DESC:FIELD OF INVENTION:
The present invention relates Cariprazine hydrochloride polymorphic forms and process for preparation thereof.

BACKGROUND OF THE INVENTION
N-[trans-4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-1-dimethylurea hydrochloride, generally known as Cariprazine hydrochloride, is an antipsychotic useful in the treatment of positive and negative symptoms associated to schizophrenia due to its ability to act as a partial agonist of dopamine receptors D2/D3. This compound has the following chemical structure.

Due to its activity as a partial agonist, Cariprazine inhibits dopamine receptors when these are over-stimulated (performing an antagonist function) or stimulating the same receptors when the level of endogenous dopamine is too low.

Cariprazine also acts on 5-HT1a receptors, although its affinity towards the latter is considerably lower than that for dopamine receptors.

Cariprazine and other similar compounds were disclosed in international patent application WO 2005/012266 A1.

The US patent no 7943621 describes Cariprazine monohydrochloride crystalline form I and process for preparation of the same.

The US patent no 7829569 describes Cariprazine monohydrochloride crystalline form III and process for preparation thereof.

Polymorphism is the ability of a compound to exist in two or more different crystalline phases that differ in arrangement of the molecules in crystal lattice. Although polymorphs have the same chemical composition, they differ in packing and geometrical arrangement and exhibit different physical properties such as melting point, X-ray diffraction patterns, density, stability, and solubility.
Extensive study is carried out in pharmaceutical industry for development of different polymorphs of various drug substances, to obtain suitable polymorphs that possess improved performance characteristics such as aqueous solubility, improved bioavailability, chemical stability, shelf life etc.

Therefore, there is a need of having alternative polymorphic forms of Cariprazine hydrochloride and processes for the preparation thereof.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: Illustrates X-ray powder diffraction (XRPD) pattern of crystalline methane sulphonate co-crystal of Cariprazine HCl.

SUMMARY OF THE INVENTION:

In one aspect, the present invention provides crystalline form of methane sulphonate co-crystal of Cariprazine HCl and process for preparation thereof.

In another aspect, the invention provides a pharmaceutical composition comprising said crystalline form of methane sulphonate co-crystal of Cariprazine HCl and at least one pharmaceutically acceptable excipient or carrier.

DETAIL DESCRIPTION
Pharmaceutical co-crystals are crystalline molecular complexes that contain the drug substance along with an additional molecule present in the same crystal structure. The additional molecule or guest has been described in the literature as a co-crystal former. A co-crystal can thus be seen to be a multiple component crystal in which the drug substance and the co-crystal former are arranged in a three dimensional repetitive structure, wherein non-covalent and non-ion pair interactions exist between the drug substance and the co-crystal former, such as hydrogen bonding, pi-stacking, and van der Waals interactions. Co-crystalline forms show different physicochemical properties compared to the drug substance alone, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density.

The term “excipient” or “pharmaceutically acceptable excipient” means a component of a 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 veterinary use as well as human pharmaceutical use. One excipient can perform more than one function.

In one embodiment the present invention provides a crystalline form crystalline form of methane sulphonic acid co-crystal of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea hydrochloride which can be identified by one or more analytical methods. The P-XRD crystalline form is provided in Fig 1.

In another embodiment , the present crystalline methane sulphonic acid co-crystal of trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea hydrochloride characterized by a X-ray powder diffraction pattern comprising one or more characteristic peaks at about 6.9, about 10.79, about 12.2, about 17.87, about 19.78, about 20.28, about 21.25 and about 23.40 +0.2 degrees 2?.

In further embodiment X-ray powder diffraction pattern comprising one or more characteristic peaks at about 13.9, 14.3, 14.69,15.9,1639,18.69,24.48, 26.62, 26.87, 27.82,28.47+ 0.2 degrees 2?

In further embodiment, the present crystalline form of methane sulphonic acid co-crystal of trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethylurea hydrochloride can also be identified by its DSC having onset value of about 219°C.

In another embodiment, the invention provides a process for preparation of a crystalline form methane sulfonate co-crystal of Cariprazine hydrochloride comprising the steps of:
a) providing a solution of Cariprazine methanesulphonate in one or more solvents;
b) treating step a) solution with HCl and
c) Isolating the crystalline form of methane sulphonate co-crystal of Cariprazine hydrochloride from the reaction mixture thereof.

The solvent employed in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, N,N-dimethylformamide, ?,?-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, formic acid, acetic acid, propionic acid or mixtures thereof.
HCl is aqueous solution of HCl, gaseous solution of HCl in organic solvents.

Alternatively, isolation can be effected by addition of suitable anti-solvent.

In another embodiment, the present invention provides a pharmaceutical composition comprising crystalline form of methane sulphonate co-crystal of Cariprazine hydrochloride.

The crystalline form of methane sulphonate co-crystal of Cariprazine hydrochloride can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.

Pharmaceutically acceptable excipients may be utilized as required for present inventions into the final pharmaceutical dosage forms and include, for example, any one or more of diluents, binders, stabilizers, lubricants, glidants, disintegrating agents, surfactants, and other additives that are commonly used in solid pharmaceutical dosage form preparations.

The pharmaceutical composition of the present inventions can be formed by various methods known in the art such as by dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering and the like. The composition or formulation may be coated or uncoated. Coating of compositions such as tablets and caplets is well known in the art.

Although for many pharmaceutical compounds oral administration in the form of a tablet or capsule is preferred, some patients, for example elderly and pediatric patients, may have difficulties in swallowing such formulations. Therefore, liquid formulations such as oral solutions may offer a suitable alternative, avoiding the need of swallowing tablets or capsules. An oral solution further provides the possibility of a more flexible dosing regimen. In order to limit the volume of an oral solution it is necessary to have a high concentration of the active ingredient in the solution, which again requires a high solubility of the active ingredient. Hence the superior solubility the present inventions makes this particular solid state form especially suitable for the preparation of liquid pharmaceutical formulations such as oral solutions.

INSTRUMENT SETTINGS:
1) Powder X-Ray Diffraction (PXRD)
The X-ray powder diffraction spectrum (XRPD) was recorded at room temperature using PANalytical X’pert PRO Diffractogram with Cu Ka radiation (?=1.54060 A°), running at 45 kv and 40mA.

EXAMPLES:

Example 1: Methanesulphonic acid Co-crystal of Cariprazine hydrochloride
Ethanol (20 ml) was added to Cariprazine methanesulphonate (1.1g) and then added HCl in ethyl acetate (0.74 ml) and stirred at room temperature for about one hour. Distilled out ethanol under vacuum. The obtained foamy solid was unloaded in a drying tray and exposed to humidity to get solid compound, which was further evaporated on rotavapour.
Yield: 1.1gm, the obtained solid was characterized by XRD (figure1).

Example 2: Preparation of Cariprazine Methane sulphonate.
Acetonitrile (185ml) was added to Cariprazine free base (7.0g) followed by addition of methanesulphonic acid (1.57g), further added methanol and stirred at room temperature. Further raised the temperature to 80°C to get the clear solution and stirred for 30mins. The reaction mixture was cooled to room temperature and evaporated on rotavapour.
,CLAIMS:1. Methanesulphonic acid co-crystal of Cariprazine hydrochloride.
2. The methanesulphonic acid co-crystal of Cariprazine hydrochloride as claimed in claim 1, characterized by P-XRD as per fig 1.
3. The methane sulphonic acid co-crystal of Cariprazine hydrochloride as claimed in claim 1, has characteristic peaks at about 6.9, 10.79, 12.2, 17.87, 19.78, 20.28, 21.25 and 23.40 +0.2 degrees 2?.
4. A process for preparation of a crystalline methane sulfonate co-crystal of Cariprazine hydrochloride comprising the steps of:
a) providing a solution of Cariprazine methanesulphonate in one or more solvents;
b) treating step a) solution with hydrochloric acid and
c) isolating the crystalline form of methane sulphonate co-crystal of Cariprazine hydrochloride from the reaction mixture thereof.
5. The process according to claim 4, the solvent employed in step a) is selected from water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, N,N-dimethylformamide, ?,?-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, formic acid, acetic acid, propionic acid or mixtures thereof.
6. The process according to claim 4, the hydrochloric acid used in step b) selected from aqueous solution of hydrochloric acid or gaseous solution of hydrochloric acid.
7. The process according to claim 4, the step c) carried out by removing of the solvent (s).