DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF VORTIOXETINE”

Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the nature of the invention and the manner in which it is to be performed.
PRIORITY
This application claims the benefit to Indian Provisional Application No. 3561/MUM/2015, filed on September 18, 2015, the contents of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of vortioxetine hydrobromide. The present invention relates to salts and solvates of vortioxetine, process for their preparation and their conversion to vortioxetine hydrobromide.
BACKGROUND OF THE INVENTION
Vortioxetine, also known as 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine, is represented by the structure of formula II.

Formula II
Vortioxetine hydrobromide, a compound of formula Ia, is indicated for the treatment of major depressive disorder (MDD).

Formula Ia
The object of the present invention is to provide a process for the preparation of vortioxetine hydrobromide via salts and solvates of vortioxetine.

SUMMARY OF THE INVENTION
The present invention provides vortioxetine salt, a compound of formula I,

Formula I
wherein, HA is selected from the group consisting of cyclamic acid, boric acid, benzoic acid.
In another embodiment, the present invention provides a process for the preparation of vortioxetine hydrobromide, a compound of formula Ia, the process comprising:

Formula Ia
a) reacting vortioxetine, a compound of formula II, with an acid to give a compound of formula I, wherein, HA is selected from benzoic acid, cyclamic acid, boric acid;

Formula II Formula I
b) providing a solution of the compound of formula I in a solvent;
c) optionally, treating the solution of step (b) with a base;
d) treating the solution of step (b) or step (c) with hydrobromic acid; and
e) isolating vortioxetine hydrobromide from the solution of step (d).
In another embodiment, the present invention provides use of vortioxetine salt, a compound of formula I,

Formula I
wherein, HA is selected from the group consisting of cyclamic acid, boric acid, benzoic acid, in the preparation of vortioxetine hydrobromide.
In another embodiment, the present invention provides a process for the preparation of beta form of vortioxetine hydrobromide, the process comprising: a) dissolving vortioxetine hydrobromide in methanol; b) cooling and stirring and the solution of step (a); and c) isolating the beta form of vortioxetine hydrobromide.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides vortioxetine salt, a compound of formula I,

Formula I
wherein, HA is selected from the group consisting of benzoic acid, cyclamic acid, boric acid, adipic acid, ascorbic acid, aspartic acid, camphoric acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid ethanesulfonic acid, galactaric acid, gentisic acid, (D)-glucoheptonic acid, (D)-gluconic acid, (D)-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactobionic acid, lauric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, palmitic acid, pamoic acid, proprionic acid, (L)-pyroglutamic acid, sebacic acid, stearic acid, thiocyanic acid, undecylenic acid.
In one embodiment, the present invention provides vortioxetine cyclamate salt.
In one embodiment, the present invention provides vortioxetine cyclamate salt characterized by 1H NMR (DMSO-d6): d 7.32-7.35 (d, 1H), 7.25 (s, 1H), 7.09-7.15 (m, 3H), 6.96-6.98 (m, 1H), 3.34 (bs, 1H), 3.19 -3.23 (m, 4H), 2.87 (m, 1H), 2.32 (s, 3H), 2.24 (s, 3H), 1.88-1.92 (m, 2H), 1.50-1.58 (m, 3H), 1.01-1.19 (m, 5H).
In one embodiment, the present invention provides vortioxetine borate salt.
In one embodiment, the present invention provides vortioxetine benzoate salt.
In one embodiment, the present invention provides vortioxetine benzoate salt characterized by 1H NMR (DMSO-d6): d 7.91-7.93 (d,2H), 7.32-7.50 (m, 4H), 7.23 (s, 1H), 7.09-7.11 (m, 3H), 6.88- 6.93(m,1H), 6.37-6.39 (dd, 1H), 5.0-6.0 (bs,2H), 3.04 (S,8H), 2.32 (S,3H), 2.237 (S,3H).
The present invention provides use of vortioxetine salt, a compound of formula I,

Formula I
wherein, HA is selected from the group as discussed supra, in the preparation of vortioxetine hydrobromide.
In one embodiment, the present invention provides use of vortioxetine cyclamate salt in the preparation of vortioxetine hydrobromide.
In one embodiment, the present invention provides use of vortioxetine borate salt in the preparation of vortioxetine hydrobromide.
In one embodiment, the present invention provides use of vortioxetine benzoate salt in the preparation of vortioxetine hydrobromide.
In one embodiment, the present invention provides use of vortioxetine salt, a compound of formula I, in the preparation of amorphous vortioxetine hydrobromide.
In one embodiment, the present invention provides use of vortioxetine salt, a compound of formula I, in the preparation of beta form of vortioxetine hydrobromide.
The present invention provides a process for the preparation of vortioxetine hydrobromide, a compound of formula Ia, the process comprising:

Formula Ia
a) reacting vortioxetine, a compound of formula II, with an acid to give a compound of formula I, wherein, HA is selected from the group consisting benzoic acid, cyclamic acid, boric acid;
b) providing a solution of the compound of formula I in a solvent;
c) optionally, treating the solution of step (b) with a base;
d) treating the solution of step (b) or step (c) with hydrobromic acid; and
e) isolating vortioxetine hydrobromide from the solution of step (d).
In the present application, the term “room temperature” means a temperature of about 25°C to about 30°C.
In (a) of the process for the preparation of vortioxetine hydrobromide, vortioxetine is reacted with an acid to give vortioxetine salt.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; hydrocarbons such as pentane, hexane, heptane, cyclohexane, toluene, xylene and the like; water or mixtures thereof. Preferably the solvent selected is ethyl acetate.
In (b) of the process for the preparation of vortioxetine hydrobromide, the compound of formula I is dissolved in a solvent to provide a solution.
The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2-pyrrolidone; or mixtures thereof. Preferably the solvent selected is ethyl acetate, methanol, 2-propanol.
In (c) of the process for the preparation of vortioxetine hydrobromide, the solution of step (b) is treated with a base.
The suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; ammonium hydroxide, organic bases such as triethylamine, diisopropylamine, dimethylaminopyridine, pyridine; diethylamine, dimethylamine.
In (d) of the process for the preparation of vortioxetine hydrobromide, the solution of step (b) or step (c) is treated with hydrobromic acid.
In one embodiment, the solution of step (b) is treated with hydrobromic acid.
In one embodiment, the solution of step (c) is treated with hydrobromic acid.
In (e) of the process for the preparation of vortioxetine hydrobromide, the compound of formula Ia is isolated from the solution of step (d).
In one embodiment, the step (e) of isolating vortioxetine hydrobromide comprises:
(i) stirring the solution obtained in (d); or (ii) removing the solvent from the solution obtained in (d); or (iii) treating the solution of step (d) with an anti-solvent.
In one embodiment, the vortioxetine hydrobromide is obtained by stirring the solution of step (d). The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 90°C.
In one embodiment, the vortioxetine hydrobromide is obtained by removing the solvent from the solution obtained in (d). Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
In one embodiment, the vortioxetine hydrobromide is obtained by adding an anti-solvent to the solution obtained in (d) to form a mixture and optionally, cooling and stirring the obtained mixture. The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 90°C.
The anti-solvent is selected such that vortioxetine hydrobromide is precipitated out from the solution.
The anti-solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
In one embodiment, the vortioxetine hydrobromide isolated is in amorphous form.
In one embodiment, the vortioxetine hydrobromide isolated is in beta form.
In one embodiment, the vortioxetine hydrobromide obtained is in a purity of at least 99% w/w, as determined by HPLC.
In one embodiment, the compound of formula II is prepared by a process comprising:
a) reacting a compound of VI with a compound of formula VII, to give a compound of formula V;

Formula VI Formula VII Formula V Formula III

b) reducing the compound of formula V to give a compound of III; and
c) reacting the compound of formula III with a compound of formula IV or salt thereof, to give vortioxetine, a compound of formula II

Formula IV
In (a) of the process for the preparation of the compound of formula (II), the compound of VI is reacted with the compound of formula VII to give the compound of formula V.
The reaction may be carried out in the presence of a base. The suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates; alkyl lithium such as n-butyl lithium; alkali metal acetates, tertiary amines such as triethylamine, N,N-diisopropylethylamine; ammonia, pyridine, piperidine, 4-dimethylaminopyridine. Preferably the base selected is potassium carbonate, potassium hydroxide.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2-pyrrolidone, water; or mixtures thereof. Preferably the solvent selected is dimethyl formamide.
In (b) of the process for the preparation of the compound of formula (II), the compound of formula V is reduced to give the compound of III.
A suitable reducing agent includes, but is not limited to sodium dithionite, zinc/acetic acid, zinc/hydrochloric acid, tin/hydrochloric acid, iron/hydrochloric acid, stannous chloride, stannous chloride/hydrochloric acid, ammonium formate, activated aluminium, salts of hydrogen sulfide, hydrazine hydrate/Raney nickel, hydrazine hydrate/palladium on carbon, hydrazine hydrate/platinum on carbon, zinc/calcium chloride dihydrate, zinc/ammonium chloride, alkali metal borohydride/alkali metal halide, alkaline earth metal borohydride/alkali metal halide, transition metal borohydride/alkali metal halide, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or reduction by catalytic hydrogenation using Raney nickel, palladium, platinum catalyst. Preferably, the compound of formula V is reduced by catalytic hydrogenation using Raney nickel, palladium catalyst to give the compound of III.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-methyl-2-pyrrolidone; acetic acid; or mixtures thereof. Preferably the solvent selected is methanol, ethyl acetate, acetic acid.
In one embodiment, the compound of formula V is reduced by catalytic hydrogenation using palladium on carbon/acetic acid, palladium on carbon/ethyl acetate to give the compound of III.
In (c) of the process for the preparation of the compound of formula (II), the compound of III is reacted with the compound of formula IV or salt thereof to give the compound of formula II.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; dimethylsulfoxide; dimethylformamide; dimethylacetamide; or mixtures thereof. Preferably the solvent selected is 1-butanol.
The present invention provides a process for the preparation of vortioxetine hydrobromide, the process comprising crystallizing vortioxetine hydrobromide in an alcoholic solvent. The alcohol includes but is not limited to methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol.
The present invention provides a process for the preparation of beta form of vortioxetine hydrobromide, the process comprising: a) dissolving vortioxetine hydrobromide in methanol; b) cooling and stirring and the solution of step (a); and
c) isolating the beta form of vortioxetine hydrobromide.
In one embodiment, the vortioxetine hydrobromide obtained is in a purity of at least 99% w/w, as determined by HPLC.
The present invention provides a process for the preparation of vortioxetine hydrobromide, a compound of formula Ia, the process comprising:
a) reacting vortioxetine, a compound of formula II, with an acid to give a compound of formula I, wherein, HA is selected from the group consisting of cyclamic acid,
boric acid, benzoic acid, adipic acid, ascorbic acid, aspartic acid, camphoric acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid ethanesulfonic acid, galactaric acid, gentisic acid, (D)-glucoheptonic acid, (D)-gluconic acid, (D)-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactobionic acid, lauric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, palmitic acid, pamoic acid, proprionic acid, (L)-pyroglutamic acid, sebacic acid, stearic acid, thiocyanic acid, undecylenic acid;
b) providing a solution of the compound of formula I in a solvent;
c) optionally, treating the solution of step (b) with a base;
d) treating the solution of step (b) or step (c) with hydrobromic acid; and
e) isolating vortioxetine hydrobromide from the solution of step (d).
The present invention provides a process for the preparation of vortioxetine salt, a compound of formula I, wherein, HA is selected from the group as discussed supra, the process comprising reacting vortioxetine, a compound of formula II, with an acid.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent is as discussed supra.
The vortioxetine salt is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
The isolated vortioxetine salt may be further dried. Drying may be suitably carried out in an equipment known in the art, such as a tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier and the like. The drying may be carried out at temperatures from about room temperature to about 100°C with or without vacuum. The drying may be carried out for any desired time until the required product quality is achieved. The drying time may vary from about 1 hour to about 20 hours, or longer.
The present invention provides a process for the preparation of solvates of vortioxetine, the process comprising: a) dissolving vortioxetine in a suitable solvent, optionally in presence of additional solvent, to form a solution; b) obtaining solvate of vortioxetine from the solution of step (a); and c) isolating the solvate of vortioxetine.
The solvate of vortioxetine includes solvate with water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, acetonitrile, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, chloroform, dichloromethane, hexane, n-heptane, toluene, N-methyl pyrrolidone, dimethyl formamide or dimethyl sulfoxide.
The suitable solvent includes water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, acetonitrile, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, chloroform, dichloromethane, hexane, n-heptane, toluene, N-methyl pyrrolidone, dimethyl formamide or dimethyl sulfoxide.
The additional solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
Suitable temperature for dissolution of vortioxetine may range from about 20°C to about 90°C. Stirring may be continued for any desired time period to achieve a complete dissolution of vortioxetine. The stirring time may range from about 30 minutes to about 10 hours, or longer.
In (b) of the process for the preparation of solvate of vortioxetine, the solvate of vortioxetine is obtained from the solution of step (a), the process comprising:
(i) cooling and stirring the solution obtained in (a); or
(ii) removing the solvent from the solution obtained in (a); or
(iii) treating the solution of step (a) with an anti-solvent to form a mixture and optionally, cooling and stirring the obtained mixture.
In one embodiment, the solvate of vortioxetine is obtained by cooling and stirring the solution of step (a). The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 90°C.
In one embodiment, the solvate of vortioxetine is obtained by removing the solvent from the solution obtained in (a). Removal of solvent may be accomplished by substantially complete evaporation of the solvent; or concentrating the solution, cooling the solution if required and filtering the obtained solid.
In one embodiment, the solvate of vortioxetine is obtained by adding an anti-solvent to the solution obtained in (a) to form a mixture and optionally, cooling and stirring the obtained mixture. The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 90°C.
The anti-solvent is selected such that the solvate of vortioxetine is precipitated out from the solution.
The anti-solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
In (c) of the process for the preparation of solvate of vortioxetine, the solvate of vortioxetine is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
The present invention provides a process for the preparation of solvates of vortioxetine hydrobromide, the process comprising: a) dissolving vortioxetine hydrobromide in a suitable solvent, optionally in presence of additional solvent, to form a solution;b) obtaining solvate of vortioxetine hydrobromide from the solution of step (a); andc) isolating the solvate of vortioxetine hydrobromide.
The present invention provides a process for the preparation of solvates of vortioxetine hydrobromide, the process comprising: a) adding hydrobromic acid to vortioxetine in a suitable solvent, optionally in presence of additional solvent, to form a reaction mass; b) obtaining solvate of vortioxetine hydrobromide from the reaction mass of step (a); and c) isolating the solvate of vortioxetine hydrobromide.
The solvate of vortioxetine hydrobromide includes solvate with water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, acetonitrile, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, chloroform, dichloromethane, hexane, n-heptane, toluene, N-methyl pyrrolidone, dimethyl formamide or dimethyl sulfoxide.
The suitable solvent is as discussed supra for solvates of vortioxetine.
The additional solvent is as discussed supra for solvates of vortioxetine.
In (b) of the process for the preparation of solvate of vortioxetine hydrobromide, the solvate of vortioxetine hydrobromide is obtained from the solution of step (a), the process comprising: (i) cooling and stirring the solution obtained in (a); or (ii) removing the solvent from the solution obtained in (a); or(iii) treating the solution of step (a) with an anti-solvent to form a mixture and optionally, cooling and stirring the obtained mixture.
In one embodiment, the solvate of vortioxetine hydrobromide is obtained by cooling and stirring the solution of step (a). The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 90°C.
In one embodiment, the solvate of vortioxetine hydrobromide is obtained by removing the solvent from the solution obtained in (a). Removal of solvent may be accomplished as discussed supra for solvates of vortioxetine.
In one embodiment, the solvate of vortioxetine hydrobromide is obtained by adding an anti-solvent to the solution obtained in (a) to form a mixture and optionally, cooling and stirring the obtained mixture. The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 90°C.
The anti-solvent is as discussed supra for solvates of vortioxetine.
In (c) of the process for the preparation of solvate of vortioxetine hydrobromide, the solvate of vortioxetine hydrobromide is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
The present invention provides a premix comprising vortioxetine hydrobromide and a pharmaceutically acceptable carrier.
In one embodiment, the present invention provides a process for the preparation of a premix comprising vortioxetine hydrobromide and a pharmaceutically acceptable carrier, the process comprising: a) dissolving vortioxetine hydrobromide in a solvent;
b) adding a pharmaceutically acceptable carrier to the solution prepared in step (a); and
c) removing the solvent from the mixture obtained in step (b).
The solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
In one embodiment, the present invention provides a premix comprising vortioxetine hydrobromide and a pharmaceutically acceptable carrier, wherein the vortioxetine hydrobromide is in substantially amorphous form.
In one embodiment, the present invention provides a premix comprising vortioxetine hydrobromide and a pharmaceutically acceptable carrier, wherein the premix contains amorphous vortioxetine hydrobromide in stable form.
In one embodiment, the present invention provides pharmaceutical compositions comprising vortioxetine or salt thereof obtained by the processes herein described, having a D50 and D90 particle size of less than about 150 microns, preferably less than about 100 microns, more preferably less than about 50 microns.
In one embodiment, the present invention provides vortioxetine HBr, where is one or more of below compounds of formula A, B, C, D, E, F, G, H, I, J, K, L, M are present less than 0.15% w/w relative to the amount of vortioxetine as determined by HPLC.

Formula A Formula B Formula C Formula H

Formula D: X= SO, R1= piperazine & R2, R3 = H; Formula E: X= SO2 and R1 = piperazine & R2, R3 = H. Formula F: X= S, R2= piperazine & R1, R3 = H; Formula G: X= S, R3= piperazine & R1, R2 = H.

Formula I: R1= CH3 and R2, R3, R4, R5 = H; Formula J: R3= CH3 and R1, R2, R4, R5 = H. Formula K: R1 & R4= CH3 and R2, R3, R5 = H; Formula L: R2 & R3= CH3 and R1, R4, R5 = H. Formula M: R1 & R5= CH3 and R2, R3, R4 = H.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES
EXAMPLE 1: Preparation of 2,4-dimethyl-1-[(2-nitrophenyl)thio]benzene
A mixture of 2,4-dimethylthiophenol (154.2g) and potassium carbonate (176.5g) in dimethylformamide (500mL) was stirred for about 30min. 1-Fluoro-2-nitrobenzene was added to it in about 120min at about 20°C to about 30°C. The reaction mixture was maintained at RT for about 4hours. Water was added to the reaction mixture, stirred then filtered washed with water and dried. Yield: 232.5g
EXAMPLE 2: Preparation of 2-[(2,4-dimethylphenyl)thio]aniline
To a stirred solution of 2,4-dimethyl-1-[(2-nitrophenyl)thio]benzene (100g) in dichloromethane (400mL) was added activated carbon at 20°C-30°C. The mixture was stirred and filtered through hyflo bed. To the filtrate, methanol was added and stirred then 10% Pd/C (15g) was added to it. The reaction mixture was stirred under hydrogen pressure of about 8kg-10kg at about 65°C-70°C for about 8 hours, then cooled to RT. The catalyst was filtered off on a hyflo bed and filtrate was concentrated under vacuum and degassed to give an oil residue. Yield: 70g
EXAMPLE 3: Preparation of 2-[(2,4-dimethylphenyl)thio]aniline
To a solution of 2,4-dimethyl-1-[(2-nitrophenyl)thio]benzene (20g) in methanol (200mL) was added Raney nickel (3g). The reaction mixture was stirred under hydrogen pressure of about 8kg-10kg at about 65°C-70°C for 8 hours. The reaction mixture was cooled to about RT and the catalyst was filtered off on a hyflo bed. The filtrate was concentrated under vacuum and degassed to give an oil residue. EXAMPLE 4: Preparation of 2-[(2,4-dimethylphenyl)thio]aniline
To a solution of 2,4-dimethyl-1-[(2-nitrophenyl)thio]benzene (15g) in acetic acid (150mL), was added 10%Pd/C (3g). The reaction mixture was stirred under hydrogen pressure for about 8 hours. The reaction mixture was cooled to about RT and the catalyst was filtered. The filtrate was concentrated under vacuum and degassed to give an oil residue. Ethyl acetate and water were added and the reaction mixture was stirred. 10% aq. NaOH solution was added to adjust pH between 9-10. The two layers were separated and the organic layer was concentrated under vacuum and degassed to give an oil residue. Yield: 12g
EXAMPLE 5: Preparation of vortioxetine cyclamate salt
To a stirred mixture of 2-[(2,4-dimethylphenyl)thio]aniline (20g) in n-butanol (200mL) was added bis(2-chloroethyl) amine hydrochloride (77.8g). The reaction mixture was heated to about 100°C-120°C and maintained for about 72 hours. The reaction mixture was cooled to about 30°C-35°C and ethyl acetate and water were added to it. 10% aq. NaOH solution was added to the organic layer to adjust the pH to about 10. The two layers were separated and the organic layer was washed with brine solution. To the organic layer was added cyclohexylsulfamic acid (19.5g) at about 20°C-30°C and stirred for about 12 hours. The solid obtained was filtered, washed with ethyl acetate and dried to yield titled compound. Yield: 17g; HPLC purity: 98%; Cyclamic acid content: 37.2%
EXAMPLE 6: Preparation of 2,4-dimethyl-1-[(2-nitrophenyl)thio]benzene
To a stirred solution of potassium hydroxide (47.6g) in dimethyl formamide (4000mL), was added 1-fluoro-2-nitrobenzene (100g) and 2,4-dimethylthiophenol (100g) at about 20°C to about 30°C. The reaction mixture was maintained at about the same temperature. Water was added to the reaction mixture and the reaction mixture was stirred. The solid obtained was filtered, washed and dried. Yield: 165g
EXAMPLE 7: Preparation of 2,4-dimethyl-1-[(2-nitrophenyl)thio]benzene
Follow similar process as described in EXAMPLE 6 wherein base is replaced by sodium carbonate. Yield: 165g
EXAMPLE 8: Preparation of 2-[(2,4-dimethylphenyl)thio]aniline
To a solution of 2,4-dimethyl-1-[(2-nitrophenyl)thio]benzene (100g) in ethyl acetate (1000mL) was added 10%Pd/C (20g). The reaction mixture was stirred under hydrogen pressure of 8kg-10kg at 65°C-75°C and then cooled to 20°C-30°C. The catalyst was filtered and the filtrate was treated with charcoal then filtered on a hyflo bed and filtrate was concentrated under vacuum to give an oil residue. Yield: 88g
EXAMPLE 9: Preparation of 2-[(2,4-dimethylphenyl)thio]aniline
To a solution of 2,4-dimethyl-1-[(2-nitrophenyl)thio]benzene (100g) in acetic acid (1000mL), was added 10%Pd/C (20g). The reaction mixture was stirred under hydrogen pressure then cooled to about 20°C-30°C. The catalyst was filtered and the filtrate was concentrated to give an oil residue. Ethyl acetate was added to the oily residue and stirred then aq. NaOH solution was added to it to adjust pH between 9 and 11. The two layers were separated and the organic layer was concentrated under vacuum and degassed to give an oil residue. Yield: 88g
EXAMPLE 10: Preparation of 2-[(2,4-dimethylphenyl)thio]aniline
Follow similar process as described in EXAMPLE 8 wherein solvent is methanol (1000mL) and catalyst is Raney nickel (20g). Yield: 165g
EXAMPLE 11: Preparation of vortioxetine cyclamate salt
To a stirred mixture of 2-[(2,4-dimethylphenyl)thio]aniline (100g) in n-butanol (1000mL) was added bis(2-chloroethyl) amine hydrochloride (310g). The reaction mixture was heated to 100°C-110°C then cooled to 20°C-30°C and ethyl acetate and water were added to it. 10% aq. NaOH solution was added to the organic layer to adjust pH to about 10-11. The two layers were separated and the organic layer was concentrated under vacuum to give an oil residue. Ethyl acetate was added to the residue followed by cyclohexylsulfamic acid (70.3g). The reaction mixture was stirred, filtered, washed and dried to yield titled compound. Yield: 130g
EXAMPLE 12: Preparation of vortioxetine cyclamate salt
To a stirred mixture of 2-[(2,4-dimethylphenyl)thio]aniline (100g) in n-butanol (1000mL) was added bis(2-chloroethyl) amine hydrochloride (310g). The reaction mixture was heated to 145°C-150°C in an autoclave under nitrogen pressure of about 5kg then cooled to 20°C-30°C and ethyl acetate and water were added to it. 10% qq. NaOH solution was added to the organic layer to adjust pH to about 10-11. The two layers were separated and the organic layer was concentrated under vacuum to give an oil residue. Ethyl acetate was added to the residue followed by cyclohexylsulfamic acid (70.3g). The reaction mixture was stirred, filtered, washed with ethyl acetate and dried to yield titled compound. Yield: 120g
EXAMPLE 13: Preparation of vortioxetine cyclamate salt
Follow similar process as described in EXAMPLE 11 wherein to a stirred mixture of 2-[(2,4-dimethylphenyl)thio]aniline in n-butanol was added bis(2-chloroethyl) amine hydrochloride (310g) and potassium iodide (7.2g). Yield: 130g
EXAMPLE 14: Preparation of vortioxetine hydrobromide
To a stirred mixture of vortioxetine cyclamate salt (100g) in ethyl acetate (700mL) and water (700mL), was added aq. ammonia solution to adjust pH to about 8-10. The two layers were separated and the organic layer was concentrated under vacuum. Methanol was added to the residue and the reaction mixture was treated with 48% aq. hydrobromic acid (35.3g). The solid obtained was filtered, washed with methanol and dried under vacuum at about 50°C to about 70°C. Yield: 79g
EXAMPLE 15: Preparation of vortioxetine hydrobromide
A mixture of vortioxetine cyclamate salt (100g) in ethyl acetate (200mL) was heated to about 65°C-70°C. 48% aq. hydrobromic acid (50mL) was added to it followed by isopropyl alcohol and reaction mixture was stirred for about 1hour at about 75°C- 80°C. The reaction mixture was cooled to 20°C-30°C, stirred, filtered, washed with ethyl acetate and dried to yield titled compound. Yield: 79g
EXAMPLE 16: Preparation of vortioxetine hydrobromide
To a stirred mixture of vortioxetine cyclamate salt (100g) in ethyl acetate (700mL) and water (700mL), was added aq. ammonia solution to adjust pH to about 8-10. The two layers were separated and the organic layer was washed with water. 48% aq. hydrobromic acid was added to the organic layer and the reaction mixture was stirred, filtered, washed with ethyl acetate, recrystallized in methanol and dried under vacuum to yield titled compound. Yield: 79g
EXAMPLE 17: Preparation of vortioxetine hydrobromide
To a stirred mixture of 2-[(2,4-dimethylphenyl)thio]aniline (100g) in n-butanol (1000mL) was added bis(2-chloroethyl) amine hydrochloride (310g). The reaction mixture was heated to about 145°C-155°C in an autoclave under pressure of about 5kg. The reaction mixture was cooled to RT and ethyl acetate and water were added to it. The organic layer was washed with water and 10% aq. NaOH solution was added to it to adjust pH to about 10-11. The two layers were separated and organic layer was concentrated under vacuum to give an oil residue. Isopropyl alcohol was added to the residue and then treated with aq. hydrobromic acid. The solid obtained was filtered, washed with isopropyl alcohol, recrystallized in methanol and dried to yield titled compound. Yield: 120g
EXAMPLE 18: Preparation of vortioxetine hydrobromide
To a mixture of vortioxetine cyclamate (100g) in ethyl acetate (700mL) was added aq. NaOH solution to adjust the pH to about 9-11. The two layers were separated and the organic layer was concentrated under vacuum. Methanol was added to the residue and the reaction mixture was treated with aq. hydrobromic acid. The reaction mixture was stirred and was distilled under vacuum. Methanol was added to the residue and heated to about 60°C-65°C. The reaction mixture was cooled to about 20°C-30°C, stirred, filtered, washed with methanol and dried to yield titled compound. Yield: 79g
EXAMPLE 19: Preparation of vortioxetine hydrobromide
A solution of vortioxetine hydrobromide (5g) in water (120mL) and methanol (30mL)
was heated to about 80°C. The solution was filtered and the filtrate was freezed using dry ice bath. The freezed reaction mass was lyophilized using lyophilizer. The solid isolated was found to be amorphous. Yield: 4.5g
EXAMPLE 20: Preparation of vortioxetine hydrobromide
Vortioxetine hydrobromide (5g) was dissolved in a mixture of dichloromethane (40mL) and methanol (10mL). The solution was filtered and the filtrate was spray dried using spray dryer. Inlet temperature was set to about 65°C, nitrogen pressure was set to about 2kg and feed rate was set to about 3mL per minute. Product was collected from the cyclone. Yield: 3g
EXAMPLE 21: Preparation of vortioxetine benzoate salt
To a stirred mixture of vortioxetine (3g) in ethyl acetate (30mL) was added a solution of benzoic acid in dichloromethane (8mL) and methanol (2mL). The reaction mixture was stirred and concentrated under vacuum to form residue. To the residue was added acetone and hexane. The reaction mixture was cooled to 5°C-10°C, stirred then temperature was raised to about 20°C-25°C and further stirred overnight. The solid obtained was filtered and dried at about 50°C-55°C to yield titled compound.
EXAMPLE 22: Preparation of vortioxetine borate salt
A mixture of vortioxetine (3g) in ethyl acetate (60mL) was stirred and heated to about 70°C-75°C. Boric acid (1.2g) was added to it and reaction mixture was stirred at same temperature then cooled to 20°C-30°C and was stirred for about 3 hours. The solid obtained was filtered, washed with ethyl acetate and dried to yield titled compound.
The following examples follow similar process with slight variation as described in EXAMPLE 22 wherein solvent and acid are replaced by below combinations.
EXAMPLE No. Solvent Salt
EXAMPLE 23 ethyl acetate Oxalic acid dihydrate
EXAMPLE 24 acetone benzene sulfonic acid
EXAMPLE 25 isopropyl alcohol D-Mandelic acid
EXAMPLE 26 ethyl acetate palmitic acid
EXAMPLE 27 ethyl acetate citric acid
EXAMPLE 28 ethyl acetate succinic acid

EXAMPLE 29: Preparation of premix of vortioxetine hydrobromide with mannitol: Vortioxetine HBr (2g) was dissolved in a mixture of dichloromethane (20mL) and methanol (8mL) at about 20°C-30°C. Mannitol (2g) was added and reaction mixture was concentrated under vacuum to give solid residue (3.8g).
EXAMPLE 30: Preparation of premix of vortioxetine hydrobromide with polyethylene glycol 4000: Vortioxetine hydrobromide (2g) was dissolved in a mixture of dichloromethane (20mL) and methanol (8mL) at about 20°C-30°C. Polyethylene glycol (2g) was added and reaction mixture was stirred and concentrated under vacuum at about 45°C to about 55°C to give solid residue (3.9g).
EXAMPLE 31: Preparation of premix of vortioxetine hydrobromide with polyvidone K30: Vortioxetine hydrobromide (5g) was dissolved in a mixture of dichloromethane (50mL) and methanol (150mL) at about 40°C-45°C. Polyvidone K30 (0.5g) was added and reaction mixture was stirred and concentrated under vacuum at about 45°C-55°C to give a solid residue.
EXAMPLE 32: Preparation of beta form of vortioxetine hydrobromide
To a mixture of vortioxetine in methanol was added aq. hydrobromic acid. The reaction mixture was stirred and then was distilled under vacuum. Methanol was added to the residue and the reaction mixture was heated to about 60°C-65°C. The reaction mixture was cooled to about 20°C-30°C, stirred, filtered, washed with methanol and dried to yield titled compound. Purity by HPLC: 99.9%
EXAMPLE 33: Preparation of 2,4-dimethyl-1-[(2-nitrophenyl)thio]benzene
To a stirred solution of potassium hydroxide (65.6g) in dimethyl formamide (500mL), was added 2-fluoro-nitrobenzene (100g) and reaction mass was cooled to about 10-15°C. 2,4-dimethylthiophenol (100g) was added to reaction mass, stirred and quenched by adding water, stirred, filtered and suck dried. Methanol was added to wet cake, heated to 55-65°C, stirred, cooled to 20-30°C. Solid was filtered, washed with methanol and dried to yield titled compound. Yield: 130g to 170g.
EXAMPLE 34: Preparation of 2-[(2,4-dimethylphenyl)thio]aniline
To a solution of 2,4-dimethyl-1-[(2-nitrophenyl)thio]benzene (100g) in ethyl acetate (1000mL), was added 10% Pd/C (20g). The reaction mixture was stirred under hydrogen pressure of about 8kg-10kg at about 70°C-80°C then cooled to about 20°C-30°C. The catalyst was filtered and filtrate was treated with charcoal, stirred and filtered on a hyflo bed. Ethyl acetate and para toluene sulfonic acid monohydrate (80.68g) was added to filtrate under stirring. The solid was filtered, washed with ethyl acetate and dried. Obtained wet cake was charged in water and aq. ammonia solution was added to get pH more than 9. Aqueous and organic layer separated then aqueous layer extracted with ethyl acetate. Combined ethyl acetate layers washed with water and brine solution. Organic layer distilled under vacuum to get oil. Yield: 60g to 88 g.
EXAMPLE 35: Preparation of 2-[(2,4-dimethylphenyl)thio]aniline
To a solution of 2,4-dimethyl-1-[(2-nitrophenyl)thio]benzene (100g) in ethyl acetate (1000mL), was added 10% Pd/C (20g). The reaction mixture was stirred under hydrogen pressure of about 8-10kg at about 70°C-80°C then cooled to about 20°C-30°C. The catalyst was filtered and filtrate was treated with charcoal, stirred and filtered on a hyflo bed. Filtrate distilled under vacuum to get oil. Oil diluted by adding ethyl acetate and pH adjusted to 9-11 by adding aq. ammonia solution. Aqueous layer was separated and organic layer was washed with water. Ethyl acetate and para toluene sulfonic acid monohydrate (80.68g) was added to filtrate under stirring. Solid was filtrated, washed with ethyl acetate and dried then wet cake charged in water and aq. ammonia solution was added to get pH more than 9. Aq. layer extracted with ethyl acetate. Combined ethyl acetate layers washed with water and brine solution. Organic layer distilled under vacuum to get oil. Yield: 60g to 88 g.
EXAMPLE 36: Preparation of vortioxetine hydrobromide
To a stirred mixture of 2-[(2,4-dimethylphenyl)thio]aniline (100g) in n-butanol (1000mL) was added bis(2-chloroethyl) amine hydrochloride (390g) and sodium iodide(65g). The reaction mass was heated to about 100°C- 120°C till the completion of reaction then cooled to about 20°C-30°C and quenched by adding water. pH of organic layer was adjusted to more than 8 by adding aq. ammonia solution. Aq. hydrobromic acid solution was added to organic layer distilled under vacuum to get oily residue. Methanol was added to residue, stirred, filtered, washed and dried to yield titled compound. Yield: 55g to 70g
EXAMPLE 37: Preparation of beta form of vortioxetine hydrobromide
A mixture of vortioxetine HBr in methanol (50ml) was heated to about 60-65°C then filtered through micron filter. Filtrate was cooled to about 10-15°C, stirred, filtered, washed with methanol and dried to yield titled compound. Yield: 65g to 80g
EXAMPLE 38: Preparation of vortioxetine Benzoate
To a stirred mixture of 2-[(2,4-dimethylphenyl)thio]aniline (100g) in n-butanol (1000mL) was added bis(2-chloroethyl) amine hydrochloride (390g) and sodium iodide (65g). The reaction mass was heated to about 100°C-120°C till the completion of reaction. The reaction mass was cooled, quenched by adding water. pH of organic layer was adjusted to more than 8 by adding aq. ammonia solution. Benzoic acid (106.5g) was added to organic layer, stirred, distilled under vacuum to residue. Ethyl acetate was added to residue, stirred, and precipitated solid was filtered, washed and dried. To dry solid methanol was added, heated to 60-70°C, then cooled to about 15-20°C, stirred, filtered, washed with methanol and dried to yield titled compound. Yield: 55g to 80g. 1H NMR (DMSO-d6): d 7.91-7.93 (d,2H), 7.32-7.50 (m, 4H), 7.23 (s, 1H), 7.09-7.11 (m, 3H), 6.88- 6.93(m,1H), 6.37-6.39 (dd, 1H), 5.0-6.0 (bs,2H), 3.04 (S,8H), 2.32 (S,3H), 2.237 (S,3H).
EXAMPLE 39: Preparation of vortioxetine hydrobromide
To a mixture of vortioxetine benzoate (100g) in methanol (400ml) was added aq. HBr solution (81.9g) and stirred for about 6 hours and filtered and washed with methanol. Methanol was added to wet solid, stirred and filtered through micron filter. Filtrate was cooled to about 10-15°C, stirred, filtered, washed with methanol and dried in VTD to yield titled compound. Yield: 60g to75g
EXAMPLE 40: Preparation of vortioxetine hydrobromide
Vortioxetine benzoate (100g) was added into a mixture of water (500ml), ethyl acetate (500ml) and aq. ammonia solution (40.5g) and then stirred. Organic layer washed with water and aq. HBr solution (81.9g) was added, stirred, filtered and then methanol was added. Reaction mass was stirred, filtered through micron filter, cooled to about 10-15°C and further stirred about 4 hours. The solid obtained was filtered, washed with methanol and dried to yield titled compound. Yield: 60g to75g.
EXAMPLE 41: Preparation of premix of vortioxetine HBr with ethyl cellulose
Vortioxetine benzoate (50g) was added in a mixture of DM water (500ml) and ethyl acetate (500ml), stirred and aq. ammonia was added and further stirred. Aq. layer was extracted with ethyl acetate and distilled under vacuum then methanol was added to residue. Ethyl cellulose (36g) and aq. HBr solution was added to reaction mass under stirring, filtered, washed and dried to yield titled compound. Yield: 25g to 35g.
EXAMPLE 42: Preparation of Vortiooxetine Hydrobromide
A mixture of vortioxetine in butanol (150 ml) was stirred and reaction mass distilled out under vacuum then degassed at about 70-75°C to get the residue mass. Acetone was added to residue, stirred and 48% aq. HBr was added then stirred at about 15-20°C for about 3 hours. Precipitated material filtered, washed with acetone and dried in air oven at about 50-55°C to get titled compound
EXAMPLE 43: Preparation of amorphous vortioxetine hydrobromide
Vortioxetine HBr (5gm) was added in a mixture of DM water (75ml) and THF (20 ml), reaction mass heated to about 40-50°C and filtered. Reaction mass was lyophilized by using lyophiliser instrument at temperature -75 to -85°C and vacuum NMT 100 Milli Torr for next 24 hours.
EXAMPLE 44: Preparation of amorphous vortioxetine hydrobromide
Vortioxetine HBr (7gm) was added in a mixture of DM water (70ml) and acetonitrile (84ml), reaction mass heated to about 40-50°C and filtered. Reaction mass was lyophilized by using lyophiliser instrument at temperature -75 to -85°C and vacuum NMT 100 Milli Torr for next 48 hours.
EXAMPLE 45: Preparation of amorphous vortioxetine hydrobromide
Vortioxetine HBr (5gm) was dissolved in MDC (100ml), filtered and obtained filtrate was spray dried by using spray dryer instrument at temperature of about 60-65°C with feed rate 20-25% the and aspirator RPM 1400.
EXAMPLE 46: Preparation of amorphous vortioxetine hydrobromide
Vortioxetine HBr (5gm) was dissolved in a mixture of methanol (50ml) and MDC (50ml), filtered and obtained filtrate was spray dried by using spray dryer instrument at temperature about 60-65°C with feed rate 20-25% and aspirator RPM 1400.
,CLAIMS:1. Vortioxetine salt, a compound of formula I, wherein, HA is selected from the group consisting of benzoic acid, cyclamic acid, boric acid.

Formula I
2. A process for the preparation of vortioxetine hydrobromide, a compound of formula Ia, the process comprising:

Formula Ia
a) reacting vortioxetine, a compound of formula II, with an acid to give formula I, wherein, HA is selected from benzoic acid, cyclamic acid, boric acid; b) providing a solution of formula I in a solvent; c) optionally, treating the solution of step (b) with a base; d) treating the solution of step (b) or step (c) with hydrobromic acid; and e) isolating vortioxetine hydrobromide from the solution of step (d).
3. The process as claimed in claim 2, wherein in step (a), the acid is benzoic acid.
4. The process as claimed in claim 2, wherein in step (b), the solvent is selected from the group consisting of haloalkanes, ketones, alcohols, ethers, esters, hydrocarbons, water, or mixtures thereof.
5. The process as claimed in claim 2, wherein in step (c), the base is selected from the group consisting of alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydroxides, alkaline earth metal hydroxides.
6. The process as claimed in claim 2, wherein the compound of formula II is prepared by a process comprising: a) reacting a compound of VI with a compound of formula VII, to give a compound of formula V;

Formula VI Formula VII Formula V Formula III

b) reducing the compound of formula V to give a compound of III; and
c) reacting the compound of formula III with a compound of formula IV or salt thereof, to give vortioxetine, a compound of formula II.

Formula IV Formula II
7. The process as claimed in claim 6, wherein the compound of VI is reacted with the compound of formula VII in the presence of a base.
8. The process as claimed in claim 7, wherein the base is selected from the group consisting of alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal hydrides.
9. A process for the preparation of beta form of vortioxetine hydrobromide, the process comprising: a) dissolving vortioxetine hydrobromide in methanol; b) cooling and stirring the solution of step (a); and c) isolating the beta form of vortioxetine hydrobromide.