WO2009101458A2 - New polymorph and amorphous forms of desvenlafaxine fumarate - Google Patents

New polymorph and amorphous forms of desvenlafaxine fumarate Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
desvenlafaxine
polymorph
formula
desvenlafaxine fumarate
fumarate
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/HU2009/000016
Other languages
French (fr)
Other versions
WO2009101458A3 (en
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
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.)
Egis Pharmaceuticals PLC
Original Assignee
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
Priority claimed from HU0800091A external-priority patent/HU0800091D0/en
Priority claimed from HU0900062A external-priority patent/HU230652B1/en
Application filed by Egis Pharmaceuticals PLC filed Critical Egis Pharmaceuticals PLC
Priority to EP09709502A priority Critical patent/EP2252573A2/en
Publication of WO2009101458A2 publication Critical patent/WO2009101458A2/en
Publication of WO2009101458A3 publication Critical patent/WO2009101458A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

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

Abstract

The present invention relates to new polymorph and amorphous forms of desvenlafaxine fumarate of the chemical formula (II). and I or III, or IV polymorph forms, of desvenlafaxine fumarate monohydrate and processes for the preparation thereof.

Description

NEW POLYMORPH AND AMORPHOUS FORMS OF DESVENLAFAXINE FUMARATE
FIELD OF THE INVENTION
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.
Particularly, 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.
As it is well-known, (±)-1-[2-dimethylamino-1-(4-hydroxyphenyl)- ethyl]-cyclohexanol (INN name: desvenlafaxine) is a serotonine and noradrenaline reuptake inhibitor having an antidepressant effect.
TECHNICAL BACKGROUND OF THE INVENTION
Desvenlafaxine was mentioned first in the description of the European patent No. 112669 by Husbands at al. The equivalent Hungarian patent No. is 199104. According to the example 26 of the patent 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 (140-1420C) and identified as an anhydrous form based on its elementary analysis. The authors do not mention the polymorphic form of the product.
Yardley et al. describe desvenlafaxine fumarate in Table 1 on page 2900 of their publication {J. Med. Chem. 1990, 33, 2899- 2905). Although the product is described as a monohydrate in this article, the melting point is the same as mentioned above (example 26 of the patent EP 112669), i.e. 140-1420C and the yield is 25% in this case. The authors do not mention the polymorph form of the product.
Yardley et al. describe in the international patent application No. WO 00/76955 that fumarate monohydrate salt is prepared from desvenlafaxine base and fumaric acid by the addition of water in a mixture of acetone and methanol. The melting point of the product is between 145-15O0C, the morphology is not observed.
Levi et al. mention three different polymorph forms of desvenlafaxine base (form A, C and D) in the description of the international patent application No. WO 2007/120925. The description contains the infrared spectra of polymorph form A and powder X-ray diffractograms of polymorph forms C and D1 furthermore the processes for the preparation of these polymorph forms.
Four different polymorph forms of desvenlafaxine succinate are disclosed by Hadfield et al. in the description of the international patent application No. WO 02/064543. Three of them are hydrate forms, one anhydrous. The preparation of amorphous form of desvenlafaxine succinate is described too. The obtained products are characterized with their powder X-ray diffractograms, differential scanning calorymetric data (DSC) and thermogravimetric (TG) data. The background of the invention according to the authors is that the properties of the desvenlafaxine fumarate salts mentioned in the description of the US patent application No. 4,535,186 are not suitable for the use for pharmaceutical purposes.
Recently there is a need for morphologically uniform pharmaceutical compounds having high purity, using reproducible processes for the preparation thereof. These are essential conditions to meet the requirements of the processes for the preparation of pharmaceutical compositions. As it is known, the different polymorph forms have very different properties, e.g. dissolution rate, biological usability and chemical stability.
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.
Neither processes, nor analytical data (infrared spectra or powder, or single crystal X-ray diffractogram) have been mentioned yet in the literature referring to morphological uniform crystalline forms of desvenlafaxine fumarate.
SUMMARY OF THE INVENTION
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.
We have found it surprising that the (±)-1-[2-dimethylamino-1- (4-methoxy-phenyl)-ethyl]-cyclohexanol fumarate salt hereafter desvenlafaxine fumarate - can be prepared in different polymorph forms, which are morphologically uniform forms according to the processes described below.
DETAILED DESCRIPTION OF THE INVENTION
It is the object of the present invention to provide monohydrate of (±)-1 -[2-dimethylamino-1 -(4-methoxy-phenyl)-ethyl]- cyclohexanol fumarate salt of the polymorph form I of the formula (I) having a powder X-ray diffractogram according to drawing 1 and the XDR data are listed below in Table 1.
Table 1 Diffraction peaks and relative intensity (>10 %)
Figure imgf000006_0001
Figure imgf000007_0001
Conditions of the power X-ray diffraction measurements:
Equipment: Bruker D8 Advance powder diffractometer
Irradiation: CuKa1 (λ=1.54060 A), CuKa2 (λ=1.54439A)
Voltage: 40 kV
Zero-signal current: 30 mA
Accessories: Gόbel mirror, Soller aperture, sample changer, transmission position.
Referent material: SRM 640c silicon powder Lot. No. H-375.
Continuous measurement Θ/Θ scan: 4°-35.00° 2Θ.
Step: 0.04°
Sample: Unpowdered, measured and stored at room temperature.
The most characteristic X-ray diffraction peaks of the monohydrate of desvenlafaxine fumarate salt of the polymorph form I according to the present invention are as follows: [2Θ (±0.2°. 2Θ)]: 10.404; 14.194; 15.396; 16.794; 26.236.
More particularly, 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: [2Θ (±0.2°. 2Θ)]: 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.
Table 2 Diffraction peaks and relative intensity (>15 %)
Figure imgf000008_0001
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: [2Θ (±0.2°. 2Θ)]: 14.777; 16.933; 19.660; 21.275; 26.706.
More particularly, 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: [2Θ (±0.2°. 2Θ)]: 10.488; 14.777; 16.933; 17.758; 19.660; 21.275; 22.067; 24.463; 26.256; 26.706.
It is a still further object of the present invention to provide the amorphous form of desvenlafaxine fumarate salt of the formula (II) having a powder X-ray diffractogram according to drawing 3.
The X-ray diffractogram was measured under the same conditions as during the examination of the polymorph form I of desvenlafaxine fumarate monohydrate.
It is a still further object of the present invention to provide a monohydrate of desvenlafaxine fumarate salt of the formula (I) of polymorph form III having a powder X-ray diffractogram according to drawing 4 and the XDR data are listed below in Table 3. Table 3 Diffraction peaks and relative intensity (>5 %)
Figure imgf000010_0001
Figure imgf000011_0001
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: [2Θ (±0.2°. 2Θ)]: 15.402; 16.777; 18.870; 24.148; 26.317.
More particularly, 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: [2Θ (±0.2°. 2Θ)]: 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.
Table 4 Diffraction peaks and relative intensity (>5 %)
Figure imgf000012_0001
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 IV according to the present invention are as follows: [2Θ (±0.2°, 2Θ)]:5.183; 10.398; 14.239; 16.335; 18.257; 26.237.
More particularly, 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: [2Θ (±0.2°, 2Θ)]: 5.183; 10.398; 11.592; 14.239; 16.335; 16.933; 18.257; 18.984; 20.914; 24.323; 24.993; 26.237.
We have found it surprising that the melting points of the polymorph forms according to the present invention are significantly different from the monohydrate of desvenlafaxine fumarate which has been described in prior art but has not been characterized by its morphological properties.
While the melting points disclosed in prior art are 140-142 0C (EP 112669 and J. Med. Chem. 1990, 33, 2899-2905) and 145- 150 0C (international patent application No. 00/76955), the melting points of the compounds according to the present invention are as follows:
Table 5
Figure imgf000014_0001
Taking into consideration that the five new forms are chemically pure and morphologically uniform, it is obvious to the person skilled in the art that the cause of the significant difference between the melting points of the new forms and the forms known from the prior art is their different crystalline structures.
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. More particularly, 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. In case 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.
According to the present invention 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.
According to the present invention 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. For the preparation of the above-mentioned polymorph I form of the desvenlafaxine fumarate hydrate C1-C4 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 0C. 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- 250C, 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 0-250C, filtering and drying the precipitated product.
In the case of using 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.
Particularly in case of the preparation of the anhydrous desvenlafaxine of polymorph form Il of formula (II), 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. For drying the reaction mixture 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.
For the preparation of anhydrous desvenlafaxine fumarate form of the polymorph form Il of formula (II) Ci-C4 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 0C. Most preferably the solvent is heated to its boiling temperature.
Most preferably, 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 0-250C, 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.
According to an other embodiment of the present invention the 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. In case of using desvenlafaxine fumarate monohydrate as starting compound anhydrous aliphatic alcohol also can be used as solvent.
In the case of suspension process the desvenlafaxine fumarate, desvenlafaxine monohydrate, the amorphous desvenlafaxine fumarate or mixtures thereof can be suspended in a solvent between 0-60 0C, 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. In case of using desvenlafaxine fumarate monohydrate as starting compound 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. In case of using desvenlafaxine fumarate monohydrate as starting material anhydrous aliphatic alcohol can also be used as solvent. Preferably, 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. Particularly, 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 0C, then the mixture is kept at a temperature between 0-40 0C, 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. In case of using desvenlafaxine fumarate monohydrate as starting compound anhydrous aliphatic alcohol also can be used as solvent.
More particularly, 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. Using desvenlafaxine fumarate monohydrate as starting compound 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.
For the preparation of the above-mentioned polymorph IV form of the desvenlafaxine fumarate hydrate CrC4 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. Preferably, 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 0C 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 0-250C 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. As solvent water or a mixture of water and aliphatic alcohol can be used. In case of using a monohydrate form of desvenlafaxine fumarate as starting compound the used solvent can be an anhydrous aliphatic alcohol. Ether, nitriles, ketones or saturated hydrocarbon type solvents can be used as antisolvents. As ether type solvent preferably diethyl ether, methyl tert.-butyl ether, diisopropyl ether can be used. As ketone type solvent aliphatic ketones, e.g. acetone or methyl ethyl ketone can be used. As nitrile type solvent saturated aliphatic nitriles, e.g. acetonitrile can be used. As 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.
According to the most preferable embodiment of the process desvenlafaxine fumarate monohydrate is dissolved in methanol, then acetone is added to the mixture, the precipitated product is separated and dried.
We found surprisingly that desvenlafaxine fumarate salt according to the present invention is more stable than the succinate salts according to the description of the International patent application No.: 02/064543.
Thermal stability of desvenlafaxine succinate monohydrate polymorph form I of formula (IV) prepared according to the International patent application No. WO 02/064543 was compared with the polymorph I form of desvenlafaxine fumarate monohydrate of the present invention. In course of this process the desvenlafaxine succinate monohydrate polymorph form I and the desvenlafaxine fumarate monohydrate polymorph form I are kept at 100 0C for 24 hours. We found that due to the effect of the 24 hours long thermal treatment 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. These very advantageous properties of the fumarate salts are very important from the point of view of the formulation and storage of a pharmaceutical composition.
A further embodiment of the present invention is a pharmaceutical composition containing as active ingredient desvenlafaxine fumarate monohydrate of polymorph forms I1 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.
The pharmaceutical 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. As 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. In case of capsule compositions 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. 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. As 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.
In course of the preparation of oral liquid compositions the active ingredient is solved in water, then suitable colouring agents, flavouring agents, stabilizing agents and thickeners can be added. 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).
Another group of the pharmaceutical compositions is 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 IV1 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.
Pharmaceutical compositions according to the present invention are prepared by processes generally used in pharmaceutical industry.
Beside the desvenlafaxine fumarate monohydrate of polymorph forms I or III or IV or anhydrous desvenlafaxine fumarate of polymorph form Il or of amorphous form or the mixtures thereof 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 polymoφh 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 need of such treatments.
An advantageous property of 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.
Further details of the present invention are to be found in the following Examples without limiting the scope of protection to said Examples.
The chemical purity of the compounds according to the Examples has been measured by high pressure liquid chromatography (HPLC)
Example 1
Desvenlafaxine fumarate monohydrate polymorph form I
In a 250 cm3 vessel 4.0 g of desvenlafaxine fumarate monohydrate and 120 ml of 2-propanol 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 300C at a speed of
1.5 °C/min under stirring of an rpm 120 min"1. The obtained suspension is cooled between 0-5 0C 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 2-propanol having a temperature between 0-5 0C and dried at 35-40 0C until constant weight.
Thus 3.4 g of title product are obtained having a melting point of
116-118 0C.
The powder X-ray diffractogram of the product corresponds to the figure 1.
Chemical purity (HPLC) >99,5 %.
Elementary analysis based on the formula C20H31NO7: calculated: C % = 60.44; H % = 7.86; N % = 3.52 measured: C % = 60.26; H % = 7.92; N % = 3.45
Example 2
Desvenlafaxine fumarate monohydrate polymorph form I In a 250 cm3 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 0C 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 0C and dried at 35-40 0C until constant weight.
Thus, 3.4 g of title product are obtained having a melting point of 116-118 0C.
The powder X-ray diffractogram of the product corresponds to the figure 1.
Chemical purity (HPLC) >99,5 %.
Elementary analysis based on the formula C20H31NO7: calculated: C % = 60.44; H % = 7.86; N % = 3.52 measured: C % = 60.21 ; H % = 7.95; N % = 3.40
Example 3
Amorphous anhydrous desvenlafaxine fumarate
In a vacuum dryer 1.5 g of venlafaxine fumarate are melted at 150 0C and kept at this temperature for 0.5 hours. The product is allowed to cool to room temperature, meanwhile it is solidified.
Thus, 1.3 g of title product are obtained having a melting point of 90-97 0C.
Chemical purity (HPLC) >99,5 %.
The powder X-ray diffractogram of the product corresponds to the Figure 3.
Elementary analysis based on the formula C2oH29N06: calculated: C % = 63.31 ; H % = 7.70; N % = 3.69 measured: C % = 62.53; H % = 7.90; N % = 3.59
Example 4
Desvenlafaxine fumarate monohydrate polymorph form I
In a 250 cm3 vessel 4.0 g of desvenlafaxine fumarate monohydrate and 40 ml of distillated water 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 300C 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 0C at the same cooling speed, then stirred at this temperature for 0.5 hour. The obtained crystalline suspension is cooled between 5-10 0C 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 distillated water having a temperature between 5-10 0C and dried at 35-40 0C until constant weight.
Thus, 3.3 g of title product are obtained having a melting point of 116-118 0C.
Chemical purity (HPLC) ≥99,5 %.
The powder X-ray diffractogram of the product corresponds to the Figure 1.
Elementary analysis based on the formula C20H31NO7: calculated: C % = 60.44; H % = 7.86; N % = 3.52 measured: C % = 60.38; H % = 7.91 ; N % = 3.46
Example 5
Anhydrous desvenlafaxine fumarate polymorph form Il
In a 250 cm3 vessel 4.0 g of amorphous anhydrous desvenlafaxine fumarate and 20 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 300C at a speed of 1.5 °C/min under stirring of an rpm 120 min'1. The obtained crystalline suspension is cooled further till reaching 0-5 0C 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 0C and dried at 35-40 0C until constant weight. Thus, 3.3 g of title product are obtained having a melting point of 158-16O 0C.
Chemical purity (HPLC) >99,5 %.
The powder X-ray diffractogram of the product corresponds to the Figure 2.
Elementary analysis based on the formula C2oH29N06: calculated: C % = 63.31 ; H % = 7.70; N % = 3.69 measured: C % = 62.95; H % = 7.80; N % = 3.58
Example 6
Anhydrous desvenlafaxine fumarate polymorph form Il
In a 2000 cm3 vessel 1.0 g of desvenlafaxine fumarate monohydrate and 1000 cm3 of toluene are added. The mixture is heated under stirring up to its boiling point, this temperature is kept for 0.5 hours, then 500 cm3 of toluene is evaporated. During this period the compound is dissolved completely. Following the complete dissolution the reaction mixture is cooled to O0C at a speed of 1.8 °C/min under stirring of an rpm 120 min"1. The obtained crystalline suspension is stirred at this temperature for 0.5 hour. Having finished the stirring the suspension is filtered, washed with a few amount of toluene having a temperature between 5-10 0C and dried at 45-50 °C until constant weight. Thus 0.77 g of title product is obtained. Chemical purity (HPLC) ≥99,5 %.
The powder X-ray diffractogram of the product corresponds to the Figure 2. Example 7
Desvenlafaxine fumarate monohydrate polymorph form III
In a 50 cm3 vessel 0.50 g of desvenlafaxine fumarate monohydrate of form IV and 25 cm3 of 2-propanol are added.
The suspension is heated to 50 0C under stirring and kept at this temperature for 24 hours. Having finished the stirring the suspension is filtered and dried at 45-50 0C until constant weight.
Thus 0.30 g of title product is obtained.
Chemical purity (HPLC) >99.5 %.
The powder X-ray diffractogram of the product corresponds to the Figure 4.
Example 8
Desvenlafaxine fumarate monohydrate polymorph form III
In a 2000 cm3 vessel 5 g of desvenlafaxine fumarate monohydrate and 1000 cm3 of ethanol are added. The suspension is heated to its boiling point under stirring and kept at this temperature for 0.5 hours. During this period the compound is dissolved completely. Following the complete dissolution the reaction mixture is cooled to 250C under stirring of an rpm 120 min"1. The obtained solution is allowed to be evaporated in a 10 days period. The residual suspension is filtered and washed with ethanol having a temperature between 5-10 0C then dried at 45-50 0C until constant weight. Thus 4.2 g of title product are obtained.
Chemical purity (HPLC) >99,5 %.
The powder X-ray diffractogram of the product corresponds to the figure Figure 4.
Water content (Karl-Fischer): 4.69%
Example 9
Desvenlafaxine fumarate monohydrate polymorph form III
In a 50 cm3 vessel 0.50 g of desvenlafaxine fumarate monohydrate of form I and 25 cm3 of 2-propanol are added. The suspension is heated to 50 0C under stirring and kept at this temperature for 24 hours. Having finished the stirring the suspension is filtered and dried at 45-50 0C until constant weight.
Thus 0.30 g of title product is obtained.
Chemical purity (HPLC) >99,5 %.
The powder X-ray diffractogram of the product corresponds to the figure Figure 4.
Example 10
Desvenlafaxine fumarate monohydrate polymorph form III
In a 250 cm3 vessel 10 g of desvenlafaxine fumarate monohydrate of form I and 100 cm3 of water are added. The suspension is heated to 50 0C under stirring and kept at this temperature for 24 hours. Following the 24 hours stirring the crystalline suspension is cooled between 0-50C at a speed of 2 °C/min under stirring of an rpm 120 min"1, then it is stirred at this temperature for 0.5 hour. Having finished the stirring the suspension is filtered, washed with a few amount of water having a temperature between 0-5 0C and dried at 35-40 0C until constant weight.
Thus 8.90 g of title product are obtained.
Chemical purity (HPLC) >99,5 %.
The powder X-ray diffractogram of the product corresponds to the Figure 4.
Example 11
Desvenlafaxine fumarate monohydrate polymorph form III
In a 500 cm3 vessel 12,1 g of desvenlafaxine fumarate monohydrate of form I and 300 cm3 of ethanol are added. The mixture is heated to 50 °C under stirring and kept at this temperature for 48 hours. Following the 48 hours stirring the warm crystalline suspension is filtered. The crystalline product is washed with a few amount of ethanol and dried at 35-40 0C until constant weight. Thus 1.80 g of title product are obtained. Chemical purity (HPLC) >99,5 %.
The powder X-ray diffractogram of the product corresponds to the Figure 4.
Example 12
Desvenlafaxine fumarate monohydrate polymorph form IV In a 250 cm3 vessel 5 g of desvenlafaxine fumarate monohydrate and 175 cm3 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 O0C, filtered, washed with a few amount of 2-propanol having a temperature between 0-5 °C and dried at 45-50 0C until constant weight. Thus 3.30 g of title product are obtained. Chemical purity (HPLC) ≥99,5 %.
The powder X-ray diffractogram of the product corresponds to the Figure 5. Water content (Karl-Fischer): 4.78%
Example 13
Desvenlafaxine fumarate monohydrate polymorph form IV
In a 250 cm3 vessel 1.0 g of desvenlafaxine fumarate monohydrate and 20 cm3 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 cm3 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 0C until constant weight.
Thus 0.84 g of title product is obtained.
Chemical purity (HPLC) >99,5 %.
The powder X-ray diffractogram of the product corresponds to the Figure 5.
Example 14
Desvenlafaxine fumarate monohydrate polymorph form IV
In a 250 cm3 vessel 6.0 g of desvenlafaxine fumarate monohydrate and 150 cm3 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 0C, 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 0C and dried at 20-30 0C until constant weight.
Thus 5.10 g of title product are obtained having a melting point between 105-1100C.
Chemical purity (HPLC) >99,5 %. The powder X-ray diffractogram of the product corresponds to the Figure 5.

Claims

Claims:
1. (±)-1 -[2-dimethylamino-1 -(4-hydroxyphenyl)-ethyl]- cyclohexanol fumarate monohydrate of polymorph I form of the chemical formula (I) characterized by X-ray diffraction peaks 2Θ (±0.2° 2Θ): 10.404; 14.194; 15.396; 16.794; 26.236.
2. (±)-1 -[2-dimethylamino-1 -(4-hydroxyphenyl)-ethyl]- cyclohexanol fumarate monohydrate of polymorph I form of the chemical formula (I) according to Claim 1 characterized by X-ray diffraction peaks 2Θ (±0.2° 2Θ): 5.174; 10.404; 13.872; 14.194; 15.396; 16.319; 16.794; 18.174; 18.887; 20.897; 24.178; 26.236.
3. (±)-1 -[2-dimethylamino-1 -(4-hydroxyphenyl)-ethyl]- cyclohexanol fumarate monohydrate of polymorph I form of the chemical formula (I) according to Claim 1 or 2 characterized by X-ray diffraction peaks 2Θ (±0.2° 2Θ) as follows:
(relative intensity >10 %)
Figure imgf000044_0001
Figure imgf000045_0001
4. Anhydrous (±)-1-[2-dimethylamino-1-(4-hydroxyphenyl)- ethyl]-cyclohexanol fumarate of polymorph Il form of the chemical formula (II) characterized by X-ray diffraction peaks 2Θ (±0.2° 2Θ): 14.777; 16.933; 19.660; 21.275; 26.706.
5. Anhydrous (±)-1-[2-dimethylamino-1-(4-hydroxyphenyl)- ethyl]-cyclohexanol fumarate of polymorph Il form of formula (II) according to Claim 4 characterized by X-ray diffraction peaks 2Θ (±0.2° 2Θ): 10.488; 14.777; 16.933; 17.758; 19.660; 21.275; 22.067; 24.463; 26.256; 26.706.
6. Anhydrous (±)-1-[2-dimethylamino-1-(4-hydroxyphenyl)- ethyl]-cyclohexanol fumarate of polymorph Il form of formula (II) according to Claim 4 or 5 characterized by X-ray diffraction peaks 2Θ (±0.2° 2Θ) as follows:
(relative intensity >15 %)
Figure imgf000046_0001
7. Anhydrous amorphous form of desvenlafaxine fumarate of formula (II).
8. (±)-1-[2-dimethylamino-1 -(4-hydroxyphenyl)-ethyl]- cyclohexanol fumarate monohydrate of polymorph III form of the chemical formula (I) characterized by X-ray diffraction peaks !Θ (±0.2° 2Θ): 15.402; 16.777; 18.870; 24.148; 26.317.
9. (±)-1 -[2-dimethylamino-1 -(4-hydroxyphenyl)-ethyl]- cyclohexanol fumarate monohydrate of polymorph III form of the chemical formula (I) according to Claim 8 characterized by X-ray diffraction peaks 2Θ (±0.2° 2Θ): 10.468; 12.007; 14.224; 15.402; 16.777; 17.397; 18.870; 24.148; 25.196; 26.317.
10. Desvenlafaxine fumarate monohydrate of polymorph III form of the chemical formula (I) according to Claim 8 or 9 characterized by X-ray diffraction peaks 2Θ (±0.2° 2Θ) as follows:
(relative intensity >5 %)
Figure imgf000047_0001
Figure imgf000048_0001
11. (±)-1-[2-dimethylamino-1-(4-hydroxyphenyl)-ethyl]- cyclohexanol fumarate monohydrate of polymorph IV form of the chemical formula (I) characterized by X-ray diffraction peaks 2Θ (±0.2° 2Θ): 5.183; 10.398; 14.239; 16.335; 18.257; 26.237.
12. (±)-1 -[2-dimethylamino-1 -(4-hydroxyphenyl)-ethyl]- cyclohexanol fumarate monohydrate of polymorph IV form of the chemical formula (I) according to Claim 11 characterized by X-ray diffraction peaks 2Θ (±0.2° 2Θ):
5.183; 10.398; 11.592; 14.239; 16.335; 16.933; 18.257; 18.984; 20.914; 24.323; 24.993; 26.237.
13. Desvenlafaxine fumarate monohydrate of polymorph IV form of the chemical formula (I) according to Claim 11 or 12 characterized by X-ray diffraction peaks (±0.2° as follows:
(relative intensity >5 %)
Figure imgf000049_0001
Figure imgf000050_0001
14. Process for the preparation of desvenlafaxine fumarate monohydrate of polymorph form I according to any of Claims 1-3 characterized in that 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 are dissolved in water or in an aliphatic alcohol or in a mixture thereof under heating, the obtained solution is cooled at a cooling speed between 0.1-2 °C/minute, preferably at a cooling speed between 1-2 °C/minute, then the obtained crystalline product is separated and dried if necessary.
15. Process according to Claim 14 characterized in that the recrystallisation of desvenlafaxine fumarate hydrate is carried out using an aliphatic alcohol as solvent.
16. Process for the preparation of desvenlafaxine fumarate monohydrate of the polymorph form I according to any of Claims 14 or 15 characterized in that Ci-C4 alcohols, preferably methanol, ethanol, 1-propanol, 2-propanol, 1- butanol, tert.-butanol, most preferably 2-propanol or ethanol is used as solvent.
17. Process for the preparation of desvenlafaxine fumarate monohydrate of polymorph form I characterized in that the desvenlafaxine fumarate hydrate is dissolved in ethanol or water or in a mixture of ethanol and water under heating, the mixture is kept at its boiling point for 0.5-2 hours, then the solution is cooled to a temperature between 0-25 0C at a cooling speed between 0.1-2 °C/minute, preferably between 1-2 °C/minute, the precipitated product is separated and dried.
18. Process for the preparation of desvenlafaxine fumarate monohydrate of polymorph form Il according to any of Claims 4-6 characterized in that 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 are dissolved in an aliphatic alcohol or in an aromatic hydrocarbon type solvent under heating, in case of using desvenlafaxine fumarate monohydrate or water containing mixture the obtained solution is dried, then the mixture is cooled and the obtained crystalline product is separated and dried if necessary.
19. Process according to Claim 18 characterized in that the solution is dried by using a dessicant agent or azeotropic distillation and in case of using azeotropic distillation a further auxiliary solvent is used if necessary.
20. Process according to any of Claims 18 or 19 characterized in that C1-C4 alcohols, preferably methanol, ethanol, 1- propanol, 2-propanol, 1-butanol, tert.-butanol, most preferably ethanol is used as aliphatic alcohol and xylene, xylene isomer mixtures, benzene, toluene preferably toluene is used as aromatic hydrocarbon type solvent.
21. Process for the preparation of anhydrous desvenlafaxine fumarate polymorph Il according to any of Claims 4-6, characterized in that anhydrous desvenlafaxine fumarate is dissolved in anhydrous ethanol or toluene under heating, the obtained solution is cooled to a temperature between 0- 25 0C, then the precipitated product is separated and dried.
22. Process for the preparation of amorphous desvenlafaxine fumarate according to Claim 7 characterized in that any kind of different polymorph or amorphous forms of desvenlafaxine fumarate, their solvates, hydrates or the mixtures thereof are melted and dried in a vacuum dryer, then cooled and powdered if necessary.
23. Process for the preparation of amorphous desvenlafaxine fumarate according to Claim 7 characterized in that 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 are dissolved in a solvent, then evaporated by a spray dryer or evaporated to dryness in a vacuum, cooled and powdered if necessary.
24. Process for the preparation of desvenlafaxine fumarate monohydrate of polymorph form III according to any of Claims 8-10 characterized in that any kind of different polymoφh or amorphous forms of desvenlafaxine fumarate, their solvates, hydrates or the mixtures thereof are suspended in water or in an aliphatic alcohol or in a mixture thereof , in case of need water is added if necessary the product is stirred, then separated and dried if necessary.
25. Process according to Claim 24 characterized in that the suspension is stirred at a temperature between 0-60 0C for 0,5-120 hours, preferably 0,5-60 hours, most preferably 24- 48 hours, then cooled, the product is separated and dried.
26. Process for the preparation of desvenlafaxine fumarate monohydrate of polymorph form III according to any of Claims 8-10 characterized in that any kind of different polymorph or amorphous forms of desvenlafaxine fumarate, their solvates, hydrates or the mixtures thereof are dissolved completely or partly in water or in an aliphatic alcohol or in a mixture thereof at a temperature between 0- 100 0C, then the mixture is kept at a temperature between 0-40 0C, preferably at room temperature for 4-300 hours, preferably 24-300 hours, the solvent is allowed to be evaporated during this period, then the product is separated and dried if necessary.
27. Process according to claim 26 characterized in that the desvenlafaxine fumarate monohydrate is dissolved in an aliphatic alcohol, preferably in ethanol at the boiling point of the solvent, then the solution is cooled to room temperature and solvent is allowed to be evaporated partly and the precipitated product is separated.
28. Process for the preparation of desvenlafaxine fumarate monohydrate of polymorph form IV according to any of Claims 11-13 characterized in that 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 are dissolved 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.
29. A process according to Claim 28 characterized in that as starting compound any kind of different polymorph or amorphous forms of desvenlafaxine fumarate hydrate is used and as solvent aliphatic alcohol is used.
30. Process according to any of Claims 29 or 30 characterized in that C1-C4 alcohols, preferably methanol, ethanol, 1- propanol, 2-propanol, 1-butanol, tert.-butanol, most preferably 2-propanol or ethanol is used as solvent.
31. Process for the preparation of desvenlafaxine fumarate monohydrate of polymorph form IV according to Claims 11- 13 characterized in that desvenlafaxine fumarate hydrate is dissolved in 2-propanol, ethanol or water, or in a mixture of ethanol and water under heating, then the obtained solution is cooled to a temperature between 0-25 0C at a cooling speed between 3-100 °C/minute, preferably between 4-10 °C/minute, the precipitated product is separated and dried.
32. Process for the preparation of desvenlafaxine fumarate monohydrate of polymorph form IV according to Claims 11- 13 characterized in that 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 are dissolved in a solvent, then the obtained solution is added to an antisolvent, or an antisolvent is added to the solution, and the precipitated product is separated an dried if necessary.
33. A process according to Claim 33 characterized in that as solvent aliphatic alcohol, water or a mixture of an aliphatic alcohol and water, preferably an aliphatic alcohol, most preferably methanol is used and as antisolvent ether, ketone, nitrile, or saturated hydrocarbon type solvents, preferably acetone are used.
34. A process according to any of Claims 32-33 for the preparation of desvenlafaxine fumarate monohydrate polymorph form IV characterized in that desvenlafaxine fumarate monohydrate is dissolved in methanol and acetone is added to the solution, then the obtained product is separated.
35. Pharmaceutical composition containing desvenlafaxine fumarate monohydrate of polymorph form I of formula (I), anhydrous desvenlafaxine fumarate of polymorph form Il of formula (II), amorphous form, desvenlafaxine fumarate monohydrate of polymorph form III of formula (I)1 desvenlafaxine fumarate monohydrate of polymorph form IV of formula (I), or mixtures thereof and at least one solid or fluid inert pharmaceutically acceptable excipient.
36. Process for the preparation of pharmaceutical compositions according to Claim 35 characterized in that 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), or mixtures thereof is mixed with solid or fluid inert pharmaceutically acceptable excipient(s) and transformed into a galenic form.
37. 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 a pharmaceutical active ingredient.
38. 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)1 for the preparation of a pharmaceutical composition 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.
39. Method of use 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 by administering 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), in a pharmaceutically effective amount to the patient in need of such treatment.
PCT/HU2009/000016 2008-02-14 2009-02-13 New polymorph and amorphous forms of desvenlafaxine fumarate Ceased WO2009101458A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP09709502A EP2252573A2 (en) 2008-02-14 2009-02-13 New polymorph and amorphous forms of desvenlafaxine fumarate

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
HU0800091A HU0800091D0 (en) 2008-02-14 2008-02-14 Novel polymorphs and amorph forms of desvenlafaxine fumarate
HUP0800091 2008-02-14
HUP0900062 2009-02-04
HU0900062A HU230652B1 (en) 2009-02-04 2009-02-04 Novel polymorph monohydrate form of desvenlafaxine fumarate

Publications (2)

Publication Number Publication Date
WO2009101458A2 true WO2009101458A2 (en) 2009-08-20
WO2009101458A3 WO2009101458A3 (en) 2010-04-08

Family

ID=89988755

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU2009/000016 Ceased WO2009101458A2 (en) 2008-02-14 2009-02-13 New polymorph and amorphous forms of desvenlafaxine fumarate

Country Status (2)

Country Link
EP (1) EP2252573A2 (en)
WO (1) WO2009101458A2 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011121452A2 (en) 2010-03-29 2011-10-06 Pliva Hrvatska D.O.O. Crystal forms of o-desmethylvenlafaxine fumarate
ES2648369A1 (en) * 2016-06-29 2018-01-02 Alparis, S.A. De C.V. NEW SOLID FORMS OF DESVENLAFAXIN (Machine-translation by Google Translate, not legally binding)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IE56324B1 (en) * 1982-12-13 1991-06-19 American Home Prod Phenethylamine derivatives and intermediates therefor
WO2000076955A1 (en) * 1999-06-15 2000-12-21 American Home Products Corporation Enantiomers of o-desmethyl venlafaxine
CA2706775A1 (en) * 2007-11-26 2009-06-04 Teva Pharmaceutical Industries Ltd. Crystal forms of o-desmethylvenlafaxine fumarate

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011121452A2 (en) 2010-03-29 2011-10-06 Pliva Hrvatska D.O.O. Crystal forms of o-desmethylvenlafaxine fumarate
WO2011121452A3 (en) * 2010-03-29 2011-12-29 Pliva Hrvatska D.O.O. Crystal forms of o-desmethylvenlafaxine fumarate
US8569371B2 (en) 2010-03-29 2013-10-29 Pliva Hrvatska D.O.O. Crystal forms of O-desmethylvenlafaxine fumarate
KR101409554B1 (en) 2010-03-29 2014-06-19 플리바 흐르바츠카 디.오.오. Crystal forms of o-desmethylvenlafaxine fumarate
ES2648369A1 (en) * 2016-06-29 2018-01-02 Alparis, S.A. De C.V. NEW SOLID FORMS OF DESVENLAFAXIN (Machine-translation by Google Translate, not legally binding)

Also Published As

Publication number Publication date
WO2009101458A3 (en) 2010-04-08
EP2252573A2 (en) 2010-11-24

Similar Documents

Publication Publication Date Title
KR100543614B1 (en) 4-phenylpiperidine compound
CN102858762A (en) Novel salts for the preparation of pharmaceutical compositions
JP2008509953A (en) 4-[[(7R) -8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-4-6-oxo-2-piperidinyl] amino] -3-methoxy-N- ( 1-methyl-4-piperidinyl) benzamide hydrates and polymorphs, processes for their preparation and their use as drugs
SK283608B6 (en) Anhydrous paroxetine hydrochloride, process for its preparation and use
JPH0819065B2 (en) Benzo-fused cycloalkane and oxa- and thia-cycloalkane trans-1,2-diamine derivatives
JP2002519422A (en) Paroxetine methanesulfonate
JP2014532673A (en) Ivabradine hydrochloride Form IV
EP3243824A1 (en) Solid forms of ibrutinib free base
EA029060B1 (en) Process for the preparation of vortioxetine salts
JP2008546719A (en) Crystalline O-desmethylvenlafaxine
WO2018184185A1 (en) Ozanimod addition salt crystal, preparation method, pharmaceutical composition, and uses
US6706710B2 (en) Form of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide
EP2252573A2 (en) New polymorph and amorphous forms of desvenlafaxine fumarate
WO2000035873A1 (en) Process for preparation of paroxetine maleate
TW202509012A (en) New polymorphs of (s)-6-chloro-2,3,4,9-tetrahydro-1h-carbazole-1-carboxamide in crystalline form
JP4711961B2 (en) 2-Methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane tartrate
RU2192416C2 (en) Method of crystallization of 1-[2-(2-naphthyl)-ethyl]-4-(3- trifluoromethylphenyl)-1,2,3,6-tetra-hydropyridine hydrochloride, prepared crystalline forms and pharmaceutical composition
EP1539161A1 (en) Novel salt and polymorphs of desloratadine hemifumarate
WO2008156748A2 (en) Crystal forms of o-desmethylvenlafaxine succinate
JP3864991B2 (en) Crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride
EP3083551B1 (en) Crystalline form of tapentadol intermediate
HUP0900062A2 (en) Novel polymorphs and amorph forms of desvenlafaxine fumarate
HUP0104872A2 (en) New polymorphic forms of venlafaxine, process for their preparation, pharmaceutical compositions containing them and their use
EP4713311A1 (en) Preparation of (s)-6-chloro-2,3,4,9-tetrahydro-1h-carbazole-1-carboxamide in enantiomerically enriched form by resolution process
EP3210975A1 (en) Cocrystals of lorcaserin

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09709502

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2009709502

Country of ref document: EP