DESC:Field of the Invention
The present invention relates to the process for the preparation of Apixaban polymorphic form N-1 of formula (I) having a particle size diameter D90 greater than100 µm using roller compaction technology

Background of the Invention
Apixaban, chemically known as 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-1H-pyrazolo[3,4-c]pyridine-3-carboxamide or 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, is represented by formula (I).

Apixaban was first disclosed in US 6,967,208 and it is used to treat and prevent blood clots such as deep vein thrombosis and pulmonary embolism.

WO 2007/001385 A2 discloses process for the preparation of Apixaban and other pyrazole-pyridine derivatives. This patent application discloses crystalline form N-1 and form H2-2 of Apixaban along with the unit cell data thereof.

WO 20110106478 A2 discloses a composition comprising crystalline Apixaban particles having a mean particle size equal to or less than about 89 µm and a pharmaceutically acceptable diluent or carrier.

CN104644593 discloses crystalline Apixaban particles (N-1) having particle size D90 equal to or less than about 70 µm.

US 2017000799 discloses composition comprising Apixaban (N-1) crystal having particle size D90 is 100 µm or less.

WO 2013164839 discloses amorphous form of Apixaban having particle size D10 less than about 50 µm, D50 less than about 200 µm and D90 less than about 400 µm.

IN 3987/MUM/2015 discloses composition comprising Apixaban (N-1), crystal having particle size D90 equal to or greater than 120 and fine fraction of D90 equal to or less than 20 micron.

All above mentioned process using crystallization techniques, which requires solvent(s) for obtaining required particle size of Apixaban. These solvent(s) may effect the environment hence there is a need for environment friendly process.

Summary of the Invention
The present invention relates to the process for the preparation of Apixaban polymorph form N-1 of formula (I) having a particle size diameter D90 greater than100 µm.

a) fix the parameter of compactor with pressure: 40-60 kg/cm2, RPM: 2 -10 and gap between roller: 2- 5 mm;
b) charge the material in feed hopper of compactor;
c) start compaction;
d) collect flakes at the outlet;
e) sieve the material through 30-80 mesh and separate oversize and undersize;
f) feed the undersize material to compacter to get flakes;
g) sieve the material through 30-80 mesh and separate oversize & undersize;
h) feed the undersize material to compacter to get flakes till no undersize;
i) collect all oversize material and milled the material through 0.5 - 3 mm sieve.

Process for the preparation of Apixaban polymorph form N-1 having a particle size diameter D90 greater than 100 µm by using compaction technique.

The crystalline form N-1 of apixaban characterized by a x-ray powder diffraction pattern comprising 2? values at 10.0°, 10.6°, 12.3°, 12.9°, 18.5° and 27.1° ±0.2.

Brief Description of the Drawings
Figure - 1 is a schematic showing the parts of an exemplary roller compactor.
Figure - 2 is comparison X-ray diffraction pattern before (Figure 2A) and after compaction (Figure 2B) of Apixaban polymorphic form N-1.
Figure - 3 is shows a representative particle size distribution Histogram.

Detailed Description of the Invention
The present invention relates to the process for the preparation of Apixaban polymorph form N-1 of formula (I) having a particle size diameter D90 greater than100 µm.

a) fix the parameter of compactor with pressure: 40-60 kg/cm2, RPM: 2 -10 and gap between roller: 2- 5 mm;
b) charge the material in feed hopper of compactor;
c) start compaction;
d) collect flakes at the outlet;
e) sieve the material through 30-80 mesh and separate oversize and undersize;
f) feed the undersize material to compacter to get flakes;
g) sieve the material through 30-80 mesh and separate oversize & undersize;
h) feed the undersize material to compacter to get flakes till no undersize;
i) collect all oversize material and milled the material through 0.5 - 3 mm sieve.

The present invention provides a process for the preparation of Apixaban polymorphic form N-1 having a particle size diameter D90 greater than 100 µm by using compaction technique.

In view of the above, the present invention provides a process for the preparation of Apixaban polymorph form N-1 having a particle size diameter D90 greater than 100 µm by using compaction technique. The main advantages of this technique is as
1) No solvent require.
2) No polymorph change.
3) This technique is applicable for continuous manufacturing and thereby achieving faster throughput time and lower operational and maintenance costs.

As used herein, compactor is MOC-SS-316 & Model and the diagram substantially the same as that shown in Figure 1.

As used herein, “Particle Size Distribution (PSD)” means the cumulative volume size distribution of equivalent spherical diameters as determined by laser diffraction in Malvern Master Sizer 2000 equipment and having PSD Histogram pattern substantially the same as that shown in Figure 3.

EXAMPLE 1
Fix the parameter of compactor with pressure: 55 kg/cm2, RPM: 3 and gap between roller: 3 mm. Apixaban crystalline powder having low particle size is taken in a feed hopper. Flakes were collected, sieved the material through 30 mesh and separated oversize and undersize particles. Again, feed the oversize and undersize to compacter to get flakes. Sieved the material through 30 mesh and separated the oversize and undersize particles. Feed the undersize material to compacter to get flakes till no undersize. Collected all oversize material & milled the material through 1 mm sieve. The material was collected and send the sample for PSD analysis by Malvern master-sizer by wet method.
The particle size is as below:

Particle size D10 (µm) D50 (µm) D90 (µm)
Input material 0.934 2.126 45.98
Output material
(after Compaction) 6.021 32.32 145.41

EXAMPLE 2
Fix the parameter of compactor with pressure: 45 kg/cm2, RPM: 3 and gap between roller: 2 mm. Apixaban crystalline powder having low particle size is taken in a feed hopper. Flakes were collected, sieved the material through 40 mesh and separated oversize and undersize particles. Again, feed the oversize and undersize to compacter to get flakes. Sieved the material through 40 mesh and separated the oversize and undersize particles. Feed the undersize material to compacter to get flakes till no undersize. Collected all oversize material & milled the material through 2 mm sieve. Sift the material with 80 mesh and separate the oversize material. The oversize material was collected and send the sample for PSD analysis by Malvern master-sizer by wet method.
The particle size is as below:

Particle size D10 (µm) D50 (µm) D90 (µm)
Input material 0.934 2.126 45.98
Output material
(after Compaction) 3.68 24.8 120.2 ,CLAIMS:1. A process for the preparation of Apixaban polymorphic form N-1 of formula (I) having a particle size diameter D90 greater than 100 µm using roller compaction technology, which comprises

a) fix the parameter of compactor with pressure: 40-60 kg/cm2, RPM: 2-10 and gap between roller: 2-5 mm;
b) charge the material in feed hopper of compactor;
c) start compaction;
d) collect flakes at the outlet;
e) sieve the material through 30-80 mesh and separate over size and undersize;
f) feed the undersize material to compacter to get flakes;
g) sieve the material through 30-80 mesh and separate over size & undersize;
h) feed the undersize material to compacter to get flakes till no undersize;
i) collect all oversize material and milled the material through 0.5-3 mm sieve.