Technical field of the Invention:

The present invention relates to polymorphic forms of Cariprazine and its pharmaceutically acceptable salts, method of manufacturing and pharmaceutical compositions thereof. More particularly, the present invention relates to amorphous form of Cariprazine, method of manufacturing; premix of amorphous Cariprazine and pharmaceutical compositions thereof.

Background of the invention:

Cariprazine (Vraylar) is an antipsychotic drug. It acts as a D2 and D3 receptor partial agonist, with high selectivity towards the D3 receptor.

The chemical name of Cariprazine is trans-4- (2-[4-(2,3-dichlorophenyl)- piperazin- 1 -yl]-ethyl} -N, N-dimethylcarbamoyl-cyclohexylamine.

Cariprazine HC1 has the following structural Formula I:

Formula I

Vraylar is used in the treatment of primary negative symptoms of schizophrenia and/or predominantly negative symptoms of schizophrenia.

Cariprazine is specifically and generically disclosed in WO2005/012266.

US7943621B2 discloses monohydrochloride, dihydrochloride, monohydrobromide, maleate and methanesulphonate salts of trans 4-{2-[4-(2,3- dichlorophenyl)-piperazine-l-yl]-ethyl}-N,N-dimethylcarbamoy l- cyclohexylamine and process of preparing them. A new polymorph of a compound possesses physical properties that differs from, and is advantageous over, other crystalline or amorphous forms and exhibit different physical properties such as melting point, X-ray diffraction patterns, density, stability, and solubility.

There remains an unmet need for additional solid state forms of Cariprazine having good physiochemical properties, desirable bioavailability, and advantageous pharmaceutical parameters.

Objectives of the invention:

An object of the invention is to provide amorphous form of Cariprazine.

Another object of the invention is to provide process for the preparation of amorphous form of Cariprazine.

Yet another object of the invention is to provide premix of Cariprazine with the pharmaceutically acceptable excipients.

Yet another object of the invention is to provide the process for the preparation of premix of Cariprazine with the pharmaceutically acceptable excipients.

Summary of the invention:

One aspect of the present invention provided herein is amorphous form of Cariprazine.

According to another aspect of the present invention there is provided amorphous form of Cariprazine which is characterized by XRD, DSC , TGA and IR.

According to yet another aspect of the present invention there is provided a process for the preparation of amorphous form of Cariprazine comprising:

a) dissolving Cariprazine in a solvent; b) evaporating the solvent; and

c) isolating amorphous Cariprazine.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising amorphous form of Cariprazine together with one or more pharmaceutically acceptable carriers, excipients or diluents.

According to another aspect of the present invention there is provided the use of amorphous form of Cariprazine in the treatment of primary negative symptoms of schizophrenia and/or predominantly negative symptoms of schizophrenia.

According to another aspect of the present invention there is provided premix of Cariprazine with the pharmaceutically acceptable excipients.

According to another aspect, provided herein is a process for preparing premix of Cariprazine with the pharmaceutically acceptable excipients, which may be carried out by the following steps:

a. dissolving Cariprazine and pharmaceutically acceptable excipients/premixing agent in a suitable solvent;

b. removing the solvent from the solution obtained in step (a) to obtain premix; and

c. drying the premix of Cariprazine.

Another aspect of the present invention is to provide a composition comprising the said premix of Cariprazine which can be easily processed into pharmaceutical formulations.

Detailed description of the invention:

In accordance with the above aspects, the invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. Many pharmaceutical solids can exist in different physical forms. Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystalline lattice.

Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).

Cariprazine exist in different polymorphic forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.

The present invention is directed to new polymorphic forms of Cariprazine and its pharmaceutically acceptable salts.

Cariprazine includes Cariprazine and its salts, hydrates, solvates, anhydrates and premix.

In an embodiment, provided herein is novel amorphous form of Cariprazine.

According to another aspect of the present invention there is provided amorphous form of Cariprazine characterized by XRD, DSC, IR, TGA.

According to another embodiment, the process for preparation of amorphous form of Cariprazine comprises the following steps;

a) dissolving Cariprazine in a solvent;

b) evaporating the solvent; and

c) isolating amorphous Cariprazine.

The solvent may be selected from the group consisting of methanol, ethanol, n- propanol, isopropanol, n-butanol, t-butanol, acetone, water, formic acid, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, 2-methyl tetrahydrofuran, N- methyl-2- pyrrolidone, and mixtures thereof.

Optionally the amorphous form may be obtained by the addition of anti- solvent. The anti-solvent may be selected from the group consisting of water, dichloromethane, and mixtures thereof.

The addition of the anti-solvent may result in the formation of a precipitate.

The isolating step of amorphous Cariprazine by this method may be achieved by filtering and drying the precipitate, distillation, spray drying, lyophilization, or agitated thin film drying.

The Cariprazine used in step (a) is selected from Cariprazine or its polymorphic forms known in the prior art.

The amorphous form of Cariprazine obtained according to the process of the present invention can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.

According to another aspect of the present invention there is provided the use of amorphous form of Cariprazine in the treatment of primary negative symptoms of schizophrenia and/or predominantly negative symptoms of schizophrenia.

According to another embodiment, of the present invention is to provide premix of Cariprazine with the pharmaceutically acceptable excipients.

The premix according to the process of the present invention may be obtained as crystalline or amorphous.

Premixes are characterized by a variety of associated properties such as stability, flow, and solubility. Although there are a variety of premixes, there is a continual search in this field of art for premixes that exhibit an improved property.

The term "premix" used herein is to describe combinations of Cariprazine and at least one pharmaceutically acceptable excipient/premixing agent.

In an embodiment, the present invention provides a Cariprazine premix having enhanced stability, dissolution properties that can be easily formulated into pharmaceutical composition.

The premix of the present invention is prepared by combining Cariprazine with suitable pharmaceutically acceptable excipients.

In an embodiment, the process for preparation of premix of Cariprazine comprising steps of; a. dissolving Cariprazine and pharmaceutically acceptable excipients/premixing agents in an suitable solvent; b. removing the solvent from the solution obtained in step (a) to obtain premix; and c. drying the premix of Cariprazine.

The pharmaceutically acceptable excipient/ premixing agents used in step (a) include, but are not limited to polyvinylpyrrolidone (also called povidone), copolymers of PVP and vinyl acetate such as copovidone (e.g. Kollidon VA 64 polyvinyl alcohol, polyethylene glycol, polyol (Mannitol), sodium starch glycolate, colloidal silicon dioxide (aerosil), hydroxypropyl methylcellulose, low substituted hydroxypropylcellulose, hydroxypropylcellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, polyvinyl acetate, Eudragit, cyclodextrins, gelatins, hypromellose phthalate, sugars, and combinations comprising one or more of the foregoing agents.

In an embodiment the weight ratio of Cariprazine and premixing agent may range from 1 : 10 to 10: 1.

The process for preparing the Cariprazine premix comprises of dissolving Cariprazine in a solvent system selected from a group of polar solvents such as Cl- C4 alcohols; chlorinated organic solvents such as chloroform, dichloromethane, ethylene dichloride alone or in combination.

In an embodiment the dissolution temperatures may range from about 10°C to about reflux temperature of the solvent, depending on the solvent used for dissolution.

In an embodiment, solvent may be removed by known techniques such a distillation, evaporation, spray drying, spray coating, lyophilisation. sublimation (typically under vacuum) and desorption or freeze drying.

The premix of Cariprazine is characterized by XRD, DSC, IR and TGA.

The Cariprazine using in step (a) is selected from the polymorphic forms of Cariprazine known in prior art.

The premix can be formulated using suitable excipients into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc using the methods known in the art.

The present invention includes administration of an effective amount of stable amorphous Cariprazine premix (either alone or as the active component of a pharmaceutical composition) used in the treatment of primary negative symptoms of schizophrenia and/or predominantly negative symptoms of schizophrenia. In yet another embodiment, the present invention provides a complex of Cariprazine and cyclodextrin.

In yet another embodiment, the present invention provides a composition comprising the said complex of Cariprazine and cyclodextrin which can be easily processed into pharmaceutical formulations.

As used herein, "a cyclodextrin" refers to the natural cyclodextrins, a- cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, and their respective derivatives.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of examples and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples:- Example 1

Amorphous pre-mix of Cariprazine hydrochloride and Eudragit

Charged 5.0 g of Cariprazine hydrochloride, 5.0 g Eudragit E PO, 25 ml ethanol and 25 ml MDC. The reaction mixture was stirred at 25-30°C to get a clear solution. The solvent was removed under reduced pressure at 40-45°C to get solid premix. Yield- 10 g

The X-ray analysis of the residue gave featureless diffractogram showing the residue was amorphous.

Example 2

Amorphous pre-mix of Cariprazine hydrochloride and Eudragit

Charged 5.0 g of Cariprazine hydrochloride, 5.0 g Eudragit E PO, 25 ml ethanol and 25 ml MDC. The reaction mixture was stirred at 25-30°C to get a clear solution. The solvent was removed under reduced pressure at 30°C to get solid premix. Yield -10 g. The X-ray analysis of the residue gave featureless diffractogram showing the residue was amorphous.

Example 3

Amorphous pre- mix of Cariprazine hydrochloride and Eudragit

Charged 5.0 g of Cariprazine hydrochloride, 5.0 g Eudragit E PO, 25 ml dimethylacetamide and 25 ml MDC. The reaction mixture was stirred at 25-30°C to get a clear solution. The solvent was removed under reduced pressure at 30°C to get solid premix.

Yield -10 g.

The X-ray analysis of the residue gave featureless diffractogram showing the residue was amorphous.

Example 4

Amorphous Cariprazine hydrochloride

Cariprazine hydrochloride (5.0 grams) was dissolved in water (200 ml) and filtered. The clear solution was then freeze dried (lyophilized) to get amorphous Cariprazine hydrochloride.

The X-ray analysis of the residue gave featureless diffractogram showing the residue was amorphous.

Example 5

Amorphous pre-mix of Cariprazine hydrochloride and Lactose

Cariprazine hydrochloride (2.5 grams) and lactose monohydrate (2.5 grams) were stirred in a 1 : 1 water/ethanol mixture (100 ml) in a round bottom flask until complete dissolution was achieved. The solution was then spray-dried, producing a residue to obtain a co-precipitate of the Cariprazine hydrochloride and the lactose. The X-ray analysis of the residue gave featureless diffractogram showing the residue was amorphous. Example 6

Preparation of Amorphous Form of Cariprazine hydrochloride

Cariprazine hydrochloride (1.0 g) and acetone (160 mL) were charged in to a round- bottom flask at 25-35° C. The contents were heated to 40-53°C and stirred to dissolve Cariprazine hydrochloride completely. The resulting solution was evaporated completely at 40-45°C under reduced pressure to afford Amorphous Form of Cariprazine hydrochloride.

Yield -900 mg.

The X-ray analysis of the residue gave featureless diffractogram showing the residue was amorphous.

Example 7

Preparation of a Solid Dispersion of Amorphous Cariprazine hydrochloride with Povidone (1:1)

Cariprazine hydrochloride (7.0 g), Povidone K-90 (7.0 g) and ethanol (700 mL) were charged in to a round-bottom flask at 27°C. The contents were stirred at 27°C to obtain clear solution. The resulting solution was evaporated completely at 50- 55°C under reduced pressure to afford solid dispersion of Amorphous Cariprazine hydrochloride.

Yield -12.0 g

The X-ray analysis of the residue gave featureless diffractogram showing the residue was amorphous.