WO2009101458A2 - Nouvelles formes polymorphes et amorphes du fumarate de desvenlafaxine - Google Patents

Nouvelles formes polymorphes et amorphes du fumarate de desvenlafaxine Download PDF

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WO2009101458A2
WO2009101458A2 PCT/HU2009/000016 HU2009000016W WO2009101458A2 WO 2009101458 A2 WO2009101458 A2 WO 2009101458A2 HU 2009000016 W HU2009000016 W HU 2009000016W WO 2009101458 A2 WO2009101458 A2 WO 2009101458A2
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WIPO (PCT)
Prior art keywords
desvenlafaxine
polymorph
formula
desvenlafaxine fumarate
fumarate
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PCT/HU2009/000016
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English (en)
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WO2009101458A3 (fr
Inventor
László Pongó
Gyula Simig
József Barkóczy
Balázs VOLK
András DANCSÓ
Zsuzsanna SZENT-KIRÁLLYI
Adrienn HEGEDŰS
Lmre Markovits
Tamás GREGOR
László SZÁZDI
György RUZSICS
Kálmán NAGY
József DEBRECZENI
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Egis Gyógyszergyár Nyilvánosan Működő
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Priority claimed from HU0800091A external-priority patent/HU0800091D0/hu
Priority claimed from HU0900062A external-priority patent/HU230652B1/hu
Application filed by Egis Gyógyszergyár Nyilvánosan Működő filed Critical Egis Gyógyszergyár Nyilvánosan Működő
Priority to EP09709502A priority Critical patent/EP2252573A2/fr
Publication of WO2009101458A2 publication Critical patent/WO2009101458A2/fr
Publication of WO2009101458A3 publication Critical patent/WO2009101458A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having 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
    • C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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 present invention relates to new crystalline polymorph forms of desvenlafaxine fumarate, crystalline polymorph and amorphous forms of desvenlafaxine fumarate, a process for the preparation thereof and pharmaceutical compositions containing the same, furthermore the use of said compositions for the treatment of depression.
  • the present invention relates to three new uniform crystalline monohydrate forms of desvenlafaxine fumarate (1 :1), anhydrous crystalline form of desvenlafaxine fumarate (1:1) and amorphous form of desvenlafaxine fumarate (1 :1), process for the preparation, and pharmaceutical compositions containing thereof, furthermore the use of these compositions for the treatment of depression.
  • ( ⁇ )-1-[2-dimethylamino-1-(4-hydroxyphenyl)- ethyl]-cyclohexanol is a serotonine and noradrenaline reuptake inhibitor having an antidepressant effect.
  • Desvenlafaxine was mentioned first in the description of the European patent No. 112669 by Husbands at al.
  • the equivalent Hungarian patent No. is 199104.
  • the desvenlafaxine base is prepared by debenzylation of the corresponding 4-benzyloxy compound by catalytic hydrogenolysis, then the obtained product is transformed to fumarate salt in a mixture of acetone and ethanol.
  • the obtained fumarate salt is characterized by its melting point (140-142 0 C) and identified as an anhydrous form based on its elementary analysis. The authors do not mention the polymorphic form of the product.
  • the morphological uniformity is very important also from technological point of view, because the different polymorph forms have very different technological properties, e.g. filterability, dryability, solubility and tablettability. Furthermore, it is very important from economical point of view of the process that the used process has to be easily reproducible in industrial scale resulting a morphologically uniform product.
  • the aim of the present invention is the preparation of new, morphologically uniform crystalline forms of desvenlafaxine fumarate salts having such physico-chemical properties and stability which meet the requirements of the pharmaceutical industry and can be produced in industrial scale.
  • This aim is achieved by the preparation of new desvenlafaxine fumarate monohydrate in different polymorph forms, and the preparation of the new anhydrous desvenlafaxine fumarate polymorph and amorphous forms.
  • the characteristic X-ray diffraction peaks of the desvenlafaxine fumarate monohydrate of the polymorph form I of the formula (I) according to the present invention are as follows: [2 ⁇ ( ⁇ 0.2°. 2 ⁇ )]: 5.174; 10.404; 13.872; 14.194; 15.396; 16.319; 16.794; 18.174; 18.887; 20.897; 24.178; 26.236.
  • a further object of the present invention is the anhydrous form of desvenlafaxine fumarate salt of the polymorph form Il of the formula (II) having a powder X-ray diffractogram according to drawing 2 and the XDR data are listed below in Table 2.
  • the X-ray diffractogram was measured under the same conditions as during the examination of the polymorph form I of desvenlafaxine fumarate monohydrate.
  • the most characteristic X-ray diffraction peaks of the anhydrous desvenlafaxine fumarate salt of the polymorph form Il of the formula (II) according to the present invention are as follows: [2 ⁇ ( ⁇ 0.2°. 2 ⁇ )]: 14.777; 16.933; 19.660; 21.275; 26.706.
  • the characteristic X-ray diffraction peaks of the anhydrous desvenlafaxine fumarate of the polymorph form Il of the formula (II) according to the present invention are as follows: [2 ⁇ ( ⁇ 0.2°. 2 ⁇ )]: 10.488; 14.777; 16.933; 17.758; 19.660; 21.275; 22.067; 24.463; 26.256; 26.706.
  • the X-ray diffractogram was measured under the same conditions as during the examination of the polymorph form I of desvenlafaxine fumarate monohydrate.
  • Table 3 Diffraction peaks and relative intensity (>5 %)
  • the X-ray diffractogram was measured under the same conditions as during the examination of the polymorph form I of desvenlafaxine fumarate monohydrate.
  • the most characteristic X-ray diffraction peaks of the desvenlafaxine fumarate monohydrate of the polymorph form III of the formula (I) according to the present invention are as follows: [2 ⁇ ( ⁇ 0.2°. 2 ⁇ )]: 15.402; 16.777; 18.870; 24.148; 26.317.
  • the characteristic X-ray diffraction peaks of the desvenlafaxine fumarate monohydrate of the polymorph form III of the formula (I) according to the present invention are as follows: [2 ⁇ ( ⁇ 0.2°. 2 ⁇ )]: 10.468; 12.007; 14.224; 15.402; 16.777; 17.397; 18.870; 24.148; 25.196; 26.317.
  • a further object of the present invention is to provide a monohydrate of desvenlafaxine fumarate of the formula (I) in polymorph form IV having a powder X-ray diffractogram according to drawing 5 and XDR data as listed below in Table 4.
  • the most characteristic X-ray diffraction peaks of the desvenlafaxine fumarate monohydrate of the polymorph form IV according to the present invention are as follows: [2 ⁇ ( ⁇ 0.2°, 2 ⁇ )]:5.183; 10.398; 14.239; 16.335; 18.257; 26.237.
  • the characteristic X-ray diffraction peaks of the desvenlafaxine fumarate monohydrate of the polymorph form IV of the formula (I) according to the present invention are as follows: [2 ⁇ ( ⁇ 0.2°, 2 ⁇ )]: 5.183; 10.398; 11.592; 14.239; 16.335; 16.933; 18.257; 18.984; 20.914; 24.323; 24.993; 26.237.
  • a further aspect of the present invention is a process for the preparation of desvenlafaxine fumarate monohydrate salt of the polymorph form I of the formula (I).
  • Desvenlafaxine fumarate monohydrate of polymorph form I can be prepared by recrystallization of any kind of polymorph or amorphous forms of desvenlafaxine fumarate from water or from a mixture of water and an aliphatic alcohol. In case the starting compound is desvenlafaxine fumarate monohydrate, an anhydrous aliphatic alcohol can also be used.
  • any kind of polymorph or amorphous forms, solvate, or hydrate forms of desvenlafaxine fumarate is dissolved in water or in a mixture of an aliphatic alcohol and water under heating, then the solution is slowly cooled at a cooling speed between 0.1-2 °C/minute, preferably at a speed between 1-2 °C/minute, then the precipitated crystals are separated and dried.
  • the starting compound is desvenlafaxine fumarate monohydrate
  • an anhydrous aliphatic alcohol can also be used because the water for the formulation of the monohydrate is provided by the starting compound.
  • the term ,recrystallisation relates not only to the generally known processes, in which a crystalline product is dissolved then re-obtained in the same or in another crystalline form with or without seeding, but those processes as well, in which an amorphous form of the compound is dissolved and crystallized, or in which the desvenlafaxine base and fumaric acid subsequently or simultaneously are dissolved in a solvent or a mixture of solvents under heating, then the appropriate crystalline form of desvenlafaxine fumarate is obtained by cooling the solution.
  • the term "separation" means all processes generally used in the pharmaceutical industry, which are suitable for the separation of solid compounds from liquids, e.g. filtration, centrifugation.
  • C 1 -C 4 alcohols preferably methanol, ethanol, 1-propanol, 2-propanol, 1-butanol or tert- butanol can be used as aliphatic alcohol. Most preferably 2- propanol and ethanol can be used.
  • the preparation of the desvenlafaxine fumarate monohydrate of polymorph form I can be carried out by the dissolution of an equimolar amount of the desvenlafaxine base and fumaric acid or the desvenlafaxine fumarate solvate or hydrate, or by the dissolution of the desvenlafaxine base and fumaric acid in a solvent listed above or in a mixture thereof under heating, then the mixture is cooled under stirring at a cooling speed between 0.1-2 °C/minute, preferably at a speed between 1-2 °C/minute to a temperature preferably between 0-25 0 C. During the heating the solvent temperature is preferably elevated to its boiling point.
  • the most preferable way is the dissolution of the desvenlafaxine fumarate or its hydrate, solvate or the mixtures thereof in water or in a mixture of ethanol and water under heating, the mixture is kept at the boiling point of the solvent for 0.5-2 hours, then the reaction mixture is cooled between 0- 25 0 C, the precipitated product is filtered and dried.
  • the above-mentioned polymorph I form of the desvenlafaxine fumarate hydrate can also be prepared by dissolving the desvenlafaxine fumarate hydrate in ethanol under heating, keeping the mixture at the boiling point of the solvent for 0.5-2 hours, then cooling the reaction mixture between 0-25 0 C, filtering and drying the precipitated product.
  • an amorphous or crystalline polymorph form of the anhydrous desvenlafaxine fumarate as starting compound at least as much water is added to the mixture during the recrystallisation process, as enough for the formation of the monohydrated form.
  • a further object of the present invention is a process for the preparation of the anhydrous desvenlafaxine fumarate of the polymorph form Il of the formula(ll).
  • the anhydrous desvenlafaxine fumarate form of the polymorph form Il can be prepared by recrystallisation of any kind of polymorph, amorphous desvenlafaxine fumarate, the solvates or mixtures thereof from an aliphatic alcohol or from an aromatic hydrocarbon type solvent.
  • the anhydrous desvenlafaxine fumarate of the polymorph form Il can be prepared by dissolution of an equimolar amount of the desvenlafaxine base and fumaric acid, or any polymorph or amorphous forms of desvenlafaxine fumarate, solvates, hydrates or their mixtures in an aliphatic alcohol or in an aromatic hydrocarbon type solvent, and in case of using desvenlafaxine hydrate form the solution is dried, then the mixture is cooled, the product is separated and dried.
  • the desvenlafaxine fumarate of any kind of polymorph, amorphous forms, solvates, hydrates or their mixtures is dissolved in an aliphatic alcohol or in an aromatic hydrocarbon type solvent under heating, in case of using the hydrate form of desvenlafaxine fumarate as starting compound, the mixture is dried, the desiccant is eliminated if necessary and the mixture is cooled. If necessary, the precipitated product is separated from the solution containing desvenlafaxine fumarate.
  • desiccants or azeotropic distillation can be used. If necessary, an auxiliary solvent can be used at the azeotropic distillation.
  • Drying is necessary, if the starting compound is hydrate or the used solvent contains water. Drying can be carried out either by using desiccants or azeotropic distillation. Solid desiccants, e.g. natural or artificial zeolites or other molecule sieves or other inorganic desiccants can be used preferably as desiccants. By means of azeotropic distillation the mixture can be dehydrated according to prior art, using biner mixtures e.g. ethanol-water, butanol-water, toluene- water or terner mixtures containing an auxiliary solvent.
  • azeotropic distillation the mixture can be dehydrated according to prior art, using biner mixtures e.g. ethanol-water, butanol-water, toluene- water or terner mixtures containing an auxiliary solvent.
  • Ci-C 4 alcohols preferably methanol, ethanol, 1-propanol, 2-propanol, 1-butanol or tert.-butanol, most preferably ethanol are used as aliphatic alcohol. Any isomers of xylene or a mixture thereof, toluene or benzene, preferably toluene are used as aromatic type hydrocarbon solvent.
  • the recrystallisation for the preparation of an anhydrous desvenlafaxine fumarate form of the polymorph form Il of formula (II) can be carried out by dissolving an equimolar amount of the desvenlafaxine base and fumaric acid, or the desvenlafaxine fumarate, its solvate, hydrate in a solvent or in a mixture of solvents mentioned above under heating, then the solution is cooled under stirring between 0-25 0 C. Most preferably the solvent is heated to its boiling temperature.
  • the anhydrous desvenlafaxine fumarate of the polymorph form Il can be prepared by the dissolution of anhydrous desvenlafaxine fumarate in ethanol or toluene under heating, the obtained mixture is boiled for 0.5-2 hours, then the solution is cooled between 0-25 0 C, the precipitated product is filtered and dried.
  • a further aspect of the present invention is a process for the preparation of the anhydrous and amorphous desvenlafaxine fumarate of the formula (II).
  • Amorphous and anhydrous desvenlafaxine fumarate can be prepared by melting in vacuum of any kind of different polymorph or amorphous forms of desvenlafaxine fumarate, the solvates, hydrates or mixtures thereof, then the melted product is cooled and powdered if necessary.
  • anhydrous and amorphous desvenlafaxine fumarate can be prepared by dissolution of equimolar amount of desvenlafaxine base and fumaric acid, or any kind of different polymorph or amorphous forms of desvenlafaxine fumarate, their solvates, hydrates or their mixtures thereof in a suitable solvent. Following the evaporation of the solvent to dryness, the dried product is cooled and powdered if necessary.
  • An amorphous product can be produced by spray drying process, too.
  • a further embodiment of the present invention is a process for the preparation of desvenlafaxine fumarate monohydrate salt of the polymorph form III of the formula (I).
  • a desvenlafaxine fumarate monohydrate salt of the polymorph form III can be prepared by suspending any kind of polymorph or amorphous desvenlafaxine fumarate, solvate, hydrate or a mixture thereof in water or in a mixture of an aliphatic alcohol and water.
  • anhydrous aliphatic alcohol also can be used as solvent.
  • the desvenlafaxine fumarate, desvenlafaxine monohydrate, the amorphous desvenlafaxine fumarate or mixtures thereof can be suspended in a solvent between 0-60 0 C, then after stirring filtered or centrifugalized.
  • the duration of the stirring is between 0.5-120 hours, preferably 0.5-60 hours, most preferably 24-48 hours.
  • anhydrous aliphatic alcohol also can be used as solvent because the starting compound provides the water necessary.
  • Desvenlafaxine fumarate monohydrate salt of the polymorph form III can be prepared from a suspension which is prepared by dissolution of any kind of polymorph or amorphous desvenlafaxine fumarate, its solvate, hydrate or a mixture thereof in water or in a mixture of an aliphatic alcohol and water, then it is allowed to be evaporated till a suspension is formed, then the obtained product is filtered.
  • anhydrous aliphatic alcohol can also be used as solvent.
  • desvenlafaxine fumarate monohydrate is dissolved in ethanol under heating, then the solution is allowed to cool to room temperature, it is allowed to be evaporated in part, then the product is filtered.
  • the slow crystallisation according to this process leads to the polymorph form III of the desvenlafaxine monohydrate.
  • the process is carried out by dissolution completely or partly of any kind of different polymorph or amorphous forms of desvenlafaxine fumarate, their solvates, hydrates or the mixtures thereof in water or in an aliphatic alcohol or in a mixture thereof at a temperature between 0-100 0 C, then the mixture is kept at a temperature between 0-40 0 C, preferably at room temperature for 4-400 hours, preferably 24-300 hours, the solvent is evaporated or allowed to be evaporated during this period, then the product is separated and dried if necessary.
  • a further aspect of the present invention is a process for the preparation of desvenlafaxine fumarate monohydrate salt of the polymorph form IV of the formula (I).
  • the process for the preparation of desvenlafaxine fumarate monohydrate of polymorph form IV can be carried out by dissolution of an equimolar amount of desvenlafaxine base and fumaric acid or any kind of different polymorph or amorphous forms of desvenlafaxine fumarate, their solvates, hydrates or the mixtures thereof, in water or in an aliphatic alcohol or in a mixture thereof under heating, the obtained solution is cooled at a cooling speed between 3-100 °C/minute, preferably at a cooling speed between 4-10 °C/minute, then the obtained crystalline product is separated and dried if necessary.
  • anhydrous aliphatic alcohol also can be used as solvent.
  • the process for the preparation of desvenlafaxine fumarate monohydrate of polymorph form IV can be carried out by dissolution of an equimolar amount of desvenlafaxine base and fumaric acid or of any kind of polymorph or amorphous forms, solvate or hydrate forms of desvenlafaxine fumarate in water or in a mixture of an aliphatic alcohol and water under heating, then the solution is cooled quickly at a cooling speed between 3-100 °C/minute, preferably at a speed between 4-10 °C/minute, the solution is seeded if necessary, then the precipitated crystalline product is filtered and dried.
  • an anhydrous aliphatic alcohol can also be used because the water for the formulation of the monohydrate is provided by the starting compound.
  • Either polymorph forms I, III or IV of the desvenlafaxine fumarate hydrate of formula (I) according to the present invention can be used as seeding crystal.
  • desvenlafaxine fumarate hydrate CrC 4 alcohols preferably methanol, ethanol, 1-propanol, 2-propanol, 1-butanol or tert.-butanol can be used as aliphatic alcohol. Most preferably 2-propanol or ethanol can be used.
  • desvenlafaxine fumarate hydrate is dissolved in 2- propanol, ethanol or water, or in a mixture of ethanol and water under heating, the solution is cooled between 0-25 0 C at a cooling speed between 3-100 °C/minute, preferably between 4- 10 "C/minute, the precipitated product is separated and dried.
  • the most preferable way is the dissolution of the desvenlafaxine fumarate or its hydrate, solvate or the mixtures thereof in 2-propanol and water under heating, the mixture is kept at the boiling point of the solvent for 0.5-2 hours, then the reaction mixture is cooled between 0-25 0 C using a cooling speed of about 5 °C/minute, the precipitated product is filtered and dried.
  • the preparation of the above-mentioned polymorph IV form of the desvenlafaxine fumarate hydrate can be carried out according to the present invention by dissolution of an equimolar amount of desvenlafaxine base and fumaric acid or any kind of polymorph or amorphous forms, solvate or hydrate forms of desvenlafaxine fumarate in a solvent, the mixture is added to an antisolvent, or an antisolvent is added to the mixture, then the precipitated product is filtered and dried.
  • solvent water or a mixture of water and aliphatic alcohol can be used.
  • the used solvent can be an anhydrous aliphatic alcohol.
  • Ether, nitriles, ketones or saturated hydrocarbon type solvents can be used as antisolvents.
  • ether type solvent preferably diethyl ether, methyl tert.-butyl ether, diisopropyl ether can be used.
  • ketone type solvent aliphatic ketones, e.g. acetone or methyl ethyl ketone can be used.
  • nitrile type solvent saturated aliphatic nitriles e.g. acetonitrile can be used.
  • saturated hydrocarbon type solvent aliphatic or cyclic hydrocarbons e.g. pentane, hexane, heptane, cyclohexane, cycloheptane or a mixture of aliphatic and/or cyclic hydrocarbons e.g. petroleum ether can be used.
  • the desvenlafaxine succinate monohydrate of polymorph form I contains a considerably high amount (0.38%) of a contaminant of the formula (III) having a molecule weight of 262, meanwhile the desvenlafaxine fumarate monohydrate of the polymorph I of the polymorph formula seems to be stable under these conditions, the contaminant mentioned above could not be detectable after the treatment.
  • the thermal stress method models the decomposition of the active ingredients in a pharmaceutical composition in an accelerated way. The result of this test shows that the desvenlafaxine fumarate salt will considerable more stable in a pharmaceutical composition than the succinate salt.
  • a further embodiment of the present invention is a pharmaceutical composition containing as active ingredient desvenlafaxine fumarate monohydrate of polymorph forms I 1 Il or IV, or anhydrous desvenlafaxine fumarate of polymorph form II, or anhydrous desvenlafaxine fumarate in amorphous form, or mixtures thereof and solid or fluid pharmaceutically accepted excipients.
  • compositions according to the present invention can be administered orally or parenterally.
  • the orally administered compositions can be e.g. tablets, capsules, film tablets, elixirs, suspensions or emulsions.
  • Pharmaceutical compositions for parenteral use can be compositions for venous or intramuscular injections.
  • the pharmaceutical composition according to the present invention can contain the usual pharmaceutical carriers and auxiliary agents.
  • carrier e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacant, methyl cellulose, sodium carboxymethylcellulose, waxes having a low melting point, cocoa-butter etc. can be used.
  • the carrier is generally the material of the capsule, therefore a further carrier is not necessary.
  • Losengs and sachets are considered as oral pharmaceutical compositions too. Tablets, powders, capsules, pills sachets and losengs are especially suitable solid oral dosage forms.
  • Suppositories contain waxes having a low melting point (e.g. a mixture of fatty acid glycerides or cocoa butter) as carrier.
  • a low melting point e.g. a mixture of fatty acid glycerides or cocoa butter
  • the wax is melted, the active ingredient is homogenised in the melt, then the melted mixture is poured into an appropriate mould and allowed to cool and solidify.
  • Tablets can be prepared by mixing the active compounds with appropriate carriers in a suitable ratio and the mixture is pressed into tablets having the desired form and size.
  • Powders are prepared by mixing of the finely powdered active ingredients and carriers.
  • liquid compositions controlled release liquid compositions, suspensions, solutions or emulsions can also be used.
  • the solutions containing water or propyleneglycol are preferable.
  • Compositions for parenteral use can be prepared as an aqueous solution containing polyethyleneglycol.
  • Suspensions for oral use can be prepared by suspension of the active ingredient in water, in the presence of semifluid materials (e.g. natural or artificial gums, waxes, methylcellulose, sodium carboxymethylcellulose or other inert suspension agents).
  • semifluid materials e.g. natural or artificial gums, waxes, methylcellulose, sodium carboxymethylcellulose or other inert suspension agents.
  • compositions are transformed to a fluid composition just before the use and is then administered.
  • the fluid compositions can be solutions, suspensions or emulsions which can contain beside the active ingredient colouring agents, flavouring agents, stabilizing agents, buffers, natural or artificial sweeteners, dispersants and thickeners etc.
  • the pharmaceutical compositions according to the present invention are prepared as unit dosage forms.
  • Unit dosage forms contain a preferred amount of the active ingredient.
  • the unit dosage forms can be marketed in packaged form, which packages contain distinct amounts of the pharmaceutical compositions (e.g. packaged tablets, capsules, powder in bottles or in ampulles).
  • the term unit dosage form refers to capsules, tablets, sachets, losengs and the packages containing thereof.
  • a further object of the present invention is to provide processes for the preparation of pharmaceutical compositions by mixing desvenlafaxine fumarate monohydrate of polymorph forms I or III, or IV 1 or anhydrous desvenlafaxine fumarate of polymorph form Il or of amorphous form, or a mixture thereof with pharmaceutically acceptable solid or liquid carriers and/or auxiliary agents and forming this mixture to a galenic form.
  • compositions according to the present invention are prepared by processes generally used in pharmaceutical industry.
  • the pharmaceutical compositions may contain further pharmaceutical active ingredients if necessary.
  • the usual daily dose of the desvenlafaxine fumarate monohydrate of polymorph form I of formula (I) or anhydrous desvenlafaxine fumarate of polymorph form Il of formula (II) or amorphous form, or desvenlafaxine fumarate monohydrate of polymorph form III of formula (I), or desvenlafaxine fumarate monohydrate of polymorph form IV of formula (I), or their mixtures is between 2-200 mg, which depends on all the circumstances (e.g. the health conditions of the patient, the seriousness of the sickness and the body weight etc.) and is determined by the doctor.
  • a further embodiment of the present invention is the use of the desvenlafaxine fumarate monohydrate of polymorph form I of formula (I) or anhydrous desvenlafaxine fumarate of polymorph form Il of formula (II) or amorphous form of formula (II), or desvenlafaxine fumarate monohydrate of polymorph form III of formula (I), or desvenlafaxine fumarate monohydrate of polymorph form IV of formula (I), as pharmaceutical active ingredient.
  • a further embodiment of the present invention is particularly the use of the desvenlafaxine fumarate monohydrate of polymorph form I of formula (I) or anhydrous desvenlafaxine fumarate of polymorph form Il of formula (II) or amorphous form of formula (II), or desvenlafaxine fumarate monohydrate of polymorph form III ' of formula (I), or desvenlafaxine fumarate monohydrate of polymo ⁇ h form IV of formula (I), for the preparation of a pharmaceutical composition for the treatment and/or prevention of depression, generalized anxiety disorder, panic disorder, social phobia, attention deficit disorder without hyperactivity or hyperactivity with attention deficit disorder.
  • a further embodiment of the present invention is the use of the desvenlafaxine fumarate monohydrate of polymorph form I of formula (I) or anhydrous desvenlafaxine fumarate of polymorph form Il of formula (II) or amorphous form of formula (II), or desvenlafaxine fumarate monohydrate of polymorph form III of formula (I), or desvenlafaxine fumarate monohydrate of polymorph form IV of formula (I), for the treatment or prevention of depression, generalized anxiety disorder, panic disorder, social phobia, attention deficit disorder without hyperactivity or hyperactivity with attention deficit disorder by administering a pharmaceutically effective amount of desvenlafaxine fumarate monohydrate of polymorph form I of formula (I) or anhydrous desvenlafaxine fumarate of polymorph form Il of formula (II) or amorphous form of formula (II), or desvenlafaxine fumarate monohydrate of polymorph form III of formula (I) 1 or desvenlafaxine fumarate monohydrate of polymorph form IV of formula (I), to the patient in
  • each active ingredient of the present invention namely the ( ⁇ )-1-[2-dimethylamino-1-(4- methoxy-phenyl)-ethyl]-cyclohexanol fumarate monohydrate of polymorph form I of formula (I), the anhydrous desvenlafaxine fumarate of polymorph form Il of formula (II), the amorphous form of formula (II), the desvenlafaxine fumarate monohydrate of polymorph form III of formula (I), the desvenlafaxine fumarate monohydrate of polymorph form IV of formula (I), is that they are morphologically uniform. Due to the morphological unity these compounds have reproducible dissolution rate, biological availability, chemical stability and industrial usability, e.g. filterability, tablettability etc. The new polymorph and amorphous compounds according to the present invention can be prepared easily in industrial scale too.
  • the powder X-ray diffractogram of the product corresponds to the figure 1.
  • Desvenlafaxine fumarate monohydrate polymorph form I In a 250 cm 3 vessel 4.0 g of desvenlafaxine fumarate monohydrate and 120 ml of ethanol are added. The mixture is heated under stirring up to its boiling point, then this temperature is kept for 0.5 hours. During this period the compound is dissolved completely. Following the complete dissolution the reaction mixture is cooled to 30°C at a speed of 1.5 °C/min under stirring of an rpm 120 min "1 . The obtained crystalline suspension is cooled between 0-5 0 C at the same cooling speed, then stirred at this temperature for 0.5 hour. Having finished the stirring the suspension is filtered, washed with a few amount of ethanol having a temperature between 0-5 0 C and dried at 35-40 0 C until constant weight.
  • the powder X-ray diffractogram of the product corresponds to the figure 1.
  • the powder X-ray diffractogram of the product corresponds to the Figure 3.
  • the powder X-ray diffractogram of the product corresponds to the Figure 1.
  • the powder X-ray diffractogram of the product corresponds to the Figure 2.
  • the suspension is heated to 50 0 C under stirring and kept at this temperature for 24 hours. Having finished the stirring the suspension is filtered and dried at 45-50 0 C until constant weight.
  • the powder X-ray diffractogram of the product corresponds to the Figure 4.
  • the powder X-ray diffractogram of the product corresponds to the figure Figure 4.
  • the powder X-ray diffractogram of the product corresponds to the figure Figure 4.
  • the powder X-ray diffractogram of the product corresponds to the Figure 4.
  • the powder X-ray diffractogram of the product corresponds to the Figure 4.
  • Desvenlafaxine fumarate monohydrate polymorph form IV In a 250 cm 3 vessel 5 g of desvenlafaxine fumarate monohydrate and 175 cm 3 of 2-propanol are added. The suspension is heated to its boiling point and kept at this temperature for 0.5 hour. During this period the crystals are dissolved completely. Having finished the dissolution of crystalline suspension is cooled to 25°C at a speed of 5 °C/min under stirring of an rpm 120 rnin "1 , then it is stirred at this temperature for one hour. Having finished the stirring the suspension is cooled to O 0 C, filtered, washed with a few amount of 2-propanol having a temperature between 0-5 °C and dried at 45-50 0 C until constant weight. Thus 3.30 g of title product are obtained. Chemical purity (HPLC) ⁇ 99,5 %.
  • a 250 cm 3 vessel 1.0 g of desvenlafaxine fumarate monohydrate and 20 cm 3 of methanol are added. The mixture is kept at 25 °C for 0.5 hour. The crystals are dissolved completely during this period. After the dissolution 200 cm 3 of acetone are added to the solution under stirring of an rpm 120 min "1 . The obtained crystalline suspension is stirred for 0.5 hour at this temperature. Having finished the stirring the suspension is filtered, washed with a few amount of acetone having a temperature of 25°C and dried at 45-50 0 C until constant weight.
  • the powder X-ray diffractogram of the product corresponds to the Figure 5.
  • a 250 cm 3 vessel 6.0 g of desvenlafaxine fumarate monohydrate and 150 cm 3 of 2-propanol are added. The mixture is heated to its boiling point under stirring, then kept at this temperature for 0.5 hour. Crystals are dissolved completely during this period. After complete dissolution of the crystals the vessel is cooled at a speed of 7 °C/min in an ice bath under stirring of a rpm 120 min "1 until the solution reaches a temperature between 0-5 0 C, seeded with desvenlafaxine fumarate monohydrate of polymorph form IV, then stirred for 2 hour at this temperature. Having finished the stirring the suspension is filtered, washed with a few amount of 2-propanol having a temperature between 0-5 0 C and dried at 20-30 0 C until constant weight.

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Abstract

La présente invention porte sur de nouvelles formes polymorphes et amorphes du fumarate de desvenlafaxine répondant à la formule chimique (II), sur les formes polymorphes I ou III ou IV du fumarate de desvenlafaxine monohydraté et sur leurs procédés de préparation.
PCT/HU2009/000016 2008-02-14 2009-02-13 Nouvelles formes polymorphes et amorphes du fumarate de desvenlafaxine WO2009101458A2 (fr)

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HU0800091A HU0800091D0 (en) 2008-02-14 2008-02-14 Novel polymorphs and amorph forms of desvenlafaxine fumarate
HUP0800091 2008-02-14
HU0900062A HU230652B1 (hu) 2009-02-04 2009-02-04 Desvenlafaxine fumarát monohidrát új polimorf módosulata
HUP0900062 2009-02-04

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011121452A2 (fr) 2010-03-29 2011-10-06 Pliva Hrvatska D.O.O. Formes cristallines du fumarate de o-desméthylvenlafaxine
ES2648369A1 (es) * 2016-06-29 2018-01-02 Alparis, S.A. De C.V. Nuevas formas sólidas de desvenlafaxina

Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0112669A2 (fr) * 1982-12-13 1984-07-04 American Home Products Corporation Dérivés de phényléthylamines et leurs produits intermédiaires
WO2000076955A1 (fr) * 1999-06-15 2000-12-21 American Home Products Corporation Enantiomeres de o-desmethyl venlafaxine
WO2009070311A2 (fr) * 2007-11-26 2009-06-04 Teva Pharmaceutical Industries Ltd. Formes cristallines de fumarate de o-desméthylvenlafaxine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0112669A2 (fr) * 1982-12-13 1984-07-04 American Home Products Corporation Dérivés de phényléthylamines et leurs produits intermédiaires
WO2000076955A1 (fr) * 1999-06-15 2000-12-21 American Home Products Corporation Enantiomeres de o-desmethyl venlafaxine
WO2009070311A2 (fr) * 2007-11-26 2009-06-04 Teva Pharmaceutical Industries Ltd. Formes cristallines de fumarate de o-desméthylvenlafaxine

Non-Patent Citations (1)

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Title
YARDLEY J P ET AL: "2-PHENYL-2-(1-HYDROXYCYCLOALKYL)ETHYLAMIN E DERIVATIVES: SYNTHESIS AND ANTIDEPRESSANT ACTIVITY" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US, vol. 33, no. 10, 1 October 1990 (1990-10-01), pages 2899-2905, XP000996354 ISSN: 0022-2623 cited in the application *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011121452A2 (fr) 2010-03-29 2011-10-06 Pliva Hrvatska D.O.O. Formes cristallines du fumarate de o-desméthylvenlafaxine
WO2011121452A3 (fr) * 2010-03-29 2011-12-29 Pliva Hrvatska D.O.O. Formes cristallines du fumarate de o-desméthylvenlafaxine
US8569371B2 (en) 2010-03-29 2013-10-29 Pliva Hrvatska D.O.O. Crystal forms of O-desmethylvenlafaxine fumarate
KR101409554B1 (ko) 2010-03-29 2014-06-19 플리바 흐르바츠카 디.오.오. Ｏ-데스메틸벤라팍신 푸마레이트의 결정형
ES2648369A1 (es) * 2016-06-29 2018-01-02 Alparis, S.A. De C.V. Nuevas formas sólidas de desvenlafaxina

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