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WO2016125190A2 - Nouvelles formes cristallines de vortioxétine, prémélanges, et procédés pour la préparation de ceux-ci - Google Patents

Nouvelles formes cristallines de vortioxétine, prémélanges, et procédés pour la préparation de ceux-ci Download PDF

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Publication number
WO2016125190A2
WO2016125190A2 PCT/IN2016/050041 IN2016050041W WO2016125190A2 WO 2016125190 A2 WO2016125190 A2 WO 2016125190A2 IN 2016050041 W IN2016050041 W IN 2016050041W WO 2016125190 A2 WO2016125190 A2 WO 2016125190A2
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Prior art keywords
vortioxetine hydrobromide
cyclodextrin
vortioxetine
premix
hydrobromide
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Ceased
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PCT/IN2016/050041
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WO2016125190A3 (fr
Inventor
Ramakoteswara Rao Jetti
Asharani GORANTLA
Satish BEERAVALLI
Sureshbabu JAYACHANDRA
Rathinapandian JEBARAJ
Anjaneyaraju Indukuri
Bommareddy AGGIRAMIREDDY
Amit Singh
Soumyajit GHOSH
Attanti Veera Venkata SRINIVASARAO
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Mylan Laboratories Ltd
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Mylan Laboratories Ltd
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Publication of WO2016125190A2 publication Critical patent/WO2016125190A2/fr
Publication of WO2016125190A3 publication Critical patent/WO2016125190A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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

Definitions

  • the present invention relates to the field of pharmaceutical sciences and more specifically to crystalline forms of vortioxetine hydrobromide and solvates thereof.
  • the present invention also relates to process for the preparation of crystalline forms of vortioxetine hydrobromide and solvates thereof.
  • the present invention further relates to a premixes of vortioxetine hydrobromide as well as a process for the preparation thereof.
  • Vortioxetine hydrobromide is chemically known as l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]- piperazinehydrobromide and is structurally represented as Formula-I below.
  • Vortioxetine hydrobromide is marketed under the trade name BRINTELLIX ® by Takeda Pharmaceuticals U.S.A., Inc. and is indicated for the treatment of major depressive disorder (MDD).
  • Vortioxetine and pharmaceutically acceptable salts thereof are disclosed in PCT Publication No. WO 2003029232.
  • PCT Publication No. WO 2007144005 discloses crystalline vortioxetine in its free -base form as well as crystalline vortioxetine salts such as hydrochloride, mesylate, fumarate, maleate, meso- tartrate, L-(+)-tartrate, D-(-)-tartrate, sulfate, phosphate, and nitrate.
  • PCT Publication No. WO 2010094285 discloses an isopropanol solvate of vortioxetine hydrobromide as well as a process for the purification of vortioxetine hydrobromide.
  • PCT Publication No. WO 2010121621 discloses crystalline forms of vortioxetine L-lactate and vortioxetine DL-lactate.
  • PCT Publication No. WO 2014044721 discloses vortioxetine hydrobromide form delta and a vortioxetine hydrobromide hydrate.
  • PCT Publication No. WO 2014177491 discloses amorphous vortioxetine hydrobromide in association with an adsorbent.
  • PCT Publication No. WO 2015044963 discloses amorphous vortioxetine hydrobromide and a solid dispersion of vortioxetine free base or salts thereof and a polymer.
  • PCT Publication No. WO2015114395 discloses vortioxetine salts such as succinate, salicylate, monocitrate monohydrate, monocitrate anhydrate, malonate, hemioxalate, L-malate, benezene sulfonate, acetate, L-(+)-mandelate, hemicitarte, and monooxalate.
  • BRINTILLIX® contains the beta ( ⁇ ) polymorph of vortioxetine hydrobromide.
  • Other polymorphs may provide different advantages in a variety of capacities, for example, in formulation, stability of the form, stability of the formulation, and in pharmacokinetic profiles. These advantages may arise from the different properties present in each polymorph.
  • the present invention provides four novel crystalline forms of vortioxetine hydrobromide as well as processes for the preparation thereof.
  • preparation of pharmaceutical dosage forms is often procedurally complex, particularly when combining the active ingredient with excipients.
  • workability or stability issues may arise when different components of the pharmaceutical dosage form come into intimate contact with one another. It may, thus, be advantageous to supply the manufacturer of pharmaceutical dosage forms with a pre-combined mixture (pre-mix) of excipients and active pharmaceutical ingredient (API) to facilitate and simplify the final processing of dosages forms.
  • pre-mix pre-combined mixture
  • API active pharmaceutical ingredient
  • One aspect of the present invention provides crystalline form-Mi of vortioxetine hydrobromide.
  • Another aspect of the present invention provides a process for the preparation of crystalline form-Mi of vortioxetine hydrobromide, which may include the steps of: a) dissolving vortioxetine hydrobromide in isobutanol to form a solution;
  • Another aspectof the present invention provides crystalline form-M 2 of vortioxetine hydrobromide.
  • Another aspect of the present invention provides a process for the preparation of crystalline form-M 2 of vortioxetine hydrobromide, which may include the steps of: a) dissolving vortioxetine hydrobromide in 2-butanol to form a solution;
  • Another aspectof the present invention provides crystalline form-M3 of vortioxetine hydrobromide.
  • Another aspect of the present invention provides a process for the preparation of crystalline form- Ms of vortioxetine hydrobromide, which may include the steps of: a) dissolving vortioxetine in isoamyl alcohol to form a vortioxetine solution;
  • Another aspect of the present invention provides crystalline form-M4 of vortioxetine hydrobromide.
  • Another aspect of the present invention provides a process for the preparation of crystalline form-Mi of vortioxetine hydrobromide, which may include the steps of: a) combining vortioxetine hydrobromide witha mixture of organic solvent and water; and b) isolating crystalline form-M4 of vortioxetine hydrobromide.
  • Another aspectof the present invention provides a process for the preparation of a premix of crystalline form-M2 of vortioxetine hydrobromide.
  • Another aspect of the present invention provides a process for the preparation of a premix of crystalline form-M2 of vortioxetine hydrobromide, which may include the steps of: a) dissolving vortioxetine hydrobromide in 2-butanol to form a solution;
  • microcrystalline cellulose is used as the pharmaceutically acceptable excipient.
  • Another aspectof the present invention provides a premix of amorphous vortioxetine hydrobromide.
  • Another aspect of the present invention provides a process for the preparation of a premix of amorphous vortioxetine,which may include the steps of: a) dissolving vortioxetine hydrobromide in a solvent to form a solution;
  • the pharmaceutically acceptable excipient may be a cyclodextrin, for example, a-cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl-P-cyclodextrin, a polyvinylpyrrolidone, a polyvinylpyrrolidone-vinyl acetate copolymer, microcrystalline cellulose,or mixtures thereof.
  • a cyclodextrin for example, a-cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl-P-cyclodextrin, a polyvinylpyrrolidone, a polyvinylpyrrolidone-vinyl acetate copolymer, microcrystalline cellulose,or mixtures thereof.
  • ⁇ -cyclodextrin, polyvinylpyrrolidone with a K-value of 30, or a polyvinylpyrrolidone-vinylacetate copolymer with a ratio of 60:40 polyvinylpyrrolidone to vinyl acetate by mass are used as pharmaceutically acceptable excipients.
  • crystalline forms of vortioxetine hydrobromide, crystalline forms of vortioxetine hydrobromide solvates, and the premixes disclosed herein may be useful in the formulation of oral pharmaceutical dosage forms.
  • These oral pharmaceutical dosage forms may include additional pharmaceutically acceptable excipients.
  • Figure 1 is a powder X-ray diffraction pattern of crystalline form-Mi of vortioxetine hydrobromide.
  • Figure 2 is a powder X-ray diffraction pattern of crystalline form-M2 of vortioxetine hydrobromide.
  • Figure 3 is a powder X-ray diffraction pattern of crystalline form-M3 of vortioxetine hydrobromide.
  • Figure 4 is a powder X-ray diffraction pattern of crystalline form-M4 of vortioxetine hydrobromide.
  • Figure Si adifferential scanning calorimetry (DSC) thermogram of crystalline form-M4 of vortioxetine hydrobromide.
  • Figure 6 is a powder X-ray diffraction pattern of a premix of crystalline form-M2 of vortioxetine hydrobromide and 10% w/w microcrystalline cellulose.
  • Figure 7 is a powder X-ray diffraction pattern of a premix of amorphous vortioxetine hydrobromide and50 % w/w ⁇ -cyclodextrin.
  • the present invention provides novel crystalline form-Mi, form-M2 , form-Ms , and form-M4 of vortioxetine hydrobromide.
  • crystalline form-M x where x is 1-4, refers to a crystalline form of vortioxetine hydrobromide.
  • each of the crystalline forms disclosed herein have a unique PXRD pattern by which they can be identified.
  • the crystalline forms of vortioxetine hydrobromide or solvates thereof disclosed herein may be characterized by their X-ray powder diffraction (PXRD) pattern.
  • the premixes disclosed herein may also be characterized by their PXRD pattern.
  • PXRD X-ray powder diffraction
  • the PXRD pattern of each crystalline form of vortioxetine hydrobromide or solvate thereof and each premix of vortioxetine hydrobromide disclosed herein was measured on a BRUKER D-8Discover powder diffractometer equipped with goniometer of ⁇ /2 ⁇ configuration and Lynx Eye detector.
  • the Cu- anode X-ray tube was operated at 40kV and 30 mA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, with 0.030° step size and 0.4 seconds step time.
  • the crystalline forms of vortioxetine hydrobromide or solvates thereof of the present invention may also be characterized by their differential scanning calorimetry (DSC) thermograms.
  • DSC measurements were carried out on TA Q1000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-260°C purging with nitrogen at a flow rate of 50mL/min. Standard aluminum crucibles covered by lids without pin holes were used.
  • One aspect of the present invention provides crystalline form-Mi of vortioxetine hydrobromide.
  • crystalline form-Mi of vortioxetine hydrobromide may be characterized by a powder X-ray diffraction having characteristic peak at about 2 ⁇ angles of 15.9, 19.4, and 30.3 ( ⁇ ) 0.2°.
  • crystal form-Mi of vortioxetine hydrobromide may be further characterized by a powder X-ray diffraction having characteristic peak at about 6.7, 15.9, 16.7, 19.4, 20.2, 22.1, 29.4, and 30.3 ( ⁇ ) 0.2°.
  • Crystalline form-Mi of vortioxetine hydrobromide may be further characterized by the PXRD pattern in Figure 1.
  • crystalline form-Mi of vortioxetine hydrobromide is an isobutanol solvate of vortioxetine hydrobromide.
  • Another aspect of the present invention provides a process for the preparation of crystalline form-Mi of vortioxetine hydrobromide, which may include the following steps: a) dissolving vortioxetine hydrobromide in isobutanol to form a solution;
  • vortioxetine hydrobromide may be dissolved in isobutanol.
  • the vortioxetine hydrobromide that is dissolved in isobutanol may be any polymorphic form or may be amorphous.
  • this step may be carried out at a temperature of about40°C to about 105°C. In some embodiments of the present invention, a temperature of about 60 °C to about 90 °C was found to be particularly useful for dissolving vortioxetine hydrobromide.
  • the term "about” means 10% above or below the value recited.
  • the solution may then be cooled to less than about 35 °C, e.g., a temperature of about 10 °C to about 35°C. In some embodiments of the present invention, the solution is cooled to a temperature of about 20°C to about 35°C. These cooling steps may result in precipitation of a solid that is form-Mi of vortioxetine hydrobromide.
  • Crystalline form-Mi of vortioxetine hydrobromide may then be isolated from this solution. Isolation may be carried out by methods well known in the art, for example, by isolation of the precipitate by filtration followed by drying.
  • Another aspect of the present invention provides crystalline form-M 2 of vortioxetine hydrobromide.
  • crystalline form-M 2 of vortioxetine hydrobromide may be characterized by a powder X-ray diffraction having characteristic peak at about 6.5, 19.0, 19.8, and 29.3 ( ⁇ ) 0.2°.
  • crystalline form-M 2 of vortioxetine hydrobromide may be further characterized by a powder X-ray diffraction having characteristic peak at about 6.5, 15.8, 17.4, 19.0, 19.8, 29.3, 30.7, and 37.0( ⁇ ) 0.2°.
  • Crystalline form-M2 of vortioxetine hydrobromide may be further characterized by the PXRD pattern in Figure 2.
  • crystalline form-M2 of vortioxetine hydrobromide is a 2-butanol solvate of vortioxetine hydrobromide.
  • Another aspect of the present invention provides a process for the preparation of crystalline form- M 2 of vortioxetine hydrobromide, which may include the following steps: a) dissolving vortioxetine hydrobromide in 2-butanol to form a solution;
  • vortioxetine hydrobromide may be dissolved in 2-butanol.
  • the vortioxetine hydrobromide that is dissolved in 2- butanol may be any polymorphic form or may be amorphous.
  • this step may be carried out at a temperature of about60°C to about 100°C. In some embodiments of the present invention, a temperature of about 80°Cto about 100 °C was found to be particularly useful for dissolving vortioxetine hydrobromide.
  • the solution may be cooled to less than about 35 °C, e.g., aboutlO °C to about 35°C. In certain embodiments of the present invention, the solution is cooled to a temperature of about 20 °C to about 35 °C. These cooling steps may result in precipitation of a solid that is form-M2 of vortioxetine hydrobromide.
  • crystalline form-M2 of vortioxetine hydrobromide may be isolated. Isolation may be carried out by methods well known in the art, for example, byisolation of the precipitate by filtration followed by drying.
  • crystalline form-M3 of vortioxetine hydrobromide may be characterized by a powder X-ray diffraction having characteristic peak at about 17.9, 19.8, 22.1, and 23.9 ( ⁇ ) 0.2°.
  • crystalline form-M 3 of vortioxetine hydrobromide may be further characterized by a powder X-ray diffraction having characteristic peak at about 6.4, 7.5, 9.9, 17.9, 18.2, 19.8, 22.1, 22.6, 23.9, 27.0, and 30.3 ( ⁇ ) 0.2°.
  • Crystalline form-M 3 of vortioxetine hydrobromide may be further characterized by the PXRD pattern in Figure 3.
  • crystalline form-M 3 of vortioxetine hydrobromide is an isoamyl alcohol solvate of vortioxetine hydrobromide.
  • Another aspect of the present invention provides a process for the preparation of crystalline form- Ms of vortioxetine hydrobromide, which may include the following steps: a) dissolving vortioxetine in isoamyl alcoholto form a solution of vortioxetine;
  • vortioxetine may be dissolved in isoamyl alcohol.
  • the vortioxetine that is dissolved in isoamyl alcohol may be any polymorphic form or may be amorphous.
  • this step may be carried out at a temperature of a temperature of about 50 °C to about 135°C. In certain embodiments of the present invention, a temperature of about 60°C to about 90°C was found to be particularly useful for dissolving vortioxetine.
  • the solution of vortioxetine may be cooled toless than about 35 °C, e.g., about 10°C to about 35 °C.
  • the solution of vortioxetine may be first cooled to about 20 °C to about 35 °C, then further cooled to about 0 °C to about 5 °C.
  • a solution of hydrobromide may be added to the vortioxetine solution.
  • the hydrobromide solution may be aqueous.
  • the aqueous hydrobromide solution is used at a concentration of 48% weight by volume.
  • the addition of the hydrobromide solution may result in the formation of aprecipitate that is crystalline form-M3 of vortioxetine hydrobromide.
  • crystalline form-M3 of vortioxetine hydrobromide may be isolated. This may be carried out by methods well known in the art, for example, by isolation of the precipitate by filtration followed by drying.
  • Another aspect of the present invention provides crystalline form-M4 of vortioxetine hydrobromide.
  • crystalline form-M4 of vortioxetine hydrobromide may be characterized by a powder X-ray diffraction having characteristic peak at about 19.4, 22.7, and 23.7 ( ⁇ ) 0.2°.
  • crystalline form-M4 of vortioxetine hydrobromide may be further characterized by a powder X-ray diffraction having characteristic peak at about 4.8,
  • crystalline form-M4 of vortioxetine hydrobromide may be further characterized by a powder X-ray diffraction having characteristic peak at about 4.8,
  • Crystalline form-M4 of vortioxetine hydrobromide may be further characterized by the PXRD pattern in Figure 4. Crystalline form-M4 of vortioxetine hydrobromide may also be further characterized by the DSC thermogram in Figure 5.
  • Another aspect of the present invention provides a process for the preparation of crystalline form- M4 of vortioxetine hydrobromide, which may include the following steps: a) combining vortioxetine hydrobromide witha mixture of an organic solvent and water; and b) isolating the crystalline form-M4 of vortioxetine hydrobromide.
  • crystalline form-M4 of vortioxetine hydrobromide vortioxetine hydrobromide is combined with a mixture of an organic solvent and water.
  • the reaction mixture may be heated to an elevated temperature, for example, about 50 °C and maintained at that temperature for an extended period of time.
  • the vortioxetine hydrobromide which is combined with a mixture of an organic solvent and water may be vortioxetine hydrobromide form-M2.
  • the reaction mixture thus formed may then be heated and maintained at that elevated temperature until a solid precipitates from solution.
  • the reaction mixtures may be heated to 50 °C and maintained at that temperature for approximately 10-20 hours.
  • the organic solvent may be a water-miscible solvent, for example, an alcoholic solvent, a nitrile solvent, a ketone solvent, anethereal solvent, or mixtures thereof.
  • Suitable alcoholic solvents include, for example, methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2- butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl- 1 -butanol, 2-methyl- 1 -butanol, 2,2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl- 1 -propanol, 1, 1 -dimethyl- 1 -propanol, and mixtures thereof.
  • a suitable nitrile solvent may be, for example acetonitrile.
  • Suitable ketone solvents include, for example, acetone, methylethyl ketone, methylisobutyl ketone, and mixtures thereof.
  • suitableethereal solvents include tetrahydrofuran, 1,4-dioxane, and mixtures thereof.
  • the ratio of organic solvent to water ranged from about 1 :0.5 to 1:3. In some embodiments, the ratio of organic solvent to water ranged from about 1: 1 to 1 :2.
  • crystalline form-M4 of vortioxetine hydrobromide may be isolated. This may be carried out by methods well known in the art, for example, by isolation of the precipitate by filtration followed by drying.
  • a premix of crystalline form-M2 of vortioxetine hydrobromide may be prepared by the following steps: a) dissolving vortioxetine hydrobromide in 2-butanol to form a solution;
  • vortioxetine hydrobromide may be dissolved in 2-butanol.
  • the vortioxetine hydrobromide may be any polymorphic form or may be amorphous.
  • this step may be carried out at a temperature of a temperature of about 60 °C to about 100°C.
  • a temperature of about 80 °C to about 100 °C was found to be particularly useful for dissolving vortioxetine.
  • the solution of vortioxetine may be cooled to about 10°C to about 35 °C.
  • the solution of vortioxetine may be cooled to about 20°C to about 35 °C.
  • cooling the solution of vortioxetine may result in precipitation of solid vortioxetine hydrobromide form-M2.
  • excipients include, for example, polysaccharides, polyvinylpyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone- vinyl acetate copolymers, Ci-C 6 polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), copolymers of polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol (e.g., the families of block copolymers based on ethylene glycol and propylene glycol sold under the PLURONIC tradename), and mixtures thereof.
  • PVAC polyvinylpyrrolidone
  • PVAC polyvinyl acetate
  • PVA polyvinyl alcohol
  • Ci-C 6 polyalkylene glycols e.g., polypropylene glycol, polyethylene glycol
  • Suitable polysaccharides include, as examples, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium salts of carboxymethyl cellulose, calcium salts of carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, cyclodextrins (e.g., ⁇ -cyclodextrin, a-cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin), and mixtures thereof.
  • cyclodextrins e.g., ⁇ -cyclodextrin, a-cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin
  • microcrystalline cellulose is used as an excipient.
  • the excipient may be included in the formulation at a massratio of about0.01: l to about 20: 1, where the mass ratio is vortioxetine: excipient. In certain embodiments, the excipient may be included in the formulation at a mass ratio of about 1: 1 to about 20: 1 with respect to vortioxetine:excipient.
  • the excipient may be included in the formulation at a mass ratio of about 1: 1 to about 10: 1, or about 2: 1 to about 10: 1, or about 4: 1 to about 10: 1, about 8: 1 to about 10: 1 with respect to vortioxetine:excipient.
  • the excipient may be included in the formulation at a mass ratio of about 1: 1, or about 2: 1, or about 3: 1, or about 4: 1, or about 5: 1, or about 6: 1, or about 7: 1, or about 8: 1, or about 9: 1, or to about 10: 1 with respect to vortioxetine:excipient.
  • Apremix of crystalline form-M2 of vortioxetine hydrobromide with 10% w/w microcrystalline cellulose may be characterized by aPXRD pattern, for example, such as the one in Figure 6.
  • a process for the preparation of the premix of amorphous vortioxetine hydrobromide may include the following steps: a) dissolving vortioxetine hydrobromide in a solvent to form a solution;
  • a first step in the formation of a premix of amorphous vortioxetine hydrobromide is the dissolution of vortioxetine hydrobromide in a solvent to form a solution.
  • the vortioxetine hydrobromide may be any polymorphic form, amorphous, a solvate, a hydrate, or the anhydrous form of vortioxetine hydrobromide.
  • the solvent used to dissolve vortioxetine hydrobromide may be, for example, an alcoholic solvent, a ketone solvent, water, or a mixture thereof.
  • the temperature of the solution may be raised appropriately to result in dissolution of vortioxetine hydrobromide.
  • Suitable alcoholic solvents include, for example, methanol, ethanol, propanol, isopropanol, n- butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-l- butanol, 2-methyl-l-butanol, 2,2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l- propanol, 1,1 -dimethyl- 1 -propanol, and mixtures thereof.
  • Suitable ketone solvents include, for example, acetone, methyl ethyl ketone, methylisobutyl ketone, andmixtures thereof.
  • vortioxetine hydrobromide is dissolved in methanol.
  • excipients may be added to the solution.
  • the excipient can be added in any form to the solution, for example, as a solid or as part of a solution by dissolving the excipient in a second solvent.
  • Suitable excipients include, for example, polysaccharides, polyvinylpyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone- vinyl acetate copolymers, Ci-C 6 polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), copolymers of polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol (e.g., the families of block copolymers based on ethylene glycol and propylene glycol sold under the PLURONIC tradename), and mixtures thereof.
  • PVAC polyvinylpyrrolidone
  • Suitable polysaccharides include, as examples, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium salts of carboxymethyl cellulose, calcium salts of carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, cyclodextrins (e.g., ⁇ -cyclodextrin, a-cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin), and mixtures thereof.
  • cyclodextrins e.g., ⁇ -cyclodextrin, a-cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin
  • the second solvent may be any of the aforementioned solvents that are suitable for dissolving vortioxetine hydrobromide and may be the same or different than the solvent in which the vortioxetine hydrobromide is dissolved.
  • ⁇ -cyclodextrin was found to be a useful excipient.In some embodiments, particularly those employing ⁇ -cyclodextrin, it was found to be useful to first dissolve ⁇ -cyclodextrin in water before adding it to the solution of vortioxetine hydrobromide.
  • hydroxypropyl- ⁇ -cyclodextrin, PLASDONE S-630 a polyvinylpyrrolidone-vinyl acetate copolymer with a ratio of 60:40 polyvinylpyrrolidone to vinyl acetate by mass
  • povidone K-30 povidone K-30
  • the excipient may be included in the formulation at a massratio of about 0.01 : 1 to about 20: 1, where the mass ratio is vortioxetine: excipient. In certain embodiments, the excipient may be included in the formulation at a mass ratio of about 1: 1 to about 20: 1 with respect to vortioxetine:excipient. In certain other embodiments, the excipient may be included in the formulation at a mass ratio of about 1: 1 to about 10: 1, or about 2: 1 to about 10: 1, or about 4: 1 to about 10: 1, about 8: 1 to about 10: 1 with respect to vortioxetine:excipient.
  • the excipient may be included in the formulation at a mass ratio of about 1: 1, or about 2: 1, or about 3: 1, or about 4: 1, or about 5: 1, or about 6: 1, or about 7: 1, or about 8: 1, or about 9: 1, or to about 10: 1 with respect to vortioxetine:excipient.
  • the solvent may be removed to isolate the premix of amorphous vortioxetine hydrobromide.This may be carried out using known techniques, for example, evaporation, distillation, spray drying, filtration, lyophilization, or agitated thin film drying. In some embodiments of the present invention, spray drying was found to be particularly useful for removing the solvent.
  • the premix of the amorphous form of vortioxetine hydrobromide may be characterized as such by a PXRD pattern.
  • Figure 7 shows a PXRD pattern of amorphous vortioxetine hydrobromide combined with50% w/w ⁇ -cyclodextrin.
  • reaction conditions e.g., reaction time, temperature
  • reaction time e.g., reaction time, temperature
  • premixes of the present disclosure possess several benefits useful for formulating dosage forms of vortioxetine hydrobromide.
  • the premixes of amorphous vortioxetine hydrobromideand of form-M2 vortioxetine hydrobromide are particularly stable and may possess pharmaceutical workability properties (e.g., tackiness, flowability)that may permit the use of formulation techniques, such as dry and/or wet granulation.
  • the premixes of amorphous vortioxetine hydrobromideand of form-M2 vortioxetine hydrobromide can be utilized in the generation of pharmaceutical formulations.
  • HPLC separations may be performed on anHPLC column and detector system, such as an XB ridge CI 8 column (150 mm x 4.5 mm, 3 ⁇ ), using a UV detector set at 210 nm with a column oven temperature of about 30 °C.
  • a flow rate of 1.5 mL/min with an injection volume of 10 ⁇ L ⁇ may be used, with a run time of approximately 45 minutes.
  • a compound or pharmaceutical composition is considered “stable” when the HPLC purity of the compound or premix changes by less than about 1% when stored at 5 ⁇ 3°C and/or at 25 °C/60% and 40°C/75% relative humidity (RH).
  • the "stable” compound or premix is stored at 5 ⁇ 3°C.
  • the “stable” compound or premix is stored at 25 °C/60% relative humidity (RH).
  • the “stable” compound or premix is stored at 40°C/75% relative humidity (RH).
  • the pharmaceutically acceptable excipient may be combined with the solution of vortioxetine hydrobromide such that the w/w% of the pharmaceutically acceptable excipient in the final premix composition is from about 10% w/w (pharmaceutically acceptable excipient/total composition mass) to about 50% w/w, which may be about 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, or between any of the aforementioned w/w percentages, including the ranges of about 10%-40%, 10%-30%, 10%-20%, 20%-50%, 20%-40%, 20%-30%, 30%-50%, 30%-40%, and 40%-50% w/w.
  • cyclodextrins in a pharmaceutical premix may impart certain advantages to dosage forms of vortioxetine hydrobromide.
  • Cyclodextrins have the ability to interact advantageously with molecules, particularly those that are hydrophobic or have low water solubility, to improve pharmaceutically relevant parameters.
  • cyclodextrin may forma complex with an active pharmaceutical ingredient.
  • Such complexes may display improved aqueous solubility, bioavailability, or stability.
  • Vortioxetine hydrobromide because it has low aqueous solubility, may be able to interact with cyclodextrins in this way to provide enhanced stability of the vortioxetine hydrobromide in the premix and final dosage form, as well as displaying improved bioavailability after administration.
  • Table 1 shows data collected on the premix of amorphous vortioxetine hydrobromide with 33% ⁇ -cyclodextrin and 50% ⁇ - cyclodextrin prepared according to the processes disclosed herein.
  • the premix of amorphous vortioxetine hydrobromide prepared with 33% ⁇ -cyclodextrin and the premix of amorphous vortioxetine hydrobromide prepared with 50% ⁇ -cyclodextrin show no significant degradationor change in PXRD pattern (e.g., is stable at 3 and 6 months) when stored at 5 ⁇ 3 °C and at 25 °C/60% and 40°C/75% relative humidity (RH).
  • the premix of amorphous vortioxetine hydrobromide is stable over six months under those conditions.
  • cyclodextrin-vortioxetine hydrobromide complex may be more stable in water, which, in turn, may improve bioavailability in an oral dosage form.
  • crystalline forms of vortioxetine hydrobromide, solvates thereof, of vortioxetine hydrobromide and premixes disclosed herein may be incorporated into oral pharmaceutical dosage forms, for example, a capsule or tablet. Dosage forms that include thecrystalline forms of vortioxetine hydrobromide, solvates thereof, of vortioxetine hydrobromide and premixes disclosed herein may be useful for the treatment of major depressive disorder.
  • the oral dosage forms containing vortioxetine hydrobromide in any of the crystalline forms disclosed herein (form-Mi, form-M 2 , form-M 3 , or form-M 4 )as well as premixes of form-M 2 or amorphous vortioxetine hydrobromide may further comprise one or more additional pharmaceutically acceptable excipients such as, for example,mannitol, microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate, magnesium stearate, as well as artificial colors and flavorings.
  • Capsules or tablets containing vortioxetine hydrobromide in any of the crystalline forms disclosed herein (form-Mi, form-M 2 , form-M 3 , or form-M 4 ) as well as premixes of form-M 2 or amorphous vortioxetine hydrobromide may include a coating that contains, for example, hypromellose, titanium dioxide, polyethylene glycol (e.g., PEG 400), iron oxide red, iron oxide yellow, or mixtures thereof.
  • PEG 400 polyethylene glycol
  • iron oxide red iron oxide yellow
  • dosage forms containing vortioxetine hydrobromide in any of the crystalline forms disclosed herein may have between about 5 mg to about 20 mg per dose, including dosages of about 5 mg, 10 mg, 15 mg, and 20 mg.
  • Vortioxetine hydrobromide (lg) was dissolved in isobutanol (50mL) at 75 ⁇ 5°C. The clear solution was filtered through HYFLO at 50 ⁇ 5°C and then washed with isobutanol (5 mL). The obtained clear solution was cooled to 25 ⁇ 3°C and maintained under agitation for 48hours at 25 ⁇ 3 °C. The resulted reaction mass was filtered and dried under vacuum at 40 °C for 5hours to yield vortioxetine hydrobromide crystalline form-Mi.
  • Vortioxetine hydrobromide (lg) was dissolved in 2-butanol (60mL) at 75 ⁇ 5°C. The clear solution was filtered through HYFLO at 50 ⁇ 5°Cand then washed with 2-butanol (5mL). The obtained clear solution was cooled to 25 ⁇ 3°C and maintained under agitation for 48 hours at 25 ⁇ 3°C. The resulted reaction mass was filtered and dried under vacuum at 40°C for 5hours to yield vortioxetine hydrobromide crystalline form-M2.
  • Vortioxetine base (5g) was dissolved in isoamyl alcohol (75 mL) at 75 ⁇ 5°C and reaction mass was cooled to 25 ⁇ 3°C. The clear solution was filtered through HYFLO to remove any undissolved particulate. The obtained clear solution was cooled to 0-5°C. To this, aqueous hydrobromide solution (3.0 mL) was added at 0-5 °C to get a milky white precipitate. The temperature was maintained at 0-5°C 24 hours. The resulting solution was filtered and dried under vacuum at 30 °C for 15 hours to yield vortioxetine hydrobromide crystalline form-M3
  • Vortioxetine hydrobromide form-M2 (100 mg) was suspended in a 1 :2 v/v ratio of isopropyl alcohol and water mixture (1 mL) at 25-30°C. The suspension was heated to 50°C and maintained under stirring for 15 hours. The reaction mass was filtered and dried under vacuum at 40°C for 15 hours. The obtained solid was identified as crystalline form-Mi.
  • Example 5 Preparation of vortioxetine hydrobromide crystalline form-M4 Vortioxetine hydrobromide form-M 2 (100 mg) was suspended in 1:2 v/v ratio of 1-propanol and water mixture (1 mL) at 25-30°C. The suspension was heated to 50°C and maintained under stirring for 15 hours. The reaction mass was filtered and dried under vacuum at 40°C for 15 hours. The obtained solid was identified as crystalline form-Mi.
  • Vortioxetine hydrobromide form-M 2 (100 mg) was suspended in 1:2 v/v ratio of acetonitrile and water mixture (1 mL) at 25-30°C. The suspension was heated to 50°C and maintained under stirring for 15 hours. The reaction mass was filtered and dried under vacuum at 40°C for 15 hours. The obtained solid was identified as crystalline form-Mi.
  • Vortioxetine hydrobromide form-M 2 (100 mg) was suspended in 1 : 1 v/v ratio of isopropyl alcohol and water mixture (1 mL) at 25-30°C. The suspension was heated to 50°C and maintained under stirring for 15 hours. The reaction mass was filtered and dried under vacuum at 40°C for 15 hours. The obtained solid was identified as crystalline form-Mi.
  • Vortioxetine hydrobromide form-M 2 (100 mg) was suspended in 1:2 v/v ratio of tetrahydrofuran and water mixture (1 mL) at 25-30°C. The suspension was heated to 50°C and maintained under stirring for 15 hours. The reaction mass was filtered and dried under vacuum at 40°C for 15 hours. The solid obtained was identified as crystalline form-Mi.
  • Vortioxetine hydrobromide form-M 2 (100 mg) was suspended in 1: 1 v/v ratio of tetrahydrofuran and water mixture (1 mL) at 25-30°C. The suspension was heated to 50°C and maintained under stirring for 15 hours. The reaction mass was filtered and dried under vacuum at 40°C for 15 hours. The obtained solid was identified as crystalline form-Mi.
  • Example 10 Preparation of a premix of crystalline form-M 2 of vortioxetine hydrobromide
  • Vortioxetine hydrobromide (5 g) was dissolved in 2-butanol (235 mL) at 75 ⁇ 5°C. The clear solution was filtered through HYFLO at 50 ⁇ 5°C and then washed with 2-butanol (15 mL). The obtained clear solution was cooled to 25 ⁇ 3°C and maintained under agitation for 20-24 hours. The resulting reaction mass was cooled to 0-5°C and maintained for 2 hours.To this, microcrystalline cellulose (0.55 g) was added and maintained under agitation for 1 hour at 0 - 5 °C, filtered, and suck-dried. The obtained solid was further dried under vacuum at 30°C for 15 hours to yield a premix of crystalline form-M2 of vortioxetine hydrobromide.
  • Vortioxetine hydrobromide (3 g) was dissolved in 2-butanol (140 mL) at 75 ⁇ 5°C. The clear solution was filtered through HYFLO at 50 ⁇ 5°C and then washed with 2-butanol (10 mL). The clear solution was cooled to 25 ⁇ 3°C and maintained under agitation for 22 hours. The resulting reaction mass was cooled to 0-5 °C and maintained 2 hours. To this, microcrystalline cellulose (0.75 g) was added and maintained under agitation for lhour at 0-5°C, filtered, and suck-dried. The obtained solid was further dried under vacuum at 30°C for 15 hours to yield a premix of crystalline form-lVL of vortioxetine hydrobromide.
  • Example 12 Preparation of a premix of crystalline form-M 2 of vortioxetine hydrobromide
  • Vortioxetine hydrobromide (5 g) was dissolved in 2-butanol (235 mL) at 75 ⁇ 5°C. The clear solution was filtered through HYFLO at 50 ⁇ 5°C and then washed with 2-butanol (15 mL). The clear solution was cooled to 25 ⁇ 3°C and maintained under agitation for 20-24 hours. The resulting reaction mass was cooled to 0-5°C and maintained for 2 hours. To this, microcrystalline cellulose (2.14 g) was added and maintained under agitation for lhour at 0- 5 °C, filtered, and suck-dried. The obtained solid was further dried under vacuum at 30°C for 15hours to yield a premix of crystalline form-lVL of vortioxetine hydrobromide.
  • Vortioxetine hydrobromide (5 g) was dissolved in 2-butanol (235 mL) at 75 ⁇ 5°C. The clear solution was filtered through HYFLO at 50 ⁇ 5°C and then washed with 2-butanol (15 mL). The clear solution was cooled to 25 ⁇ 3°C and maintained under agitation for 20-24 hours. The resulting reaction mass was cooled to 0-5 °C and maintained for 2 hours.To this, microcrystalline cellulose (5 g) was added and maintained under agitation for 1 hour at 0-5 °C, filtered, and suck- dried. The obtained solid was further dried under vacuum at 30°C for 15 hours to yield a premix of crystalline form-M2 of vortioxetine hydrobromide.
  • Vortioxetine hydrobromide (4 g) was dissolved in methanol (80 mL) at 60 ⁇ 5°C.
  • ⁇ -cyclodextrin (4 g) was dissolved in water (76 mL) at 25 ⁇ 5°C.
  • This clear solution was added to the vortioxetine hydrobromide methanol solution at same temperature.
  • the resulting clear solution was filtered through HYFLO to remove any undissolved particulate and subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with feed rate of the solution 10 mL/min and inlet temperature at 70°C to yield a premix of amorphous vortioxetine hydrobromide.
  • Vortioxetine hydrobromide (5 g) was dissolved in methanol (100 mL) at 60 ⁇ 5°C. In another flask ⁇ -cyclodextrin (2.5 g) was dissolved in water (95 mL) at 25 ⁇ 5°C and this clear solution was added to Vortioxetine hydrobromide methanol solution at same temperature. The resulting clear solution was filtered through HYFLO to remove any undissolved particulate and subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with feed rate of the solution 10 mL/min and inlet temperature at 70°C to yield a premix of amorphous vortioxetine hydrobromide.
  • Vortioxetine hydrobromide (10 g) was dissolved in methanol (100 mL) at 60 ⁇ 5°C.
  • ⁇ -cyclodextrin (1.1 g) was dissolved in water (90 mL) at 25 ⁇ 5°C and this clear solution was added to Vortioxetine hydrobromide solution at same temperature.
  • the resulting clear solution was filtered through HYFLO to remove any undissolved particulate and subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with feed rate of the solution 10 mL/min and inlet temperature at 70°C to yield a premix of amorphous vortioxetine hydrobromide.
  • Example 17 Preparation of a premix of amorphous vortioxetine hydrobromide
  • Vortioxetine hydrobromide (5 g) was dissolved in methanol (100 mL) at 60 ⁇ 5°C.To this, hydroxypropyl ⁇ -cyclodextrin (0.55 g) was added at same temperature. The resulting clear solution was filtered through HYFLO at 25 ⁇ 5°C to remove any undissolved particulate and subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with feed rate of the solution lOmL/min and inlet temperature at 70°C to yield a premix of amorphous vortioxetine hydrobromide.
  • Vortioxetine hydrobromide (5 g) was dissolved in methanol (100 mL) at 60 ⁇ 5°C. To this, PLASDONE S-630 (0.55g) was added at same temperature. The resulting clear solution was filtered through HYFLO at 25 ⁇ 5°C to remove any undissolved particulate and subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with feed rate of the solution 10 mL/min and inlet temperature at 70°C to yield a premix of amorphous vortioxetine hydrobromide.
  • Vortioxetine hydrobromide (5 g) was dissolved in methanol (100 mL) at 60 ⁇ 5°C. To this, povidone K-30 (0.55g) was added at same temperature. The resulting clear solution was filtered through HYFLO at 25 ⁇ 5°C to remove any undissolved particulate and subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with feed rate of the solution 10 mL/min and inlet temperature at 70°C to yield a premix of amorphousvortioxetine hydrobromide.
  • Example 21 Preparation of a premix of amorphous vortioxetine hydrobromide premix
  • Vortioxetine hydrobromide (5 g) was dissolved in methanol (100 mL) at 60 ⁇ 5°C.To this, hydroxypropyl ⁇ -cyclodextrin (0.55g) was added at same temperature. The resulting clear solution was filtered through HYFLO at 25 ⁇ 5°C to remove any undissolved particulate and subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with feed rate of the solution 10 mL/min and inlet temperature at 70°C to yield a premix of amorphous vortioxetine hydrobromide.

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Abstract

La présente invention concerne des formes cristallines de bromhydrate de vortioxétine, désignées comme forme-M1, forme-M2, forme-M3, et forme-M4. La présente invention concerne également un prémélange pharmaceutique d'une forme-M2 cristalline de bromhydrate de vortioxétine et d'excipients pharmaceutiquement acceptables et un procédé de préparation associé, ainsi qu'un prémélange pharmaceutique de bromhydrate de vortioxétine amorphe et d'excipients pharmaceutiquement acceptables et un procédé de préparation associé. Dans certains modes de réalisation, la génération d'un prémélange qui comprend du bromhydrate de vortioxétine amorphe et de la β-cyclodextrine s'est avérée particulièrement stable et avantageuse.
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WO2017045655A1 (fr) * 2015-09-16 2017-03-23 Zentiva, K.S. Forme amorphe de bromhydrate de vortioxétine stabilisée par une cyclodextrine
WO2017125504A1 (fr) * 2016-01-20 2017-07-27 Amneal Pharmaceuticals Company Gmbh Formes polymorphes de tert-butanolate de bromhydrate de vortioxétine
WO2018042168A1 (fr) * 2016-08-29 2018-03-08 King, Lawrence Composition pharmaceutique stable de bromhydrate de vortioxétine
WO2018154451A1 (fr) * 2017-02-23 2018-08-30 Unichem Laboratories Ltd Procédé amélioré de préparation et de purification de bromhydrate de vortioxétine
CN110372635A (zh) * 2018-04-12 2019-10-25 浙江京新药业股份有限公司 氢溴酸沃替西汀α晶型的制备方法
US10519121B2 (en) 2016-12-30 2019-12-31 Apicore Us Llc Process and novel polymorphic form of vortioxetine and its pharmaceutically acceptable salts
CN111330018A (zh) * 2018-12-18 2020-06-26 浙江京新药业股份有限公司 沃替西汀-环糊精包合物、制备方法及其药物组合物
CN115160258A (zh) * 2022-06-24 2022-10-11 辰欣药业股份有限公司 一种氢溴酸沃替西汀γ晶型的制备方法

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WO2017045655A1 (fr) * 2015-09-16 2017-03-23 Zentiva, K.S. Forme amorphe de bromhydrate de vortioxétine stabilisée par une cyclodextrine
WO2017125504A1 (fr) * 2016-01-20 2017-07-27 Amneal Pharmaceuticals Company Gmbh Formes polymorphes de tert-butanolate de bromhydrate de vortioxétine
WO2018042168A1 (fr) * 2016-08-29 2018-03-08 King, Lawrence Composition pharmaceutique stable de bromhydrate de vortioxétine
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WO2018154451A1 (fr) * 2017-02-23 2018-08-30 Unichem Laboratories Ltd Procédé amélioré de préparation et de purification de bromhydrate de vortioxétine
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CN110372635A (zh) * 2018-04-12 2019-10-25 浙江京新药业股份有限公司 氢溴酸沃替西汀α晶型的制备方法
CN110372635B (zh) * 2018-04-12 2021-06-04 浙江京新药业股份有限公司 氢溴酸沃替西汀α晶型的制备方法
CN111330018A (zh) * 2018-12-18 2020-06-26 浙江京新药业股份有限公司 沃替西汀-环糊精包合物、制备方法及其药物组合物
CN111330018B (zh) * 2018-12-18 2023-07-21 浙江京新药业股份有限公司 沃替西汀-环糊精包合物、制备方法及其药物组合物
CN115160258A (zh) * 2022-06-24 2022-10-11 辰欣药业股份有限公司 一种氢溴酸沃替西汀γ晶型的制备方法
CN115160258B (zh) * 2022-06-24 2023-11-17 辰欣药业股份有限公司 一种氢溴酸沃替西汀γ晶型的制备方法

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