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WO2010139980A1 - Procédé de préparation d'un monohydrate de dasatinib cristallin - Google Patents

Procédé de préparation d'un monohydrate de dasatinib cristallin Download PDF

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Publication number
WO2010139980A1
WO2010139980A1 PCT/GB2010/050893 GB2010050893W WO2010139980A1 WO 2010139980 A1 WO2010139980 A1 WO 2010139980A1 GB 2010050893 W GB2010050893 W GB 2010050893W WO 2010139980 A1 WO2010139980 A1 WO 2010139980A1
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WO
WIPO (PCT)
Prior art keywords
process according
reaction mixture
crystalline dasatinib
dasatinib monohydrate
monohydrate
Prior art date
Application number
PCT/GB2010/050893
Other languages
English (en)
Inventor
Vinayak Govind Gore
Laxmikant Patkar
Amit Bagul
Priyesh Surendra Vijaykar
Mahesh Edake
Original Assignee
Generics [Uk] Limited
Mylan India Private Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Generics [Uk] Limited, Mylan India Private Limited filed Critical Generics [Uk] Limited
Publication of WO2010139980A1 publication Critical patent/WO2010139980A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 present invention relates to processes for the preparation of crystalline N-(2-chloro-6- methylphenyl) -2- [[6- [4- (2-hydroxyethyl) - 1 -piperazinyl] -2-methyl-4-pyrimidinyl] amino] -5- thiazolecarboxamide (dasatinib) monohydrate.
  • the invention further relates to pure polymorphs, to pharmaceutical compositions comprising said polymorphs and to uses thereof.
  • Dasatinib is an active pharmaceutical ingredient approved for the treatment of cancer, in particular treatment of adults with chronic, accelerated or blast phase chronic myeloid leukaemia (CML) with resistance or intolerance to prior therapy including imatinib mesilate. Dasatinib is also indicated for the treatment of adults with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) and lymphoid blast CMT, with resistance or intolerance to prior therapy.
  • CML chronic myeloid leukaemia
  • ALL Philadelphia chromosome positive
  • ALL acute lymphoblastic leukaemia
  • lymphoid blast CMT lymphoid blast CMT
  • US 2006/0004067 discloses four crystalline forms of dasatinib. A monohydrate, a 'neat' crystalline form, a butanol solvate and an ethanol solvate and processes for their preparation are described.
  • Dasatinib was dissolved in ethanol : water (22:3 volumes w.r.t. dasatinib) by heating at approximately 75-80 0 C. Water (8 volumes) was added at such a rate that the temperature was maintained between 75-80 0 C. The mixture was slowly cooled to 70 0 C and maintained at this temperature for 1 hour and then cooled to 5°C over 2 hours resulting in a slurry. Dasatinib monohydrate crystals may be added as seeding during the initial cooling. Filtration of the solid and drying the material at ⁇ 50°C gave the monohydrate form of dasatinib. This form was characterized by XRPD and DSC. The moisture content by KF was in the range of 3.4-4.1%.
  • an aqueous suspension of dasatinib, seeded with the monohydrate form was heated to 70 0 C for 4 hours. The slurry gave the dasatinib monohydrate form on cooling. 3.
  • an aqueous solution of an acetate salt of dasatinib was heated to 80 0 C to give the monohydrate form of dasatinib.
  • dasatinib was heated in a mixture of ethanol, butanol and water and seeded with monohydrate crystals before cooling to afford the monohydrate form of dasatinib. 5.
  • a solution of dasatinib in solvents such as NMP or DMA was treated with water until the solution turned cloudy. The reaction mixture was maintained at 75-80 0 C for several hours to obtain the monohydrate form after cooling and filtration.
  • the butanol solvate of dasatinib was prepared by heating dasatinib in butanol at a concentration of 1 g in 25 ml of solvent at 116-118°C. On cooling, the butanol solvate crystallises out of the solution.
  • the butanol solvate was characterised by XRPD.
  • the ethanol solvate of dasatinib was prepared by an elaborate process. As outlined in Figure 2 of US 2006/0004067 which is hereby incorporated herein by reference, intermediate 3 and N-(2-hydroxyethyl)piperazine (HEP) were heated together in butanol at 120 0 C in the presence of the base diisopropylethylamine. On cooling the reaction mixture, a precipitate formed which was isolated by filtration and washings. This solid was then heated to 77°C in ethanol : water. On further cooling, a solid precipitated which when isolated was characterised as ethanol solvate.
  • HEP N-(2-hydroxyethyl)piperazine
  • HEP N-(2-hydroxyethyl)piperazine
  • the crystalline dasatinib monohydrate is prepared directly without first isolating any other forms of dasatinib.
  • solvents were added to the reaction mixture.
  • one or more additional solvent(s) is/are added to the reaction mixture.
  • the additional solvent(s) comprise one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2- pyrrolidone or dimethyl sulphoxide.
  • crystalline dasatinib monohydrate could be prepared without the need for first preparing dasatinib, isolating the dasatinib and then the subsequent processing steps required by the prior art.
  • the crystalline dasatinib monohydrate of the invention is prepared in pure form in a simple process.
  • the crystalline dasatinib monohydrate prepared according to the invention is even further purified.
  • the process is still only a simple two step process.
  • a base preferably an alkyl amine, most preferably d ⁇ sopropylethylamine, is further added to the reaction mixture.
  • alkyl amine most preferably d ⁇ sopropylethylamine
  • d ⁇ sopropylethylamine was particularly advantageous.
  • 2 molar equivalents of d ⁇ sopropylethylamine with respect to intermediate 3 are added to the reaction mixture.
  • the reaction mixture in step (i) is heated until a clear solution is formed, preferably the reaction mixture is heated to between about 50 0 C and 70 0 C, preferably to about 60 0 C, however, in alternative embodiments when d ⁇ sopropylethylamine is added to the reaction mixture, the mixture is preferably heated to between about 100 0 C and 120 0 C.
  • the crystalline dasatinib monohydrate is isolated by cooling the reaction mixture until a precipitate is formed.
  • the reaction mixture is allowed to cool to about 20-30 0 C.
  • the reaction mass is cooled to about 80-90 0 C.
  • the crystalline dasatinib monohydrate is isolated by adding an anti-solvent to the reaction mixture.
  • the anti-solvent is water, most preferably between 10 to 50 molar equivalents of water with respect to intermediate 3 are added to the reaction mixture.
  • the crystalline dasatinib monohydrate from step ( ⁇ ) is: (a) isolated by filtration;
  • step (c) dried.
  • the isolated crystalline dasatinib monohydrate in step (c) is dried in a vacuum tray drier at about 50 0 C preferably until a constant weight is achieved, most preferably for between about 8-12 hours.
  • the crystalline dasatinib monohydrate prepared according to the invention may be further purified by recrystallisation from a polar organic solvent system.
  • Preferred embodiments for further purification of crystalline dasatinib monohydrate comprise refluxing the crystalline dasatinib monohydrate in a solution comprising an alcohol and allowing the reaction mixture to cool.
  • the solution comprises an alcohol and water
  • most preferably the solution comprises ethanol and water, which in particularly preferred embodiments comprises ethanol : water in a ratio of about 22:3.
  • a second aspect according to the invention provides crystalline dasatinib monohydrate having a chemical purity of greater than 99% (as measured by HPLC).
  • a third aspect provides crystalline dasatinib monohydrate having a chemical purity of greater than 99.5% (as measured by HPLC).
  • a fourth aspect provides crystalline dasatinib monohydrate having a chemical purity of greater than 99.7% (as measured by HPLC).
  • the dasatinib monohydrate according to the invention or prepared by a process according to the invention has a chemical purity of greater than 99%, more preferably greater than 99.5%, more preferably greater than 99.7%, most preferably greater than
  • the dasatinib monohydrate according to the invention or prepared by a process according to the invention has a polymorphic purity of greater than 95%, more preferably greater than 98%, more preferably greater than 99%, more preferably greater than 99.5%, most preferably greater than 99.8% (as measured by
  • a fifth aspect provides a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline dasatinib monohydrate prepared by a process according to the invention or crystalline dasatinib monohydrate according to the second, third or fourth aspects of the invention, and one or more pharmaceutically acceptable excipients.
  • compositions are provided for use in the treatment of adults with chronic, accelerated or blast phase chronic myeloid leukaemia (CML) with resistance or intolerance to prior therapy including imatinib mesilate or in the treatment of adults with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) or lymphoid blast CML with resistance or intolerance to prior therapy.
  • CML chronic myeloid leukaemia
  • ALL Philadelphia chromosome positive
  • ALL acute lymphoblastic leukaemia
  • lymphoid blast CML with resistance or intolerance to prior therapy.
  • a seventh aspect provides crystalline dasatinib monohydrate prepared by a process according to the first aspect and accompanying embodiments or according to any of the second, third or fourth aspects of the invention for use in medicine, preferably for use in the treatment cancer, most preferably for use in the treatment of adults with chronic, accelerated or blast phase chronic myeloid leukaemia (CML) with resistance or intolerance to prior therapy including imatinib mesilate or in the treatment of adults with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) or lymphoid blast CML with resistance or intolerance to prior therapy.
  • CML chronic myeloid leukaemia
  • ALL Philadelphia chromosome positive
  • ALL acute lymphoblastic leukaemia
  • lymphoid blast CML with resistance or intolerance to prior therapy.
  • An eighth aspect of the invention provides use of crystalline dasatinib monohydrate according to the invention in the manufacture of a medicament for treating cancer.
  • the medicament is for treating adults with chronic, accelerated or blast phase chronic myeloid leukaemia (CML) with resistance or intolerance to prior therapy including imatinib mesilate or for treating adults with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) or lymphoid blast CMT, with resistance or intolerance to prior therapy.
  • CML chronic, accelerated or blast phase chronic myeloid leukaemia
  • imatinib mesilate or for treating adults with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) or lymphoid blast CMT, with resistance or intolerance to prior therapy.
  • Ph+ Philadelphia chromosome positive
  • ALL acute lymphoblastic leukaemia
  • lymphoid blast CMT lymphoid blast CMT
  • a ninth aspect of the invention provides a method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of crystalline dasatinib monohydrate according to the invention or a therapeutically effective amount of the pharmaceutical composition according to the invention.
  • the method is for treating adults with chronic, accelerated or blast phase chronic myeloid leukaemia (CML) with resistance or intolerance to prior therapy including imatinib mesilate or for treating adults with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) or lymphoid blast CML with resistance or intolerance to prior therapy.
  • the patient is a mammal, preferably a human.
  • Figure 1 shows an XRP diffractogram of crystalline dasatinib monohydrate according to the invention.
  • Figure 2 shows a differential scanning calorimetry (DSC) trace of crystalline dasatinib monohydrate according to the invention.
  • FIG. 3 shows a thermogravimetric analysis (TGA) trace of crystalline dasatinib monohydrate according to the invention.
  • crystalline dasatinib monohydrate according to the invention can be substantially pure in having a purity of greater than 99%, where the remaining less than 1% of material comprises reaction and/or processing impurities arising from its preparation. This level of consistent chemical purity has not been seen before in the prior art.
  • a first aspect of the invention provides a process for preparing crystalline dasatinib monohydrate, comprising reacting an intermediate having a formula 3 with N-(2-hydroxyethyl)piperazine (HEP), characterised in that the HEP is employed as a reactant, base and solvent.
  • HEP N-(2-hydroxyethyl)piperazine
  • solvents were added to the reaction mixture.
  • the solvent system comprises polar organic solvents.
  • one or more additional solvent(s) is/are added to the reaction mixture.
  • the additional solvent(s) comprise one or more of N ,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulphoxide.
  • highly polar organic solvents such as those described above were particularly advantageous in the preparation of the monohydrate form of dasatinib
  • the HEP, intermediate 3 and solvent may all be added simultaneously.
  • the reaction mixture comprising the polar solvent and intermediate 3 are heated to effect dissolution.
  • the mixture is heated to around 60 0 C, but any temperature that effects dissolution could be employed.
  • the solvent system comprises one or more of N 5 N- dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidone, and a base, preferably diisopropylethylamine, is added to the reaction mixture, the mixture is preferably heated to between about 100 0 C and 120 0 C.
  • Other embodiments may comprise stirring or sonication to dissolve the intermediate 3. The skilled person would of course be aware of such techniques.
  • the crystalline dasatinib monohydrate is isolated by cooling the reaction mixture until a precipitate is formed.
  • the reaction mixture is allowed to cool to about 20-30 0 C, which is approximately ambient temperature.
  • the reaction mass is cooled to about 80-90 0 C.
  • the initial reaction mixture has generally been heated to between about 100 0 C to about 120 0 C.
  • the inventors found that adding an anti-solvent to the reaction mixture is particularly suitable.
  • the anti-solvent is water.
  • Most preferably between 10 to 50 molar equivalents of water with respect to intermediate 3 are added to the reaction mixture.
  • the inventors found maintaining the reaction mixture including the water anti-solvent at the cooled temperature for a period of time to be particularly advantageous.
  • Most preferably the resultant crystalline dasatinib monohydrate is filtered and may be further washed.
  • the solid is washed in about 20 volumes of water, but any amount sufficient to remove traces of the initial solvent may be employed.
  • the isolated crystalline dasatinib monohydrate may be dried in any of a number ways.
  • the inventors dried the dasatinib monohydrate obtained by the process of the invention under a number of conditions: (a) in a vacuum tray drier at 50 0 C for 8-12 hours; (b) in a rotary evaporator at 25-30 0 C for 8-12 hours; and (c) at ambient temperature for 2 days.
  • the conditions above can all be varied within the scope of the invention.
  • the important factors ate that the end point of drying occurs when a constant weight is achieved and to ensure that there is no degradation or conversion to another form. All the tested conditions resulted in chemically pure crystalline dasatinib monohydrate having a crystalline structure with the XRDP as shown in Figure 1. It can thus be seen that the processes of the invention provide a stable product.
  • Illustrative of the invention is a pharmaceutical composition made by mixing crystalline dasatinib monohydrate according to the invention and one or more pharmaceutically acceptable excipients.
  • Solid pharmaceutical compositions of the present invention include powders, granulates, aggregates and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
  • the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical arts. Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs.
  • the dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or a soft shell.
  • the shell may be made from gelatin and optionally contain a plasticizer such as glycerine and sorbitol, and an opacifying agent or colourant.
  • the active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.
  • a composition for tabletting or capsule filling may be prepared by wet granulation.
  • wet granulation some or all of the active ingredient and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules.
  • the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
  • the granulate may then be tabletted or other excipients may be added prior to tabletting, such as a glidant and/or a lubricant.
  • a tabletting composition may be prepared conventionally by dry granulation.
  • the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
  • a blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
  • Direct compression produces a uniform tablet without granules.
  • Excipients that are particularly well suited for direct compression tabletting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tabletting is known to those in the art with experience and skill in particular formulation challenges of direct compression tabletting.
  • a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tabletting, however, they are not subjected to a final tabletting step.
  • compositions of the invention may further comprise one or more additional active ingredients.
  • Example 1 Intermediate 3 (5 g, 1 equivalent) was added to dimethyl sulfoxide (DMSO) (13 volumes) and heated to 60 0 C. When the reaction mixture became clear, HEP (3 molar equivalents) was added. The reaction mixture was maintained at 60-65 0 C for 2 hours. The reaction mass was allowed to cool to 25-30 0 C and water (20 volumes) was added and maintained at same temperature for 45 minutes. The resultant solid was filtered and washed with water and dried in a vacuum tray drier at 50 0 C for 8-12 hours. The isolated solid weighed 4.4 g. XRPD characterisation showed the isolated product to be crystalline dasatinib monohydrate substantially matching the XRP diffractogram according to Figure 1. Chemical Purity > 97% as measured by HPLC.
  • DMSO dimethyl sulfoxide
  • the DSCs were recorded on a Perkin Elmer Pyris 1.
  • the DSC sample chamber was purged with 40 ml/min of ultra high purity indium. The accuracy of the measured sample temperature with this method is within about + 1°C.
  • the sample was placed into a closed aluminium DSC pan with pinhole. At least 2 mg of sample powder was placed in the pan and sealed.
  • the instrument was programmed to heat at a rate of 10 0 C per minute in the temperature range between 25°C and 350 0 C.
  • the TGAs were recorded on a Perkin Elmer Pyris 1. Samples of at least 10 mg were analysed at a heating rate of 10 0 C per minute in the temperature range between 25°C and about 350 0 C.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

Cette invention concerne des procédés de préparation de monohydrates de N-(2-chloro-6-méthylphényl)-2-[[6-[4-(2-hydroxyéthyl)-1-pipérazinyl]-2- méthyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide (dasatinib) cristallins. Cette invention concerne, en outre, des polymorphes purs, des compositions pharmaceutiques contenant lesdits polymorphes et leurs utilisations.
PCT/GB2010/050893 2009-06-03 2010-05-28 Procédé de préparation d'un monohydrate de dasatinib cristallin WO2010139980A1 (fr)

Applications Claiming Priority (2)

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IN827/KOL/2009 2009-06-03
IN827KO2009 2009-06-03

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Cited By (12)

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CN102086195A (zh) * 2011-01-28 2011-06-08 南京卡文迪许生物工程技术有限公司 达沙替尼多晶型物及其制备方法和药用组合物
US20120309968A1 (en) * 2010-02-08 2012-12-06 Nan Jing Cavendish Bio-Engineering Technology Co., Ltd. Polymorphs of dasatinib, preparation methods and pharmaceutical compositions thereof
WO2013065063A1 (fr) 2011-11-03 2013-05-10 Cadila Healthcare Limited Forme anhydre du dasatinib, son procédé de préparation et son utilisation
WO2013157019A3 (fr) * 2012-04-20 2013-12-19 Shilpa Medicare Ltd. Procédé pour la préparation de dasatinib monohydraté
CN103819469A (zh) * 2012-11-16 2014-05-28 重庆医药工业研究院有限责任公司 一种达沙替尼的晶型及其制备方法
CN104341410A (zh) * 2013-08-09 2015-02-11 上海科胜药物研发有限公司 一种达沙替尼新晶型及其制备方法
WO2015049645A3 (fr) * 2013-10-04 2015-08-13 Alembic Pharmaceuticals Limited Procédé perfectionné de préparation de dasatinib
WO2019209908A1 (fr) 2018-04-25 2019-10-31 Johnson Matthey Public Limited Company Formes cristallines de dasatinib
CN111303142A (zh) * 2020-04-01 2020-06-19 上海博氏医药科技有限公司 达沙替尼一水合物的制备方法
US10799459B1 (en) 2019-05-17 2020-10-13 Xspray Microparticles Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
CN112043712A (zh) * 2016-06-21 2020-12-08 上海方予健康医药科技有限公司 嘧啶化合物的盐酸盐在制备用于治疗与flt3相关的疾病或障碍的药物中的应用
US10940149B1 (en) 2018-06-15 2021-03-09 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof

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Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8884013B2 (en) * 2010-02-08 2014-11-11 Nan Jing Cavendish Bio-Engineering Technology Co., Ltd. Polymorphs of Dasatinib, preparation methods and pharmaceutical compositions thereof
US20120309968A1 (en) * 2010-02-08 2012-12-06 Nan Jing Cavendish Bio-Engineering Technology Co., Ltd. Polymorphs of dasatinib, preparation methods and pharmaceutical compositions thereof
CN102086195B (zh) * 2011-01-28 2013-04-03 南京卡文迪许生物工程技术有限公司 达沙替尼多晶型物及其制备方法和药用组合物
CN102086195A (zh) * 2011-01-28 2011-06-08 南京卡文迪许生物工程技术有限公司 达沙替尼多晶型物及其制备方法和药用组合物
WO2013065063A1 (fr) 2011-11-03 2013-05-10 Cadila Healthcare Limited Forme anhydre du dasatinib, son procédé de préparation et son utilisation
WO2013157019A3 (fr) * 2012-04-20 2013-12-19 Shilpa Medicare Ltd. Procédé pour la préparation de dasatinib monohydraté
US9145406B2 (en) 2012-04-20 2015-09-29 Shilpa Medicare Limited Process for preparing dasatinib monohydrate
CN103819469A (zh) * 2012-11-16 2014-05-28 重庆医药工业研究院有限责任公司 一种达沙替尼的晶型及其制备方法
CN104341410A (zh) * 2013-08-09 2015-02-11 上海科胜药物研发有限公司 一种达沙替尼新晶型及其制备方法
WO2015049645A3 (fr) * 2013-10-04 2015-08-13 Alembic Pharmaceuticals Limited Procédé perfectionné de préparation de dasatinib
CN112043712B (zh) * 2016-06-21 2022-04-29 上海方予健康医药科技有限公司 嘧啶化合物的盐酸盐在制备用于治疗与flt3相关的疾病或障碍的药物中的应用
CN112043712A (zh) * 2016-06-21 2020-12-08 上海方予健康医药科技有限公司 嘧啶化合物的盐酸盐在制备用于治疗与flt3相关的疾病或障碍的药物中的应用
WO2019209908A1 (fr) 2018-04-25 2019-10-31 Johnson Matthey Public Limited Company Formes cristallines de dasatinib
US11440908B2 (en) 2018-04-25 2022-09-13 Johnson Matthey Public Limited Company Crystalline forms of dasatinib
US11007195B2 (en) 2018-06-15 2021-05-18 Handa Oncology, Llc Kinase inhibitor salts, and compositions thereof
US10940149B1 (en) 2018-06-15 2021-03-09 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof
US12064428B2 (en) 2018-06-15 2024-08-20 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof
US12064430B2 (en) 2018-06-15 2024-08-20 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof
US11160805B2 (en) 2018-06-15 2021-11-02 Handa Onocology, Llc Kinase inhibitor salts and compositions thereof
US11052088B2 (en) 2018-06-15 2021-07-06 Handa Oncology, Llc Kinase inhibitor salts, and compositions thereof
US10869837B1 (en) 2019-05-17 2020-12-22 Xspray Pharma Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US10869836B1 (en) 2019-05-17 2020-12-22 Xspray Pharma Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US10894017B1 (en) 2019-05-17 2021-01-19 Xspray Pharma Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US10894018B1 (en) 2019-05-17 2021-01-19 Xspray Pharma Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US10799459B1 (en) 2019-05-17 2020-10-13 Xspray Microparticles Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US11344500B2 (en) 2019-05-17 2022-05-31 Xspray Pharma Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US11833249B2 (en) 2019-05-17 2023-12-05 Xspray Pharma Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US10874613B1 (en) 2019-05-17 2020-12-29 Xspray Pharma Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US10874614B1 (en) 2019-05-17 2020-12-29 Xspray Pharma Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
CN111303142A (zh) * 2020-04-01 2020-06-19 上海博氏医药科技有限公司 达沙替尼一水合物的制备方法

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