FIELD OF THE INVENTION The present invention relates to stable amorphous solid dispersions of Vortioxetine hydrobromide with Hydroxyethyl cellulose (HEC), methods for the preparation, pharmaceutical compositions, and method of treating thereof. The present invention also relates to stable amorphous solid dispersions of Vortioxetine hydrobromide with soluplus, hypromellose and copovidone, methods for the preparation, pharmaceutical compositions, and method of treating thereof.

BACKGROUND OF THE INVENTION U.S. Patent No. 7,144,884 B2 (hereinafter referred to as the '884 patent) discloses a variety of phenyl-piperazine derivatives as serotonin reuptake inhibitors. These compounds are useful in the treatment of an affective disorder, including depression, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder. Among them, Vortioxetine, chemically named 1 -[2-[(2,4-dimethylphenyl)sulfanyl] phenyl]piperazine, is a serotonergic antidepressant that acts as an antagonist on the 5-HT3, 5-HT and 5-HT1D receptors, antagonist on the 5-HT1A receptor, a partial agonist on the 5-HT1B receptor, and an inhibitor of the serotonin transporter. Vortioxetine Hydrobromide is represented by the following structural formula:

Vortioxetine Hydrobromide was approved by the FDA for use in the United States to treat major depressive disorder and it is sold under the trade name BRINTELLIX . BRINTELLIX is available in the market as 5 mg, 10 mg, 15 mg and 20 mg immediate release tablets.

Various processes for the preparation of Vortioxetine, its intermediates, and pharmaceutical acceptable salts thereof are apparently described in U.S. Patent Nos.7,144,884 and 8,722,684B2; U.S. Patent Application Publication No.

2014/0343287A1; PCT Publication Nos. WO2007/144005A1, WO 2013/102573A1, WO2014/128207A1, WO2014/161976A1, WO2014/191548A1; Chinese Patent Application Nos. CN103788019A, CN103788020A, CN103936694A, CN104109135A, CN104130212A, CN104230852, CN104292183A, CN104356092A, CN104447621A; and Journal of Medicinal Chemistry 54, 3206-3221, 2011.

Various polymorphic forms of Vortioxetine hydrobromide are disclosed in U.S. Patent Nos. US 8,722,684, US 8,598,348, US 8,940,746; PCT Publication No. WO2014/044721A1; and Chinese Patent Application Nos. CN104119298, CN104119299 and CN104447622.

U.S. Patent No. 8,722,684 (hereinafter referred to as the US'684 patent), assigned to Lundbeck, discloses several solid state forms of Vortioxetine and its pharmaceutically acceptable salts thereof, which include crystalline Vortioxetine free base, hydrobromide (form a), hydrobromide (form P), hydrobromide (form y), hydrobromide (hydrate), hydrobromide (ethylacetate solvate), hydrochloride, hydrochloride (monohydrate), mesyalte, hydrogenfumarate, hydrogenmaleate, mesohydrogentartrate, L-(+)-hydrogentartrate, D-(-)-hydrogentartrate, hydrogen sulphate, dihydrogen phosphate, nitrate, and haracterizes them by powder X-ray diffraction (XRPD) patterns.

According to the US'684 patent, crystalline Vortioxetine free base is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 11.10, 16.88, 17.42 and 22.23 degrees; hydrobromide (form a) is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 5.85, 9.30, 17.49 and 18.58 degrees; hydrobromide (form P) is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 6.89, 9.73, 13.78 and 14.62 degrees; hydrobromide (form y) is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 11.82, 16.01, 17.22 and 18.84 degrees; hydrobromide (hydrate) is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 10.69, 11.66, 15.40 and 17.86 degrees; hydrobromide (ethylacetate solvate) is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 8.29, 13.01, 13.39 and 16.62 degrees; hydrochloride, hydrochloride (monohydrate) is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 7.72, 13.45, 15.39 and 17.10 degrees; mesyalte is characterized by a powder X-ray diffraction spectrum having peaks expressed as '2-theta angle positions at 8.93, 13.39, 15.22 and 17.09 degrees; hydrogenfumarate is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 5.08, 11.32, 17.12 and 18.04 degrees ; hydrogenmaleate is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 9.72, 13.19, 14.72 and 17.88 degrees; mesohydrogentartrate is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 9.51, 10.17, 16.10 and 25.58 degrees; L-(+)-hydrogentartrate is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 13.32, 13.65, 14.41 and 15.80 degrees; D-(-)-hydrogentartrate is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 13.32, 13.65, 14.41 and 15.80 degrees; hydrogen sulphate is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 11.82, 17.22, 17.72 and 20.13 degrees; dihydrogen phosphate is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 7.91, 11.83, 15.69 and 17.24 degrees; nitrate is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 12.50, 17.41, 18.12 and 18.47 degrees.

U.S. Patent No. 8,598,348 (hereinafter referred to as the US'348 patent), assigned to Lundbeck, discloses Vortioxetine hydrobromide isopropanol solvate, process for the preparation, and characterizes the isopropanol solvate by powder X-ray diffraction (XRPD) peaks, Thermo Gravimetric Analyses (TGA) curve and Differential Scanning Calorimetric (DSC) thermogram.

According to US'348 patent, Vortioxetine hydrobromide isopropanol solvate is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 6.44, 8.13, 8.77 and 10.41 degrees.

U.S. Patent Application No. US 2016/0015706A1 (hereinafter referred to as the US'706 application) discloses three crystalline forms of Vortioxetine hydrobromide namely X, co and a, process for their preparation and pharmaceutical composition thereof, and characterizes the crystalline forms by X-ray diffraction (XRPD) peaks, an infrared (FT-IR) spectrum, and Differential Scanning Calorimetric (DSC) thermogram.

According to US'706 application, Vortioxetine hydrobromide form X is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 4.0, 8.0, 12.0, 12.7, 15.7, 16.0, 16.4, 19.0, 20.1 and 20.3 degrees. Vortioxetine hydrobromide form co is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 3.8, 11.3, 17.5, 18.7, 18.9, 19.7, 20.5, 20.6, 22.6, 23.9, 27.1 and 28.4 degrees. Vortioxetine hydrobromide form a is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 3.8, 11.6, 13.0, 14.0, 14.4, 15.5, 18.2, 18.4, 19.2, 20.0, 20.2, 21.0, 21.4, 22.3, 23.4, 23.8, 27.0 and 28.2 degrees.

PCT Publication No. WO 2014/044721A1 (hereinafter referred to as WO'721 publication) discloses Vortioxetine hydrobromide (form 8) and monohydrate, process for the preparation, and characterizes by powder X-ray diffraction (XRPD) peaks, Fourier transform infra-red spectrum (FTIR), and Thermo Gravimetric Analyses curve (TGA). According to WO'721 publication, Vortioxetine hydrobromide (form 5) is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 5.5, 14.8, 16.7, 20.0, 27.6, 28.1, 28.4, 28.6, 29.1, 30.5 and 34.4 degrees; and an infra-red spectrum comprising peaks at wavenumbers of 3166 ± 2, 2959 ± 2, 2931 ± 2, 2786 ± 2, 2753 ± 2, 2713 ± 2, 2621 ± 2, 2596 ± 2, 2484 ± 2, 2472 ± 2, 1601 ± 2, 1586 ± 2, 1471 ± 2, 1454 ± 2, 1438 ± 2, 1398 ± 2, 1375 ± 2, 1346 ± 2, 1329 ± 2, 1312 ± 2, 1267 ± 2, 1243 ± 2, 1227.±2, 1149 ±2, 1122 ±2, 1081 ±2, 1043 ± 2, 925 ± 2, 910 ± 2, 873 ± 2, 813 ± 2, and 764 ± 2, 725 ± 2, 685 ± 2, 629 ± 2 cm-1.

PCT Publication No. WO 2015/044963A1 (hereinafter referred to as WO'963 publication) describes an amorphous solid dispersion of vortioxetine free base or salts thereof and a polymer, wherein the polymer comprises hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose (HPMC), methacrylic acid copolymers and polyvinyl pyrrolidone (PVP).

PCT Publication No. WO 2015/166379A2 (hereinafter referred to as WO'379 publication) discloses an amorphous co-precipitates of Vortioxetine hydrobromide with pharmaceutically acceptable excipients such as copovidone, povidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, soluplus, starch, microcrystalline cellulose, crosspovidone, methylcellulose, cellulose ethers, sodium carboxymethylcellulose, dextrose, lactose, sucrose, sorbitol, mannitol, polyvinylpyrrolidone, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, carmellose, carmellose sodium, glycerol monostearate or starch.

However, amorphous solid dispersions of Vortioxetine hydrobromide with Hydroxyethyl cellulose (HEC) have not been prepared, isolated and/or characterized in the literature.

Polymorphism is the ability of a solid material to exist in more than one form or crystal structure. Amorphous solids consist of disordered arrangement of molecules and do not possess a distinguishable crystal lattice. The amorphous form is generally more soluble than the crystalline form and thus contributes more in the bioavailability.

An important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered pharmaceutical compound may reach the patient's bloodstream. The rate of dissolution is a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.

The discovery of new solid state forms of a pharmaceutical compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a pharmaceutical compound with a targeted release profile or other desired characteristics.

Solid dispersions can reduce the drug particle size into molecular level. They also improve the bioavailability, wettability, enhance the porosity and contribute towards polymorphic change. The fast dissolution or water absorption of carrier molecules surrounding drug particles can improve the drug wettability. This reduces the risk of agglomeration of drug particles in the dissolution media and increase the dissolution rate of the drug. Many polymers can act as 'Solubilizers' to enhance drug solubility. Solid dispersions also have high porous structure, thus increasing the porosity, surface specific area and the dissolution rate of drug.

Hence, there is a need in the art for highly pure and stable amorphous solid dispersions of Vortioxetine hydrobromide, a process for the preparation and a pharmaceutical composition thereof with improved physiochemical characteristics that assist in the effective bioavailability and which are suitable for formulation.

SUMMARY OF THE INVENTION
In one aspect, provided herein are stable and water-soluble amorphous solid dispersions of Vortioxetine hydrobromide with a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from the group consisting of hydroxyethyl cellulose (HEC), soluplus, hypromellose (also called as hydroxypropyl methylcellulose or HPMC), copovdione and mixtures thereof.

The amorphous solid dispersions of Vortioxetine hydrobromide disclosed herein have high purity, adequate stability and better solubility and dissolution properties.

The solubility of drugs in water and in buffer solutions with a pH of 6.8 and pH of 7.4 is fundamentally important for drug development and manufacturing. Drugs administered orally as a solid or in suspension have to dissolve in the aqueous gastric fluid before they can be absorbed and transported via the systemic circulation to their site of action. The rate and extent of dissolution of a drug is a major factor in controlling the absorption of that drug. This is because the concentration of the drug in the fluid in the gut lumen is one of the main factors governing the transfer of the drug through the membranes of the gastrointestinal tract (GIT). The rate of dissolution depends on the surface of the solid, which is dependent on both the physical nature of the dosage form of the drug and the chemical structure of the drug. However, the extent of dissolution depends only on the drug's solubility.

It has been surprisingly and unexpectedly found that the amorphous solid dispersions of Vortioxetine hydrobromide with hydroxyethyl cellulose (HEC), soluplus and copovidone as disclosed herein have excellent aqueous solubility and bioavailability when compared with that of the crystalline form of Vortioxetine hydrobromide.
The amorphous solid dispersions of Vortioxetine hydrobromide of the present invention can be advantageously used for immediate release and extended release dosage forms as it shows better solubility in water as well as in the buffer solutions with a pH of 6.8 and pH of 7.4, and it is also having good solubility in 0.1N HC1, thereby having improved bioavailability when compared to the crystalline form of Vortioxetine hydrobromide.

In another aspect, encompassed herein is a process for preparing the novel and stable amorphous solid dispersions of Vortioxetine hydrobromide with pharmaceutically acceptable excipients.

In another aspect, provided herein are pharmaceutical compositions comprising the amorphous solid dispersions of Vortioxetine hydrobromide with pharmaceutically acceptable excipients.

In another aspect, encompassed herein is a process for preparing a pharmaceutical formulations comprising combining the amorphous solid dispersions of Vortioxetine hydrobromide with pharmaceutically acceptable excipients.

In another aspect, the amorphous solid dispersions of Vortioxetine hydrobromide with pharmaceutically acceptable excipients has a D90 particle size of less than or equal to about 400 microns, specifically about 1 micron to about 300 microns, and most specifically about 10 microns to about 150 microns.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of Amorphous Solid
dispersion of Vortioxetine hydrobromide with hydroxyethyl cellulose (1 : 1.5) obtained
according to the example 1.
Figure 2 is a characteristic X-ray powder diffraction (XRPD) pattern of Amorphous Solid
dispersion of Vortioxetine hydrobromide with soluplus (1:2) obtained according to
example 3.
Figure 3 is a characteristic powder X-ray diffraction (XRPD) pattern of Amorphous Solid
dispersion of Vortioxetine hydrobromide with hypromellose (1 : 1) obtained according to
example 4.
Figure 4 is characteristic X-ray powder diffraction (XRPD) pattern of Amorphous Solid
dispersion of Vortioxetine hydrobromide with copovidone (1 : 1.25) obtained according to
example 5.
Figure 5 is a characteristic Infrared (IR) spectrum of Amorphous Solid dispersion of
Vortioxetine hydrobromide with hydroxyethyl cellulose (1 : 1.5) obtained according to the
example 1.
Figure 6 is a characteristic Infrared (IR) spectrum of Amorphous Solid dispersion of
Vortioxetine hydrobromide with soluplus (1:2) obtained according to example 3.
Figure 7 is a characteristic Infrared (IR) spectrum of Amorphous Solid dispersion of
Vortioxetine hydrobromide with hypromellose (1:1) obtained according to example 4.

Figure 8 is a characteristic Infrared (IR) spectrum of Amorphous Solid dispersion of
Vortioxetine hydrobromide with copovidone (1 : 1.25) obtained according to example 5.
Figure 9 is a characteristic Differential Scanning Calorimetry (DSC) thermogram of
Amorphous Solid dispersion of Vortioxetine hydrobromide with hydroxy ethyl cellulose (1
: 1.5) obtained according to the example 1.
Figure 10 is a characteristic Differential Scanning Calorimetry (DSC) thermogram of
Amorphous Solid dispersion of Vortioxetine hydrobromide with soluplus (1 : 2) obtained
according to example 3.
Figure 11 is a characteristic Differential Scanning Calorimetry (DSC) thermogram of
Amorphous Solid dispersion of Vortioxetine hydrobromide with hypromellose (1 : 1)
obtained according to example 4.
Figure 12 is a characteristic Differential Scanning Calorimetry (DSC) thermogram of
Amorphous Solid dispersion of Vortioxetine hydrobromide with copovidone (1 : 1.25)
obtained according to example 5.
Figure 13 is a characteristic Thermo Gravimetric Analysis (TGA) curve of Amorphous
Solid dispersion of Vortioxetine hydrobromide with hydroxy ethyl cellulose (1 : 1.5)
obtained according to the example 1.
Figure 14 is a characteristic Thermo Gravimetric Analysis (TGA) curve of Amorphous
Solid dispersion of Vortioxetine hydrobromide with soluplus (1 : 2) obtained according to
example 3.
Figure 15 is a characteristic Thermo Gravimetric Analysis (TGA) curve of Amorphous
Solid dispersion of Vortioxetine hydrobromide with hypromellose (1 : 1) obtained
according to example 4.
Figure 16 is a characteristic Thermo Gravimetric Analysis (TGA) curve of Amorphous
Solid dispersion of Vortioxetine hydrobromide with copovidone (1 : 1.25) obtained
according to example 5.
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a stable and water-soluble amorphous solid dispersion of Vortioxetine hydrobromide and hydroxyethyl cellulose (HEC) having improved physicochemical characteristics that assist in the effective bioavailability of Vortioxetine hydrobromide.

According to another aspect, there are provided stable and water-soluble amorphous solid dispersions of Vortioxetine hydrobromide and a pharmaceutically acceptable excipient having improved physicochemical characteristics that assist in the effective bioavailability of Vortioxetine hydrobromide. In one embodiment, the pharmaceutically acceptable excipient is selected from the group consisting of soluplus, hypromellose (also called as hydroxypropyl methylcellulose or HPMC) and copovidone.

According to another aspect, there are provided pharmaceutical compositions comprising amorphous solid dispersions of Vortioxetine hydrobromide, and one or more pharmaceutically acceptable excipients.

The amorphous solid dispersions of Vortioxetine hydrobromide with a pharmaceutically acceptable carrier obtained by the processes disclosed herein may be characterized by one or more of their powder X-ray diffraction (XRD) pattern, Infrared absorption (IR) spectrum, Differential Scanning Calorimetry (DSC) thermogram and Thermo Gravimetric Analyses (TGA) curve.

In one embodiment, the amorphous solid dispersion of Vortioxetine hydrobromide with hydroxyethyl cellulose (1 : 1.5) is characterized by a powder XRD pattern substantially in accordance with Figure 1. The X-ray powder diffraction pattern shows a plain halo with no well-defined peaks, thus demonstrating the amorphous nature of the product.

In another embodiment, the amorphous solid dispersion of Vortioxetine hydrobromide with hydroxyethyl cellulose (1 : 1.5) is characterized by an infrared (FT-IR) spectrum having main bands at about 3434, 2922, 2852, 1742, 1629, 1514, 1466, 1453, 1383, 1231, 1123, 1020, 924, 808, 760, 721 and 665 ± 2 cm*1 substantially in accordance with Figure 5.

In another embodiment, the amorphous solid dispersion of Vortioxetine hydrobromide with soluplus (1 : 2) is characterized by a powder XRD pattern substantially in accordance with Figure 2. The X-ray powder diffraction pattern shows a plain halo with no well-defined peaks, thus demonstrating the amorphous nature of the product.

In another embodiment, the amorphous solid dispersion of Vortioxetine hydrobromide with soluplus (1 : 2) is characterized by an infrared (FT-IR) spectrum having main bands at about 3450, 2928, 2856, 2464, 1738, 1638, 1442, 1333, 1238, 1196,

1148, 1084, 972, 927, 841, 818, 751 and 680 ± 2 cm'1 substantially in accordance with Figure 6.
In another embodiment, the amorphous solid dispersion of Vortioxetine hydrobromide with hypromellose (1 : 1) is characterized by a powder XRD pattern substantially in accordance with Figure 3. The X-ray powder diffraction pattern shows a plain halo with no well-defined peaks, thus demonstrating the amorphous nature of the product.

In another embodiment, the amorphous solid dispersion of Vortioxetine hydrobromide with hypromellose (1 : 1) is characterized by an infrared (FT-IR) spectrum having main bands at about 3434, 2924, 2466, 1724, 1581, 1472, 1378, 1123, 1041, 925, 814, 760 and 681 ± 2 cm"1 substantially in accordance with Figure 7.

In another embodiment, the amorphous solid dispersion of Vortioxetine hydrobromide with copovidone (1 : 1.25) is characterized by a powder XRD pattern substantially in accordance with Figure 4. The X-ray powder diffraction pattern shows a plain halo with no well-defined peaks, thus demonstrating the amorphous nature of the product.

In another embodiment, the amorphous solid dispersion of Vortioxetine hydrobromide with copovidone (1 : 1.25) is characterized by an infrared (FT-IR) spectrum having main bands at about 3433, 2956, 2923, 2460, 1736, 1678, 1581, 1374, 1288, 1242, 1123, 1042, 927, 816, 762 and 682 ± 2 cm'1 substantially in accordance with Figure 8.

According to another aspect, there is provided a process for preparing a stable and water-soluble amorphous solid dispersion of Vortioxetine hydrobromide and a pharmaceutically acceptable excipient, comprising:
a) providing a solution of Vortioxetine hydrobromide in a solvent wherein the solvent is an organic solvent which is selected from the group consisting of an alcohol, a ketone, a halogenated hydrocarbon, a nitrile, an ester, and mixtures thereof;

b) providing a solution of pharmaceutically acceptable excipient in a solvent wherein the solvent is an organic solvent which is selected from the group consisting of an alcohol, a ketone, a halogenated hydrocarbon, a nitrile, an ester, and mixtures thereof;
c) addition of a solution obtained in step-(a) to the solution obtained in step-(b);
d) optionally, filtering the solvent solution, to remove insoluble matter; and

e) substantially removing the solvent from the solution obtained in step-(c) or step-(d) to produce the stable and water-soluble amorphous solid dispersion of Vortioxetine hydrobromide with pharmaceutical^ acceptable excipient.
In one embodiment, the pharmaceutical^ acceptable excipient used in step-(a) is hydroxyethyl cellulose, soluplus, hypromellose, copovidone and mixtures thereof.
The process can produce amorphous solid dispersions of Vortioxetine hydrobromide with the pharmaceutical^ acceptable excipient in substantially pure form.

The term "substantially pure amorphous solid dispersion of Vortioxetine hydrobromide with the pharmaceutically acceptable excipient" refers to the amorphous solid dispersions of Vortioxetine hydrobromide having a purity, greater than about 99%, specifically greater than about 99.5%, and more specifically greater than about 99.95% (measured by HPLC). For example, the total purity of the amorphous solid dispersions of Vortioxetine hydrobromide obtained by the process disclosed herein can be about 99.5% to about 99.99% as measured by HPLC.

The amorphous solid dispersions of Vortioxetine hydrobromide obtained by the process disclosed herein are stable, consistently reproducible and have good flow properties, and which is particularly suitable for bulk preparation and handling. The novel solid dispersions obtained by the process disclosed herein are suitable for formulating Vortioxetine hydrobromide.

The amorphous solid dispersions of Vortioxetine hydrobromide with hydroxyethyl cellulose as disclosed herein shows better solubility in water (38.33 mg/ml) than the crystalline form of Vortioxetine hydrobromide which shows comparatively very low solubility in water (5 mg/ml). This is a distinct advantage from a drug developing and manufacturing standpoint as the dissolution of a drug is directly related to its absorption when administered.

The amorphous solid dispersions of Vortioxetine hydrobromide with soluplus as disclosed herein shows better solubility in water (38.7 mg/ml) than the crystalline form of Vortioxetine hydrobromide which shows comparatively very low solubility in water (5 mg/ml). This is a distinct advantage from a drug developing and manufacturing standpoint as the dissolution of a drug is directly related to its absorption when administered.

The amorphous solid dispersions of Vortioxetine hydrobromide with copovidone as disclosed herein shows better solubility in water (26.7 mg/ml) than the crystalline form Of Vortioxetine hydrobromide which shows comparatively very low solubility in water (5 mg/ml). This is a distinct advantage from a drug developing and manufacturing standpoint as the dissolution of a drug is directly related to its absorption when administered.
The amorphous solid dispersions of Vortioxetine hydrobromide with hydroxyethyl cellulose of the present invention also shows better solubility (59.68 mg/ml) in a buffer solution with a pH of 6.8 than the prior art crystalline form of Vortioxetine hydrobromide which shows comparatively very low solubility (1.62 mg/ml). The amorphous solid dispersions of Vortioxetine hydrobromide with hydroxyethyl cellulose of the present invention also shows better solubility (30.85 mg/ml) in a buffer solution with a pH of 7.4 than the prior art crystalline form of Vortioxetine hydrobromide which shows comparatively very low solubility (2.31 mg/ml). The amorphous solid dispersions of Vortioxetine hydrobromide with hydroxyethyl cellulose of the present invention also shows better solubility (30 mg/ml) in 0.1N HC1 solution with a pH of 1.2 when compared with that of the crystalline form of Vortioxetine hydrobromide (21.27 mg/ml).

The amorphous solid dispersions of Vortioxetine hydrobromide with soluplus of the present invention also shows better solubility (64.8 mg/ml) in a buffer solution with a pH of 6.8 than, the prior art crystalline form of Vortioxetine hydrobromide which shows comparatively very low solubility (1.62 mg/ml). The amorphous solid dispersions of Vortioxetine hydrobromide with soluplus of the present invention also shows better solubility (23 mg/ml) in a buffer solution with a pH of 7.4 than the prior art crystalline form of Vortioxetine hydrobromide which shows comparatively very low solubility (2.31 mg/ml). The amorphous solid dispersions of Vortioxetine hydrobromide with soluplus of the present invention also shows better solubility (77.9 mg/ml) in 0.1N HC1 solution with a pH of 1.2 when compared with that of the crystalline form of Vortioxetine hydrobromide (21.27 mg/ml).

The amorphous solid dispersions of Vortioxetine hydrobromide with copovidone of the present invention also shows better solubility (30.29 mg/ml) in a buffer solution with a pH of 6.8 than the prior art crystalline form of Vortioxetine hydrobromide which shows comparatively very low solubility (1.62 mg/ml). The amorphous solid dispersions of Vortioxetine hydrobromide with copovidone of the present invention also shows better solubility (7.8 mg/ml) in a buffer solution with a pH of 7.4 than the prior art crystalline form of Vortioxetine hydrobromide which shows comparatively very low solubility (2.31

mg/ml). The amorphous solid dispersions of Vortioxetine hydrobromide with copovidone of the present invention also shows better solubility (89.8 mg/ml) in 0.1N HC1 solution with a pH of 1.2 when compared with that of the crystalline form of Vortioxetine hydrobromide (21.27 mg/ml).

In one embodiment, the solvent used in step-(a) and step-(b) is selected from the group consisting of an alcohol, a ketone, a halogenated hydrocarbon, a nitrile, an ester, and mixtures thereof. Specifically the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, acetone, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethoxyethane, and mixtures thereof. Most specifically the solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, dichloromethane and mixtures thereof.
Step-(a) of providing a solution includes dissolving Vortioxetine hydrobromide in the solvent, or such a solution is obtained directly from a reaction in which Vortioxetine hydrobromide is formed.

Step-(b) of providing a solution includes dissolving pharmaceutically acceptable excipient in the solvent.

Step-(c) of addition of a solution of step-(a) to step-(b) is carried out at a temperature of about 15°C to about 120°C, specifically at about 20°C to about 100°C, and more specifically at about 25°C to about 85°C.

In another embodiment, the solution obtained in step-(c) is subjected to carbon treatment or silica gel treatment. The carbon treatment or silica gel treatment may be carried out by methods known in the art, for example by stirring the solution with finely powdered carbon or silica gel at a temperature of below about 70°C for at least 5 minutes, specifically at a temperature of about 40°C to about 70°C for at least 30 minutes; and filtering the resulting mixture through hyflo bed to obtain a filtrate containing Vortioxetine hydrobromide by removing charcoal or silica gel. Preferably, a finely powdered carbon is an active carbon. In one embodiment, a specific mesh size of silica gel is 40-500 mesh, and more specifically 60-120 mesh.

The solution obtained in step-(c) is stirred at a temperature of about 20°C to the reflux temperature of the solvent used for at least 10 minutes, and specifically at a temperature of about 20°C to about 80°C for about 20 minutes to about 2 hours.

Removal of solvent in step-(e) is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution, or distillation of solvent, under inert atmosphere to obtain amorphous solid dispersions comprising Vortioxetine hydrobromide and the pharmaceutically acceptable excipient.

In one embodiment, the removal of solvent in step-(e) is carried out by distillation. The distillation process can be performed at atmospheric pressure or at reduced pressure.

Specifically the distillation process is performed at reduced pressure. In one embodiment, the solvent is removed at a pressure of about 760 mm Hg or less, specifically at about 400 mm Hg or less, more specifically at about 80 mm Hg or less, and most specifically from about 30 to about 80 mm Hg.
In a preferred embodiment, the distillation process is performed under reduced pressure and at a temperature of about 70°C to about 120°C, and most specifically at a temperature of about 75°C to about 90°C.

In another embodiment, the solvent is removed by evaporation. Evaporation can be achieved at sub-zero temperatures by lyophilisation or freeze-drying techniques. Th solution may also be completely evaporated in, for example, a pilot plant Rota vapor, a Vacuum Paddle Dryer or in a conventional reactor under vacuum above about 720 mm Hg by flash evaporation techniques by using an agitated thin film dryer ("ATFD").
In another embodiment, the removal of solvent in step-(e) may also be accomplished by spray-drying. The air inlet temperature to the spray drier used may range from about 50°C to about 150°C, specifically from about 60°C to about 120°C and most specifically from about 70°C to about 100°C; and the outlet air temperature used may range from about 30°C to about 90°C,

The dried product obtained by the process disclosed herein above can optionally be milled to get desired particle sizes. Milling or micronization can be performed prior to drying, or after the completion of drying of the product. The milling operation reduces the size of particles and increases surface area of particles. Drying is more efficient when the particle size of the material is smaller and the surface area is higher, hence milling will frequently be performed prior to the drying operation.

Milling can be done suitably using jet milling equipment like an air jet mill, or using other conventional milling equipment.

The resulting amorphous powder compositions disclosed herein have improved solubility properties and hence also have improved bioavailability.

The amorphous solid dispersions of Vortioxetine hydrobromide with the pharmaceutically acceptable excipients obtained by the process disclosed herein are a random distribution of the Vortioxetine hydrobromide and the pharmaceutically acceptable excipient in a particle matrix. Without being held to any particular theory, the solid dispersions have the characteristics of solid dispersions at a molecular level, being in the nature of solid solutions. The solid solutions, or molecular dispersions, provide homogeneous particles in which substantially no discrete areas of only amorphous Vortioxetine hydrobromide and/or only pharmaceutically acceptable excipient can be observed.
Further encompassed herein is the use of the amorphous solid dispersions of Vortioxetine hydrobromide and the pharmaceutically acceptable excipients for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.

A specific pharmaceutical composition of the amorphous solid dispersions of Vortioxetine hydrobromide is selected from a solid dosage form and an oral suspension.

In one embodiment, the amorphous solid dispersions of Vortioxetine hydrobromide and the pharmaceutically acceptable excipient, has a D90 particle size of less than or equal to about 400 microns, specifically about 1 micron to about 300 microns, and most specifically about 10 microns to about 150 microns.

In another embodiment, the amorphous solid dispersions of Vortioxetine hydrobromide and the pharmaceutically acceptable excipient, disclosed herein for use in the pharmaceutical compositions has a D90 particle size of less than or equal to about 400 microns, specifically about 1 micron to about 300 microns, and most specifically about 10 microns to about 150 microns.
In another embodiment, the particle sizes of the amorphous solid dispersions of Vortioxetine hydrobromide and the pharmaceutically acceptable excipient, can be achieved by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.

According to another aspect, there is provided a method for treating major depressive disorder (MDD), comprising administering a therapeutically effective amount of the amorphous solid dispersion of Vortioxetine hydrobromide, or a pharmaceutical composition that comprises a therapeutically effective amount of amorphous solid dispersion of Vortioxetine hydrobromide along with pharmaceutical^ acceptable excipients.

According to another aspect, there are provided pharmaceutical compositions comprising amorphous solid dispersions of Vortioxetine hydrobromide prepared according to the processes disclosed herein and one or more pharmaceutically acceptable excipients.

According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining amorphous solid dispersions of Vortioxetine hydrobromide prepared according to the process disclosed herein, with one or more pharmaceutically acceptable excipients.

Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of the amorphous co-precipitate of solid dispersions of Vortioxetine hydrobromide. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, elixir, aerosol, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, lozenges, elixirs and the like.

The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinafter.

In one embodiment, capsule dosage forms contain the amorphous solid dispersions of Vortioxetine hydrobromide within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. Suitable enteric coating agents include phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, the coating agents may be employed with suitable plasticizers and/or extending agents. A coated capsule or tablet may have a coating on the surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric-coating.

Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions described herein may contain diluents such as cellulose-derived materials like powdered lactose monohydrate, cellulose, microcrystalline cellulose, micro fine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols such as mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutical^ acceptable dyes and glidants such as silicon dioxide.

INSTRUMENTAL DETAILS: X-ray Powder Diffraction (P-XRD):
The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper-Ka radiation). Approximately 1 gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 38.4 seconds. The sample was simply placed on the sample holder. The sample was applied with a voltage of 40 KV and current of 35 mA.

Infra-Red Spectroscopy (FT-IR):
FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the
production of the KBr compacts approximately 5 mg of sample was powdered with 200
mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm"1 to
650 cm-1.
Differential Scanning Calorimetry (DSC):
Differential Scanning Calorimetry (DSC) measurements were performed with a
Differential Scanning Calorimeter (DSC Q200 V23.10 Build 79, Universal V4.4A TA
Instruments). Approximately 1.5 mg sample was taken in a sample holder, equilibrated at
40°C and Ramp at a scan rate of 10°C per minute to 210°C.
Thermal Gravimetry Analysis (TGA):
Thermal Gravimetry Analysis (TGA) measurements were performed with a Perkin-Elmer,
Pyris 1 TGA analyser. Approximately 5 mg to lOmg sample was loaded in a sample cup
and heated from 30°C to 150°C over a ramp of 10°C/min.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.
EXAMPLES Example 1 Preparation of Amorphous Solid dispersion of Vortioxetine hydrobromide with Hydroxy Ethyl Cellulose (HEC) (1: 1.5)
Hydroxy Ethyl Cellulose (7.5 g) and Methanol (300 ml) were taken into a reaction flask, and the contents were heated to 75-80°C. To the resulting hot solution, Vortioxetine hydrobromide (5.0 g) and methanol (75 ml) were added and maintained at 75-80°C for 15-20 minutes, followed by removal of solvent under reduced pressure at 75-80°C for 3 hours to 3 hours 30 minutes. The solid obtained was grinded and dried for a period of 4 hours to 4 hours 30 minutes at 40-45°C to produce 8.8 g of amorphous solid dispersion of Vortioxetine hydrobromide with hydroxy ethyl cellulose (1 : 1.5) as a beige colored powder.

Characterization Data:
The resulting amorphous solid dispersion of Vortioxetine hydrobromide with hydroxy ethyl cellulose (1 : 1.5) is characterized by an X-ray powder diffraction pattern, showing a plain halo with no peaks, as shown in Figure 1; a Fourier transformer infra-red spectrum (FTIR) as shown in Figure 5; a Differential Scanning Calorimetry curve (DSC) as shown in Figure 9 and Thermo Gravimetric Analyses (TGA) curve as shown in Figure 13.

Example 2 Preparation of Amorphous Solid dispersion of Vortioxetine hydrobromide with Hydroxy Ethyl Cellulose (HEC) (1 : 2)
Hydroxy Ethyl Cellulose (10.0 g) and Methanol (450 ml) were taken into a reaction flask, and the contents were heated to 75-80°C. To the resulting hot solution, Vortioxetine hydrobromide (5.0g) and methanol (50 ml) were added and maintained at 75-80°C for 15-20 minutes, followed by removal of solvent under reduced pressure at 75-80°C for 3 hours to 3 hours 30 minutes. The solid obtained was grinded and dried for a period of 4 hours to 4 hours 30 minutes at 40-45°C to produce 13.0 g of amorphous solid dispersion-of Vortioxetine hydrobromide with hydroxy ethyl cellulose (1 : 2) as a beige colored powder.

Example 3 Preparation of Amorphous Solid dispersion of Vortioxetine hydrobromide with Soluplus (1 :2)
Soluplus (10.0 g) and Methanol (400 ml) were taken into a reaction flask, and the contents were heated to 75-80°C. To the resulting hot solution, Vortioxetine hydrobromide (5.0 g) and methanol (50 ml) were added and maintained at 75-80°C for 30 minutes, followed by removal of solvent under reduced pressure at 75-80°C for 3 hours 30 minutes to 4 hours. The solid obtained was grinded and dried for a period of 3hours to 4 hours at 50°C to produce 12.8 g of amorphous solid dispersion of Vortioxetine hydrobromide with soluplus (1 : 2) as a beige colored powder. Characterization Data:
The resulting amorphous solid dispersion of Vortioxetine hydrobromide with soluplus (1 : 2) is characterized by an X-ray powder diffraction pattern, showing a plain halo with no peaks, as shown in Figure 4; a Fourier transformer infra-red spectrum (FTIR) as shown in

Figure 8; a Differential Scanning Calorimetry curve (DSC) as shown in Figure 12 and Thermo Gravimetric Analyses (TGA) curve as shown in Figure 14.

Example 4 Preparation of Amorphous Solid dispersion of Vortioxetine hydrobromide with Hydroxypropyl mehylcellulose (Hypromellose) (1 : 1)

Hydroxypropyl mehylcellulose (5.0 g) and Methanol (275 ml) were taken into a reaction flask, and the contents were heated to 75-80°C. To the resulting hot solution, Vortioxetine hydrobromide (5.0g) and methanol (25 ml) were added and maintained at 75-80°C for 30 minutes, followed by removal of solvent under reduced pressure at 75-80°C for 4 hours to 5 hours. The solid obtained was grinded and dried for 5 hours at 50°C to produce 9.8 g of amorphous solid dispersion of Vortioxetine hydrobromide with Hydroxypropyl mehylcellulose (Hypromellose) (1 : 1) as a beige colored powder. Characterization Data:

The resulting amorphous solid dispersion of Vortioxetine hydrobromide with Hydroxypropyl mehylcellulose (Hypromellose) (1 : 1) is characterized by an X-ray powder diffraction pattern, showing a plain halo with no peaks, as shown in Figure 2; a Fourier transformer infra-red spectrum (FTIR) as shown in Figure 6; a Differential Scanning Calorimetry curve (DSC) as shown in Figure 10 and Thermo Gravimetric Analyses (TGA) curve as shown in Figure 15.

Example 5 Preparation of Amorphous Solid dispersion of Vortioxetine hydrobromide with Copovidone (1 :1.25)

Copovidone (6.25 g) and Methanol (300 ml) were taken into a reaction flask, and the contents were heated to 75-80°C. To the resulting hot solution, Vortioxetine hydrobromide (5.0g) and methanol (50 ml) were added and maintained at 75-80°C for 15-20 minutes, followed by removal of solvent under reduced pressure at 75-80°C for 3 hours to 4 hours. The solid obtained was grinded and dried for a period of 2 hours to 3 hours at 50°C to produce 10.0 g of amorphous solid dispersion of Vortioxetine hydrobromide with copovidone (1 : 1.25) as a beige colored powder.

Characterization Data:
The resulting amorphous solid dispersion of Vortioxetine hydrobromide with copovidone (1 : 1.25) is characterized by an X-ray powder diffraction pattern, showing a plain halo with no peaks, as shown in Figure 3; a Fourier transformer infra-red spectrum (FTIR) as shown in Figure 7; a Differential Scanning Calorimetry cruve (DSC) as shown in Figure 11 and Thermo Gravimetric Analyses (TGA) curve as shown in Figure 16.

Example 6 Test for Improved Properties of Solid dispersions: (1) Solubility Studies:
Solubility of the Vortioxetine hydrobromide API [crystalline form p, prepared by the process as disclosed in the U.S. Patent No. 8.722,684, hereinafter referred to as API] and the four amorphous solid dispersions of Vortioxetine hydrobromide namely hydroxyethyl cellulose (A), soluplus (B), hypromellose (C) and copovidone (D) (prepared as per the processes exemplified in Examples 1, 3, 4 and 5 of the present invention) was studied in water, 0.1 N HC1, pH 6.8 buffer and in pH 7.4 buffer. The solubility data is represented below in Table 1:

It could be concluded from the above solubility data that when compared with the solubility of the API, all of the four solid dispersions have increased solubility in water, Q.l N HC1, pH 6.8 buffer and pH 7.4 buffer.

(2) Partition Coefficient Studies: The partition co-efficient values of Vortioxetine hydrobromide (crystalline form p, hereinafter referred to as API) and the four solid dispersions namely hydroxyethyl cellulose (A), soluplus (B), hypromellose (C) and

copovidone (D) was determined in octanol/water, chloroform/water and butanol/water and are presented below in Table 2:

It is evident from the above data that all the four solid dispersions (A to D) have their log P values lesser than 1 indicating them to be more hydrophilic, in nature. Whereas the API itself has its log P values higher than 1, showing it to be lipophilic, in nature. (3) Pre-Formulation [Solid Dosage Form (Tablets)] studies:

Characteristic pre-formulation studies, specifically for solid dosage (Tablet) form were also conducted with the Vortioxetine hydrobromide crystalline form p and the four solid dispersions to examine the suitability of solid dispersions for tablet formulation. For this purpose, the tablets of 5 mg, 10 mg and 20 mg were punched using the API and solid dispersions using the prescribed excipients in the below given proportions:
API/Solid dispersion - q.s
Mannitol - 4.5 mg
Microcrystalline cellulose - 25.0 mg
HPMC - 5 mg
Sodium starch glycolate - 3.0 mg
Magnesium stearate - 2.0 %
All the above specified ingredients of solid dosage (tablet) form, in their specified quantities were weighed and the tablets were punched by direct compression method. These different tablet formulations were studied for their normal properties, viz. Hardness, Friability, Weight variation, Disintegration and Dissolution and the results are tabulated and presented, separately for the API and its four solid dispersions namely Hydroxyethyl cellulose (A), soluplus (B)5 hypromellose (C) and copovidone (D).

(a) Hardness Test: The hardness test was performed for all the tablets using MONSANTA Hardness Tester and the values were found to be well within the acceptable limits.cvbv

(b) Friability Test: The friability test was conducted using a REMI Friability instrument and taking 20 tablets for each type. The experimental values were found to be within agreeable limits.
(c) Weight Variation Test: The weight variation test was conducted using a SHIMADZU electronic balance and taking 20 tablets of each kind. The observed variations were also found to be within the normal limits.
(d) Disintegration Test: The disintegration test was performed for all the batches of tablets using REMI-6 Basket Disintegration apparatus. The results show that the disintegration time for all the kinds of tablets including that of API falling between 40 to 80 seconds.
The experimental observations recorded in all the above four tests (a to d) for all the four kinds of tablets using solid dispersions material (A to D) and also that of pure API Vortioxetine hydrobromide are presented in the below separate Tables 3 to 7:

Solid Dosage (Tablet) Forms & Their Dissolution studies:
Dissolution studies for each dosage form for each category (API, A to D) were conducted using the LAB INDIA Dissolution Apparatus - USP Type - II (P) in water, 0.1N HC1, pH6.8 buffer and pH 7.4 buffer, and the experimental data are presented in the below Tables 8 to 27:

As the samples A, B, C & D have shown increased solubility in water, 0.1 N HC1, pH 6.8 buffer and pH 7.4 buffer, these formulations can get absorbed in entire GIT, at all pH levels and they will have increased bioavailability comparing with the pure API.
It was observed that the dissolution data of all the solid dosage (Tablet) forms are perfectly matching with the solubility data of API and the respective solid dispersion materials (A to D). Further, the solid dosage forms of all the four solid dispersions (A to D) exhibited improved solubility than the API itself.
Thus from the experimental studies, it can be concluded that all these four solid dispersions are quite suitable to go for their dosage formulation. Further, these solid dispersions of Vortioxetine hydrobromide show improved solubility with an ability to get absorbed in all parts of intestine and hence better bioavailability. Therefore, it is concluded that all the four (A to D) solid dispersions of Vortioxetine hydrobromide possess improved characteristics than the pure API itself and all the polymers (excipients) used in their preparation are inert and compatible.
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term "micronization" used herein means a process or method by which the size of a population of particles is reduced.
As used herein, the term "micron" or "|im" both are equivalent and refer to "micrometer" which is 1 x 10"6 meter.

As used herein, "Particle Size Distribution (P.S.D)" means the cumulative volume size distribution of equivalent spherical diameters as determined by laser diffraction in Malvern Master Sizer 2000 equipment or its equivalent.
The important characteristics of the PSD are the (D90), which is the size, in microns, below which 90% of the particles by volume are found, and the (D50), which is the size, in microns, below which 50% of the particles by volume are found. Thus, a D90 or d(0.9) of less than 300 microns means that 90 volume-percent of the particles in a composition have a diameter less than 300 microns.
The term "solid dispersion" as used herein refers to compositions comprising Vortioxetine hydrobromide together with at least one pharmaceutically acceptable excipient, being prepared by removing solvent from a solution containing both of them.
The term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for veterinary use and/or human pharmaceutical use.
The term "pharmaceutical composition" is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.
The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
The term "delivering" as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.

The term "buffering agent" as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other such materials known to those of ordinary skill in the art.
The term "sweetening agent" as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.
The term "binders" as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.
The term "diluents" or "filler" as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
The term "glidant" as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "lubricant" as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
The term "disintegrant" as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
The term "wetting agent" as used herein is intended to mean a compound used to
aid in attaining intimate contact between solid particles and liquids. Exemplary wetting
agents include, by way of example and without limitation, gelatin, casein, lecithin
(phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride,
calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying
wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as
cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty
acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide,
phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium,
carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,
hydroxylpropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).
Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by

applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

We claim:
1. A stable and water-soluble amorphous solid dispersion comprising Vortioxetine hydrobromide and a pharmaceutical^ acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from the group consisting of hydroxyethyl cellulose (HEC), soluplus, hypromellose, copovidone, and mixtures thereof.
2. The amorphous solid dispersion of Vortioxetine hydrobromide of claim 1, wherein amorphous solid dispersion is amorphous solid dispersion of Vortioxetine hydrobromide with hydroxyethyl cellulose (1 : 1.5) characterized by a powder XRD pattern, showing no peaks, substantially in accordance with Figure 1; wherein amorphous solid dispersion is amorphous solid dispersion of Vortioxetine hydrobromide with soluplus (1:2) characterized by a powder XRD pattern, showing no peaks, substantially in accordance with Figure 2; wherein amorphous solid dispersion is amorphous solid dispersion of Vortioxetine hydrobromide with hypromellose (1 : 1) characterized by a powder XRD pattern, showing no peaks, substantially in accordance with Figure 3; and wherein amorphous solid dispersion is amorphous solid dispersion of Vortioxetine hydrobromide with copovidone (1 : 1.25) characterized by a powder XRD pattern, showing no peaks, substantially in accordance with Figure 4.
3. The amorphous solid dispersion of Vortioxetine hydrobromide of claim 3, wherein the amorphous solid dispersion of Vortioxetine hydrobromide with hydroxyethyl cellulose (1 : 1.5) is further characterized by an infrared (FT-IR) spectrum having main bands at about 3434, 2922, 2852, 1742, 1629, 1514, 1466, 1453, 1383, 1231, 1123, 1020, 924, 808, 760, 721 and 665 ± 2 cm*1 substantially in accordance with Figure 5; wherein the amorphous solid dispersion of Vortioxetine hydrobromide with soluplus (1 : 2) is further characterized by an infrared (FT-IR) spectrum having main bands at about 3450, 2928, 2856, 2464, 1738, 1638, 1442, 1333, 1238, 1196, 1148, 1084, 972, 927, 841, 818, 751 and 680 ± 2 cm'1 substantially in accordance with Figure 6; wherein the amorphous solid dispersion of Vortioxetine hydrobromide with hypromellose (1 : 1) is further characterized by an infrared (FT-IR) spectrum having main bands at about 3434, 2924, 2466, 1724, 1581, 1472, 1378, 1123,1041, 925, 814, 760 and 681 ± 2 cm"1 substantially in accordance with Figure 7; and wherein the amorphous solid dispersion

of Vortioxetine hydrobromide with copovidone (1 : 1.25) is further characterized by an infrared (FT-IR) spectrum having main bands at about 3433, 2956, 2923, 2460, 1736, 1678, 1581, 1374, 1288, 1242, 1123, 1042, 927, 816, 762 and 682 ± 2 cm"1 substantially in accordance with Figure 8.
4. A process for the preparation of the amorphous solid dispersion of Vortioxetine
hydrobromide of claim 1, comprising:
a) providing a solution of Vortioxetine hydrobromide in a solvent wherein the solvent is an organic solvent which is selected from the group consisting of an alcohol, a ketone, a halogenated hydrocarbon, a nitrile, an ester, and mixtures thereof;
b) providing a solution of pharmaceutical^ acceptable excipient in a solvent wherein the solvent is an organic solvent which is selected from the group consisting of an alcohol, a ketone, a halogenated hydrocarbon, a nitrile, an ester, and mixtures thereof;
c) addition of a solution obtained in step-(a) to the solution obtained in step-(b);
d) optionally, filtering the solvent solution, to remove insoluble matter; and
e) substantially removing the solvent from the solution obtained in step-(c) or step-(d) to produce the amorphous solid dispersion of Vortioxetine hydrobromide with pharmaceutical^ acceptable excipient;
wherein the pharmaceutical^ acceptable excipient is selected from the group consisting of hydroxyethyl cellulose (HEC), soluplus, hypromellose, copovidone, and mixtures thereof.
5. The process of claim 4, wherein the solvent used in step-(a) and step-(b), is each
independently, selected from the group consisting of methanol, ethanol, n-propanol,
isopropyl alcohol, acetone, dichloromethane, acetonitrile, tetrahydrofuran, N,N-
dimethylformamide, dimethoxyethane, and mixtures thereof; and wherein the removal
of solvent in step-(e) is accomplished by distillation or complete evaporation of the
solvent, spray drying, vacuum drying, lyophilization or freeze drying, agitated thin-
film drying, or a combination thereof.
6. A pharmaceutical composition comprising the stable and water-soluble amorphous solid
dispersion of Vortioxetine hydrobromide of claim 1, and one or more pharmaceutical^ acceptable excipients.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is a solid dosage form, an oral suspension, a liquid, a powder, an elixir, an aerosol, or an injectable solution.
8. The pharmaceutical composition of claim 6, wherein the amorphous solid dispersion of Vortioxetine hydrobromide has a D90 particle size of less than or equal to about 400 microns.
9. The pharmaceutical composition of claim 6, wherein the amorphous solid dispersion of Vortioxetine hydrobromide has a D90 particle size of about 1 micron to about 300 microns.
10. A method for treating major depressive disorder (MDD), comprising administering a therapeutically effective amount of the stable and water-soluble amorphous solid dispersion of Vortioxetine hydrobromide of claim 1, or a pharmaceutical composition that comprises a therapeutically effective amount of the stable and water-soluble amorphous solid dispersion of Vortioxetine hydrobromide of claim 1 along with pharmaceutically acceptable excipients.