Claims:We Claim:
1. A process for the preparation of a stable and highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms, comprising:
a) providing a solution of Lorcaserin hemitartrate in a solvent medium comprising water and 50% aqueous sodium hydroxide solution;
b) extracting the resulting solution with dichloromethane and washing the resulting organic layer with water;
c) subjecting the solution obtained in step-(b) to carbon treatment to obtain a filtrate;
d) acidifying the filtrate obtained in step-(c) using isopropanolic HCl while adjusting the pH to 1-2 and stirring the resulting mass;
e) removing the solvent from the resulting mass completely to obtain a solid;
f) combining the solid obtained in step-(e) with cyclohexane to form a slurry; and
g) recovering the highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms.

2. The process as claimed in claim 1, wherein the crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms obtained by the process is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about as 2-theta angle positions at about 13.80, 14.98, 15.58, 15.91, 16.75, 20.14 and 21.51 ± 0.2 degrees substantially in accordance with Figure 1; and/or an infra red (FT-IR) spectrum having main bands at about 3368, 2946, 2501, 1584, 1473, 1392, 1331, 1267, 1177, 934, 881 and 829 cm-1 ± 5 cm-1 substantially in accordance with Figure 2; and/or a Differential Scanning Calorimetric (DSC) thermogram having a broad dehydration endotherm at about 93.91°C and a sharp endothermic peak at about 200.09°C substantially in accordance with Figure 3.

3. The process as claimed in claim 2, wherein the crystalline Form III of Lorcaserin hydrochloride hemihydrate is further characterized by an X-ray powder diffraction pattern having additional 2-theta peaks at about 10.35, 12.82, 19.00, 19.28, 22.78, 23.31, 23.61 and 24.08 ± 0.2 degrees substantially in accordance with Figure 1.

4. The process as claimed in claim 1, wherein the solution in step-(a) is prepared by dissolving Lorcaserin hemitartrate in the solvent medium comprising water and 50% sodium hydroxide solution at a temperature of about 15°C to about 50°C; wherein the acidification in step-(d) is accomplished by adding isopropanolic HCl to the filtrate while adjusting the pH to 1-2 at the room temperature; wherein the removal of solvent in step-(e) is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution, or distillation of solvent, under inert atmosphere; and wherein the recovering in step-(g) is carried out by the methods such as filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.

5. The process as claimed in claim 4, wherein the solution in step-(a) is prepared by dissolving Lorcaserin hemitartrate in the solvent medium comprising water and 50% sodium hydroxide solution at a temperature of about 25°C to about 30°C; and wherein the removal of solvent in step-(e) is carried out by distillation.

6. Highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms, characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 13.80, 14.98, 15.58, 15.91, 16.75, 20.14 and 21.51 ± 0.2 degrees substantially in accordance with Figure 1; and/or an infra red (FT-IR) spectrum having main bands at about 3368, 2946, 2501, 1584, 1473, 1392, 1330, 1267, 1177, 934, 881 and 829 cm-1 ± 5 cm-1 substantially in accordance with Figure 2; and/or a Differential Scanning Calorimetric (DSC) thermogram having a broad dehydration endotherm at about 94.29°C and a sharp endothermic peak at about 200.20°C substantially in accordance with Figure 3.

7. A pharmaceutical composition comprising highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms, wherein the crystalline Form III of Lorcaserin hydrochloride hemihydrate has a D90 particle size of less than or equal to about 200 microns; and wherein the crystalline Form III of Lorcaserin hydrochloride hemihydrate has a D50 particle size of less than or equal to about 100 microns.

8. The pharmaceutical composition of claim 7, wherein the crystalline Form III of Lorcaserin hydrochloride hemihydrate has a D90 particle size of about 2 microns to about 180 microns; and wherein the crystalline Form III of Lorcaserin hydrochloride hemihydrate has a D50 particle size of about 2 microns to about 80 microns.
, Description:FIELD OF THE INVENTION
The present invention relates to an improved, consistently reproducible and commercially viable process for the production of highly pure and stable crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other polymorphic forms.
BACKGROUND OF THE INVENTION
U.S. Patent No. 6,953,787 (hereinafter referred to as the US‘787 patent) discloses a variety of 5HT2c receptor agonist compounds, methods of modulating 5HT2c receptors, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds act as modulators of 5HT2c receptors. Among them, Lorcaserin hydrochloride, chemically named (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride hemihydrate, is a selective 5HT2c receptor agonist used for treatment of disorders of the central nervous system, damage to the central system, cardiovascular disorders, gastrointestinal disorders, diabetes insipidus, and sleep apnea. The US’787 patent claims Lorcaserin and pharmaceutically acceptable salts, solvates and hydrates thereof. Lorcaserin hydrochloride is represented by the following structural formula I:

Lorcaserin hydrochloride was developed by Arena Pharmaceuticals and is approved by FDA and EMEA for the treatment of an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg/m2 or greater (obese), or 27 kg/m2 or greater (overweight) in the presence of at least one weight related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes).
Lorcaserin hydrochloride is marketed under the trade name Belviq® and is administered orally as 10 mg tablet twice daily.
The synthesis of Lorcaserin was first described in the U.S. Patent No. 6,953,787. Example 26 of the US’787 patent discloses the process of preparation of racemic 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine as an oil. This racemic compound was further resolved and hydrolysed into respective enantiomers in Example 55. The US’787 patent discloses different enantiomers of compounds of formula (I).
The US’787 patent discloses that the compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like, such as the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) and incorporated herein by reference.
The US’787 patent also discloses that the acid addition salts can be obtained as the direct products of compound synthesis. In the alternative, the free base can be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. The compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
Lorcaserin hydrochloride is known to exhibit polymorphism and various crystalline forms, salts and amorphous form and processes for their preparation are apparently disclosed in U.S. Patent Nos. US 8,168,624 B2; US 9,045,431 B2; US 9,248,133 B2; US 9,365,521 B2; US Publication Nos. US 2014/0148442 A1; US2014/0187538 A1.
U.S. Patent No. 8,168,624 (hereinafter referred to as the US’624 patent), assigned to Arena Pharmaceuticals, discloses three crystalline forms of Lorcaserin hydrochloride namely Form I, Form II and Form III, processes for their preparation, and characterizes the crystalline forms by X-ray powder diffraction pattern (XRPD), Differential Scanning Calorimetry (DSC), Thermo Gravimetric Analysis (TGA) and Dynamic Vapour Sorption scan (DVS).
Further, the US’624 patent teaches that, crystalline Form I and Form II of Lorcaserin hydrochloride are anhydrous forms which are hygroscopic in nature and hence they are readily converted to the stable hemihydrate crystalline form of Lorcaserin hydrochloride (Form III).
According to the US’624 patent, the crystalline Form I of Lorcaserin hydrochloride is characterised by XRPD 2-theta peaks at about 6.5, 9.6, 10.2, 12.9, 17.1, 17.5, 17.8, 18.5, 19.5 and 19.8 ± 0.2 degrees; and a DSC thermogram having an endothermic peak at about 201°C.
According to US’624 patent, the crystalline Form II of is characterised by XRPD 2-theta peaks at about 6.5, 9.6, 10.2, 11.4, 12.9, 17.1, 17.5, 17.8, 18.5, 19.5 and 19.8 ± 0.2 degrees; and a DSC thermogram having an endothermic peak at about 201°C.
According to US’624 patent, the crystalline Form III of Lorcaserin hydrochloride hemihydrate is characterised by XRPD 2-theta peaks at about 13.7, 14.9, 15.4, 15.8, 16.7, 20.1 and 21.4 ± 0.2 degrees; and DSC thermogram having a relatively broad dehydration endotherm at about 90°C to about 110°C and a further endotherm at about 200°C. The crystalline Form III of Lorcaserin hydrochloride hemihydrate is prepared in Example 2 of the US’624 patent, by treating (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (160 g) with isopropanol (359.36 g) under Nitrogen atmosphere followed by heating the resulting mixture at 60°C to obtain a clear solution. To the resulting solution water (12.43 g) and cyclohexane (960 g) were added at 40-60°C. Afterwards the solution is cooled to 20-25°C over 2 hours with slow stirring. The resulting suspension is cooled to 0-5°C and then stirred at the same temperature for additional 3 hours. The suspension is filtered and the filter cake is washed with cyclohexane and the product is dried at 35-45°C at 50 mbar to produce crystalline Form III of Lorcaserin hydrochloride hemihydrate as a colorless crystalline solid.
However, the process described in the US’624 patent has failed to consistently produce pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other polymorphic forms.
Further, US’624 patent teaches that, the diffraction patterns of Form I and II share essentially the same peaks, except that Form II has at least one unique peak at about 11.4° (2?) which is not substantially present in diffraction patterns of Form I. The diffraction pattern of Form III, is having several unique peaks, differs significantly from the diffraction patterns of both Form I and II.
US Patent No. 9,045,431 (hereinafter referred to as the US’431 patent), assigned to Arena Pharmaceuticals, discloses Lorcaserin hydrochloride salt Form I, Lorcaserin hydrochloride salt Form II and Lorcaserin hydrochloride salt hemihydrate Form III, Lorcaserin hydrochloride salt Form IV, processes for their preparation and characterizes by X-ray powder diffraction pattern (XRPD), Differential Scanning Calorimetry (DSC), Thermo Gravimetric Analysis (TGA) and Dynamic Moisture Sorption (DMS).
According to the US’431 patent, Lorcaserin hydrochloride salt Form I is characterized by XRPD 2-theta peaks at about 11.45, 23.33, 25.52, 22.97, 22.44, 29.84, 22.86, 23.90, 27.99, 27.68, 23.60 and 27.58 ± 0.2 degrees; and a DSC thermogram having two endotherms with extrapolated onset temperatures at about 139°C and about 199°C. According to the US’431 patent, Lorcaserin hydrochloride salt Form II is characterized by XRPD 2-theta peaks at about 12.9, 19.5, 19.8, 21.3, 21.6, 24.8 and 25.9 ± 0.2 degrees; and DSC thermogram having an onset temperature of about 199°C.
According to the US’431 patent, Lorcaserin hydrochloride salt hemihydrate Form III is characterized by XRPD 2-theta peaks at about 13.7, 14.9, 15.4, 15.8, 16.7, and 18.9 ± 0.2 degrees; and a DSC thermogram having a dehydration endotherm at about 95°C and melting/decomposition endotherm at about 200-201°C. Form III is prepared by solution mediated phase transformation of Form IV or by exposing Form IV to relative humidity of 50% RH to 60% RH [during Dynamic Moisture Sorption (DMS)].
However, the process described in the US’431 patent has failed to consistently produce pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other polymorphic forms. Moreover, the processes exemplified in the US’431 patent has failed to disclose the actual quantities of the raw materials and solvents that are required for producing crystalline Form III of Lorcaserin hydrochloride.
According to the US’431 patent, Lorcaserin hydrochloride anhydrous Form IV is characterized by XRPD 2-theta peaks at about 10.67, 15.34, 17.77, 18.27, 19.33, 19.83, 20.23, 23.27, 24.25, 25.13 and 35.82 ± 0.2 degrees; and DSC thermogram having two onset temperatures at about 170°C and 199°C.
US Patent No. 9,248,133 (hereinafter referred to as US’133 patent), assigned to Arena Pharmaceuticals, discloses Lorcaserin (1S)-(+)-10-camsylate salt, Lorcaserin hemi-L-malate salt, Lorcaserin L-glutamate salt, Lorcaserin L-aspartate salt, Lorcaserin hemimucate salt, Lorcaserin pyroglutamate salt and Lorcaserin glucuronate salt, pharmaceutically acceptable solvates and hydrates thereof; processes for their preparation, pharmaceutical compositions thereof and characterizes the salts by X-ray powder diffraction pattern (XRPD), Differential Scanning Calorimetry (DSC), Thermo Gravimetric Analysis (TGA) and Dynamic Moisture Sorption (DMS).
US Patent No. 9,365,521 (hereinafter referred to as US’521 patent), assigned to Arena Pharmaceuticals, discloses Lorcaserin hemi-edisylate salt, Lorcaserin phosphate salt, Lorcaserin citrate salt, Lorcaserin hemi-oxalate salt, Lorcaserin succinate salt, Lorcaserin oxoglutarate salt, Lorcaserin oxoglutarate salt solvate, processes for their preparation, pharmaceutical composition thereof; and characterizes the salts by X-ray powder diffraction pattern (XRPD), Differential Scanning Calorimetry (DSC), Thermo Gravimetric Analysis (TGA), Dynamic Moisture Sorption (DMS) and Deliquescence relative humidity (DRH) measurements.
US Patent Application Publication No. US 2014/0187538 discloses the amorphous form of Lorcaserin hydrochloride, process for preparation and pharmaceutical composition thereof.
US Patent Application Publication No. US 2014/0148442 discloses Lorcaserin bisulfate salt, Lorcaserin hemisulfate salt, Lorcaserin mesylate salt, Lorcaserin hydrobromide salt, Lorcaserin nitrate salt, Lorcaserin sesqui-oxalate salt-cocrystal, Lorcaserin adipate salt, Lorcaserin malonate salt, Lorcaserin hemimalonate salt and Lorcaserin glycolate salt, pharmaceutically acceptable solvates and hydrates thereof, processes for their preparation, pharmaceutical composition thereof; and characterizes the salts by X-ray powder diffraction pattern (XRPD), Differential Scanning Calorimetry (DSC), Thermo Gravimetric Analysis (TGA) and Dynamic Moisture Sorption (DMS).
However, the processes described in the aforementioned prior art have failed to consistently produce pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other polymorphic forms. The prior art processes suffer from several disadvantages such as lack of reproducibility, use of excess quantities of solvents, cumbersome and tedious processes, formation of mixture of crystalline forms, formation of different and undesired crystalline forms.
However, a need still remains for simple, cost effective, consistently reproducible and environmentally friendly processes for preparing the stable and highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms.

SUMMARY OF THE INVENTION
The present inventors have found that highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms can be consistently produced by a process comprising: (a) providing a solution of Lorcaserin hemitartrate in a solvent medium comprising water and 50% aqueous sodium hydroxide solution at room temperature and then stirring for at least 10 minutes at the same temperature; (b) extracting the resulting solution with dichloromethane and washing the organic layer with water; (c) subjecting the resulting solution to carbon treatment; (d) acidifying the resulting filtrate using isopropanolic HCl while adjusting the pH to 1-2 and then stirring the resulting mass; (e) removing the solvent from the resulting mass completely to obtain a solid; (f) combining the solid obtained in step-(e) with cyclohexane at room temperature followed by stirring the resulting slurry at the same temperature; and (g) isolating the highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms.
Provided herein is a simple, cost effective and consistently reproducible process for the preparation of highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms.
In another aspect, provided herein is a pharmaceutical composition comprising highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms made by the process disclosed herein, and one or more pharmaceutically acceptable excipients.
In another aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms made by the process disclosed herein with one or more pharmaceutically acceptable excipients.
In another aspect, the highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 200 microns, specifically about 2 microns to about 180 microns, and most specifically about 4 microns to about 150 microns.
In another aspect, the highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D50 particle size of less than or equal to about 100 microns, specifically about 2 microns to about 80 microns, and most specifically about 4 microns to about 60 microns.
As used herein, the term “room temperature” or “RT” refer to a temperature of about 15ºC to about 35ºC. For example, “RT” refers to a temperature of about 20ºC to about 30ºC, and more specifically about 25ºC to about 30ºC.
As used herein, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
The term “crystalline Form III of Lorcaserin hydrochloride hemihydrate”, otherwise called “Lorcaserin hydrochloride crystalline Form III”, as used herein is intended to mean the polymorph form III of Lorcaserin hydrochloride hemihydrate as implicitly disclosed in the U.S. Patent No. 6,953,787, which is later explicitly disclosed in the U.S. Patent No. 8,168,624.
In one embodiment, the crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms obtained by the process disclosed herein is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 13.80, 14.98, 15.58, 15.91, 16.75, 20.14 and 21.51 ± 0.2 degrees substantially in accordance with Figure 1; and/or an infra red (FT-IR) spectrum having main bands at about 3368, 2946, 2501, 1584, 1473, 1392, 1331, 1267, 1177, 934, 881 and 829 cm-1 ± 5 cm-1 substantially in accordance with Figure 2; and/or a Differential Scanning Calorimetric (DSC) thermogram having a broad dehydration endotherm at about 94.29°C and a sharp endothermic peak at about 200.20°C substantially in accordance with Figure 3.
In one embodiment, the crystalline Form III of Lorcaserin hydrochloride hemihydrate obtained by the processes disclosed herein is essentially free from other solid state forms of Lorcaserin hydrochloride detectable by Powder X-ray diffraction technique.
The term “crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms” means that no other polymorphic forms of Lorcaserin hydrochloride can be detected within the limits of a powder X-ray diffractometer. The term “other polymorphic forms of Lorcaserin hydrochloride” is intended to mean the polymorphic forms of Lorcaserin hydrochloride other than crystalline Form III.
The process disclosed herein advantageously produces the crystalline Form III of Lorcaserin hydrochloride hemihydrate with high chemical and polymorphic purity.
The highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate obtained by the process disclosed herein has a chemical purity of greater than about 99.5%, specifically greater than about 99.7%, and most specifically greater than about 99.9% as measured by HPLC.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of crystalline Form III of Lorcaserin hydrochloride hemihydrate.
Figure 2 is a characteristic infra-red (IR) spectrum of crystalline Form III of Lorcaserin hydrochloride hemihydrate.
Figure 3 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of crystalline Form III of Lorcaserin hydrochloride hemihydrate.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a process for the preparation of a stable and highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms, comprising:
a) providing a solution of Lorcaserin hemitartrate in a solvent medium comprising water and 50% aqueous sodium hydroxide solution;
b) extracting the resulting solution with dichloromethane and washing the resulting organic layer with water;
c) subjecting the solution obtained in step-(b) to carbon treatment to obtain a filtrate;
d) acidifying the filtrate obtained in step-(c) using isopropanolic HCl while adjusting the pH to 1-2 and stirring the resulting mass;
e) removing the solvent from the resulting mass completely to obtain a solid;
f) combining the solid obtained in step-(e) with cyclohexane to form a slurry; and
g) recovering the highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms.
Step-(a) of providing a solution of Lorcaserin hemitartrate includes dissolving Lorcaserin hemitartrate in the solvent medium comprising water and 50% sodium hydroxide solution at a temperature of about 15°C to about 50°C, preferably at a temperature of about 20°C to about 35°C, and most preferably at a temperature of about 25°C to about 30°C. After complete dissolution of Lorcaserin hemitartrate, the resulting solution is stirred at room temperature for at least 10 minutes, and specifically for about 10 minutes to about 20 minutes.
The carbon treatment in step-(c) is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon at the room temperature for at least 5 minutes, specifically for about 10 minutes to about 20 minutes, and filtering the resulting mixture through charcoal bed to obtain a filtrate. Specifically, finely powdered carbon is a special carbon or an active carbon.
In one embodiment, the acidification in step-(d) is accomplished by adding isopropanolic HCl to the filtrate while adjusting the pH to 1-2 at the room temperature. After adjusting the pH, the resulting solution is stirred at the room temperature for at least 10 minutes, and specifically for about 10 minutes to about 1 hour.
Removal of solvent in step-(e) is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution, or distillation of solvent, under inert atmosphere.
In one embodiment, the removal of solvent in step-(e) is carried out by distillation. The distillation process can be performed at atmospheric pressure or at reduced pressure.
Specifically the distillation process is performed at reduced pressure. In one embodiment, the solvent is removed at a pressure of about 760 mm Hg or less, specifically at about 400 mm Hg or less, more specifically at about 80 mm Hg or less, and most specifically from about 30 to about 80 mm Hg.
In a preferred embodiment, the distillation process is performed under reduced pressure and at a temperature of about 40°C to about 120°C, and most specifically at a temperature of about 60°C to about 90°C.
Combining of the solution of the solid with cyclohexane in step-(f) is done in a suitable order, for example, the solid is added to cyclohexane, or alternatively, the cyclohexane is added to the solid. The addition is, for example, carried out drop wise or in one portion or in more than one portion. The addition is specifically carried out under stirring at a temperature of about 20°C to about 50°C, and most specifically at about 25°C to about 35°C.
In one embodiment, the slurry obtained in step-(f) is stirred for at least 10 minutes, and preferably for about 30 minutes to about 2 hours, at the room temperature.
The recovering in step-(g) is carried out by the methods such as filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
In one embodiment, the highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate, obtained by the process described herein, remains in the same crystalline form and is found to be stable.
In one embodiment, the crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms obtained by the process disclosed herein is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 13.80, 14.98, 15.58, 15.91, 16.75, 20.14 and 21.51 ± 0.2 degrees substantially in accordance with Figure 1; and/or an infra red (FT-IR) spectrum having main bands at about 3368, 2946, 2501, 1585, 1473, 1392, 1330, 1267, 1177, 934, 881 and 829 cm-1 ± 5 cm-1 substantially in accordance with Figure 2; and/or a Differential Scanning Calorimetric (DSC) thermogram having a broad dehydration endotherm at about 94.29°C and a sharp endothermic peak at about 200.20°C substantially in accordance with Figure 3.
In another embodiment, the highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate obtained by the process disclosed herein is further characterized by an X-ray powder diffraction pattern having additional 2-theta peaks at about 10.35, 12.82, 19.00, 19.28, 22.78, 23.31, 23.61 and 24.08 ± 0.2 degrees substantially in accordance with Figure 1.
The highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
Preferably, the drying is carried out at atmospheric pressure at temperatures such as about 25°C to about 80°C, and most preferably at about 50°C to about 65°C. In one embodiment, the drying is carried out for any desired time period that achieves the desired result, preferably for a period of about 1 hour to 30 hours, and more preferably about 20 to 24 hours. Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.
Unless otherwise specified, the Lorcaserin hemitartrate as used herein as starting material can be obtained by the processes known in the prior art, for example, as per the processes described in the U.S. Patent No. 6,953,787 or U.S. Patent No. 8,168,782.
The stable and highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate obtained by the processes disclosed herein is free from other crystalline forms, which has very good flow properties and is consistently reproducible, and is found to be more stable. The crystalline Form III of Lorcaserin hydrochloride hemihydrate obtained by the processes disclosed herein exhibits properties making it suitable for formulating Lorcaserin hydrochloride hemihydrate.
Further encompassed herein is the use of the highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate obtained by the processes disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
A specific pharmaceutical composition of highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate obtained by the processes disclosed herein is selected from a solid dosage form and an oral suspension.
In another aspect, the highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 200 microns, specifically about 2 microns to about 180 microns, and most specifically about 4 microns to about 150 microns.
In another aspect, the highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D50 particle size of less than or equal to about 100 microns, specifically about 2 microns to about 80 microns, and most specifically about 4 microns to about 60 microns.
In another embodiment, the particle sizes of the highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate obtained by the processes disclosed herein are accomplished by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.
The term “micronization” used herein means a process or method by which the size of a population of particles is reduced.
As used herein, the term “micron” or “µm” both are equivalent and refer to “micrometer” which is 1x10–6 meter.
As used herein, “crystalline particles” means any combination of single crystals, aggregates and agglomerates.
According to another aspect, there are provided pharmaceutical compositions comprising highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate obtained by the processes disclosed herein and one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate obtained by the processes disclosed herein, with one or more pharmaceutically acceptable excipients.
Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of highly pure crystalline Form III of Lorcaserin hydrochloride hemihydrate obtained by the processes disclosed herein. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, and transdermal routes or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, lozenges, elixirs and the like.
The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinbelow.
Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

INSTRUMENTAL DETAILS:
X-Ray Powder Diffraction (P-XRD):
The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper-Ka radiation). Approximately 300 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 0.4 seconds. The sample was simply placed on the sample holder. The instrument is operated at a voltage 40 KV and current 35 mA.
Infra-Red Spectroscopy (FT-IR):
FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the production of the KBr compacts approximately 5 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm-1 to 650 cm-1.
Differential Scanning Calorimetry (DSC):
Differential Scanning Calorimetry (DSC) measurements were performed with a Differential Scanning Calorimeter (DSC Q200, Q Series Version-2.7.0.380, TA Instruments-Waters LLC) equilibrated at 50°C and Ramp at a scan rate of 10°C per minute to 250°C.
Particle Size Method of Analysis (PSD):
Particle Size Distribution (PSD) is determined by laser diffraction in a Malvern Mastersizer 2000 (Ver. 5.60) equipment or its equivalent under the following conditions: Accessory Name = Hydro 2000S; Dispersant = Liquid paraffin light; Dispersant Refractive Index = 1.468; Absorption = 1; Obscuration limit = 5% to 15%; Measurement time = 10 seconds; Background time = 10 seconds.
HPLC Method for measuring Chemical Purity:
The chemical purity was measured by HPLC system with UV detector or its equivalent under the following conditions: Column = Symmetry C18, (250 x 4.6) mm, 5 µm; Detector wavelength = 220 nm; Flow Rate = 1.3 ml/minute; Injection volume = 10 µL; Oven temperature = 40°C; Run time = 60 minutes; Diluent = A mixture of acetonitrile and water (10:90 v/v); Elution = Gradient; and Sample Concentration: 0.6 mg/ml.
Mobile Phase-A: A mixture of buffer and methanol 90:10 (v/v)
Mobile Phase-B: A mixture of Acetonitrile and methanol 70:30 (v/v).

The following example is given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.
EXAMPLE 1
Preparation of pure crystalline Form III of Lorcaserin hydrochloride hemihydrate
Water (65 ml) and 50% aqueous sodium hydroxide solution (3.8 ml) were taken into a reaction flask at room temperature. To the resulting mixture, Lorcaserin hemitartrate (10 g) was added at room temperature (25-30ºC) and then stirred for 10-20 minutes at the same temperature. The resulting solution was extracted twice with dichloromethane (150 ml x 2). The organic layers were combined and washed with water (150 ml). To the resulting mass, carbon powder (1.2 g) was added and stirred for 10 minutes at room temperature. The carbon powder was filtered and the carbon bed was washed with dichloromethane (50 ml). Isopropanolic HCl (22 ml) was added to the resulting filtrate at room temperature while adjusting the pH to 1-2 and the resulting mass was stirred for 10-20 minutes at the same temperature. The solvent was distilled off completely to separate the solid. To the resulting solid, cyclohexane (100 ml) was added at room temperature and the resulting slurry was stirred for 30 minutes to 1 hour at the same temperature. The solid obtained was filtered and washed with cyclohexane (20 ml x 2) and then dried the material in air for 2 hours and further dried for 8 hours at 40-50°C to produce 7.5 g of crystalline Form III of Lorcaserin hydrochloride hemihydrate [Purity by HPLC: 99.9%; Particle Size: (D90): 117.79 µm; (D50): 41.39 µm].

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term “pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for veterinary use and/or human pharmaceutical use.
The term “pharmaceutical composition” is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.
The term “therapeutically effective amount” as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
The term “delivering” as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host, e.g., human, animal, etc.
The term “buffering agent” as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other such materials known to those of ordinary skill in the art.
The term “sweetening agent” as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.
The term “binders” as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.
The term “diluents” or “filler” as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “glidant” as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “lubricant” as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “disintegrant” as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “wetting agent” as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).

All ranges disclosed herein are inclusive and combinable. While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.