US20080214561A1 - Solid forms of [4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl-[5-methanesulfonyl-2-((s)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone - Google Patents

Solid forms of [4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl-[5-methanesulfonyl-2-((s)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone Download PDF

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US20080214561A1
US20080214561A1 US12/002,997 US299707A US2008214561A1 US 20080214561 A1 US20080214561 A1 US 20080214561A1 US 299707 A US299707 A US 299707A US 2008214561 A1 US2008214561 A1 US 2008214561A1
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piperazin
methanesulfonyl
trifluoro
fluoro
phenyl
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Andre Bubendorf
Annette Deynet-Vucenovic
Ralph Diodone
Olaf Grassmann
Kai Lindenstruth
Emmanuel Pinard
Franziska E. Rohrer
Urs Schwitter
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Hoffmann La Roche Inc
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Hoffmann La Roche Inc
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Assigned to HOFFMANN-LA ROCHE, INC. reassignment HOFFMANN-LA ROCHE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: F. HOFFMANN-LA ROCHE AG
Assigned to F. HOFFMANN-LA ROCHE AG reassignment F. HOFFMANN-LA ROCHE AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BUBENDORF, ANDRE, DEYNET-VUCENOVIC, ANNETTE, DIODONE, RALPH, GRASSMANN, OLAF, LINDENSTRUTH, KAI, PINARD, EMMANUEL, ROHRER, FRANZISKA E., SCHWITTER, URS
Publication of US20080214561A1 publication Critical patent/US20080214561A1/en
Priority to US12/841,195 priority Critical patent/US8039473B2/en
Priority to US13/188,486 priority patent/US20110295007A1/en
Priority to US13/495,093 priority patent/US20120309969A1/en
Priority to US13/798,358 priority patent/US20130197225A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings

Definitions

  • the present invention provides four distinct crystalline forms and to an amorphous form of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone, and to their use in the preparation of pharmaceutical compositions.
  • the four distinct crystalline forms and amorphous form of 4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone are suitable for preparing a pharmaceutical formulation.
  • the present invention relates to three distinct crystalline forms A, B and C of the following compound:
  • the present invention relates to the amorphous form of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • the present invention relates to a methylparaben cocrystal form of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form A, B, C or an amorphous form or a methylparaben cocrystal form of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone as an active ingredient.
  • the invention relates to a method for the treatment of treating psychoses, pain, neurodegenerative disfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease which comprises administering a therapeutically effective amount of a crystalline form A, B, C or an amorphous form or a methylparaben cocrystal form of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • the aforementioned solid forms can be distinguished by physical and chemical properties that can be characterized by infra-red spectra, X-ray powder diffraction patterns, melting behavior or glass transition temperatures.
  • FIG. 1 shows a XRPD (Powder X-Ray Powder Diffraction) pattern of a typical lot of form A of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • XRPD Powder X-Ray Powder Diffraction
  • FIG. 2 shows an IR (Infra Red Spectroscopy) spectrum of a typical lot of form A of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • FIG. 3 shows a DSC (Differencial Scanning Calorimetry) curve of a typical lot of form A of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • FIG. 4 shows a TGA (Thermo Gravimetric Analysis) curve of a typical lot of form A of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • TGA Thermo Gravimetric Analysis
  • FIG. 5 shows a XRPD (Powder X-Ray Diffraction) pattern of a typical lot of form B of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • XRPD Powder X-Ray Diffraction
  • FIG. 6 shows an IR (Infra Red) spectrum of a typical lot of form B of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • FIG. 7 shows a DSC (Differencial Scanning Calorimetry) curve of a typical lot of form B of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • FIG. 8 shows a TGA (Thermo Gravimetric Analysis) curve of a typical lot of form B of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • TGA Thermo Gravimetric Analysis
  • FIG. 9 shows a XRPD (Powder X-Ray Diffraction) pattern of a typical lot of form C of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • XRPD Powder X-Ray Diffraction
  • FIG. 10 shows an IR (Infra Red) spectrum of a typical lot of form C of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • FIG. 11 shows a DSC (Differencial Scanning Calorimetry) curve of a typical lot of form C of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • FIG. 12 shows a TGA (Thermo Gravimetric Analysis) curve of a typical lot of form C of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • TGA Thermo Gravimetric Analysis
  • FIG. 13 shows a XRPD (Powder X-Ray Diffraction) pattern of a typical lot of the amorphous form of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • XRPD Powder X-Ray Diffraction
  • FIG. 14 shows an IR (Infra Red) spectrum of a typical lot of the amorphous form of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • FIG. 15 shows DSC (Differencial Scanning Calorimetry) curves of two typical lots of the amorphous form of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • FIG. 16 shows a TGA (Thermo Gravimetric Analysis) curve of a typical lot of the amorphous form of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • TGA Thermo Gravimetric Analysis
  • FIG. 17 shows a DVS (Dynamic Vapor Sorption) isotherm of a typical lot of the amorphous form of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • DVS Dynamic Vapor Sorption
  • FIG. 18 shows a XRPD (Powder X-Ray Diffraction) pattern of a typical lot of the methylparaben cocrystal form of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-A]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • XRPD Powder X-Ray Diffraction
  • FIG. 19 shows an IR (Infra Red) spectrum of a typical lot of the methylparaben cocrystal form of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • IR Infra Red
  • FIG. 20 shows a DSC (Differencial Scanning Calorimetry) curve of a typical lot of the methylparaben cocrystal form of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • DSC Dermat Configuration Scanning Calorimetry
  • FIG. 21 shows a TGA (Thermo Gravimetric Analysis) curve of a typical lot of the methylparaben cocrystal form of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • TGA Thermo Gravimetric Analysis
  • amorphous forms denotes a material that lacks long range order and as such does not show sharp X-ray peaks, i.e. a Bragg diffraction peak.
  • the XRPD pattern of an amorphous material is characterized by one or more amorphous halos.
  • An amorphous halo is an approximately bell-shaped diffraction maximum in the X-ray powder diffraction pattern of an amorphous substance.
  • the FWHM of an amorphous halo is bigger than two degrees in 2-theta.
  • FWHM means full width at half maximum, which is a width of a peak appearing in an XRPD pattern at its half height.
  • API is used herein as an acronym of Active Pharmaceutical Ingredient.
  • DSC Differencial Scanning Calorimetry
  • amorphous forms For the measurements of amorphous forms, approximately 2-6 mg of sample were placed in aluminum pans, accurately weighed and hermetically closed. The samples were then heated under a flow of nitrogen of about 100 mL/min using heating rates of 10 K/min.
  • DVS Dynamic Vapor Sorption
  • DVS-1 SMS Surface Measurements Systems
  • the sorption/desorption isotherms were measured stepwise in a range of 0% R H to 90% RH at 25° C.
  • a weight change of ⁇ 0.002 mg/min was chosen as criterion to switch to the next level of relative humidity (with a maximum equilibration time of six hours, if the weight criterion was not met).
  • the data were corrected for the initial moisture content of the samples; that is, the weight after drying the sample at 0% relative humidity was taken as the zero point.
  • Form A is used herein as abbreviation for the crystalline form A of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • Form B is used herein as abbreviation for the crystalline form B of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • Form C is used herein as abbreviation for the crystalline form C of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • Methods for the methylparaben cocrystal form is used herein as abbreviation for the methylparaben cocrystal form of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.
  • IR is used herein as an acronym of Infra Red, hence “IR spectrum” means Infra Red Spectrum.
  • the IR-spectrum of the sample was recorded as film of a Nujol suspension consisting of approx. 5 mg of sample and few Nujol between two sodium chloride plates, with an FT-IR spectrometer in transmittance.
  • the Spectrometer was a NicoletTM 205XB or equivalent (resolution: 2 cm ⁇ 1 , 32 or more coadded scans, MCT detector).
  • XRPD is used herein as an acronym of X-Ray Powder Diffraction.
  • X-ray diffraction patterns were recorded at ambient conditions in transmission geometry with a STOE STADI P diffractometer (Cu K ⁇ radiation, primary monochromator, position sensitive detector, angular range 3 to 42 2Theta (deg), approximately 60 minutes total measurement time). The samples were prepared and analyzed without further processing (e.g. grinding or sieving) of the substance.
  • X-ray diffraction patterns were recorded in transmission geometry with a STOE STADIP diffractometer with Cu K ⁇ radiation (1.54 ⁇ ) and a position sensitive detector.
  • the samples (approximately 50 mg) were prepared between thin polymer (or aluminum) films and analyzed without further processing (e.g. grinding or sieving) of the substance.
  • X-ray diffraction patterns were also measured on a Scintag X1 powder X-ray diffractometer equipped with a sealed copper K ⁇ 1 radiation source. The samples were scanned from 2 to 36 2 Theta (deg) at a rate of 1 degree 2 Theta per minute with incident beam slit widths of 2 and 4 mm and diffracted beam slit widths of 0.3 and 0.2 mm.
  • TGA Thermo Gravimetric Analysis. TGA curves were measured on a Mettler-ToledoTM thermogravimetric analyzer (TGA850 or TGA851). System suitability tests and calibrations were carried out according to the internal standard operation procedure.
  • thermogravimetric analyses approx. 5 to 10 mg of sample were placed in aluminum pans, accurately weighed and hermetically closed with perforation lids. Prior to measurement, the lids were automatically pierced resulting in approx. 1.5 mm pin holes. The samples were then heated under a flow of nitrogen of about 50 mL/min using a heating rate of 5 K/min.
  • “Pharmaceutically acceptable” such as pharmaceutically acceptable carrier, excipient, adjuvant, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying the osmotic pressure, buffers, masking agents or antioxidants, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
  • “Pharmaceutically acceptable” hence means substantially non-toxic to the subject to which the pharmaceutically acceptable material is administered.
  • a “cocrystal” is formed between a molecular or ionic API and a cocrystal former that is a solid under ambient conditions, i.e. a cocrystal is a multi-component crystalline material comprising two or more solids (at ambient conditions).
  • “Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • the present invention relates to four novel crystalline forms and to an amorphous form of the following compound:
  • [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone can be isolated, depending upon the method of preparation, as form A, B, C or methylparaben cocrystal form and in an amorphous form.
  • Forms A, B and C can be isolated from several different crystallization methods of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone as described hereinafter.
  • the amorphous form can be obtained by lyophilization or fast concentration of a [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone solution as described hereinafter.
  • the methylparaben cocrystal form can be obtained by, digestion or re-crystallization of form A, B, C or amorphous form and methylparaben as described hereinafter.
  • form A can be prepared by method comprising:
  • form A can be obtained by recrystallization of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone in ethanol at certain temperature and concentration after seeding with subsequent crystallization during cooling.
  • Form A can be obtained normally by recrystallization of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone in ethanol and spontaneous crystallization below 40° C., without seeding, with subsequent precipitation during cooling.
  • the formation of form A is not limited to ethanol, ethanol/water, methanol, methanol/water, toluene, 2-propanole, dioxane/water and dioxane.
  • Form A is a solvent-free form as no significant weight loss is observed in the TGA curve prior to decomposition.
  • Form A can be characterized by at least three peaks selected from the following X-ray diffraction peaks obtained with a CuK ⁇ radiation expressed in degrees 2Theta at approximately: 13.1, 14.3, 15.4, 16.2, 17.1, 17.2, 17.6, 18.0, 19.8, 20.1, 20.4, 21.0, 22.6, 24.3.
  • Form A can be characterized by at least five peaks selected from the following X-ray diffraction peaks obtained with a CuK ⁇ radiation expressed in degrees 2Theta at approximately: 13.1, 14.3, 15.4, 16.2, 17.1, 17.2, 17.6, 18.0, 19.8, 20.1, 20.4, 21.0, 22.6, 24.3.
  • Form A can be characterized by at least seven peaks selected from the following X-ray diffraction peaks obtained with a CuK ⁇ radiation expressed in degrees 2Theta at approximately: 13.1, 14.3, 15.4, 16.2, 17.1, 17.2, 17.6, 18.0, 19.8, 20.1, 20.4, 21.0, 22.6, 24.3.
  • Form A can also be characterized by the following X-ray diffraction peaks obtained with a CuK ⁇ radiation expressed in degrees 2Theta at approximately: 13.1, 14.3, 15.4, 16.2, 17.1, 17.2, 17.6, 18.0, 19.8, 20.1, 20.4, 21.0, 22.6 and 24.3.
  • Form A can also be characterized by the X-ray diffraction pattern as substantially shown in FIG. 1 .
  • Form A can also be characterized by an infrared spectrum having sharp bands at 3032, 1645, 1623, 1600, 1581, 1501, 1342, 1331, 1314, 1291, 1266, 1245, 1154, 1130, 1088, 1054, 1012, 976, 951, 922, 889, 824, 787, 758, 739, 714 and 636 cm ⁇ 1 ( ⁇ 3 cm ⁇ 1 ).
  • Form A can also be characterized by the infrared spectrum as substantially shown in FIG. 2 .
  • Form A can also be characterized by a melting point with onset temperature (DSC) in the range of about 138° C. to 144° C.
  • DSC melting point with onset temperature
  • FIGS. 1 to 4 These characteristics and others are shown in FIGS. 1 to 4 .
  • the compound [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone comprises at least 70% of a crystalline polymorph of form A as described above; in a certain embodiment, it comprises at least 90% of a crystalline polymorph of form A as described above; in a certain embodiment, it comprises at least 96% of a crystalline polymorph of form A as described above; in a certain embodiment, it comprises at least 99% of a crystalline polymorph of form A as described above.
  • form B can be prepared by a method comprising:
  • Form B can be obtained by seeding of an ethanol solution and subsequent cooling. Form B can be obtained occasionally without seeding of an ethanol solution and subsequent cooling. Form B can also be prepared by re-crystallization of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone in several solvents and seeding with form B.
  • Form B is a solvent-free form as no significant weight loss is observed in the TGA curve prior to decomposition.
  • Form B can be characterized by at least three peaks selected from the following X-ray diffraction peaks obtained with a CuK ⁇ radiation expressed in degrees 2Theta at approximately: 11.4, 15.4, 16.2, 16.2, 16.4, 17.8, 18.3, 19.2, 20.1, 21.0, 22.0, 22.5, 26.4.
  • Form B can be characterized by at least five peaks selected from the following X-ray diffraction peaks obtained with a CuK ⁇ radiation expressed in degrees 2Theta at approximately: 11.4, 15.4, 16.2, 16.2, 16.4, 17.8, 18.3, 19.2, 20.1, 21.0, 22.0, 22.5, 26.4.
  • Form B can be characterized by at least seven peaks selected from the following X-ray diffraction peaks obtained with a CuK ⁇ radiation expressed in degrees 2Theta at approximately: 11.4, 15.4, 16.2, 16.2, 16.4, 17.8, 18.3, 19.2, 20.1, 21.0, 22.0, 22.5, 26.4.
  • Form B can also be characterized by the following X-ray diffraction peaks obtained with a CuK ⁇ radiation expressed in degrees 2Theta at approximately: 11.4, 15.4, 16.2, 16.2, 16.4, 17.8, 18.3, 19.2, 20.1, 21.0, 22.0, 22.5 and 26.4.
  • Form B can also be characterized by the X-ray diffraction pattern as substantially shown in FIG. 5 .
  • Form B can also be characterized by an infrared spectrum having sharp bands at: 1644, 1635, 1621, 1599, 1567, 1514, 1488, 1398, 1343, 1328, 1291, 1266, 1183, 1155, 1090, 1022, 1003, 973, 958, 938, 920, 897, 822, 783, 753, 740, 683 and 638 cm ⁇ 1 (+3 cm ⁇ 1 ).
  • Form B can also be characterized by an infrared spectrum as substantially shown in FIG. 6 .
  • Form B can also be characterized by a melting point with onset temperature (DSC) in the range of about 151° C. to 154° C.
  • DSC melting point with onset temperature
  • FIGS. 5 to 8 These characteristics and others are shown in FIGS. 5 to 8 .
  • the compound [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone comprises at least 70% of a crystalline polymorph of form B as described above, in a certain embodiment, it comprises at least 90% of a crystalline polymorph of form B as described above; in a certain embodiment, it comprises at least 96% of a crystalline polymorph of form B as described above; in a certain embodiment, it comprises at least 99% of a crystalline polymorph of form B as described above.
  • form C can be prepared by a method comprising:
  • Form C can be obtained by crystallization from a toluene or toluene/n-heptane solution at 100° C.
  • Form C can also be prepared by crystallization of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone in several solvents and seeding with form C.
  • form C can be obtained by tempering of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone at 150° C. for 2 hours and subsequent rapid cooling.
  • Form C is a solvent-free form as no significant weight loss is observed in the TGA curve prior to decomposition.
  • Form C can be characterized by at least three peaks selected from the following X-ray diffraction peaks obtained with a CuK ⁇ radiation expressed in degrees 2Theta at approximately: 14.9, 15.7, 16.7, 17.7, 17.8, 18.7, 19.7, 21.8, 22.0, 25.2.
  • Form C can be characterized by at least five peaks selected from the following X-ray diffraction peaks obtained with a CuK ⁇ radiation expressed in degrees 2Theta at approximately: 14.9, 15.7, 16.7, 17.7, 17.8, 18.7, 19.7, 21.8, 22.0, 25.2.
  • Form C can be characterized by at least seven peaks selected from the following X-ray diffraction peaks obtained with a CuK ⁇ radiation expressed in degrees 2Theta at approximately: 14.9, 15.7, 16.7, 17.7, 17.8, 18.7, 19.7, 21.8, 22.0, 25.2.
  • Form C can also be characterized by the following X-ray diffraction peaks obtained with a CuK ⁇ radiation expressed in degrees 2Theta at approximately: 14.9, 15.7, 16.7, 17.7, 17.8, 18.7, 19.7, 21.8, 22.0 and 25.2.
  • Form C can also be characterized by the X-ray diffraction pattern as substantially shown in FIG. 9 .
  • Form C can also be characterized by an infrared spectrum having sharp bands at: 1641, 1622, 1601, 1581, 1566, 1514, 1398, 1378, 1341, 1322, 1309, 1294, 1281, 1159, 1087, 1023, 1009, 966, 934, 917, 901, 822, 784, 757, 681 and 640 cm ⁇ 1 ( ⁇ 3 cm ⁇ 1 ).
  • Form C can also be characterized by infrared spectrum as substantially shown in FIG. 10 .
  • Form C can also be characterized by a melting point with onset temperature (DSC) in the range of about 152° C. to 156° C.
  • DSC melting point with onset temperature
  • FIGS. 9 to 12 These characteristics and others are shown in FIGS. 9 to 12 .
  • the compound [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone comprises at least 70% of a crystalline polymorph of form C as described above; in a certain embodiment, it comprises at least 90% of a crystalline polymorph of form C as described above; in a certain embodiment, it comprises at least 96% of a crystalline polymorph of form C as described above; in a certain embodiment, it comprises at least 99% of a crystalline polymorph of form C as described above.
  • the amorphous form can be prepared by a method comprising:
  • the amorphous form can be obtained from an ethanol solution upon fast evaporation at about 40° C. under vacuum.
  • the amorphous form can also be obtained by lyophilization of a solution of 1.0 g of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone in 50 mL acetonitrile (condensator at ⁇ 46° C. and vacuum at 0-1 mbar)
  • the amorphous form can be characterized by the lack of sharp X-ray diffraction peaks in its XRPD pattern.
  • the amorphous form can also be characterized by the X-ray diffraction pattern as substantially shown in FIG. 13 .
  • the amorphous form can be also be characterized by an infrared spectrum having sharp bands at 1642, 1622, 1599, 1579, 1509, 1487, 1399, 1329, 1293, 1253, 1159, 1124, 1090, 1016, 960, 920, 903, 889, 827, 782, 763, 739 and 636 cm ⁇ 1 ( ⁇ 3 cm ⁇ 1 ).
  • the amorphous form can also be characterized by infrared spectrum as substantially shown in FIG. 14 .
  • the amorphous form can be also be characterized by a glass transition temperature (DSC, heating rate 10 K/min, closed pan) of about 48° C. to about 65° C. (The glass transition temperature is largely dependent on the solvent/water content).
  • FIGS. 13 to 17 These characteristics and others are shown in FIGS. 13 to 17 .
  • the compound [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone comprises at least 70% of an amorphous form as described above; in a certain embodiment, it comprises at least 90% of an amorphous form as described above; in a certain embodiment, it comprises at least 96% of an amorphous form as described above; in a certain embodiment, it comprises at least 99% of an amorphous form as described above.
  • the methylparaben cocrystal form can be prepared by a method comprising re-crystallization of form A, B, C or amorphous form and methylparaben with or without seeding in solvent systems.
  • the methylparaben cocrystal form can be produced by digestion in solvents as e.g. ethanol and water. It can also be prepared by re-crystallization of form A, B, C or amorphous form and methylparaben with or without seeding in solvent systems comprising but not limited to ethanol.
  • 4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone-methylparaben ratio can range from 1:1 to 1:10.
  • the methylparaben cocrystal form can be characterized by at least three peaks selected from the following X-ray diffraction peaks obtained with a CuK ⁇ radiation expressed in degrees 2Theta at approximately: 8.0, 8.9, 10.5, 12.6, 15.2, 16.1, 17.7, 18.5, 19.8, 20.2, 21.7, 22.9, 24.2, 25.9.
  • the methylparaben cocrystal form can be characterized by at least five peaks selected from the following X-ray diffraction peaks obtained with a CuK ⁇ radiation expressed in degrees 2Theta at approximately: 8.0, 8.9, 10.5, 12.6, 15.2, 16.1, 17.7, 18.5, 19.8, 20.2, 21.7, 22.9, 24.2, 25.9.
  • the methylparaben cocrystal form can be characterized by at least seven peaks selected from the following X-ray diffraction peaks obtained with a CuK ⁇ radiation expressed in degrees 2Theta at approximately: 8.0, 8.9, 10.5, 12.6, 15.2, 16.1, 17.7, 18.5, 19.8, 20.2, 21.7, 22.9, 24.2, 25.9.
  • the methylparaben cocrystal form can also be characterized by the following X-ray diffraction pattern obtained with a CuK ⁇ radiation expressed in degrees 2Theta at approximately: 8.0, 8.9, 10.5, 12.6, 15.2, 16.1, 17.7, 18.5, 19.8, 20.2, 21.7, 22.9, 24.2 and 25.9.
  • the methylparaben cocrystal form can also be characterized by the X-ray diffraction pattern as substantially shown in FIG. 18 .
  • the methylparaben cocrystal form can also be characterized by an infrared spectrum having sharp bands at 3154, 3081, 1709, 1614, 1586, 1378, 1337, 1313, 1247, 1189, 1172, 1124, 1085, 1019, 959, 928, 916, 908, 894, 857, 783, 772, 729 and 702 cm ⁇ 1 ( ⁇ 3 cm ⁇ 1 ).
  • the methylparaben cocrystal form can also be characterized by the infrared spectrum as substantially shown in FIG. 19 .
  • FIGS. 18 to 21 These characteristics and others are shown in FIGS. 18 to 21 .
  • the compound comprises at least 70% of a methylparaben cocrystal of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone as described above; in a certain embodiment, it comprises at least 90% of a methylparaben cocrystal as described above; in a certain embodiment, it comprises at least 96% of a methylparaben cocrystal as described above; in a certain embodiment, it comprises at least 99% of a methylparaben cocrystal as described above.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more of crystalline forms A, B, C or methylparaben cocrystal form or amorphous form as the active ingredient.
  • compositions according to the invention in addition to one of the crystalline or amorphous forms according to the invention mentioned hereinabove, can contain a pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carriers include pharmaceutically inert, inorganic and organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard shell capsules.
  • Suitable carriers for soft shell capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
  • Suitable carriers for the solutions include, for example, water, polyols, sucrose, invert sugar, glucose, and the like.
  • the active ingredient can be formulated at low or high concentrations in a composition further comprising usual pharmaceutically acceptable adjuvants known in the art.
  • compositions can be in the form of tablets, coated tablets, dragées, hard and soft shell capsules, solutions, emulsions or suspensions.
  • the invention also provides a process for the production of such compositions, which comprises bringing the aforementioned modifications and forms into a galenical administration form together with one or more therapeutically inert carriers.
  • compositions can contain pharmaceutically acceptable preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the dosage at which the active ingredient, i.e. the crystalline or amorphous forms according to the invention that can be administered can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
  • the dosage for adults can vary from about 0.01 mg to about 1000 mg, preferably from about 1 mg to about 240 mg, and still more preferably from about 3 mg to about 120 mg per day.
  • the daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
  • Form A can be produced by digestion in solvents as e.g. methanol, ethanol, 2-propanol, isopropylacetate, t-butyl methyl ether, toluene or solvent mixtures as acetone/water (e.g. 1:1, w/w), water/methanol (e.g. 1:1, w/w), water/ethanol (e.g. 0.4:0.6, w/w).
  • solvents as e.g. methanol, ethanol, 2-propanol, isopropylacetate, t-butyl methyl ether, toluene or solvent mixtures as acetone/water (e.g. 1:1, w/w), water/methanol (e.g. 1:1, w/w), water/ethanol (e.g. 0.4:0.6, w/w).
  • Form A seeding crystals can be prepared by digestion of a slurry of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone in solvent systems comprising but not limited to ethanol, methanol and water mixtures of ethanol/water (e.g. 0.4:0.6 w/w). After stirring the slurry at room temperature for several days form A crystals could be filtered and were dried at 50° C./0-20 mbar for 14 h. It might be necessary to repeat this procedure several times.
  • XRPD-pattern, IR-spectrum, DSC curve, and TG curve of form A are listed in FIGS. 1 to 4 .
  • Form B can be prepared by re-crystallization of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone with or without seeding in different solvent systems comprising methanol, ethanol, 1,4-dioxane and water mixtures of these.
  • Form B seeding crystals can be prepared by rapid cooling of a highly saturated solution of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone in solvent systems comprising but not limited to ethanol, tetrahydrofurane, toluene or 1,4-dioxane.
  • XRPD-pattern, IR-spectrum, DSC curve, and TG curve of form B are listed in FIGS. 5 to 8 .
  • Form C can be produced by digestion in solvents as n-heptane, toluene, o-xylene or solvent mixtures as n-heptane/toluene (e.g. 1:0.8, w/w). It can also be prepared by re-crystallization of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone with seeding in different solvent systems.
  • XRPD-pattern, IR-spectrum, DSC curve, and TG curve of form C are listed in FIGS. 9 to 12 .
  • FIGS. 13 to 17 XRPD-pattern, IR-spectrum, DSC curve, and TG curve and moisture sorption/desorption isotherms of the amorphous form are listed in FIGS. 13 to 17 .
  • Cocrystals of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone and methylparaben can be produced by digestion in solvents as e.g. ethanol and water.
  • the [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone-methylparaben ratio can range from 1:1 to 1:10.
  • XRPD-pattern, IR-spectrum, DSC curve, and TG curve of the methylparaben cocrystal are listed in FIGS. 18 to 21 .

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US12/002,997 2006-12-28 2007-12-19 Solid forms of [4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl-[5-methanesulfonyl-2-((s)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone Abandoned US20080214561A1 (en)

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US13/188,486 US20110295007A1 (en) 2006-12-28 2011-07-22 Solid forms of [4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl-[5-methanesulfonyl-2-((s)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone
US13/495,093 US20120309969A1 (en) 2006-12-28 2012-06-13 Solid forms of [4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl-[5-methanesulfonyl-2-((s)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone
US13/798,358 US20130197225A1 (en) 2006-12-28 2013-03-13 New Solid Forms of [4-(3-Fluoro-5-Trifluoromethyl-Pyridin-2-Yl)-Piperazin-1-Yl-[5-Methanesulfonyl-2-((S)-2,2,2-Trifluoro-1-Methyl-Ethoxy)-Phenyl]Methanone

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US13/495,093 Abandoned US20120309969A1 (en) 2006-12-28 2012-06-13 Solid forms of [4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl-[5-methanesulfonyl-2-((s)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone
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WO2013174694A1 (fr) * 2012-05-25 2013-11-28 Basf Se Forme cristalline b de 1,5-dimethyl-6-thioxo-3-(2,2,7-trifluoro-3-oxo-4-(prop-2-ynyl)-3,4-dihydro-2h-benzo[b][1,4]oxazin-6-yl)-1,3,5-triazinane-2,4-dione
US8927412B1 (en) * 2013-08-01 2015-01-06 Taiwan Semiconductor Manufacturing Company, Ltd. Multi-chip package and method of formation
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JP2023509792A (ja) 2020-01-09 2023-03-09 ディスク・メディシン・インコーポレイテッド グリシン輸送阻害剤を用いて骨髄性プロトポルフィリン症、ｘ連鎖プロトポルフィリン症または先天性赤血球生成性ポルフィリン症を処置する方法
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