FIELD OF THE INVENTION

The present invention primarily discloses novel processes for the preparation of amorphous Apixaban in a mixture of solvents using spray drying technique.
BACKGROUND OF THE INVENTION
Apixaban, an anti-coagulant used for treatment of venous thromboembolic events and prevention of strokes in people having atrial fibrillation and sold under the trade name 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 nonvalvular atrial fibrillation and DVT prevention. DVTs may lead to PE in knee or hip replacement surgery patients. Treatment of both DVT and PE is required 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: the patient's 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 is highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa (fXa) and 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. Vase. 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 first disclosed in US Patent Number 6,967,208 wherein its requirement as an antithrombotic agent was indicated and thus developed for oral administration.
US patent number 7,153,960 discloses the process for preparation of Apixaban wherein the 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 process for preparation of formula (D) and (E) is complex, tedious, time consuming and involves too many operations in order to isolate these intermediates, formula (D) and (E), and also requires purification to obtain pure compound.
Several routes for the 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 the 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).

WO2010/030983 disclosed a similar pathway for synthesis of Apixaban with marginal increase in yield of the Ullmann reaction (-29% yield is reported).
WO2012/168364 discloses the preparation of Apixaban by using the base as K3PO4 and N, N-Dimethylethylenediamine in toluene as a solvent with slight improvement 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 the intermediate (C) in 68% yield. The same instant application also teaches the requirement of expensive organic cuprous compound Cu(PPh3)3Br as a catalyst for the Ullmann coupling reaction in order to enhance yield up to 68%.
US patent application number 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 a process for preparation of Apixaban intermediates, namely ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate and 6-(4-pyridinone)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-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 4 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 IN4137/MUM/2015 provides an improved process for preparing l-(4-iodophenyl) piperidine-2-one, which is an intermediate in the synthesis of active substance Apixaban. The product l-(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 describing processes for the preparation of Apixaban (US 20070027186 and US 20070203178).
International (PCT) publication- WO 03/047520 A2- discloses the 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(11 A) Pg. 10, (2012) discloses synthesis of Apixaban by reduction of nitro group of ethyl l-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate by usage of 10% Pd/C catalyst in the presence of formic acid and potassium formate and amidation with ethylene glycol saturated with ammonia to obtain 6-(4-aminophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-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)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide.
IP.com Journal, Vol. 12(12A) Pg. 21 (2012) discloses the preparation of Apixaban
precursor 6-(4-aminophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-
pyrazolo[3,4-c]pyridine-3-carboxamide by treatment of ethyl 6-(4-aminophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-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 the process for the preparation of Apixaban by cychzation of p-nitroaniline with 5-chloro-pentanoyl chloride or 5-bromo-pentanoyl chloride; the resulting l-(4-nitrophenyl)-2-piperidinone underwent dichlorination with phosphorus pentachloride followed elimination; the resulting 3-chloro-5,6-dihydro-l-(4-nitrophenyl)-

2(lH)-pyridinone underwent reaction with ethyl (2Z)-chloro[(4-
methoxyphenyl)hydrazono]acetate; the resulting ethyl 4,5,6,7-tetrahydro-l-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-lH-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 the 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 US7396932 B2. Anhydrous Form A of Apixaban is reported in EP2752414A1 by Lek Pharma / Sandoz. Amorphous Form of Apixaban is also reported by Dr. Reddy's in US9045473B2. It basically uses spray drying techniques to yield amorphous compound.
Yet another patent application WO2013164839 also provides the method of preparation of amorphous Apixaban using methanol by spray drying technique. But Apixaban in pure form is not soluble in methanol.
Morepen's own patent application IN 201911042344 describes a novel and effective purification process for removal of critical impurity from Apixaban.
As none of the literature process reports commercially applicable process for the preparation amorphous Apixaban, therefore, there was a need to develop a process which can be used at commercial scale for the production of amorphous Apixaban. To fulfill this requirement, the process for highly pure amorphous Apixaban was developed which

can be used at commercial scale for the production of highly pure amorphous Apixaban in plant.
The superior biopharmaceutical properties of amorphous pharmaceuticals are overshadowed by their inherent physical and chemical instabilities. Amorphous solids are metastable and exhibit higher degradation than their crystalline counterparts. Extensive efforts are underway to prevent the crystallization of amorphous pharmaceuticals by preparing stable amorphous solid dispersions using suitable excipients. A solid dispersion is a mixture consisting of one or more active ingredients molecularly dispersed in an inert carrier or matrix. Solid dispersions are prepared by the melt, solvent or solvent-melt methods and the excipients stabilize the amorphous product by one or more of the above-mentioned approaches. These approaches typically require the excipient concentration to exceed 20 % w/w. The chemical stability of amorphous pharmaceuticals can be enhanced by excipients through several mechanisms which include: changing the crystallinity of small APIs or the secondary structure of a protein, altering the molecular mobility of the API in the matrix, reacting with the drug, and modifying the polarity of the matrix.
The X-Ray diffraction (XRD) study for amorphous Apixaban (API) thus prepared shows the formation of amorphous Apixaban free from any crystalline form of Apixaban.
SUMMARY OF THE INVENTION
The present invention primarily describes a novel process for preparation of amorphous Apixaban using spray drying technique in various solvent mixtures. To start with, feed stock solution of Apixaban is conveniently prepared by dissolving solvents that may include but are not limited to a mixture of one or more of alcohols such as methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, t- butyl alcohol, and the like chlorinated

aliphatic hydrocarbons such as methylene dichloride, chloroform, carbon tetrachloride, ethylene dichloride. The second step involves isolation of an amorphous form of Apixaban from the fine filtered feed solution. The isolation may be affected by removing the solvent. Suitable techniques which may be used for the removal of solvent include using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophihzation), and the like or any other suitable technique.
The current invention provides spray drying a solution of Apixaban that involves the spray drying of feed stock, wherein any crystalline form of Apixaban may be used. The feedstock is dozed into the spray-drying instrument JISL Mini Spray-drier LSD-48 and spray drying is carried out under specific parameters which are elaborated in further part of the current invention.
In another preferred feature, the spray drying of Apixaban may be performed on JISL Mini Spray-drier LSD-48 by maintaining following parameters: a) maintaining the feed rate of the feed stock preferably at 20-30 ml/hr; b) maintaining the inlet temperature in the range of 35°C-80°C, preferably, 50°C-70°C; c) maintaining the aspirator rate between 30-50 rpm; d) maintaining the outlet temperature in the range of 30°C to 40° C; e) maintaining air flow at 2-4 Kg/cm, preferably 2 Kg/cm; f) maintaining the vacuum at 60-80 mm of Hg. Further, the optional use of excipients polyethylene glycol (PEG)-6000 and Hydroxypropylmethylcellulose (HPMC)-5CPC is established to promote/enhance the formation & stability of amorphous material as premix.
In the present invention, feedstock of Apixaban in solvent system is spray-dried. The thus obtained spray-dried compound is in amorphous form. This fact is again confirmed by the

X-ray powder diffractogram of spray-dried Apixaban. The parameters of obtaining the
XRD diffractogram are mentioned below:
a) Scan Axis - Gonio
b) Start Position [°20] - 4.00
c) End Position [°20] - 50.00
d) Step Size [°20] - 0.0170
e) Scan Step Time [s] - 40.0050
f) Scan Type - Continuous
g) PSD Mode - Scanning
h) PSD Length [°20] -2.12
i) Offset [°20] - 0.0000
j) Divergence Slit Type - Fixed
k) Divergence Slit Size [°] - 0.4354
1) Specimen Length [mm] - 10.00
m) Measurement Temperature [°C] - 25.00
n) Anode Material - Cu
o) K-Alphal [A] - 1.54060
p) K-Alpha2 [A] - 1.54443

q) K-Beta[A]- 1.39225 r) K-A2 / K-Al Ratio - 0.50000 s) Generator Settings - 40 mA, 45 kV t) Diffractometer Type - 0000000011023505 u) Diffractometer Number - 0 v) Goniometer Radius [mm] - 240.00 w) Dist. Focus-Diverg. Slit [mm] - 100.00 x) Incident Beam Monochromator - No y) Spinning- Yes The complete process details are disclosed in next section.
DETAILED DESCRIPTION OF THE INVENTION
According to the current embodiment of the present invention, a novel process for preparation of amorphous l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5-Dihydro pyrazolo [3,4-c]pyridine-3-carboxamide or amorphous Apixaban is disclosed which comprises:
i. dissolving any crystalline form of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo piperidin-l-yl)phenyl]-4,5-Dihydro pyrazolo[3,4-c]pyridine-3-carboxamide or Apixaban in suitable solvent mixture of two or more solvents in a specific ratio, first of which may be selected from aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol and the

second solvent is selected from a halogenated aliphatic hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or mixture thereof;
ii. stirring the reaction mass to 25-35°C for 30 minutes to ensure complete dissolution followed by fine filtration and using it as feed stock / solution in spray drier;
iii. the spray drying of Apixaban is to be performed on JISL Mini Spray-drier LSD-48 by: a) maintaining the feed rate of the feed stock preferably 20-30 ml/hr; b) maintaining the inlet temperature in the range of 35°C-80°C, preferably, 50°C-70°C; c) maintaining the aspirator rate between 30-50 rpm; d) maintaining the outlet temperature in the range of 30°C to 40° C; e) maintaining air flow at 2-4 Kg/cm, preferably 2 Kg/cm; f) maintaining the vacuum at 60-80 mm of Hg; and
iv. isolating the pure amorphous Apixaban from cyclone flask in almost powdered form which is further dried at 50-60°C for 15-30 hours.
According to another aspect of the current invention, the ratio of solvent system used for dissolution is 1:12 (Example 1), 1:9 (Example 2, 3 & 4).
According to the second embodiment of the present invention, a novel process for the preparation of premix of stabilized amorphous l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5-Dihydro pyrazolo [3,4-c]pyridine-3-carboxamide or amorphous premix Apixaban is disclosed which comprises:
i. dissolving any crystalline form of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo piperidin-l-yl)phenyl]-4,5-Dihydro pyrazolo[3,4-c]pyridine-3-carboxamide or Apixaban in suitable solvent mixture of two or more solvents in a specific ratio,

first of which may be selected from aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol and the second solvent is selected from a halogenated aliphatic hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or mixture thereof;
ii. adding polyethylene glycol (PEG)-6000 and
Hydroxypropylmethylcellulose(HPMC)-5CPC in varying ratio;
iii. stirring the reaction mass to 25-35°C for 30 minutes to ensure complete dissolution followed by fine filtration and using it as feed stock / solution in spray drier;
iv. the spray drying of Apixaban is to be performed on JISL Mini Spray-drier LSD-48 by: a) maintaining the feed rate of the feed stock at preferably 20-30 ml/hr; b) maintaining the inlet temperature in the range of 35°C-80°C, preferably, 50°C-70°C; c) maintaining the aspirator rate between 30-50 rpm; d) maintaining the outlet temperature in the range of 30°C to 40° C; e) maintaining air flow at 2-4 Kg/cm, preferably 2 Kg/cm; f) maintaining the vacuum at 60-80 mm of Hg;
v. isolating the pure premix of amorphous Apixaban from cyclone flask in almost powdered form which is further dried at 50-60°C for 15-30 hours.
According to another aspect of the current embodiment, the ratio of solvent system used for dissolution is 1:3 (Example 5, 6 & 7).
According to yet another aspect of the current embodiment, the ratio of excipients varies from 1:5 & 1:3.

The current invention is supported by following non limited examples.
Example 1:
25g of Apixaban was added in a mixture of methanol-methylene chloride (1:12). The reaction mass was stirred for 30 minutes at 25 to 35°C to get a clear solution. After fine filtration, the solution was followed by spray drying under below conditions:

S.No. Parameter Conditions
a) Feed Pump Rate 30 rpm
b) Inlet Temperature 60°C
c) Outlet Temperature 30-40°C
d) Aspiration Rate 34 to 44 rpm
e) Vacuum 60-80 mm of Hg
f) Hot Air Supply 2 Kg/cm2
After completion of feeding, the product was collected from the cyclone and dried for 15-30 hours at 50-60°C. The obtained solid (lO.Og) was amorphous Apixaban as shown by X-Ray diffraction pattern- Figure 1.
Example 2:
25g of Apixaban was added in a mixture of methanol-methylene chloride (1:9). The reaction mass was stirred for 30 minutes at 25 to 35°C to get a clear solution. After fine filtration, the solution was followed by spray drying under below conditions.

S.No. Parameter Conditions
a) Feed Pump Rate 25 rpm
b) Inlet Temperature 60°C

c) Outlet Temperature 30-40°C
d) Aspiration Rate 34 to 44 rpm
e) Vacuum 60-80 mm of Hg
f) Hot Air Supply 2 Kg/cm2
After completion of feeding, the product was collected from the cyclone and dried for 15-30 hours at 50-60°C. The obtained solid (llg) was amorphous Apixaban as shown by X-Ray diffraction pattern- Figure 2.
Example 3:
25g of Apixaban was added in a mixture of methanol-methylene chloride (1:9). The reaction mass was stirred for 30 minutes at 25 to 35°C to get clear solution. After fine filtration, the solution was followed by spray drying under below conditions:

S.No. Parameter Conditions
a) Feed Pump Rate 22 rpm
b) Inlet Temperature 60°C
c) Outlet Temperature 30-40°C
d) Aspiration Rate 34 to 44 rpm
e) Vacuum 60-80 mm of Hg
f) Hot Air Supply 2 Kg/cm2
After completion of feeding, the product was collected from the cyclone and dried for 15-30 hours at 50-60°C. The obtained solid (12g) was amorphous Apixaban as shown by X-Ray diffraction pattern- Figure 3.

Example 4:
50g of Apixaban was added in a mixture of methanol-methylene chloride (1:9). The reaction mass was stirred for 30 minutes at 25 to 35°C to get a clear solution. After fine filtration, the solution was followed by spray drying under below conditions:

S.No. Parameter Conditions
a) Feed Pump Rate 22rpm
b) Inlet Temperature 60°C
c) Outlet Temperature 30-40°C
d) Aspiration Rate 34 to 44 rpm
e) Vacuum 60-80 mm of Hg
f) Hot Air Supply 2 Kg/cm2
After completion of feeding, the product was collected from the cyclone and dried for 15-30 hours at 50-60°C. The obtained solid (24g) was amorphous Apixaban as shown by X-Ray diffraction pattern- Figure 4.
Example 5
lOg of Apixaban was added in a mixture of methanol-methylene chloride (3:9). To this was added PEG-6000 (5g) and HPMC-5cpc (25 g). The reaction mass was stirred for 30 minutes at 25 to 35°C to get a clear solution. After fine filtration, the solution was followed by spray drying under below conditions:

S.No. Parameter Conditions
g) Feed Pump Rate 22 rpm
h) Inlet Temperature 60°C

1) Outlet Temperature 30-40°C
j) Aspiration Rate 34 to 44 rpm
k) Vacuum 60-80 mm of Hg
1) Hot Air Supply 2 Kg/cm2
After completion of feeding, the product was collected from the cyclone and dried for 15-30 hours at 50-60°C. The obtained solid (lO.Og) was amorphous premix Apixaban as shown by X-Ray diffraction partem- Figure 5.
Example 6:
lOg of Apixaban was added in a mixture of methanol-methylene chloride (3:9). To this was added PEG-6000 (7.5g) and HPMC-5cpc (22.5 g). The reaction mass was stirred for 30 minutes at 25 to 35°C to get a clear solution. After fine filtration, the solution was followed by spray drying under below conditions.

S.No. Parameter Conditions
a) Feed Pump Rate 22 rpm
b) Inlet Temperature 60°C
c) Outlet Temperature 30-40°C
d) Aspiration Rate 34 to 44 rpm
e) Vacuum 60-80 mm of Hg
f) Hot Air Supply 2 Kg/cm2
After completion of feeding, the product was collected from the cyclone and dried for 15-30 hours at 50-60°C. The obtained solid (lO.Og) was amorphous premix Apixaban as shown by X-Ray diffraction partem- Figure 6.

Example 7:
lOg of Apixaban was added in a mixture of methanol-methylene chloride (3:9). To this was added PEG-6000 (lOg) and HPMC-5cpc (30g). The reaction mass was stirred for 30 minutes at 25 to 35°C to get a clear solution. After fine filtration, the solution was followed by spray drying under below conditions:

S.No. Parameter Conditions
a) Feed Pump Rate 22rpm
b) Inlet Temperature 60°C
c) Outlet Temperature 30-40°C
d) Aspiration Rate 34 to 44 rpm
e) Vacuum 60-80 mm of Hg
f) Hot Air Supply 2 Kg/cm2
After completion of feeding, the product was collected from the cyclone and dried for 15-30 hours at 50-60°C. The obtained solid (lO.Og) was amorphous premix Apixaban as shown by X-Ray diffraction partem- Figure 7.

WE CLAIM:

An improved process for preparation of amorphous l-(4-methoxyphenyl)-7-oxo-6-
[4-(2-oxopiperidin-l-yl)phenyl]-4,5-Dihydro pyrazolo [3,4-c]pyridine-3-
carboxamide or amorphous Apixaban which comprises:
a) dissolving any crystalline form of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo piperidin-l-yl)phenyl]-4,5-Dihydro pyrazolo[3,4-c]pyridine-3-carboxamide or Apixaban in a mixture of two or more solvents in a specific ratio, first of which is an aliphatic alcohol and second solvent is an aliphatic halogenated hydrocarbon;
b) stirring the reaction mass to 25-35°C for 30 minutes to ensure complete dissolution followed by fine filtration and using it as feed stock/solution in spray drier;
c) spray drying the reaction mass using spray-drier as per the following parameters:

• maintaining the feed rate of the feed stock preferably at 20-30 ml/hr;
• maintaining the inlet temperature in the range of 35°C-80°C, preferably, 50°C-70°C;
• maintaining the aspirator rate between 30-50 rpm;
• maintaining the outlet temperature in the range of 30°C to 40°C;
• maintaining air flow at 2-4 Kg/cm, preferably 2 Kg/cm; and
• maintaining the vacuum at 60-80 mm of Hg;
d) isolating the pure amorphous Apixaban from cyclone flask in almost powdered
form which is further dried at 50-60°C for 15-30 hours.

2. An improved process for preparation of stabilized premix of amorphous l-(4-

methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5-Dihydro pyrazolo [3,4-c]pyridine-3-carboxamide or amorphous Apixaban which comprises:
a) dissolving any crystalline form of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo piperidin-l-yl)phenyl]-4,5-Dihydro pyrazolo[3,4-c]pyridine-3-carboxamide or Apixaban in mixture of two or more solvents in a specific ratio, first of which is an aliphatic alcohol and the second solvent is a aliphatic halogenated hydrocarbon;
b) adding excipients polyethylene glycol (PEG)-6000 and hydroxypropylmethyl cellulose (HPMQ-5CPC in the ratio 1:5 or 1:3;
c) stirring the reaction mass to 25-35°C for 30 minutes to ensure complete dissolution followed by fine filtration and using it as feed stock/solution in spray drier;
d) spray drying the reaction mass using spray-drier as per following parameters:

• maintaining the feed rate of the feed stock preferably 20-30 ml/hr;
• maintaining the inlet temperature in the range of 35°C-80°C, preferably, 50°C-70°C;
• maintaining the aspirator rate between 30-50 rpm;
• maintaining the outlet temperature in the range of 30°C to 40° C;
• maintaining air flow at 2-4 Kg/cm, preferably 2 Kg/cm; and
• maintaining the vacuum at 60-80 mm of Hg;
e) isolating the pure stabilized premix amorphous Apixaban from cyclone flask in
almost powdered form which is further dried at 50-60°C for 15-30 hours.
The aliphatic alcohol as claimed in claims 1(a) and 2(a) is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol.
4. The aliphatic halogenated hydrocarbon as claimed in claims 1(a) and 2(a) is
selected from methylene dichloride, chloroform and carbon tetrachloride.
5. The ratio of solvent system used for dissolution as claimed in claims 1(a) and 2(a)
is either 1:3 or 1:9 or 1:12.