WO2017016512A1 - Nouvelle forme cristalline du mésylate de masitinib et son procédé de préparation - Google Patents
Nouvelle forme cristalline du mésylate de masitinib et son procédé de préparation Download PDFInfo
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- WO2017016512A1 WO2017016512A1 PCT/CN2016/092224 CN2016092224W WO2017016512A1 WO 2017016512 A1 WO2017016512 A1 WO 2017016512A1 CN 2016092224 W CN2016092224 W CN 2016092224W WO 2017016512 A1 WO2017016512 A1 WO 2017016512A1
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- compound
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- methanesulfonate
- crystal form
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- WJEOLQLKVOPQFV-UHFFFAOYSA-N masitinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3SC=C(N=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 WJEOLQLKVOPQFV-UHFFFAOYSA-N 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 50
- 239000013078 crystal Substances 0.000 claims description 39
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 30
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 29
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 22
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 239000012453 solvate Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 15
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- HJERCYPQHAGQIR-UHFFFAOYSA-N C(Cl)(Cl)Cl.CS(=O)(=O)O Chemical compound C(Cl)(Cl)Cl.CS(=O)(=O)O HJERCYPQHAGQIR-UHFFFAOYSA-N 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 150000004292 cyclic ethers Chemical class 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000005119 centrifugation Methods 0.000 claims description 3
- 150000008282 halocarbons Chemical class 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- 208000015114 central nervous system disease Diseases 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 16
- 238000003860 storage Methods 0.000 abstract description 8
- 230000007774 longterm Effects 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 238000002411 thermogravimetry Methods 0.000 description 12
- 238000000113 differential scanning calorimetry Methods 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000002441 X-ray diffraction Methods 0.000 description 6
- 238000001179 sorption measurement Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- -1 masatinib mesylate salt Chemical class 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000012395 formulation development Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000000048 melt cooling Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000000399 optical microscopy Methods 0.000 description 1
- 239000002859 orphan drug Substances 0.000 description 1
- 229940000673 orphan drug Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007613 slurry method Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 238000004441 surface measurement Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
Definitions
- the invention relates to the field of chemical medicine, in particular to a new crystal form of macetinib mesylate and a preparation method thereof.
- Marsetinib (a compound of formula I) is a novel orally administered tyrosine kinase inhibitor developed by AB Sciences that inhibits a limited number of kinase-targeted mast cells and macrophages. Based on its unique mechanism of action, Marsetini has the potential to develop a variety of diseases such as tumors, inflammatory diseases, and central nervous system.
- the mesylate salt of masatinib is used in clinical research and is currently in clinical phase III.
- AB Science will submit a conditional marketing approval application to the European Medicines Agency EMA for the treatment of amyotrophic lateral sclerosis (ALS) disease.
- Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and may also have different effects on drug stability, bioavailability, and efficacy. Therefore, in the development of drugs, the issue of drug polymorphism should be fully considered.
- the patent CN103342701A of AB Science discloses the mesylate salt of the compound of the formula (I). a polymorph (ie, Form I below) characterized by an X-ray diffraction pattern comprising 2 ⁇ values at about 7.269, 9.120, 11.038, 13.704, 14.481, 15.483, 15.870, 16.718, 17.087, 17.473, 18.224, 19.248, 19.441, 19.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.681, 25.754, 26.777, 28.975, 29.609, 30.073 with characteristic peaks, the crystal form Extremely high humidity, not conducive to drug storage.
- the inventors of the present invention surprisingly discovered in the course of the research that there is also a stable, industrially produced crystal form of the macetinib mesylate salt. In order to keep the drug stable during preparation, storage and formulation development, it provides more and better choice for drug development.
- the present invention provides a crystalline form A of a mesylate salt of the compound of the formula (I) (ie, Masitinib mesylate),
- the X-ray powder diffraction pattern has characteristic peaks at 2theta values of 20.7 ° ⁇ 0.2 °, 18.2 ° ⁇ 0.2 °, and 21.1 ° ⁇ 0.2 °.
- the X-ray powder diffraction pattern of Form A is still in 2theta
- the values have characteristic peaks at 20.3 ° ⁇ 0.2 °, 23.6 ° ⁇ 0.2 °, and 11.5 ° ⁇ 0.2 °.
- the X-ray powder diffraction pattern of Form A also has a characteristic peak at a 2theta value of 19.9 ° ⁇ 0.2 °, 29.6 ° ⁇ 0.2 °, and 10.5 ° ⁇ 0.2 °.
- the X-ray powder diffraction pattern of Form A also has a characteristic peak at a 2theta value of 10.5 ⁇ 0.2° and/or 11.5 ° ⁇ 0.2°.
- the X-ray powder diffraction pattern of Form A also has a characteristic peak at a 2theta value of 18.6 ⁇ 0.2° and/or 27.4 ° ⁇ 0.2°.
- the X-ray powder diffraction pattern of Form A of the present invention is substantially as shown in FIG.
- the crystal form A provided by the present invention is further characterized in that an endothermic peak starts to appear near the temperature of 108 ° C, and an exothermic peak starts to appear near the temperature of 178 ° C, and another endothermic peak starts to appear near the temperature of 232 ° C, and its DSC basically as shown in Figure 2.
- the crystal form A provided by the present invention is further characterized in that it has a weight loss gradient of about 6.44% when heated to 100 ° C, and its TGA is substantially as shown in FIG. It can be calculated from the TGA chart that when heated to 100 ° C, Form A loses about 2 molecules of water.
- Another object of the present invention is to provide a process for the preparation of Form A comprising the amorphous or solvate of the methanesulfonate salt of the compound of the formula (I) in a cyclic ether, an aromatic hydrocarbon, a halogenated hydrocarbon organic solvent or Crystallization is carried out in a mixed solvent with water.
- the cyclic ether solvent is preferably 2-methyltetrahydrofuran.
- the halogenated hydrocarbon solvent is preferably dichloromethane.
- the means or manner of crystallization is preferably stirred and crystallized.
- the methanesulfonate chloroform solvate of the compound of the formula (I) is suspended in 2-methyltetrahydrofuran, dichloromethane or a mixture of the two, stirred at 10 ° C or less, and centrifuged. The lower layer of solid was dried overnight at a constant temperature to obtain Form A.
- the stirring is carried out at 5 ° C and below, for example 5 ° C.
- Form A can be obtained by subjecting the methanesulfonate chloroform solvate of the compound of the formula (I) to humidity control-induced crystallization (transcrystallization). Further, humidity control induced crystallisation can be performed on an existing dynamic moisture adsorption tester, and the conditions employed can be the usual test conditions.
- the selected initial humidity may be from 40% relative humidity to 80% relative humidity, and the selected endpoint humidity is from 90% relative humidity to 95% relative humidity.
- the induction temperature selected is from 0 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C.
- the residence time of each humidity condition is not higher than 180 minutes, and the humidity change interval is not more than 10% relative humidity.
- the preparation method of the present invention further comprises the step of suspending the amorphous methanesulfonate salt of the compound of the formula (I) in chloroform and stirring to obtain a methanesulfonate chloroform solvate of the compound of the formula (I).
- the amorphous methanesulfonate of the compound of the formula (I) can be obtained by dissolving a crystalline form such as CN103342701A in a solvent such as methanol, ethanol or a mixed solvent thereof with other solvents, followed by rapid evaporation, and other solvents such as isopropyl.
- a solvent such as methanol, ethanol or a mixed solvent thereof with other solvents
- it can also be obtained by freeze-drying a product solution containing the methanesulfonate salt of the compound of the formula (I).
- crystal or “crystal form” refers to the characterization by the X-ray diffraction pattern shown.
- Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
- the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
- the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
- the influence of experimental factors such as height will cause an overall shift in the peak angle, usually allowing a certain offset.
- the X-ray diffraction pattern of one crystal form in the present invention need not be identical to the X-ray diffraction pattern in the examples referred to herein. Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
- One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
- Crystal form and “polymorph” and other related terms are used in the present invention to mean that a solid compound exists in a specific crystalline state in a crystal structure.
- the difference in physical and chemical properties of polymorphs can be reflected in storage stability, compressibility, density, dissolution rate and the like. In extreme cases, differences in solubility or dissolution rate can cause drug inefficiencies and even toxicity.
- the novel crystalline form of the masatinib mesylate salt in the present invention, Form A is pure, unitary, and substantially free of any other crystalline form.
- substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
- Polymorphic forms of the drug can be obtained by methods including, but not limited to, melt recrystallization, melt cooling, solvent recrystallization, solvent loss, rapid volatilization, rapid temperature drop, slow temperature drop, vapor diffusion, and sublimation. Sometimes, different methods may also achieve the same crystallization. Polymorphs can be obtained by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), optical microscopy, Hygroscopicity, etc. to detect, discover and classify.
- XRPD X-ray powder diffraction
- DSC differential scanning calorimetry
- TGA thermogravimetric analysis
- optical microscopy Hygroscopicity, etc.
- the crystal form adopted by the crystal form of the present invention is a crystal slurry method in which a supersaturated solution of a sample (in the presence of insoluble solids) is stirred and crystallized in a solvent system, and the crystallization time is usually 24-72 hours.
- Another object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of Form A of a compound of formula (I) mesylate and a pharmaceutically acceptable adjuvant.
- a therapeutically effective amount of Form A of the methanesulfonate salt of a compound of formula (I) is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation in the pharmaceutical field.
- the pharmaceutical composition may also comprise other crystalline forms or amorphous forms of pharmaceutically acceptable methicinib or a salt thereof, including, but not limited to, the known crystal forms disclosed in, for example, the patents CN103342701A and US20150166524 A1. .
- the present invention also provides the use of the crystalline form A of the methanesulfonate salt of the compound of the formula (I) for the preparation of a pharmaceutical preparation for treating various diseases such as tumors, inflammatory diseases, and central nervous system.
- the present invention also provides the use of the crystalline form A of the mesylate salt of the compound of the formula (I) or a pharmaceutical composition comprising the same for the treatment of diseases such as tumors, inflammatory diseases, central nervous system and the like.
- the crystal form A of the compound of the formula (I) provided by the invention has a significantly lower wettability than the existing crystal form, and is convenient for preparation and long-term storage of the medicine, and has higher industrial application value.
- Figure 1 is an XRPD pattern of the mesylate salt form A of the compound of formula (I)
- Figure 2 is a DSC chart of the methanesulfonate salt form A of the compound of formula (I);
- Figure 3 is a TGA diagram of the methanesulfonate salt form A of the compound of formula (I);
- Figure 4 is a 1 H-NMR chart of the methanesulfonate salt form A of the compound of the formula (I);
- Figure 5 is an infrared spectrum of the methanesulfonate crystal form A of the compound of the formula (I);
- Figure 6 is a DVS dynamic moisture adsorption diagram of the methanesulfonate salt form A of the compound of formula (I);
- Figure 7 is an XRPD pattern of the methanesulfonate crystal form A of the compound of the formula (I) before and after DVS (the upper graph is an XRPD pattern before DVS, and the lower graph is an XRPD pattern after DVS);
- Figure 8 is an XRPD pattern of the methanesulfonate salt form A of the compound of the formula (I) before and after being placed at 5 ° C for 270 days (the upper graph is obtained before the test, and the lower graph is obtained after the test);
- Figure 9 is an XRPD diagram of the compound (I) mesylate salt Form A before and after 270 days of standing at 25 ° C, 60% relative humidity. The figure is the pre-placement test, the lower figure is the test after placement;
- Figure 10 is an XRPD pattern of the compound (I) mesylate salt form A before and after being placed at 40 ° C, 75% relative humidity for 270 days. The figure above shows the pre-placement test, and the lower figure shows the test after placement.
- the starting material is the methanesulfonate salt of the compound of formula (I).
- XRPD X-ray powder diffraction
- DSC differential scanning calorimetry
- the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
- the method parameters of the X-ray powder diffraction described in the present invention are as follows:
- the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
- the method parameters of differential scanning calorimetry (DSC) according to the present invention are as follows: scan rate: 10 ° C / min; protective gas: nitrogen.
- thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
- the method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows: scan rate: 10 ° C / min; protective gas: nitrogen.
- Example 1 The solid obtained in Example 1 was suspended in 15.0 mL of chloroform, stirred at 5 ° C for 24 hours, and the lower solid was removed by centrifugation, and dried at 25 ° C overnight.
- the obtained solid was a chloroform solvate of the methanesulfonate salt of the compound of the formula (I).
- the solvate temperature of the chloroform solvate is 130-150 °C.
- the XRPD pattern of the crystal form A obtained in this example is shown in Fig. 1, and the X-ray powder diffraction data is shown in Table 1.
- the DSC chart of Form A is shown in Fig. 2, the TGA chart is shown in Fig. 3, the NMR spectrum is shown in Fig. 4, and the infrared spectrum is shown in Fig. 5. among them:
- the infrared spectrum peaks are as follows: 410.06, 456.14, 528.31, 582.75, 624.26, 675.17, 722.83, 762.33, 779.69, 806.04, 821.41, 858.11, 883.70, 916.75, 982.61, 1006.59, 1027.47, 1123.50 ,1176.82,1217.89,1277.78,1316.66,1357.31,1406.30,1448.99,1527.63,1558.05,1599.06,1665.09,2789.99,3260.24,3415.16.
- the methanesulfonate crystal form A is induced by the humidity control to induce the chloroform solvate of the compound mesylate salt.
- the specific operation is as follows: 60.2 mg of the chloroform solvate of the methanesulfonate salt of the compound of the formula (I) is placed in the dynamic moisture.
- the experiment was started according to a preset humidity cycle, and the X-ray powder diffraction data of the solid obtained after the completion of the experiment are shown in Table 3, indicating that the solid was the crystal form A.
- the dynamic moisture adsorption (DVS) experiment of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.), and the parameters used are shown in Table 4.
- the dynamic moisture adsorption (DVS) test was carried out on the methanesulfonate crystal form disclosed in CN103342701A, and the moisture content at 80% relative humidity and 95% relative humidity is shown in Table 5.
- the methanesulfonate crystal form A of the compound of the formula (I) of the present invention is placed at 5 ° C; 25 ° C, 60% relative humidity; and 40 ° C, 75% relative humidity, respectively, for 270 days, and X before and after the sample is placed.
- Ray powder diffraction test the results are shown in Figure 8-10.
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Abstract
La présente invention concerne une forme cristalline A du mésylate de masitinib, son procédé de préparation et une utilisation médicale de celle-ci. L'hygroscopicité de la forme cristalline A est remarquablement réduite. Par conséquent, elle se révèle commode pour la préparation de médicaments et le stockage à long terme.
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WO2018177854A1 (fr) | 2017-03-31 | 2018-10-04 | Sandoz Ag | Forme cristalline de masitinib |
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US20150166524A1 (en) * | 2013-12-18 | 2015-06-18 | Sandoz Ag | Crystalline form of masitinib |
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US8153792B2 (en) * | 2007-02-13 | 2012-04-10 | Ab Science | Process for the synthesis of 2-aminothiazole compounds as kinase inhibitors |
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US20150166524A1 (en) * | 2013-12-18 | 2015-06-18 | Sandoz Ag | Crystalline form of masitinib |
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WO2018177854A1 (fr) | 2017-03-31 | 2018-10-04 | Sandoz Ag | Forme cristalline de masitinib |
US10961235B2 (en) | 2017-03-31 | 2021-03-30 | Sandoz Ag | Crystalline form of masitinib |
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