DESC:FIELD OF INVENTION
The present invention relates to amorphous form of Cariprazine, amorphous solid dispersion of Cariprazine, process for its preparation and pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION
Trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-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. 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. This compound has the following chemical structure.

Cariprazine also acts as partial agonist on serotonin 5-HT1A receptors and antagonist at serotonin 5-HT2A receptors, although its affinity towards the serotonin receptors is considerably lower than that for dopamine receptors. Cariprazine forms two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR) that have in vitro receptor binding profiles similar to the parent drug.

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

The US patent no. 7,943,621 describes Cariprazine monohydrochloride crystalline form I and process for preparation of the same.

The US patent no. 7,829,569 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. Polymorphic forms in the present context refer to crystalline and amorphous forms as well as solvate and hydrate forms.

Amorphous forms can be understood as liquids that have been solidified by the removal of thermal energy or a solvent, in a manner that circumvents crystallization. The amorphous form can have different solubility, stability, and mechanical behavior that can be exploited by pharmaceutical scientists. The solubility of a given solid is a sum of crystal packing energy, cavitation, and solvation energy. Different crystalline forms of a given drug will have different crystal packing energies. The amorphous forms of the same drug require minimal packing energy disruption when dissolving due to absence of an ordered crystal lattice. Thus, the amorphous forms provide the maximal solubility advantage as compared to the crystalline forms of a drug. The apparent solubility and dissolution advantage offered by these systems is a vital approach to enhance bioavailability of poorly water soluble drugs.

Extensive studies are 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, bioavailability, chemical stability, shelf life etc.

There always remain a need to provide new polymorphic forms and processes for making new polymorphic forms.

Cariprazine hydrochloride is a BCS class-II (Biopharmaceutical Classification System) drug having low solubility and high permeability, therefore there is a need to improve solubility of Cariprazine hydrochloride to enhance bioavailability of the same. One way to increase the oral bioavailability is to increase the concentration of the dissolved drug in the GI fluids. This can be achieved by increasing the dissolution rate, increasing the drug solubility, or the combination of both. One of the most remarkable approaches to achieve faster dissolution and higher solubility is converting crystalline drug to amorphous drug.

Therefore, there is a need to develop stable polymorphic form(s) of Cariprazine and its pharmaceutical compositions which will have higher solubility, faster dissolution, and improved bioavailability and is prepared by a robust and economic process.

Solid dispersions (also be referred as premix) technique have been used for increasing the solubility/dissolution rate and thus improving the bioavailability of a wide range of poorly soluble drugs. Solid dispersions are characterized by a variety of associated properties such as improved solubility profile, stability, flow properties and high drug loading. Although there are a variety of solid dispersions, there is a continual research in this field of art for solid dispersion that exhibit an improved combination of properties. The instant invention provides a solid dispersion wherein Cariprazine exists in stable amorphous form and process of manufacture of the solid dispersion; and pharmaceutical compositions comprising solid dispersion of Cariprazine and its process of preparation.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Illustrates Powder X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Cariprazine HCl and Eudragit S-100.

Figure 2: Illustrates Differential Scanning Calorimetry (DSC) plot of amorphous solid dispersion of Cariprazine HCl and Eudragit S-100.

Figure 3: Illustrates Thermo Gravimetric Analysis (TGA) plot of amorphous solid dispersion of Cariprazine HCl and Eudragit S-100.

Figure 4: Illustrates Powder X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Cariprazine HCl and Kollidon

Figure 5: Illustrates Differential Scanning Calorimetry (DSC) plot of amorphous solid dispersion of Cariprazine HCl and Kollidon

Figure 6: Illustrates Thermo Gravimetric Analysis (TGA) plot of amorphous solid dispersion of Cariprazine HCl and Kollidon

SUMMARY OF THE INVENTION
In one aspect, the present invention provides stable amorphous form of Cariprazine, its salts, esters and solvates.

In another aspect, the present invention provides stable amorphous solid dispersion of Cariprazine HCl and polyacrylates and process for preparation thereof.

In yet another aspect, the present invention provides stable amorphous solid dispersion of Cariprazine HCl and polymethacrylates and process for preparation thereof.

In further aspect, the present invention provides stable amorphous solid dispersion of Cariprazine HCl and Eudragit and process for preparation thereof.
In another aspect, the present invention provides stable amorphous solid dispersion of Cariprazine HCl and Eudragit S-100 and process for preparation thereof.

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

In further aspect, the invention provides a pharmaceutical composition comprising said stable amorphous solid dispersion of Cariprazine HCl and Eudragit and at least one pharmaceutically acceptable excipient or carrier.

In yet another aspect, the invention provides a pharmaceutical composition comprising said stable amorphous solid dispersion of Cariprazine HCl and Eudragit S-100 and at least one pharmaceutically acceptable excipient or carrier.

In another aspect, the present invention provides pharmaceutical composition comprising said stable amorphous solid dispersion of Cariprazine HCl and Eudragit S-100 that can be formulated into solid formulations such as powder, granules, capsules, tablets, pellets, or the like and liquid formulations such as solution, suspension, or the like etc.

DETAILED DESCRIPTION OF THE INVENTION
The term Cariprazine used in present invention can be free base, its different salts, esters, solvates or hydrates.

The Cariprazine HCl can be substituted by free base, its different salts, esters, solvates or hydrates.

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 certain embodiments, a solid dispersion as disclosed herein includes an active ingredient Cariprazine and its pharmaceutically acceptable salts dispersed among at least one other component. Solid dispersion can also be referred as premix.

Various types of solid dispersions are known including but not limited to solid eutectic mixture, solid solution (continuous and discontinuous solid solution, substitutional and interstitial solid solution), glass solution, glass suspension and amorphous precipitation in crystalline carriers.

Solid dispersions can be prepared by various techniques including but not limited to hot melt method (fusion method), solvent evaporation method, hot melt extrusion, kneading method, spray drying, supercritical fluid method, co-precipitation, electrospinning method, lyophilization technique.

The term, “amorphous solid dispersion” as used herein, refers to stable solid dispersions comprising amorphous drug substance together with one or more pharmaceutically acceptable carriers, wherein at least 80% of the drug substance in the dispersion is in an amorphous form. More preferably at least 90% and most preferably at least 95% of the drug substance in the dispersion is in amorphous form. A solid that is in the “amorphous” solid state means that it is in a non-crystalline state.

Pharmaceutically acceptable carriers that may be used for the preparation of solid dispersions of Cariprazine of the present invention include, but are not limited to; water soluble sugar derivatives including any pharmaceutically acceptable water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to lactose, fructose, dextrose, sucrose, maltose, galactose, mannitol, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, or the like; pharmaceutical polymeric carriers such as polyvinylpyrrolidones (homopolymers or copolymers of N-vinyl pyrrolidone), crospovidone, polyacrylates, polymethacrylates (copolymer of methacrylic acid and an acrylic or methacrylic ester), gums, cellulose derivatives (including hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose and others), polymers of carboxymethyl celluloses, cyclodextrins, gelatins, hypromellose phthalates, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, polyethylene glycols, polyethylene oxides, polyvinyl alcohols, propylene glycol derivatives, pectins, chitosan, galactomannan, or the like; or organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, guanidine or its derivatives, or the like; or acids such as citric acid, succinic acid, tartaric acid, or the like; or surfactants such as polyoxyethylene stearate, poloxamer 188, gelucire 44/14, lutrol F-127, soluplus®, deoxycholic acid, tweens, spans or the like; or the carriers like triacetin, stearic acid, butylated hydroxy toulene, butylated hydroxy anisole, vitamin E, urea, urethane, pentaerythritol, pentaerythrityl tetracetate, hydroxy alkyl xanthins or the like. The use of mixtures of more than one of the pharmaceutical carriers to provide desired properties is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.

The term “excipient” or “pharmaceutically acceptable excipient” means a component of a pharmaceutical product that is not an active ingredient, and including but not limited to fillers/ diluents selected from including but not limited to lactose, starch, sucrose, microcrystalline cellulose, sodium hydrogen carbonate, mannitol, xylitol, sorbitol, dibasic calcium phosphate, maltodextrin, magnesium oxide, magnesium aluminometasilicate, threlose, or the like; binders including but not limited to hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, sodium alginate, gelatin, ethyl cellulose, methyl cellulose, starch, or the like; disintegrants including but not limited to starch, crospovidone, croscarmellose sodium, sodium starch glycolate, or the like; glidants including but not limited to colloidal silicone dioxide, sodium lauryl sulfate, talc, cornstarch, or the like; lubricants including but not limited to hydrogenated castor oil, magnesium stearate, stearic acid, sodium stearyl fumarate, sodium benzoate, glycerol behenate, calcium stearate, zinc stearate, mineral oil, polyethylene glycol, or the like; stabilizers including but not limited to titanium dioxide, butylated hydroxy toulene, butylated hydroxy anisole, a-tocopherol, propylgallate, or the like; surface active agents including but not limited to sodium lauryl sulfate, polyoxyethylene stearate, poloxamer 188, texafor AIP, deoxycholic acid, tweens, spans, or the like 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 stable amorphous form of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea which can be identified by one or more analytical methods.

In another embodiment, the present invention provides a stable amorphous form of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride which can be identified by one or more analytical methods.

In yet another embodiment, the present invention provides a stable amorphous solid dispersion of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea and polyacrylates which can be identified by one or more analytical methods

In further another embodiment, the present invention provides a stable amorphous solid dispersion of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea and polyacrylates which is stable at normal and at elevated temperature.

In another embodiment, the present invention provides a stable amorphous solid dispersion of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride and polyacrylates which can be identified by one or more analytical methods.

In further another embodiment, the present invention provides a stable amorphous solid dispersion of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydro-chloride and polyacrylates which is stable at normal and at elevated temperature.

In yet another embodiment, the present invention provides a stable amorphous solid dispersion of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea and poly-methacrylates which can be identified by one or more analytical methods.

In another embodiment, the present invention provides a stable amorphous solid dispersion of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea and poly-methacrylates which is stable at normal and at elevated temperature.

In further embodiment, the present invention provides a stable amorphous solid dispersion of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride and polymethacrylates which can be identified by one or more analytical methods.

In another embodiment, the present invention provides a stable amorphous solid dispersion of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride and polymethacrylates which is stable at normal and at elevated temperature.

In yet another embodiment, the present invention provides stable amorphous solid dispersion of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride and Eudragit S-100 can be identified by its characteristic Powder X-ray Diffraction (PXRD) pattern as provided in Figure- 1.

In another embodiment, the present stable amorphous solid dispersion of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride and Eudragit S-100 can be identified by its characteristic Differential Scanning Calorimetry (DSC) pattern as provided in Figure- 2.

In further embodiment, the present stable amorphous solid dispersion of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride and Eudragit S-100 can be identified by its characteristic Thermo Gravimetric Analysis (TGA), as g in Figure- 3.

In yet another embodiment, the present invention provides stable amorphous solid dispersion of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride and Kollidon can be identified by its characteristic Powder X-Ray Diffraction (PXRD) pattern as provided in Figure-4.

In another embodiment, the present stable amorphous solid dispersion of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride and Kollidon can be identified by its characteristic Differential Scanning Calorimetry (DSC) pattern as provided in Figure-5.

In further embodiment, the present stable amorphous solid dispersion of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride and Kollidon can be identified by its characteristic Thermo Gravimetric Analysis (TGA), as provided in Figure-6.

In yet another embodiment, the present amorphous solid dispersion of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride and polymethacrylates 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 further embodiment, the present amorphous solid dispersion of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride and Eudragit S-100 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.

In further embodiment, the invention provides a process for preparation of an amorphous solid dispersion of Cariprazine hydrochloride and pharmaceutically acceptable carriers comprising the steps of:
a) providing a solution of pharmaceutically acceptable carriers in one or more solvents;
b) adding Cariprazine HCl to above solution; and
c) isolating the amorphous solid dispersion of Cariprazine hydrochloride from the reaction mixture thereof.
In yet another embodiment, the invention provides a process for preparation of an amorphous solid dispersion of Cariprazine hydrochloride and polyacrylates comprising the steps of:
a) providing a solution of polyacrylates carriers in one or more solvents;
b) adding Cariprazine HCl to above solution; and
c) isolating the amorphous solid dispersion of Cariprazine hydrochloride from the reaction mixture thereof.

In another embodiment, the invention provides a process for preparation of an amorphous solid dispersion of Cariprazine hydrochloride and polymethacrylates comprising the steps of:
a) providing a solution of polymethacrylates carriers in one or more solvents;
b) adding Cariprazine HCl to above solution; and
c) isolating the amorphous solid dispersion of Cariprazine hydrochloride from the reaction mixture thereof.

The term polyacrylates are polymer of acrylate. Acrylate monomers used to form acrylate polymers are based on the structure of acrylic acid, which consists of a vinyl group and a carboxylic acid terminus. Other typical acrylate monomers are derivatives of acrylic acid, such as methyl methacrylate in which one vinyl hydrogen and the carboxylic acid hydrogen are both replaced by methyl groups, and acrylonitrile in which the carboxylic acid group is replaced by the related nitrile group. Various acrylate monomers are methyl acrylate, ethyl acrylate, 2-ethylhexyl acrylate, hydroxyethyl methacrylate, butyl methacrylate etc. The most preferable polyacrylates are polymethylacrylate.

The solvent employed in step a) is selected from the group which includes but not limited to water, methanol, ethanol, isopropanol, 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 amorphous solid dispersion 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), addition of antisolvent and the like or any other suitable technique as discussed above.

In another embodiment, the invention provides a process for preparation of an amorphous solid dispersion of Cariprazine hydrochloride and Eudragit comprising the steps of:
a) providing a solution of Eudragit in one or more solvents;
b) adding Cariprazine HCl to above solution; and
c) isolating the amorphous solid dispersion of Cariprazine hydrochloride and Eudragit from the reaction mixture thereof.

The solvent employed in step a) is selected from the group which includes but not limited to water, methanol, ethanol, isopropanol, 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 solid dispersion 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), addition of antisolvent and the like or any other suitable technique as discussed above.

The commercially available Eudragit polymers are offered in a wide range of different physical forms. Eudragit used in the preparation of the invention include, but are not limited to Eudragit L 30 D-55, Eudragit L 100-55, Eudragit L 100, Eudragit L 12.5, Eudragit S 100, Eudragit S 12.5, Eudragit FS 30D, Eudragit E 100, Eudragit E-12.5, Eudragit E PO, Eudragit RL 100, Eudragit RL PO, Eudragit RL 30 D, Eudragit RL 12.5, Eudragit RS 100, Eudragit RS PO, Eudragit RS 30 D, Eudragit RS 12.5, Eudragit NE 30 D, Eudragit NE 40 D and Eudragit NM 30 D.

The other examples of polymers which can be used for preparing solid dispersion include, but are not limited to water soluble sugar derivatives including any pharmaceutically acceptable water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to lactose, fructose, dextrose, sucrose, maltose, galactose, mannitol, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, or the like; pharmaceutical polymeric carriers such as polyvinylpyrrolidones (homopolymers or copolymers of N-vinyl pyrrolidone), crospovidone, polyacrylates, polymethacrylates (copolymer of methacrylic acid and an acrylic or methacrylic ester), gums, cellulose derivatives (including hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, microcrystalline celluloses and others), polymers of carboxymethyl celluloses, cyclodextrins, gelatin, hypromellose phthalates, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, polyethylene glycols, polyethylene oxides, polyvinyl alcohols, propylene glycol derivatives, pectins, chitosan, galactomannan, or the like; or organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, guanidine or its derivatives, or the like; or acids such as citric acid, succinic acid, tartaric acid, or the like; or surfactants such as polyoxyethylene stearate, poloxamer 188, gelucire 44/14, lutrol F-127, soluplus®, deoxycholic acid, tweens, spans, or the like; or other carriers like triacetin, stearic acid, butylated hydroxy toulene, butylated hydroxy anisole, vitamin E, urea, urethane, pentaerythritol, pentaerythrityl tetracetate, hydroxy alkyl xanthins, or the like. The use of mixtures of more than one of the pharmaceutical carriers to provide desired properties is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.

In another aspect, the invention provides pharmaceutical composition comprising amorphous solid dispersion of Cariprazine hydrochloride and polymeric materials together with one or more pharmaceutically acceptable excipients.

A solid dispersion of Cariprazine together with one or more pharmaceutically acceptable excipients of the present invention may be further formulated as, solid oral dosage forms such as, but not limited to powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.

In yet another aspect, the invention provides pharmaceutical composition comprising amorphous solid dispersion of Cariprazine hydrochloride and one or more polymeric materials selected from the group including but not limited to polyvinylpyrrolidones (homopolymers or copolymers of N-vinyl pyrrolidone), crospovidone, polyacrylates, polymethacrylates (copolymer of methacrylic acid and an acrylic or methacrylic ester), gums, cellulose derivatives (including hydroxypropyl methylcelluloses, hydroxypropyl celluloses, hydroxyethyl cellulose, microcrystalline celluloses and others), polymers of carboxymethyl celluloses, cyclodextrins, gelatins, hypromellose phthalates, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, polyethylene glycols, polyethylene oxides, polyvinyl alcohols, propylene glycol derivatives, pectins, chitosan, galactomannan together with one or more pharmaceutically acceptable excipients.

In further aspect, the invention provides pharmaceutical composition comprising amorphous solid dispersion of Cariprazine hydrochloride and polyacrylates together with one or more pharmaceutically acceptable excipients.

In another aspect, the invention provides pharmaceutical composition comprising amorphous solid dispersion of Cariprazine hydrochloride and Eudragit together with one or more pharmaceutically acceptable excipients

The amorphous solid dispersion of Cariprazine hydrochloride and Eudragit can be formulated into solid formulations such as powder, granules, capsules, tablets, pellets, or the like and liquid formulations such as solution, suspension, or the like etc.

In further aspect, the invention provides pharmaceutical composition comprising amorphous solid dispersion of Cariprazine hydrochloride and sugar carrier together with one or more pharmaceutically acceptable excipients.

In another aspect, the invention provides pharmaceutical composition comprising amorphous solid dispersion of Cariprazine hydrochloride and one or more sugar selected from the group including but not limited to dextrose, sucrose, galactose, sorbitol, maltose, xylitol, mannitol, lactose together with one or more pharmaceutically acceptable excipients.

In yet another aspect, the amorphous solid dispersion of Cariprazine hydrochloride and one or more sugar selected from the group including but not limited to dextrose, sucrose, galactose, sorbitol, maltose, xylitol, mannitol lactose which can be formulated into solid formulations such as powder, granules, capsules, tablets, pellets, or the like and liquid formulations such as solution, suspension, or the like etc.

In another aspect, the invention provides pharmaceutical composition comprising amorphous solid dispersion of Cariprazine hydrochloride and acidic carriers together with one or more pharmaceutically acceptable excipients.
In further aspect, the invention provides pharmaceutical composition comprising amorphous solid dispersion of Cariprazine hydrochloride and one or more acidic carrier selected from the group including but not limited to citric acid, succinic acid, tartaric acid together with one or more pharmaceutically acceptable excipients.

The amorphous solid dispersion of Cariprazine hydrochloride and one or more acids selected from the group including but not limited to citric acid, succinic acid and tartaric acid which can be formulated into solid formulations such as powder, granules, capsules, tablets, pellets, or the like and liquid formulations such as solution, suspension, or the like etc.

In further another aspect, the invention provides pharmaceutical composition comprising amorphous solid dispersion of Cariprazine hydrochloride and surfactant carrier together with one or more pharmaceutically acceptable excipients.

In yet another aspect, the invention provides pharmaceutical composition comprising amorphous solid dispersion of Cariprazine hydrochloride and one or more surfactants selected from the group including but not limited to polyoxyethylene stearate, renex, poloxamer 188, texafor AIP, deoxycholic acid, tweens, spans together with one or more pharmaceutically acceptable excipients.

The amorphous solid dispersion of Cariprazine hydrochloride and one or more surfactants selected from the group including but not limited to polyoxyethylene stearate, renex, poloxamer 188, texafor AIP, deoxycholic acid, tweens and spans which can be formulated into solid formulations such as powder, granules, capsules, tablets, pellets, or the like and liquid formulations such as solution, suspension, or the like etc.

Pharmaceutically acceptable excipients may be utilized as required for present inventions into the final pharmaceutical dosage forms and include, but not limited to fillers/ diluent selected from but not limited to lactose, starch, sucrose, microcrystalline cellulose, sodium hydrogen carbonate, mannitol, xylitol, sorbitol, dibasic calcium phosphate, maltodextrin, magnesium oxide, magnesium aluminometasilicate, threlose; binders including but not limited to hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, sodium alginate, gelatin, ethyl cellulose, methyl cellulose, starch; disintegrants including but not limited to starch, crospovidone, croscarmellose sodium, sodium starch glycolate; glidants including but not limited to colloidal silicone dioxide, sodium lauryl sulfate, talc, cornstarch; lubricants including but not limited to hydrogenated castor oil, magnesium stearate, stearic acid, sodium stearyl fumarate, sodium benzoate, glycerol behenate, calcium stearate, zinc stearate, mineral oil, polyethylene glycol, stabilizers including but not limited to titanium dioxide, butylated hydroxy toulene, butylated hydroxy anisole, a-tocopherol, propylgallate; surface active agents including but not limited to sodium lauryl sulfate, polyoxyethylene stearate, poloxamer 188, texafor AIP, deoxycholic acid, tweens, spans, 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.

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.

INSTRUMENT SETTINGS

1) Powder X-Ray Diffraction (PXRD)
The Powder X-Ray Diffraction (PXRD) 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: Solid Dispersion of Amorphous Cariprazine HCl and Eudragit S-100
Procedure: Methanol (90 ml) was added to Eudragit S-100 (8.5g) and heated to 40°C-45°C till clear solution is obtained. To this clear solution Cariprazine HCl (8.5g) was added at same temperature and stirred for 2 hrs at same temperature. The reaction mixture was distilled off to get titled compound.
Yield: 16.3gm, the obtained solid was characterized by PXRD (Figure-1), DSC (Figure-2), and TGA (Figure-3)

Example 2: Solid Dispersion of Amorphous Cariprazine HCl and Kollidon
Procedure: Methanol (20ml) was added to mixture of Cariprazine HCl (1gm), Kollidon (1gm). The solution was heated to temperature at 50°C-55°C to become completely soluble. This solution was distilled off, the material was unloaded and dried in oven at 40°C for overnight to get the titled compound. The solid was characterized by PXRD (Figure-4), DSC (Figure-5) and TGA (Figure-6).

Example 3: Preparation of Capsule Formulation comprising Cariprazine HCl

S. No. Ingredients % w/w
1 Cariprazine HCl and Eudragit Solid Dispersion 13.34
2 Pregelatinized starch 83.66
3 Croscarmellose Sodium 2
4 Magnesium Stearate 1
Fill Weight 100

Procedure: Cariprazine HCl solid dispersion and other excipients except lubricant were sieved together through a #60 sieve and mixed in a blender for 15 minutes. Lubricant was sieved through #20 sieve and added to the blend and further mixed for 5 minutes. The final blend was filled into empty capsule shells and packed in suitable packaging.

Example 4: Preparation of Capsule Formulation comprising Cariprazine HCl

S. No. Ingredients % w/w
1 Cariprazine HCl and Eudragit Solid Dispersion 13.34
2 Lactose Anhydrous 83.66
3 Sodium Starch Glycolate 2
4 Sodium Starch Fumarate 1
Fill Weight 100

Procedure: Cariprazine HCl solid dispersion and other excipients except lubricant were sieved together through a #60 sieve and mixed in a blender for 15 minutes. Lubricant was sieved through #20 sieve and added to the blend and further mixed for 5 minutes. The final blend was filled into empty capsule shells and packed in suitable packaging.

Example 5: Preparation of Capsule Formulation comprising Cariprazine HCl

S. No. Ingredients % w/w
1 Cariprazine HCl and Eudragit Solid Dispersion 13.34
2 Microcrystalline Cellulose 83.66
3 Crospovidone 2
4 Stearic Acid 1
Fill Weight 100

Procedure: Cariprazine HCl solid dispersion and other excipients except lubricant were sieved together through a #60 sieve and mixed in a blender for 15 minutes. Lubricant was sieved through #20 sieve and added to the blend and further mixed for 5 minutes. The final blend was filled into empty capsule shells and packed in suitable packaging.

Example 6: Preparation of Capsule Formulation comprising Cariprazine HCl

S. No. Ingredients % w/w
1 Cariprazine HCl and Kollidon Solid Dispersion 13.34
2 Microcrystalline Cellulose 78.66
3 Hydroxypropyl Cellulose 5.00
4 Crospovidone 2
5 Magnesium Stearate 1
Fill Weight 100

Procedure: Cariprazine HCl solid dispersion and other excipients except lubricant were sieved together through a #60 sieve and mixed in a blender for 15 minutes. Lubricant was sieved through #20 sieve and added to the blend and further mixed for 5 minutes. The final blend was filled into empty capsule shells and packed in suitable packaging.

Example 7: Preparation of Capsule Formulation comprising Cariprazine HCl

S. No. Ingredients % w/w
Intragranular
1 Cariprazine HCl and Eudragit Solid Dispersion 13.34
2 Microcrystalline Cellulose 78.66
3 Hydroxypropyl Cellulose 5.00
4 Crospovidone 2
Extra-granular
5 Microcrystalline Cellulose 20
6 Crospovidone 2
7 Magnesium Stearate 1
Fill Weight -

Procedure: Cariprazine HCl solid dispersion was sifted with microcrystalline cellulose, crospovidone and hydroxypropyl cellulose as intragranular portion. Microcrystalline cellulose and crospovidone were sifted separately and blended with intragranular portion. Magnesium stearate was sifted and mixed with the blend. The final blend was filled into empty capsule shells and packed in suitable packaging.
,CLAIMS:Claim 1: Amorphous Cariprazine its salts, esters and solvates.

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

Claim 3: The process according to claim 2, wherein solvent is selected from water, methanol, ethanol, isopropanol, 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.

Claim 4: The process according to claim 2, wherein isolation of amorphous compound is carried out by using techniques selected from rotary evaporation, spray drying, agitated thin film drying, freeze drying, addition of anti-solvent or other suitable technique.

Claim 5: An amorphous solid dispersion comprising Cariprazine or its salts and one or more pharmaceutically acceptable carriers.

Claim 6: A process for the preparation of an amorphous solid dispersion of Cariprazine and pharmaceutically acceptable carriers comprising the steps of:
a) providing a solution of pharmaceutically acceptable carriers in one or more solvents;
b) adding Cariprazine to above solution; and
c) isolating the amorphous solid dispersion of Cariprazine from the reaction mixture thereof.

Claim 7: The process according to claim 6, wherein solvent is selected from water, methanol, ethanol, isopropanol, 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.

Claim 8: The process according to claim 6, wherein isolation of amorphous form is carried out by using techniques selected from rotary evaporation, spray drying, agitated thin film drying, freeze drying, addition of anti-solvent or other suitable technique.

Claim 9: A pharmaceutical composition comprising amorphous solid dispersion of Cariprazine and one or more pharmaceutically acceptable carrier.

Claim 10: The pharmaceutical composition according to claim 9, wherein the composition is formulated as solid, semisolid or liquid formulation.