DESC:Field of the Invention:
The present invention provides novel salts of vortioxetine and process for their preparation.
Background of the Invention:
Vortioxetine is chemically known as 1-[2-(2, 4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine. Vortioxetine is new antidepressant that has been approved for the treatment of Major Depressive Disorder (MDD). Hydrobromide salt of vortioxetine, represented by the structural formula depicted below, is marketed in USA and Europe under the trade name of Brintellix®.

Vortioxetine is intended to have combined effects on multiple 5-HT receptors and on the serotonin transporter. It has been shown in recombinant cell lines to combine 5-HT3 and 5-HT7 receptor antagonism, 5-HT1B receptor partial agonism, 5-HT1A receptor agonism, and serotonin transporter inhibition.
Extensive study is carried out in pharmaceutical industry for development of different polymorphs of various drug substances, to obtain suitable polymorphs that possess improved performance characteristics such as aqueous solubility, improved bioavailability, chemical stability, shelf life etc.
Literature survey reveals that Vortioxetine can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties and pharmacokinetics. The reported polymorphs and salts of vortioxetine are incorporated here by the way of reference.
PCT application WO 2003029232 A1 by Lundbeck discloses Vortioxetine free base.
PCT application WO2007144005 by Lundbeck discloses crystalline Vortioxetine and its pharmaceutically acceptable salts in its crystalline form with their XPRD which includes alpha, beta & gamma form of hydrobromide salts, hemihydrate form of HBr salt, crystalline base, mixture of the ethyl acetate solvate and the alpha form of the hydrobromide salt, hydrochloride salt, monohydrate of hydrochloride salt, Mesylate salt, Fumarate salt, Maleate salt, Meso-tatrate salt, L-(+)-tatrate salt, D-(-)-tatrate salt, Sulphate salt, Phosphate salt and Nitrate salt.
PCT application WO 2010094285 A1 by Lundbeck discloses an isopropanol solvate of vortioxetine hydrobromide as well as a process for the purification of vortioxetine and pharmaceutically acceptable salts thereof.
PCT application WO 20100121621 A1 by Lundbeck discloses crystalline forms of vortioxetine L, D and DL-lactate.
PCT application WO 2014177491 by Lek pharmaceuticals discloses amorphous vortioxetine hydrobromide in association with an adsorbent.
PCT application WO 2014177491 by Lek pharmaceuticals discloses vortioxetine acetate in crystalline form.
Salts often improve physical and biological characteristics of mother compounds without modifying primary pharmacological activity, based on mechanism of action. Thus there is a continuing need to obtain new salts of Vortioxetine having improved physical and/or chemical properties. The present invention satisfies this need by providing new salts of vortioxetine with enhanced solubility in water or aqueous media as an essential property of active pharmaceutical ingredients determining the performance of pharmaceutical formulation.

Description of drawings:
Figure 1: illustrates X-ray powder diffraction pattern of crystalline benzoate salt of vortioxetine.
Figure 2: illustrates X-ray powder diffraction pattern of crystalline succinate salt of vortioxetine.
Figure 3: illustrates X-ray powder diffraction pattern of crystalline salicylate salt of vortioxetine.
Figure 4: illustrates X-ray powder diffraction pattern of crystalline oxalate salt of vortioxetine.
Figure 5: illustrates X-ray powder diffraction pattern of crystalline citrate salt of vortioxetine.
Figure 6: illustrates X-ray powder diffraction pattern of crystalline L-malate salt of vortioxetine.
Figure 7: illustrates X-ray powder diffraction pattern of an amorphous L-malate salt of vortioxetine.

Summary of the Invention:
The present invention provides solid state forms of vortioxetine, viz., benzoate salt, succinate salt, salicylate salt, oxalate salt, citrate salt, L-malate salt and an amorphous L-malate salt of vortioxetine and process for their preparation.
The present invention provides novel crystalline salts of vortioxetine, viz., benzoate salt, succinate salt, salicylate salt, oxalate salt, citrate salt, L-malate salt of vortioxetine and process for their preparation.
Detail Description of the Invention:
The present invention provides solid state forms of vortioxetine, viz., benzoate salt, succinate salt, salicylate salt, oxalate salt, citrate salt, L-malate salt and an amorphous L-malate salt of vortioxetine and process for their preparation.
The present invention provides novel crystalline salts of vortioxetine, viz., benzoate salt, succinate salt, salicylate salt, oxalate salt, citrate salt, L-malate salt of vortioxetine and process for their preparation.
In one embodiment, the invention provides a novel crystalline benzoate salt of vortioxetine, represented by formula I, which is characterized by XRPD (X-ray powder diffractogram) which comprises of peaks expressed as 2? at 6.7, 10.4, 13.4, 13.9, 15.7, 17.0, 18.5, 18.8, 19.7, 20.2, 23.4, 23.8 ± 0.2 degrees. The XRPD of crystalline benzoate salt of vortioxetine is depicted in figure 1.

In another embodiment, the present invention provides a process for preparation of benzoate salt of vortioxetine, which comprises steps of:
a) Dissolving Vortioxetine or its salt in organic solvent,
b) optionally neutralizing the solution of step (a),
c) Adding solution of benzoic acid,
d) Isolation of salt formed by conventional methods.
The organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, acetone, propanone, butanone, ethyl acetate, acetonitrile, n pentane, hexane, toluene, benzene, ethyl methyl ketone, diethyl ether, ethyl methyl ether, diisopropyl ether, cyclic ethers such as tetrahydrofuran, dioxane,; most preferably acetone.
The salt formation is carried out at a temperature of 10 to 100°C, most preferably at 20 to 25°C. The crystalline solid salt which precipitates out is isolated by conventional techniques known in prior art such as filtration, centrifugation concentration, spray drying, Agitated Thin Film Dryer (ATFD) and lyophilization etc.
In another embodiment, the invention provides a novel crystalline succinate salt of vortioxetine, represented by formula II, which is characterized by XRPD (X-ray powder diffractogram) which comprises of peaks expressed as 2? at 3.7, 7.7, 11.2, 14.8, 15.4, 16.4, 17.5, 18.6, 22.6, 23.2 ± 0.2 degrees. The XRPD of crystalline succinate salt of vortioxetine is depicted in figure 2.

In another embodiment, the present invention provides a process for preparation of succinate salt of vortioxetine, which comprises steps of:
a) Dissolving vortioxetine or its salt in organic solvent,
b) optionally neutralizing the solution of step (a),
c) Adding solution of succinic acid,
d) Isolation of salt formed by conventional methods.
The organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, acetone, propanone, butanone, ethyl acetate, acetonitrile, n pentane, hexane, toluene, benzene, ethyl methyl ketone, diethyl ether, ethyl methyl ether, diisopropyl ether, cyclic ethers such as tetrahydrofuran, dioxane,; most preferably ethyl acetate.
The salt formation is carried out at a temperature of 10 to 100°C, most preferably at 20 to 30°C. The crystalline solid salt which precipitates out is isolated by conventional techniques known in prior art such as filtration, centrifugation etc.
In another embodiment, the invention provides a novel crystalline salicylate salt of vortioxetine, represented by formula III, which is characterized by XRPD (X-ray powder diffractogram) which comprises of peaks expressed as 2? at 8.3, 11.6, 13.2, 13.7, 14.3, 16.5, 16.8, 17.8, 18.6, 19.8, 20.2, 22.6, 23.9, 27.3 ± 0.2 degrees. The XRPD of crystalline salicylate salt of vortioxetine is depicted in figure 3.

In another embodiment, the present invention provides a process for preparation of salicylate salt of vortioxetine, which comprises steps of:
a) Dissolving vortioxetine or its salt in organic solvent,
b) optionally neutralizing the solution of step (a),
c) Adding solution of salicylic acid,
d) Isolation of salt formed by conventional methods.
The organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, acetone, propanone, butanone, ethyl acetate, acetonitrile, n pentane, hexane, toluene, benzene, ethyl methyl ketone, diethyl ether, ethyl methyl ether, diisopropyl ether, cyclic ethers such as tetrahydrofuran, dioxane,; most preferably ethyl acetate.
The salt formation is carried out at a temperature of 10 to 100°C, most preferably at 20 to 30°C. The crystalline solid salt which precipitates out is isolated by conventional techniques known in prior art such as filtration, centrifugation etc.
In another embodiment, the invention provides a novel crystalline oxalate salt of vortioxetine, represented by formula IV, which is characterized by XRPD (X-ray powder diffractogram) which comprises of peaks expressed as 2? at 3.8, 10.1, 13.6, 14.4, 15.3, 17.4, 17.7, 18.9, 20.3, 23.1, 23.8, 27.5, 28.0 ± 0.2 degrees. The XRPD of crystalline oxalate salt of vortioxetine is depicted in figure 4.
In another embodiment, the present invention provides a process for preparation of oxalate salt of vortioxetine, which comprises steps of:
a) Dissolving vortioxetine or its salt in organic solvent,
b) optionally neutralizing the solution of step (a),
c) Adding solution of oxalic acid,
d) Isolation of salt formed by conventional methods.
The organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, acetone, propanone, butanone, ethyl acetate, acetonitrile, n pentane, hexane, toluene, benzene, ethyl methyl ketone, diethyl ether, ethyl methyl ether, diisopropyl ether, cyclic ethers such as tetrahydrofuran, dioxane,; most preferably ethyl acetate.
The salt formation is carried out at a temperature of 10 to 100°C, most preferably at 20 to 25°C. The crystalline solid salt which precipitates out is isolated by conventional techniques known in prior art such as filtration, centrifugation etc.
In another embodiment, the invention provides a novel crystalline citrate salt of vortioxetine, represented by formula V, which is characterized by XRPD (X-ray powder diffractogram) which comprises of peaks expressed as 2? at 5.9, 11.6, 11.9, 14.9, 16.4, 17.0, 21.2, 22.6, 23.8 and 24.0 ± 0.2 degrees. The XRPD of crystalline citrate salt of vortioxetine is depicted in figure 5.

In another embodiment, the present invention provides a process for preparation of citrate salt of vortioxetine, which comprises steps of:
a) Dissolving vortioxetine or its salt in organic solvent,
b) optionally neutralizing the solution of step (a),
c) Adding solution of citric acid,
d) Isolation of salt formed by conventional methods.
The organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, acetone, propanone, butanone, ethyl acetate, acetonitrile, n pentane, hexane, toluene, benzene, ethyl methyl ketone, diethyl ether, ethyl methyl ether, diisopropyl ether, cyclic ethers such as tetrahydrofuran, dioxane; most preferably ethyl acetate.
The salt formation is carried out at a temperature of 10 to 100°C, most preferably at 20 to 25°C. The crystalline solid salt which precipitates out is isolated by conventional techniques known in prior art such as filtration, centrifugation etc.
In another embodiment, the invention provides a novel crystalline L-malate salt of vortioxetine, represented by formula VI, which is characterized by XRPD (X-ray powder diffractogram) which comprises of peaks expressed as 2? at 5.4, 9.5, 14.5, 15.4, 16.2, 16.6, 18.1, 18.3, 19.2, 19.6, 20.0, 22.5, 22.7, 23.0 ± 0.2 degrees. The XRPD of crystalline L-malate salt of vortioxetine is depicted in figure 6.

In another embodiment, the present invention provides a process for preparation of L-malate salt of vortioxetine, which comprises steps of:
a) Dissolving vortioxetine or its salt in organic solvent,
b) optionally neutralizing the solution of step (a),
c) Adding solution of L-malic acid,
d) Isolation of salt formed by conventional methods.
The organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, acetone, propanone, butanone, ethyl acetate, acetonitrile, n pentane, hexane, toluene, benzene, ethyl methyl ketone, diethyl ether, ethyl methyl ether, diisopropyl ether, cyclic ethers such as tetrahydrofuran, dioxane,; most preferably ethyl acetate.
The salt formation is carried out at a temperature of 10 to 100°C, most preferably at 20 to 30°C. The crystalline solid salt which precipitates out is isolated by conventional techniques known in prior art such as filtration, centrifugation etc.
In another embodiment, the invention provides a novel amorphous L-malate salt of vortioxetine, represented by formula VI, which is characterized by XRPD (X-ray powder diffractogram) The XRPD of an amorphous L-malate salt of vortioxetine is depicted in figure 7.
In another embodiment, the present invention provides a process for preparation of an amorphous L-malate salt of vortioxetine, which comprises steps of:
a) Dissolving vortioxetine hydrobromide in organic solvent,
b) Adding 3M sodium hydroxide solution,
b) Adding solution of L-malic acid,
c) Isolation of salt formed by conventional methods.
The organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, acetone, propanone, butanone, ethyl acetate, acetonitrile, n pentane, hexane, toluene, benzene, ethyl methyl ketone, diethyl ether, ethyl methyl ether, diisopropyl ether, cyclic ethers such as tetrahydrofuran, dioxane,; most preferably ethyl acetate.
The salt formation is carried out at a temperature of 10 to 100°C, most preferably at 20 to 30°C. The solid salt which precipitates out is isolated by conventional techniques known in prior art such as filtration, centrifugation, concentration, evaporation of solvent, spray drying, Agitated Thin Film Dryer (ATFD) and lyophilization etc.
The present invention is illustrated by the following examples. However it should be understood that the invention is not limited to the specific details of these details.
Examples:
Example 1:
Preparation of benzoate salt of vortioxetine:
30 ml of acetone was added to 2.0 g of vortioxetine and stirred to obtain clear solution. Slowly added a solution of benzoic acid (0.82 g) in acetone (20 ml) and the reaction mass was stirred at 20-25 0C for 15 minutes to precipitate the salt. The solid obtained was filtered, washed with acetone and dried under reduced pressure to give 1.4 g (50%) of desired product.
Example 2:
Preparation of succinate salt of vortioxetine:
30 ml of ethyl acetate was added to 2.0 g of vortioxetine and stirred to obtain clear solution. Slowly added a solution of succinic acid (0.8 g) in acetone (20 ml) and the reaction mass was stirred at 20-30 0C for 1 hour to precipitate the salt. The solid obtained was filtered, washed with ethyl acetate and dried under reduced pressure to give 2.8 g (100%) of desired product.

Example 3:
Preparation of salicylate salt of vortioxetine:
30 ml of ethyl acetate was added to 2.0 g of Vortioxetine and stirred to obtain clear solution. Slowly added a solution of salicylic acid (0.925 g) in acetone (20 ml) and the reaction mass was stirred at 20-30 0C for 1 hour to precipitate the salt. The solid obtained was filtered, washed with ethyl acetate and dried under reduced pressure to give 2.4 g (82%) of desired product.
Example 4:
Preparation of oxalate salt of vortioxetine:
40 ml of ethyl acetate was added to 2.0 g of vortioxetine and stirred to obtain clear solution. Slowly added a solution of oxalic acid dehydrate (0.84 g) in acetone (10 ml) and the reaction mass was stirred at 20-30 0C for 20 minutes to precipitate the salt. The solid obtained was filtered, washed with ethyl acetate and dried under reduced pressure to give 2.2 g (85%) of desired product.
Example 5:
Preparation of citrate salt of vortioxetine:
30 ml of ethyl acetate was added to 2.0 g of vortioxetine and stirred to obtain clear solution. Slowly added a solution of citric acid (1.31 g) in acetone (20 ml) and the reaction mass was stirred at 20-25 0C for 20 minutes to precipitate the salt. The solid obtained was filtered, washed with ethyl acetate and dried under reduced pressure to give 3.3 g (100%) of desired product.
Example 6:
Preparation of crystalline L-malate salt of vortioxetine:
30 ml of ethyl acetate was added to 2.0 g of vortioxetine and stirred to obtain clear solution. Slowly added a solution of L-malic acid (0.90 g) in acetone (20 ml) and the reaction mass was stirred at 20-30 0C for 20 minutes to precipitate the salt. The solid obtained was filtered, washed with ethyl acetate and dried under reduced pressure to give 2.4 g (83%) of desired product.
Example 7:
Preparation of amorphous L-malate salt of vortioxetine:
25 ml of ethyl acetate was added to 2.8 g of vortioxetine hydrobromide, followed by sodium hydroxide 3M solution (25 ml) and stirred the reaction mixture. Organic layer formed was separated, washed with 15% brine and added L- malic acid solution in ethanol (25 ml). Again reaction mass was allowed stirred for 30 minutes and distilled of the solvents under reduced pressure to give 2.9 g (100%) of desired product.
,CLAIMS:1. A crystalline benzoate and L- malate salts of vortioxetine.
2. The benzoate salt of vortioxetine of claim 1, is characterized by XRPD pattern comprising pecks in terms of 2? at 6.7, 10.4, 13.4, 15.7, 17.0, 18.5, 19.7, and 23.4 ± 0.2 degrees.
3. The L-malate salt of vortioxetine of claim 1, is characterized by XRPD pattern comprising pecks in terms of 2? at 5.4, 9.5, 14.5, 16.6, 18.1, 19.6 and 22.7 ± 0.2 degrees.
4. A process for the preparation of crystalline acid addition salts of vortioxetine comprising,
a) dissolving vortioxetine or salt in organic solvent,
b) optionally neutralizing the solution of step (a),
c) adding solution of acid,
d) isolating salts thereof,
wherein acid in step (c) is selected from benzoic acid or L-malic acid.
5. The process according to claim 4, the organic solvent used for step (i) is selected from methanol, ethanol, n-propanol, isopropanol, acetone, propanone, butanone, ethyl acetate, acetonitrile, n pentane, hexane, toluene, benzene, ethyl methyl ketone, diethyl ether, ethyl methyl ether, diisopropyl ether, cyclic ethers such as tetrahydrofuran, dioxane.
6. The process of claim 4, wherein step (d) product is isolated by filtration or centrifugation.
7. An amorphous benzoate and L-malate salts of vortioxetine.
8. The amorphous L-malate salt of vortioxetine of claim 4, is depicted in fig. 7.
9. The process for the preparation of amorphous acid addition salts of vortioxetine of claim 7, comprising,
a) dissolving vortioxetine or salt in organic solvent,
b) optionally neutralizing the solution of step (a),
c) adding solution of acid,
d) isolating salts thereof,
wherein acid in step (c) is selected from benzoic acid or L-malic acid.
10. The process according to claim 9, involves isolation of salt by using any one of technique such as evaporation of solvent, spray drying, agitated Thin Film Dryer (ATFD) or lyophilization.