DESC:
FIELD OF INVENTION
The present invention relates to solvates of Vortioxetine and pharmaceutically acceptable salts thereof. This invention further relates to Vortioxetine trifluoroacetate salt, its preparation, and its use for the preparation of Vortioxetine and its pharmaceutically acceptable salts and/or solvates.

BACKGROUND
Vortioxetine is approved as hydrobromide salt and marketing as “TRINTELLIX” which is an anti-depressant indicated for the treatment of major depressive disorder (MDD) in adults.
Vortioxetine hydrobromide is described chemically as 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine. The chemical structure of Vortioxetine hydrobromide salt is:

Formula-I
Vortioxetine hydrobromide salt is a white to very slightly beige powder that is slightly soluble in water.

U.S. Patent Number 7,144,884 B2 discloses Vortioxetine.

U.S. Patent Number 8,722,684 B2 discloses salts of Vortioxetine such as hydrochloride, hydrobromide, mesylate salt, fumarate, maleate, meso-tatrate salt, L-(+)-tatrate, D-(-)-tatrate, sulphate, phosphate, nitrate and solvates such as ethyl acetate solvate.

This patent further discloses crystalline forms alpha, beta and gamma of Vortioxetine hydrobromide and processes of preparation thereof.

U.S. Patent Number 8,598,348 B2 discloses Vortioxetine hydrobromide isopropanol solvate, its crystalline form and processes of preparation thereof.

U.S. Patent Number. 1,007,1092 B2 discloses Vortioxetine hydrobromide benzyl alcohol solvate, its crystalline form and processes of preparation thereof.

U.S. Patent Number. 1,051,9121 B2 discloses Vortioxetine hydrobromide propylene glycol solvate its crystalline form and processes of preparation thereof.

Indian Patent Application Number. No. 4010/MUM/2015 discloses Vortioxetine hydrobromide tert-butanol solvate and processes of preparation thereof.

New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. Hence, there is a continuing need for development of new solvates and polymorphs of Vortioxetine and its pharmaceutically acceptable salts.

The new solvates of Vortioxetine and its pharmaceutically acceptable salts that may have advantageous physico-chemical and biokinetic properties such as suitable solubility, thermal stability, hygroscopicity, dissolution profile, compatibility with excipients and combined active ingredients or special properties for final dosage form design.

An organic compound may give rise to a variety of solid forms either crystalline or amorphous having distinct physical properties. The variation in the physical properties frequently results in differences in bioavailability, stability, etc.

SUMMARY
One aspect of the present invention provides solvates of Vortioxetine and its pharmaceutically acceptable salts.
Another aspect of the present invention provides 2-pentanol solvate of Vortioxetine and its pharmaceutically acceptable salts.
Another aspect of the present invention provides process for the preparation of 2-pentanol solvate of Vortioxetine and its pharmaceutically acceptable salts, comprising.
a) Dissolving Vortioxetine free base in 2-pentanol,
b) Adding corresponding acid,
c) Isolating 2-pentanol solvate of Vortioxetine and its pharmaceutically acceptable salts.
Another aspect of the present invention provides Trifluoroacetate salt of Vortioxetine.
Another aspect of the present invention provides process for the preparation of Vortioxetine trifluoroacetate, comprising:
a) Dissolving Vortioxetine and its pharmaceutically acceptable salts in water or organic solvent or mixtures thereof,
b) Adding Trifluoracetic acid,
c) Isolating Vortioxetine trifluoroacetate.
Another aspect of the present invention provides process for the preparation of Vortioxetine and its pharmaceutically acceptable salts and/or solvates comprising:
a) Dissolving Vortioxetine free base in water or organic solvent or mixtures thereof,
b) Adding Trifluoracetic acid,
c) Optionally isolating Vortioxetine trifluoroacetate,
d) Adding suitable base,
e) Optionally isolating Vortioxetine free base,
f) Adding suitable organic solvent and an acid,
g) Isolating Vortioxetine and its pharmaceutically acceptable salts and/or solvates.
Another aspect of the present invention provides use of Vortioxetine trifluoroacetate for the preparation of Vortioxetine and its pharmaceutically acceptable salts and/or solvates.

Another aspect of the present invention provides pharmaceutical composition comprising 2-pentanol solvate of Vortioxetine and its pharmaceutically acceptable salts.

Brief description of Drawings:
Figure-1: Illustrates the XRD pattern of 2-pentanol solvate of Vortioxetine hydrobromide.
Figure-2: Illustrates the XRD pattern of Vortioxetine trifluoroacetate.
Figure-3: Illustrates DSC of 2-pentanol solvate of Vortioxetine hydrobromide.
Figure-4: Illustrates DSC of Vortioxetine trifluoroacetate.

DESCRIPTION OF THE CURRENT EMBODIMENTS:
One embodiment of the present invention provides for solvates of Vortioxetine and its pharmaceutically acceptable salts.
Another embodiment of the present invention provides 2-pentanol solvate of Vortioxetine and its pharmaceutically acceptable salts.
Wherein pharmaceutically acceptable salts of Vortioxetine are selected from hydrochloride, hydrobromide, phosphate, fumarate, tartrate salts etc.
Another embodiment of the present invention provides crystalline 2-pentanol solvate of Vortioxetine hydrobromide.
Another embodiment of the present invention provides crystalline 2-pentanol solvate of Vortioxetine hydrobromide characterized by XRD pattern of Figure 1.
Yet another embodiment of the present invention provides crystalline 2-pentanol solvate of Vortioxetine hydrobromide characterized by DSC of Figure 3.
Another embodiment of the present invention provides process for the preparation of 2-pentanol solvate of Vortioxetine and its pharmaceutically acceptable salts, comprising.
a) Dissolving Vortioxetine free base in 2-pentanol,
b) Adding corresponding acid,
c) Isolating 2-pentanol solvate of Vortioxetine and its pharmaceutically acceptable salts.
Wherein the acid used in step (b) is selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, phosphoric acid etc, preferably hydrobromic acid.
The isolation of 2-pentanol solvate of Vortioxetine and its pharmaceutically acceptable salts can be carried out by conventional techniques known to a person skilled in the art.
In other embodiment of the present invention provides a process for the preparation of 2-pentanol solvate of Vortioxetine hydrobromide, comprising.
a) Dissolving Vortioxetine free base in 2-pentanol,
b) Adding hydrobromic acid,
c) Isolating 2-pentanol solvate of Vortioxetine hydrobromide.
One more embodiment of the present invention provides Vortioxetine trifluoroacetate.
Another embodiment of the present invention provides crystalline form of Vortioxetine trifluoroacetate.
Another embodiment of the present invention provides crystalline form of Vortioxetine trifluoroacetate characterized by XRD pattern of Figure 2.
Another embodiment of the present invention provides crystalline form of Vortioxetine trifluoroacetate characterized by DSC of Figure 4.
Another embodiment of the present invention provides process for the preparation of Vortioxetine trifluoroacetate, comprising:
a) Dissolving Vortioxetine and its pharmaceutically acceptable salts in water or an organic solvent or mixtures thereof,
b) Adding Trifluoracetic acid,
c) Isolating Vortioxetine trifluoroacetate.
Wherein the organic solvent used in step (a) is selected from the group comprising of alcohols, ketones, ethers, esters, halogenated hydrocarbons, aromatic hydrocarbons and/or mixtures.

Another embodiment of the present invention provides process for the preparation of Vortioxetine and its pharmaceutically acceptable salts and/or solvates comprising:
a) Dissolving Vortioxetine free base free base in water or an organic solvent or mixtures thereof,
b) Adding Trifluoracetic acid,
c) Optionally isolating Trifluoroacetate salt of Vortioxetine,
d) Adding suitable base,
e) Optionally isolating Vortioxetine free base,
f) Adding suitable organic solvent and an acid,
g) Isolating Vortioxetine and its pharmaceutically acceptable salts and/or solvates.
Wherein the organic solvent used in step (a) is selected from the group comprising of alcohols, ketones, ethers, esters, halogenated hydrocarbons, aromatic hydrocarbons and/or mixtures, mixtures with water.
Wherein the suitable base used in step (d) is selected from the group comprising of alkali metal hydroxides, alkali metal carbonates/bicarbonate and the like.
Wherein the acid used in step (f) is selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, phosphoric acid etc, preferably hydrobromic acid.
Wherein the organic solvent used in step (f) is selected from the group comprising of alcohols such as methanol, ethanol, propanol, pentanol, 2-pentanol, amyl alcohols, preferably 2-pentanol.
Another embodiment of the present invention provides use of Vortioxetine trifluoroacetate for the preparation of Vortioxetine and its pharmaceutically acceptable salts and/or solvates.
One more embodiment of the present invention provides use of Vortioxetine trifluoroacetate for the preparation of solvates of Vortioxetine hydrobromide, preferably 2-pentanol solvate of Vortioxetine hydrobromide.
Other embodiment of the present invention provides pharmaceutical composition comprising 2-pentanol solvate of Vortioxetine and its pharmaceutically acceptable salts.

Advantages of 2-pentanol solvate of Vortioxetine hydrobromide:

• Thermally stable.
• Provides good yield and purity
• Suitable for pharmaceutical composition

Examples:
Example 1: Preparation of Trifluoro acetate salt of Vortioxetine.
To a round bottom flask added Vortioxetine free base (10g) and water. Trifluoro acetic acid was added to the above reaction mass. The reaction mass was heated to above 50oC. The reaction mass was cooled to room temperature. The reaction mass was filtered and dried under vacuum to obtain trifluoroacetate salt of Vortioxetine.
Example 2: Preparation of Trifluoro acetate salt of Vortioxetine.
To a round bottom flask was added Vortioxetine free base (10g) and methanol. Trifluoro acetic acid was added to above reaction mass. The reaction mass heated to above 50oC. The mass cooled to room temperature. The mass was filtered and dried under vacuum to obtain trifluoroacetate salt of Vortioxetine.
Example 3: Preparation of 2-pentanol solvate of Vortioxetine hydrobromide
To a round bottom flask added Vortioxetine free base (10g) and 2-pentanol. The reaction mass heated to above 40oC. Aqueous HBr was added to the above reaction mass. The mass cooled to room temperature. The mass was filtered and dried under vacuum to obtain 2-pentanol solvate of Vortioxetine hydrobromide.
Example 4: Preparation of 2-pentanol solvate of Vortioxetine hydrobromide
To a round bottom flask added Vortioxetine free base (10g) and 2-pentanol. The reaction mass heated to above 40 oC. Added HBr in acetic acid to the above reaction mass. The mass cooled to room temperature. The mass was filtered and dried under vacuum to obtain 2-pentanol solvate of Vortioxetine hydrobromide.
Example 5: Preparation of 2-pentanol solvate of Vortioxetine hydrobromide
To a round bottom flask added Vortioxetine free base (10g) and 2-pentanol. Added aqueous HBr to the above reaction mass. Stirred the reaction mass for more than 8 hours. The mass cooled to 0-10 oC. The mass was filtered and dried under vacuum to obtain 2-pentanol solvate of Vortioxetine hydrobromide.
Example 6: Preparation of 2-pentanol solvate of Vortioxetine hydrobromide
To a round bottom flask added Vortioxetine free base (10g) and 2-pentanol. Added HBr in acetic acid to the above reaction mass. Stirred the reaction mass for more than 8 hours. The mass cooled to 0-10 oC. The mass was filtered and dried under vacuum to obtain 2-pentanol solvate of Vortioxetine hydrobromide.
Example 7: Preparation of Vortioxetine hydrobromide.
To a round bottom flask added Vortioxetine trifluoroacetate (10g) and DCM. To the above reaction mass sodium hydroxide solution was added and stirred. Added water to the above reaction mass and separated the layers. Concentrated the organic layer and then added 2-pentanol. The reaction mass was heated above 40 oC. Aqueous HBr added to the reaction mass. The reaction mass was cooled to room temperature. The reaction mass was filtered and dried under vacuum to obtain Vortioxetine hydrobromide.
Example 8: Preparation of Vortioxetine hydrobromide.
To a round bottom flask added Vortioxetine trifluoroacetate (10g) and DCM. To the above reaction mass added sodium hydroxide solution. Stirred the reaction mass. Added water to the above reaction mass and separated the layers. Concentrated the organic layer and then added 2-pentanol. The reaction mass was heated above 40 oC. HBr in acetic acid was added to the reaction mass. The reaction mass was cooled to room temperature. The reaction mass was filtered and dried under vacuum to obtain Vortioxetine hydrobromide.
,CLAIMS:
1. 2-pentanol solvate of Vortioxetine and its pharmaceutically acceptable salts.

2. 2-pentanol solvate of Vortioxetine hydrobromide.

3. A process for the preparation of 2-pentanol solvate of Vortioxetine and its pharmaceutically acceptable salts, comprising.
a) dissolving Vortioxetine free base in 2-pentanol,
b) adding corresponding acid,
c) isolating 2-pentanol solvate of Vortioxetine and its pharmaceutically acceptable salts.

4. Trifluoroacetate salt of Vortioxetine.

5. A process for the preparation of Vortioxetine trifluoroacetate, comprising:
a) Dissolving Vortioxetine and its pharmaceutically acceptable salts in water or organic solvent or mixtures thereof,
b) Adding Trifluoracetic acid,
c) Isolating Vortioxetine trifluoroacetate.

6. A process for the preparation of Vortioxetine and its pharmaceutically acceptable salts and/or solvates comprising:
a) Dissolving Vortioxetine free base in water or organic solvent or mixtures thereof,
b) Adding Trifluoracetic acid,
c) Optionally isolating Vortioxetine trifluoroacetate,
d) Adding suitable base,
e) Optionally isolating Vortioxetine free base,
f) Adding suitable organic solvent and an acid,
g) Isolating Vortioxetine and its pharmaceutically acceptable salts and/or solvates.

7. The process according to claim 6, wherein the suitable base is selected from the group comprising of alkali metal hydroxides, alkali metal carbonates/bicarbonate.

8. The process according to claim 3 or 6, wherein the acid is selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid and phosphoric acid.

9. The process according to claim 5 or 6, wherein the organic solvent is selected from the group comprising of alcohols, ketones, ethers, esters, halogenated hydrocarbons, aromatic hydrocarbons and/or mixtures thereof.

10. Use of Vortioxetine trifluoroacetate for the preparation of Vortioxetine and its pharmaceutically acceptable salts and/or solvate thereof.