FORM 2
THE PATENT ACT 1970 (39 of 1970) & The Patents Rules,2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
An amorphous form of Betrixaban maleate
2. APPLICANT (S)
(a) NAME: Enaltec Labs Pvt. Ltd.
(b) NATIONALITY:
An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS:
Enaltec Labs Pvt. Ltd., 17th Floor, Kesar Solitaire, Plot No. 5, Sector 19, Sanpada, Navi Mumbai- 400705, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and manner in which it is to be performed

TECHNICAL FIELD OF THE INVENTION
The present invention relates to process for preparation of an amorphous form of Betrixaban maleate represented by structural formula I.

BACKGROUND OF THE INVENTION
Betrixaban maleate is chemically known as N-(5-chloropyridin-2-yl)-2[4-(N,N-dimethylcarbamimidoyl)-benzoylamino]-5-methoxybenzamide maleate and was first disclosed in U.S. patent number 6,376,515 and is represented by structural formula I.


Betrixaban maleate is well tolerated and effective drug indicated as a factor Xa (FXa) inhibitor indicated for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE.
U.S. patent number 7,598,276 discloses a crystalline form of Betrixaban maleate characterized by X-ray powder diffraction peaks at about 4.9, 9.7, 13.8, 14.1, 15.2, 17.6, 18.5, 20.8, 21.6, 22.7, 24.1, 26.3, and 26.8 degrees 28.
U.S. patent number 8,946,269 discloses a crystalline form II of Betrixaban maleate characterized by X-ray powder diffraction peaks at about 10.1, 14.6, 18.0, and 22.0 degrees 28 (±0.1 degrees 28). Furthermore, said patent also discloses a crystalline form III of Betrixaban maleate characterized by X-ray powder diffraction peaks at about 15.1, 2.2, 4.9, 17.4, 10.0, 22.4, 26.5, 2.9, 24.6, 19.4, and 24.2 degrees 28.
It is well known that amorphous form of an active pharmaceutical ingredient possess physical properties that are advantageous over those of other crystalline forms. These properties include hygroscopicity, melting temperature, solubility, dissolution rate and stability under various storage conditions.
Accordingly there is a need in the art to develop a process for preparation of amorphous form of Betrixaban maleate.
OBJECT OF THE INVENTION
i) An object of present invention is to provide an improved process for the
preparation of an amorphous form of Betrixaban maleate.

ii) Another object of present invention is to provide a simple, cost efficient and environment friendly process for preparation of an amorphous form of Betrixaban maleate.
SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide an amorphous form of Betrixaban maleate.
A second aspect of the present invention is to provide a process for the preparation of an amorphous form of Betrixaban maleate, comprising the steps of
a. providing a solution of Betrixaban maleate in a suitable solvent and
b. isolating an amorphous form of Betrixaban maleate thereof by the removal of
the solvent by spray-drying or freeze-drying technique or under reduced
pressure.
A third aspect of the present invention is to provide process for the preparation of an amorphous form of Betrixaban maleate, comprising the steps of
a. providing a solution of Betrixaban maleate in a suitable solvent and
b. isolating an amorphous form of Betrixaban maleate thereof by the method of
slow precipitation.
A fourth aspect of the present invention is to provide a process for the preparation an amorphous form of Betrixaban maleate, comprising the steps of
a. treating Betrixaban free base with maleic acid in a suitable solvent to get
Betrixaban maleate
b. isolating an amorphous form of Betrixaban maleate thereof by the method of
by slow evaporation, slow cooling or antisolvent precipitation.

Another aspect of the present invention is to provide a pharmaceutical composition comprising an amorphous form of Betrixaban maleate and pharmaceutical acceptable excipients.
DETAILED DESCRIPTION OF INVENTION:
Crystalline Betrixaban maleate is prepared by the process known in the art such as those described in U.S. patent number 6,376,515, U.S. patent number 7,598,276 or U.S. patent number 8,946,269 which are incorporated herein by reference only.
In an embodiment of the present invention is to provide a process for the preparation of an amorphous form of Betrixaban maleate, comprising the steps of
a. providing a solution of Betrixaban maleate in a suitable solvent and
b. isolating an amorphous form of Betrixaban maleate thereof by the removal of
the solvent by spray-drying technique.
In accordance with an embodiment of the present invention a solution of crystalline Betrixaban maleate in an organic solvent may be prepared by dissolving crystalline Betrixaban maleate in an organic solvent at a temperature in the range of 25°C to 80°C.
In accordance with an embodiment of the present invention an organic solvent used in the step (a) is selected from the group consisting of ketones, alcohols or mixtures thereof.
In specific embodiment of the present invention the ketone solvents may be selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof.

In specific embodiment of the present invention the alcohol solvents may be selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.
The solvent may be removed from the solution by a technique of spray drying.
Another aspect of the present invention is to provide process for the preparation of an amorphous form of Betrixaban maleate, comprising the steps of
a. providing a solution of Betrixaban maleate in a suitable solvent;
b. precipitating an Betrixaban maleate by addition of antisolvent and
c. isolating the amorphous for of Betrixaban maleate by filtration method.
In accordance with another aspect of the present invention the temperature used in the step (a) is 25 °C to 80°C.
In accordance with an embodiment of the present invention an organic solvent used in the step (a) is selected from the group consisting of ketones, alcohols or mixtures thereof.
In specific embodiment of the present invention the ketone solvents may be selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof.
In specific embodiment of the present invention the alcohol solvents may be selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.
In accordance with another aspect of the present invention the temperature used in the step (b) is 40°C to 70°C.

In accordance with another aspect of the present invention the anti-solvent used in the step (b) is selected from the group consisting of organic hydrocarbons.
In specific embodiment of the present invention the organic hydrocarbons are selected from the group consisting of hexane, heptane, cyclohexane, cycloheptane or the mixture thereof.
An amorphous form of Betrixaban maleate may be isolated by the steps of filtration, centrifugation, washing, drying or the combinations thereof.
The amorphous form of Betrixaban maleate may be further dried under vacuum at a temperature in the range of 40°C to 60°C for a period of 1 hour to 8 hours to obtain amorphous form of Betrixaban maleate with desired residual solvent content.
Yet another aspect of the present invention is to provide process for the preparation of an amorphous form of Betrixaban maleate, comprising the steps of
a. treating Betrixaban base with maleic acid in a suitable solvent;
b. precipitating an Betrixaban maleate by addition of antisolvent and
c. isolating the amorphous for of Betrixaban maleate by filtration method.
In accordance with yet another aspect of the present invention the temperature used in the step (a) is 25°C to 80°C.
In accordance with an embodiment of the present invention an organic solvent used in the step (a) is selected from the group consisting of ketones, alcohols or mixtures thereof.
In specific embodiment of the present invention the ketone solvents may be selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof.

In specific embodiment of the present invention the alcohol solvents may be selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.
In accordance with another aspect of the present invention the temperature used in the step (b) is 40°C to 70°C.
In accordance with another aspect of the present invention the anti-solvent used in the step (b) is selected from the group consisting of organic hydrocarbons.
In specific embodiment of the present invention the organic hydrocarbons are selected from the group consisting of hexane, heptane, cyclohexane, cycloheptane or the mixture thereof.
An amorphous form of Betrixaban maleate may be isolated by the steps of filtration, centrifugation, washing, drying or the combinations thereof.
The amorphous form of Betrixaban maleate may be further dried under vacuum at a temperature in the range of 40°C to 60°C for a period of 1 hour to 8 hours to obtain amorphous form of Betrixaban maleate with desired residual solvent content.
EXAMLES:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the processes of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of substantially pure amorphous form of Betrixaban maleate.
A solution of Crystalline Betrixaban maleate (10 gm) in acetone (150 ml) was heated to a temperature in the range of 55°C to 60°C. The clear solution was subjected to filtration through hyflo bed. Filtrate was heated to a temperature in the range of 55°C

to 60°C. Reaction mass was cooled at a temperature in the range of 45°C to 55°C. Added n-heptane (200 ml) at a temperature in the range of 45°C to 55°C. Cooled the reaction mass to a temperature in the range of 25°C to 30°C. The resulting solid was isolated by filtration, washed with n-Heptane and dried. Betrixaban maleate in an amorphous form was thus isolated. Yield: 9.5 gm; Purity: 99.8% (By HPLC)
Example 2: Preparation of substantially pure amorphous form of Betrixaban maleate.
A solution of Betrixaban free base (10 gm) in acetone (100 ml) was heated to a temperature in the range of 55°C to 60°C. A solution of maleic acid (5.13 gm) in acetone (50 ml) was added to the reaction mass at a temperature in the range of 55°C to 60°C. Reaction mass was stirred for 30 minutes at a temperature in the range of 55°C to 60°C. The clear solution was subjected to filtration through hyflo bed. Filtrate was heated to a temperature in the range of 55°C to 60°C. Reaction mass was cooled at a temperature in the range of 45°C to 55°C. Added n-heptane (200 ml) at a temperature in the range of 45°C to 55°C. Cooled the reaction mass to a temperature in the range of 25°C to 30°C. The resulting solid was isolated by filtration, washed with n-Heptane and dried. Betrixaban maleate in an amorphous form was thus isolated. Yield: 11.3 gm; Purity: 99.7% (By HPLC)

We Claim:
1. A process for the preparation of an amorphous form of Betrixaban maleate,
comprising the steps of
a. providing a solution of Betrixaban maleate in a suitable solvent;
b. precipitating an Betrixaban maleate by addition of antisolvent, and
c. isolating the amorphous for of Betrixaban maleate.
2. The process as claimed in claim 1, step (a) wherein solvent used is ketone solvents selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof, alcohol solvents selected from group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.
3. The process as claimed in claim 1, step (a) wherein solution of Betrixaban maleate in a suitable solvent is provided at a temperature in the range of 25°C to 80°C.
4. The process as claimed in claim 1, step (b) wherein amorphous form of Betrixaban maleate is precipitated by addition of organic hydrocarbons as antisolvent, which is selected from the group consisting of hexane, heptane, cyclohexane, cycloheptane or the mixture thereof.
5. A process for the preparation of an amorphous form of Betrixaban maleate, comprising the steps of
a. treating Betrixaban base with maleic acid in a suitable solvent;
b. precipitating an Betrixaban maleate by addition of antisolvent, and
c. isolating the amorphous for of Betrixaban maleate.

6. The process as claimed in claim 5, step (a) wherein solvent used is ketone solvents selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof, alcohol solvents selected from group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.
7. The process as claimed in claim 5, step (a) wherein Betrixaban base is treated with maleic acid in a suitable solvent at a temperature in the range of 25°C to 80°C.
8. The process as claimed in claim 5, step (b) wherein amorphous form of Betrixaban maleate is precipitated by addition of organic hydrocarbons as antisolvent, which is selected from the group consisting of hexane, heptane, cyclohexane, cycloheptane or the mixture thereof.