CLIAMS:1. Crystalline form A of Apixaban having X-ray powder diffraction pattern comprising peaks at about 8.4, 10.0, 10.5, 11.2, 13.9, 17.0, 22.2+0.2 degrees 2?.

2. Process for the preparing crystalline form A of Apixaban having an X-ray powder diffraction pattern comprising peaks at about 8.4, 10.0, 10.5, 11.2, 13.9, 17.0, 22.2+0.2 degrees 2? comprising the steps of
i) providing a solution of Apixaban in alcohol
ii) heating the said solution
iv) optionally removing solvent
iii) cooling the said solution
iv) isolating crystalline form A

3. The process according to claim 2 where in alcohol is selected form the group comprising ethylene glycol, methanol, ethanol, isopropyl alcohol, butanol, pentanol or the mixtures thereof.

4. Crystalline form B of Apixaban having X-ray powder diffraction pattern comprising peaks at about 6.0, 7.0, 13.55, 17.5, , 22.7+0.2 degrees 2?.

5. Process for the preparing crystalline form B of Apixaban having an X-ray powder diffraction pattern comprising peaks at about 6.0, 7.0, 13.55, 17.5, , 22.7+0.2 degrees 2? comprising the steps of
i) providing a solution of Apixaban in acetonitrile, alcohol, ester and chlorinated solvents or in a mixture of two or more solvents
ii) heating the said solution
iv) optionally removing solvent
iii) cooling the said solution
iv) isolating crystalline form B

6. The process according to claim 5 where in Alcohols are selected form the group comprising of ethylene glycol, methanol, ethanol, isopropyl alcohol, butanol, pentanol and the like.. Esters are selected form the group comprising of ethyl acetate, propyl acetate and the like. Chlorinated solvents are selected form the group comprising of Dichloromethane, chloroform, dicchloroethane, chlororbenzene and the like.
7. Crystalline form C of Apixaban having X-ray powder diffraction pattern comprising peaks at about 5.8, 7.3, 11.6, 13.4, 13.9, 15.9, 17.8, 23.5, 25.0+0.2 degrees 2?.

8. Process for the preparing crystalline form C of Apixaban comprising peaks at about 5.8, 7.3, 11.6, 13.4, 13.9, 15.9, 17.8, 23.5, 25.0+0.2 degrees 2? comprising the steps of
i) providing a solution of Apixaban in suitable solvent.
ii) optionally adding water to the said solution
iii) isolating crystalline form C

9. The process as claimed in claim 8 wherein solvent is selected form the group comprising of DMF, DMSO , acetic acid or mixture thereof.
,TagSPECI:Field of the invention

The present invention relates to novel crystalline form A, form B and Form C of Apixaban (I) and process for their preparation.

(I)
BACKGROUND OF THE INVENTION

Apixaban (BMS-562247-01, tradename Eliquis) is an anticoagulant for the prevention of venous thromboembolism and venous thromboembolic events. It is a direct factor Xa inhibitor.

US6967208B2 discloses a series of coagulation factor Xa inhibitors 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydropyrazolo[5,4-c]pyridine-3-carboxamide (also known as Apixaban). US7396932 discloses process for the preparation of Apixaban.

US2007/0203178 A1 discloses crystalline dimethyl formamide and formamide solvates of Apixaban.
Further, US7396932 B2 discloses crystalline form N-1 and H2-2 of Apixaban.

There exists a need for reproducible methods for the manufacture of crystalline forms of apixaban to permit its feasible commercialization..

Our endeavor of developing new forms of Apixaban has led to the development of three new forms of Apixaban.

The present invention provides novel crystalline form of Apixaban i.e, Form A, Form B and Form C.
The present invention also provides process for the preparation of crystalline form A, form B and Form C of Apixaban.

Object of the invention:

Accordingly, it is an object of the present invention to provide novel crystalline form A, Form B and Form C of Apixaban.

Further object of the present invention is to provide novel crystalline form A of Apixaban having X-ray powder diffraction pattern comprising peaks at about 8.4, 10.0, 10.5, 11.2, 13.9, 17.0, 22.2+0.2 degrees 2?.
Another object of present invention is to provide process for the preparation of crystalline form A comprising peaks at about 8.4, 10.0, 10.5, 11.2, 13.9, 17.0, 22.2+0.2 degrees 2? comprising the steps of
i) providing a solution of Apixaban in alcohol
ii) heating the said solution
iv) optionally removing solvent
iii) cooling the said solution
iv) isolating crystalline form A

According to this embodiment the present invention provides process of preparing crystalline form A of Apixaban comprising dissolving Apixaban in alcohol such as ethylene glycol, methanol, ethanol, isopropyl alcohol, butanol, pentanol or the mixtures thereof.

Yet another object of the present invention is to provide novel crystalline form B of Apixaban having X-ray powder diffraction pattern comprising peaks at about 6.0, 7.0, 13.55, 17.5, , 22.7+0.2 degrees 2?.

Another object of present invention is to provide process for the preparation of crystalline form B comprising peaks at about 6.0, 7.0, 13.55, 17.5, , 22.7+0.2 degrees 2? comprising the steps of
i) providing a solution of Apixaban in suitable solvent system
ii) Heating the said solution
iv) optionally removing solvent
iii) cooling the said solution
iv) isolating crystalline form B

The suitable solvent system may be selected form nitriles, alcohols, esters and halogenated solvents or in a mixture of two or more solvents, nitriles selected form C1-C2-alkylnitriles such as acetonitrile; alcohols are selected form the group comprising of ethylene glycol, methanol, ethanol, isopropyl alcohol, butanol, pentanol and the like; Esters are selected form the group comprising of ethyl acetate, propyl acetate and the like; chlorinated solvents are selected form the group comprising of Dichloromethane, chloroform, dicchloroethane, chlororbenzene and the like.

Yet another object of the present invention is to provide novel crystalline form C of Apixaban having X-ray powder diffraction pattern comprising peaks at about 5.8, 7.3, 11.6, 13.4, 13.9, 15.9, 17.8, 23.5, 25.0+0.2 degrees 2?.

Further object of present invention is to provide process for the preparation of crystalline form C comprising peaks at about 5.8, 7.3, 11.6, 13.4, 13.9, 15.9, 17.8, 23.5, 25.0+0.2 degrees 2? comprising the steps of
i) providing a solution of Apixaban in suitable solvent.
ii) heating the said solution
iii) optionally adding water to the said solution
iv) isolating crystalline form C.

The suitable solvent system may be selected form a solvent such as DMF, DMSO and acetic acid.
Brief description of Drawings:
Fig 1: X-ray powder diffraction (XRD) pattern of form A of Apixaban
Fig 2: X-ray powder diffraction (XRD) pattern of form B of Apixaban.
Fig 3: X-ray powder diffraction (XRD) pattern of form C of Apixaban.

Detailed description of the invention:
An embodiment of the present invention provides novel crystalline form A, Form B and Form C of Apixaban.

In another embodiment of present invention provides novel crystalline form A of Apixaban having X-ray powder diffraction pattern comprising peaks at about 8.4, 10.0, 10.5, 11.2, 13.9, 17.0, 22.2+0.2 degrees 2?.
Further embodiment of present invention provides process for the preparation of crystalline form A of Apixaban comprising peaks at about 8.4, 10.0, 10.5, 11.2, 13.9, 17.0, 22.2+0.2 degrees 2? comprising the steps of
i) providing a solution of Apixaban in alcohol
ii) heating the said solution
iv) optionally removing solvent
iii) cooling the said solution
iv) isolating crystalline form A

According to this embodiment the present invention provides process of preparing crystalline form A of Apixaban comprising dissolving Apixaban in alcohol such as ethylene glycol, methanol, ethanol, isopropyl alcohol, butanol, pentanol or the mixtures thereof.

The solution of Apixaban is heated at a temperature in the range between 40 0C and refluxing temperature of the solvent, preferably between 50 0C and refluxing temperature of the solvent, suitably the Apixaban is heated at reflux temperature.

The term ‘refluxing temperature of the solvent’ as used here in relates to a temperature in the range of boiling temperature of a particular solvent to the boiling temperature plus 15 0C, i.e. the reflux temperature of the methanol is in the range from 78 to 93 0C.

The solution of Apixaban is cooled at temperature in the range of 25 0C to -200C, preferably between 15 to -100C, more preferably between 10 to 0 0C.

The amount of solvent that preferably used is less then 1 to 50 volume corresponding to Apixaban, more preferred is 1 to 30 volume, even more preferred is 1 to 20 volume and most preferred is 1 to 10 volume.

The crystalline form A obtained by the present invention is in high yield which typically more then 80%, preferably more then 90%.

Further the purity of crystalline form A obtained by process of present invention is more then 98 area % determined by HPLC, preferably more the 99 area % determined by HPLC. It is however preferred to use a starting material having a purity of more than 90 area % by HPLC and even more preferred to use starting material with more than 95 area % by HPLC when carrying out the process of the present invention.

Another embodiment of the present invention is to provide novel crystalline form B of Apixaban having X-ray powder diffraction pattern comprising peaks at about 6.0, 7.0, 13.55, 17.5, , 22.7+0.2 degrees 2?.

Further embodiment of present invention is to provide process for the preparation of crystalline form B comprising peaks at about 6.0, 7.0, 13.55, 17.5, , 22.7+0.2 degrees 2? comprising the steps of
i) providing a solution of Apixaban in a suitable solvent system.
ii) heating the said solution
iv) optionally removing solvent
iii) cooling the said solution
iv) isolating crystalline form B

The suitable solvent system may be selected form nitriles, alcohols, esters and halogenated solvents or in a mixture of two or more solvents, nitriles selected form C1-C2-alkylnitriles such as acetonitrile; alcohols are selected form the group comprising of ethylene glycol, methanol, ethanol, isopropyl alcohol, butanol, pentanol and the like; Esters are selected form the group comprising of ethyl acetate, propyl acetate and the like; chlorinated solvents are selected form the group comprising of Dichloromethane, chloroform, dicchloroethane, chlororbenzene and the like.

The solution of Apixaban is heated at a temperature in the range between 30 0C to 800C, preferably between 30 0C to 70 0C, suitably at 40 0C to 60 0C.

The amount of solvent that preferably used is less then 1 to 50 volume corresponding to Apixaban, more preferred is 1 to 30 volume, even more preferred is 1 to 20 volume and most preferred is 1 to 10 volume.

The crystalline form B obtained by the present invention is in high yield which typically more then 80%, preferably more then 90%.

Further the purity of crystalline form B obtained by process of present invention is more then 98 area % determined by HPLC, preferably more the 99 area % determined by HPLC. It is however preferred to use a starting material having a purity of more than 90 area % by HPLC and even more preferred to use starting material with more than 95 area % by HPLC when carrying out the process of the present invention.

Another embodiment of the present invention provides novel crystalline form C of Apixaban having X-ray powder diffraction pattern comprising peaks at about 5.8, 7.3, 11.6, 13.4, 13.9, 15.9, 17.8, 23.5, 25.0+0.2 degrees 2?.

Further embodiment of the present invention provides process for the preparation of crystalline form C comprising peaks at about 5.8, 7.3, 11.6, 13.4, 13.9, 15.9, 17.8, 23.5, 25.0+0.2 degrees 2? comprising the steps of
i) providing a solution of Apixaban in suitable solvent.
ii) Heating the said solution
iii) optionally adding water to the said solution
iv) isolating crystalline form C

The suitable solvent system may be selected form DMF, DMSO and acetic acid.

The solution of Apixaban is heated at a temperature in the range between 40 0C to 900C, preferably between 40 0C to 70 0C, suitably at 40 0C to 60 0C.

The amount of solvent that preferably used is less then 1 to 50 volume corresponding to Apixaban, more preferred is 1 to 30 volume, even more preferred is 1 to 20 volume and most preferred is 1 to 10 volume.
The amount of water added to the solution of Apixaban is preferably less then 35 volume corresponding to Apixaban, more preferred is 25 volume, even more preferred is 20 volume and most preferred is 10 volume.

The crystalline form C obtained by the present invention is in high yield which typically more then 80%, preferably more then 90%.

Further the purity of crystalline form C obtained by process of present invention is more then 98 area % determined by HPLC, preferably more the 99 area % determined by HPLC. It is however preferred to use a starting material having a purity of more than 90 area % by HPLC and even more preferred to use starting material with more than 95 area % by HPLC when carrying out the process of the present invention.

The process described in the present invention is illustrated in the following examples which should not be construed to limit the scope of the invention in any way.

Examples

PREPARATION OF FORM – A

EXAMPLE-1

Apixaban (2 g) was added to Ethylene glycol (20 ml) and the mixture was heated to 120°C and maintained for 1 hour. Reaction mixture was gradually cooled to 5-10 °C and stirred for 1 hour at 5-10 °C. The obtained solid crystals were filtered, washed with water (2x40ml) and dried for 10-12 h at 80-85°C. Yield-1.9g.

EXAMPLE-2
Apixaban (2 g) was added to Methanol (70 ml) and the mixture was heated to reflux and maintain for 1 h. The mixture was filtered through filter paper and filtrate was cooled to 5-10°C and maintained for 1 h. The solid was filtered and washed with methanol (10 ml). Solid was dried for 2-3 h at 80-85°C.
Yield- 1.8g.

EXAMPLE-3
Apixaban (2 g) was added to Ethanol (60 ml) and the mixture was heated to reflux and maintain for 1 h. The mixture was filtered through filter paper and filtrate was cooled to 5-10°C and maintained for 1 h. The solid was filtered and washed with Ethanol (10 ml). Solid was dried for 2-3 h at 80-85°C.
Yield- 1.75g.

EXAMPLE-4
Apixaban (2 g) was added to 1-pentanol (36 ml) and the mixture was heated to reflux and maintain for 1 h. The mixture was filtered through filter paper and filtrate was cooled to 5-10°C and maintained for 1 h. The solid was filtered and washed with 1-pentanol (10 ml). Solid was dried for 3-4 h at 80-85°C.
Yield-1.8g.

PREPARATION OF FORM – B

EXAMPLE-6
Apixaban (2 g) was added to acetonitrile (50 ml) and the mixture was heated to reflux and maintain for 30 min. The mixture was filtered through filter paper and filtrate was cooled to 25-30°C and maintained for 2 h. The solid was filtered and washed with acetonitrile (10 ml). Solid was dried for 2-3 h at 80-85°C.Yield-1.85g.

EXAMPLE-7
Apixaban (2 g) was added to mixture of Methanol (10 ml) and MDC (20 ml). The mixture was stirred at room temperature for 5 min after then solvents was distilled under reduce pressure at 40-45°C. Solid was dried for 2-3 h at 80-85°C.
Yield-1.75g.

EXAMPLE-8
Apixaban (2 g) was added to mixture of Methanol (10 ml) and MDC (20 ml). The mixture was stirred at room temperature for 5 min after then solvents was distilled under reduce pressure at 40-45°C. 1:1 mixture of Ethyl acetate and MDC (200 ml) was added to the residue and mixture was heated to reflux and maintain for 1 h. The mixture was filtered through filter paper and filtrate was cooled to 5-10°C and maintained for 1 h. The solid was filtered and washed with 50% mixture of Ethyl acetate and MDC (10 ml). Solid was dried for 2-3 h at 80-85°C.

EXAMPLE-9
Apixaban (2 g) was added to mixture of Methanol (10 ml) and MDC (20 ml). The mixture was stirred at room temperature for 5 min after then solvents was distilled out atmospherically at 45-50°C. Further ethanol (20 ml) was added to reaction mixture and mixture was heated to 60°C and maintain for 30 min. After that mixture was allowed to room temperature and maintained for 2 h. The solid was filtered and washed with Ethanol (10 ml). Solid was dried for 2-3 h at 80-85°C.

PREPARATION OF FORM – C

EXAMPLE-10
Apixaban (3 g) was added to Acetic acid (9 ml) and the mixture was heated to 50-55°C and maintained till clear solution. After that mixture was allowed to room temperature and slowly added to water (36 ml) at 10-20°C. The mixture was stirred at room temperature for 1h. The solid was filtered and washed with water (9 ml). Solid was dried for 2-3 h at 80-85°C.
Yield-2.7g.

EXAMPLE-11
Apixaban (2 g) was added to DMF (16 ml) and the mixture was heated to 60-65°C and maintained till clear solution. The mixture slowly added to water (40 ml) at room temperature and maintained for 1 h. The solid was filtered and washed with water (10 ml). Solid was dried for 2-3 h at 80-85°C.
Yield-1.75g.