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

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

2. The stable crystalline form of Vortioxetine Hydrobromide of claim 1, 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 having peaks at about 5.87, 9.31, 14.12, 18.19, 18.60, 23.03, 23.54, and 28.00 ? 0.2?.
iii. a differential scanning calorimetric (DSC) thermogram substantially in accordance with FIG. 2,

3. A process for the preparation of stable crystalline form of Vortioxetine Hydrobromide, the process comprises the steps of
a) dissolving vortioxetine hydrobromide in a methylene dichloride,
b) adding reaction mixture obtained in step a) to ether solvent,
c) isolating crystalline form of Vortioxetine Hydrobromide

4. The process of claim 3, wherein ether solvent is selected from one or more comprising diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6 ethers. Most preferably the ether solvent is methyl t-butyl ether.

5. The process of claim 4, wherein ether solvent is methyl t-butyl ether.

6. The process of claim 3, wherein the purity of stable crystalline form of Vortioxetine Hydrobromide, has purity more than 97 %.
, Description:Field of Invention

The present invention relates to novel stable crystalline form of Vortioxetine Hydrobromide, has purity more than 97 % when measured by HPLC. In particular, of the present invention directs to process for the preparation of novel stable crystalline form of Vortioxetine Hydrobromide, has purity more than 97 % 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 provides a novel stable 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 stable crystalline form of Vortioxetine Hydrobromide, has purity more than 90 % when measured by HPLC.

The present invention also provides a process for the preparation of stable crystalline form of Vortioxetine Hydrobromide, has purity more than 97 %.

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

Brief Description of the Drawings

Figure 1 shows an illustrative example of X-ray powder diffraction pattern of a stable crystalline form of crude Vortioxetine Hydrobromide prepared according to Example 1.

Figure 2 shows an illustrative example of differential scanning calorimetry thermogram of stable crystalline 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 Ka radiation, having the wavelength 1.54 Å.

In one aspect of the present invention provides a stable 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 stable crystalline form of Vortioxetine Hydrobromide, having an 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 a-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 5.87, 9.31, 14.12, 18.19, 18.60, 23.03, 23.54, and 28.00 ? 0.2?.

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

Crystalline XRD Crude Vortioxetine Hydrobromide
2 Theta peaks d-spacing [Aº] Relative Intensity [%]
5.87 15.03 41.77
7.09 12.46 10.93
9.31 9.49 44.91
12.86 6.88 3.98
14.12 6.27 24.64
14.39 6.15 27.37
16.29 5.43 10.52
17.51 5.06 15.91
18.19 4.87 26.98
18.60 4.76 100.0
19.36 4.58 11.77
20.43 4.34 11.88
21.14 4.20 9.11
21.57 4.11 9.35
22.19 4.00 14.53
23.03 3.86 51.51
23.54 3.77 32.03
25.62 3.47 5.16
28.00 3.18 39.33
29.31 3.04 11.06
30.59 2.92 8.61
31.44 2.84 16.84
32.97 2.71 12.69
35.32 2.54 3.35
37.51 2.39 6.34

The stable 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 stable crystalline form of crude Vortioxetine Hydrobromide, includes the steps of
a) dissolving vortioxetine hydrobromide in a methylene dichloride,
b) adding reaction mixture obtained in step a) to ether solvent,
c) isolating crystalline form of Vortioxetine Hydrobromide

The step a) of the present invention involves dissolving Vortioxetine Hydrobromide in a methylene chloride and stir for a period of 5-10 minutes at temperature 35ºC.

The step b) of the present invention involves filtering the reaction mixture obtained in step a) through celite followed by washing with methylene chloride and collecting the filtrate. The filtrate obtained is added slowly to the ether solvent; wherein ether solvent is selected from comprising one or more of diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6 ethers. Most preferably the ether solvent is methyl t-butyl ether.

The step c) involves isolating crystalline form of Vortioxetine Hydrobromide by means of filtration. The solution obtained in step b) was stirred for a period of 2 hours. The resulting precipitate was filtered and dried under vacuum at temperature 40 ºC for a period of 7 to 8 hours to obtain crystalline solid

The present invention provides Vortioxetine Hydrobromide produced by the process of the present invention is characterized by purity greater than 97 % when measured by HPLC.

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

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 methylene dichloride (700ml) to Vortioxetine hydrobromide (25.0 g) and stirred for a period of 5 to 10 minutes at temperature 35ºC. The reaction mixture was filtered through celite followed by washing with methylene chloride and collecting the filtrate. The filtrate obtained was added slowly to the methyl tertiary butyl ether (1.5 L) within 15- 20 minutes. The solution was again stirred for a period of 2 hours. The resulting precipitate was filtered and dried under vacuum at temperature 40 ºC for a period of 7 to 8 hours to obtain crystalline solid as titled compound.
Yield: 23.0 g
HPLC Purity: >97%