CN116283919A - Novel crystal form of Vimseltinib and preparation method thereof - Google Patents
Novel crystal form of Vimseltinib and preparation method thereof Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 73
- TVGAHWWPABTBCX-UHFFFAOYSA-N vimseltinib Chemical compound O=C1N(C)C(NC(C)C)=NC=C1C(N=C1C)=CC=C1OC1=CC=NC(C2=CN(C)N=C2)=C1 TVGAHWWPABTBCX-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 229940074572 vimseltinib Drugs 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title abstract description 19
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 24
- 238000001228 spectrum Methods 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
- 230000000694 effects Effects 0.000 claims abstract description 9
- 239000004480 active ingredient Substances 0.000 claims abstract description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 150000001298 alcohols Chemical class 0.000 claims description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 15
- 150000002825 nitriles Chemical class 0.000 claims description 14
- 150000002170 ethers Chemical class 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 10
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 10
- 229940011051 isopropyl acetate Drugs 0.000 claims description 9
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 9
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical group CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 7
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 229930195733 hydrocarbon Natural products 0.000 claims description 6
- 150000002430 hydrocarbons Chemical class 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
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- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000001757 thermogravimetry curve Methods 0.000 claims description 2
- 208000007990 Giant Cell Tumor of Tendon Sheath Diseases 0.000 claims 1
- 201000008754 Tenosynovial giant cell tumor Diseases 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 claims 1
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- 150000001875 compounds Chemical class 0.000 description 6
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- 229940100514 Syk tyrosine kinase inhibitor Drugs 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
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- 238000005119 centrifugation Methods 0.000 description 1
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- 230000007613 environmental effect Effects 0.000 description 1
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- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- 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
- C07D401/14—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 three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention provides a crystal form B of Vimseltinib, wherein an X-ray powder diffraction spectrum of the crystal form B has characteristic peaks at the positions of 10.1+/-0.2 DEG and 13.0+/-0.2 DEG of 2 theta values and has one or more of the following characteristic peaks: characteristic peaks at 10.4+ -0.2 °, 11.3+ -0.2 °, 12.1+ -0.2 °, 15.5+ -0.2 °, 17.6+ -0.2 °, 19.7+ -0.2 °, 22.2+ -0.2 ° and 23.3+ -0.2 °; the crystal form B has the advantages of high purity, good stability, good crystallinity, good solubility and the like. The preparation method of the crystal form B is simple, the solvent is cheap and easy to obtain, the crystallization condition is mild, and the preparation method is suitable for industrial mass production. The crystal form B has good crystal form stability and low hygroscopicity, can better resist the problems of uneven content of active ingredients, reduced purity, increased impurities and the like caused by factors such as ambient temperature and humidity in the processes of drug manufacture and/or storage and the like, reduces the risk of curative effect reduction and the risk of safety caused by the uneven content of active ingredients, reduced purity, increased impurities and the like, and is beneficial to accurate quantification in the drug manufacture, and improving the uniformity of the preparation and the storage and transportation in the later period.
Description
Technical Field
The invention relates to a novel crystal form of a drug and a preparation method thereof, in particular to a novel crystal form of Vimseltinib and a preparation method thereof.
Background
Vimseltinib (DCC-3014, chinese name 2- (isopropylamino) -3-methyl-5- (6-methyl-5- ((2- (1-methyl-1H-pyrazol-4-yl) pyridin-4-yl) oxy) pyridin-2-yl) pyrimidin-4 (3H) -one, CAS number 1628606-05-2), its chemical formula is shown in formula (I):
vimseltinib is a c-FMS (CSF-IR) and c-KIT dual inhibitor with anticancer and antiproliferative activities, can excite tyrosine protein kinase activity, influence protooncogene transcription, and is widely applied to research of anticancer drugs as an active molecule.
CN105120864B discloses heating the reaction mixture in a sealed tube at 100 ℃ for 2 days. The mixture was then cooled to room temperature, the solids were removed by filtration and the filtrate was concentrated to dryness and purified by silica gel chromatography to give 2- (isopropylamino) -3-methyl-5- (6-methyl-5- ((2- (1-methyl-1H-pyrazol-4-yl) pyridin-4-yl) oxy) pyridin-2-yl) pyrimidin-4 (3H) -one, amorphous form described.
CN113880812a reports another preparation method of Vimseltinib, and a small amount of target product meeting the requirement is finally obtained through a column chromatography purification process. The preparation method has complicated process and is not beneficial to industrialized mass production. There is no mention in this patent of reports on solid or crystalline forms of the compound of formula (I), and the purification process of column chromatography (EA/meoh=120:1 to 100:1) was repeated to give form a.
In view of the pharmaceutical value of the compound, the stability, uniformity, bioavailability, curative effect and safety of the medicament can be affected to different degrees by different crystal forms, and the development of the novel crystal form of the Vimseltinib with the advantage performance of the compound has very important significance, so that more and better choices are provided for the subsequent development of the medicament.
Disclosure of Invention
The invention aims to provide a novel crystal form of Vimseltinib and a preparation method thereof, and the novel crystal form of Vimseltinib has the advantages of good purity, high crystallinity, small hygroscopicity, and excellent dissolution performance and physical and chemical stability. The crystal form has simple preparation process, high yield and good product property, and thus has good patent medicine prospect.
The invention provides a compound B of formula (I), a preparation method and application thereof.
The invention provides a crystal form B of Vimseltinib (called as 'crystal form B' in the invention) and a preparation method thereof, wherein the crystal form B is an anhydrous substance.
In an X-ray powder diffraction pattern using a radiation source of Cu-K alpha, the X-ray powder diffraction pattern of the crystal form B has characteristic peaks at the 2 theta values of 10.1+/-0.2 DEG and 13.0+/-0.2 DEG and one or more of the following characteristic peaks: 10.4±0.2°, 11.3±0.2°, 12.1±0.2°, 15.5±0.2°, 17.6±0.2°, 19.7±0.2°, 22.2±0.2° and 23.3±0.2°.
Preferably, the crystal form B has specific peaks at diffraction angles 2θ of 10.1±0.2°, 10.4±0.2°, 11.3±0.2°, 13.0±0.2°, 15.5±0.2°, 17.6±0.2°, 19.7±0.2° and 20.0±0.2° in an X-ray powder diffractogram using a radiation source of cu—kα, and has one or more of the following characteristic peaks: 12.1±0.2°, 14.6±0.2°, 14.9±0.2°, 15.8±0.2°, 17.1±0.2°, 19.1±0.2°, 20.7±0.2°, 22.2±0.2°, 22.6±0.2°, 23.3±0.2°, 25.7±0.2° and 26.6±0.2°.
Or preferably crystal B, has an XRPD pattern consistent with figure 5.
Further, in the X-ray powder diffraction pattern of the crystal form B with the radiation source of Cu-K alpha, at diffraction angles 2θ of 10.1±0.2°, 10.4±0.2°, 11.3±0.2°, 12.1±0.2°, 12.7±0.2°, 13.0±0.2°, 14.6±0.2°, 14.9±0.2°, 15.5±0.2°, 15.8±0.2°, 17.1±0.2°, 17.6±0.2°, 18.0±0.2°, 19.1±0.2°, 19.7±0.2°, 20.0±0.2°, 20.7±0.2°, characteristic peaks are found at 21.3.+ -. 0.2 °, 21.8.+ -. 0.2 °, 22.2.+ -. 0.2 °, 22.6.+ -. 0.2 °, 22.8.+ -. 0.2 °, 23.3.+ -. 0.2 °, 24.4.+ -. 0.2 °, 25.2.+ -. 0.2 °, 25.7.+ -. 0.2 °, 26.0.+ -. 0.2 °, 26.2.+ -. 0.2 °, 26.6.+ -. 0.2 °, 29.5.+ -. 0.2 °, 30.2.+ -. 0.2 °, 31.4.+ -. 0.2 ° and 32.5.+ -. 0.2 °.
In one embodiment of the present invention, without limitation, the X-ray powder diffraction pattern of form B is shown in fig. 5.
In a specific embodiment of the present invention, without limitation, form B provided herein has an endothermic peak at 213±5 ℃ when subjected to Differential Scanning Calorimetry (DSC) to heat up from 25 ℃ to 300 ℃ at a heating rate of 10 ℃/min.
Further, the DSC spectrum of the crystal form B of the Vimseltinib is basically consistent with that of FIG. 6.
In a specific embodiment of the present invention, but not limited thereto, form B of the present invention, when heated at a rate of 10 ℃/min using a thermogravimetric analyzer (TGA) from room temperature to 300 ℃, loses no more than 0.5% weight at room temperature to 110 ℃, and further loses no more than 0.2% weight at room temperature to 110 ℃, is anhydrous.
Further, the TGA profile of form B of the present invention is substantially the same weight loss as shown in fig. 7.
The invention also provides a preparation method of the Vimseltinib crystal form B, which comprises the following steps:
1) The Vimseltinib is put in a mixed solvent to obtain suspension;
2) Stirring for a period of time at a proper temperature to precipitate solid, and drying to obtain the crystal form B.
In certain embodiments, the mixed solvent in step 1) is selected from the group consisting of alcohols and esters, alcohols and ketones, alcohols and nitriles, nitriles and hydrocarbons, nitriles and ethers, ethers and esters, and alcohols and ethers.
In some embodiments, the mixed solvent in the step 1) is preferably an alcohol-ketone, ether-ester or alcohol-ether mixed solvent.
In certain embodiments, the volume ratio of alcohols to esters, alcohols to ketones, alcohols to nitriles, nitriles to hydrocarbons, nitriles to ethers, ethers to esters or alcohols to ethers in step 1) is from 1:10 to 2:1, preferably from 1:1 to 2:1.
In certain embodiments, the alcohol of step 1) is preferably methanol, ethanol, isopropanol, n-propanol; esters are preferably isopropyl acetate, ethyl acetate; the ether is preferably anisole, methyl tertiary butyl ether or isopropyl ether; the nitrile is preferably acetonitrile; the ketone is preferably methyl isobutyl ketone or acetone; the hydrocarbon is preferably toluene.
In certain embodiments, the mixed solvent of step 1) is preferably methanol and isopropyl ether, ethanol and methyl tert-butyl ether, isopropanol and isopropyl acetate, isopropanol and anisole, isopropanol and acetonitrile, acetonitrile and toluene, anisole and isopropyl acetate, acetonitrile and methyl tert-butyl ether or isopropanol and methyl isobutyl ketone, and more preferably methanol and isopropyl ether, ethanol and methyl tert-butyl ether, isopropanol and anisole, anisole and isopropyl acetate or isopropanol and methyl isobutyl ketone.
In certain embodiments, the mass to volume ratio of the Vimseltinib to the mixed solvent in the suspension of the step 1) is 1:5-100 mg/mL, preferably 1:15-30 mg/mL.
In certain embodiments, step 2) is suitably at a temperature selected from 0 ℃ to 50 ℃, preferably 20 ℃ to 50 ℃; the stirring time is preferably 1 to 5 days, preferably 2 to 5 days.
In certain embodiments, the drying of step 2) is preferably vacuum or atmospheric drying at 20-30 ℃; preferably the drying time is 1 to 24 hours.
Preferably, filtration is carried out as conventional in the art, said filtration being conventional in the art, preferably centrifugation.
The invention also provides a pharmaceutical composition comprising the crystalline form B of the invention described above and a pharmaceutically acceptable carrier.
The present invention also provides a pharmaceutical composition having anticancer pharmaceutical activity, which contains the above-described crystalline form B of the present invention as an active ingredient.
The present invention provides a therapeutic agent for solid tumors, tenosynovial megacytomas and sarcomas, which contains the above-described crystalline form B of the present invention as an active ingredient.
The beneficial technical effects of the invention are as follows: the crystal form B has the advantages of high purity, good stability, good crystallinity, good solubility and the like. The preparation method of the crystal form B is simple, the solvent is cheap and easy to obtain, the crystallization condition is mild, and the preparation method is suitable for industrial mass production. The crystal form B has good crystal form stability and low hygroscopicity, can better resist the problems of uneven content of active ingredients, reduced purity, increased impurities and the like caused by factors such as ambient temperature and humidity in the processes of drug manufacture and/or storage and the like, reduces the risk of curative effect reduction and the risk of safety caused by the uneven content of active ingredients, reduced purity, increased impurities and the like, and is beneficial to accurate quantification in the drug manufacture, and improving the uniformity of the preparation and the storage and transportation in the later period. The crystal form B has better stability, so that the crystal form B is more controllable in the crystallization process, mixed crystals are not easy to occur, and the consistent and controllable quality of medicines is ensured. The crystal form B is anhydrous and is more suitable for dry granulation.
Compared with the prior art, the compound crystal form B of the formula (I) has advantages in at least one aspect of solubility, melting point, stability, dissolution, hygroscopicity, adhesiveness, fluidity, biological effectiveness, processability, purification effect, preparation production, safety and the like, provides a new better choice for preparing a pharmaceutical preparation containing the compound of the formula (I), and has very important significance for drug development.
Drawings
FIG. 1 is an X-ray powder diffraction (XPRD) spectrum of form A of the present invention;
FIG. 2 is a DSC of form A of the present invention;
FIG. 3 is a TGA spectrum of form A of the present invention;
FIG. 4 is a PSD spectrum of form A of the present invention;
FIG. 5 is an X-ray powder diffraction (XPRD) spectrum of form B of the present invention;
FIG. 6 is a DSC of form B of the present invention;
FIG. 7 is a TGA spectrum of form B of the present invention;
FIG. 8 is a PSD spectrum of form B of the present invention.
Detailed Description
The invention will be further illustrated with reference to specific examples. It should be understood that the following embodiments are used to describe the technical solution of the present invention in detail, and will help to further understand advantages and effects of the technical solution of the present invention, and the embodiments do not limit the protection scope of the present invention, which is determined by the claims.
The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer.
The raw materials or reagents used in the examples were commercially available unless otherwise specified.
Unless otherwise indicated, the reagents described were used without purification. All solvents were purchased from commercial suppliers such as Aldrich (Aldrich) and used without treatment.
XPRD is collected on a Bruker D8 advanced diffractometer, and the method parameters of the X-ray powder diffraction are as follows:
x-ray reflection parameters: cu, K alpha
Tube voltage: 40 kilovolts (kV)
Tube current: 40 milliamperes (mA)
Slit: the primary optical path cable-stayed slit is 2.5 degrees, and the secondary optical path cable-stayed slit is 2.5 degrees
Scanning mode: continuous scanning
Step angle: 0.02 °, sampling time: 0.1 s/step;
scanning range: from 3.0 to 40.0 DEG
The TGA spectrum was acquired on a TAInstruments Discovery TGA instrument, and the method parameters of the thermogravimetric analysis were as follows:
scanning rate: 10 ℃/min
Protective gas: nitrogen gas
DSC spectrum is obtained by collecting on TAInstruments Discovery DSC250 instrument
Test conditions: heating from 25 ℃ to 300 ℃ at a speed of 10 ℃/min;
detecting environmental conditions: room temperature: 21 ℃.
Preparation of form A
The Vimseltinib starting material is obtained by the method of example 4, step 7 of patent CN 113880812A. Characterized by XRPD, form a was identified. The XRPD patterns are shown in figure 1, and the DSC and TGA patterns are shown in figures 2 and 3, respectively.
Example 1
30mg of Vimseltinib is taken, 1.0mL of a mixed solution of methanol and IPE (volume ratio is 1:1) is added, the mixture is stirred for 5 days at 30 ℃, then the mixture is filtered, the mixture is centrifugally filtered, a filter cake is dried for 24 hours at 30 ℃ in vacuum, crystals are obtained, the weight of the crystals is 25.5mg, and the yield is 85%. Characterized by XRPD, form B was identified. The XRPD patterns are shown in fig. 5, and the DSC and TGA patterns are shown in fig. 6 and 7, respectively.
Example 2
30mg of Vimseltinib is taken, 2.0mL of a mixed solution of ethanol and MTBE (volume ratio is 2:1) is added, the mixture is stirred for 2 days at 25 ℃, then the mixture is filtered, the mixture is centrifugally filtered, a filter cake is dried for 16h at 30 ℃ in vacuum, crystals are obtained, the weight of the crystals is 26.1mg, and the yield is 87%. Characterized by XRPD, form B was identified.
Example 3
30mg of Vimseltinib is taken, 1.0mL of a mixed solution of isopropanol and anisole (volume ratio is 1:1) is added, the mixture is stirred for 5 days at 50 ℃, then the mixture is filtered, centrifugal filtration is carried out, a filter cake is dried for 16h at 30 ℃ in vacuum, crystals are obtained, the weight is 25.9mg, and the yield is 86%. Characterized by XRPD, form B was identified.
Example 4
30mg of Vimseltinib is taken, 1.0mL of a mixed solution of anisole and isopropyl acetate (volume ratio is 1:1) is added, the mixture is stirred for 5 days at 50 ℃, then the mixture is filtered, the centrifugal filtration is carried out, the filter cake is dried for 16h at 30 ℃ in vacuum, crystals are obtained, the weight is 27.1mg, and the yield is 90%. Characterized by XRPD, form B was identified.
Example 5
30mg of Vimseltinib is taken, 1.6mL of a mixed solution of isopropanol and methyl isobutyl ketone (volume ratio is 1:1) is added, the mixture is stirred for 4 days at 50 ℃, then the mixture is filtered, the centrifugal filtration is carried out, the filter cake is dried for 16h at 30 ℃ in vacuum, crystals are obtained, the weight is 26.1mg, and the yield is 87%. Characterized by XRPD, form B was identified.
Example 6
About 10mg of each of the crystal form A and the crystal form B of the invention is weighed, respectively placed on a glass slide, a little vacuum silicone oil is dripped to disperse a sample, then a cover glass is covered, and the glass slide are placed under a polarized light microscope for observation. The crystal form B of the invention has better crystal habit than the crystal form A.
Example 7
About 10mg of each of the crystal form A and the crystal form B of the invention is weighed, respectively placed on a glass slide, a little vacuum silicone oil is dripped to disperse a sample, then a cover glass is covered, and the glass slide are placed under a polarized light microscope for observation. The crystal form B of the invention has better crystal habit than the crystal form A.
Example 8
Stability test
Form a and form B samples obtained in any of the examples above were left open for 16 days at different temperatures and different humidity conditions and XRPD, HPLC, were measured on the samples and the results are shown in table 1 below.
TABLE 1 stability study
From the data in table 1 above, both form B and form a of the present invention show particularly outstanding form stability and physicochemical stability at 25 ℃/60% rh, but form B shows higher stability than form a at 40 ℃/75% rh.
Example 9
Crystal form stability study under high humidity condition
Form a and form B samples were placed in a brown desiccator at 92.5% rh for 48 hours and the mass was measured by sampling, showing that form a increased by 1.6% and form B increased by 1.8% and form B remained unchanged.
The experiment shows that the quality of the crystal form A and the crystal form B is not obviously changed under the high humidity condition, and the hygroscopicity is small. More precisely, the water content of the crystal form is not easy to change even under the high humidity condition, and the crystal form can be kept stable for a certain period of time under the environment condition.
Example 10
Particle size distribution contrast study
Weighing about 30-50mg of each of the crystal form A and the crystal form B, adding the crystal form A and the crystal form B into 40mL of water, fully and uniformly mixing a sample to be tested, adding the mixture into a Hydro EV sampling system to enable the shading degree to reach a proper range, starting an experiment, and carrying out particle size distribution test after ultrasonic treatment for 30 seconds. The PSD spectrum of the crystal form A is shown in fig. 4, the PSD spectrum of the crystal form B is shown in fig. 8, and the PSD spectrum is analyzed by the spectrum: the crystal form B has more uniform particle size distribution than the crystal form A.
Claims (10)
1. Form B of Vimseltinib having an X-ray powder diffraction pattern with characteristic peaks at 2Θ values of 10.1 ± 0.2 ° and 13.0 ± 0.2 ° and having one or more of the following characteristic peaks: characteristic peaks are arranged at 10.4+/-0.2 degrees, 11.3+/-0.2 degrees, 12.1+/-0.2 degrees, 15.5+/-0.2 degrees, 17.6+/-0.2 degrees, 19.7+/-0.2 degrees, 22.2+/-0.2 degrees and 23.3+/-0.2 degrees.
2. Form B of vims eltinib according to claim 1, characterized in that: the X-ray powder diffraction pattern has specific peaks at the 2 theta values of 10.1+/-0.2 DEG, 10.4+/-0.2 DEG, 11.3+/-0.2 DEG, 13.0+/-0.2 DEG, 15.5+/-0.2 DEG, 17.6+/-0.2 DEG, 19.7+/-0.2 DEG and 20.0+/-0.2 DEG and one or more of the following characteristic peaks: 12.1±0.2°, 14.6±0.2°, 14.9±0.2°, 15.8±0.2°, 17.1±0.2°, 19.1±0.2°, 20.7±0.2°, 22.2±0.2°, 22.6±0.2°, 23.3±0.2°, 25.7±0.2° and 26.6±0.2°;
or preferably crystal B, has an XRPD pattern consistent with figure 5.
3. Form B according to claim 1, characterized in that: the DSC spectrum of the crystal B comprises an absorption peak at 213+/-5 ℃;
or preferably crystal B, has a DSC profile consistent with figure 6.
4. Crystal B according to claim 1, characterized in that: the weight loss is not more than 0.5% when the temperature is raised to 110 ℃ at room temperature, and further, the weight loss is not more than 0.2% when the temperature is raised to 110 ℃ at room temperature, and the crystal form B is an anhydrous substance;
or preferably form B, has a TGA profile substantially the same weight loss as shown in figure 7.
5. A process for preparing the crystal B according to any one of claims 1 to 4, comprising the steps of:
1) The Vimseltinib is put in a mixed solvent to obtain suspension;
2) Stirring for a period of time at a proper temperature to precipitate solid, and drying to obtain the crystal form B.
6. The method of manufacturing according to claim 5, wherein: the mixed solvent in the step 1) is selected from alcohols and esters, alcohols and ketones, alcohols and nitriles, nitriles and hydrocarbons, nitriles and ethers, ethers and esters or alcohols and ethers; the mixed solvent is preferably an alcohol-ketone, ether-ester or alcohol-ether mixed solvent;
preferably, the volume ratio of the alcohols to the esters, the alcohols to the ketones, the alcohols to the nitriles, the nitriles to the hydrocarbons, the nitriles to the ethers, the ethers to the esters or the alcohols to the ethers is 1:10 to 2:1, preferably 1:1 to 2:1;
preferably, the alcohol is methanol, ethanol, isopropanol or n-propanol; esters are isopropyl acetate and ethyl acetate; ethers are anisole, methyl tertiary butyl ether and isopropyl ether; the nitrile is acetonitrile; the ketone is methyl isobutyl ketone or acetone; the hydrocarbon is toluene;
preferably, the mixed solvent in the step 1) is methanol and isopropyl ether, ethanol and methyl tert-butyl ether, isopropyl alcohol and isopropyl acetate, isopropyl alcohol and anisole, isopropyl alcohol and acetonitrile, acetonitrile and toluene, anisole and isopropyl acetate, acetonitrile and methyl tert-butyl ether or isopropyl alcohol and methyl isobutyl ketone, and more preferably methanol and isopropyl ether, ethanol and methyl tert-butyl ether, isopropyl alcohol and anisole, anisole and isopropyl acetate or isopropyl alcohol and methyl isobutyl ketone.
7. The method of manufacturing according to claim 5 or 6, characterized in that: the mass volume ratio of the Vimseltinib to the mixed solvent in the suspension in the step 1) is 1:5-100 mg/mL, preferably 1:15-30 mg/mL.
8. The method of manufacturing according to claim 5 or 6, characterized in that: step 2) is suitably carried out at a temperature selected from the range of from 0 ℃ to 50 ℃, preferably from 20 ℃ to 50 ℃; the stirring time is preferably 1 to 5 days, preferably 2 to 5 days.
9. The method of manufacturing according to claim 5 or 6, characterized in that: the drying in the step 2) is preferably carried out at 20-30 ℃ under vacuum or normal pressure; preferably the drying time is 1 to 24 hours.
10. A pharmaceutical composition comprising the crystal B of any one of claims 1-4 and a pharmaceutically acceptable carrier;
a pharmaceutical composition preferably having anticancer pharmaceutical activity, comprising the crystal B of any one of claims 1 to 4 as an active ingredient;
or preferably solid tumors, tenosynovial giant cell tumors and sarcomas, comprising the crystal B according to any one of claims 1 to 4 as an active ingredient.
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