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.

Premixes are characterized by a variety of associated properties such as stability, flow, and solubility. Typical premixes represent a compromise of the above properties, as for example, an increase in stability and dissolution properties of the premix. Although there are a variety of premixes, there is a continual search in this field of art for premixes that exhibit an improved mix of properties. Thus, the instant invention provides a premix in which Cariprazine hydrochloride exists in stable amorphous form and process of manufacture of the premix and pharmaceutical compositions comprising said Cariprazine hydrochloride premix.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: Illustrates X-ray powder diffraction (XRPD) pattern of Amorphous Cariprazine HCl.
Figure 2: Illustrates differential scanning calorimetry (DSC) plot of Amorphous Cariprazine HCl.
Figure 3. Illustrates thermo gravimetric analysis (TGA) plot of Amorphous Cariprazine HCl.
Figure 4: Illustrates X-ray powder diffraction (XRPD) pattern of crystalline form of Cariprazine HCl (Form L)
Figure 5: Illustrates differential scanning calorimetry (DSC) plot of crystalline form of Cariprazine HCl (Form L).
Figure 6: Illustrates X-ray powder diffraction (XRPD) pattern of formic acid solvate of Cariprazine HCl (Form L1)
Figure 7: Illustrates differential scanning calorimetry (DSC) plot of formic acid solvate of Cariprazine HCl. (Form L1)
Figure 8. Illustrates thermo gravimetric analysis (TGA) plot of formic acid solvate of Cariprazine HCl (Form L1)
Figure 9: Illustrates X-ray powder diffraction (XRPD) pattern of crystalline acetic acid solvate of Cariprazine free base.
Figure 10: Illustrates differential scanning calorimetry (DSC) plot of crystalline acetic acid solvate of Cariprazine free base.
Figure 11. Illustrates thermo gravimetric analysis (TGA) plot of crystalline acetic acid solvate of Cariprazine free base.
Figure 12. Illustrates X-ray powder diffraction (XRPD) pattern of crystalline Cariprazine phosphate salt.
Figure 13: Illustrates X-ray powder diffraction (XRPD) pattern of amorphous Cariprazine phosphate salt.
Figure 14: Illustrates differential scanning calorimetry (DSC) plot of amorphous Cariprazine phosphate salt.
Figure 15. Illustrates thermo gravimetric analysis (TGA) plot of amorphous Cariprazine phosphate salt.

SUMMARY OF THE INVENTION:
In one aspect, the present invention provides amorphous Cariprazine HCl and process for preparation thereof.

In another aspect, the invention provides a pharmaceutical composition comprising said amorphous Cariprazine HCl and at least one pharmaceutically acceptable excipient or carrier.

In another aspect, the present invention provides amorphous Cariprazine HCl premix and process for preparation thereof.

In another aspect, the invention provides a pharmaceutical composition comprising said amorphous Cariprazine HCl premix and at least one pharmaceutically acceptable excipient or carrier.

In another aspect, the present invention provides crystalline form L of Cariprazine HCl and process for preparation thereof.

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

In another aspect, the present invention provides crystalline formic acid solvate of Cariprazine HCl (Form L1) and process for preparation thereof.

In another aspect, the invention provides a pharmaceutical composition comprising said formic acid solvate Cariprazine HCl (Form L1) and at least one pharmaceutically acceptable excipient or carrier.

In another aspect, the present invention provides crystalline acetic acid solvate of Cariprazine free base and process for preparation thereof.

In another aspect, the invention provides a pharmaceutical composition comprising said acetic solvate Cariprazine free base and at least one pharmaceutically acceptable excipient or carrier.

In another aspect, the present invention provides phosphate salt of Cariprazine and process for preparation thereof.

In another aspect, the invention provides a pharmaceutical composition comprising said phosphate salt Cariprazine and at least one pharmaceutically acceptable excipient or carrier.

DETAIL DESCRIPTION
The term “premix” is used herein to describe combinations of Cariprazine hydrochloride and at least one pharmaceutically acceptable excipient, wherein individual particles of the components cannot be distinguished using techniques such as optical microscopy. In embodiments, the drug is considered as being uniformly or non-uniformly distributed over surfaces of excipient particles. In other embodiments, the premixes are considered to be in the nature of molecular dispersions, or solid solutions. Simple mixtures of powdered ingredients will not constitute premixes.

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 an amorphous form 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 pattern of amorphous form is provided in Fig 1.
In another embodiment present invention provides a stable amorphous form of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea hydrochloride which is stable at normal and at elevated temperature.

In further embodiment, the present amorphous form of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea hydrochloride can also be identified by its characteristic differential scanning calorimetry (DSC), as provided in Fig 2.

In further embodiment, the present amorphous form of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea hydrochloride can also be identified by its characteristic thermo gravimetric analysis (TGA), as provided in Fig 3.

In further embodiment, the present amorphous form of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea hydrochloride is a pure form. By pure, it is meant polymorphically pure and/or free from impurities. By polymorphically pure, it is meant that the pure amorphous Cariprazine hydrochloride is free from crystalline Cariprazine polymorphs, including solvates.

In another embodiment, the invention provides a process for preparation of an amorphous form of Cariprazine hydrochloride comprising the steps of:
a) providing a solution of Cariprazine hydrochloride in one or more solvents; and
b) isolating the amorphous form 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.

Step b) involves isolation of an amorphous form of Cariprazine hydrochloride from the solution of step a). The isolation may be affected by removing the solvent(s). Suitable techniques which may be used for the removal of solvent include using a rotational distillation device such as a rotary evaporator (e.g., Buchi Rotavapor), spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique.

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

In another embodiment, the present invention provides a pharmaceutical composition comprising an amorphous form of Cariprazine hydrochloride.

The amorphous form of Cariprazine hydrochloride can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.
In another embodiment, the invention provides a process for preparation of amorphous Cariprazine hydrochloride premix comprising the steps of:
(i) providing a solution of Cariprazine hydrochloride in a solvent;
(ii) adding suitable premixing agent(s); and
(iii) substantially removing the solvents from the solution to afford stable amorphous Cariprazine hydrochloride.

The term “substantially removing” the solvent refers to at least 80%, specifically greater than about 85%, more specifically greater than about 90%, still more specifically greater than about 99%, and most specifically essentially complete (100%), removal of the solvent from the solvent solution.

The solvent employed in step (i) is selected from halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride; alcohols such as methanol, ethanol, isopropyl alcohol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and t-butyl alcohol; ketones such as acetone, ethyl methyl ketone, diethyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate and t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether, methyl t-butyl ether and 1,4-dioxane; nitriles such as acetonitrile and propionitrile; water; and mixtures thereof.

In another embodiment the present invention provides amorphous Cariprazine hydrochloride premix comprising Cariprazine hydrochloride and atleast one pharmaceutically acceptable excipient.

In another embodiment present invention provides a stable amorphous form of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea hydrochloride premix which is stable at normal and elevated temperature.

Any of the pharmaceutically acceptable excipient described in the specification can be used in the process of preparing amorphous Cariprazine hydrochloride premix.

The pharmaceutically acceptable excipients used in the process of preparing stable amorphous Cariprazine hydrochloride premix may also be termed as “premixing agents”.

The stable amorphous premix can further be mixed with other pharmaceutically acceptable excipients to prepare a pharmaceutical formulation or composition of the present invention.

The suitable premixing agent or pharmaceutically acceptable excipient(s) discussed in the specification includes but not limited to diluents, lubricants, disintegrants, glidants, stabilizers & surface active agents or mixtures thereof. Preferably the premixing agents or pharmaceutically acceptable excipients used in the process of preparing stable amorphous Cariprazine hydrochloride can be selected from the group consisting of polyvinylpyrrolidone (also called povidone), polyvinyl alcohol, polyethylene glycol, polyol(Mannitol), sodium starch glycolate, colloidal silicon dioxide(aerosil), hydroxypropyl methylcellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, polyvinyl acetate, cyclodextrins, gelatins, hypromellose phthalate, corn starch, sugars and combinations comprising one or more of the foregoing agents, Preferably selected from povidone, mannitol, polyethylene glycol (PEG) and aerosol 200.

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

In another embodiment , the present crystalline form L 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 12.98, about 15.3, about 17.8 and about 19.3+0.2 degrees 2?.

In further embodiment X-ray powder diffraction pattern comprising one or more characteristic peaks at about 6.6, 6.9, 7.3 13.9, 15.9, 17.5, 21.0, 22.4, 23.9, 24.7+ 0.2 degrees 2?.

In further embodiment, the present crystalline form L of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea hydrochloride can also be identified by its characteristic differential scanning calorimetry (DSC), as provided in Fig 5.

In another embodiment, the present invention provides a process for the preparation of a crystalline form L of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea hydrochloride, which comprises the steps of:
i) providing a solution of Cariprazine hydrochloride in aqueous acetic acid;
ii) isolating the crystalline form L of Cariprazine hydrochloride.

In one embodiment, step (i) is carried out at a temperature of about 0°C to about 70°C.

The isolation of crystalline form L Cariprazine hydrochloride of step (ii) could be done by conventional techniques known to a person skilled in the art such as filtration, centrifugation etc.

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

In another embodiment, the present invention provides a pharmaceutical composition comprising a crystalline form L of Cariprazine hydrochloride.

The crystalline form L of Cariprazine hydrochloride can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.

In another embodiment, the present invention provides a Form L1 of formic acid solvate of trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethylurea hydrochloride which can be identified with more one or more analytical methods. The P-XRD pattern of Form L1 of formic acid solvate of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea hydrochloride is provided in Fig 6.

In another embodiment, the present invention provides a Form L1 of formic acid solvate of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea hydrochloride characterized by comprising one or more characteristic peaks at about 7.06, at about 9.35, at about 9.45, at about 13.8 and at about 17.35 + 2?.

In further embodiment X-ray powder diffraction pattern comprising one or more characteristic peaks at about 13.4, 14.14, 20.78,21.27, 21.87, 22.43,22.95, 25.95, 27.61 + 2?.

In further embodiment, the present a Form L1 of formic acid solvate of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea hydrochloride can also be identified by its characteristic differential scanning calorimetry (DSC), as provided in Fig 7.

The thermogravimetrtic analysis (TGA) for the present form L1 of formic acid solvate of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea hydrochloride is shown in Figure 8.

In another embodiment, the present Form L1 formic acid solvate of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea hydrochloride may be prepared by
i) providing a mixture Cariprazine hydrochloride in formic acid;
ii) isolating the crystalline L1 of formic acid solvate Cariprazine hydrochloride.

In one embodiment, step (i) is carried out at a temperature of about 0 to about 70°C.The isolation of crystalline form L1 of formic acid solvate of Cariprazine hydrochloride of step (ii) could be done by conventional techniques known to a person skilled in the art such as filtration, centrifugation etc.

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

In another embodiment, the present invention provides a pharmaceutical composition comprising a Form L1 of formic acid solvate of Cariprazine hydrochloride.

The Form L1 of formic acid solvate of Cariprazine Hydrochloride can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.

In another embodiment, the present invention provides an acetic solvate of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea which can be identified with more one or more analytical methods. The P-XRD pattern of crystalline form is provided in Fig 9.

In another embodiment, the present invention provides an acetic acid solvate of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea characterized by comprising one or more characteristic peaks at about 10.8, at about 13.70, at about 18.35, at about 18.7and at about 20.03 + 2?.

In further embodiment X-ray powder diffraction pattern comprising one or more characteristic peaks at about 5.70, 9.73, 14.46, 17.10, 17.69, 21.49,21.78 + 2?.

In further embodiment, the present acetic acid solvate of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea can also be identified by its characteristic differential scanning calorimetry (DSC), as provided in Fig 10.

In further embodiment, the present acetic acid solvate of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea can also be identified by its characteristic differential scanning calorimetry (TGA) , as provided in Fig 11.

In another embodiment, the present invention provides a process for the preparation of acetic acid solvate of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea, which comprises the steps of:
a) providing a mixture Cariprazine free base in aqueous acetic acid;
b) isolating the crystalline acetic acid solvate Cariprazine free base.

In one embodiment, step (a) is carried out at a temperature of about 0 to about 70°C.

The isolation of crystalline acetic acid solvate of Cariprazine free base of step (ii) could be done by conventional techniques known to a person skilled in the art such as filtration, centrifugation, lypholization etc.

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

In another embodiment, the present invention provides a pharmaceutical composition comprising an acetic acid solvate of Cariprazine free base.

The acetic acid solvate of Cariprazine free base can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.

In another embodiment, the present invention provides a phosphate salt of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea.

In another embodiment, the present invention provides a phosphate salt of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea in solid form.

In another embodiment, the present invention provides a crystalline phosphate salt of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea which can be identified with more one or more analytical methods. The P-XRD pattern of crystalline phosphate salt of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea is provided in Fig 12.

In another embodiment, the present invention provides a crystalline phosphate salt of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea characterized by comprising one or more characteristic peaks at about 7.6, at about 14.03, at about 15.26, at about 15.69 ,at about 18.5 and at about 22.17 + 2?.

In further embodiment X-ray powder diffraction pattern comprising one or more characteristic peaks at about 6.0.8.8, 10.15, 11.14, 11.37, 12.56, 13.19, 16.09, 17.38, 17.70, 21.52, 21.9, 23.4, 24.36,25.24, 26.25, 29.30+ 2?.
In another embodiment, the present invention provides a process for the preparation of a phosphate salt of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea, which comprises the steps of:
a) providing a mixture Cariprazine free base in aqueous orthophosphoric acid;
b) isolating the crystalline phosphate salt of Cariprazine.

In one embodiment, step (a) is carried out at a temperature of about 0 to about 70°C.

The isolation of crystalline phosphate salt of Cariprazine of step (b) could be done by conventional techniques known to a person skilled in the art such as filtration, centrifugation etc.

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

In another embodiment, the present invention provides a pharmaceutical composition comprising a phosphate salt of Cariprazine.

The crystalline phosphate salt of Cariprazine can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.

In another embodiment, the present invention provides an amorphous phosphate salt of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea which can be identified with more one or more analytical methods. The P-XRD pattern is provided in Fig 13.

In further embodiment, the present amorphous phosphate of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea can also be identified by its characteristic differential scanning calorimetry (DSC), as provided in Fig 14.

In further embodiment, the present amorphous phosphate salt of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea can also be identified by its characteristic differential scanning calorimetry (TGA), as provided in Fig 15.

In another embodiment, the present invention provides a process for the preparation of an amorphous phosphate salt of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea, which comprises the steps of:
a) providing a mixture Cariprazine in aqueous orthophosphoric acid;
b) isolating the amorphous phosphate salt Cariprazine.

In one embodiment, step (a) is carried out at a temperature of about 0 to about 70°C.

Step b) involves isolation of amorphous phosphate salt of Cariprazine from the solution of step a). The isolation may be affected by removing the solvent(s). Suitable techniques which may be used for the removal of solvent include using a rotational distillation device such as a rotary evaporator (e.g., Buchi Rotavapor), spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique.

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

The amorphous phosphate salt of Cariprazine 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.

2) Thermogravimetric analysis
Thermogravimetric analysis was performed using a Pyris 1 TGA PERKIN ELMER measurement unit. 2-5 mg samples were placed in open Platinum pans and heated from 25 °C to 300 °C in a dry nitrogen atmosphere at a heating rate of 10 °C/min.

3) Differential Scanning Calorimetry
Differential Scanning Calorimetry was performed using a Diamond DSC PERKIN ELMER differential instrument. 2-3 mg samples were placed in crimped aluminum pans and heated from 30 °C to 250 °C in a dry nitrogen atmosphere at a heating rate of 10 °C/minute.

EXAMPLES:
Example 1: Amorphous Cariprazine HCl
Methanol (10 ml) was added to Cariprazine hydrochloride (1g) and heated to 60°C .After heating the solution became completely soluble, the solution was sprayed in round bottom flak slowly under vacuum at 60°C. The material obtained was unloaded and dried under vacuum at 45°C.
Yield: 0.1gm, the obtained solid was characterized by XRD (figure1), DSC (figure 2), TGA (fig 3)

Example 2: Crystalline Cariprazine HCl
Acetic acid (2ml) and Water (9ml) was added to Cariprazine hydrochloride (1g) and heated to 60°C. The reaction mixture was heated at same temperature for 50 minutes and the solvent was distilled off using rotavapor, the material was dried under vacuum. Yield = 1gm, the obtained solid was characterized by XRD (figure 4); DSC (figure 5)

Example 3: Formic acid solvate of Cariprazine HCl
Formic acid (2ml) was added to Cariprazine HCl ( 1gm) , the reaction mixture was heated to 50°C to get completely soluble , and filtered the reaction mass. To this reaction mass, ethyl acetate 20ml was added dropwise at 30°C, stirred and heated to 45°C for 2 hrs. The reaction mass was cooled to 25°C. The solvent was distilled off under vacuum, to get a sticky material. To this sticky material n -heptane (30ml) was added , heated to about 60°C to get white solid which was filtered and dried under vacuum .Yield: 0.6gm The obtained solid was Characterized by XRD (figure 6); DSC (figure 7), TGA (figure 8)

Example 4: Formic acid solvate of Cariprazine HCl
Formic acid (4ml) was added to Cariprazine HCl (2gm), the reaction mixture was heated to 50°C to get completely soluble, solution was distilled off, material was dried under vacuum to get sticky mass, to this sticky was added n-heptane heated to about 60°C to get white solid which was filtered and dried under vacuum .Yield: 1.75gm The obtained solid was Characterized by XRD (figure 6); DSC (figure 7), TGA (figure 8).

Example 5: Acetic acid solvate of Cariprazine free base.
Acetic acid (2.5ml) and Water (18ml) was added to Cariprazine (2g) and heated to 50°C. The reaction mixture was heated at same temperature for 15 minutes and filtered. The filtrate was distilled off using rotavapor and the material was dried under vacuum. Yield = 2gm, the obtained solid was characterized by XRD (figure 9); DSC (figure 10), TGA (figure 11).

Example 6: Acetic acid solvate of Cariprazine free base.
Acetic acid (2.5ml) and Water (18ml) was added to Cariprazine (2g) and heated to 50°C. The reaction mixture was heated at same temperature for 15 minutes and filtered, the filtrate was cooled to 5°C and further aqueous solution was lyophilized at -73°C under 145m tor pressure for overnight. The obtained material was unloaded and dried under vacuum. Yield: 1.8 gm the obtained solid was characterized by XRD (figure 9); DSC (figure 10), TGA (figure 11).

Example 7: Crystalline Cariprazine Phosphate.
Orthophosphoric acid (1ml) and Water (18ml) was added to Cariprazine (2g) in round bottom flask. The reaction mixture was heated to 60°C to become completely soluble and solution was distilled off under vacuum to get oily mass. This oily was kept for drying in oven for overnight at temperature 45°C. To the oily mass was added water (10ml) and distilled off, further ethyl acetate (20ml) was added and distilled off, then toluene (20ml) was added and distilled off. To this water ( 10 ml) was added , the solution was heated to 60°C to get white solid which was filtered and dried under vacuum. Yield 0.8gm, Characterized by XRD (figure 12);

Example 7: Amorphous Cariprazine Phosphate
Orthophosphoric acid (1ml) and Water (18ml) was added to Cariprazine (2g) in round bottom flask. The reaction mixture was heated at same temperature for 15 minutes and filtered, the filtrate was cooled to 5°C and further aqueous solution was lyophilized at -73°C under 145m tor pressure for overnight. The obtained material was unloaded and dried under vacuum. Yield 2.4 gm, XRD (figure 13); DSC (figure 14), TGA (figure 15).
,CLAIMS:1. Amorphous Cariprazine Hydrochloride.

2. Process for the preparation of an amorphous form of Cariprazine hydrochloride comprising the steps of:
a) providing a solution of Cariprazine hydrochloride in one or more solvents; and
b) isolating the amorphous form of Cariprazine hydrochloride from the reaction mixture thereof.

3.The process according to claim 2 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.

4. The process according to claim 2 Step b) involves isolation of an amorphous form of Cariprazine hydrochloride from the solution of step a). The isolation may be affected by removing the solvent(s).

5. Crystalline form L of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea hydrochloride.

6. The crystalline form L as claimed in claim 5, can be characterized by one or more properties chosen from a powder X-ray diffraction diagram comprising characteristic peaks at 2? of 12.98, about 15.3, about 17.8 and about 19.3+0.2 degrees 2?; an endothermic trace comprising an endothermic peak around 264°C; a thermo gravimetric analysis (TGA), as provided in Fig 3.

7. A process for the preparation of a crystalline form L of trans-1{4-[2-[4-(2, 3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3, 3-dimethyl urea hydrochloride, comprising the steps of:
i) providing a solution of Cariprazine hydrochloride in aqueous acetic acid; and
ii) isolating the crystalline form L of Cariprazine hydrochloride.

8. The process for the preparation of a crystalline form L according to claim 7 comprises step (i) heating carried out at a temperature of about 10°C to about 70°C.