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WO2003042161A1 - Polymorphes de chlorhydrate de venlafaxine - Google Patents

Polymorphes de chlorhydrate de venlafaxine Download PDF

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Publication number
WO2003042161A1
WO2003042161A1 PCT/HU2002/000121 HU0200121W WO03042161A1 WO 2003042161 A1 WO2003042161 A1 WO 2003042161A1 HU 0200121 W HU0200121 W HU 0200121W WO 03042161 A1 WO03042161 A1 WO 03042161A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystalline form
hydrochloride
ethyl
cyclohexanol
dimethylamino
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/HU2002/000121
Other languages
English (en)
Inventor
József Barkóczy
Péter KÓTAY NAGY
Gyula Simig
Károly HORVÁTH
Zsuzsa SZENT KIRÁLLYI
Béla FARKAS
Tamás GREGOR
Kálmán NAGY
György Krasznai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
Original Assignee
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
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 Egyt Gyogyszervegyeszeti Gyar, Egis Pharmaceuticals PLC filed Critical Egyt Gyogyszervegyeszeti Gyar
Publication of WO2003042161A1 publication Critical patent/WO2003042161A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention relates to new polymorphs of venlafaxine hydrochloride, a process for the preparation thereof, pharmaceutical compositions containing the new polymorphs and use thereof for the treatment of depression.
  • the invention is concerned with new crystalline forms I, II and III of venlafaxine hydrochloride, a process for the preparation thereof, pharmaceutical compositions containing the new polymorphs and use thereof for the treatment of depression.
  • Venlafaxine was first described in EP 112,669 which corresponds to HU 199,204. According to this patent specification venlafaxine base is prepared by chromatography and the base is converted into the hydrochloride salt by reacting with an isopropanol solution of hydrogen chloride. No reference is made to any crystalline form ofthe product.
  • venlafaxine base is dissolved in ethyl acetate and a solution of hydrogen chloride in 2-propanol is added to the solution. There is no teaching relating to the polymorphy of the product obtained.
  • venlafaxine hydrochloride is prepared by reacting the base with a solution of hydrogen chloride in 2-propanol.
  • the patent specification is silent in teaching further details ofthe process or the crystalline form of the product.
  • venlafaxine hydrochloride is a polymorph substance. Two polymorphs are mentioned, one of them being regarded as a kinetical product of the crystallization process. It is also disclosed that on heating in the crystallization solvent one of the polymers is transformed into the other polymorph. It is not disclosed, however, which solvent is used for recrystallization. According to a further disclosure the polymorphs differ from each other in their IR spectrum and X- ray power diffraction pattern. However neither the IR spectra nor the X-ray powder-diffraction patterns are given. The text is completely silent in teaching the conditions used in the preparation ofthe polymorphs (solvent etc).
  • racemic venlafaxine hydrochloride exists in the form of two polymorphs and the single crystal X-ray diffraction pattern of one of the polymorphs could be prepared. However no details of the preparation ofthe single crystal are disclosed and there is no disclosure ofthe X-ray powder-diffraction patterns either.
  • the powder diffraction pattern ofthe new crystalline polymorphs ofthe present invention is determined under the following conditions:
  • the measurement is continuous: ⁇ /2 ⁇ scan: 4.5° - 40.00° 2 ⁇
  • Sample surface plain, width 0.5 mm, in quartz sample holder, measured and stored at room temperature.
  • Crystalline form I ( ⁇ )-l-[2-dimethylamino-l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride ofthe Formula I and hydrates thereof are prepared by recrystallizing or suspending amorphous or crystalline form II or III ( ⁇ )-l-[2-dimethylamino- l-(4-methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof from a mixture of a lower alkanol and water, or a mixture of a water-miscible dipolar aprotic organic solvent and water.
  • lower alkanol preferably methanol, ethanol, n-propanol, 2- propanol, n-butanol or tert. butanol, particularly ethanol or 2- propanol can be used.
  • dipolar aprotic solvent preferably acetonitrile or acetone can be used.
  • the mixture of lower alkanol and water or the mixture ofthe dipolar aprotic solvent and water can contain 0.01-5 by weight % of water.
  • Recrystallization can be preferably carried out by dissolving amorphous or crystalline form II or III ( ⁇ )-l-[2-dimethylamino- l-(4-methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof in the solvent under heating, and thereafter cooling the solution under stirring, preferably to 0-5 °C. It is preferred to heat the solution to 60-65 °C.
  • the suspending procedure can be accomplished by suspending amorphous or crystalline form II or III ( ⁇ )-l-[2-dimethylamino-l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof in the solvent at about room temperature, stirring the suspension and thereafter filtering or centrifuging the product.
  • the suspension is preferably stirred for 2-120 hours.
  • Crystalline form II ( ⁇ )-l-[2-dimethylamino-l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride ofthe Formula I and hydrates thereof are prepared by recrystallizing crystalline form I or III ( ⁇ )-l-[2-dimethylamino-l-(4-methoxy-phenyl)-ethyl]- cyclohexanol-hydrochloride or a hydrate thereof from an anhydrous lower alkanol or an anhydrous mixture of a dipolar aprotic solvent and a lower alkanol.
  • lower alkanol preferably methanol, ethanol, n-propanol, 2- propanol, n-butanol or tert. butanol, particularly 2-propanol can be used.
  • a mixture of a dipolar aprotic solvent and a lower alkanol preferably a mixture of ethyl acetate and methanol or ethyl acetate and 2-propanol can be used.
  • One may proceed particularly preferably by using a 4:1 vol. mixture of ethyl acetate and methanol.
  • Recrystallization can be carried out by dissolving crystalline form I or III ( ⁇ )-l-[2-dimethylamino-l-(4-methoxy-phenyl)- ethyl]-cyclohexanol-hydrochloride or a hydrate thereof in the solvent under heating, cooling the solution and isolating the crystalline form II polymorph.
  • One may proceed preferably by heating the solution to the boiling point of the solvent, thereafter cooling to 0-5°C and isolating the precipitated crystalline form II ( ⁇ )-l-[2-dimethylamino-l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride.
  • Crystalline form III ( ⁇ )-l-[2-dimethylamino-l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride ofthe Formula I and hydrates thereof are prepared by recrystallizing or suspending crystalline form I or II ( ⁇ )-l-[2-dimethylamino-l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof from a mixture of a dipolar aprotic organic solvent and water.
  • aprotic solvent preferably a halogenated aliphatic hydrocarbon (e.g. dichloro ethane, dichloro methane or chloroform) or an ester (e.g. ethyl acetate) can be used.
  • a halogenated aliphatic hydrocarbon e.g. dichloro ethane, dichloro methane or chloroform
  • an ester e.g. ethyl acetate
  • One may proceed preferably by using dichloro methane, dichloro ethane or ethyl acetate as aprotic solvent.
  • the mixture ofthe aprotic solvent and water can contain preferably 2-5 by weight % of water.
  • the process can be preferably carried out by dissolving or suspending crystalline form I or II ( ⁇ )-l-[2-dimethylamino-l- (4-methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof in the solvent at 20-40°C, stirring and thereafter isolating the crystalline form III ( ⁇ )-l-[2-dimethylamino-l-(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride polymorph. Stirring can be continued for a longer period of time, preferably for 20-240 hours.
  • the precipitated crystalline form III polymorph is isolated, preferably by filtration or centrifuging.
  • a pharmaceutical composition comprising as active ingredient crystalline form I, II or III ( ⁇ )-l-[2-dimethylamino-l-(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof in admixture with inert solid or liquid pharmaceutical carriers and/or auxiliary agents.
  • compositions according to the present invention can be administered preferably orally or parenterally.
  • Oral pharmaceutical compositions may be e.g. tablets, capsules, dragees, solutions, elixirs, suspensions or emulsions.
  • parenteral administration preferably intravenous or intramuscular injections can be used.
  • the pharmaceutical composition according to the present invention can contain conventional pharmaceutically acceptable carriers and/or auxiliary agents.
  • carrier e.g. magnesium carbonate, magnesium stearate, talc, lactose, pectine, dextrine, starch gelatine, tragacanth, methyl cellulose, sodium carboxy methyl cellulose, lower melting wax, cocoa butter etc.
  • Soft gelatine capsules can also be prepared without a carrier whereby the capsule material plays the role ofthe carrier.
  • Oral pharmaceutical compositions can be preferably prepared in the form of tablets, powders, capsules, cachets, pills, losenges.
  • the suppositories preferably contain as carrier a lower melting wax (e.g. a mixture of fatty acid triglycerides or cocoa butter). Suppositories are prepared preferably by melting the wax and uniformly distributing the active ingredient in the melt. The homogenous melt mixture is poured into a form of suitable size and allowed to solidify under cooling. Tablets can be prepared by admixing the active ingredient with suitable carriers and auxiliary agents and pressing the mixture into tablets ofthe desired weight and size.
  • a lower melting wax e.g. a mixture of fatty acid triglycerides or cocoa butter
  • Powders can be prepared by admixing the finally powdered active ingredient with the finely powdered carriers.
  • the liquid compositions can be solutions, suspensions or emulsions.
  • the active ingredient can also be released from the composition in a controlled or sustained manner.
  • Liquid compositions for parenteral administration can be preferably prepared in the form of aqueous polyethylene glycol solutions.
  • Orally administrable liquid solutions can be prepared by dissolving the active ingredient in water in the presence of further additives e.g. stabilizers, emulsifiers, wetting agents, colourants, thickening agents etc.
  • further additives e.g. stabilizers, emulsifiers, wetting agents, colourants, thickening agents etc.
  • Liquid compositions for oral administration can be prepared by suspending the active ingredient in water in the presence of viscous additives (e.g. natural or synthetic gums, resins, methyl cellulose, sodium carboxy methyl cellulose or other known suspending agents).
  • viscous additives e.g. natural or synthetic gums, resins, methyl cellulose, sodium carboxy methyl cellulose or other known suspending agents.
  • the liquid compositions can be solutions, suspensions or emulsions which contain in addition to the active ingredient further additives, e.g. colourants, flavourants, stabilizers, buffers, synthetic or natural sweeteners, dispersing agents, thickening agents etc.
  • further additives e.g. colourants, flavourants, stabilizers, buffers, synthetic or natural sweeteners, dispersing agents, thickening agents etc.
  • compositions according to the present invention can be preferably prepared in dosage unit form.
  • dosage units contain the desired amount of the active ingredient.
  • the dosage units can be put on the market in packaged form which contain discrete amounts ofthe composition (e.g. packaged tablets, capsules, vials or ampoules which contain a powder).
  • the term "dosage unit" relates to the tablets, capsules, losenges per se and also to the packaged form which contains the desired number of dosage units.
  • a process for the preparation of the pharmaceutical composition described above which comprises admixing crystalline form I, II or III ( ⁇ )-l-[2-dimethylamino-l-(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof with inert solid or liquid pharmaceutical carriers and/or auxiliary agents and bringing the mixture to galenic form.
  • compositions can be prepared by methods of pharmaceutical industry known per se.
  • compositions ofthe present invention can contain in addition to crystalline form I, II or III ( ⁇ )-l-[2- dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride or a hydrate thereof further compatible pharmaceutical active ingredients.
  • the daily dose of crystalline form I, II or III ( ⁇ )-l-[2- dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride or a hydrate thereof depends on various factors (e.g. the age, condition and body weight ofthe patient, the seriousness of the disease to be treated, the form of administration) and is determined by the physician.
  • crystalline form I, II or III ( ⁇ )-l-[2-dimethylamino-l-(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof, for use as pharmaceutical active ingredient.
  • crystalline form I, II or III ( ⁇ )-l-[2-dimethylamino-l-(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof, for use as antidepressant.
  • crystalline form I, II or III ( ⁇ )-l-[2- dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride or a hydrate thereof for the treatment of depression.
  • a method of treatment of depression which comprises administering to the patient in need of such treatment a therapeutically efficient amount of crystalline form I, II or III ( ⁇ )- 1 -[2-dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]- cyclohexanol-hydrochloride or a hydrate thereof.
  • the advantage ofthe present invention is that the new ( ⁇ )-l-[2- dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride polymorphs are of a uniform morphology and therefore possess well reproducible properties in relation to dissolution velocity, bioavailability, chemical stability and working-up (filtrability, drying, tabletting).
  • the new polymo ⁇ hs ofthe present invention can be manufactured in a reproducible manner on industrial scale too.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Emergency Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne de nouvelles formes cristallines I, II et III de (+/-)-1-[2-diméthylamino-1-(4-méthoxy-phényl)-éthyl]-cyclohexanol-chlorhydrate représenté par la formule (I) ainsi que des hydrates desdites formes cristallines. Les nouveaux polymorphes selon l'invention présentent une morphologie uniforme et peuvent être utilisés en thérapie en tant qu'antidépressif.
PCT/HU2002/000121 2001-11-13 2002-11-13 Polymorphes de chlorhydrate de venlafaxine Ceased WO2003042161A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU0104872A HUP0104872A3 (en) 2001-11-13 2001-11-13 New polymorphic forms of venlafaxine, process for their preparation, pharmaceutical compositions containing them and their use
HUP0104872 2001-11-13

Publications (1)

Publication Number Publication Date
WO2003042161A1 true WO2003042161A1 (fr) 2003-05-22

Family

ID=89979881

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU2002/000121 Ceased WO2003042161A1 (fr) 2001-11-13 2002-11-13 Polymorphes de chlorhydrate de venlafaxine

Country Status (2)

Country Link
HU (1) HUP0104872A3 (fr)
WO (1) WO2003042161A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0797991A1 (fr) * 1996-03-25 1997-10-01 American Home Products Corporation Compositions de venlafaxine à libération prolongée
WO2002036542A1 (fr) * 2000-10-31 2002-05-10 Ciba Specialty Chemicals Holding Inc. Formes cristallines de chlorhydrate de venlafaxine
WO2002046140A1 (fr) * 2000-12-07 2002-06-13 Dr. Reddy's Laboratories Ltd. Nouvelles formes polymorphes cristallines d'hydrochlorure de venlafaxine et procede permettant leur fabrication
WO2002045658A2 (fr) * 2000-10-19 2002-06-13 Teva Pharmaceutical Industries Ltd. Base cristalline de venlafaxine et nouveaux polymorphes de chlorhydrate de venlafaxine, et preparation de ceux-ci

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0797991A1 (fr) * 1996-03-25 1997-10-01 American Home Products Corporation Compositions de venlafaxine à libération prolongée
WO2002045658A2 (fr) * 2000-10-19 2002-06-13 Teva Pharmaceutical Industries Ltd. Base cristalline de venlafaxine et nouveaux polymorphes de chlorhydrate de venlafaxine, et preparation de ceux-ci
WO2002036542A1 (fr) * 2000-10-31 2002-05-10 Ciba Specialty Chemicals Holding Inc. Formes cristallines de chlorhydrate de venlafaxine
WO2002046140A1 (fr) * 2000-12-07 2002-06-13 Dr. Reddy's Laboratories Ltd. Nouvelles formes polymorphes cristallines d'hydrochlorure de venlafaxine et procede permettant leur fabrication

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
VEGA D ET AL: "1-Ä2-(1-HYDROXYCYCLOHEXYL)-2-(4-METHOXYPHENYL)ETHYLÜDIMETHYL-AMMONIUM CHLORIDE (VENLAFAXINE HYDROCHLORIDE)", ACTA CRYSTALOGRAPHICA SECTION C. CRYSTAL STRUCTURE COMMUNICATIONS, MUNKSGAARD, COPENHAGEN, DK, vol. C56, 2000, pages 1009 - 1010, XP001040413, ISSN: 0108-2701 *
YARDLEY J P ET AL: "2-PHENYL-2-(1-HYDROXYCYCLOALKYL)ETHYLAMINE DERIVATIVES: SYNTHESIS AND ANTIDEPRESSANT ACTIVITY", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 33, 1990, pages 2899 - 2905, XP000891765, ISSN: 0022-2623 *

Also Published As

Publication number Publication date
HUP0104872A2 (hu) 2003-08-28
HU0104872D0 (en) 2002-01-28
HUP0104872A3 (en) 2004-04-28

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