CLIAMS:1. A stable amorphous form of Vortioxetine Hydrobromide, compound of Formula I,

Formula I
has purity more than 99 % when measured by HPLC

2. The stable amorphous form of Vortioxetine Hydrobromide of claim 1, characterized by powder X-ray diffraction pattern in accordance of Figure 1.

3. A process for the preparation of stable amorphous form of Vortioxetine Hydrobromide, comprising the step of

Formula I
a) dissolving vortioxetine Hydrobromide in water
b) freeze-drying or lyophilizing the solution of step (a);
c) isolating stable amorphous Vortioxetine Hydrobromide

4. The process of claim 3, wherein the lyophilization technique is carried out at temperature in between range of -80°C to about -90 °C for time in between range 12 hours to 14 hours.
5. The process of claim 3, wherein the step (a) is carried out at temperature in between range of 10°C to about 40 °C.

6. A amorphous Vortioxetine Hydrobromide is stable at 20-25°C at least for a month.

7. A pharmaceutical composition comprising the stable amorphous form of Vortioxetine Hydrobromide of claim 1 and at least one pharmaceutically acceptable excipients.

8. The pharmaceutical composition of claim 7, wherein the pharmaceutically acceptable excipients is selected from the group comprising one or more of diluents, sweeteners, buffering agents, glidants, flowing agents, flavouring agents, lubricants, preservatives, surfactants, wetting agents, binders, disintegrants and thickeners.

9. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is in an oral dosage form.

10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition is a tablet and/or capsule.
,TagSPECI:Field of Invention

The present invention relates to novel stable amorphous form of Vortioxetine Hydrobromide, has purity more than 99 % by HPLC. In present invention particular directs to process for the preparation of novel stable amorphous form of Vortioxetine Hydrobromide, has purity more than 99 % when measured by HPLC

Background of the invention

Vortioxetine (trade name Brintellix and Trintellix in Canada) is an atypical antidepressant made by Lundbeck and Takeda. It has chemical name 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine, Hydrobromide and has the structural formula I,

Formula I
Vortioxetine or a pharmaceutically acceptable salt thereof are described in the US patent No. 7,144,884 and US 8,110,567 with its process for the preparation. The process for the preparation also described in several patents, e.g. US patent No. 8,598,348; Chinese Patents No. 103788019; 103788020, 104109135, 103936694.

Summary of the Invention

The present invention also provides a stable amorphous form of Vortioxetine Hydrobromide compound of Formula I,

Formula I
has purity more than 99 % by HPLC.

The present invention also provides a process for the preparation of stable amorphous form of Vortioxetine Hydrobromide, has purity more than 99 % by HPLC.

The present invention also provides the conversion of stable amorphous form of Vortioxetine Hydrobromide to other crystalline forms of Vortioxetine Hydrobromide.

A further aspect of the present invention is directed to a pharmaceutical composition comprising the stable amorphous form of Vortioxetine Hydrobromide of the present invention and at least one pharmaceutically acceptable excipients.

In addition the present invention relates to the use of the stable amorphous form of Vortioxetine Hydrobromide of the present invention for the preparation of a solid medicament.

In further aspect of present invention relates to solid pharmaceutical compositions comprising an effective amount of the stable amorphous form of Vortioxetine Hydrobromide of the present and a pharmaceutically acceptable carrier for use in the treatment of major depressive disorder and/or generalized anxiety disorder.

Brief Description of the Drawings

Figure 1 shows an illustrative example of X-ray powder diffraction pattern of stable amorphous form of Vortioxetine Hydrobromide prepared according to Example 1.
Description of the Invention

For purposes of the present invention, the following terms are defined below.

The X-ray diffraction powder patterns of the present invention were obtained using a Bruker or PANalytical export Pro Powder X-ray Diffractometer at Cu Kα radiation, has the wavelength 1.54 Å.

In one another, aspect of the present invention provides a stable amorphous form of Vortioxetine Hydrobromide, compound of Formula I,

Formula I
has purity more than 99 % when measured by HPLC.

In another aspect, the present invention provides a stable amorphous form of Vortioxetine Hydrobromide, has an X-ray diffraction pattern as depicted in Figure 1, which is expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a copper K α-radiation source.

The stable amorphous form of Vortioxetine Hydrobromide obtained by the process of the invention is stored at 20 to 25°C for a period of three months and no contamination of other polymorphic form has been observed.

In one another, aspect of the present invention provides the process for the preparation of stable amorphous form of Vortioxetine Hydrobromide,

Formula I
which includes the steps of;
a) dissolving Vortioxetine Hydrobromide in water,
b) freeze-drying or lyophilizing the solution of step a),
c) isolating stable amorphous Vortioxetine Hydrobromide.

The step (a) involves the vortioxetine Hydrobromide dissolved in water. The step (a) is carried out at temperature in between range of 10°C to about 40 °C.

The step (b) and (c) involves freeze drying or lyophilization of solution obtained in step (a) to get amorphous form of Vortioxetine Hydrobromide. The lyophilization technique is carried out at temperature in between range of -80°C to about -90 °C for time in between range 12 hours to 14 hours.

The lyophilizer used in step (b) is VirTis Ultra 35L lyophilizer, which creates vacuum with pressure in between 230 to 250 millitorr.

The present invention provides Vortioxetine Hydrobromide produced by the process of preparation of the present invention is characterized by purity greater than 99 % when measured by HPLC.

In one another, aspect of the present invention provides the pharmaceutical compositions comprising the stable amorphous form of Vortioxetine Hydrobromide of the present invention may further comprise one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients selected from the group comprising one or more diluents, sweeteners, buffering agents, glidants, flowing agents, flavouring agents, lubricants, preservatives, surfactants, wetting agents, binders, disintegrants and thickeners. Other excipients known in the field of pharmaceutical compositions may also be used. Furthermore the pharmaceutical composition may comprise a combination of two or more excipients also within one of the members of the above mentioned group.

The wetting agents selected from the group comprising one or more sodium lauryl sulphate, sodium dioctyl sulfosuccinate, sodium starch glyocolate, polyethylene glycol sorbitan fatty acid esters, such as Tween 20, 60 and 80.

The binders selected from the group comprising one or more alkylcelluloses such as methylcellulose, hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyl ethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose, hydroxyalkyl alkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose, carboxyalkylcelluoses such as carboxymethylcellulose, alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose, carboxyalkylalkyl celluloses such as carboxymethyl ethylcellulose, carboxyalkylcellulose esters, starches such as starch 1551 , pectins such as sodium carboxymethylamylopectin, chitin derivatives such as chitosan, heparin and heparinoids, polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar- agar, gum arabic, guar gum and xanthan gum, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts thereof, methacrylate copolymers, polyvinylalcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, e.g. poloxamers and poloxamines, copovidone.

The diluents selected from the group comprising one or more calcium carbonate, dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose including silicified microcrystalline cellulose, powdered cellulose, dextrates, dextrin, dextrose excipients, fructose, kaolin, lactitol, lactose anhydrous, lactose monohydrate, mannitol, sorbitol, starch, modified starch, sodium chloride, sucrose, compressible sugar, confectioner's sugar, a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25), commercially available as Microcelac®, a co-processed spray-dried mixture of microcrystalline cellulose and colloidal silicon dioxide (98:2), commercially available as Prosolv®.

The glidants selected from the group comprising one or more talc, colloidal silicon dioxide, starch and magnesium stearate.

The disintegrants selected from the group comprising one or more starch, ion exchange resins, e.g. Amberlite, cross-linked polyvinylpyrrolidone, modified cellulose gum, e.g. croscarmellose sodium, sodium starch glycolate, sodium carboxymethylcellulose, sodium dodecyl sulphate, modified corn starch, microcrystalline cellulose, magnesium aluminium silicate, alginic acid, alginate and powdered cellulose.

The lubricants selected from the group comprising one or more magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulphate and magnesium lauryl sulphate.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

Examples

Example-1: Preparation of Amorphous Vortioxetine Hydrobromide

1.5 g Vortioxetine HBr was dissolved in 300 ml of water. The solution was filtered through hyflo bed. The filtrate was lyophilized for overnight at between range of -80°C to about -90 °C to get the amorphous Vortioxetine Hydro bromide. This amorphous form was found stable for 3-4 days under nitrogen at 20-25 0C.
Yield: 1.5 g
HPLC purity: 99.64%