WO2018229794A1 - Forme amorphe de cariprazine - Google Patents

Forme amorphe de cariprazine Download PDF

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Publication number
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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WO
WIPO (PCT)
Prior art keywords
cariprazine
cariprazine hydrochloride
amorphous
solvent
premix
Prior art date
Application number
PCT/IN2018/050385
Other languages
English (en)
Inventor
Annie VERGHESE
Geena Malhotra
Original Assignee
Cipla Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cipla Limited filed Critical Cipla Limited
Publication of WO2018229794A1 publication Critical patent/WO2018229794A1/fr

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Classifications

    • 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
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une forme amorphe de cariprazine, un procédé de fabrication ; un prémélange de cariprazine amorphe et des compositions pharmaceutiques de celle-ci.
PCT/IN2018/050385 2017-06-13 2018-06-12 Forme amorphe de cariprazine WO2018229794A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201721020643 2017-06-13
IN201721020643 2017-06-13

Publications (1)

Publication Number Publication Date
WO2018229794A1 true WO2018229794A1 (fr) 2018-12-20

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PCT/IN2018/050385 WO2018229794A1 (fr) 2017-06-13 2018-06-12 Forme amorphe de cariprazine

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022247883A1 (fr) * 2021-05-26 2022-12-01 上海博志研新药物技术有限公司 Composition de film à dissolution orale de cariprazine, procédé de préparation associé et application associée

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005012266A1 (fr) 2003-08-04 2005-02-10 Richter Gedeon Vegyészeti Gyár Rt. Derives de (thio) carbamoyl-cyclohexane utilises en tant qu'antagonistes des recepteurs d3/d2
US7943621B2 (en) 2007-05-11 2011-05-17 Richter Gedeon Nyrt. Salts of piperazine compounds as D3/D2 antagonists
WO2011073705A1 (fr) * 2009-12-17 2011-06-23 Richter Gedeon Nyrt. Nouveau procédé pour la préparation de composés de pipérazine et de sels chlorhydrates de ceux-ci
WO2015056164A1 (fr) * 2013-10-14 2015-04-23 Chemo Research, S.L. Dérivés de 1,4-cyclohexylamine et leurs procédés de préparation
CN106560179A (zh) * 2015-09-30 2017-04-12 石药集团中奇制药技术（石家庄）有限公司 盐酸卡利拉嗪药物组合物及其制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005012266A1 (fr) 2003-08-04 2005-02-10 Richter Gedeon Vegyészeti Gyár Rt. Derives de (thio) carbamoyl-cyclohexane utilises en tant qu'antagonistes des recepteurs d3/d2
US7943621B2 (en) 2007-05-11 2011-05-17 Richter Gedeon Nyrt. Salts of piperazine compounds as D3/D2 antagonists
WO2011073705A1 (fr) * 2009-12-17 2011-06-23 Richter Gedeon Nyrt. Nouveau procédé pour la préparation de composés de pipérazine et de sels chlorhydrates de ceux-ci
WO2015056164A1 (fr) * 2013-10-14 2015-04-23 Chemo Research, S.L. Dérivés de 1,4-cyclohexylamine et leurs procédés de préparation
CN106560179A (zh) * 2015-09-30 2017-04-12 石药集团中奇制药技术（石家庄）有限公司 盐酸卡利拉嗪药物组合物及其制备方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
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 (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022247883A1 (fr) * 2021-05-26 2022-12-01 上海博志研新药物技术有限公司 Composition de film à dissolution orale de cariprazine, procédé de préparation associé et application associée

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