Claims:1. A process for the preparation of a highly pure crystalline dihydrate Form H2-2 of Apixaban essentially free of other crystalline forms, comprising:
(a) providing a solution of Apixaban in acetic acid;
(b) combining the solution obtained in step-(a) with ice or ice-cold water to cause crystallization; and
(c) collecting the highly pure crystalline dihydrate Form H2-2 of Apixaban essentially free of other crystalline forms obtained in step-(c);
wherein the crystalline dihydrate Form H2-2 of Apixaban essentially free of other crystalline forms obtained is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 5.87, 7.42, 16.0, 20.19, 23.57 and 25.22 ± 0.2 degrees substantially in accordance with Figure 1; an infra red (FT-IR) spectrum having main bands at about 3449, 3928, 3247, 3179, 1669, 1543, 1463, 1442, 1299, 1256, 1149, 1111, 1090, 1031, 1021, 1004, 981, 898, 758 and 703 ± 5 cm-1 substantially in accordance with Figure 2; and a Differential Scanning Calorimetric (DSC) thermogram having endothermic peaks at about 90°C, 167.10°C and 238.48°C substantially in accordance with Figure 3; and wherein the highly pure crystalline dihydrate Form H2-2 of Apixaban obtained has a chemical purity of greater than about 99.5% as measured by HPLC.
2. The process as claimed in claim 1, wherein the crystalline dihydrate Form H2-2 of Apixaban obtained has a chemical purity of greater than about 99.8%, and most specifically greater than about 99.9% as measured by HPLC; and wherein the highly pure crystalline Form H2-2 of Apixaban obtained has a D90 particle size [also known as “D(0.90) particle size”] of greater than or equal to about 90 microns, specifically about 200 microns to about 500 microns, and most specifically about 340 microns to about 380 microns.
3. The process as claimed in claim 1, wherein the amount of acetic acid employed in step-(a) is about 3 volumes to about 10 volumes with respect to the quantity of Apixaban used; wherein the solution in step-(a) is provided by dissolving Apixaban (crude or pure) in acetic acid at a temperature of about 60°C to about 80°C; wherein the solution obtained after complete dissolution of Apixaban is stirred at a temperature of about 60°C to about 80°C; wherein the solution obtained in step-(a) is optionally subjected to carbon treatment; wherein the combining of the solution with ice or ice-cold water in step-(b) is done in a suitable order including the solution of Apixaban is added to the ice or ice-cold water, or alternatively, the ice or ice-cold water is added to the solution; and wherein collection of the solid in step-(c) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
4. The process as claimed in claim 3, wherein the amount of acetic acid employed in step-(a) is about 5 volumes with respect to the quantity of Apixaban used; wherein the solution in step-(a) is provided by dissolving Apixaban (crude or pure) in acetic acid at a temperature of about 70°C to about 75°C; wherein the solution obtained after complete dissolution of Apixaban is stirred at a temperature of about 70°C to about 75°C; wherein the carbon treatment is carried out by stirring the solution with finely powdered carbon at a temperature of about 40°C to about 70°C; and wherein the combining of the solution with ice or ice-cold water in step-(b) is done by adding the solution of Apixaban slowly to the ice or ice-cold water.
5. A process for the preparation of a stable and highly pure crystalline Form N-1 of Apixaban essentially free of other crystalline forms, comprising:
(a) providing a solution of Apixaban in solvent or a mixture of solvents at temperature of above about 50ºC;
(b) optionally, adding water to the solution obtained in step-(a);
(c) cooling the solution obtained in step-(a) or step-(b) to cause crystallization; and
(d) collecting the highly pure crystalline Form N-1 of Apixaban essentially free of other crystalline forms;
wherein the crystalline anhydrous Form N-1 of Apixaban essentially free of other crystalline forms obtained by the process disclosed herein is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 10.09, 10.55, 12.35, 12.92, 18.52 and 27.0 ± 0.2 degrees substantially in accordance with Figure 4; an infra red (FT-IR) spectrum having main bands at about 3482, 3311, 1682, 1630, 1595, 1546, 1517, 1462, 1435, 1397, 1294, 1255, 1143, 974, 847, 814, 759 and 702 cm-1 ± 5 substantially in accordance with Figure 5; and a Differential Scanning Calorimetric (DSC) thermogram having a sharp endothermic peak at about 238.7°C substantially in accordance with Figure 6; and wherein the highly pure crystalline Form N-1 of Apixaban obtained has a chemical purity of greater than about 99.5% as measured by HPLC.
6. The process as claimed in claim 5, wherein the crystalline Form N-1 of Apixaban obtained has a chemical purity of greater than about 99.8%, and most specifically greater than about 99.9% as measured by HPLC; and wherein the highly pure crystalline Form N-1 of Apixaban obtained has a D90 particle size of less than or equal to about 100 microns, specifically about 30 microns to about 60 microns, and most specifically about 45 microns to about 55 microns.
7. The process as claimed in claim 5, wherein the solvent used in step-(a) is selected from the group consisting of methanol, N,N-dimethylformamide, and a mixture thereof; wherein the solution in step-(a) is provided by dissolving Apixaban (crude or pure) in the solvent at a temperature of about 50°C to the reflux temperature of the solvent used; wherein the amount of solvent or solvent mixture employed in step-(a) is about 3 volumes to about 35 volumes with respect to the quantity of Apixaban used; wherein the solution obtained after complete dissolution of Apixaban is stirred at a temperature of about 50°C to the reflux temperature of the solvent used; wherein the solution obtained in step-(a) is optionally subjected to carbon treatment; wherein the addition of water in step-(b) is carried out at a temperature of about 30°C to about 75°C; wherein the crystallization in step-(c) is accomplished by cooling the solution while stirring to a temperature of below about 40°C for at least 20 minutes; and wherein the collection of the precipitated solid in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
8. The process as claimed in claim 7, wherein the solution in step-(a) is provided by dissolving Apixaban (crude or pure) in the solvent at a temperature of about 60°C to about 75°C; wherein the amount of solvent or solvent mixture employed in step-(a) is about 5 volumes to about 30 volumes with respect to the quantity of Apixaban used; wherein the solution obtained after complete dissolution of Apixaban is stirred at a temperature of about 50°C to the reflux temperature of the solvent used; wherein the addition of water in step-(b) is carried out at a temperature of about 40°C to about 70°C; and wherein the crystallization in step-(c) is accomplished by cooling the solution while stirring at a temperature of about 25°C to about 35°C for about 30 minutes to about 1 hour.
9. A process for the preparation of a stable and highly pure crystalline anhydrous Form N-1 of Apixaban, comprising:
(a) providing a suspension of Apixaban in methanol at a temperature of below about 40°C;
(b) stirring the suspension formed in step-(a) at room temperature; and
(c) collecting the highly pure crystalline anhydrous Form N-1 of Apixaban essentially free of other crystalline forms.
10. A pharmaceutical composition comprising highly pure crystalline dihydrate Form H2-2 of Apixaban obtained by the processes as claimed in claim 1, and one or more pharmaceutically acceptable excipients.
11. A pharmaceutical composition comprising highly pure crystalline Form N-1 of Apixaban obtained by the processes as claimed in claim 5 or claim 9, and one or more pharmaceutically acceptable excipients.
12. A highly pure crystalline dihydrate Form H2-2 of Apixaban characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 5.87, 7.42, 16.0, 20.19, 23.57 and 25.22 ± 0.2 degrees substantially in accordance with Figure 1; an infra red (FT-IR) spectrum having main bands at about 3449, 3928, 3247, 3179, 1669, 1543, 1463, 1442, 1299, 1256, 1149, 1111, 1090, 1031, 1021, 1004, 981, 898, 758 and 703 ± 5 cm-1 substantially in accordance with Figure 2; and a Differential Scanning Calorimetric (DSC) thermogram having endothermic peaks at about 90°C, 167.10°C and 238.48°C substantially in accordance with Figure 3; and wherein the purity of the crystalline dihydrate Form H2-2 of Apixaban is about 99.8% to about 99.99% as measured by HPLC.
13. A highly pure crystalline anhydrous Form N-1 of Apixaban characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 10.09, 10.55, 12.35, 12.92, 18.52 and 27.0 ± 0.2 degrees substantially in accordance with Figure 4; an infra red (FT-IR) spectrum having main bands at about 3482, 3311, 1682, 1630, 1595, 1546, 1517, 1462, 1435, 1397, 1294, 1255, 1143, 974, 847, 814, 759 and 702 cm-1 ± 5 substantially in accordance with Figure 5; and a Differential Scanning Calorimetric (DSC) thermogram having a sharp endothermic peak at about 238.7°C substantially in accordance with Figure 6; and wherein the purity of the crystalline Form N-1 of Apixaban is about 99.8% to about 99.99% as measured by HPLC. , Description:FIELD OF THE INVENTION
The present invention relates to improved, commercially viable and consistently reproducible processes for the production of highly pure and stable crystalline forms of Apixaban (designated as Form N-1 and H2-2), which are free from other polymorphic forms.

BACKGROUND OF THE INVENTION
U.S. Patent No. 6,967,208 (hereinafter referred to as the ‘208 patent), assigned to Bristol-Myers Squibb Pharma, discloses a variety of lactam-containing compounds and derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds are anticoagulants which inhibit the coagulation factor Xa with increased selectivity. Among them, Apixaban, 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazole-[3,4-c]pyridine-3-carboxamide, acts as an inhibitor of clotting factor Xa and which is used as an agent for the prophylaxis and/or treatment of thromboembolic disorders. Apixaban is represented by the following structural formula 1:

Apixaban was approved by the FDA for use in United States as a factor Xa (FXa) inhibitor and it is sold by Bristol-Myers Squibb under the trade name Eliquis®. It is orally administered as tablets containing 2.5 mg and 5 mg of Apixaban.
The synthesis of Apixaban was first described in the US’208 patent. Various processes for the preparation of Apixaban, its intermediates, and related compounds are disclosed in U.S. Patent Nos. US 7,396,932 and US 6,919,451; U.S. Patent Application Publication No. US2014/058107; PCT Publication No. WO 2012/168364; Drugs of the Future 2008, 33(4), 293-301; and Synthetic Communications 43, 72-79, 2013.
The synthetic route of Apixaban as described in the US’208 patent is shown in the below scheme-1:

Apixaban is known to exhibit polymorphism. Various crystalline forms, solvate forms and processes for their preparation are apparently disclosed in U.S. Patent Nos. US 7,396,932, US 8,884,016, US 8,969,561, US 9,920,051, U.S. Publication Nos. US 2007/0203178, US 2015/018386, PCT Publication Nos. WO 2013/119328, WO 2013/164839 A2 and IPCOM000216217D.
U.S. Patent No. 7,396,932 (hereinafter referred to as the US’932 patent), assigned to Bristol-Myers Squibb Company, discloses two crystalline forms of Apixaban designated as anhydrous Form N-1 and dihydrate Form H2-2, and processes for the preparation thereof. As per Example 6 of US’932 patent, crystalline Form N-1 is prepared by amidation reaction of Apixaban ethyl ester using anhydrous ammonia in propylene glycol and performing the reaction for at least 12 hours at 90ºC to produce crystalline anhydrous Form N-1.
As per Example 7 of the US’932 patent, Apixaban crystalline dihydrate Form H2-2 is prepared by dissolving Apixaban ethyl ester in N,N-dimethylformamide and formamide followed by the addition of trimethylorthoformate, trifluoroacetic acid. To the resulting mass, Sodium methoxide solution in methanol was added and stirred for 2 hours. After completion of reaction, the resulting mass was subjected to usual work-up procedure to produce crystalline dihydrate Form H2-2.
The US’932 patent further characterizes the crystalline Form N-1 and Form H2-2 by XRPD 2-theta peaks and unit cell parameters. As per the US’932 patent, Crystalline Form N-1 is characterized by X-ray powder diffraction peak positions at about 10.0, 10.6, 12.3, 12.9, 18.5 and 27.1 ± 0.1 degrees 2-theta. Crystalline Form H2-2 is characterized by X-ray powder diffraction peak positions at about 5.8, 7.4, 16.0, 20.2, 23.5 and 25.2 ± 0.1 degrees 2-theta.
Furthermore, crystalline Form N-1 is characterized by the following Unit cell data: T (°C) = +22, Cell dimensions: a(A°) = 10.233(1), b(A°) = 13.852(1), c(A°) = 15.806(1), a = 90°, ß = 92.98° (1), ? = 90°, V(A°3) = 2237.4(5), Z’ = 1, Vm (Volume) = 559, SG (Spatial Group) = P21/n, Dcalc = 1.364, R = 0.05. Crystalline Form H2-2 is characterized by the following Unit cell data: Solvate = Dihydrate, T (°C) = +22, a(A°) = 6.193(1), b(A°) = 30.523(1), c(A°) = 13.046(1), a = 90°, ß = 90.95° (1), ? = 90°, V(A°3) = 2466.0(5), Z’ (No. of molecules per asymmetric unit) = 1, Vm (Volume) = 617, SG (Spatial Group) = P21/n, Dcalc = 1.335, R = 0.09, Sol. sites = 2 H2O.
U.S. Patent No. 8,884,016 (Assigned to Dipharma Francis, hereinafter referred to as the US’016 patent) discloses Form a of Apixaban having water content between about 3 and 7%, which is designated as sesquihydrate. Apixaban Form a is characterized by having a powder X-ray diffraction (XRPD) pattern having peaks expressed as 2-theta angle positions at 6.0, 7.1, 11.0, 11.9, 12.9, 13.6, 15.1, 16.1, 17.6, 19.1, 20.3, 21.6, 22.7, 24.5, 26.0, 26.7, 27.2, 28.8 and 30.1° ± 0.2 degrees 2-theta; Differential Scanning Calorimetry (DSC) having main thermal events at about 60°C-110°C (endotherm), 145°C-155°C (endotherm), 175°C-185°C (exotherm) and 234°C (melting endotherm), and D50 value of between about 25 and 250 µm.
U.S. Patent No. 9,920,051 (Assigned to Fabbrica Italiana Sintetici, hereinafter referred to as the US’051 patent), teaches that, according to the regulatory information provided by the originator, Apixaban Form N-1 is the form currently on the market, so that, with the aim of providing an active pharmaceutical ingredients which provides exactly the same physical-chemical and therapeutical properties of that the originator for the generic market, it is important to find a method for the preparation of Apixaban which provides the polymorphic Form N-1.
U.S. Publication No. US20070203178A1 (Applicant: Bristol Myers Squibb, hereinafter referred to as the US’178 publication) teaches crystalline dimethyl formamide solvate (DMF-5) and formamide solvate (FA-2) of Apixaban and processes of their preparation. The crystalline DMF-5 solvate is characterized by having a powder X-ray diffraction (XRPD) pattern having peaks expressed as 2-theta angle positions at about 5.6±0.1, 7.1±0.1, 8.6±0.1, 14.3±0.1, 20.3±0.1, and 24.7±0.1 degrees 2-theta and crystalline FA-2 solvate is characterized by having a powder X-ray diffraction (XRPD) pattern having peaks expressed as 2-theta angle positions at about 8.9±0.1, 11.7±0.1, 15.8±0.1, 16.5±0.1, and 25.1±0.1 degrees 2-theta. Further, crystalline DMF-5 solvate is characterized by the following Unit cell data: Cell dimensions: a = 6.307(1) Å, b = 31.385(6) Å, c = 13.635(3) Å, a = 90°, ß = 90.15(3)°, ? = 90°, Space group: P21/n, Molecules/asymmetric unit =1. Crystalline Form FA-2 solvate is characterized by the following Unit cell data: Cell dimensions: a = 6.304(1) Å, b = 30.164(3) Å, c = 12.960(3) Å, a = 90°, ß = 92.17(3)°, ? = 90°, Space group P21/n, Molecules/asymmetric unit = 1.
U.S. Publication No. US2015/018386 (hereinafter referred to as the US’386 publication) discloses amorphous form of Apixaban and process for preparation and pharmaceutical composition thereof.
PCT Publication No.WO2013/119328A1 (Applicant: Assia Chemical Industries, hereinafter referred to as the WO’328 publication) discloses three crystalline forms of Apixaban namely Form I, Form II and Form III solid state forms, processes for preparation and pharmaceutical compositions thereof.
According to the WO’328A1 publication the crystalline Form I is characterized by a powder X-ray diffraction spectrum having main peaks expressed as 2-theta angle positions at about 5.5, 11.0, 15.9, 16.3, 20.3, 21.2, 22.6, 24.6, 25.1 and 31.2 ± 0.2 degrees. The crystalline Form II is characterized by a powder X-ray diffraction spectrum having main peaks expressed as 2-theta angle positions at about 7.6, 12.7, 15.2, 16.3, 16.9, 18.1, 19.6, 20.1, 21.5 and 22.9 ± 0.2 degrees. The crystalline Form III is characterized by a powder X-ray diffraction spectrum having main peaks expressed as 2-theta angle positions at about 7.8, 9.5, 10.9, 11.7, 15.6, 18.0, 18.8, 19.5, 20.6 and 22.2 ± 0.2 degrees.
The Journal article IPCOM000216217D teaches four solid state forms of Apixaban namely Form I, Form II, Form III and Form IV.
According to the IPCOM’217 article, the crystalline Form I is characterized by a powder X-ray diffraction spectrum having main peaks expressed as 2-theta angle positions at about 5.5, 8.5, 10.5, 11.0, 12.7, 14.1, 15.5, 15.9, 16.2, 16.9, 17.7, 18.9, 19.4, 19.7, 20.3, 21.2, 22.0, 22.4, 23.0, 23.9, 24.5, 25.0, 25.7, 26.8, 27.5, 28.1, 28.4, 29.6, 30.1, 30.6, 31.2, 31.7, 32.1, 33.1, 34.0, 36.3 and 37.0 ± 0.2 degrees. The crystalline Form II is characterized by a powder X-ray diffraction spectrum having main peaks expressed as 2-theta angle positions at about 6.5, 7.6, 8.1, 10.1, 11.7, 12.7, 13.7, 14.3, 14.6, 15.2, 15.6, 16.3, 16.9, 17.2, 17.9, 18.2, 19.2, 19.5, 20.1, 20.8, 21.5, 22.1, 22.9, 23.9, 24.9, 25.3, 26.0, 26.7, 26.9, 27.3, 27.8, 28.7, 29.1, 29.3, 29.5, 30.4, 30.7, 31.3, 32.5, 33.0, 36.9 and 38.1 ± 0.2 degrees. The crystalline Form III is characterized by a powder X-ray diffraction spectrum having main peaks expressed as 2-theta angle positions at about 7.8, 8.6, 9.5, 10.9, 11.4, 11.7, 12.9, 13.9, 15.6, 16.0, 16.6, 17.2, 18.0, 18.8, 19.5, 20.5, 21.0, 22.2 and 23.1 ± 0.2 degrees. The crystalline Form IV is characterized by a powder X-ray diffraction spectrum having main peaks expressed as 2-theta angle positions at about 7.8, 8.6, 9.5, 10.9, 11.4, 11.7, 12.9, 13.9, 15.6, 16.0, 16.6, 17.2, 18.0, 18.8, 19.5, 20.5, 21.0, 22.2 and 23.1 ± 0.2 degrees.
However, the processes described in the aforementioned prior art have failed to consistently produce the highly pure crystalline Form N-1 and Form H2-2 of Apixaban essentially free of other polymorphic forms.
A need still remains for simple, commercially viable, consistently reproducible and industrially advantageous processes for the preparation of highly pure crystalline Form N-1 and Form H2-2 of Apixaban essentially free of other crystalline forms.

SUMMARY OF THE INVENTION
Extensive research and experimentation has been carried out by the present inventors to develop efficient, consistently reproducible and commercially viable processes for production of highly pure crystalline Form N-1 of Apixaban (anhydrous) and Form H2-2 of Apixaban (dihydrate) essentially free of other crystalline forms.
As a result, the present inventors have surprisingly and unexpectedly found that highly pure crystalline dihydrate Form H2-2 of Apixaban essentially free of other crystalline forms, can be obtained by an efficient, consistently reproducible and commercially viable process comprising providing a solution of Apixaban in acetic acid at a temperature of about 70°C, adding ice-cold water to the solution, cooling the solution to below about room temperature to cause crystallization, and then collecting the highly pure crystalline Form H2-2 (dihydrate) of Apixaban essentially free of other crystalline forms.
The present inventors have surprisingly and unexpectedly found that highly pure crystalline anhydrous Form N-1 of Apixaban essentially free of other crystalline forms, can be obtained by an efficient, consistently reproducible and commercially viable process comprising providing a solution of Apixaban in a solvent or mixture of solvents; optionally adding water to the resulting solution, cooling the solution to below about room temperature to cause crystallization; and then recovering the highly pure crystalline Form N-1 (anhydrous) of Apixaban essentially free of other crystalline forms.
Further, the present inventors have surprisingly and unexpectedly found that highly pure crystalline anhydrous Form N-1 of Apixaban essentially free of other crystalline forms, can also be obtained by another process comprising providing a suspension of Apixaban in solvent, stirring the suspension at a temperature of about 40°C; collecting the highly pure crystalline Form N-1 of Apixaban essentially free of other crystalline forms.
Provided herein are simple, cost effective and consistently reproducible processes for the preparation of highly pure crystalline Form N-1 of Apixaban and crystalline Form H2-2 of Apixaban essentially free of other crystalline forms.
Surprisingly, the processes disclosed herein advantageously produce the crystalline Form N-1 of Apixaban and crystalline Form H2-2 of Apixaban with high purity (greater than about 99.5% as measured by HPLC).
In another aspect, provided herein is a pharmaceutical composition comprise highly pure crystalline Form N-1 of Apixaban essentially free from other crystalline forms made by the process disclosed herein, and one or more pharmaceutically acceptable excipients.
In another aspect, provided herein is a pharmaceutical composition comprise highly pure crystalline Form H2-2 of Apixaban essentially free from other crystalline forms made by the process disclosed herein, and one or more pharmaceutically acceptable excipients.
In still further aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline anhydrous Form N-1 of Apixaban essentially free of other crystalline forms made by the process disclosed herein with one or more pharmaceutically acceptable excipients.
In still further aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form H2-2 of Apixaban essentially free of other crystalline forms made by the process disclosed herein with one or more pharmaceutically acceptable excipients.
In another aspect, the highly pure crystalline Form H2-2 of Apixaban essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size [also known as “D(0.90) particle size”] of greater than or equal to about 90 microns, specifically about 200 microns to about 500 microns, and most specifically about 340 microns to about 380 microns.
In another aspect, the highly pure crystalline Form H2-2 of Apixaban essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D50 particle size [also known as “D(0.50) particle size”] of greater than or equal to about 20 microns, specifically about 25 microns to about 50 microns, and most specifically about 30 microns to about 40 microns.
In another aspect, the highly pure crystalline Form N-1 of Apixaban essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size of Less than or equal to about 100 microns, specifically about 30 microns to about 60 microns, and most specifically about 45 microns to about 55 microns.
In another aspect, the highly pure crystalline Form N-1 of Apixaban essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D50 particle size of Less than or equal to about 20 microns, specifically about 5 microns to about 15 microns, and most specifically about 12 microns to about 14 microns.
In one embodiment, the crystalline Forms of Apixaban obtained by the processes disclosed herein are essentially free from other solid state forms of Apixaban detectable by the spectral methods typically used, e.g., Powder X-ray diffraction.
The process disclosed herein above advantageously produces the crystalline forms of Apixaban (Form N-1 and Form H2-2) with high chemical and polymorphic purity.
The highly pure crystalline forms of Apixaban (Form N-1 and Form H2-2) obtained by the processes disclosed herein have a chemical purity of greater than about 99.3%, specifically greater than about 99.5%, and most specifically greater than about 99.9% as measured by HPLC.
Unless otherwise specified, the term “crude or impure form of Apixaban” refers to any form of Apixaban having purity less than or equal to about 99.3% as measured by HPLC.
The processes for the preparation of crystalline forms of Apixaban (Form N-1 and Form H2-2) described herein have the following advantages over the processes described in prior art:
i) the processes produce the product with high yield and purity;
ii) the processes avoid the use of expensive and highly hazardous solvents like propylene glycol, trimethyl orthoformate and trifluoroacetic acid;
iii) the processes do not require the use of tedious and cumbersome procedures like desolvation by drying the solvated forms at higher temperatures under vacuum for prolonged time periods; and
(iv) the processes involve easy work-up methods and simple isolation/crystallization processes, and there is a reduction in chemical waste.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of Form H2-2
of Apixaban.
Figure 2 is a characteristic infra-red (IR) spectrum of Form H2-2 of Apixaban.
Figure 3 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of
Form H2-2 of Apixaban.
Figure 4 is a characteristic powder X-ray diffraction (XRPD) pattern of Form N-1 of
Apixaban.
Figure 5 is a characteristic infra-red (IR) spectrum of Form N-1 of Apixaban.
Figure 6 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of Form N-1 of Apixaban.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a process for the preparation of a stable and highly pure crystalline dihydrate Form H2-2 of Apixaban essentially free of other crystalline forms, comprising:
a) providing a solution of Apixaban in acetic acid;
b) combining the solution obtained in step-(a) with ice or ice-cold water to cause crystallization; and
c) collecting the highly pure crystalline dihydrate Form H2-2 of Apixaban obtained in step-(c).
The present inventors have found that the use of acetic acid as a solvent is critical in order to consistently produce the highly pure crystalline dihydrate Form H2-2 of Apixaban essentially free of other crystalline forms.
Usually, the amount of acetic acid employed in step-(a) is about 3 volumes to about 10 volumes, specifically about 5 volumes, with respect to the quantity of Apixaban used.
In one embodiment, the solution in step-(a) is provided by dissolving Apixaban (crude or pure) in acetic acid at a temperature of about 60°C to about 80°C, and preferably at a temperature of about 70°C to about 75°C, or obtaining an existing solution from a previous processing step.
After complete dissolution of Apixaban, the resulting solution is stirred at a temperature of about 60°C to about 80°C, and preferably at a temperature of about 70°C to about 75°C, for at least 10 minutes, and specifically for about 20 minutes to about 30 minutes.
The solution obtained in step-(a) is optionally subjected to carbon treatment. The carbon treatment is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon at a temperature of about 40°C to about 70°C for at least 5 minutes, specifically at a temperature of about 45°C to about 50°C; and filtering the resulting mixture through charcoal bed to obtain a filtrate containing Apixaban by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
Combining of the solution with ice or ice-cold water in step-(b) is done in a suitable order, for example, the solution of Apixaban is added to the ice or ice-cold water, or alternatively, the ice or ice-cold water is added to the solution. In a preferred embodiment, the solution of Apixaban is added slowly to the ice or ice-cold water. The addition is, for example, carried out slowly, drop wise or in one portion or in more than one portion. The addition is specifically carried out under stirring at a temperature of below about 45°C, and most specifically at about 20°C to about 30°C, to cause crystallization. After completion of the addition process, the resulting mass is stirred at a temperature of below 35°C for at least 10 minutes and specifically at a temperature of about 25°C to about 30°C for about 20 minutes to about 1 hour.
The collection of the solid in step-(c) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
In one embodiment, the highly pure crystalline dihydrate Form H2-2 of Apixaban, obtained by the process described herein, remains in the same crystalline form and is found to be stable, when stored at a temperature of about 25±2°C and at a relative humidity of about 55±5%, for a period of at least 2 years.
In one embodiment, the crystalline dihydrate Form H2-2 of Apixaban essentially free of other crystalline forms obtained by the process disclosed herein is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 5.87, 7.42, 16.0, 20.19, 23.57 and 25.22 ± 0.2 degrees substantially in accordance with Figure 1; an infra red (FT-IR) spectrum having main bands at about 3449, 3928, 3247, 3179, 1669, 1543, 1463, 1442, 1299, 1256, 1149, 1111, 1090, 1031, 1021, 1004, 981, 898, 758 and 703 ± 5 cm-1 substantially in accordance with Figure 2; and a Differential Scanning Calorimetric (DSC) thermogram having endothermic peaks at about 90°C, 167.10°C and 238.48°C substantially in accordance with Figure 3.
In another embodiment, the highly pure Form H2-2 of Apixaban obtained by the process disclosed herein is further characterized by an X-ray powder diffraction pattern having additional 2-theta peaks at about 11.67, 13.53, 13.90, 16.26, 16.85, 17.49, 17.93, 18.78, 19.83, 20.49, 20.79, 21.30, 21.78, 22.25, 24.84, 25.90, 26.46, 26.70, 27.85, 29.29, 30.12, 30.41, 30.89, 31.29, 31.80, 32.38, 35.53, and 38.22 ± 0.2 degrees substantially in accordance with Figure 1; an infra red (FT-IR) spectrum having main bands at about 3042, 2943, 2898, 2841, 1516, 1485, 1400, 1374, 1336, 965, 951, 937, 833, 816, 798, 790, 719, and 666 ± 5 cm-1 substantially in accordance with Figure 2.
The highly pure crystalline dihydrate Form H2-2 of Apixaban obtained by the process disclosed herein has a chemical purity of greater than about 99.5%, specifically greater than about 99.8%, and most specifically greater than about 99.9% as measured by HPLC.
According to another aspect, there is provided a highly pure crystalline dihydrate Form H2-2 of Apixaban characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 5.87, 7.42, 16.0, 20.19, 23.57 and 25.22 ± 0.2 degrees substantially in accordance with Figure 1; an infra red (FT-IR) spectrum having main bands at about 3449, 3928, 3247, 3179, 1669, 1543, 1463, 1442, 1299, 1256, 1149, 1111, 1090, 1031, 1021, 1004, 981, 898, 758 and 703 ± 5 cm-1 substantially in accordance with Figure 2; and a Differential Scanning Calorimetric (DSC) thermogram having endothermic peaks at about 90°C, 167.10°C and 238.48°C substantially in accordance with Figure 3; and wherein the purity of the crystalline dihydrate Form H2-2 of Apixaban is about 99.8% to about 99.99% as measured by HPLC.
Unless otherwise specified, the term “crude or impure form of Apixaban” refers to any form of Apixaban having purity less than about 99.5% as measured by HPLC.
As used herein, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
As used herein, the term “room temperature” refers to a temperature of about 20°C to about 35°C, and specifically to a temperature of about 25°C to about 30°C.
According to another aspect, there is provided a process for the preparation of a stable and highly pure crystalline Form N-1 of Apixaban essentially free of other crystalline forms, comprising:
a) providing a solution of Apixaban in solvent or a mixture of solvents at temperature of above about 50ºC, wherein the solvent is selected from the group consisting of an alcohol, a polar aprotic solvent, and mixtures thereof;
b) optionally, adding water to the solution obtained in step-(a);
c) cooling the solution obtained in step-(a) or step-(b) to cause crystallization; and
d) collecting the highly pure crystalline Form N-1 of Apixaban essentially free of other crystalline forms.
The solvent used in step-(a) is selected from the group consisting of methanol, N,N-dimethylformamide, and a mixture thereof.
The present inventors have surprisingly and unexpectedly found that the use of crystallizing in solvents like methanol, N,N-dimethylformamide and mixtures thereof consistently produces the highly pure crystalline Form N-1 of Apixaban essentially free of other crystalline forms.
In one embodiment, the solution in step-(a) is provided by dissolving Apixaban (crude or pure) in the solvent at a temperature of about 50°C to the reflux temperature of the solvent used, and preferably at a temperature of about 60°C to about 75°C, or obtaining an existing solution from a previous processing step.
Usually, the amount of solvent or solvent mixture employed in step-(a) is about 3 volumes to about 35 volumes, specifically about 5 volumes to about 30 volumes, with respect to the quantity of Apixaban used.
After complete dissolution of Apixaban, the resulting solution is stirred at a temperature of about 50°C to the reflux temperature of the solvent used, and preferably at a temperature of about 60°C to about 75°C, for at least 10 minutes, and specifically for about 20 minutes to about 30 minutes.
The solution obtained in step-(a) is optionally subjected to carbon treatment. The carbon treatment is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon at a temperature of about 40°C to about 70°C for at least 5 minutes, specifically at a temperature of about 45°C to about 50°C; and filtering the resulting mixture through charcoal bed to obtain a filtrate containing Apixaban by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
In one embodiment, the addition of water in step-(b) is carried out at a temperature of about 30°C to about 75°C, and preferably at a temperature of about 40°C to about 70°C.
In one embodiment, the crystallization in step-(c) is accomplished by cooling the solution while stirring to a temperature of below about 40°C for at least 20 minutes, and more specifically at a temperature of about 25°C to about 35°C for about 30 minutes to about 1 hour.
The collection of the precipitated solid in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
According to another aspect, there is provided a process for the preparation of a stable and highly pure crystalline anhydrous Form N-1 of Apixaban, comprising:
a) providing a suspension of Apixaban in methanol at a temperature of below about 40°C;
b) stirring the suspension formed in step-(a) at room temperature; and
c) collecting the highly pure crystalline anhydrous Form N-1 of Apixaban essentially free of other crystalline forms.
Usually, the amount of methanol employed in step-(a) is about 3 volumes to about 10 volumes, specifically about 5 volumes, with respect to the quantity of Apixaban used.
In one embodiment, the suspension in step-(b) is stirred at a temperature of about 20°C to about 40°C for at least 45 minutes; more specifically at a temperature of about 25°C to about 35°C for about 1 hour to about 2 hours.
The collection of the solid in step-(c) is carried out by the methods such as filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
In one embodiment, the crystalline anhydrous Form N-1 of Apixaban essentially free of other crystalline forms obtained by the process disclosed herein is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 10.09, 10.55, 12.35, 12.92, 18.52 and 27.0 ± 0.2 degrees substantially in accordance with Figure 4; an infra red (FT-IR) spectrum having main bands at about 3482, 3311, 1682, 1630, 1595, 1546, 1517, 1462, 1435, 1397, 1294, 1255, 1143, 974, 847, 814, 759 and 702 cm-1 ± 5 substantially in accordance with Figure 5; and a Differential Scanning Calorimetric (DSC) thermogram having a sharp endothermic peak at about 238.7°C substantially in accordance with Figure 6.
In another embodiment, the highly pure crystalline anhydrous Form N-1 of Apixaban obtained by the process disclosed herein is further characterized by an X-ray powder diffraction pattern having additional 2-theta peaks at about 8.53, 11.24, 13.99, 15.24, 16.31, 17.08, 17.38, 18.86, 19.64, 21.20, 21.63, 22.31, 24.83, 25.42, 27.78, 28.77, 29.22, 30.00, 30.74, 32.78 and 35.16 ± 0.2 degrees substantially in accordance with Figure 4; an infra red (FT-IR) spectrum having main bands at about 3260, 3170, 2974, 1483, 1375, 1345, 1223, 1190, 1162, 1108, 1080, 1037, 1002, 941, 894, 814, 793, and 668 ± 5 cm-1 in accordance with Figure 5.
According to another aspect, there is provided a highly pure crystalline anhydrous Form N-1 of Apixaban characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 10.09, 10.55, 12.35, 12.92, 18.52 and 27.0 ± 0.2 degrees substantially in accordance with Figure 4; an infra red (FT-IR) spectrum having main bands at about 3482, 3311, 1682, 1630, 1595, 1546, 1517, 1462, 1435, 1397, 1294, 1255, 1143, 974, 847, 814, 759 and 702 cm-1 ± 5 substantially in accordance with Figure 5; and a Differential Scanning Calorimetric (DSC) thermogram having a sharp endothermic peak at about 238.7°C substantially in accordance with Figure 6; and wherein the purity of the crystalline Form N-1 of Apixaban is about 99.8% to about 99.99% as measured by HPLC.
The highly pure crystalline forms of Apixaban (Form H2-2 and Form N-1) obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rotavapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
Preferably, the drying is carried out at temperatures such as about 25°C to about 80°C and most preferably at about 25°C to about 75°C. In one embodiment, the drying is carried out for any desired time period that achieves the desired result, preferably for a period of about 1 hour to 20 hours, and more preferably about 14 to 18 hours. Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.
The highly pure crystalline Form N-1 of Apixaban obtained by the process disclosed herein has a chemical purity of greater than about 99.5%, specifically greater than about 99.8%, and most specifically greater than about 99.9% as measured by HPLC.
Unless otherwise specified, the crude or pure Apixaban as used herein as starting material can be obtained by the processes known in the prior art, for example, as per the processes described in the U.S. Patent No. 6,967,208 or PCT Publication No. WO2015/177801A1.
The highly pure crystalline dihydrate Form H2-2 and crystalline anhydrous Form N-1 of Apixaban obtained by the processes disclosed herein are free from other crystalline forms, which have very good flow properties and is consistently reproducible, and is found to be more stable. The crystalline dihydrate Form H2-2 and crystalline anhydrous Form N-1 of Apixaban obtained by the processes disclosed herein exhibit properties making it suitable for formulating Apixaban.
Further encompassed herein is the use of the highly pure crystalline dihydrate Form H2-2 and crystalline anhydrous Form N-1 of Apixaban obtained by the processes disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
A specific pharmaceutical composition of highly pure crystalline dihydrate Form H2-2 or crystalline anhydrous Form N-1 of Apixaban obtained by the processes disclosed herein is selected from a solid dosage form and an oral suspension.
In one embodiment, the highly pure crystalline Form H2-2 of Apixaban essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size [also known as “D(0.90) particle size”] of greater than or equal to about 90 microns, specifically about 200 microns to about 500 microns, and most specifically about 340 microns to about 380 microns.
In another embodiment, the highly pure crystalline Form H2-2 of Apixaban essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D50 particle size [also known as “D(0.50) particle size”] of greater than or equal to about 20 microns, specifically about 25 microns to about 50 microns, and most specifically about 30 microns to about 40 microns.
In one embodiment, the highly pure crystalline Form N-1 of Apixaban essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 100 microns, specifically about 30 microns to about 60 microns, and most specifically about 45 microns to about 55 microns.
In another embodiment, the highly pure crystalline Form N-1 of Apixaban essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D50 particle size of Less than or equal to about 20 microns, specifically about 5 microns to about 15 microns, and most specifically about 12 microns to about 14 microns.
In another embodiment, the particle sizes of the highly pure crystalline dihydrate Form H2-2 and crystalline anhydrous Form N-1 of Apixaban obtained by the processes disclosed herein are accomplished by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.
The term “micronization” used herein means a process or method by which the size of a population of particles is reduced.
As used herein, the term “micron” or “µm” both are equivalent and refer to “micrometer” which is 1x10–6 meter.
As used herein, “crystalline particles” means any combination of single crystals, aggregates and agglomerates.
According to another aspect, there is provided a pharmaceutical composition comprising highly pure crystalline dihydrate Form H2-2 of Apixaban obtained by the processes disclosed herein and one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided pharmaceutical composition comprising highly pure crystalline anhydrous Form N-1 of Apixaban obtained by the processes disclosed herein and one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline dihydrate Form H2-2 of Apixaban obtained by the processes disclosed herein, with one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline anhydrous Form N-1 of Apixaban obtained by the processes disclosed herein, with one or more pharmaceutically acceptable excipients.
Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of highly pure crystalline dihydrate Form H2-2 or crystalline anhydrous Form N-1 of Apixaban obtained by the processes disclosed herein. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, elixir, aerosol, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral and parenteral routes or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, lozenges, elixirs and the like.
The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinbelow.
Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

INSTRUMENTAL DETAILS:
X-Ray Powder Diffraction (P-XRD):
The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper-Ka radiation). Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 0.4 seconds. The sample was simply placed on the sample holder. The instrument is operated at a voltage 40 KV and current 35 mA.

Infra-Red Spectroscopy (FT-IR):
FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the production of the KBr compacts approximately 2 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm-1 to 650 cm-1.
Differential Scanning Calorimetry (DSC):
Differential Scanning Calorimetry (DSC) measurements were performed with a Differential Scanning Calorimeter (DSC Q200, Q Series Version-2.7.0.380, TA Instruments-Waters LLC) equilibrated at 50°C and Ramp at a scan rate of 10°C per minute to 250°C.

HPLC Method for measuring Chemical Purity:
The chemical purity was measured by HPLC system with UV detector or its equivalent under the following conditions: Column = Unison UK C18, 250 mm x 4.6 mm, 3µm; Detector wavelength = 220 nm; Flow Rate = 1.2 ml/minute; Injection volume = 10 µL; Oven temperature = 30°C; Run time = 70 minutes; Diluent = Methanol; Elution = Gradient; and Sample Concentration: 1.0 mg/ml.
Mobile Phase-A: A mixture of buffer and Acetonitrile 90:10 (v/v)
Mobile Phase-B: A mixture of buffer and Acetonitrile 17:83 (v/v)

The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.
EXAMPLES
Example 1
Preparation of pure crystalline dihydrate Form H2-2 of Apixaban
Acetic acid (125 ml) was added to crude Apixaban (25 g, Purity by HPLC: 99.2%) at 25-30ºC, the resulting suspension was heated to 70-75ºC to form a clear solution, and then stirred for 10 minutes at the same temperature. The resulting solution was slowly poured into ice cold water (625 ml). The resulting mass was cooled to room temperature (25-30ºC), followed by stirring the mass for 30 minutes at the same temperature. The separated solid was filtered, washed the solid with chilled water (100 ml x 2) and then dried the material at room temperature to produce 24.5 g of crystalline Form H2-2 of Apixaban. [Purity by HPLC: 99.9%; Particle Size Data: D90 = 363.05 µm and D50 = 36.39 µm].

Example 2
Preparation of pure crystalline dihydrate Form H2-2 of Apixaban
Acetic acid (125 ml) was added to crude Apixaban (25 g, Purity by HPLC: 99.2%) at 25-30ºC, the resulting suspension was heated to 70-75ºC to form a clear solution, and then stirred for 10 minutes at the same temperature. The resulting mass was poured into ice (625 g), followed by stirring the mass for 30 minutes at the same temperature. The resulting mass was cooled to room temperature (25-30ºC), followed by stirring for 30 minutes at the same temperature. The separated solid was filtered, washed the solid with chilled water (100 ml x 2) and then dried the material at room temperature to produce 24.6 g of crystalline Form H2-2 of Apixaban. (Purity by HPLC: 99.85%).

Example 3
Preparation of pure crystalline anhydrous Form N-1 of Apixaban
Methanol (1000 ml) was added to crude Apixaban (200 g, Purity by HPLC: 99.2%) at 25-30ºC and the resulting suspension was stirred at room temperature for 1 to 2 hours. The separated solid was filtered, washed the solid with methanol (50 ml x 2) and then dried the material at room temperature overnight, which was further dried in oven at 70-75ºC for 24 hours to produce 178 g of crystalline Form N-1 of Apixaban. (Purity by HPLC: 99.8%).

Example 4
Preparation of pure crystalline anhydrous Form N-1 of Apixaban
Methanol (1000 ml) was added to crude Apixaban (200 g, Purity by HPLC: 99.2%) at 25-30ºC and the resulting suspension was heated to reflux temperature and then stirred for 30 minutes at the same temperature to form a clear solution. The resulting solution was cooled to room temperature (25-30ºC), followed by stirring the mass for 30 minutes at the same temperature. The solid separated was filtered, washed the solid with chilled methanol (10 ml) and then dried the material at 70-75ºC for 24 hours to produce 172 g of crystalline Form N-1 of Apixaban. [Purity by HPLC: 99.9%; Particle Size Data: D90 = 51.565 µm and D50 = 13.285 µm].

Example 5
Preparation of pure crystalline anhydrous Form N-1 of Apixaban
A mixture (7 : 3) of methanol and dimethylformamide (260 ml) was added to crude Apixaban (10 g, Purity by HPLC: 99.2%) at 25-30ºC, the resulting suspension was heated to 70-75ºC and then stirred for 10-15 minutes at the same temperature to form a clear solution. The resulting solution was cooled to room temperature, followed by stirring the mass for 30 minutes at the same temperature. The separated solid was filtered, washed the solid with a mixture (7:3) of methanol and dimethylformamide (10 ml) and then dried the material at room temperature overnight, which was further dried in oven at 70-75ºC for 24-48 hours to produce 7.6 g of crystalline Form N-1 of Apixaban. [Purity by HPLC: 99.8%].

Example 6
Preparation of pure crystalline anhydrous Form N-1 of Apixaban
Dimethylformamide (80 ml) was added to crude Apixaban (10 g, Purity by HPLC: 99.2%) at 25-30ºC, the resulting suspension was heated to 70-75ºC and then stirred for 20-30 minutes at the same temperature to form a clear solution. To the resulting solution, water (120 ml) was added slowly at 70-75ºC and then stirred for 20-30 minutes at the same temperature. The resulting mass was cooled to room temperature (25-30ºC), followed by stirring the mass for 30 minutes at the same temperature. The separated solid was filtered, washed the solid with water (20 ml x 2) and then dried the material at room temperature overnight, which was further dried at 70-75ºC for 24-48 hours to produce 8.0 g of crystalline Form N-1 of Apixaban. (Purity by HPLC: 99.88%).
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term “pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for human pharmaceutical use.
The term “pharmaceutical composition” is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, and pharmaceutically acceptable excipients.
The term “therapeutically effective amount” as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
The term “delivering” as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host, e.g., human, animal, etc.
The term “buffering agent” as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other such materials known to those of ordinary skill in the art.
The term “sweetening agent” as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.

The term “binders” as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.
The term “diluents” or “filler” as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “glidant” as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “lubricant” as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “disintegrant” as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “wetting agent” as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).
All ranges disclosed herein are inclusive and combinable. While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.