7.0
Opadry yellow II --

Brief manufacturing procedure:
1. Co-sift apixaban, lactose, microcrystalline cellulose, croscarmellose sodium through 40 # ASTM S.S. sieve.
2. Mix the step-1 blend in suitable blender for 25 minutes.
3. Sift Magnesium stearate through 60# ASTM S.S. sieve and add to step 2 blend and lubricate the blend for 5 minutes.
4. Load the step-3 blend on roller compactor and compact the material of step-3 on roller compactor to get desired compacted flakes and milled through oscillating granulator.
5. Load the milled material on the vibratory sifter. Collect the undersize of #25 mesh (710 µm) S.S. Sieve and oversize of #60 mesh (250 µm) S.S. sieve.
6. Pass the undersize of #60 mesh material of step-5 again through roller compactor to get compacted flakes.
7. Repeat steps 4 to 6 until the granules (# 25 mesh) and fines (# 60 mesh) attain ratio of 60 ± 5.0%: 40 ± 5.0%.
8. Load granules and fines, in suitable blender and mix for 5 minutes.
9. Sift croscarmellose sodium and poloxamer through 40# ASTM S.S. seive and load to step 8 blend and mix for 10 minutes.
10. Sift magnesium stearate through 60# ASTM S.S. seive and add to step 9 blend and lubricate the blend for 5 minutes.
11. Compress the tablet with step-10 blend using 9.8 x 5.2 mm oval shaped bevel concave punches on a compression machine with suitable parameter.
Coating solution preparation:
12. Add and disperse quantity of opadry pink under continuous stirring in purified water and stir for 45 minutes to get 10% w/w dispersion.
13. Load the tablets of step-11 into perforated coating pan and coat the tablet with an inlet air temperature 60 ± 5oC till 3.5% w/w ± 0.25% weight build up is attained.
14. Dry the tablet of step-10 for 60 minutes at inlet air temperature 50 ± 5oC with intermittent jogging.

Table 1: Dissolution data of the formulations of Example 1 and Example 2:

Dissolution (Dissolution media volume: 900 mL, Paddle, 75 RPM) pH 6.8 Phosphate buffer with 0.05% SLS
Time (Minutes) % Dissolved
Example 1 Example 2
5 53 47
10 84 81
15 89 87
30 94 95

Example 3
Ingredients mg/ tablet
Intra-granular
Apixaban 5.0
Lactose 93.4
Microcrystalline cellulose 79.0
Croscarmellose sodium 5.0
Magnesium stearate 1.5
Extra - granular
Poloxamer 4.0
Sodium lauryl sulfate 6.0
Croscarmellose sodium 5.0
Magnesium stearate 1.1
Film coating
Opadry pink II 7.0

Brief manufacturing procedure:
1. Co-sift apixaban, lactose, microcrystalline cellulose, croscarmellose sodium through 40# ASTM S.S. seive.
2. Mix the step-1 blend in suitable blender for 25 minutes.
3. Sift magnesium stearate through 60# ASTM S.S. seive and add to step 2 blend and lubricate the blend for 5 minutes.
4. Load the step-3 blend on roller compactor and compact the material of step-3 on roller compactor to get desired compacted flakes and milled through oscillating granulator.
5. Load the milled material on the vibratory sifter. Collect the undersize of #25 mesh (710 µm) S.S. sieve and oversize of #60 mesh (250 µm) S.S. sieve.
6. Pass the undersize of #60 mesh material of step-5 again through roller compactor to get compacted flakes.
7. Repeat steps 4 to 6 until the granules (# 25 mesh) and fines (# 60 mesh) attain ratio of 60 ± 5.0%: 40 ± 5.0%.
8. Load granules and fines, in suitable blender and mix for 5 minutes.
9. Sift croscarmellose sodium, poloxamer and sodium lauryl sulfate through 40# ASTM S.S. seive and load to step 8 blend and mix for 10 minutes.
10. Sift magnesium stearate through 60# ASTM S.S. seive and add to step 9 blend and lubricate the blend for 5 minutes.
11. Compress the tablet with step-10 blend using 9.8 × 5.2 mm oval shaped bevel concave punches on a compression machine with suitable parameter.
Coating solution preparation:
12. Add and disperse quantity of opadry pink under continuous stirring in purified water and stir for 45 minutes to get 10% w/w dispersion.
13. Load the tablets of step-11 into perforated coating pan and coat the tablet with an inlet air temperature 60 ± 5oC till 3.5 % w/w ± 0.25% weight build up is attained.
14. Dry the tablet of step-10 for 60 minutes at inlet air temperature 50 ± 5oC with intermittent jogging.

Table 2: Dissolution data of the formulation of Example 3:

Dissolution (Dissolution media volume: 900 mL, Paddle, 75 RPM) pH 6.8 Phosphate buffer with 0.05% SLS
Time (Minutes) % Dissolved
5 44
10 68
15 78
30 86

Example 4
Ingredients mg/ tablet
Intra-granular
Apixaban 2.5
Poloxamer 2.5
Lactose 47.75
Microcrystalline cellulose 28.75
Croscarmellose sodium 3.00
lsopropyl alcohol Q.S.
Methylene dichloride Q.S.
Extra - granular
Microcrystalline cellulose 12.00
Croscarmellose sodium 2.50
Magnesium stearate 0.50
Film coating
Opadry pink --
Opadry yellow 3.50

Brief manufacturing procedure:
1. Sift lactose, microcrystalline cellulose, croscarmellose sodium through 40# ASTM S.S. seive.
2. Load the step 1 blend in fluidised bed process.
3. Dissolve apixaban in methylene dichloride.
4. Dissolve poloxamer in isopropyl alcohol.
5. Add step 4 solution to step 3 solution under stirring and mix the solution for 15 minutes.
6. Granulate step 2 blend with using step 5 solution in fluidised bed process with suitable parameters.
7. Dry the granules after granulation for 15 minutes at bed temperature of 35-40°C.
8. Pass the dried granules through ASTM # 25 mesh.
9. Sift croscarmellose sodium and microcrystalline cellulose 102 through 40# ASTM S.S. sieve and load to step 8 blend and mix for 10 minutes.
10. Sift magnesium stearate through 60# ASTM S.S. sieve and add to step 9 blend and lubricate the blend for 5 minutes.
11. Compress the tablet with step-10 blend using 6.0 mm round shaped bevel concave punches on a compression machine with suitable parameter.
Coating solution preparation:
12. Add and disperse quantity of opadry yellow under continuous stirring in purified water and stir for 45 minutes to get 10% w/w dispersion.
13. Load the tablets of step-11 into perforated coating pan and coat the tablet with an inlet air temperature 55± 5°C till 3.5% w/w ± 0.25% weight build up is attained.
14. Dry the tablet of step-10 for 60 minutes at inlet air temperature 55± 5°C with intermittent jogging.

Table 3: Dissolution data of the formulation of Example 4:

Dissolution (Dissolution media volume: 900 mL, Paddle, 75 RPM) pH 6.8 Phosphate buffer with 0.05% SLS
Time (Minutes) % Dissolved
5 85
10 93
15 96
30 97

Example 5
Ingredients mg/ tablet
Intra-granular
Apixaban 5.0
Lactose 91.0
Microcrystalline cellulose 79.0
Croscarmellose sodium 6.0
Binder solution
Hydroxy propyl methyl cellulose E5 5.0
Purified water Q.S.
Extra - granular
Croscarmellose sodium 5.0
Magnesium stearate 1.0
Film coating
Opadry pink II 7.0
Opadry yellow II --

Brief manufacturing procedure:
1. Co-sift apixaban, lactose, microcrystalline cellulose, croscarmellose sodium through 40# ASTM S.S. seive.
2. Load the step 1 blend in rapid mixer granulator and mix the blend for 15 minutes at slow impellor speed and chopper off.
3. Add and dissolve hydroxy propyl methyl cellulose E5 in purified water under stirring.
4. Granulate the step 2 blend with addition of step 3 binder solution under slow impellor and chopper speed.
5. Dry the wet granules in rapid dryer at 550C till LOD becomes below 1.5 to 2.0% at 1050C for 10 minutes.
6. Pass the dried granules of step-5 through 25# and load to the suitable blender.
7. Sift croscarmellose sodium through 40# ASTM S.S. seive and load to step 6 blend and mix for 10 minutes.
8. Sift magnesium stearate through 60# ASTM S.S. seive and add to step 7 blend and lubricate the blend for 5 minutes.
9. Compress the tablet with step-8 blend using 9.8 × 5.2 mm oval shaped bevel concave punches on a compression machine with suitable parameter.
Coating solution preparation:
10. Add and disperse quantity of opadry pink under continuous stirring in purified water and stir for 45 minutes to get 10% w/w dispersion.
11. Load the tablets of step-9 into perforated coating pan and coat the tablet with an inlet air temperature 60 ± 5oC till 3.5% w/w ± 0.25% weight build up is attained.
12. Dry the tablet of step-11 for 60 minutes at inlet air temperature 50 ± 5oC with intermittent jogging.

Table 4: Dissolution data of the formulation of Example 5:

Dissolution (Dissolution media volume: 900 mL, Paddle, 75 RPM) pH 6.8 Phosphate buffer with 0.05% SLS
Time (Minutes) % Dissolved
5 27
10 41
15 55
30 70

,CLAIMS:1. A pharmaceutical composition comprising crystalline apixaban and a pharmaceutically acceptable carrier, wherein the mean particle size of the crystalline apixaban is more than 89 µm.

2. The pharmaceutical composition of claim 1, wherein the mean particle size of the crystalline apixaban is at least about 100 µm.

3. The pharmaceutical composition of claim 1, wherein the mean particle size of the crystalline apixaban is at least about 110 µm.

4. The pharmaceutical composition of claim 1, wherein the apixaban particles have a D90 more than 89 µm.

5. The pharmaceutical composition of claim 1, wherein the apixaban particles have a D90 at least about 100 µm.

6. The pharmaceutical composition of claim 1, wherein the apixaban particles have a D90 at least about 110 µm.

7. The pharmaceutical composition of claims 1-6, wherein the crystalline apixaban is Form M.

8. The pharmaceutical composition of claims 1-7, wherein the composition comprises one or more surfactants.

9. The pharmaceutical composition of claim 8, wherein the one or more surfactants comprise about 0.1% to 5 % w/w of the pharmaceutical composition.

10. The pharmaceutical composition of claim 9, wherein the surfactant is sodium lauryl sulfate.

11. The pharmaceutical composition of claim 9, wherein the surfactant is a Poloxamer.

12. The pharmaceutical composition of claim 9, wherein the surfactant is a mixture of sodium lauryl sulfate and a poloxamer.

13. The pharmaceutical composition of claim 1, wherein at least 85 wt % of the crystalline apixaban dissolves within 30 minutes in a pH 6.8 phosphate buffer containing one or more surfactants.

14. The pharmaceutical composition of claim 13, wherein the surfactant used in the composition is in an amount from about 0.1% to 5 % by weight.

15. A pharmaceutical composition of claim 13 or claim 14, wherein the surfactant used is either sodium lauryl sulfate, a poloxamer or mixture of both.

16. A pharmaceutical composition of claim 1, wherein the composition comprises therapeutically effective amount of apixaban.

17. The pharmaceutical composition of claim 16, wherein the composition comprises from about 2.5 mg to about 5 mg of apixaban.

18. The pharmaceutical composition according to any one of claims 1-17, for the use in the treatment of thromboembolic disorders.

19. Use of a composition as defined in any one of claims 1-18, in the preparation of a medicament for use in treating thromboembolic disorders.

20. A process of manufacturing the pharmaceutical tablet composition of any one of claims 1-18, comprising blending the crystalline apixaban with one or more excipients, granulating the mixture, adding one or more extragranular excipients to form a blend, compressing the blend into tablets, and optionally film coating the tablet.

21. The process of manufacturing the pharmaceutical composition according to claim 20, wherein the granulation step is a dry granulation process.

22. The process of manufacturing the pharmaceutical composition according to claim 20, wherein the granulation step is a wet granulation process.