Field of the invention:

The present invention relates to novel polymorphs of (i?)-8-chloro-l-mefhyl-2,3,4,5-tetrahydro-l/f-3-benzazepine hydrochloride which is represented by structural formula-1 and process for its preparation.

Background of the invention:

The "(i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-l#-3-benzazepine hydrochloride" is commonly known as Lorcaserin hydrochloride. It is a 5-HT2C receptor agonist, used for chronic weight management. It is developed by Arena pharmaceuticals under the brand name "BELVIQ". It is approved as lorcaserin hydrochloride hemihydrate in United States on June 27th, 2012.

Serotonin (5-HT) neurotransmission plays an important role in physiological processes both in health and in psychiatric disorders.

(i?)-8-chloro-l-memyl-2,3,4,5-tetrahydro-l#-3-benzazepine and its process for preparation are first disclosed in US6953787. Process for the preparation of Hydrochloride salt of (^-S-chloro-l-methyl^^^jS-tetrahydro-l/Z-S-benzazepine is first disclosed in US8367657.

Polymorphic forms such as anhydrous crystalline form-I, anhydrous crystalline form-II and hemihydrate crystalline form-Ill of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-l//-3-benzazepine hydrochloride are disclosed in US8168624.

Anhydrous crystalline form-IV of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-li/-3-benzazepine hydrochloride is disclosed in US2013158013.

Polymorphism is the occurrence of different solid state forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids having the same molecular formula and different physical properties such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with desired solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry and differential scanning calorimetry. Solvent medium and mode of crystallization play very important role in obtaining a polymorphic form over the other.

The present invention provides novel polymorphs of (J?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-l//-3-benzazepine hydrochloride and its process for preparation.

Brief description of the invention:

The first aspect of the present invention is to provide an amorphous solid dispersion of (i?)-8-chloro-l -methyl-2,3,4,5-tetrahydro-l#-3-benzazepine hydrochloride.

The second aspect of the present invention is to provide a process for the preparation of an amorphous solid dispersion of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-l#-3-benzazepine hydrochloride.

The third aspect of the present invention is to provide a novel crystalline form of (R)-S-chloro-l-methyl^S^S-tetrahydro-liW-benzazepine hydrochloride, herein after referred as crystalline form-M.

The fourth aspect of the present invention is to provide a process for the preparation of crystalline form-M of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-li/-3-benzazepine hydrochloride.

The fifth aspect of the present invention is to provide a novel crystalline form of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-li/-3-benzazepine hydrochloride, herein after referred
as crystalline form-N.

The sixth aspect of the present invention is to provide a process for the preparation of crystalline form-N of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-l//-3-benzazepine hydrochloride.

The seventh aspect of the present invention is to provide an amorphous form of (i?)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 //-3-benzazepine hydrochloride.

Brief description of the drawings:

Figure-1: Illustrates the powder X-ray diffractogram of amorphous solid dispersion of (7?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-l/f-3-benzazepine hydrochloride with povidone k90.

Figure-2: Illustrates the powder X-ray diffractogram of crystalline form-M of (i?)-8-chloro- 1 -methyl-2,3,4,5-tetrahydro-1H-3 -benzazepine hydrochloride.

Figure-3: Illustrates the DSC thermogram of crystalline form-M of (i?)-8-chloro-l-methyl-
2,3,4,5-tetrahydro-l.ff-3-benzazepine hydrochloride.

Figure-4: Illustrates the powder X-ray diffractogram of crystalline form-N of (i?)-8-chloro-l- methyl-2,3,4,5-tetrahydro-li/-3-benzazepine hydrochloride.

Detailed description of the invention:

The term "suitable solvent" used in the present invention includes, but not limited to "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate and the like; "ether solvents" such as tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane and the like; "hydrocarbon solvents" such as toluene, hexane, heptane, pet ether, xylene, cyclohexane and the like; "polar aprotic solvents" such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol and the like; "chloro solvents" such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride and the like; "nitrile solvents" such as acetonitrile, butyronitrile, isobutyronitrile and the like; "protic solvent" such as acetic acid; "polar solvent" such as water or mixtures thereof.

The term "amorphous" refers to a solid without long-range crystalline order. The amorphous form of the present invention preferably contain less than about 20% crystalline forms, more preferably less than 5% crystalline forms, and still more preferably less than 1 % or is essentially free of crystalline forms. "Essentially free of crystalline forms" means that no crystalline polymorph forms can be detected within the limits of an X-ray Powder Diffractometer.

The term "Spray drying" refers to a technique that involves injecting the solution of active pharmaceutical substance and solvent into a chamber of spray dryer as a liquid stream. The liquid stream separates the solute as a solid and the solvent into a vapor. The solid is usually collected in a drum or cyclone.

The term "solid dispersion" refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components. In the present invention, one component of solid dispersion is active pharmaceutical ingredient such as (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-li/-3 benzazepine hydrochloride and other component is a pharmaceutically acceptable excipient.

The term "pharmaceutically acceptable excipient" refers to a component of pharmaceutical product that is not an active ingredient and includes but not limited to filler, diluent, disintegrants, glidants, stabilizers, surface active agents etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and neither biologically nor otherwise undesirable and are acceptable for human pharmaceutical use. One excipient can perform more than one function.

Exemplary pharmaceutically acceptable excipients used in the present inventions include, but are not limited to polyvinylpyrrolidone (also called povidone), polyvinyl alcohol, polyethylene glycol, polyol (Mannitol), sodium starch glycolate, colloidal silicon dioxide (aerosil), hydroxypropyl methylcellulose, hydroxy propyl cellulose, microcrytsalline cellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, polyvinyl acetate, cyclodextrins, gelatins, hypromellose phthalate, sugars or mixtures thereof.

The first aspect of the present invention provides an amorphous solid dispersion of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-li7-3-benzazepine hydrochloride, which comprises of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-l//-3-benzazepine hydrochloride and a suitable pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient used in the present invention is povidone k90.

The amorphous solid dispersion of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-li/-3-benzazepine hydrochloride with povidone k90 is characterized by powder X-ray diffraction pattern as illustrated in Figure-1.

The second aspect of the present invention provides a process for the preparation of an amorphous solid dispersion of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-l/7-3-benzazepine hydrochloride, comprising of:
Dissolving (i?)-8-chloro-l-methyl-2,3,4,54etrahydro-l#-3-benzazepine hydrochloride in a suitable solvent, adding a suitable pharmaceutically acceptable excipient to the solution obtained in step-(a), stirring the reaction mixture, removing the solvent from the solution obtained in step-(c) to get amorphous solid dispersion of (7?)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 //-3-benzazepine hydrochloride.

A preferred embodiment of the present invention provides a process for the preparation of an amorphous solid dispersion of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lif-3-benzazepine hydrochloride, comprising of:

Dissolving (i?)-8-chloro-l-methyl-2,3,4,5 tetrahydro-l#-3-benzazepine hydrochloride in water, adding povidone k90 to the solution obtained in step-(a), stirring the reaction mixture, removing the solvent from the solution obtained in step-(c) to get amorphous solid
dispersion of (i?)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /f-3-benzazepine hydrochloride with povidone k90.

The third aspect of the present invention provides a novel crystalline form of (7?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-l//-3-benzazepine hydrochloride, herein after referred as crystalline form-M. The crystalline form-M is characterized by:

Its powder X-ray diffraction pattern having peaks at 6.0, 12.2, 25.0 and 31.7 ± 0.2 degrees of 2-theta, its powder X-ray diffraction pattern substantially as shown in figure-2, and its DSC thermogram showing a sharp endotherm peak at 221.82°C and broad endotherm peak at 169.85°C as shown in figure-3.

The fourth aspect of the present invention provides a process for the preparation of crystalline form-M of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-li/-3-benzazepine hydrochloride, comprising of:
Dissolving (i?)-8-chloro-1 -methyl-2,3,4,5 tetrahydro-1 //-3-benzazepine hydrochloride in a suitable solvent, removing the solvent from solution obtained in step-(a) to get crystalline form-M of (i?)-8-chloro-1 -methyl-2,3,4,5 -tetrahydro-1H-3 -benzazepine hydrochloride, Wherein, the suitable solvent used in step-a) is selected from tetrahydrofuran, chloroform, dichloromethane and acetone. The solvent may be removed in step b) by using various drying techniques, for example, spray drying, vacuum drying, freeze drying, or agitated thin film drying.

A preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-l#-3-benzazepine hydrochloride, comprising of:

Dissolving (i?)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 H-3 -benzazepine hydrochloride in dichloromethane, removing the solvent from the solution obtained in step-(a) by spray drying at a temperature ranging from 120-200°C to get crystalline form-M of (i?)-8-chloro-l- methyl-2,3,4,5-tetrahydro-l//-3-benzazepine hydrochloride.

The fifth aspect of the present invention provides a novel crystalline form of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-17/-3-benzazepine hydrochloride, herein after referred as crystalline form-N. The crystalline form-N is characterized by:

Its powder X-ray diffraction pattern having peaks at 6.0, 12.1, 24.9, 31.7 and 37.1 ± 0.2 degrees of 2-theta, and its powder X-ray diffraction pattern substantially as shown in figure-4.

The sixth aspect of the present invention provides a process for the preparation of crystalline form-N of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-17f-3-benzazepine hydrochloride, comprising of:
Dissolving (i?)-8-chloro-1 -methyl-2,3,4,5 tetrahydro-l/f-3-benzazepine hydrochloride in ethylene glycol, removing the solvent from the solution obtained in step-(a) to get crystalline form-N of (i?)-8-chloro-l-methyl-2,3,4,5 tetrahydro-l//-3-benzazepine hydrochloride.

The seventh aspect of the present invention provides an amorphous form of (i?)-8-chloro-1 methyl-2,3,4,5-tetrahydro-1 //-3-benzazepine hydrochloride.

PXRD analysis of the amorphous, crystalline form-M and crystalline form-N of the present invention was carried out by using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A0 and at continuous scan speed of 0.03°/min.

Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10°C per minute.

Water content of the novel polymorphs of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3 benzazepine hydrochloride of the present invention was measured by using a karl fisher titrator.

The novel polymorphs of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride which are obtained by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.

The novel polymorphs of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride produced by the present invention can be utilized in the preparation of medicament.

The (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride used in the present invention can be prepared by the method disclosed in US8367657.

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation of the scope of the invention.

Examples:
Example-1: Preparation of amorphous solid dispersion of (R)-8-chloro-l-methyl-
2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride with povidone k90 Dissolved the (R)-8-chloro-l -methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hydrochloride (2.0 g) in water (30 ml) at 25-30°C. Povidone k90 (2.0 g) was added to the reaction mixture at 25-30°C and stirred for 30 mins.

Distilled off the solvent from the reaction mixture under reduced pressure to get the title compound. Yield: 3.3 g; water content: 3.73% w/w.

The Powder X-ray diffraction pattern of the obtained compound is shown in figure-1.
Example-2: Preparation of crystalline form-M of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride (4.0 g) was dissolved in dichloromethane (32 ml) at 25-30°C. Removing the solvent from the obtained solution by spray drying at a temperature of 120°C. The obtained solid was collected to get the title compound. Yield: 3.0 g; MR: 206-208°C; water content: 1.7%.

The Powder X-ray diffraction pattern of the obtained compound is shown in figure-2 and Differential scanning calorimetry thermogram is shown in figure-3.

ExampIe-3: Preparation of crystalline form-N of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride using ethylene glycol
(R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride (2.0 g) was dissolved in ethylene glycol (10 ml) at 25-30°C. Distilled off the solvent from the obtained solution under reduced pressure and the obtained solid was collected to get title compound. Yield: 1.5 g; MR: 186-188°C; water content: 1.5% w/w.

The powder X-ray diffraction pattern of the obtained compound is shown in figure-4.

We Claim:

1. A crystalline form-M of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-l#-3-benzazepine
hydrochloride, which is characterized by:
Its powder X-ray diffraction pattern having peaks at 6.0, 12.2, 25.0 and 31.7 ± 0.2 degrees of 2-theta, its powder X-ray diffraction pattern substantially as shown in figure-2, and its DSC thermogram showing a sharp endotherm peak at 221.82°C and broad endotherm peak at 169.85°C as shown in figure-3.

2. A process for the preparation of crystalline form-M of (i?)-8-chl oro-1-methyl-2,3,4,5- tetrahydro-li/-3-benzazepine hydrochloride, comprising of:
Dissolving (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-1 //"-3-benzazepine hydrochloride in a suitable solvent, removing the solvent from solution obtained in step-(a) to get crystalline form-M of (7?)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1H-3 -benzazepine hydrochloride, A process according to claim-2, wherein the suitable solvent used in step-a) is selected from tetrahydrofuran, chloroform, dichloromethane and acetone.

A process according to claim-2, comprising of:
Dissolving (R)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride in dichloromethane, removing the solvent from the solution obtained in step-(a) by spray drying at a temperature ranging from 120-200°C to get crystalline form-M of (i?)-8-chloro-l-methyl 2,3,4,5-tetrahydro-1 H-3 -benzazepine hydrochloride.

5. A crystalline form-N of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-l//-3-benzazepine hydrochloride, which is characterized by:
a) Its powder X-ray diffraction pattern having peaks at 6.0, 12.1, 24.9, 31.7 and 37.1 ± 0.2 degrees of 2-theta, and

b) its powder X-ray diffraction pattern substantially as shown in figure-4.

6. A process for the preparation of crystalline form-N of (i?)-8-chloro-l-methyl-2,3,4,5-tetrahydro-l//-3-benzazepine hydrochloride, comprising of:
Dissolving (i?)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 H-3 -benzazepine hydrochloride in ethylene glycol, Removing the solvent from the solution obtained in step-(a) to get crystalline form-N of (i?)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 H-3 -benzazepine hydrochloride.