DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

PROCESS FOR THE PREPARATION OF APIXABAN POLYMORPHIC FORM N-1 WITH PARTICLE SIZE DIAMETER D90 GREATER THAN 90 µm WITH PLATE SHAPE

Applicant : NEULAND LABORATORIES LIMITED
Nationality : India
Address : Neuland Laboratories Limited, 11th Floor, 5th Office Level, Plot No. 573A-III, Phoenix IVY Building, Road No.82, Jubilee Hills, Hyderabad-500033, Telangana, India.

The following specification particularly describes nature of the invention and manner in which it is to be performed.

Title of the Invention
A process for the preparation of Apixaban polymorphic form N-1 having a particle size diameter D90 greater than 90 µm with plate shape.

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 than 90 µm.

The present invention also relates to the plate shape of Apixaban N-1 having a particle size diameter D90 greater than 90 µm.

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 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 2011106478 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 microns.

In all prior-art references, particle shape is not reported for Apixaban N-1 form. In general, rod shape or plate shape are preferred in manufacturing to obtain better yields.

Therefore, there is a need for process for the preparation of Apixaban polymorph N-1 form having particle size greater than 90 µm with rod shape or plate shape.

Summary of the Invention
In one aspect of the present invention provide a process for the preparation of Apixaban polymorph form N-1 of formula (I) having a particle size diameter D90 greater than 90 µm with plate shape,

which comprises:
a) dissolving Apixaban in a mixture of dichloromethane and methanol;
b) adding Norit carbon to obtained solution in step a);
c) distilled off the solvents under vacuum at a suitable temperature;
d) dissolving the compound obtained in step c) with dimethyl sulfoxide;
e) cooling the solution in step d) and adding methanol;
f) optionally seeding Apixaban with high particle size to step e) solution at 50 °C to 70 °C;
g) cooling the solution in step f) to -5 °C to 10 °C; and
h) isolating Apixaban polymorph form N-1 of formula (I).

In another aspect of the present invention is to provide a process for the preparation of Apixaban polymorph form N-1 having a particle size diameter D90 greater than 90 µm of plate shape.

Brief Description of the Drawings
Figure - 1 is shows a representative Microscopic Image of Apixaban N-1 form having a particle size diameter D90 greater than 90 µm of plate shape.
Figure - 2 is shows X-ray diffraction pattern of Apixaban N-1 form having a particle size diameter D90 greater than 90 µm of plate shape.

Detailed Description of the Invention

In one embodiment, 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 than 90 µm with plate shape,

which comprises:
a) dissolving Apixaban in a mixture of dichloromethane and methanol;
b) adding Norit carbon to obtained solution in step a);
c) distilled off the solvents under vacuum at a suitable temperature;
d) dissolving the compound obtained in step c) with dimethyl sulfoxide;
e) cooling the solution in step d) and adding methanol;
f) optionally seeding Apixaban with high particle size to step e) solution at 50 °C to 70 °C;
g) cooling the solution in step f) to -5 °C to 10 °C; and
h) isolating Apixaban polymorph form N-1 of formula (I).

The starting compound i.e., Apixaban can be prepared according to the methods known in the art. The Apixaban used herein is selected from the group consisting of but not limited to freebase, crystalline form, amorphous form or any solvate.

The step a) of aforementioned process involves the dissolution of Apixaban in a mixture of dichloromethane and methanol can be carried out at a suitable temperature of about 20 °C to about 40 °C; preferably at 25 °C to 35 °C and stirred for sufficient period of time; preferably 15 minutes to get clear solution.

The step b) of aforementioned process involves the addition of norit carbon to obtained solution in step a) can be carried out at a suitable temperature of about 20 °C to about 40 °C; preferably at 25 °C to 35 °C and stirred for sufficient period of time; preferably 30 minutes. Filter the contents and washed with mixture of dichloromethane and methanol (1:1) in a dry cylindrical glass reactor.

The step c) of aforementioned process involves the solvents were distilled off under vacuum at below 60°C; preferably at 50 °C to get thick slurry mass.

The step d) of aforementioned process involves the addition of dimethyl sulfoxide to the slurry mass obtained in step c) and maintained for 1 to 3 hours; preferably 2 hours at 45 °C to 60 °C; preferably 50 °C to 55 °C. Degas and heated the reaction mass to 70 °C 95 °C; preferably 80 °C 85 °C with stirred for sufficient period of time; preferably 15 to 30 minutes to get clear solution.

The step e) of aforementioned process involves the reaction mass obtained in step d) was cooled to 50 °C to 70 °C; preferably 60 °C to 65 °C for sufficient period of time; preferably 1 hour, slowly addition of methanol over a period of 30 to 120 minutes; preferably 30 to 60 minutes at the same temperature to get clear solution.

The step f) of aforementioned process involves optionally seeded with Apixaban high particle size can be carried out at a suitable temperature of about 50 °C to about 70 °C; preferably at 60 °C to 65 °C and stirred for sufficient period of time; preferably 60 minutes, till complete formation of crystals; the Apixaban seed is having a particle size diameter D90 is 130 to 200 µm.

The step g) of aforementioned process involves the reaction mass was further cooled to -10 °C to 10 °C; preferably -5 °C to 10 °C for sufficient period of time; preferably 3 to 4 hours.

The step h) of aforementioned process involves the isolation of Apixaban polymorph form N-1 of formula (I) can be carried out by any conventional techniques known in the art, for example filtration of the solid and drying at suitable temperature.

In another embodiment, the present invention provides a process for preparation of Apixaban polymorphic form N-1 having a particle size diameter D90 greater than 90 µm of plate shape.
PXRD Analysis Method:
X-Ray Powder Diffractions were performed on PANalytical X-Ray powder diffractometer model X'Pert PRO, Cu-tube, X’Celerator detector. PANalytical sample holder Pw1811/16 with a Pw1811/00 holder by back-loading technique using the Pw1770/10 sample preparation tool kit. Scanning parameters: range 2-40° 2?, continuous scan, Time per step: 20 seconds, Step size: 0.01671°.

Particle Size Distribution Analysis Method:
Particle size is performed by using Malvern MASTERSIZER 3000 in wet method (Accessory name: Hydro MV). Absorption index 0.100, Dispersant name: Water, Obscuration low limit 10-20%, Stirrer speed 2000 rpm.

Microscopic Image Instrument Conditions:
Microscopic Image of Apixaban N-1 form plate shape is determined by Olympus BX53M with 10X zoom and 10X magnification.

EXPERIMENTAL PORTION:
The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.

Examples:
Example 1: Preparation of Apixaban polymorph form N-1 of formula (I) having a particle size diameter D90 greater than 90 µm
To a clean and dry RBF, Apixaban (100 grams; 1 equivalent), dichloromethane (1500 mL; 15 volumes) and methanol (300 mL; 3 volumes) were added at 25 °C to 35 °C, stirring for 15 minutes to get clear solution. Norit carbon (5 grams; 0.05 volumes) was added at 25 °C to 35 °C and stirred for 30 minutes. Filtered the contents and washed with a mixture of dichloromethane and methanol (1:1) in a dry cylindrical glass reactor. Distilled off filtrate under vacuum at 50 °C to get thick slurry mass. Dimethyl sulfoxide (500 mL; 5 volumes) was added at 50 °C to 55 °C and maintained for 2 hours at the same temperature. Degas and heated the reaction mass to 80 °C to 85 °C and maintained for 15 to 30 minutes to get clear solution. Slowly cool the reaction mass to 60 °C to 65 °C and maintained for 1 hour. Methanol (1200 mL; 12 volumes) was added slowly at 60 °C to 65 °C over a period of 30 to 60 minutes to get clear solution at the same temperature. Seeded with Apixaban (1 gram; 0.01 times) with higher particle size at 60 °C to 65 °C and maintained for 60 minutes. Cooled the reaction mass slowly to 0 °C to 5 °C over period of 3 to 4 hours and maintained for 2 hours. The solid obtained was filtered off, washed with methanol (100 mL; 1 volume) and then dried to get the title compound.

Example 2: Particle Size Distribution Information is mentioned in below table 1
Table 1:
S. No. Input (grams) Ouput (grams) Yield (w/w) PSD D(90) NLT 90 µm
1. 200 160 80 177
2. 200 160 80 180
3. 200 157 78.5 212
,CLAIMS:We claim:

1. A process for the preparation of Apixaban polymorphic form N-1 of formula (I) having a particle size diameter D90 greater than 90 µm,

comprising:
a) dissolving Apixaban in a mixture of dichloromethane and methanol;
b) adding Norit carbon to obtained solution in step a);
c) distilled off the solvents under vacuum at a suitable temperature;
d) dissolving the compound obtained in step c) with dimethyl sulfoxide;
e) cooling the solution in step d) and adding methanol;
f) optionally seeding Apixaban with high particle size to step e) solution at 50 °C to 70 °C;
g) cooling the solution in step f) to -5 °C to 10 °C; and
h) isolating Apixaban polymorph form N-1 of formula (I).

2. The process as claimed in claim 1, the obtained crystal shape is plate shape.

Dated this 17th day of February 2025.
Signature:
Dr. P.S.R.C. Murthy, Ph.D
Indian Patent Agent - 2438
Director & Head - IPR
Neuland Laboratories Limited.