WO2018229794A1 - Amorphous form of cariprazine - Google Patents
Amorphous form of cariprazine Download PDFInfo
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- WO2018229794A1 WO2018229794A1 PCT/IN2018/050385 IN2018050385W WO2018229794A1 WO 2018229794 A1 WO2018229794 A1 WO 2018229794A1 IN 2018050385 W IN2018050385 W IN 2018050385W WO 2018229794 A1 WO2018229794 A1 WO 2018229794A1
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- cariprazine
- cariprazine hydrochloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
Definitions
- 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.
- Cariprazine is an antipsychotic drug. It acts as a D2 and D3 receptor partial agonist, with high selectivity towards the D3 receptor.
- 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:
- 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-dimethylcarbamoyl- 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.
- 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.
- One aspect of the present invention provided herein is amorphous form of Cariprazine.
- amorphous form of Cariprazine which is characterized by XRD, DSC , TGA and IR.
- a pharmaceutical composition comprising amorphous form of Cariprazine together with one or more pharmaceutically acceptable carriers, excipients or diluents.
- amorphous form of Cariprazine in the treatment of primary negative symptoms of schizophrenia and/or predominantly negative symptoms of schizophrenia.
- premix of Cariprazine with the pharmaceutically acceptable excipients there is provided premix of Cariprazine with the pharmaceutically acceptable excipients.
- a process for preparing premix of Cariprazine with the pharmaceutically acceptable excipients which may be carried out by the following steps:
- step (b) removing the solvent from the solution obtained in step (a) to obtain premix
- 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.
- 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).
- XRD X-ray diffraction
- DSC Differential Scanning Calorimetry
- IR Infrared spectrometry
- 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.
- novel amorphous form of Cariprazine is provided herein.
- amorphous form of Cariprazine characterized by XRD, DSC, IR, TGA.
- the process for preparation of amorphous form of Cariprazine comprises the following steps;
- 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.
- 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.
- amorphous form of Cariprazine in the treatment of primary negative symptoms of schizophrenia and/or predominantly negative symptoms of schizophrenia.
- 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.
- premix used herein is to describe combinations of Cariprazine and at least one pharmaceutically acceptable excipient/premixing agent.
- 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.
- 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.
- 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.
- 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.
- the dissolution temperatures may range from about 10°C to about reflux temperature of the solvent, depending on the solvent used for dissolution.
- 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.
- the present invention provides a complex of Cariprazine and cyclodextrin.
- the present invention provides a composition comprising the said complex of Cariprazine and cyclodextrin which can be easily processed into pharmaceutical formulations.
- a cyclodextrin refers to the natural cyclodextrins, a- cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin, and their respective derivatives.
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Abstract
The present invention discloses amorphous form of Cariprazine, method of manufacturing; premix of amorphous Cariprazine and pharmaceutical compositions thereof.
Description
AMORPHOUS FORM OF CARIPRAZINE
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-dimethylcarbamoyl- 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.
Claims
1. Amorphous form of Cariprazine hydrochloride.
2. A process for preparation of amorphous form of Cariprazine hydrochloride comprises the following steps;
a) dissolving Cariprazine hydrochloride in a solvent;
b) evaporating the solvent; and
c) isolating amorphous Cariprazine hydrochloride.
3. The process as claimed in claim 2, wherein, the solvent is 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.
4. The process as claimed in claim 2, wherein, the amorphous Cariprazine hydrochloride is optionally obtained by the addition of anti-solvent.
5. The process as claimed in claim 4, wherein, the anti-solvent is selected from the group consisting of water, dichloromethane and mixtures thereof.
6. The process as claimed in claim 2, wherein, the isolation of amorphous Cariprazine hydrochloride is achieved by filtering and drying the precipitate, distillation, spray drying, lyophilization, or agitated thin film drying.
7. The process as claimed in claim 2, wherein, the Cariprazine hydrochloride used in step (a) is selected from Cariprazine hydrochloride or its known polymorphic forms.
8. Amorphous Cariprazine hydrochloride premix comprising Cariprazine hydrochloride and one or more pharmaceutically acceptable premixing agents.
9. The Cariprazine hydrochloride premix as claimed in claim 8, wherein, the pharmaceutical premixing agents are selected from the group consisting of polyvinylpyrrolidone (also called povidone), co-polymers 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 thereof.
10. The amorphous Cariprazine hydrochloride premix as claimed in claim 9, wherein, the weight ratio of Cariprazine and premixing agent may range from 1 : 10 to 10: 1.
11. A process for preparation of premix of amorphous Cariprazine hydrochloride comprising steps of;
a) dissolving Cariprazine hydrochloride and pharmaceutically acceptable excipients 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 hydrochloride.
12. The process as claimed in claim 11, wherein, the solvent is selected from a group consisting of polar solvents such as C1-C4 alcohols; chlorinated organic solvents such as chloroform, dichloromethane, ethylene dichloride alone or in combination.
13. The process as claimed in claim 11, wherein, the dissolution temperatures may range from about 10°C to about reflux temperature of the solvent.
14. The process as claimed in claim 2, wherein solvent is removed by techniques such as distillation, evaporation, spray drying, spray coating, lyophilisation. sublimation (typically under vacuum) and desorption or freeze drying.
15. A pharmaceutical composition comprising amorphous Cariprazine hydrochloride premix as claimed in claim 8 along with one or more pharmaceutical excipients.
16. The pharmaceutical composition as claimed in claim 15, wherein the composition is formulated into various dosage forms selected from powder, granules, capsules, tablets, pellets.
17. A Pharmaceutical complex of Cariprazine hydrochloride and cyclodextrin.
18. The pharmaceutical complex as claimed in claim 17, wherein, the cyclodextrin is selected from the group consisting of a- cyclodextrin, β- cyclodextrin, and γ-cyclodextrin, and their respective derivatives.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115400099A (en) * | 2021-05-26 | 2022-11-29 | 上海博志研新药物技术有限公司 | Carilazine oral film composition, preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005012266A1 (en) | 2003-08-04 | 2005-02-10 | Richter Gedeon Vegyészeti Gyár Rt. | (thio) carbamoyl-cyclohexane derivatives as d3/d2 receptor antagonists |
| US7943621B2 (en) | 2007-05-11 | 2011-05-17 | Richter Gedeon Nyrt. | Salts of piperazine compounds as D3/D2 antagonists |
| WO2011073705A1 (en) * | 2009-12-17 | 2011-06-23 | Richter Gedeon Nyrt. | Novel process for the preparation of piperazine compounds and hydrochloride salts thereof |
| WO2015056164A1 (en) * | 2013-10-14 | 2015-04-23 | Chemo Research, S.L. | 1,4-cyclohexylamine derivatives and processes for the preparation thereof |
| CN106560179A (en) * | 2015-09-30 | 2017-04-12 | 石药集团中奇制药技术（石家庄）有限公司 | Cariprazine hydrochloride drug composition and preparation method thereof |
-
2018
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005012266A1 (en) | 2003-08-04 | 2005-02-10 | Richter Gedeon Vegyészeti Gyár Rt. | (thio) carbamoyl-cyclohexane derivatives as d3/d2 receptor antagonists |
| US7943621B2 (en) | 2007-05-11 | 2011-05-17 | Richter Gedeon Nyrt. | Salts of piperazine compounds as D3/D2 antagonists |
| WO2011073705A1 (en) * | 2009-12-17 | 2011-06-23 | Richter Gedeon Nyrt. | Novel process for the preparation of piperazine compounds and hydrochloride salts thereof |
| WO2015056164A1 (en) * | 2013-10-14 | 2015-04-23 | Chemo Research, S.L. | 1,4-cyclohexylamine derivatives and processes for the preparation thereof |
| CN106560179A (en) * | 2015-09-30 | 2017-04-12 | 石药集团中奇制药技术（石家庄）有限公司 | Cariprazine hydrochloride drug composition and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| ALLERGAN: "VRAYLAR(TM) (cariprazine) capsules, for oral use", 1 June 2015 (2015-06-01), pages 1 - 30, XP055497846, Retrieved from the Internet <URL:https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204370lbl.pdf> [retrieved on 20180807] * |
| BRUNO C HANCOCK ET AL: "Characteristics and Significance of the Amorphous State in Pharmaceutical Systems", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 86, no. 1, 1 January 1997 (1997-01-01), pages 1 - 12, XP055274556, DOI: 10.1021/js9601896 * |
| SUNIL S. JAMBHEKAR ET AL: "Cyclodextrins in pharmaceutical formulations I: structure and physicochemical properties, formation of complexes, and types of complex", DRUG DISCOVERY TODAY, vol. 21, no. 2, 1 February 2016 (2016-02-01), AMSTERDAM, NL, pages 356 - 362, XP055497919, ISSN: 1359-6446, DOI: 10.1016/j.drudis.2015.11.017 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115400099A (en) * | 2021-05-26 | 2022-11-29 | 上海博志研新药物技术有限公司 | Carilazine oral film composition, preparation method and application thereof |
| WO2022247883A1 (en) * | 2021-05-26 | 2022-12-01 | 上海博志研新药物技术有限公司 | Cariprazine oral dissolving film composition and preparation method therefor and application thereof |
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