DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of earlier Indian provisional patent application IN 201841048633 filed on December 21, 2018 which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION

The present disclosure generally relates to the field of pharmaceutical sciences and specifically relates to novel acid addition salts of Betrixaban and process for their preparation thereof. The present disclosure more specifically relates Betrixaban addition salts namely formate salt, cinnamate salt, salicylate salt and processes for the preparation thereof.
BACKGROUND OF THE INVENTION

Betrixaban is chemically known as N-(5-chloropyridin-2-yl)-2-([4-(N, N-dimethyl carbamimidoyl)benzoyl] amino)-5-methoxybenzamide), having the structure shown in Formula-I.

Betrixaban maleate is chemically known as N-(5-chloropyridin-2-yl)-2-([4-(N,N-dimethyl carbamimidoyl)benzoyl] amino)-5-methoxybenzamide) maleate, having the structure shown in formula-II, is a factor Xa inhibitor.

Betrixaban maleate is 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 and is marketed in the US under the brand name BEVYXXA®.

Betrixaban and its pharmaceutically acceptable salts disclosed in the United States Pat. No. US 6376515.

Use of a substance for pharmaceutical purposes places high demands on the substance quality. The most efficient purification operation is crystallization. In the case of preparation of substances in amorphous form it is very difficult to achieve internationally appreciated quality criteria defined by the ICH guidelines. In those cases, purification by way of preparation of acid addition salts could be very useful which on neutralization will lead to substances with improved purity. Therefore, various Betrixaban salt forms could be used to enhance the purity of Betrixaban or its maleate salt.

Different salt forms of the same pharmaceutically active moiety differ in their physical properties such as melting point, solubility, etc. These properties may appreciably influence pharmaceutical properties such as dissolution rate and bioavailability.

Towards this end, it has been the endeavor of pharmaceutical scientists to provide novel salts of drug substances. Therefore, there remains a need to provide and characterize new Betrixaban salts. Further, it would be desirable to have reliable processes for producing these Betrixaban salt forms.

OBJECT AND SUMMARY OF THE INVENTION

The principle object of the present invention is to provide novel acid addition salts of Betrixaban with acids selected from formic acid, cinnamic acid and salicylic acid.

Another aspect of the present invention is to provide a process for the preparation of acid addition salts of Betrixaban, comprising:
a) providing Betrixaban free base in a solvent;
b) adding acid to the step (a);
c) isolating the salt of Betrixaban;
wherein, acid in the step (b) is selected from formic acid, cinnamic acid and salicylic acid

Another aspect of the present invention is to provide a pharmaceutical composition comprising Betrixaban acid addition salt, wherein acid is selected from formic acid, cinnamic acid and salicylic acid; and one or more pharmaceutically acceptable excipients. These acid addition salts can be crystalline or amorphous in nature.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides novel acid addition salts of Betrixaban with acids selected from formic acid, cinnamic acid and salicylic acid.

In another embodiment, the present invention provides a process for the preparation of acid addition salts of Betrixaban, comprising:
a) providing of Betrixaban free base in a solvent;
b) adding acid to step (a);
c) isolating the salt of Betrixaban
wherein, acid in the step (b) is selected from formic acid, cinnamic acid and salicylic acid
According to the present embodiment, Betrixaban free base in step a) may be a suspension or a solution. It may be obtained, by providing free base of Betrixaban in a solvent.
Within the context of this embodiment, the solvent may be a polar solvent, or mixtures thereof. Suitable polar solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, methanol, water, or a mixture of methanol and water is used as the solvent.
Next, according to the present embodiment, acid may be added the above reaction solution. Within the context of this embodiment, formic acid, cinnamic acid or salicylic acid may be added to the above reaction solution
Further, the above reaction mas may be maintained under stirring for about 2-6 hours at the at room temperature or ambient temperature or if required reaction mass can be heated to elevated temperatures or up to about the reflux temperatures and maintained for a time from about 10 minutes to about 5 hours or longer.
Next, according to the present embodiment, Betrixaban salts may be isolated from the reaction mixture. The isolation of salts of Betrixaban may be induced by using conventional techniques known in the art. For example, useful techniques include but are not limited to, concentrating, cooling, stirring, shaking, combining with an anti-solvent, evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, or the like. Evaporation as used herein refers to distilling of solvent almost completely at atmospheric pressure or under reduced pressure.

Further, the resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 1 hour to about 15 hours, or longer.

The salts of the present invention if desired can be purified by re-crystallization from an appropriate re-crystallization solvent or mixture of solvents.

In another embodiment, the present application provides a pharmaceutical composition comprising novel acid addition salts of Betrixaban and one or more pharmaceutically acceptable excipients.

Such further excipients and adjuvants are known to the person skilled in the art and may include one or more fillers; diluents, for example microcrystalline cellulose, lactose, mannitol, dibasic calcium phosphate, pregelatinized starch and the like; binders such as PVP, HPMC, HPC and the like; disintegrants, for example, sodium starch glycolate, crospovidone, croscarmellose sodium and the like; lubricants, for example, magnesium stearate, sodium stearyl fumarate and the like; sweeteners, for example, sucrose, saccharin and the like; flavoring agents, for example, peppermint, methyl salicylate, orange flavoring and the like; colorants; preservatives; buffers; and/or other excipients depending on the dosage form used.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

EXAMPLES

Example 1: Preparation of Betrixaban Formate salt

To a suspension of Betrixaban base (1g, 0.0022 moles), in water and methanol mixture (10mL:10mL), Formic acid (0.14g, 0.0027moles) was added. After stirring the reaction mass for 3-4 hrs. at ambient temperature, solids were removed by filtration and filter cake was washed with water (2mL). Finally, obtained product was dried under reduced pressure to yield Betrixaban Formate.

Example 2: Preparation of Betrixaban Salicylate salt

To a suspension of Betrixaban base (1g, 0.0022 moles), in water and methanol mixture (10mL:10mL), Salicylic acid (0.37g, 0.0027moles) was added. After stirring the reaction mass for 3-4 hrs. at ambient temperature, solids were removed by filtration and filter cake was washed with water (2mL). Finally, obtained product was dried under reduced pressure to yield Betrixaban Salicylate.

Example 3: Preparation of Betrixaban Cinnamate salt

To a suspension of Betrixaban base (1g, 0.0022 moles), in water and methanol mixture (10mL:10mL), Cinnamic acid (0.39g, 0.0027moles). was added. After stirring the reaction mass for 3-4 hrs. at ambient temperature, solids were removed by filtration and filter cake was washed with water (2mL). Finally, obtained product was dried under reduced pressure to yield Betrixaban Cinnamate.
,CLAIMS:1. An acid addition salt of Betrixaban of formula (I)

wherein the addition salt is selected from formic acid, cinnamic acid and salicylic acid.
2. A process for the preparation of an acid addition salt of Betrixaban, comprising:
a) providing of Betrixaban free base in a solvent;
b) adding acid to step (a);
c) isolating the salt of Betrixaban, wherein, acid in the step (b) is selected from formic acid, cinnamic acid and salicylic acid
3. The process as claimed in claim 2, wherein the solvent is selected from the group consisting of an alcohol, water and mixtures thereof.

4. The process as claimed in claim 3, wherein the alcohol solvent is selected from methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof.

5. The process as claimed in claim 2, a mixture of methanol and water is used as solvent.

6. A pharmaceutical composition comprising acid addition salts of Betrixaban of claims 1 and one or more pharmaceutically acceptable excipients.

7. A pharmaceutical composition comprising acid addition salts of Betrixaban of claims 1 and one or more pharmaceutically acceptable excipients.

8. The pharmaceutically acceptable excipients as claimed in claim 7, selected from microcrystalline cellulose, lactose, mannitol, calcium phosphate and starch.