DESC:Field of the Invention:
The present invention provides novel hydrated form of Vortioxetine hydrobromide, process for its preparation and pharmaceutical composition thereof.

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

Vortioxetine is intended to have combined effects on multiple 5-HT receptors and on the serotonin transporter. It has been shown in recombinant cell lines to combine 5-HT3 and 5-HT7 receptor antagonism, 5-HT1B receptor partial agonism, 5-HT1A receptor agonism, and serotonin transporter inhibition.

Extensive study is carried out in pharmaceutical industry for development of different polymorphs of various drug substances, to obtain suitable polymorphs that possess improved performance characteristics such as aqueous solubility, improved bioavailability, chemical stability, shelf life etc.

Literature survey reveals that Vortioxetine hydrobromide can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties and pharmacokinetics. The reported polymorphs of Vortioxetine hydrobromide are incorporated here by way of reference.

PCT application WO 2003029232 A1 by Lundbeck discloses Vortioxetine free base.

PCT application WO2007144005 by Lundbeck discloses crystalline Vortioxetine and its pharmaceutically acceptable salts in its crystalline form with their XRPD which includes alpha, beta & gamma form of hydrobromide salts, hemihydrate form of HBr salt, crystalline base, mixture of the ethyl acetate solvate and the alpha form of the hydrobromide salt, hydrochloride salt, monohydrate of hydrochloride salt, Mesylate salt, Fumarate salt, Maleate salt, Meso-tatrate salt, L-(+)-tatrate salt, D-(-)-tatrate salt, Sulphate salt, Phosphate salt and Nitrate salt.

PCT application WO 2010094285 A1 by Lundbeck discloses an isopropanol solvate of Vortioxetine hydrobromide as well as a process for the purification of Vortioxetine and pharmaceutically acceptable salts thereof.

PCT application WO 2014177491 by Lek pharmaceuticals discloses amorphous Vortioxetine hydrobromide in association with an adsorbent.

PCT application WO 2015044963 by Cadila pharmaceuticals discloses amorphous Vortioxetine hydrobromide.

PCT application WO 2014044721 by Sandoz AG pharmaceuticals discloses anhydrous and hydrated forms of Vortioxetine hydrobromide. The same application describes that hydrated form of Vortioxetine hydrobromide is not stable at room temperature and converts to form alpha form of WO 2007/144005 A1 within about 4 weeks.

Now the present invention overcomes the stability problems and gives novel and stable hydrated form of Vortioxetine hydrobromide.

Polymorphs often improve physical and biological characteristics of mother compounds without modifying primary pharmacological activity, based on mechanism of action. Thus there is a continuing need to obtain new polymorphs of Vortioxetine hydrobromide having improved physical and/or chemical properties. The present invention satisfies this need by providing new polymorphs of Vortioxetine hydrobromide with enhanced bioavailability and solubility in water or aqueous media as an essential property of active pharmaceutical ingredients determining the performance of pharmaceutical formulation.

Description of drawings:

Figure 1: illustrates X-ray powder diffraction pattern of crystalline Vortioxetine hydrobromide monohydrate designated as Form L1.

Figure 2: Differential Scanning Calorimetry thermogram of crystalline Vortioxetine hydrobromide monohydrate designated as Form L1.

Figure 3: Thermogravimetric analysis curve of crystalline Vortioxetine hydrobromide monohydrate designated as Form L1.

Summary of the Invention:

In one aspect, the invention provides crystalline monohydrate Vortioxetine hydrobromide (Form L1).

In another aspect, the invention provides process for preparation of crystalline monohydrate of Vortioxetine hydrobromide (Form L1).

In another aspect, the invention provides for pharmaceutical compositions comprising said stable crystalline monohydrate Vortioxetine hydrobromide (Form L1).

Detail Description of the Invention:

In one embodiment, the present invention provides crystalline monohydrate form L1 of Vortioxetine hydrobromide.

In another embodiment, the present invention provides crystalline monohydrate form L1 of Vortioxetine hydrobromide, which is characterized by XRPD (X-ray powder diffractogram) which comprises of peaks expressed as 2? at 11.28, 13.07, 13.69, 15.26, 16.55, 17.11, 17.49, 18.65, 19.74, 20.49, 20.63, 22.18, 22.59, 26.31, 27.02, 28.98, 29.47, 30.80, 31.63, 31.94, 32.18, 33.67, 35.02, 36.04, 36.75 ± 0.2 degrees.

The moisture content of the crystalline monohydrate Form L1 of Vortioxetine hydrobromide is about 3.5 to 4.5%.

In another embodiment, the present invention provides a process for preparation of crystalline monohydrate Form L1 of Vortioxetine hydrobromide, which comprising the steps of:

i) dissolving Vortioxetine hydrobromide in organic solvent;
ii) adding water to the above solution;
iii) cooling the solution in order to initiate crystallization; and
iv) isolating crystalline monohydrate of Vortioxetine hydrobromide Form L1.

The organic solvent of step i) selected from the halogenated and alcoholic solvents, such as but not limited to carbon tetrachloride, chloroform, chloromethane, bromomethane, chlorobenzene, chlorofluorocarbon, 1,2-dichloroethene, dichloromethane, diiodomethane, 1,1-dichloroethane, methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, n-pentanol, isoamyl alcohol, cyclohexanol, ethylene glycol, propylene glycol.

The reaction of step (i) can be carried out at a temperature of 20 to 65°C, most preferably at 50 - 60°C.

The reaction of step (ii) can be carried out at room temperature.

The reaction of step (iii) can be carried out at a temperature of 0 to 30°C, most preferably at 5 to 10°C.

The isolation of crystalline monohydrate Form L1 of Vortioxetine hydrobromide of step (iv) could be done by conventional techniques known to a person skilled in the art such as filtration, centrifugation etc.

In another embodiment, the present invention provides a pharmaceutical composition comprising crystalline monohydrate Form L1 of Vortioxetine hydrobromide with pharmaceutically acceptable excipients. The Form L1 of Vortioxetine hydrobromide can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.

The pharmaceutical composition of the invention can be formed by various methods known in the art such as by dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering and the like. The composition or formulation may be coated or uncoated. Coating of compositions such as tablets and caplets is well known in the art.

Although for many pharmaceutical compounds oral administration in the form of a tablet or capsule is preferred, some patients, for example elderly and paediatric patients, may have difficulties in swallowing such formulations. Therefore, liquid formulations such as oral solutions may offer a suitable alternative, avoiding the need of swallowing tablets or capsules. An oral solution further provides the possibility of a more flexible dosing regimen. In order to limit the volume of an oral solution it is necessary to have a high concentration of the active ingredient in the solution, which again requires a high solubility of the active ingredient. Hence the superior solubility of Form L of crystalline Vortioxetine hydrobromide of the present invention makes this particular solid state form especially suitable for the preparation of liquid pharmaceutical formulations such as oral solutions.

Pharmaceutically acceptable excipients may be utilized as required for conversion of the crystalline monohydrate Form L1 of Vortioxetine hydrobromide into the final pharmaceutical dosage forms and include, for example, any one or more of diluents, binders, stabilizers, lubricants, glidants, disintegrating agents, surfactants, and other additives that are commonly used in solid pharmaceutical dosage form preparations.

The present invention includes administration of an effective amount of crystalline monohydrate form L1 of Vortioxetine hydrobromide (either alone or as the active component of a pharmaceutical composition), in particular for use in the treatment of mood disorders; major depressive disorder; general anxiety disorder; post-traumatic stress disorder; depression associated with cognitive impairment, Alzheimer's disease or anxiety; depression with residual symptoms; chronic pain; or eating disorders.

In a further embodiment, the present invention relates to a method for the treatment of mood disorders; major depressive disorder; general anxiety disorder; post-traumatic stress disorder; depression associated with cognitive impairment, Alzheimer's disease or anxiety; depression with residual symptoms; chronic pain; or eating disorders, in a subject in need of such treatment, which method comprises administering to such subject a therapeutically effective amount of Form L of crystalline Vortioxetine hydrobromide.

The present invention includes the use of crystalline monohydrate Form L1 of Vortioxetine hydrobromide in combination with an antidepressant agent.

The diluents, binders, stabilizers, lubricants, glidants, disintegrating agents, surfactants, and other additives that are commonly used in solid pharmaceutical dosage form preparations includes

Diluents:
Various useful fillers or diluents include but are not limited to starches, lactose, mannitol (PearlitolTM SD200), cellulose derivatives, confectioner's sugar and the like. Different grades of lactose include but are not limited to lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, FlowlacTM, PharmatoseTM and others. Different starches include but are not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinized starch and starch 1500, starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch and others. Different cellulose compounds that can be used include crystalline celluloses and powdered celluloses. Examples of crystalline cellulose products include but are not limited to CEOLUSTM KG801, AvicelTM PH101, PH102, PH301, PH302 and PH-F20, PH112 microcrystalline cellulose 114, and microcrystalline cellulose 112. Other useful diluents include but are not limited to carmellose, sugar alcohols such as mannitol (PearlitolTM SD200), sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.

Binders:
Various useful binders include but are not limited to hydroxypropylcelluloses, also called HPC (KlucelTM LF, Klucel EXF) and useful in various grades, hydroxypropyl methylcelluloses, also called hypromelloses or HPMC (MethocelTM) and useful in various grades, polyvinylpyrrolidones or povidones (such as grades PVP-K25, PVP-K29, PVP-K30, and PVP-K90), PlasdoneTM S-630 (copovidone), powdered acacia, gelatin, guar gum, carbomers (CarbopolTM), methylcelluloses, polymethacrylates, and starches.

Disintegrants:
Various useful disintegrants include but are not limited to carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium, crospovidones, examples of commercially available crospovidone products including but not limited to crosslinked povidone, KollidonTM CL, PolyplasdoneTM XL, XI-10, and INF-10 and low-substituted hydroxypropylcelluloses. Examples of low-substituted hydroxypropylcelluloses include but are not limited to low-substituted hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33. Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, and starches.

Stabilizers:
Various useful stabilizers include basic inorganic salts, such as but not limited to basic inorganic salts of sodium, potassium, magnesium and calcium. Examples of basic inorganic salts of sodium are sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and the like. Examples of basic inorganic salts of potassium are potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, and the like. Examples of basic inorganic salts of magnesium are heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg6Al2(OH)16.CO3.4H2O], aluminum hydroxide-magnesium [2.5MgO.Al2O3.xH2O], and the like. Examples of basic inorganic salts of calcium include precipitated calcium carbonate, calcium hydroxide, and the like.

Surface-Active Agents:
Useful surface-active agents include non-ionic, cationic and anionic surface-active agents. Useful non-ionic surface-active agents include ethylene glycol stearates, propylene glycol stearates, diethylene glycol stearates, glycerol stearates, sorbitan esters (SPANTM) and polyhydroxyethylenically treated sorbitan esters (TWEENTM), aliphatic alcohols and PEG ethers, phenol and PEG ethers. Useful cationic surface-active agents include quaternary ammonium salts (e.g. cetyltrimethylammonium bromide) and amine salts (e.g. octadecylamine hydrochloride). Useful anionic surface-active agents include sodium stearate, potassium stearate, ammonium stearate, and calcium stearate, triethenolamine stearate, sodium lauryl sulphate, sodium dioctylsulphosuccinate, and sodium dodecylbenzenesulphonate. Natural surface-active agents may also be used, such as for example phospholipids, e.g. diacylphosphatidyl glycerols, diaceylphosphatidyl cholines, and diaceylphosphatidic acids, the precursors and derivatives thereof, such as for example soybean lecithin and egg yolk.

Lubricants:
An effective amount of any pharmaceutically acceptable tableting lubricant can be added to assist with compressing tablets. Useful tablet lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid and combinations thereof.

Glidants:
One or more glidant materials, which improve the flow of powder blends and minimize dosage form weight variations can be used. Useful glidants include but are not limited to silicone dioxide, talc and combinations thereof.

Coloring Agents:
Coloring agents can be used to color code the compositions, for example, to indicate the type and dosage of the therapeutic agent therein. Suitable coloring agents include, without limitation, natural and/or artificial compounds such as FD&C coloring agents, natural juice concentrates, pigments such as titanium oxide, silicon dioxide, iron oxides, zinc oxide, combinations thereof, and the like.

Useful additives for coatings include but are not limited to plasticizers, antiadherents, opacifiers, solvents, and optionally colorants, lubricants, pigments, antifoam agents, and polishing agents.

Various useful plasticizers include but are not limited to substances such as castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate. Also, mixtures of plasticizers may be utilized. The type of plasticizer depends upon the type of coating agent. An opacifier like titianium dioxide may also be present, typically in an amount ranging from about 10% to about 20% based on the total weight of the coating.

Examples:
Example 1:
Preparation of crystalline monohydrate of Vortioxetine hydrobromide (Form L1):

170 ml of dichloromethane was added to round bottom flask containing 1-[2-(2, 4-dimethylphenylsulfanyl) phenyl] piperazine-HBr (5.0 gm) and heated at 600C for 1 h to obtain clear solution. Optionally filtered the solution and charged with 300 ml of water. Reaction mass was stirred at room temperature for 2 h. Dichloromethane was distilled off using rotor evaporator then cooled to precipitate the salt. The solid obtained was filtered and dried under reduced pressure to give 3.9 g of desired product.
,CLAIMS:
1) A crystalline vortioxetine hydrobromide Form L1.

2) The crystalline Form L1 according to claim 1, characterized by powder x-ray diffraction pattern peaks expressed in terms of 2? values 13.07, 15.26, 17.11, 17.49, 18.65, 22.59 and 26.31 ± 0.2 degrees.

3) The crystalline Form L1 according to claim 1, having moisture content of about 3.5 to 4.5%.

4) A process for preparation of crystalline Form L1 of vortioxetine hydrobromide comprising steps of:
i) dissolving vortioxetine hydrobromide in organic solvent;
ii) adding water to the above solution;
iii) cooling the solution in order to initiate crystallization; and
iv) isolating crystalline Form L1 of vortioxetine hydrobromide.

5) The process according to claim 4, wherein the organic solvent of step (i) is selected from chloroform, chloromethane, chlorobenzene, 1,2-dichloroethene, dichloromethane, ethanol, isopropanol, n-propanol, n-butanol, isoamyl alcohol and ethylene glycol.

6) A pharmaceutical composition comprising crystalline vortioxetine hydrobromide Form L1 and pharmaceutically acceptable excipients.