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WO2012071425A1 - Formes à l'état solide de bésylate de sorafénib et procédés de préparation - Google Patents

Formes à l'état solide de bésylate de sorafénib et procédés de préparation Download PDF

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Publication number
WO2012071425A1
WO2012071425A1 PCT/US2011/061868 US2011061868W WO2012071425A1 WO 2012071425 A1 WO2012071425 A1 WO 2012071425A1 US 2011061868 W US2011061868 W US 2011061868W WO 2012071425 A1 WO2012071425 A1 WO 2012071425A1
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Prior art keywords
sorafenib
besylate
theta
degrees
crystalline
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PCT/US2011/061868
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English (en)
Inventor
Francesca Scarpitta
Tomislav Biljan
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Teva Pharmaceutical Industries Ltd.
Teva Pharmaceuticals Usa, Inc.
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Publication of WO2012071425A1 publication Critical patent/WO2012071425A1/fr

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    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to solid state forms of Sorafenib besylate, preparation thereof and pharmaceutical compositions thereof.
  • Sorafenib and its salts, and a process for preparation thereof are disclosed in WO 00/41698 Al.
  • WO 00/042012 Al describes sorafenib base, pharmaceutically acceptable salts and their use.
  • WO 06/034796 Al discloses processes for preparing sorafenib base and its tosylate salt.
  • WO 06/034797 reports crystalline forms I, II, and III of sorafenib tosylate, a methanol solvate, an ethanol solvate and preparation thereof.
  • WO2010/142678 discloses salts and crystalline forms of Sorafenib, including a besylate salt.
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single molecule like Sorafenib or a salt thereof, may give rise to a variety of polymorphs having distinct crystal structures.
  • These distinct crystal structures typically have distinct physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA”, or differential scanning calorimetry - "DSC”), X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. Analytical methods that measure one or more of these physical properties may be used to distinguish different polymorphic forms of a compound.
  • Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification.
  • such new forms can provide desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
  • New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. They also serve to enlarge the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional polymorphs of Sorafenib Besylate.
  • the invention encompasses novel solid state forms of Sorafenib Besylate, referred to herein as Forms IV, V and VI; processes for preparing them; and formulations comprising these forms.
  • the invention further encompasses the above described solid state forms of Sorafenib
  • Besylate for use in the preparation of other salts of Sorafenib, solid state forms thereof and pharmaceutical formulations containing them.
  • the invention further encompasses the above described solid state forms of Sorafenib Besylate for use in the treatment of cancers, particularly, renal and hepatocellular cancer.
  • the present invention further provides a pharmaceutical composition comprising any one, or a mixture of, the solid state forms of Sorafenib Besylate of the present invention.
  • This pharmaceutical composition may additionally comprise at least one pharmaceutically acceptable excipient.
  • the present invention also provides a method of treating a person suffering from cancer, particularly renal or hepatocellular cancer, comprising administering a therapeutically effective amount of a pharmaceutical composition, comprising at least one, or a combination, of the solid state forms of Sorafenib Besylate of the present invention, and optionally comprising at least one pharmaceutically acceptable excipient, to a patient in need of such treatment.
  • Figure 1 shows a powder XR pattern of crystalline Sorafenib Besylate form IV.
  • Figure 2 shows a powder XRD pattern of crystalline Sorafenib Besylate form V.
  • Figure 3 shows a powder XRD pattern of crystalline Sorafenib Besylate form VI.
  • Figure 4 shows a solid state C NMR pattern of crystalline Sorafenib Besylate form IV.
  • Figure 5 shows a scanning electron microscope (“SEM”) image of crystalline
  • FIG. 6 shows a thermogravimetric analysis (TGA) thermogram of crystalline
  • Figure 7 shows a solid state 13 C NMR pattern of crystalline Sorafenib Besylate form
  • Figure 8 shows a scanning SEM image of crystalline Sorafenib Besylate form VI.
  • the invention relates to solid state forms of Sorafenib besylate, preparation thereof and pharmaceutical compositions thereof.
  • a crystal form may be referred to herein as being characterized by graphical data "as depicted in" a Figure.
  • Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. The skilled person will understand that such graphical data
  • representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, all of which are well known to the skilled person.
  • crystal form will be understood to include any crystal form of Sorafenib besylate characterized by the graphical data shown in the Figure including any such small variations that are well known to the skilled person.
  • the crystalline forms of the present invention may be substantially pure, i.e. substantially free of any other crystalline (or polymorphic) forms.
  • the expressions "substantially pure” and/or “substantially free of any other forms” will be understood to mean that the crystalline form contains 20% or less, 10% or less, 5% or less, 2% or less, or 1% or less of any other forms of the subject compound as measured, for example, by XRPD.
  • polymorphs of Sorafenib besylate described herein as substantially free of any other polymorphic forms would be understood to contain greater than 80% (w/w), greater than 90% (w/w), greater than 95% (w/w), greater than 98% (w/w), or greater than 99% (w/w) of the subject polymorphic form of Sorafenib besylate. Accordingly, in some embodiments of the invention, the described polymorphs of Sorafenib besylate may contain from 1% to 20% (w/w), from 5% to 20% (w/w), or from 5% to 10% (w/w) of one or more of other crystal forms of Sorafenib and Sorafenib besylate.
  • Room temperature refers to a temperature between about 20 °C and about 30 °C. Usually, room temperature ranges from about 20°C to about 25 °C.
  • wet crystalline form refers to a polymorph that was not dried using any conventional techniques to remove residual solvent.
  • conventional techniques can be, but not limited to, evaporation, vacuum drying, oven drying, drying under a flow of nitrogen or other inert gas, etc.
  • dry crystalline form refers to a polymorph that was dried using any conventional techniques to remove residual solvent. Examples for such
  • conventional techniques can be, but not limited to, evaporation, vacuum drying, oven drying, drying under a flow of nitrogen or other inert gas, etc.
  • anhydrous in relation to the crystalline forms of Sorafenib besylate of the present invention relates to a crystalline form of Sorafenib besylate which contains not more than 1% (w/w), more preferably not more than 0.5% (w/w) of either water or organic solvents as measured by TGA.
  • the terms “stable” and “stability,” as used herein, and unless indicated otherwise, in relation to the Sorafenib besylate solid form means that, based on a property of the solid form measurable by XRPD, there is during the storage less than 20% conversion of the Sorafenib besylate solid form to any other solid forms of Sorafenib besylate or Sorafenib base over a period of at least 6 months at the above specified conditions, wherein the conversion is measured by XRPD.
  • the "stable" Sorafenib Besylate solid form is converted to any other solid forms of Sorafenib besylate or Sorafenib base when stored at about room temperature and atmospheric pressure over a period of at least 6 months.
  • the conversion is less than 10%, less than 5%, less than 1%, or even less than 0.5%.
  • the conversion is l%-20%, 1%-10% or l%-5%, preferably, 0.5%-5%, and more preferably 0.5%- 1%.
  • the invention encompasses crystalline Sorafenib Besylate, designated form IV.
  • Form IV can be characterized by data selected from: a powder XRD pattern having peaks at 12.4, 19.4, 20.0, 21.7 and 24.3 degrees 2-theta ⁇ 0.2 degrees 2-theta; a powder XRD pattern substantially as depicted in Figure 1; a solid-state 13 C NMR spectrum having characteristic peaks at 28.2, 112.6, 122.3, 144.9 and 152.1 ppm ⁇ 0.2 ppm; a solid- state 13 C NMR spectrum substantially as depicted in Figure 4; and any combination thereof.
  • Form IV can be further characterized by additional powder XRD peaks at 16.3, 17.5, 17.9, 20.4 and 22.6 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Sorafenib Besylate form IV can be characterized by a powder XRD pattern with peaks at 12.4, 19.4, 20.0, 21.7 and 24.3 degrees two theta ⁇ 0.2 degrees two theta; and also having any one, two, three, four or five peaks selected from 16.3, 17.5, 17.9, 20.4 and 22.6 degrees two theta ⁇ 0.2 degrees two theta.
  • Form IV can be anhydrous, which can be particularly attractive for preparing pharmaceutical formulations.
  • Sorafenib Besylate form IV of the present invention has advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.
  • the crystalline Sorafenib Besylate form IV of the present invention has plate shaped morphology. This feature provides the bulk product with excellent compaction properties that are beneficial for pharmaceutical formulations.
  • Figure 5 shows a SEM image of sorafenib besylate form IV.
  • the Sorafenib besylate form IV shows stability (i.e., being stable) in storage under ambient room conditions, i.e. at about room temperature and atmospheric pressure, for a period of at least 6 months.
  • stability i.e., being stable
  • Sorafenib besylate or Sorafenib base occurs over a period of 6 months at the above specified conditions, wherein conversion is measured by XRPD.
  • the conversion is less than 10%, less than 5%, less than 1%, or even less than 0.5%.
  • the conversion is l%-20%, 1%-10% or l%-5%, preferably, 0.5%-5%, and more preferably 0.5%-l %.
  • the invention encompasses crystalline Sorafenib Besylate, designated form V.
  • Form V can be characterized by data selected from: a powder XRD pattern having peaks at 8.3, 15.9, 20.8, 22.3 and 24.9 degrees 2-theta ⁇ 0.2 degrees 2-theta; a powder XRD pattern substantially as depicted in Figure 2; and any combination thereof.
  • Form V can be further characterized by additional powder XRD peaks at 9.5, 13.5, 16.2, 18.6 and 26.7 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Sorafenib Besylate form V can be characterized by a powder XRD pattern with peaks at 8.3, 15.9, 20.8, 22.3 and 24.9 degrees two theta ⁇ 0.2 degrees two theta; and also having any one, two, three, four or five peaks selected from 9.5, 13.5, 16.2, 18.6 and 26.7 degrees two theta ⁇ 0.2 degrees two theta.
  • Form V can be further characterized by TGA thermogram as depicted in Figure 6.
  • Form V can have a methanol content of about 4.9% (w/w as measured by TGA), and can be a methanol solvate.
  • the invention encompasses crystalline Sorafenib Besylate, designated form VI.
  • Form VI can be characterized by data selected from: a powder XRD pattern having peaks at 7.6, 8.3, 10.3, 19.0 and 25.3 degrees 2-theta ⁇ 0.2 degrees 2-theta; a powder XRD pattern substantially as depicted in Figure 3; a solid-state C NMR spectrum having characteristic peaks at 27.1, 120.6, 140.1, 159.1 and 174.9 ppm ⁇ 0.2 ppm; a solid- state 13 C NMR spectrum substantially as depicted in Figure 7; and any combination thereof.
  • Form VI can be further characterized by additional powder XRD peaks at 7.9, 11.8, 12.1 , 16.0 and 23.1 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Sorafenib Besylate form VI can be characterized by a powder XRD pattern with peaks at 7.6, 8.3, 10.3, 19.0 and 25.3 degrees two theta ⁇ 0.2 degrees two theta; and also having any one, two, three, four or five peaks selected from 7.9, 11.8, 12.1, 16.0 and 23.1 degrees two theta ⁇ 0.2 degrees two theta.
  • Form VI can be anhydrous form, which can be particularly attractive for preparing pharmaceutical formulations.
  • Sorafenib besylate form VI shows stability (i.e., being stable) in storage under ambient room conditions, i.e. at about room temperature and atmospheric pressure, for a period of at least 6 months.
  • stable and stable as used herein, and unless indicated otherwise, in relation to crystalline Sorafenib besylate form VI are as defined above.
  • Sorafenib Besylate form VI of the present invention has advantageous properties selected from at least one of: chemical purity, fiowability, solubility, morphology or crystal habit, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, low content of residual solvents.
  • the crystalline Sorafenib Besylate form VI of the present invention has prism-shaped morphology. This feature provides the bulk product with excellent fiowability properties that are beneficial for pharmaceutical formulations and processing thereof.
  • Figure 8 shows a SEM image of sorafenib besylate form VI.
  • Sorafenib Besylate can be used to prepare other Sorafenib salts and solid state forms thereof, in particular Sorafenib tosylate, and/or pharmaceutical compositions thereof.
  • the present invention encompasses a process for preparing a Sorafenib salt comprising preparing any one or a combination of Sorafenib Besylate solid state forms of the present invention and converting them to said Sorafenib salt.
  • the conversion can comprise, for example, basifying a solution containing Sorafenib Besylate to produce Sorafenib base, and reacting the thus-obtained Sorafenib base with an appropriate acid to obtain the corresponding salt.
  • Appropriate acids include, for example, mineral acids such as
  • hydrochloric acid sulfuric acid, phosphoric acid and nitric acid
  • organic acids such as methane sulfonic acid, ethanesulfonic acid, toluenesulfonic acid, camphor sulfonic acid, fumaric acid, tartaric acid, and maleic acid, and preferably para-toluenesulfonic acid.
  • the resulting sorafenib salts can be used to prepare a pharmaceutical composition of the sorafenib salt.
  • this process comprises preparing any one or a combination of Sorafenib Besylate solid state forms of the present invention, and converting the solid state form or forms to Sorafenib tosylate, for example, by basifying Sorafenib Besylate and reacting the obtained Sorafenib base with />-toluenesulfonic acid.
  • the resulting sorafenib tosylate can be used to prepare a pharmaceutical composition of sorafenib tosylate.
  • Sorafenib Besylate can also be used to prepare pharmaceutical compositions, either of sorafenib besylate or of other sorafenib salts, such as sorafenib tosylate.
  • the present invention further encompasses 1) a pharmaceutical composition comprising any one or a combination of solid state Forms of Sorafenib Besylate, as described above, and at least one pharmaceutically acceptable excipient; 2) the use of any one or a combination of the above-described solid state Forms of Sorafenib Besylate, in the manufacture of a pharmaceutical composition; 3) a method of treating renal or hepatocellular cancer comprising administering an effect amount of any one or a combination of solid state Forms of Sorafenib Besylate, e.g., Forms IV, V and VI, as described above to a subject in need of the treatment; and 4) one or a combination of solid state forms of Sorafemb Besylate as described above, as a medicament, particularly for treating renal or hepatocellular cancer.
  • the pharmaceutical composition can be useful for preparing a medicament.
  • the present invention also provides crystalline forms as described above for use as a medicament.
  • the samples Prior to analysis the samples were gently ground using a mortar and pestle in order to obtain a fine powder and the powder was applied directly on a silicon zero background holder.
  • the scanning parameters were: range: 3-40 degrees two-theta; scan mode: continuous scan; step size: 0.0167°; and time per step: 37 sec.
  • the described peak positions were determined by using a silicon powder as an internal standard in an admixture with the sample measured.
  • the position of the silicon (Si) peak was corrected to the silicone theoretical peak: 28.45 degrees two theta, and the positions of the measured peaks were corrected respectively. No correction was performed on the diffractograms presented in the figures.
  • the pulse sequence used for acquiring the spectrum was a standard cross-polarization MAS pulse sequence with high-power proton decoupling during acquisition. Repetition delay was 5 s and the number of scans was 500. TGA method
  • TGA analysis was performed under flow of nitrogen (60 ml/min) on TGA 2950 TA instrument, with heating rate of 10 °C/min. Standard platinum open pan was used, in temperature range from room temperature to 300°C. Sample mass was about 10 mg.
  • Sorafenib base employed in the present examples may be obtained according to the processes disclosed in US 7,235,576, in particular, method Cla, the disclosures of US 7,235,576 are herein incorporated by reference.
  • Sorafenib Base (4 g, 8.6 mmol,) was suspended in absolute ethanol (water content ⁇ 0.1%) (80 ml). Benzenesulfonic acid (1.5g, 9.5mmol) was added portionwise at room temperature over about 5 minutes. A solution was obtained at the end of the addition and then precipitation occurred and a suspension was obtained. The suspension was stirred at room temperature for 2 hours. Then it was filtered and the collected residue was washed with 8ml of absolute ethanol and dried at 50°C under vacuum for about 16 hours. Sorafenib besylate (3.96g, 74% yield) was obtained..
  • Sorafenib base (10 g, 21.5 mmol) was suspended in dry methanol (water content ⁇ 0.1%) (50 ml).
  • Benzenesulfonic acid (4.47 g, 28.2mmol) was added portionwise at room temperature over about 5 minutes. A solution was obtained at the end of the addition, and then precipitation occurred and a suspension was obtained.
  • the suspension was stirred at room temperature for 5 hours, then cooled to 0°C over 2 hours and then stirred overnight at 0°C. Then, the solid was filtered off and the residue was washed with 10ml of dry methanol and dried at 50°C under vacuum for about 16 hours. Sorafenib besylate (12 g, 90% yield) was obtained.
  • Sorafenib base (6.5 g, 14.0 mmol) was suspended in 32.5 ml of dry methanol.
  • a solution of benzenesulfonic acid (2.88 g, 18.2mmol) in methanol (solution volume 19.5 ml) was added at room temperature over about 5 minutes.
  • a solution was obtained at the end of the addition and then precipitation occurred.
  • the resulting suspension was stirred at room temperature for 0.5 hours, and then cooled to 0°C over 2 hours, and then stirred for 15 minutes at 0°C. The suspension was then filtered and the collected residue was washed with 13ml of dry methanol.
  • Example 4 Preparation of Sorafenib Besylate form V
  • Sorafenib base (6.5 g, 14.0 mmol) was suspended in 162.5 ml of methanol.
  • a solution of benzenesulfonic acid (2.43 g, 15.3mmol) in 5ml of water was added at room temperature over about 5 minutes. Dissolution occurred and then precipitation started.
  • the resulting suspension was stirred at room temperature for 0.5 hours, then cooled to 0°C over 2 hours and stirred for 10 minutes at 0°C. The suspension was then filtered and the residue was washed with 13ml of methanol and analyzed by PXRD.
  • Sorafenib base (5g, 10.7 mmol) was suspended in 100 ml of dry isopropanol (water content ⁇ 0.1%), and the resulting mixture was heated to reflux (about 80°C).
  • Benzenesulphonic acid (1.9g, 12 mmol) was added to the mixture at reflux and a solution was obtained at the end of the addition. The solution was stirred at 80°C for half an hour and then cooled to 50°C, at which temperature precipitation started. The resulting suspension was cooled to 25 °C over 2 hours. The suspension was then stirred at room temperature for one hour. The suspension was then filtered, and the residue was washed with 8ml of dry isopropanol and dried at 65°C under vacuum for 16 hours. Sorafenib besylate (5g, 80% yield) was obtained.
  • Sorafenib base (5g, 10.7 mmol) was suspended in 100 ml of acetone (water content about 0.2-0.3%) and the resulting mixture was heated to reflux (about 56°C).
  • Benzenesulphonic acid (1.9g, 12 mmol) was added to the reaction mixture at reflux. A solution was obtained at the end of the addition and immediately precipitation occurred.
  • the resulting suspension was stirred at 56°C for half an hour and then cooled to 25°C and stirred for an additional 2 hours. The solid was then filtered off and the residue was washed with acetone (8ml). Then, the solid was dried at 65°C under vacuum for 16 hours. Sorafenib besylate (4.5g, 70% yield) was obtained.

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Abstract

La présente invention concerne des formes à l'état solide, nommées dans ce document formes IV, V et VI, de bésylate de sorafénib; les procédés de préparation de ces formes; ainsi que des compositions et des formulations pharmaceutiques contenant ces formes. En outre, l'invention concerne les formes à l'état solide de bésylate de sorafénib décrites ci-dessus destinées à servir dans la préparation d'autres sels de sorafénib, des formes à l'état solide associées et des formulations pharmaceutiques les contenant, ainsi que leur utilisation dans le traitement du cancer, en particulier, le cancer rénal et le cancer hépatocellulaire.
PCT/US2011/061868 2010-11-22 2011-11-22 Formes à l'état solide de bésylate de sorafénib et procédés de préparation WO2012071425A1 (fr)

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US41601410P 2010-11-22 2010-11-22
US61/416,014 2010-11-22
US41689510P 2010-11-24 2010-11-24
US61/416,895 2010-11-24
US201161437771P 2011-01-31 2011-01-31
US61/437,771 2011-01-31

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Publication number Priority date Publication date Assignee Title
WO2014012480A1 (fr) * 2012-07-18 2014-01-23 苏州泽璟生物制药有限公司 Polymorphes d'oméga-diphénylurée deutérée ou de ses sels
CN103570613A (zh) * 2012-07-18 2014-02-12 苏州泽璟生物制药有限公司 氘代ω-二苯基脲或其盐的多晶型物
CN103570613B (zh) * 2012-07-18 2016-06-15 苏州泽璟生物制药有限公司 氘代ω-二苯基脲或其盐的多晶型物
RU2600929C2 (ru) * 2012-07-18 2016-10-27 Сучжоу Зельген Биофармасьютикалс Ко., Лтд. Полиморфы дейтерированной омега-дифенилмочевины или ее солей
US9573900B2 (en) 2012-07-18 2017-02-21 Suzhou Zelgen Biopharmaceutical Co., Ltd. Polymorphs of deuterated omega-diphenylurea or salts thereof
US9889123B2 (en) 2012-07-18 2018-02-13 Suzhou Zelgen Biopharmaceutical Co., Ltd. Polymorphs of deuterated omega-diphenylurea or salts thereof
CN103896833A (zh) * 2012-12-27 2014-07-02 上海创诺制药有限公司 索拉非尼对甲苯磺酸盐溶剂化物多晶型物及其制法和用途
CN103896833B (zh) * 2012-12-27 2016-12-28 上海创诺制药有限公司 索拉非尼对甲苯磺酸盐溶剂化物多晶型物及其制法和用途
US11332469B2 (en) 2016-08-09 2022-05-17 Teva Pharmaceuticals International Gmbh Solid state forms of lumateperone ditosylate salt
US11760757B2 (en) 2016-08-09 2023-09-19 Teva Pharmaceuticals International Gmbh Solid state forms of lumateperone ditosylate salt
WO2020112941A3 (fr) * 2018-11-27 2020-07-09 Teva Czech Industries S.R.O Formes à l'état solide de sels de lumatépérone et procédés de préparation de lumatépérone et de ses sels

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