CLIAMS:We Claim:

1. A crystalline form of Lorcaserin hydrochloride, 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 5.72, 11.45, 11.67, 20.26, 21.33, 21.48, 22.99, 23.29, 23.38, 24.27, 24.38  0.2,
iii. a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 2,
iv. a thermogavimetric Analysis (TGA) substantially in accordance with Figure 3.

2. The crystalline form of claim 1, wherein crystalline form Lorcaserin hydrochloride can be converted in to any other crystalline or amorphous form of Lorcaserin hydrochloride.

3. A process for the preparation of crystalline form of Lorcaserin hydrochloride, has purity more than 99 % when measured by HPLC, the process comprises the steps of
a) dissolving Lorcaserin camsylate in presence of aqueous base solution in a mixture of organic solvent,
b) adding hydrochloric acid solution in a alcoholic solvent to the solution of step (a),
c) isolating crystalline form of Lorcaserin hydrochloride.

4. The process of claim 3, wherein base comprises one or more of organic base and inorganic base.

5. The process of claim 4, wherein organic base is selected from the group comprising one or more of dimethylamine, diethylamine, ammonia, potassium t-butoxide and triethylamine.

6. The process of claim 4, wherein inorganic base is selected from the group comprising one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide and potassium t-butoxide.

7. The process of claim 3, wherein organic solvents is selected from the group comprising one or more of dichloromethane, water and mixture thereof.

8. The process of claim 7, wherein organic solvents is dichloromethane and water, in ratio of 1: 0.5 to 0.75.

9. The process of claim 3, wherein the alcoholic solvent is selected from group comprises one or more of methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, propylene glycol and mixtures thereof.

10. A pharmaceutical composition comprising crystalline form of Lorcaserin hydrochloride of claim 1 with one or more pharmaceutically acceptable excipients.
,TagSPECI:Field of Invention

The present invention relates to novel crystalline form of Lorcaserin Hydrochloride. In particular aspect of the present invention directs to process for the preparation of crystalline form of Lorcaserin Hydrochloride, has purity more than 99 % when measured by HPLC. In the further aspect of present invention relates to a pharmaceutical composition comprising the crystalline form of Lorcaserin Hydrochloride of the present invention with one or more pharmaceutically acceptable excipients.

Background of the invention

Lorcaserin hydrochloride is a serotonin 2C receptor agonist for oral administration used for chronic weight management. It has the chemical name ((R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride hemihydrate and has the structural formula I,

Formula I

Lorcaserin hydrochloride is marketed under the name BelviqTM in the United States.
Lorcaserin or a pharmaceutically acceptable salt was first described in U.S. Patent No. 6,953,787 with its process for the preparation. The process for the preparation Lorcaserin or pharmaceutically acceptable salt also described in several patents, e.g. US patent Nos. US 8,546,379; US 7,977,329; US 8,367,657; US 8,168,624 and US 8,697,686.

Summary of the Invention

The present invention provides a crystalline form of Lorcaserin hydrochloride, compound of Formula I,

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

The present invention also provides a process for the preparation of crystalline form of Lorcaserin Hydrochloride, has purity more than 99 % when measure by HPLC, the process includes the steps of;
a) dissolving Lorcaserin camsylate in presence of base in a mixture of organic solvent,
b) adding hydrochloric acid in an alcoholic solvent to step (a),
c) isolating crystalline form of Lorcaserin hydrochloride.

The present invention also provides the conversion of crystalline form of Lorcaserin hydrochloride of present invention to other crystalline form or amorphous form of Lorcaserin hydrochloride.

A further aspect of the present invention is directed to a pharmaceutical composition comprising the crystalline form of Lorcaserin hydrochloride 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 Lorcaserin hydrochloride 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 Lorcaserin hydrochloride of the present and a pharmaceutically acceptable carrier for use for chronic weight management.

Brief Description of the Drawings

Figure 1 shows an illustrative example of X-ray powder diffraction pattern of a crystalline form of Lorcaserin hydrochloride

Figure 2 shows an illustrative example of differential scanning calorimetry thermogram of crystalline form of Lorcaserin hydrochloride

Figure 3 shows an illustrative example of thermogravimetric analysis curve of crystalline form of Lorcaserin hydrochloride.

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 Lorcaserin hydrochloride, compound of Formula I,

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

In another aspect, the present invention provides a crystalline of Lorcaserin hydrochloride is characterized by its X-ray powder diffraction pattern substantially as shown in Figure 1, differential scanning calorimetry thermogram as shown in Figure 2 and thermo gravimetric analysis as shown in Figure 3.

In another aspect, the present invention provides a crystalline form of Lorcaserin hydrochloride, 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 5.72, 11.45, 11.67, 20.26, 21.33, 21.48, 22.99, 23.29, 23.38, 24.27 and 24.38  0.2.

The XRPD characteristic peaks of the crystalline form of Lorcaserin hydrochloride, has purity more than 99 %, further defined from the Table 1:

Crystalline XRD Lorcaserin hydrochloride
2 Theta peaks d-spacing [Aº] Relative Intensity [%]
5.72 15.43 74.50
10.46 8.45 21.26
11.45 7.72 100.00
11.67 7.57 42.29
12.08 7.32 12.97
13.94 6.34 20.49
14.93 5.93 23.76
15.80 5.60 10.43
17.21 5.15 22.39
17.57 5.04 5.74
19.03 4.66 30.46
20.26 4.38 78.66
20.68 4.29 33.12
21.33 4.16 58.61
21.48 4.13 40.04
22.11 4.01 30.48
22.99 3.86 77.29
23.29 3.81 43.66
23.38 3.80 41.97
23.81 3.73 18.73
24.27 3.66 58.79
24.38 3.64 82.14
25.81 3.45 25.89
26.12 3.41 20.16
26.63 3.34 10.10
28.09 3.17 26.21
28.57 3.12 20.15
29.38 3.03 3.92
29.87 2.99 15.02
30.11 2.96 18.01
31.56 2.83 7.74
31.93 2.80 7.10
33.67 2.66 8.62
34.34 2.61 13.66
34.92 2.56 8.65
35.50 2.52 6.10
36.49 2.46 23.45
37.29 2.41 5.22
38.70 2.32 5.26

The crystalline form of Lorcaserin hydrochloride 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 Lorcaserin hydrochloride, has purity more than 99 %, when measured by HPLC, the process includes the steps of
a) dissolving Lorcaserin camsylate in presence of base in a mixture of organic solvent,
b) adding hydrochloric acid solution in a alcoholic solvent to step (a),
c) isolating crystalline form of Lorcaserin hydrochloride.

The step a) of the present invention involves dissolving Lorcaserin camsylate salt in presence of aqueous base solution in mixture of organic solvent. Organic solvent layer is separated, washed with water and concentrated in vacuum to obtain Lorcaserin, wherein base is selected from the group comprising one or more of organic base and inorganic base. The organic base include of one or more of dimethylamine, diethylamine or triethylamine and ammonia. Inorganic base include of one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide and potassium t-butoxide. The organic solvent is selected from the group comprising one or more of halogenated solvent, water and mixture thereof.

The halogenated solvent is selected from group comprises one or more of dichloromethane, dichloreoethane, chloroform, carbon tetrachloride and mixture thereof.

The step (b) of the present invention involve the addition of hydrochloric acid solution in a alcoholic solvent to the Lorcaserin obtained in step (a), followed by stirring the reaction mixture for period of 0.5 to 1 hour.

The alcoholic solvent is selected from group comprises one or more of methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, propylene glycol and mixtures thereof.

The step (c) of the present invention involves removal of solvent from the reaction mixture of step (b) under vacuum such as drying in rotary evaporator at temperature in between range of 40°C to 50°C. The concentrated mass obtained is dissolved in cyclohexane to isolate Lorcaserin hydrochloride, wherein isolation is carried out by means of filtering and drying the reaction mass.

The present invention also provides the conversion of crystalline form of Lorcaserin hydrochloride to other crystalline form or amorphous form of Lorcaserin hydrochloride.

In one another, aspect of the present invention provides the pharmaceutical compositions comprising the crystalline form of Lorcaserin hydrochloride 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 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 Lorcaserin base

Charged (R)-8-Chloro-1-methyl-2,3,4,5-tetra-hydro-1H-3-benzapine (1S)-(+)-10-camsylate salt (110 gm) in mixture of dichloromethane (330 ml) and water (220 ml) followed by sodium hydroxide solution (12.3 gm sodium hydroxide in 110 ml water) was added. Reaction mixture was stirred for 30 minutes and dichloromethane layer was separated, washed with water (200 ml) and concentrated to obtain Lorcaserin base.
Yield: 50.5 gm

Example-2: Preparation of Crystalline Lorcaserin hydrochloride

Charged isopropyl alcohol (100 ml) and isopropyl alcohol hydrochloric acid solution in (76.6 gm, 18.5 %) was added to the concentrated reaction mass Lorcaserin base (50.5 gm) as obtained in Example-1. The reaction mass was stirred for a period of 30 minutes and further concentrated under vacuum at temperature 40°C to 50 °C to obtain a concentrated mass. To the concentrated mass charged isopropyl alcohol (50 ml) and heated to get the clear solution. Cyclohexane (500 ml) was added at the same temperature. Reaction mass is gradually cooled to 5 °C and filtered. Wet cake was dried to isolate the titled compound in crystalline form.
Yield: 52 g
HPLC Purity: 99.92%
Moisture content: 3.82 % w/w
M.P.: 95.5-97.8 °C
Chloride content: 16.46 %
Enantiomeric purity: 99.15 %
(S) Enantiomer: 0.74 %