Claims:1. A anhydrous crystalline form of Apixaban, compound of Formula I,

Formula I
characterized by at least one of the following properties
i. a powder X-ray diffraction pattern substantially in accordance with Figure 1;
ii. a powder X-ray diffraction pattern has peaks at about 12.87, 13.92, 16.98, 18.43, 21.12, 21.54 and 22.07± 0.2º;
iii. a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 2,

2. The anhydrous crystalline form of claim 1, has purity more than 99.9 %, when measured by HPLC.

3. The anhydrous crystalline form of claim 1, wherein crystalline form Apixaban can be converted in to any other crystalline or amorphous form of Apixaban.

4. A process for the preparation of anhydrous crystalline form of Apixaban, has purity more than 99 % when measured by HPLC, the process comprises the steps of
a) dissolving Apixaban in dimethylsulphoxide
b) adding water to the mixture of step a) at suitable temperature
c) isolating crystalline form of Apixaban.

5. The process of claim 4, wherein the step b) used water is cooled at temperature in between range of 0°C to 5°C.

6. The process of claim 4, wherein the step (b) is carried out at temperature in between range of 0°C to 10°C.

7. The process of claim 4, wherein water can be seeded with about 0.5% w/w to 1.0% w/w anhydrous crystalline form of Apixaban.
, Description:Field of Invention

The present invention relates to a anhydrous crystalline form of Apixaban. In particular, the present invention directs to process for the preparation of crystalline form of Apixaban, has purity more than 99 % when measured by HPLC.

Background of the invention

Apixaban is an anticoagulant for the treatment of venous thromboembolic events, indicated for the treatment of venous thromboembolic events. Apixaban is a factor Xa inhibitor, chemically described as 1-(4methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl) phenyl]-4, 5, 6, 7-tetrahydro-1H-pyrazolo [3, 4c] pyridine-3-carboxamide as a compound of Formula (I).

Formula-I
US Patent No. 6,967,208 describes the Apixaban and its process for the preparation. US Patent Nos. 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 application describe processes for the preparation of Apixaban US 20070027186 and US 20070203178.

The following PCT Publications describe the synthesis of Apixaban: WO2003/026652, WO20003/049681, WO 2007/001385, WO 2003047520 A2, WO 2010/030983 A2, W02010/030980 and WO 2014/108919 A2

Crystalline forms of Apixaban, Form H2-2 and Form N-1 are described in the PCT Publication No. W02007/001385
Summary of the Invention

The present invention provides a anhydrous crystalline form of Apixaban, compound of Formula I,

Formula I
has purity more than 99 % when measured by HPLC

The present invention also provides a process for the preparation of anhydrous crystalline form of Apixaban, has purity more than 99 %, the process includes the steps of
a) dissolving Apixaban in a dimethylsulphoxide
b) adding water to the mixture of step a) at suitable temperature
c) isolating crystalline form of Apixaban.

The present invention also provides the conversion of anhydrous crystalline form of Apixaban of present invention to other anhydrous crystalline or amorphous form of Apixaban.

Brief Description of the Drawings

Figure 1 shows an illustrative example of X-ray powder diffraction pattern of anhydrous crystalline form of Apixaban
Figure 2 shows an illustrative example of anhydrous differential scanning calorimetry thermogram of crystalline form of Apixaban
Description of the Invention

For purposes of the present invention, the following terms are defined below.

The X-ray diffraction powder patterns of the present invention were obtained using a Bruker or PANalytical export Pro Powder X-ray Diffractometer at Cu Ka radiation, has the wavelength 1.54 Å.

In one aspect of the present invention provides a anhydrous crystalline form of Apixaban, compound of Formula I,

Formula I
has purity more than 99 % when measured by HPLC.

In another aspect, the present invention provides a anhydrous crystalline form of Apixaban is characterized by its X-ray powder diffraction pattern substantially as shown in Figure 1, differential scanning calorimetry thermogram as shown in Figure 2.

In another aspect, the present invention provides a anhydrous crystalline form of Apixaban, is characterized by X-ray diffraction pattern according to Figure 1, which is expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a copper K a-radiation source, wherein said X-ray powder diffraction pattern includes two or more peaks selected from the group comprising of peaks with 2 theta angles of 12.87, 13.92, 16.98, 18.43, 21.12, 21.54 and 22.07± 0.2º.

The XRPD characteristic peaks of anhydrous crystalline form of Apixaban, has purity more than 99 %, further defined from the Table 1:

Crystalline XRD Apixaban
2 Theta peaks d-spacing [Aº] Relative Intensity [%]
8.46 10.44 8.76
10.02 8.82 9.11
10.51 8.41 12.24
11.17 7.91 7.59
12.30 7.19 15.95
12.87 6.87 52.19
13.92 6.36 51.61
15.18 5.83 4.98
15.80 5.60 3.27
16.24 5.45 21.83
16.98 5.21 100.0
17.27 5.13 11.27
18.43 4.81 82.67
18.80 4.71 22.36
19.58 4.53 17.01
21.12 4.20 36.09
21.54 4.12 32.59
22.07 4.02 45.31
22.24 3.99 24.86
24.10 3.69 5.24
24.75 3.59 20.24
25.34 3.51 8.30
25.89 3.44 4.92
26.96 3.30 26.61
27.72 3.21 10.43
28.01 3.18 5.87
28.65 3.11 10.06
29.19 3.05 7.60
29.93 2.98 12.00
30.64 2.91 6.44
31.77 2.81 5.34
32.71 2.73 6.04
34.99 2.56 5.84
35.72 2.51 2.99
37.42 2.40 3.81
37.91 2.37 3.22
38.81 2.32 2.36

The anhydrous crystalline form of Apixaban obtained by the process of the invention is stored at 25°C for a period of 3 months and no contamination of other polymorphic form has been observed.

In one another, aspect of the present invention provides the process for the preparation of crystalline form of Apixaban, has purity more than 99 % when measured by HPLC, the process includes the steps of
a) dissolving Apixaban in a dimethylsulphoxide
b) adding water to the mixture of step a) at suitable temperature
c) isolating crystalline form of Apixaban.

The present invention involves the dissolving Apixaban in dimethylsulphoxide to get a clear solution and filter the clear solution to make it free from foreign particles, followed by addition of obtained solution, in chilled purified water, wherein purified water can be seeded with about 0.5% w/w to 1.0% w/w anhydrous crystalline form of Apixaban at temperature in between range of 0°C to 5°C. The mixture is stirred and further cooled at temperature in between the range of 0°C to 10°C for a period of 1 hour. The reaction mixture is brought to temperature in between the range of 25°C to 35 °C and stirred for a period of 1 hour. The precipitate is filtered, washed with water and dried under vacuum at temperature in between range of 60°C to 80°C for a period of 24 hours to obtain the anhydrous crystalline form of Apixaban.

The present invention provides the process for the preparation of anhydrous crystalline form of Apixaban comprises the use of water or water miscible solvent, wherein water or water miscible solvent can be seeded with about 0.5% w/w to 1.0% w/w anhydrous crystalline form of Apixaban at temperature in between range of 0°C to 5°C.

The present invention also provides the conversion of crystalline form of Apixaban to other crystalline or amorphous form of Apixaban.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

Example

Example-1: Preparation of Anhydrous Crystalline Apixaban

Charged Apixaban (100 gm) in dimethyl sulphoxide (3.5 L) to get a clear solution and filter the clear solution to make it free from foreign particles. The clear solution was added to purified chilled water (14.0 L) at temperature about 0°C to 5°C. The mixture was stirred and further cooled at temperature of about 0°C to 10°C for a period of 1 hour. The reaction mixture was heated to temperature of about 25°C to 35 °C and stirred for a period of 1 hour. The precipitate was filtered, washed with water (2.0 L) and dried under vacuum at temperature about 60°C to 80°C for a period of 24 hours to obtain the anhydrous crystalline form of Apixaban.
Yield: 90 g
HPLC Purity: 99.5%
Moisture content (m/c): 0.5 % w/w
Melting point: 238-240 °C