Claims:1. A process for preparing an oral stable pharmaceutical composition of Rivaroxaban, wherein the process comprises the steps of:
(i) Mixing Rivaroxaban and one or more pharmaceutically acceptable excipients
(ii) Preparing a solution comprising a solvent and surfactant.
(iii) Granulating the blend of step (i) with the solution of step (ii).
(iv) mixing the granulating mixture in rapid mixer granulation to form the Rivaroxaban granules.
(v) compress the granules obtained in step (iv) into solid dosage form.
2. The process as claimed in claim 1, wherein one or more pharmaceutically acceptable excipients are selected from diluents, disintegrants, lubricants, surfactants, solvents and combinations thereof.
3. The process as claimed in claim 2, wherein the diluent is selected from the group comprising of 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.
4. The process as claimed in claim 2 & 3, wherein the disintegrant is selected from the group comprising of 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.
5. The process as claimed in claim 3, wherein the lubricant is selected from the group comprising of calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, fumaric acid, sodium stearyl fumarate," stearic acid, talc, vegetable oil, zinc stearate, castor wax and combination thereof.
6. The process as claimed in claim 1, wherein the surfactant is selected are selected from Tyloxapol®, Triton X-100®, polysorbates, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearates, sorbitan monolaureates, sodium lauryl sulphate, polyethylene-propylene glycol copolymer (poloxamer), cremophor-40, propylene glycol and combination thereof.
7. The process as claimed in claim 1, wherein the solvent is water or alcohol solvents.
8. The process as claimed in claim 1, wherein the solid dosage form is selected from tablet, film coated tablet or capsule.

, Description:FORM 2
THE PATENTS ACT 1970
(39 OF 1970)

COMPLETE SPECIFICATION
(Section 10, rule 13)

“STABLE PHARMACEUTICAL COMPOSITION OF RIVAROXABAN”

OPTIMUS PHARMA PRIVATE LIMITED,
SY NO. 37/A & 37/P, PLOT NO. 6P, 2nd FLOOR
SIGNATURE TOWERS, KOTHAGUDA, KONDAPUR, HYDERABAD
TELANGANA, INDIA 500084
A company incorporated under Indian Company Act, 1956

The following specification particularly describes the nature of this invention and the manner in which it is to be performed
TITLE OF THE INVENTION:
“STABLE PHARMACEUTICAL COMPOSITION OF RIVAROXABAN”
FIELD OF THE INVENTION:
The present invention relates to a process of preparing a stable pharmaceutical composition of Rivaroxaban by avoiding hydrophilic binding agent. The solid composition is used for prophylaxis of venous thromboembolic disorders, stroke and systemic embolisms and for prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism.
BACKGROUND OF THE INVENTION:
Rivaroxaban is an oral anticoagulant which is a factor Xa (FXa) inhibitor. It indirectly inhabits the platelet aggregation by decreasing thrombin generation. It was developed by Janssen Pharms and currently marketed in the United States under the trade name XARELTO.

Rivaroxaban is an oxazolidinone derivative compound, which is chemically known as 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5yl}methyl)-2-thiophenecarboxamide. It is disclosed in US 7157456, US 7585860 and US 7592339.
The pharmaceutical industry uses various methods of manufacturing solid dosage forms by using different pharmaceutical agents. Among various such methods of manufacturing solid dosage forms, granulation technique is preferable.
Granulation is a process in which granules are formed from drug substance with excipients in order to improve the properties of drug substance or dosage form. Granules are solid agglomerates of powder particles. Granulation may be dry granulation or wet granulation.
Wet granulation differs from dry granulation in having a granulation liquid, an aqueous or non-aqueous solvents are used alone or in combination with any of the pharmaceutical excipients as granulating solution. It improves compatibility of powder excipients, uniform content of drug substance and good segregation of components.
IN 256522 disclose a process for the preparation of a solid, orally administrable pharmaceutical composition comprising Rivaroxaban in hydrophilized form, in which (a) first granules comprising the active compound in hydrophilized form are prepared by moist granulation, wherein the active compound treated with the granulating liquid a solvent, a hydrophilic binding agent and the granules are then converted into the pharmaceutical composition, with addition of pharmaceutically suitable additives. IN’522 states that the tablet produced by a fluidized bed granulation process showed superior bioavailability as compared to a tablet produced by direct tableting, while tablets produced via mixer granulation showed no significant difference in bioavailability as compared to a tablet produced by direct tableting.
IN 2562/DELNP/2008 discloses solid pharmaceutical dosage forms of Rivaroxaban in amorphous form which can be prepared by melting active ingredient with one or more excipients.
WO 2010146179 discloses solid pharmaceutical compositions of Rivaroxaban, prepared dry granulation of the Rivaroxaban with at least one excipient, co-milling Rivaroxaban with the excipients, hot melt granulation with a molten excipient, or hot melt extrusion with an excipient. The mixture may then be agglomerated, granulated with a granulation liquid, or milled before compressing to form a tablet.
The above prior art references discloses different process for the preparation of solid oral dosage form of Rivaroxaban. However, the inventors of the present invention developed simple, cost effective alternate process which is more advantageous by means of comparable dissolution and bioavailability with respect to the marketed formulation of Xarelto tablets by avoiding hydrophilic binding agents.

SUMMARY OF THE INVENTION:
The present invention relates to a process of preparing a stable pharmaceutical composition of Rivaroxaban by avoiding hydrophilic binding agent.
In one aspect of the present invention relates to a process of preparing a stable pharmaceutical composition of Rivaroxaban with one or more pharmaceutical acceptable excipients in without hydrophilic binding agent.
In yet another aspect of the present invention provides the process of preparing a stable pharmaceutical composition of Rivaroxaban, comprising the steps of;
(i) Mixing Rivaroxaban and one or more pharmaceutically acceptable excipients.
(ii) Preparing a solution comprising a solvent and surfactant.
(iii) Granulating the blend of step (i) with the solution of step (ii).
(iv) mixing the granulating mixture in rapid mixer granulation to form the rivaroxaban granules.
(v) compress the granules obtained in step (iv) into solid dosage form.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to a process of preparing a stable pharmaceutical composition of Rivaroxaban by avoiding hydrophilic binding agent.
In one aspect of the present invention relates to a process of preparing a stable pharmaceutical composition of Rivaroxaban with one or more pharmaceutical acceptable excipients in without hydrophilic binding agent.
In one another aspect of the present invention relates to a process of preparing a stable pharmaceutical composition of Rivaroxaban with diluent, disintegrant, surfactant, solvent and lubricant in without hydrophilic binding agent.
In yet another aspect of the present invention provides the process of preparing a stable pharmaceutical composition of Rivaroxaban, comprising the steps of;
(i) Mixing Rivaroxaban and one or more pharmaceutically acceptable excipients
(ii) Preparing a solution comprising a solvent and surfactant.
(iii) Granulating the blend of step (i) with the solution of step (ii).
(iv) mixing the granulating mixture in rapid mixer granulation to form the rivaroxaban granules.
(v) compress the granules obtained in step (iv) into solid dosage form.
The term "pharmaceutical acceptable excipient" as used herein refers to additives useful for converting pharmacologically active compounds into pharmaceutical dosage forms which are suitable for administration to patients. volume mean particle size (D90) of 1 to 30 um, more preferably of 4 to 20 um, still more preferably of 8 to 15 um. Suitable excipients include diluents, binders, disintegrants, surfactants, lubricants, glidants and coloring agents. Other pharmaceutically acceptable excipients can also be included.
The term “composition” or “pharmaceutical composition” or “ solid dosage forms” such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.
The term ‘stable’ refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.
The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "a diluent" means one diluent or more than one diluent.
Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", “having”, “containing” "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
According to the embodiments of the present invention, wherein one or more pharmaceutically acceptable excipients are selected from diluents, disintegrants and combinations thereof.
According to the embodiments of the present invention, wherein one or more extragranular excipients are selected from disintegrants, lubricant and combinations thereof.
According to the embodiments of the present invention suitable "diluents" used according to the present invention 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.
According to the embodiments of the present invention suitable disintegrants used according to the present invention are 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.
According to the embodiments of the present invention suitable lubricants used according to the present invention are selected from calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, fumaric acid, sodium stearyl fumarate," stearic acid, talc, vegetable oil, zinc stearate, castor wax and combination thereof.
According to the embodiments of the present invention suitable "solvent" is water or alcohol solvents like isopropyl alcohol, propylene glycol, ethanol, polyethylene glycol etc.,
According to the embodiments of the present invention suitable surfactants are selected from Tyloxapol®, Triton X-100®, polysorbates, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearates, sorbitan monolaureates, sodium lauryl sulphate, polyethylene-propylene glycol copolymer (poloxamer), cremophor-40, propylene glycol and combination thereof.
According to the embodiments of the present invention suitable film coating polymers used according to the present invention are selected from polyvinyl alcohol (part hydrolyzed), titanium dioxide, macrogol (polyethylene glycol 3350), Hypromellose, Lactose, Triacetin, Talc, Titanium oxide and iron oxide and the like or mixtures thereof.
According to embodiment of the present invention composition will provide stable product, as well as improved content uniformity, blend uniformity and bioavailability.
The process details of the invention is provided in the example given below, which is provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Examples-1
Table 1
S.No. Ingredients Quantity (mg)
2.5mg 10mg 15mg 20mg
1. Rivaroxaban 2.50 10.00 15.00 20.00
2. Cellulose, microcrystalline 64.00 56.50 54.00 51.50
3. Lactose monohydrate 26.90 26.90 24.40 21.90
4. Croscarmellose sodium 4.00 4.00 4.00 4.00
5. Sodium lauryl sulphate 1.00 1.00 1.00 1.00
6. Purified water QS QS QS QS
8. Croscarmellose sodium 3.00 3.00 3.00 3.00
9. Magnesium stearate 0.60 0.60 0.60 0.60
10. Opadry II Yellow 3.06 - - -
11. Opadry II Pink - 3.06 - -
12. Opadry II Brown - - 3.06 -
13. Opadry II Red - - - 3.06
14. Purified water QS QS QS QS

The processing steps involved in manufacturing of oral stable pharmaceutical composition of Rivaroxaban given in example 1 is given below:
Manufacturing Process:
1. Sifting: Co-sift Rivaroxaban, Cellulose, microcrystalline, Lactose monohydrate and Croscarmellose sodium.
2. Granulation fluid preparation: Add required quantity of Purified water and kept under stirring, to that add weighed quantity of sodium lauryl sulfate without stirring.
3. Granulation: Granulate the step 1 with step 2 to attain desired granules, and mill through co mill fitted with 6.00 mm screen and dried to attain desired %LOD and mill with 1.00 mm screen until all the dried granules.
4. Sifting of extra-granular material
a. Sift Croscarmellose sodium through sieve #40 ASTM (420 µm).
b. Sift Magnesium stearate through sieve #60 ASTM (250 µm).

.
5. Blending and Lubrication:
c. Load the granules of step-3 and step-4a materials in blender and mix for 10 minutes at slow speed
d. Add pre sifted magnesium stearate to above material (step 5c) and mix for 5 minutes at slow speed.
6. Compression: Compress the lubricated blend of step 5 using suitable punches.
7. Film Coating:
i. Disperse Opadry II in purified water (15% m/m solids) under stirring and continue stirring for 45 minutes to form uniform dispersion.
ii. Load the core tablets of step-6 in coating pan and coat the tablets for 3.0 ± 1.0% m/m with following coating parameters. After achieving the desired mass gain dry the coated tablets for 15 minutes with low inlet temperature.

Dissolution profile results:
Table 2. Dissolution profile of Rivaroxaban Tablets, 10mg, 15mg & 20mg (RLD Vs Test) in office of generic drugs (OGD) media.
Strength 10 mg 15mg 20mg
Time (min) Reference Test Reference Test Reference Test
10 78 82 87 90 86 86
15 83 86 90 93 88 89
20 85 87 92 94 90 90
30 88 89 93 94 92 91
45 90 91 94 95 92 91

Figure 1. Comparison of dissolution profiles of Rivaroxaban Tablets, 10 mg (Test Vs RLD).

Figure 2. Comparison of dissolution profiles of Rivaroxaban Tablets, 15 mg (Test Vs RLD).

Figure 3. Comparison of dissolution profiles of Rivaroxaban Tablets, 20 mg (Test Vs RLD).