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

Formula I
characterized by at least one of the following properties ;
i. a powder X-ray diffraction pattern substantially in accordance with Figure 1,
ii. a powder X-ray diffraction pattern has peaks at about 6.86, 8.40, 9.70, 13.20, 14.58, 18.93, 19.45, 20.67, 22.65, 25.34 and 29.34 ± 0.2°,
iii. a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 2,

2. The crystalline form of claim 1, wherein crystalline form Vortioxetine Hydrobromide converted in to any other crystalline or amorphous form of Vortioxetine Hydrobromide.

3. A process for the preparation of crystalline form of Vortioxetine Hydrobromide, has purity more than 97 % when measured by HPLC, the process comprises the steps of;
a) dissolving Vortioxetine free base in a mixture of organic solvent,
b) adding aqueous hydrobromic acid in the solution of step (a),
c) heating of step b) at temperature to about 60C to 80C to obtain residue,
d) dissolving the residue obtained in step c) in a mixture of methanol and diethyl ether at temperature to about 25°C to 35°C,
e) isolating crystalline form of Vortioxetine Hydrobromide.
4. The process of claim 3, wherein mixture organic solvents are mixture of ethyl acetate, methanol and tetrahydrofuran.

5. The process of claim 3, wherein the ratio of mixture ethyl acetate, methanol, tetrahydrofuran is 1: 1: 1.

6. The process of claim 3, wherein the ratio of mixture methanol and diethyl ether is 1: 1.

7. A pharmaceutical composition comprising crystalline form of Vortioxetine Hydrobromide of claim 1 with one or more one pharmaceutically acceptable excipient.

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 crystalline form of Vortioxetine Hydrobromide. In particular, of the present invention directs to process for the preparation of crystalline form of Vortioxetine Hydrobromide, has purity more than 97 % when measured by HPLC. In the further aspect of present invention relates to a pharmaceutical composition comprising the crystalline form of Vortioxetine Hydrobromide of the present invention with one or more pharmaceutically acceptable excipients.

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 provides a crystalline form of Vortioxetine Hydrobromide, compound of Formula I,

Formula I
has purity more than 97 % when measured by HPLC

The present invention also provides a process for the preparation of crystalline form of Vortioxetine Hydrobromide, has purity more than 97 %, the process includes the steps of;
a) dissolving Vortioxetine free base in mixture of organic solvent,
b) adding aqueous hydrobromic acid in the solution of step (a),
c) heating of step b) at temperature to about 60C to 90C to obtain residue,
d) dissolving the residue obtained in step c) in a mixture of methanol and diethyl ether at temperature to about 25C to 35C,
e) isolating crystalline form of Vortioxetine Hydrobromide.

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

A further aspect of the present invention is directed to a pharmaceutical composition comprising the crystalline form of Vortioxetine Hydrobromide of the present invention with one or more pharmaceutically acceptable excipients.

In addition the present invention relates to the use of the crystalline 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 crystalline 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 a crystalline form of Vortioxetine Hydrobromide

Figure 2 shows an illustrative example of differential scanning calorimetry thermogram of crystalline form of Vortioxetine Hydrobromide

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 aspect of the present invention provides a crystalline form of Vortioxetine Hydrobromide, compound of Formula I,

Formula I
has purity more than 97 % when measured by HPLC.

In another aspect, the present invention provides a crystalline of Vortioxetine Hydrobromide is characterized by its X-ray powder diffraction pattern substantially as shown in Figure 1 and differential scanning calorimetry thermogram as shown in Figure 2.

In another aspect, the present invention provides a crystalline form of Vortioxetine Hydrobromide, is characterized by X-ray diffraction pattern according to Figure 1, which is expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a copper K α-radiation source, wherein said X-ray powder diffraction pattern includes two or more peaks selected from the group comprising of peaks with 2 theta angles of 6.86, 8.40, 9.70, 13.20, 14.58, 18.93, 19.45, 20.67, 22.65, 25.34 and 29.34  0.2.

The XRPD characteristic peaks of the crystalline form of Vortioxetine Hydrobromide, has purity more than 97 %, further defined from the Table 1:

Crystalline XRD Vortioxetine Hydrobromide
2 Theta peaks d-spacing [Aº] Relative Intensity [%]
6.86 12.87 23.70
8.40 10.52 8.61
9.70 9.11 60.64
11.88 7.44 7.48
13.20 6.70 36.29
13.74 6.44 16.26
14.58 6.07 41.69
15.28 5.79 5.04
15.66 5.65 12.94
16.10 5.50 19.51
16.95 5.23 24.83
17.45 5.08 6.93
18.60 4.77 29.25
18.93 4.68 36.73
19.45 4.56 100.0
20.06 4.42 11.18
20.67 4.29 35.13
21.86 4.06 21.93
22.28 3.98 10.49
22.65 3.92 65.31
22.90 3.88 14.71
23.05 3.85 13.48
23.67 3.75 12.00
23.85 3.73 10.26
24.31 3.66 23.92
24.68 3.60 22.15
25.34 3.51 40.84
26.26 3.39 12.00
26.59 3.35 4.87
28.07 3.17 12.97
28.45 3.13 16.08
29.34 3.04 33.27
29.65 3.01 19.53
30.16 2.96 14.98
31.61 2.82 10.64
32.53 2.75 4.38
33.86 2.64 6.85
35.09 2.55 6.82
36.15 2.48 6.24
37.16 2.41 6.87
37.54 2.39 4.88
38.24 2.35 4.93

The crystalline form of Vortioxetine Hydrobromide obtained by the process of the invention is stored at 25°C for a period of 3 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 crystalline form of crude Vortioxetine Hydrobromide, has purity more than 97 % when measured by HPLC, the process includes the steps of ;
a) dissolving Vortioxetine free base in mixture of organic solvent,
b) adding aqueous hydrobromic acid in the solution of step (a),
c) heating of step b) at temperature to about 60C to 90C to obtain residue,
d) dissolving the residue obtained in step c) in a mixture of methanol and diethyl ether at temperature to about 25C to 35C,
e) isolating crystalline form of Vortioxetine Hydrobromide.

The step a) of the present invention involves dissolving Vortioxetine hydrobromide in mixture of organic solvent, wherein organic solvent ethyl acetate, methanol and tetrahydrofuran, wherein the molar ratio of each solvent is about 1:1:1.

The step b) of the present invention involves the addition of aqueous hydrobromic acid in the reaction mixture of step (a) followed by step c) which involves the heating the reaction mixture at temperature in between range of 80°C to 90°C for period of 4 to 6 hours to obtain brown residue.

The step d) of the present invention involves dissolving the brown residue obtained in step c) in a mixture of methanol and diethyl ether and stirred for a period of 60 minutes to 90 minutes at temperature in between the range of 25C to 35C.

The step e) of the present invention involves isolating crystalline form of Vortioxetine Hydrobromide by means of removal of solvent, wherein removal of solvent may be carried out by means of filtration, followed by washing and drying under vacuum at 60°C such as drying in rotary evaporator.

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

In one another, aspect of the present invention provides the pharmaceutical compositions comprising the crystalline 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 Crystalline Vortioxetine Hydrobromide

Charged Vortioxetine free base (3.5 g) in the solution of ethyl acetate (50 ml), methanol (50 ml) tetrahydrofuran (50 ml), followed by addition of 48 % aqueous hydrobromide (25 ml). The obtained solution was heated at temperature range of 80°C to 90°C for 4 hours. Further, the reaction mixture is allowed to cool and the solvent was removed under vacuum at temperature 60°C to obtain brown color residue. Charged mixture of methanol (25 ml) and diethylether (25 ml) to the residue and the reaction mixture was stirred for the period of 60 to 90 minute at temperature of about 25C to 35C. The reaction was filtered and washed with mixture of diethylether (20 ml) and methanol (20 ml). Dry it under vacuum to get the titled compound in crystalline form.
Yield: 3.5 g
HPLC purity: 97%