DESC:FIELD OF THE INVENTION
The present invention relates to a process for the preparation of an oral administrable pharmaceutical composition comprising rivaroxaban and other pharmaceutical acceptable excipients.

BACKGROUD OF INVENTION:
Rivaroxaban with the chemical name 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo4-morpholinyl) phenyl]-1, 3-oxazolidin-5-yl} methyl)-2-thiophenecarboxamide is a low molecular weight inhibitor of coagulation factor Xa which can be administered orally. The structural formula of rivaroxaban is as shown below:

Rivaroxaban is used for prophylaxis and treatment of thromboembolic diseases such as heart attack, angina pectoris, reocclusion and restenosis following angioplasty or bypass, cerebral apoplexy, transient ischemic attack, peripheral arterial obstructive diseases, pulmonary embolism, and venous thrombosis.

Rivaroxaban is a selective inhibitor of FXa. It does not require a cofactor (such as anti-thrombin III) for activity. Rivaroxaban inhibits free FXa and prothrombinase activity. Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, rivaroxaban decreases thrombin generation.

Rivaroxaban and its pharmaceutically acceptable salts have been first time disclosed in US patent 7,157,456. The said patent is silent about any pharmaceutical composition of rivaroxaban.

It is necessary in the development of formulations to take account of the physiological and biological properties of the active ingredient. Rivaroxaban is characterized by a very low solubility in the water (about 7 mg/mL) and a relatively high melting point (about 230°C). Due to the lower solubility of rivaroxaban , the use of small particle size is required in order to obtain the bioavailable compositions. On the contrary the small particle size adversely impacts the blend flowability, which in turn makes the manufacturing process of the rivaroxaban pharmaceutical composition difficult especially with regard to reproducibility and uniformity. Thus, to improve the solubility of this poorly soluble drug, various techniques are disclosed in the prior art.

US patent 9,415,053 teaches the process for the preparation of a solid, orally administrable pharmaceutical composition comprising rivaroxaban in hydrophilized form, wherein the granulate is prepared by moist granulation using fluidized bed granulator. The tablets comprising hydrophilized active agent are shown to exhibit enhanced bioavailability as compared with tablets comprising non- hydrophilized active agent. However, the moist granulation technique used for hydrophilization of the rivaroxaban is complex and difficult to operate at industrial scale.

Another, US patent 8,586,082 discloses immediate release forms comprising the use of amorphous or semi-stable crystalline modifications of rivaroxaban and other pharmaceutically acceptable excipients, wherein said pharmaceutical composition is prepared by using melt extrusion technique. The requirement of energy for melt extrusion process is much higher and might not be suited to the thermo- liable substances at high temperatures that are used during the process. Due to high melting point of active ingredient, process involves melting of rivaroxaban which may result into significant decomposition and makes the process unattractive from industrial point of view.

A US patent publication US2011/0300214 teaches an alternate method of preparing pharmaceutical composition by emulsifying the rivaroxaban with a solubilizer and emulsifier to increase the solubility of rivaroxaban. Further, as per the illustration given in said patent application hot melt granulation technique is used for the preparation of the composition in which rivaroxaban is melted with other excipients at high temperature. Such process conditions can result into degradation of rivaroxaban.

An Indian patent IN374786 discloses an immediate release oral pharmaceutical composition comprising rivaroxaban wherein the composition is prepared by drug layering technology. The process comprises of dissolving binder, disintegrant, surfactant in a mixture of ethanol and water followed by dispensing the drug in the solution. The dispersion formed in the previous step is sprayed on the sugar pellets. Finally, the extra granular materials are added to the pellets followed by compression.

An Indian patent publication, IN781/MUM/2014 relates to a solid oral dosage form comprising rivaroxaban prepared by the process involving preparation of inert granules having a hydrophilic polymer and one or more pharmaceutically acceptable excipients. Further, co-milling rivaroxaban, surfactant followed by addition of said mixture with inert granules (free of rivaroxaban) prepared initially. Afterwards, blending the said mixture and finally compressing the mixture blend into tablets. The use of surfactant along with rivaroxaban in co-milling process results in generation of dust which is hazardous if inhaled by the operators working in that environment. Further co-milling is a time consuming and energy driven process.

Another Indian patent publication, IN201717037252 discloses a process for preparing an oral pharmaceutical composition of rivaroxaban in non-hydrophilized form. The process comprises of mixing rivaroxaban and other pharmaceutically acceptable inert excipients to form a dry mix followed by granulating the dry mix in a rapid mixer granulator. The granulating liquid used herein is non-aqueous. Finally, drying the granules obtained in rapid mixer granulator in a fluidized bed dryer.

One another Indian patent publication, IN202041047780 relates to a process of preparing a solid oral pharmaceutical composition of rivaroxaban, which is free of binder wherein the process comprises of mixing active compound and one or more pharmaceutically acceptable excipients. Afterwards a solution comprising a surfactant and solvent is prepared and added to the previous mixture. Finally, the granulating mixture is mixed uniformly in a rapid mixer granulator to form granules. The granules are then compressed into solid dosage form.

In most of the prior art processes, several techniques have been pursued to improve the dissolution profile of poorly soluble rivaroxaban such as hydrophilization, particle size reduction (micronization), modification of crystal habit, drug dispersion in carrier, emulsification but still due to some complexity in the process the dissolution profile of desired product is not up to the mark. Most of preceding methods are poorly reproducible, necessitating the optimization of experimental conditions. So, there is an urgent need to develop a simple and economic process for preparing a stable pharmaceutical composition of rivaroxaban.

OBJECT OF THE INVENTION
Another object of the present invention is to provide a process for the preparation of solid oral pharmaceutical composition of rivaroxaban which shows an enhanced dissolution and oral bioavailability of the drug.
One another object of the present invention is to provide a solid oral pharmaceutical composition which is simple and reproducible at industrial scale.

SUMMARY OF INVENTION:
Accordingly, the present invention relates to a process for preparing a stable pharmaceutical composition of rivaroxaban with one or more pharmaceutical acceptable excipients wherein the composition involves preparation of inert granules which is devoid of active compound.
In one embodiment the pharmaceutical composition of the present invention comprises rivaroxaban and one or more pharmaceutically acceptable excipients, wherein the composition comprises steps of:
i. dry mixing of one or more pharmaceutically acceptable excipients,
ii. preparing a solution comprising a solvent and optionally one or more pharmaceutically acceptable excipients, or taking a suitable solvent,
iii. granulating the dry mix powder obtained in step (i) with the solution/solvent of step (ii) to form inert granules,
iv. drying the granules in a fluidized bed dryer (FBD),
v. blending the dried granules with rivaroxaban optionally with one or more pharmaceutical acceptable excipients,
vi. lubricating the above blend of step (v) with a suitable lubricant,
vii. compressing the lubricated blend into solid dosage form, and
viii. optionally, coating the solid dosage form.
In another embodiment the pharmaceutical composition comprising rivaroxaban and other pharmaceutically acceptable excipients, wherein the inert granules are devoid of an active pharmaceutical ingredient (rivaroxaban).
DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides an efficient process for the preparation of solid oral pharmaceutical composition comprising rivaroxaban and one or more pharmaceutical excipients. More specifically, the inert granules in said composition are free from active pharmaceutical ingredient.
The term "active pharmaceutical ingredient" (used interchangeably with "active" or "active substance" or "drug") as used herein includes rivaroxaban or its pharmaceutically acceptable salt and its polymorphic form (crystalline).
The term “inert granules” as used herein refers to the pharmaceutical acceptable excipients which are granulated using a granulating liquid. Preferably, the active pharmaceutical ingredient is not a part of the inert granules, wherein the process to prepare inert granules is known as inert granulation.
The term “granulating liquid” used according to the present invention contains a solvent and/or one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients in this case are dispersed in the granulating liquid or preferably dissolved therein.
The term “pharmaceutically acceptable excipients” as used herein includes but are not limited to diluents, disintegrants, lubricants, binders, surfactants, solubilizers, solvents, coloring agents, glidants and plasticizers. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function.
The term “composition” or “pharmaceutical composition” or “solid dosage forms” refers to granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, beads, particles, and the like; and liquid dosage forms refers to solutions, suspensions, emulsions, colloids and the like, meant for oral administration.
Diluents are selected from lactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, xylitol, lactitol, starch, modified starches, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and combination thereof.
Disintegrants include but limited to croscarmellose sodium, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone; cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose; sodium starch glycolate; ion-exchange resins; starch and modified starches including pregelatinized starch; formalin-casein; alginates, gums and combination thereof.
Surfactants/solubilizers are selected from a group which may include but not limited to Tyloxapol®, Triton X-100®, polysorbates, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated 7 castor oil, polyoxyl 40 stearates, sorbitan monolaureates, sodium lauryl sulphate, polyethylene propylene glycol copolymer (poloxamer), cremophor-40, polyethylene glycol (PEG) and combination thereof.
Lubricants which include but are not limited to calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, fumaric acid, sodium stearyl fumarate, stearic acid, talc, zinc stearate, castor wax and combination thereof.
Binders are hydrophilic polymers whereas hydrophilic polymers are selected from a group which may include but not limited to polyvinyl pyrrolidone (Povidone), polyvinyl alcohol, copolymers of vinylpyrrolidone with other vinyl derivatives (crospovidone), hydroxypropyl methylcellulose, hydroxypropyl cellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates and pregelatinized starch.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one ordinarily skilled in the art and mixtures thereof.
In one embodiment of the present invention suitable “solvent” can be an alcohol and mixture of alcohol and water. The alcohol used herein may include but not limited to isopropyl alcohol, ethanol or methanol or mixture thereof.
In another embodiment of the present invention the film coat in step (viii), can be selected from a film-forming agent, porosity agent, a plasticizer, an anti-tacking agent and optionally one or more pigments. The film coat may provide taste masking and additional stability to the final tablet.
In one aspect the suitable “film-forming agent” can be selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate copolymer, ethyl cellulose, polyvinyl alcohol and combination thereof. Most preferable, film-forming agent used in the present composition is hydroxypropyl methylcellulose.
In one aspect the suitable “porosity agent” can be selected from lactose monohydrate thereof.
In another aspect the suitable “plasticizer” can be selected from low molecular weight polyethylene glycol (PEG), propylene glycol, triethyl citrate, dibutyl sebacate, diethyl phthalate, dextrin, lecithin and triacetin thereof.
In another aspect the suitable “anti-tacking agent” can be selected from talc, metal salts of fatty acids, colloidal silicone dioxide or combination thereof. Optionally, the anti-tacking agents can be utilized in the present invention.
The “pigments” used in the above film coat can be selected from iron oxide, preferably including iron oxide red and/or yellow.
In another aspect the film coat as used in pharmaceutical composition of the present invention, is commercially available ready to use coating materials such as Opadry® provided by Colorcon, Instacoat Universal, DR coat FCU.
In another embodiment the pharmaceutical composition according to the present invention, film coat can be used in combination with a surfactant. Most preferably, surfactant used in the present composition is sodium lauryl sulfate.
In another embodiment rivaroxaban as the active substance is employed in a micronized form. That means, the active substance of the pharmaceutical composition of the present invention has a volume mean particle size (D90) of 1 to 50 µm, more preferably less than 10 µm, still more preferably less than 5 µm. Rivaroxaban can be used in any crystalline, partly crystalline or amorphous form or modification. Preferably, rivaroxaban is used in crystalline form.
The term "D90" as used herein means at least 90% of the particles have volume diameter in the specified range when measured by a suitable method for example laser diffraction using a Malvern Mastersizer laser diffraction instrument.
In one of the preferred embodiments, the invention provides an efficient process for the preparation of pharmaceutical composition of rivaroxaban which comprises the following steps:
i. dry mixing of one or more pharmaceutically acceptable excipients,
ii. preparing a solution comprising a solvent and optionally one or more pharmaceutically acceptable excipients, or taking a suitable solvent,
iii. granulating the dry mix powder obtained in step (i) with the solution/solvent of step (ii) to form inert granules,
iv. drying the granules in a fluidized bed dryer (FBD),
v. blending the dried granules with rivaroxaban optionally with one or more pharmaceutical acceptable excipients,
vi. lubricating the above blend of step (v) with a suitable lubricant,
vii. compressing the lubricated blend into solid dosage form, and
viii. optionally, coating the solid dosage form.
The dosage form of the present invention may be mono or multiparticulate. The multiparticulate tablets are typically filled into capsules. Preferably, the dosage form is monoparticulate.
In the process of the present invention, one or more pharmaceutically acceptable excipients comprises of diluents, disintegrants, lubricants, binders, surfactants, solubilizers, solvents, coloring agents, glidants and plasticizers.
The pharmaceutical composition of present invention may comprise combination of above-mentioned excipients along with the active pharmaceutical ingredient. The ratio of excipient(s) employed will depend upon how much API is to be used. One excipient can perform more than one function.
The active pharmaceutical ingredient may be present in the pharmaceutical composition in the range of about 2.5 to about 25 % w/w, preferably about 2.81 to about 22.73 % w/w, and more preferably about 2.84 to about 22.47 % w/w, based on the total weight of the pharmaceutical composition.
In one embodiment the pharmaceutical composition of the present invention the diluent is typically in the range of about 20-80% w/w of the pharmaceutical composition. Preferably, the amount of diluent is 25-70 % w/w, based on the total weight of the pharmaceutical composition.
The binder in the pharmaceutical composition can be typically in the range of 1 to 10 % w/w preferably 1-5 % w/w, based on the total weight of the pharmaceutical composition.
The surfactant may be present in the pharmaceutical composition in the range of about 0.5 to about 10 % w/w, preferably about 0.8 to about 8 % w/w, and more preferably about 1 to about 5 % w/w, based on the total weight of the pharmaceutical composition.
The pharmaceutical composition may contain the disintegrant in a concentration range of about 1 to about 25 % w/w, preferably about 2 to about 22 % w/w, and preferably about 2 to about 20 % w/w based on the total weight of the pharmaceutical composition.
In one embodiment, the pharmaceutical composition of the present invention comprises mixing of lactose monohydrate, microcrystalline cellulose plain, polyvinyl pyrrolidone (PVP K-30), sodium lauryl sulphate and croscarmellose sodium. The said excipients are sifted through sieve no 40. Afterwards, in a rapid mixer granulator (RMG) at moderate to high speed the mixture is rotated till a uniformity is obtained.
Further, the solvent is added to the uniform dry mixed powder obtained in above step till a granular mass is observed. The solvent used herein can be added to the mixture as per desired granular mass. Alternatively, a solution, comprising of a solvent and optionally one or more pharmaceutically acceptable excipients. The excipients can be selected from binders. Binders can be selected from the group consisting of polyvinyl pyrrolidone (povidone) and hydroxypropyl cellulose. Preferably, the excipient can be polyvinyl pyrrolidone (povidone). The dry mixed powder was granulated with solution of excipients in solvent to obtain granular mass.
Thereafter, the wet granular mass is dried in a fluidized bed dryer (FBD) to obtain inert granules until loss on drying (LOD) is in the range of 2.5-3.5 %. The granular mass is dried in the temperature range of 40-70 °C, most preferably the range is 50-60 °C.
The dried inert granules are passed through sieve no 60 to collect the fine granules. The fine granules are mixed with the active compound i.e., micronized rivaroxaban in a fixed proportion. Afterwards disintegrant, glidant, preferably crospovidone and colloidal silicon dioxide respectively are geometrically combined with the mixture (rivaroxaban and fine granules) followed by co-shifting the mixture through sieve no 40. Finally, the sieved mixture is placed in a blender for uniform mixing at slow RPM (revolutions per minute) to obtain a pre-lubricated blend.
In another embodiment pharmaceutical composition of the present invention, fine granules are mixed with the active compound i.e., micronized rivaroxaban in a fixed proportion. Afterwards surfactant/solubilizer, disintegrant, glidant and mixture thereof can be combined with the mixture (rivaroxaban and fine granules) followed by co-shifting the mixture through sieve no 40. Finally, the sieved mixture is placed in a blender for uniform mixing at slow RPM (revolutions per minute) to obtain a pre-lubricated blend.
The final blend is compressed into dosage forms. The dosage forms according to the invention include, but are not limited to, capsules, powders, tablets, minitablets, microtablets, coated or uncoated tablets, coated or uncoated minitablets, coated or uncoated microtablets, coated pellets, pills, and the like. Preferably, the pharmaceutical dosage form according to the invention is uncoated or coated tablet. Thereafter, the compressed tablets are coated using a film coat. The film coating applied onto the solid pharmaceutical composition was composed of at least one film forming polymer for coating and at least one further pharmaceutically acceptable excipient, which can be selected from but not limited to surfactant, plasticizers, anti-tacking agents, pigments and coloring agents, pore formers and any mixture thereof.
In another embodiment, pharmaceutical composition of the present invention exhibits greater than 85% of drug release within 30 minutes, preferably greater than 90%, more preferably greater than 95%. The dissolution profile of the final dosage form complies with the regulatory requirements. Specifically, the pharmaceutical composition of the present invention exhibits more than 85% of drug release within 30 minutes in 500 ml of 0.1 N HCl (Office of Generic Drugs dissolution database) using a USP I apparatus (basket) at a temperature of 37±0.5° C. and a rotation speed of 100 revolutions per minute.
The pharmaceutical composition of the present invention boosts dissolution properties at physiologic pH. The dissolution studies of compositions comprising rivaroxaban, having dissolution more than 85% within 30 minutes wherein rivaroxaban is present in an amount of 2.5 to 25% of the total weight of the pharmaceutical composition.
The total weight of the pharmaceutical composition may be in the range of 80 mg to 90 mg. Most preferable range is in between 85 mg to 89 mg.
In accordance with another embodiment of the present invention, there is provided a pharmaceutical composition which is stable at 40°C and 75% relative humidity. The level of impurities is controlled within the composition as per regulatory guidelines.
The following examples are intended to further illustrate the invention but are not to be construed as limiting the invention.
Examples
Example 1
Product Name Rivaroxaban 20 mg
SN Ingredients mg/Tablet
Intragranular Part
1 Microcrystalline Cellulose Plain 38.550
2 Lactose monohydrate 10.000
3 Polyvinyl Pyrrolidine (PVP K-30) 3.000
4 Sodium Lauryl Sulphate 1.000
5 Croscarmellose Sodium 5.500
Binder
6 Isopropyl alcohol qs
Pre-Lubrication
7 Rivaroxaban (Micronized) 20.000
8 Crospovidone XL 10 5.000
9 Colloidal Silicon Dioxide 1.500
Lubrication
10 Magnesium Stearate 0.450
Average Weight of uncoated tablets 85.000
Film Coating
11 DR Coat FCU 2.750
12 Red oxide of Iron 0.250
13 Purified Water qs
Average Weight of Coated Tablets 88.000
Procedure:
1) Lactose monohydrate, microcrystalline cellulose, polyvinyl pyrrolidone (PVP K-30), sodium lauryl sulphate and croscarmellose sodium were sifted through a sieve no 40 and mixed uniformly in a rapid mixer granulator.
2) The dry mixed powder prepared in step 1 was granulated with isopropyl alcohol to obtain inert granules.
3) The granules of step 2 were dried in a fluidized bed dryer (FBD) to obtain inert dried granules.
4) The inert granules were passed through a sieve no 60 and geometrically mixed with rivaroxaban (micronized) followed by addition of colloidal silicon dioxide and crospovidone XL-10 to obtain pre- lubricated granules.
5) The pre-lubricated granules obtained in step 4 were lubricated with magnesium stearate.
6) The lubricated blend was compressed into tablet.
7) The compressed tablet obtained in step 6 was coated by using DR coat FCU, red oxide of iron and water to get tablet of an average wt. of 88 mg.
Example 2
Product Name Rivaroxaban 20 mg
Sr No Ingredients mg/tablet
Intragranular Part
1 Microcrystalline Cellulose Plain 30.100
2 Lactose monohydrate 10.000
3 Polyvinyl Pyrrolidine (PVP K-30) 3.000
4 Sodium Lauryl Sulphate 2.200
5 Croscarmellose Sodium 5.500
Binder
6 Isopropyl alcohol qs
Pre-Lubrication
7 Rivaroxaban (Micronized) 20.000
8 PEG 6000 4.000
9 Crospovidone XL 10 8.000
10 Colloidal Silicon Dioxide 1.500
Lubrication
11 Magnesium Stearate 0.700
Average Weight of uncoated tablets 85.000
Film Coating
12 Instacoat Universal 1308 3.865
13 Red oxide of Iron 0.135
14 Purified Water qs
Average Weight of Coated Tablets 89.000
Procedure:
1) Lactose monohydrate, microcrystalline cellulose, polyvinyl pyrrolidone (PVP K-30), sodium lauryl sulphate and croscarmellose sodium were sifted through a sieve no 40 and mixed in a rapid mixer granulator.
2) The dry mixed powder prepared in step 1 was granulated with isopropyl alcohol to obtain inert granules.
3) The granules of step 2 were dried in a fluidized bed dryer (FBD) to obtain inert dried granules.
4) The inert granules were passed through a sieve no 60 and geometrically mixed with rivaroxaban (micronized) followed by addition of PEG 6000, colloidal silicon dioxide and crospovidone XL-10 to obtain pre- lubricated granules.
5) The pre-lubricated granules obtained in step 4 were lubricated with magnesium stearate.
6) The lubricated blend was compressed into tablet.
7) The compressed tablet obtained in step 6 was coated by using Instacoat universal 1308, red oxide of iron and water to get tablet of an average weight of 89 mg.
Example 3
Product Name Rivaroxaban 15 mg
Sr No Ingredients mg/tablet
Intragranular Part
1 Microcrystalline Cellulose Plain 43.300
2 Lactose monohydrate 10.000
3 Polyvinyl Pyrrolidine (PVP K-30) 3.000
4 Sodium Lauryl Sulphate 1.000
5 Croscarmellose Sodium 5.500
Binder
6 Isopropyl alcohol qs
Pre-Lubrication
7 Rivaroxaban (Micronized) 15.000
8 Crospovidone XL 10 5.000
9 Colloidal Silicon Dioxide 1.500
Lubrication
10 Magnesium Stearate 0.700
Average Weight of uncoated tablets 85.000
Film Coating
11 DR Coat FCU 2.750
12 Red oxide of Iron 0.250
13 Purified Water qs
Average Weight of Coated Tablets 88.000
Procedure:
1) Lactose monohydrate, microcrystalline cellulose, polyvinyl pyrrolidone (PVP K-30), sodium lauryl sulphate and croscarmellose sodium were sifted through a sieve no 40 and mixed in a rapid mixer granulator.
2) The dry mixed powder prepared in step 1 was granulated with isopropyl alcohol to obtain inert granules.
3) The granules of step 2 were dried in a fluidized bed dryer (FBD) to obtain inert dried granules.
4) The inert granules were passed through a sieve no 60 and geometrically mixed with rivaroxaban (micronized) followed by addition of colloidal silicon dioxide and crospovidone XL-10 to obtain pre- lubricated granules.
5) The pre-lubricated granules obtained in step 4 were lubricated with magnesium stearate.
6) The lubricated blend was compressed into tablet.
7) The compressed tablet obtained in step 6 was coated by using DR coat FCU, red oxide of iron and water to get tablet of an average weight of 88 mg.
Example 4
Product Name Rivaroxaban 10 mg
Sr No Ingredients mg/tablet
Intragranular Part
1 Microcrystalline Cellulose Plain 48.300
2 Lactose monohydrate 10.000
3 Polyvinyl Pyrrolidine (PVP K-30) 3.000
4 Sodium Lauryl Sulphate 1.000
5 Croscarmellose Sodium 5.500
Binder
6 Isopropyl alcohol qs
Pre-Lubrication
7 Rivaroxaban (Micronized) 10.000
8 Crospovidone XL 10 5.000
9 Colloidal Silicon Dioxide 1.500
Lubrication
10 Magnesium Stearate 0.700
Average Weight of uncoated tablets 85.000
Film Coating
11 DR Coat FCU 2.750
12 Red oxide of Iron 0.250
13 Purified Water qs
Average Weight of Coated Tablets 88.000

Procedure:
1) Lactose monohydrate, microcrystalline cellulose, polyvinyl pyrrolidone (PVP K-30), sodium lauryl sulphate and croscarmellose sodium were sifted through a sieve no 40 and mixed in a rapid mixer granulator.
2) The dry mixed powder prepared in step 1 was granulated with isopropyl alcohol to obtain inert granules.
3) The granules of step 2 were dried in a fluidized bed dryer (FBD) to obtain inert dried granules.
4) The inert granules were passed through a sieve no 60 and geometrically mixed with rivaroxaban (micronized) followed by addition of colloidal silicon dioxide and crospovidone XL-10 to obtain pre- lubricated granules.
5) The pre-lubricated granules obtained in step 4 were lubricated with magnesium stearate.
6) The lubricated blend was compressed into tablet.
7) The compressed tablet obtained in step 6 was coated by using DR coat FCU, red oxide of iron and water to get tablet of an average weight of 88 mg.
Example 5
Product Name Rivaroxaban 10 mg
Sr No Ingredients mg/tablet
Intragranular Part
1 Microcrystalline Cellulose Plain 47.100
2 Lactose monohydrate 10.000
3 Polyvinyl Pyrrolidine (PVP K-30) 3.000
4 Sodium Lauryl Sulphate 2.200
5 Croscarmellose Sodium 5.500
Binder
6 Isopropyl alcohol qs
Pre-Lubrication
7 Rivaroxaban (Micronized) 10.000
8 Crospovidone XL 10 5.000
9 Colloidal Silicon Dioxide 1.500
Lubrication
10 Magnesium Stearate 0.700
Average Weight of uncoated tablets 85.000
Film Coating
11 DR Coat FCU 2.570
12 Red oxide of Iron 0.250
13 Sodium Lauryl sulphate 0.180
14 Purified Water qs
Average Weight of Coated Tablets 88.000
Procedure:
1) Lactose monohydrate, microcrystalline cellulose, polyvinyl pyrrolidone (PVP K-30), sodium lauryl sulphate and croscarmellose sodium were sifted through a sieve no 40 and mixed in a rapid mixer granulator.
2) The dry mixed powder prepared in step 1 was granulated with isopropyl alcohol to obtain inert granules.
3) The granules of step 2 were dried in a fluidized bed dryer (FBD) to obtain inert dried granules.
4) The inert granules were passed through a sieve no 60 and geometrically mixed with rivaroxaban (micronized) followed by addition of colloidal silicon dioxide and crospovidone XL-10 to obtain pre- lubricated granules.
5) The pre-lubricated granules obtained in step 4 were lubricated with magnesium stearate.
6) The lubricated blend was compressed into tablet.
7) The compressed tablet obtained in step 6 was coated by using DR coat FCU, red oxide of iron, sodium lauryl sulphate and water to get tablet of an average weight of 88 mg.
Example 6
Product Name Rivaroxaban 15 mg
Sr No Ingredients mg/tablet
Intragranular Part
1 Microcrystalline Cellulose Plain 42.100
2 Lactose monohydrate 10.000
3 Polyvinyl Pyrrolidine (PVP K-30) 3.000
4 Sodium Lauryl Sulphate 2.200
5 Croscarmellose Sodium 5.500
Binder
6 Isopropyl alcohol qs
Pre-Lubrication
7 Rivaroxaban (Micronized) 15.000
8 Crospovidone XL 10 5.000
9 Colloidal Silicon Dioxide 1.500
Lubrication
10 Magnesium Stearate 0.700
Average Weight of uncoated tablets 85.000
Film Coating
11 DR Coat FCU 2.620
12 Red oxide of Iron 0.200
13 Sodium Lauryl sulphate 0.180
14 Purified Water qs
Average Weight of Coated Tablets 88.000
Procedure:
1) Lactose monohydrate, microcrystalline cellulose, polyvinyl pyrrolidone (PVP K-30), sodium lauryl sulphate and croscarmellose sodium were sifted through a sieve no 40 and mixed in a rapid mixer granulator.
2) The dry mixed powder prepared in step 1 was granulated with isopropyl alcohol to obtain inert granules.
3) The granules of step 2 were dried in a fluidized bed dryer (FBD) to obtain inert dried granules.
4) The inert granules were passed through a sieve no 60 and geometrically mixed with rivaroxaban (micronized) followed by addition of colloidal silicon dioxide and crospovidone XL-10 to obtain pre- lubricated granules.
5) The pre-lubricated granules obtained in step 4 were lubricated with magnesium stearate.
6) The lubricated blend was compressed into tablet.
7) The compressed tablet obtained in step 6 was coated by using DR coat FCU, red oxide of iron, sodium lauryl sulphate and water to get tablet of an average weight of 88 mg.
Example 7
Product Name Rivaroxaban 20 mg
Sr No Ingredients mg/tablet

Intragranular Part
1 Microcrystalline Cellulose Plain 37.100
2 Lactose monohydrate 10.000
3 Polyvinyl Pyrrolidine (PVP K-30) 3.000
4 Sodium Lauryl Sulphate 2.200
5 Croscarmellose Sodium 5.500
Binder
6 Isopropyl alcohol qs
Pre-Lubrication
7 Rivaroxaban (Micronized) 20.000
8 Crospovidone XL 10 5.000
9 Colloidal Silicon Dioxide 1.500
Lubrication
10 Magnesium Stearate 0.700
Average Weight of uncoated tablets 85.000
Film Coating
11 DR Coat FCU 2.720
12 Red oxide of Iron 0.100
13 Sodium Lauryl sulphate 0.180
14 Purified Water qs
Average Weight of Coated Tablets 88.000
Procedure:
1) Lactose monohydrate, microcrystalline cellulose, polyvinyl pyrrolidone (PVP K-30), sodium lauryl sulphate and croscarmellose sodium were sifted through a sieve no 40 and mixed in a rapid mixer granulator.
2) The dry mixed powder prepared in step 1 was granulated with isopropyl alcohol to obtain inert granules.
3) The granules of step 2 were dried in a fluidized bed dryer (FBD) to obtain inert dried granules.
4) The inert granules were passed through a sieve no 60 and geometrically mixed with rivaroxaban (micronized) followed by addition of colloidal silicon dioxide and crospovidone XL-10 to obtain pre- lubricated granules.
5) The pre-lubricated granules obtained in step 4 were lubricated with magnesium stearate.
6) The lubricated blend was compressed into tablet of an average weight of 85 mg.
7) The compressed tablet obtained in step 6 was coated by using DR coat FCU, red oxide of iron, sodium lauryl sulphate and water to get tablet of an average weight of 88 mg.
Example 8
Product Name Rivaroxaban 5 mg
Sr No Ingredients mg/tablet
Intragranular Part
1 Microcrystalline Cellulose Plain 52.100
2 Lactose monohydrate 10.000
3 Polyvinyl Pyrrolidine (PVP K-30) 3.000
4 Sodium Lauryl Sulphate 2.200
5 Croscarmellose Sodium 5.500
Binder
6 Isopropyl alcohol qs
Pre-Lubrication
7 Rivaroxaban (Micronized) 5.000
8 Crospovidone XL 10 5.000
9 Colloidal Silicon Dioxide 1.500
Lubrication
10 Magnesium Stearate 0.700
Average Weight of uncoated tablets 85.000
Film Coating
11 DR Coat FCU 2.800
12 Red oxide of Iron 0.020
13 Sodium Lauryl sulphate 0.180
14 Purified Water qs
Average Weight of Coated Tablets 88.000
Procedure:
1) Lactose monohydrate, microcrystalline cellulose, polyvinyl pyrrolidone (PVP K-30), sodium lauryl sulphate and croscarmellose sodium were sifted through a sieve no 40 and mixed in a rapid mixer granulator.
2) The dry mixed powder prepared in step 1 was granulated with isopropyl alcohol to obtain inert granules.
3) The granules of step 2 were dried in a fluidized bed dryer (FBD) to obtain inert dried granules.
4) The inert granules were passed through a sieve no 60 and geometrically mixed with rivaroxaban (micronized) followed by addition of colloidal silicon dioxide and crospovidone XL-10 to obtain pre- lubricated granules.
5) The pre-lubricated granules obtained in step 4 were lubricated with magnesium stearate.
6) The lubricated blend was compressed into tablet of an average weight of 85 mg.
7) The compressed tablet obtained in step 6 was coated by using DR coat FCU, red oxide of iron, sodium lauryl sulphate and water to get tablet of an average weight of 88 mg.
Example 9
Product Name Rivaroxaban 10 mg
Sr No Ingredients mg/tablet
Intragranular Part
1 Microcrystalline Cellulose Plain 47.100
2 Lactose monohydrate 10.000
3 Sodium Lauryl Sulphate 2.200
4 Croscarmellose Sodium 5.500
Binder
5 Isopropyl alcohol qs
6 Polyvinyl Pyrrolidine (PVP K-30) 3.000
Pre-Lubrication
7 Rivaroxaban (Micronized) 10.000
8 Crospovidone XL 10 5.000
9 Colloidal Silicon Dioxide 1.500
Lubrication
10 Magnesium Stearate 0.700
Average Weight of uncoated tablets 85.000
Film Coating
11 DR Coat FCU 2.570
12 Red oxide of Iron 0.250
13 Sodium Lauryl sulphate 0.180
14 Purified Water qs
Average Weight of Coated Tablets 88.000
Procedure:
1) Lactose monohydrate, microcrystalline cellulose, sodium lauryl sulphate and croscarmellose sodium were sifted through a sieve no 40 and mixed in a rapid mixer granulator.
2) Polyvinyl pyrrolidone (PVP K-30) was dissolved in isopropyl alcohol to obtain binder solution.
3) The dry mixed powder prepared in step 1 was granulated with binder solution of step 2 to obtain inert granules.
4) The granules of step 3 were dried in a fluidized bed dryer (FBD) to obtain inert dried granules.
5) The inert granules were passed through a sieve no 60 and geometrically mixed with rivaroxaban (micronized) followed by addition of colloidal silicon dioxide and crospovidone XL-10 to obtain pre- lubricated granules.
6) The pre-lubricated granules obtained in step 5 were lubricated with magnesium stearate.
7) The lubricated blend was compressed into tablet.
8) The compressed tablet obtained in step 7 was coated by using DR coat FCU, red oxide of iron, sodium lauryl sulphate and water to get tablet of an average weight of 88 mg.
Example 10: Stability Studies
The different compositions of rivaroxaban were stored at 40°C/75% RH and were tested for impurities at specific intervals. The results are tabulated in Table 1.
Table 1:

Initial
6 M
Assay
(90.0 to 110.0%) Individual unspecified imp (NMT 0.2%)
Total Impurity
(NMT 0.3%) Assay
(90.0 to 110.0%) Individual unspecified imp (NMT 0.2%) Total Impurity
(NMT 0.3%)
Ex. 5 101.9 0.04 0.12 98.4 0.13 0.23
Ex. 6 103.4 0.06 0.21 104.1 0.14 0.26
Ex. 7 99.1 0.06 0.20 101.3 0.07 0.11

ND: Not detected; NMT: Not more than
Example 11: Dissolution Studies
Dissolution studies of different compositions of rivaroxaban were conducted in 500 mL 0.1N HCl media with USP Apparatus II (Paddle) and release of rivaroxaban at time point of 30 minutes on stability at 40° C/75% RH are as follows in Table 2.
TABLE 2:

% Drug Release Initial % Drug Release 6M
40° C /75% RH
Ex. 5 97% 93%
Ex. 6 100% 98%
Ex. 7 91% 94%

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples are provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.

,CLAIMS:1. A pharmaceutical composition comprising rivaroxaban with one or more pharmaceutical acceptable excipients wherein the composition involves inert granule which is devoid of rivaroxaban.

2. The pharmaceutical composition as claimed in claim 1, comprising rivaroxaban in an amount of 2.5% to 25% w/w, diluent ranging from 20% to 80% w/w, binder ranging from 1% to 10% w/w, disintegrant ranging from 1% to 25% w/w, surfactant ranging from 0.5% to 10% w/w, relative to the total weight of the pharmaceutical dosage form.

3. The pharmaceutical composition as claimed in claims 2, wherein diluent is selected from a group consisting to lactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, xylitol, lactitol, starch, modified starches, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and combination thereof; binder is selected from polyvinyl pyrrolidone (povidone), polyvinyl alcohol, copolymers of vinylpyrrolidone with other vinyl derivatives, hydroxypropyl methylcellulose, hydroxypropyl cellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates and pregelatinized starch; disintegrant is selected from croscarmellose sodium, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone; cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose; sodium starch glycolate; ion-exchange resins; starch and modified starches including pregelatinized starch; formalin-casein; alginates, gums and combination thereof; surfactant is selected from Tyloxapol®, Triton X-100®, polysorbates, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated 7 castor oil, polyoxyl 40 stearates, sorbitan monolaureates, sodium lauryl sulphate, polyethylene propylene glycol copolymer (poloxamer), cremophor-40, polyethylene glycol (PEG) and combination thereof.

4. The pharmaceutical composition as claimed in claim 2, wherein composition further comprises lubricant, glidant, film coat material.

5. The pharmaceutical composition as claimed in claim 4, wherein lubricant is selected from calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, fumaric acid, sodium stearyl fumarate, stearic acid, talc, zinc stearate, castor wax and combination thereof; glidant is selected from silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel; film coat material is selected from a film-forming agent, porosity agent, a plasticizer, an anti-tacking agent and optionally one or more pigments.

6. The pharmaceutical composition as claimed in claim 5, wherein film-forming agent is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate copolymer, ethyl cellulose, polyvinyl alcohol and combination thereof; porosity agent is selected from lactose monohydrate; plasticizer is selected from low molecular weight polyethylene glycol (PEG), propylene glycol, triethyl citrate, dibutyl sebacate, diethyl phthalate, dextrin, lecithin and triacetin thereof; anti-tacking agent is selected from talc, metal salts of fatty acids, colloidal silicone dioxide or combination thereof; pigments is selected from iron oxide red and/or yellow.

7. The pharmaceutical composition as claimed in claim 5, wherein film coat is used in combination with a surfactant, wherein surfactant is selected from sodium lauryl sulfate.

8. A process for the preparation of pharmaceutical composition of rivaroxaban, which comprises:
i. dry mixing of one or more pharmaceutically acceptable excipients,
ii. preparing a solution comprising a solvent and optionally one or more pharmaceutically acceptable excipients, or taking a suitable solvent,
iii. granulating the dry mix powder obtained in step (i) with the solution/solvent of step (ii) to form inert granules,
iv. drying the granules in a fluidized bed dryer (FBD),
v. blending the dried granules with rivaroxaban optionally with one or more pharmaceutical acceptable excipients,
vi. lubricating the above blend of step (v) with a suitable lubricant,
vii. compressing the lubricated blend into solid dosage form, and
viii. optionally, coating the solid dosage form.

9. The process as claimed in claim 8, wherein a suitable solvent is selected from alcohol such as methanol, ethanol, isopropanol or mixtures thereof.

10. The pharmaceutical composition as claimed in proceeding claims, wherein rivaroxaban is present in an amount of 2.5-25% of the total weight of the pharmaceutical composition having dissolution more than 85% within 30 minutes.