DESC:FIELD OF THE INVENTION:
The present invention relates to novel process for the preparation of crystalline polymorphic Form H3 of Apixaban.
BACKGROUND OF THE INVENTION:
Apixaban, an anti-coagulant for the treatment of venous thromboembolic events and the prevention of strokes in people having atrial fibrillation and sold under the tradename Eliquis, is an oral drug. It is a direct factor Xa inhibitor.
Apixaban was approved in Europe in 2012. It was approved in the US in 2014 for treatment and secondary prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE). It was developed in a joint venture by Pfizer and Bristol-Myers Squibb.
Apixaban is used to lower the risk of stroke and embolism in people with non-valvular atrial fibrillation, deep vein thrombosis (DVT) prevention. DVTs may lead to pulmonary embolism (PE) in knee or hip replacement surgery patients. Apixaban is used in treatment of both DVT and PE to reduce the risk of recurring DVT and PE after initial therapy.
Apixaban is recommended by the National Institute for Health and Clinical Excellence for the prevention of stroke and systemic embolism in people with non-valvular atrial fibrillation and at least one of the following risk factors: prior stroke or transient ischemic attack, age 75 years or older, diabetes mellitus, or symptomatic heart failure.
Apixaban and other newer anti-coagulants (Dabigatran, Edoxaban and Apixaban) appear equally effective as Warfarin in preventing non-hemorrhagic stroke in people with atrial fibrillation and are associated with lower risk of intracranial bleeding.
Only Apixaban can be used in patients with severely decreased renal function and those on hemodialysis. The FDA-approved prescription information states that full dose Apixaban (5 mg [bid]) can be used in such patients, unless at least two of the following characteristics apply: patient age is 80 years or older, body weight is 60 kg or less, and serum creatinine is 1.5 mg/dL or higher, in which case dose reduction to 2.5 mg bid is indicated.
Apixaban is a highly selective, orally bioavailable, and reversible direct inhibitor of free and clot-bound factor Xa. Factor Xa catalyzes the conversion of prothrombin to thrombin, the final enzyme in the coagulation cascade that is responsible for fibrin clot formation. Apixaban has no direct effect on platelet aggregation but by inhibiting factor Xa, it indirectly decreases clot formation induced by thrombin. Apixaban was approved for the prevention of stroke in people with atrial fibrillation on December 28, 2012. On March 14, 2014, it was approved for the additional use of preventing deep vein thrombosis and pulmonary embolism in people that had recently undergone knee or hip replacement.
Apixaban which is highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa (fXa), was developed in a late-stage clinic trial for the prevention and treatment of thromboembolic diseases by Bristol-Myers Squibb. [Thromb. Haemost. 2010, 104, 301-310 and J. cardiovasc. Pharm. 2010, 55, 609-616]. It could be marketed for the treatment of deep vein thrombosis (DVT) and venous thrombosis as a new-generation anticoagulant. [J. Thromb. Haemost. 2008, 6, 1313-1318] Moreover, it has also shown promise in treating acute coronary syndrome (ACS), [Thromb. Haemost. 2010, 104, 976-983] cerebrovascular ischemia, and cancer [Arterioscler. Thromb. Vasc. Biol. 2007, 27, 1238-1247].
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Apixaban was firstly disclosed in US patent number 6,967,208 wherein Apixaban has indicated first as its requirement for the use as an antithrombotic agent and thus being developed for oral administration.
US patent number 7,153,960 discloses the process for preparation of Apixaban wherein formula-D (Scheme-1) is prepared by the cycloaddition reaction of formula (A) and formula (B) to form formula (C) which is in-situ converted to formula (D) by treatment with acid in specifically aprotic solvent. Further formula (D) is subsequently converted to formula (E) by Ullmann coupling reaction. The processes for preparation of formula (D) and (E) are complex, tedious, and time-consuming and involve too many operations in order to isolate these intermediates, formula (D) & (E), and also require purification to obtain pure compound.
Several routes for preparation of Apixaban have been reported; J. Med. Chem. 2007, 50, 5339-5356 reported a similar strategy for the synthesis of formula (I). Out of this, one route is as scheme mentioned in scheme-1, however, only 21% yield was obtained in the key Ullmann coupling reaction of cycloadduct formula (D) with d-Valerolactum to obtain formula (E).
WO-2010/030983 discloses a similar pathway for synthesis of Apixaban with marginal increase in yield of the Ullmann reaction ? 29% yield is reported.
WO-2012/168364 discloses preparation of Apixaban by using the base as K3PO4 and N,N-Dimethylethylenediamine in toluene as a solvent with slight improved in yield up to 67% after the crystallization of residue in ethyl acetate.
WO2003/049681 discloses alternate methodology which underwent an Ullmann coupling with iodide in the presence of cuprous iodide to obtain intermediate(C) in 68% yield. The instant application also teaches the requirement of expensive organic cuprous compound Cu(PPh3)3Br as catalyst for the Ullmann coupling reaction in order to enhanced yield up to 68%.
US Patent 20170008886 provides a process for preparation of Apixaban (formula-I) or pharmaceutically accepted salts or solvates or hydrate form. This instant invention further relates to process for preparation of Apixaban intermediates, namely ethyl 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate and 6-(4-pyridinone)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetra hydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate.
A Journal titled “Alternate Synthesis of Apixaban (BMS-562247), an inhibitor of blood coagulation factor XA” basically provides an alternate approach to synthesize Apixaban. The synthesis features a novel and cost-effective synthetic strategy to construct a key N-phenylvalerolactam intermediate from 4-nitroaniline. In addition, the modified synthetic route avoids the use of expensive reagents and significantly improves reaction yields. As demonstrated practically, Apixaban was successfully synthesized in overall good yield (35%).
Another Indian patent application IN 4137/MUM/2015 provides an improved process for preparing 1-(4-iodophenyl) piperidine-2-one which is an intermediate in the synthesis of active substance Apixaban. The product 1-(4-iodophenyl) piperidine-2-one obtained according to the present invention has a HPLC purity of greater than or equal to 99.5%.
US patent numbers 6,919,451; 7,153,960; 7,396,932; 8,969,561 and 8,884,016 describe various processes for the preparation of Apixaban and other pyrazole-pyridine derivatives. There are also some pending US patent applications which describe processes for the preparation of Apixaban US 20070027186 and US 20070203178.
International (PCT) publication WO 03/047520 A2 discloses process for the preparation of 1-(4-iodophenyl) piperidine-2-one by reacting 4-iodoaniline with 5-bromopentanoyl chloride in presence of trimethylamine in THF followed by cyclization with potassium tertiary butoxide to obtain 1-(4-iodophenyl) piperidine-2-one.
International (PCT) publication WO 2010/030983 A2 discloses process for the preparation of 1-(4-iodophenyl) piperidine-2-one starting from 4-iodoaniline and 5- bromopentanoyl chloride.
International (PCT) publication WO 2014/108919 A2 discloses process for the preparation of 1-(4-iodophenyl) piperidine-2-one by reacting 4-iodoaniline with 5-bromopentanoyl chloride in presence of triethylamine in toluene followed by cyclization with sodium tertiary butoxide to obtain 1-(4-iodophenyl) piperidine-2-one.
Journal of Labelled Compounds and Radiopharmaceuticals Vol. 54(8) Pg. 418-425 (2011) discloses a nine-step synthesis for the preparation of [14C] Apixaban with the label in the central lactam ring and three-step synthesis for the preparation of [14C] Apixaban with the label in the outer lactam ring starting from 4-nitroaniline.
IP.com Journal Vol. 12(11A) Pg. 10, (2012) discloses synthesis of Apixaban by reduction of nitro group of ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate by usage of 10% Pd/C catalyst in presence of formic acid and potassium formate and amidation with ethylene glycol saturated with ammonia to obtain 6-(4-aminophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide followed by N-acylation with 5-bromovaleroyl chloride and intramolecular heterocyclization of the intermediate 6-(4-(5-bromopentanamido)phenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide.
IP.com Journal Vol. 12(12A) Pg. 21 (2012) discloses preparation of Apixaban precursor 6-(4-aminophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide by treatment of ethyl 6-(4-aminophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate with ammonia. The crystalline forms of intermediates are also reported and characterized by the powder x-ray diffraction analysis.
CN 102675314 A discloses process for preparation of Apixaban by cyclization of p-nitroaniline with 5-chloro-pentanoyl chloride or 5-bromo-pentanoyl chloride; the resulting 1-(4-nitrophenyl)-2-piperidinone underwent dichlorination with phosphorus pentachloride followed elimination; the resulting 3-chloro-5,6-dihydro-1-(4-nitrophenyl)-2(1H)-pyridinone underwent reaction with ethyl (2Z)-chloro[(4-methoxyphenyl)hydrazono]acetate; the resulting ethyl 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-1H-pyrazolo [3,4-c]pyridine-3-carboxylate underwent reduction followed by cyclization with 5-chlorovalaroyl chloride or 5-bromovalaroyl chloride; the resulting intermediate underwent amidation to give Apixaban.
Journal of Medicinal Chemistry (2007), 50(22), 5339-5356 discloses the process for preparation of Apixaban and other derivatives.
Various crystalline polymorphs of Apixaban are reported in the literature. Polymorph Form H2-2 is disclosed by Bristol Meyers Squibb in US 7396932 B2. Anhydrous Form A of Apixaban is reported in EP 2752414 A1 by Lek Pharma / Sandoz. Amorphous Form of Apixaban is also reported by Dr. Reddy’s in US 9045473 B2. It basically uses spray drying techniques to yield amorphous compound. This patent also provides the method of preparation of Form H3. It was basically prepared by treating Ethyl 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate, 600 mL of 1,2 propandiol and 300 mL of liquid NH3 were charged in autoclave, heated to 90°C and stirred for 12 hours. 400 mL of water was added to the cooled mixture. Precipitate was washed twice with 300 mL of water and dried. The obtained product was suspended in 450 mL of ethanol and the suspension was heated. After cooling, the crystalline Form H3 of Apixaban was obtained.
As the literature process for preparation of Apixaban Form H3 cannot reduce critical impurities from Apixaban Form H3 due to insolubility of Apixaban in ethanol, therefore, there was a need to develop effective process for preparation of Apixaban Form H3 which is capable to remove critical impurities from Apixaban. To fulfill this requirement, effective process for preparation of Apixaban Form H3 was developed to reduce or remove all critical impurities resulting in highly pure Apixaban Form H3.
The X-Ray diffraction (XRD) study for Apixaban (API) prepared using novel process for the preparation of Apixaban Form H3 confirms the formation of Apixaban Form H3.
SUMMARY OF THE INVENTION:
The present invention provides a novel process for the preparation of crystalline Apixaban, characterized herein as Apixaban Form H3, which is pharmaceutically acceptable in view of physical stability and equilibrium solubility.
The main aspects of the present invention are as follows:
A crystalline Form H3 of Apixaban having an X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in literature (EP 2752414 by Lek Pharma).
Apixaban Form H3 can be prepared by dissolving any form of Apixaban i.e. 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide) (Formula I).

DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, a novel process for preparation of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo piperidin-1-yl)phenyl]-4,5-Dihydropyrazolo [3,4-c]pyridine-3-carboxamide Form H3 or Apixaban Form H3 is disclosed (Example 1) which comprises:
i. Dissolving any polymorphic form of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo piperidin-1-yl)phenyl]-4,5-Dihydro pyrazolo[3,4-c]pyridine-3-carboxamide in suitable solvent selected from aliphatic nitriles like acetonitrile, propionitrile, etc. or aliphatic alcohols like methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof.
ii. Heating the reaction mass to 70-80°C to ensure complete dissolution.
iii. Cooling the reaction mass to 20-30°C.
iv. Stirring for 2-3 hours to ensure complete crystallization.
v. Isolating Apixaban Form H3 by filtration and drying of the wet cake at 40-50°C for 15-20 hours as confirmed by its XRD reported in Figure 1.
According to the second embodiment of the present invention, a novel process for preparation of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-Dihydro pyrazolo [3,4-c]pyridine-3-carboxamide Form H3 or Apixaban Form H3 is disclosed which comprises (Example 2):
i. Dissolving any polymorphic form of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo piperidin-1-yl)phenyl]-4,5-Dihydro pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban) in suitable solvent selected from chlorinated aliphatic alkanes like methylene dichloride, chloroform, etc. and aliphatic alcohols like methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof.
ii. Heating the reaction mass to 30-40°C to ensure complete dissolution.
iii. Complete recovery of solvent under vacuum.
iv. Isolating Apixaban Form H3 after drying for 15-20 hours at 40-50°C as confirmed from its XRD reported in Fig. 2.
According to the third embodiment of the present invention, a novel process for the preparation of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-Dihydro pyrazolo [3,4-c]pyridine-3-carboxamide Form H3 or Apixaban Form H3 is disclosed (Example 3) which comprises:
i. Dissolving any form of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo piperidin-1-yl)phenyl]-4,5-Dihydro pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban) in suitable solvent selected from chlorinated aliphatic alkanes like methylene dichloride, chloroform, etc. or mixture thereof and aliphatic alcohols like methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof.
ii. Heating the reaction mass to 30-40°C to ensure complete dissolution.
iii. Adding solution of step ii. into aliphatic ethers like methyl tert butyl ether, diisopropyl ether, etc. or aliphatic alkanes like n-heptane, n-hexane, etc. or a mixture thereof.
iv. Stirring for 1-3 hours to ensure complete crystallization.
v. Isolating Apixaban by filtration and drying of the wet cake at 40-50°C for 15-20 hours as confirmed from its XRD reported in Fig. 3.
The HPLC Method used for the related substance analysis of Apixaban is as given below:
Reagents
n-Pentane sulphonic acid sodium salt (AR Grade)
Acetonitrile (HPLC Grade)
Orthophosphoric acid (HPLC Grade)
Milli Q wáter
Buffer Preparation-A: 0.96 gram n-Pentane sulphonic acid sodium salt is added to 1000 ml water and the pH is adjusted to 4.5 with dilute Orthophosphoric acid.
Mobile Phase Composition
Mobile phase A : Buffer-100%
Mobile phase B : Buffer : Acetonitrile (300:700)
Preparation of Diluent: Acetonitrile: Water (50:50)
Chromatographic Parameters
Use a suitable High Performance Liquid Chromatography (HPLC) with following parameters.
Column : Durashell C18, 150*4.6mm,5 micron or equivelent
Detector : UV at ?=225 nm
Injection volume : 10 µL
Run time : 60 min
Column Temp : 35°C
Delay time : 10 min
Gradient Programme :
Time Flow MP A MP B Curve
00 0.6 50 50 -----
10 0.6 50 50 6
30 0.6 30 70 6
60 0.6 30 70 6
61 0.6 50 50 1

Preparation of system suitability solution
Accurately weigh and transfer about 4.5 mg each (AX01), (AX02), (AX04) & (AXS02) to be analyzed in a 100 ml of volumetric flask. Dissolve in 10.0 ml diluent by sonication if necessary and dilute to volume with diluent. Then accurately dilute 1 ml of this solution + 30.0 mg AX05 in 100 ml with diluent.
Preparation of diluted standard solution
Accurately weigh and transfer about 45.0 mg Apixaban Standard in to a 100.0 ml of volumetric flask. Dissolve in 10 ml diluent by sonication if necessary and dilute to a volume with diluent solution (A). Then accurately dilute 1 ml of solution (A) into 100 ml with diluent solution (B). Then accurately dilute 1 ml of solution (B) into 10 ml with diluent.
Preparation of sample solution
Accurately weigh and transfer about 30.0 mg sample in to a 100.0 ml of volumetric flask. Dissolve in 10.0 ml diluent by sonication if necessary and dilute to volume with diluent. Examine the blank run chromatogram for any extraneous peaks and disregard peaks due to blank and area below 0.05% observed in the chromatogram of the sample solution.
Injection Sequence as below:

Sr. No Sample ID No. of Injections
1.0 Blank 01
2.0 SST 01
3.0 Diluted standard Solution 02
4.0 Sample Solution 01

RT of Apixaban as below
Sr. No: Name Approximate Retention Time
(Minute) RRT w.r.t
Apixaban Response Factor
1 DMOPP(AX02) 5.1 0.65 2.21
2 AX05/ AXI05 (API) 7.9 1.00 --
3 IPMDHO (AX01) 19.9 2.52 2.04
4 EMOPTPC (AX04) 24 3.04 1.07
5 ECMHA(AXS02) 28.3 3.58 1.73

Evaluation of System Suitability
The chromatographic system is suitable for analysis if and only if Resolution NLT 4.0 between Apixaban and DMOPP (AX02) impurity in SST solution. The % RSD for two replicate injections of diluted standard is NMT 10.0. If the system suitability passes, inject sample solution and record the chromatograms

Calculation
AT AT
% Known Impurity = ------ X 0.15 X RF, % Unknown Impurity = ------ X 0.15
AS AS

Where,
AT = Area of individual impurity in test
AS = Average area of Apixaban in diluted standard

The above-mentioned invention is supported by the following non-limiting examples:
Example 1:
10g of Apixaban (HPLC purity= 99.79%; Highest individual impurity= 0.10%) was dissolved in a mixture of acetonitrile (200 ml) and methanol (60ml) in a round bottom flask at 70-80°C with stirring. After complete dissolution, the clear solution was cooled to 20-30°C and stirred for 2-3 hours. The crystallized material was isolated by filtration and dried at 40-50°C for 15-20 hours to get 7g of Apixaban Form H3 having HPLC Purity= 99.97% (Individual impurities = 0.03%) and XRD pattern as reported in Figure 1.
Example 2:
10g of Apixaban (HPLC purity= 99.79%; Highest individual impurity= 0.10%) was dissolved in a mixture of methylene dichloride (100 ml) and methanol (70 ml) in a round bottom flask at 30-40°C with stirring. Complete recovery of solvent was done under vacuum and the crystallized material was isolated and dried for 15-20 hours to get 9 g of pure Apixaban Form H3 having HPLC Purity= 99.90% (Individual impurities = 0.04%, 0.04%, 0.02%) and XRD pattern as reported in Figure 2.
Example 3:
10g of Apixaban (HPLC purity= 99.79%; Highest individual impurity= 0.10%) was dissolved in a mixture of methylene dichloride (100 ml) and methanol (70 ml) in a round bottom flask at 30-40°C with stirring. The resulting solution was added to methyl tert butyl ether (70ml) and stirred for 1-3 hours. The crystallized material was isolated by filtration and dried at 40-50°C for 15-20 hours to get 8g of Apixaban having HPLC Purity= 99.93% (Individual impurities = 0.03%, 0.03%, 0.01%) and XRD pattern as reported in Figure 3.

,CLAIMS:1. A novel process for the preparation of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo piperidin-1-yl)phenyl]-4,5-Dihydropyrazolo [3,4-c]pyridine-3-carboxamide Form H3 or Apixaban Form H3, which comprises
a) dissolving any polymorphic form of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 yl)phenyl]-4,5-Dihydropyrazolo[3,4-c]pyridine-3-carbox amide or Apixaban in any solvent selected from aliphatic nitriles like acetonitrile, propionitrile or aliphatic alcohols like methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof;
b) heating the reaction mass to 70-80°C to obtain a clear mass;
c) cooling the reaction mass to room temperature;
d) stirring for 2-3 hours; and
e) isolating the material by filtration and drying the wet cake for 15-20 hours at 40-50°C to give desired crystalline Apixaban Form H3.
2. A novel process for the preparation of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo piperidin-1-yl)phenyl]-4,5-Dihydropyrazolo [3,4-c]pyridine-3-carboxamide Form H3 or Apixaban Form H3, which comprises:
a) dissolving any polymorphic form of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-Dihydropyrazolo[3,4-c]pyridine-3-carbox amide or Apixaban in solvent selected from halogenated hydrocarbons such as methylene dichloride, chloroform, etc. and aliphatic alcohols like methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof;
b) heating the reaction mass to 30-40°C to obtain a clear mass;
c) performing complete recovery of solvent from reaction mass by vacuum distillation; and
d) isolating the desired crystalline Apixaban Form H3 by drying the wet cake for 15-20 hours at 40-50°C.
3. A novel process for the preparation of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo piperidin-1-yl)phenyl]-4,5-Dihydropyrazolo [3,4-c]pyridine-3-carboxamide Form H3 or Apixaban Form H3, which comprises:
a) dissolving any polymorphic form of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-Dihydropyrazolo[3,4-c]pyridine-3-carbox amide or Apixaban in solvent selected from halogenated hydrocarbons such as methylene dichloride, chloroform, etc. and aliphatic alcohols like methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof;
b) heating the reaction mass to 30-40°C to obtain a clear mass;
c) drop wise adding aliphatic ethers like methyl tert butyl ether, diisopropyl ether or aliphatic alkanes like n-heptane, n-hexane or a mixture thereof;
d) stirring for 2-3 hours; and
e) isolating the material by filtration and drying the wet cake for 15-20 hours at 40-50°C to give the desired crystalline Apixaban Form H3.