CN109988112A - The crystal form and preparation method thereof that logical sequence is cut down for Buddhist nun's mesylate - Google Patents
The crystal form and preparation method thereof that logical sequence is cut down for Buddhist nun's mesylate Download PDFInfo
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- CN109988112A CN109988112A CN201811531876.3A CN201811531876A CN109988112A CN 109988112 A CN109988112 A CN 109988112A CN 201811531876 A CN201811531876 A CN 201811531876A CN 109988112 A CN109988112 A CN 109988112A
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- mesylate
- crystal form
- buddhist nun
- logical sequence
- cut down
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- 239000013078 crystal Substances 0.000 title claims abstract description 187
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 title claims abstract description 148
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 47
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 51
- 239000007787 solid Substances 0.000 claims description 48
- 239000002904 solvent Substances 0.000 claims description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
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- 238000003756 stirring Methods 0.000 claims description 17
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- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 4
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- 208000024770 Thyroid neoplasm Diseases 0.000 claims 1
- 238000007707 calorimetry Methods 0.000 claims 1
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- 201000002510 thyroid cancer Diseases 0.000 claims 1
- 208000015799 differentiated thyroid carcinoma Diseases 0.000 abstract description 7
- 238000000034 method Methods 0.000 description 28
- 238000004458 analytical method Methods 0.000 description 17
- 238000000113 differential scanning calorimetry Methods 0.000 description 13
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 12
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- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 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
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- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
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- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 3
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- 238000007873 sieving Methods 0.000 description 3
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- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 229910017488 Cu K Inorganic materials 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
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- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
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- -1 formyl amine mesylate Chemical compound 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
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- 229910052757 nitrogen Inorganic materials 0.000 description 2
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- 239000012453 solvate Substances 0.000 description 2
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- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 101000851030 Homo sapiens Vascular endothelial growth factor receptor 3 Proteins 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 208000032005 Spinocerebellar ataxia with axonal neuropathy type 2 Diseases 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
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- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 208000033361 autosomal recessive with axonal neuropathy 2 spinocerebellar ataxia Diseases 0.000 description 1
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- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical group 0.000 description 1
- 238000012926 crystallographic analysis Methods 0.000 description 1
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
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- 230000000694 effects Effects 0.000 description 1
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- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- XMBWDFGMSWQBCA-RNFDNDRNSA-M iodine-131(1-) Chemical compound [131I-] XMBWDFGMSWQBCA-RNFDNDRNSA-M 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000005950 photosensitized reaction Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The crystal form for Buddhist nun's mesylate, preparation method, the pharmaceutical composition comprising crystal form and the crystal form, which are cut down, the invention discloses a kind of logical sequence is preparing the purposes in the drug for treating invasion, differentiated thyroid carcinoma.The logical sequence is cut down for the crystal form of Buddhist nun's mesylate, and X-ray powder diffraction figure is included in about 16.1 ± 0.2 °, and 17.8 ± 0.2 °, 18.8 ± 0.2 °, 25.0 ± 0.2 °, the peak at 25.4 ± 0.2 ° of the angle of diffraction (2 θ).
Description
Technical field
The present invention relates to a kind of logical sequences to cut down the crystal form and preparation method thereof for Buddhist nun's mesylate.
Background technique
Logical sequence is cut down for Buddhist nun's mesylate, and it is the anticancer drug that material research and development are defended by Japan for Buddhist nun that logical sequence, which is cut down for Buddhist nun also known as happy cut down, in
Hitting property of FDA approval treatment invasion, differentiated invasion, differentiated thyroid carcinoma (DTC) patient are obtained on February 13rd, 2015, is applicable in
In the patient of the disease progression after receiving radioiodine therapy.The chemical name of the drug is the 4- [chloro- 4- (cyclopropylamino of 3-
Carbonyl) amino-benzene oxygen] -7- methoxyl group -6- quinoline formyl amine mesylate, the chemical formula of mesylate is
C21H19ClN4O4·CH4O3S, relative molecular mass are 522.96, and chemical structural formula is as follows:
Logical sequence cut down for Buddhist nun's mesylate be a kind of multiple target point inhibitor (mainly inhibit VEGFR1 (FLT1), VEGFR2 (KDR),
VEGFR3 (FLT4), RTKs), it is by blocking certain albumen that growth of cancer cells and differentiation is helped to work；According to extracorporeal receptor
Tyrosine, serine, threonine experiment, logical sequence, which is cut down, can inhibit FLT1, KDR and FLT4 for Buddhist nun's mesylate, so as to effectively inhibit
Angiogenesis, VEGF/KDR and SCF/KIT signal path.
Japanese Wei Cai house journal CN01819710.8 discloses logical sequence at first and cuts down for the compound structure of Buddhist nun's mesylate, then
Occur cutting down the document patent report for Buddhist nun's mesylate compound medicinal solid form about logical sequence successively.1)
CN200810145600.1 discloses logical sequence first and cuts down five kinds of crystal forms for Buddhist nun's mesylate, respectively anhydrous polymorphic type A, B, C, vinegar
Acid closes object crystal form I and hydrate crystal forms F.Wherein anhydrous crystal forms B can be changed into C crystal form or brilliant with C under the conditions of different humidity
The mixed crystal of type, crystal form I can also be changed into C crystal form or the mixed crystal with C crystal form, therefore crystal form B and crystal form I under the conditions of different humidity
Less stable.2) WO2016184436 discloses a kind of crystal form M of solvate forms, there is a possibility that dissolvent residual is exceeded,
There are drug safety risks.
Therefore it provides a kind of stability it is good, it is highly-safe, be suitable for industrial production, and cut down with the logical sequence of good patent medicine prospect
For the crystal form of Buddhist nun's mesylate, become those skilled in the art's urgent problem to be solved.
Summary of the invention
The object of the present invention is to provide a kind of logical sequences to cut down for the crystal form of Buddhist nun's mesylate, solves logical sequence in the prior art and cuts down for Ni Jia
The stability of crystal form of sulfonate is bad, has security risks, is unable to the problems such as large-scale production.
In order to solve the above technical problems, technical scheme is as follows:
A kind of logical sequence is cut down for the crystal form of Buddhist nun's mesylate, and X-ray powder diffraction figure is included in about 16.1 ± 0.2 °, 17.8 ±
0.2 °, 18.8 ± 0.2 °, 25.0 ± 0.2 °, the peak at 25.4 ± 0.2 ° of the angle of diffraction (2 θ).
In certain embodiments, the X-ray powder diffraction figure of the crystal form is included in about 8.0 ± 0.2 °, 11.2 ±
0.2 °, 12.6 ± 0.2 °, 16.1 ± 0.2 °, 17.8 ± 0.2 °, 18.8 ± 0.2 °, 19.7 ± 0.2 °, 20.2 ± 0.2 °, 22.9 ±
0.2 °, 23.7 ± 0.2 °, 24.2 ± 0.2 °, 25.0 ± 0.2 °, 25.4 ± 0.2 °, 27.0 ± 0.2 ° and 28.3 ± 0.2 ° of diffraction
Peak at angle (2 θ).
In certain embodiments, the X-ray powder diffraction figure of the crystal form is included in about 8.0 ± 0.2 °, 11.2 ±
0.2 °, 12.6 ± 0.2 °, 16.1 ± 0.2 °, 17.2 ± 0.2 °, 17.8 ± 0.2 °, 18.1 ± 0.2 °, 18.8 ± 0.2 °, 19.7 ±
0.2 °, 20.2 ± 0.2 °, 20.6 ± 0.2 °, 21.9 ± 0.2 °, 22.1 ± 0.2 °, 22.9 ± 0.2 °, 23.3 ± 0.2 °, 23.7 ±
0.2 °, 24.2 ± 0.2 °, 25.0 ± 0.2 °, 25.4 ± 0.2 °, 26.3 ± 0.2 °, 27.0 ± 0.2 °, 28.3 ± 0.2 °, 28.8 ±
Peak at 0.2 ° and 29.4 ± 0.2 ° of the angle of diffraction (2 θ).
In certain embodiments, the X-ray powder diffraction figure of the crystal form is as shown in Figure 1.
In certain embodiments, the temperature of the endothermic peak of the differential scanning calorimetry (DSC) of the crystal form is respectively
108.1 ± 5 DEG C and 159.0 ± 5 DEG C.
In certain embodiments, the temperature of the endothermic peak of the differential scanning calorimetry (DSC) of the crystal form is respectively
108.1 ± 2 DEG C and 159.0 ± 2 DEG C.
In certain embodiments, the water content of the crystal form is 5%~8%, contains 1.5~2.5 molecular crystalline water.
The present invention also provides the preparation methods that the logical sequence cuts down the crystal form for Buddhist nun's mesylate, comprising the following steps:
Step A: it logical sequence is cut down to be added in solvent for Buddhist nun's mesylate solid is configured to suspension；
Step B: crystal seed being added into suspension, and purified water is added dropwise, stirs 10~30h at 20~30 DEG C of Yu Wendu, later
Magma is filtered to obtain, drying is cut down to constant weight to get the logical sequence for the crystal form of Buddhist nun's mesylate；The solvent is selected from water, alcohol
One of class, ketone, alkanes, ethers are a variety of.
In preferred embodiments, it is that logical sequence cuts down solid shape for Buddhist nun's mesylate that the logical sequence, which is cut down for Buddhist nun's mesylate solid,
Formula, preferably amorphous forms.
In preferred embodiments, the solvent is selected from one of water, ethers or alkanes or a variety of；Preferably,
The ethers is selected from one of ether, isopropyl ether, methyl tertiary butyl ether(MTBE), cyclopentyl-methyl ether or a variety of, described alkane
Class is selected from one or more of n-hexane, hexamethylene, normal heptane, isooctane.
In preferred embodiments, the suspension concentration is 0.01~0.05g/ml, preferably 0.02~0.04g/ml.
In preferred embodiments, the stirring rate is 200~500r/min, preferably 300r/min.
In preferred embodiments, the purified water and the volume ratio of solvent are 1:100~1:300, preferably 1:150
~1:200；The additional amount of the crystal seed is that logical sequence cuts down 0.1%~1% (w/w) for Buddhist nun's mesylate solid, preferably 0.1%
~0.5% (w/w).
In preferred embodiments, the mixing time is 15~20h.
The present invention also provides the preparation methods that the logical sequence described in another kind cuts down the crystal form for Buddhist nun's mesylate, including following step
It is rapid:
Step A1: it logical sequence is cut down to be added in mixed solution for Buddhist nun's mesylate solid is configured to suspension；
Crystal seed is added in B1: Xiang Shangshu suspension liquid system of step, stirs 10~15h at Yu Wendu 30-50 DEG C, filters later
Magma is obtained, drying is cut down to constant weight to get the logical sequence for the crystal form of Buddhist nun's mesylate.
In preferred embodiments, it is that logical sequence cuts down solid shape for Buddhist nun's mesylate that the logical sequence, which is cut down for Buddhist nun's mesylate solid,
Formula, preferably amorphous forms.
In preferred embodiments, the mixed solution is that organic solvent and water mix reach solution according to a certain percentage
Stratification state, it is preferred that the volume ratio of the organic solvent and water be 100:1~300:1, more preferable volume ratio be 150:1~
200:1.The organic solvent is selected from one of ethers, aromatic or alkanes or a variety of；Preferably, the ethers
Selected from one of ether, isopropyl ether, methyl tertiary butyl ether(MTBE), propyl ether, methyl phenyl ethers anisole or a variety of, the aromatic is selected from first
One or both of benzene, dimethylbenzene, the alkanes are selected from one or both of pentane, n-hexane.
In preferred embodiments, the suspension concentration is 0.01~0.05g/ml, preferably 0.02~0.04g/ml.
In preferred embodiments, the additional amount of the crystal seed is that logical sequence is cut down for the 0.1%~1% of Buddhist nun's mesylate solid
(w/w), preferably 0.1%~0.5% (w/w).
In preferred embodiments, the stirring rate is 200~500r/min, preferably 300r/min.
Another aspect of the present invention relates to a kind of pharmaceutical compositions, and it includes the logical sequences to cut down for the crystalline substance of Buddhist nun's mesylate
Type and one or more pharmaceutically acceptable carriers.
Another aspect of the present invention has further related to the crystal form that the logical sequence is cut down for Buddhist nun's mesylate and has invaded in preparation for treating
Attacking property, differentiated thyroid carcinoma drug in purposes.
Another aspect of the present invention further relates to cut down for the logical sequence for treating invasion, differentiated thyroid carcinoma for Buddhist nun's mesylate
Crystal form.
Another aspect of the present invention also provides treatment invasion, the method for differentiated thyroid carcinoma, and the method includes
A effective amount of logical sequence is administered to the individual of needs to cut down for the crystal form of Buddhist nun's mesylate.
Compared with prior art, the present invention have it is following the utility model has the advantages that
It includes but is not limited to higher solubility, preferable medicine that logical sequence of the invention, which is cut down for the advantage of the crystal form of Buddhist nun's mesylate,
For kinetic characteristics and good stability, it is suitble to prepare pharmaceutical preparation, and the preparation method of the crystal form is simple and effective, easily
It is produced in amplification.
Crystal form of the invention have excellent physical property comprising but be not limited to solubility, dissolution rate, light shine,
Agent of low hygroscopicity, heat-resisting quantity, resistance to height be moist, mobility and the viscous stickiness being obviously improved etc..For example, crystal form of the invention is in preparation
It can obviously reduce filtration time in the process, shorten the production cycle, save the cost.Also there is crystal form of the invention good light to stablize
Property, thermal stability and wet stability, it is ensured that reliability of the crystal form in storage and transport, to guarantee the safety of preparation
Property, and the crystal form does not need to prevent from being illuminated by the light, the influence of temperature and humidity and take extra package to handle, to reduce
Cost.The crystal form will not influence to generate degradation because of illumination, high temperature and high humidity, improve the safety and long-term storage of preparation
Validity afterwards.The patient for taking the crystal form will not worry preparation and generate photosensitized reaction because being exposed under daylight.
Crystal form of the invention few or less degradation when storing or transport at ambient temperature, the crystal form is in differential scanning
Melting or desolvation when being greater than 50C are shown in calorimetric (DSC) analysis, and there is preferable thermal stability, it can be steady for a long time
It is fixed to keep, and it is suitable for the formulation manufacturing processes of standard.
Crystal form of the invention has good chemical stability and physical stability, easily prepared and be particularly suited for making
The preparation of agent.For example, crystal form of the invention is milled into fine powder, it is sieved with 500 μm and 250 μm of screens.It mills sieving
The X-ray powder diffraction peak of crystal form and previous cause of being sieved of milling afterwards.
Crystal form good fluidity of the invention, compressibility is good, and heap density is big, and hygroscopicity is low, even particle size distribution.
Crystal form of the invention has the effect of excellent in treatment invasion, differentiated thyroid carcinoma, is able to maintain enough
Bioactivity, dose therapeutically effective can be provided in vivo.
Crystal form of the invention is suitble to and convenient for a large amount of preparation, and the preparation being prepared with above-mentioned crystal form can reduce irritation simultaneously
It improves and absorbs, so that the problem of accretion rate aspect is addressed, toxicity is remarkably reduced, and safety is improved, effectively
Ground ensure that the quality and efficiency of preparation.
Crystal form purity of the invention is high, is not organic solvate, organic solvent-free remains risk, highly-safe.
Detailed description of the invention
Fig. 1 is that logical sequence of the present invention cuts down the XRPD map for the crystal form of Buddhist nun's mesylate；
Fig. 2 is that logical sequence of the present invention cuts down DSC the and TGA analysis chart for the crystal form of Buddhist nun's mesylate；
Fig. 3 is that logical sequence prepared by embodiment 6 cuts down powder diagram of crystal form under the conditions of different placements for Buddhist nun's mesylate
Compose comparative situation；
Fig. 4 cuts down for logical sequence of the present invention and is ground into fine powder for the crystal form of Buddhist nun's mesylate, with 500 μm and 250 μm of screen mistake
Map is compared with the powder diffraction before sieving of milling after sieve.
Specific embodiment
The present invention is further explained below, it should be appreciated that the term is intended to describe purpose, rather than limits this hair
It is bright.
General definition and term
Unless otherwise indicated, the technical and scientific term used herein has and those skilled in the art of the invention
The identical meaning being generally understood.Contradiction if it exists, then be subject to definition provided by the present application.When with range, preferred scope,
Or the form of preferred numerical upper limits and preferred numerical lower limits state some amount, concentration or other values or parameter when
It waits, it should be understood that be equivalent to and specifically disclose by by any pair of range limit or preferred value and any range lower limit or excellent
Any range that numerical value combines is selected, without considering whether the range specifically discloses.Unless otherwise indicated, listed herein
The endpoint and all integers and score (decimal) within the scope of this that numberical range is intended to include range.
Term " about ", " about " are when being often referred to the numerical value of the variable and all numbers of the variable with numerical variable and the used time
Value is in experimental error (such as in the confidence interval of average value 95%) or in ± the 10% of specified numerical value or wider model
In enclosing.
Statement "comprising" or with its synonymous similar statement " comprising ", " containing " and " having " etc. be it is open, do not arrange
Except additional unlisted element, step or ingredient.State " Consists of " exclude unspecified any element, step or at
Point.Statement "consisting essentially of ..." how is limited in specified element, step or ingredient, in addition what is be optionally present will not be real
Element, step or the ingredient of the basic and new feature of theme claimed are influenced in matter.It should be appreciated that statement "comprising"
Cover statement "consisting essentially of ..." and " Consists of ".
Term as used herein " optional " " optionally " refers to that the event then described or situation may occur or can
It can not occur, which includes that the event or situation occurs and the event or situation does not occur.
Unless otherwise indicated, the percentage of this paper, number etc. be all by weight.
Term " logical sequence is cut down for Buddhist nun's mesylate solid " refers to that logical sequence is cut down for the solid form of Buddhist nun's mesylate, for example, can be crystalline substance
Body form or amorphous forms.
Term " unformed " refers to any solid matter in three-dimensional without sequence.In some cases, amorphous solid can
It is characterized by known technology, the technology includes XRPD crystallographic analysis, differential scanning calorimetry (DSC), solid state nmr
(ssNMR) Spectrum Analysis or the combination of these technologies.As explained below, the XRPD map that amorphous solid generates is without apparent
Diffractive features peak.
As used herein, term " crystal form " or " crystal " refer to any solid matter that three-dimensional sequence is presented, with nothing
Amorphous solid substance is on the contrary, it generates the characteristic XRPD map with the peak of clear border.
As used herein, term " crystal seed " refers in crystallisation, by the way that insoluble additive is added, is formed brilliant
The growth of crystal form therewith or the identical enantiomter crystallization of spatial configuration is accelerated or promoted to core.
As used herein, term " X-ray powder diffraction pattern (XRPD map) " refers to the diffraction pattern of Germicidal efficacy
Or parameter, data or value derived from it.XRPD map is usually characterized by peak position (abscissa) and/or peak intensity (ordinate).
As used herein, term " 2 θ " refers to based on the peak indicated with degree (°) being arranged in x-ray diffraction experiment
Position, and be usually the abscissa unit in diffracting spectrum.If reflection is spread out when incident beam and certain lattice plane shape into θ angle
It penetrates, then experimental setup needs to record reflecting bundle with 2 angles θ.It should be appreciated that the specific 2 θ value for the specific crystal formation mentioned herein is anticipated
Figure is indicated using 2 θ values (being indicated with degree) measured by x-ray diffraction experiment condition as described herein.For example, such as this paper institute
It states, uses Cu-K α (K α 11.5206) it is used as radiation source.XRPD map herein is preferably in PANalytacal
It is acquired on Empyrean powder diffraction analysis instrument, transmission mode is preferably in PANalytacal EmpyreanX ray powder diffraction
It is acquired on analyzer.
As used herein, the term " substantially the same " at X-ray diffraction peak is meant representative peak position and
Strength Changes are taken into account.For example, it will be understood by those skilled in the art that peak position (2 θ) can show some variations, usually up to 0.1-
0.2 degree, and the instrument for measuring diffraction also results in some variations.In addition, it will be understood by those skilled in the art that opposite peak
Intensity can because between instrument difference and crystallinity degree, preferred orientation, the sample surfaces of preparation and those skilled in the art
Known other factors and change, and should be regarded as only observational measurement.
As used herein, term " alcohols " preferably means the alcohol with 1-10 carbon atom comprising but it is unlimited
In methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, sec-butyl alcohol and the tert-butyl alcohol.
As used herein, term " ethers " preferably means the ether with 2-6 carbon atom comprising but be not limited to
Ether, isopropyl ether, methyl tertiary butyl ether(MTBE), cyclopentyl-methyl ether.
As used herein, term " ketone " preferably with 3-6 carbon atom ether comprising but be not limited to acetone,
Methyl ethyl ketone, espeleton, methylisobutylketone, cyclohexanone.
As used herein, term " alkanes " preferably means the alkane with 5-10 carbon atom comprising but
It is not limited to n-hexane, hexamethylene, normal heptane, isooctane.
The crystal form and preparation method thereof that logical sequence is cut down for Buddhist nun's mesylate
In certain embodiments, the present invention provides logical sequence and cuts down for the crystal form of Buddhist nun's mesylate, the X-ray powder of the crystal form
Last diffraction pattern is included in about 16.1 ± 0.2 °, and 17.8 ± 0.2 °, 18.8 ± 0.2 °, 25.0 ± 0.2 °, 25.4 ± 0.2 ° of diffraction
Peak at angle (2 θ).
In certain embodiments, logical sequence cut down the X-ray powder diffraction figure for the crystal form of Buddhist nun's mesylate be included in about 8.0 ±
0.2 °, 11.2 ± 0.2 °, 12.6 ± 0.2 °, 16.1 ± 0.2 °, 17.8 ± 0.2 °, 18.8 ± 0.2 °, 19.7 ± 0.2 °, 20.2 ±
0.2 °, 22.9 ± 0.2 °, 23.7 ± 0.2 °, 24.2 ± 0.2 °, 25.0 ± 0.2 °, 25.4 ± 0.2 °, 27.0 ± 0.2 ° and 28.3
Peak at ± 0.2 ° of the angle of diffraction (2 θ).
In certain embodiments, logical sequence cut down the X-ray powder diffraction figure for the crystal form of Buddhist nun's mesylate be included in about 8.0 ±
0.2 °, 11.2 ± 0.2 °, 12.6 ± 0.2 °, 16.1 ± 0.2 °, 17.2 ± 0.2 °, 17.8 ± 0.2 °, 18.1 ± 0.2 °, 18.8 ±
0.2 °, 19.7 ± 0.2 °, 20.2 ± 0.2 °, 20.6 ± 0.2 °, 21.9 ± 0.2 °, 22.1 ± 0.2 °, 22.9 ± 0.2 °, 23.3 ±
0.2 °, 23.7 ± 0.2 °, 24.2 ± 0.2 °, 25.0 ± 0.2 °, 25.4 ± 0.2 °, 26.3 ± 0.2 °, 27.0 ± 0.2 °, 28.3 ±
Peak at 0.2 °, 28.8 ± 0.2 ° and 29.4 ± 0.2 ° of the angle of diffraction (2 θ).
In a further embodiment, logical sequence cut down the X-ray powder diffraction figure for the crystal form of Buddhist nun's mesylate be included in
Peak at the lower angle of diffraction (2 θ), see Table 1 for details.
Table 1
In further embodiment, logical sequence cut down the X-ray powder diffraction figure for the crystal form of Buddhist nun's mesylate include with
Peak at the substantially the same angle of diffraction shown in Fig. 1 (2 θ).In further embodiment, logical sequence is cut down for the crystalline substance of Buddhist nun's mesylate
The peak position of the X-ray powder diffraction figure of type is substantially the same with shown in Fig. 1.
In certain embodiments, logical sequence cuts down the endothermic peak of the differential scanning calorimetry (DSC) of the crystal form for Buddhist nun's mesylate
Temperature be respectively 108.1 ± 5 DEG C and 159.0 ± 5 DEG C.
In certain embodiments, logical sequence cuts down the endothermic peak of the differential scanning calorimetry (DSC) of the crystal form for Buddhist nun's mesylate
Temperature be respectively 108.1 ± 2 DEG C and 159.0 ± 2 DEG C.
In preferred embodiments, logical sequence cut down the DSC map for the crystal form of Buddhist nun's mesylate include with shown in Fig. 2 substantially
Characteristic peak at identical temperature.In a more preferred embodiment, logical sequence cuts down the spy of the DSC map for the crystal form of Buddhist nun's mesylate
It is substantially the same with shown in Fig. 2 to levy peak position.
In certain embodiments, logical sequence, which is cut down, shows that dehydration weight percent is for the TGA map of the crystal form of Buddhist nun's mesylate
5.0%~8.0%.
In preferred embodiments, logical sequence, which is cut down, shows dehydration weight percent for the TGA map of the crystal form of Buddhist nun's mesylate
About 6.23%.
In preferred embodiments, logical sequence cuts down TGA map for the crystal form of Buddhist nun's mesylate and substantially phase shown in Fig. 2
Together.
In certain embodiments, logical sequence cut down the crystal form for Buddhist nun's mesylate use Karl_Fischer method measure its water content for
5.0%~8.0%.In preferred embodiments, logical sequence cuts down the crystal form for Buddhist nun's mesylate using Karl_Fischer method to measure its aqueous
Amount is 6.0%~8.0%.
In certain embodiments, logical sequence, which is cut down, contains 1.5~2.5 molecular crystalline water for the crystal form of Buddhist nun's mesylate.
The present invention provides the preparation methods that logical sequence cuts down the crystal form for Buddhist nun's mesylate comprising following steps:
Step A: it logical sequence is cut down to be added in solvent for Buddhist nun's mesylate solid is configured to suspension；Preferably, described molten
Agent is selected from one of water, alcohols, ketone, alkanes, ethers or a variety of；
Step B: crystal seed being added into suspension, and purified water is added dropwise, stirs 10~30h at 20~30 DEG C of Yu Wendu, later
Magma is filtered to obtain, drying is cut down to constant weight to get the logical sequence for the crystal form of Buddhist nun's mesylate.
In above-mentioned preparation method of the invention, a kind of solvent is can be used in the solvent, also can be used two kinds or
The mixture of two or more solvents, such as the mixture of water and alcohols, the mixture of alcohols and ketone.
In preferred embodiments, it is that logical sequence cuts down solid shape for Buddhist nun's mesylate that the logical sequence, which is cut down for Buddhist nun's mesylate solid,
Formula, preferably amorphous forms.
In preferred embodiments, the solvent is selected from one of water, ethers or alkanes or a variety of.Ethers is for example
Ether, isopropyl ether, methyl tertiary butyl ether(MTBE), cyclopentyl-methyl ether, alkanes such as n-hexane, hexamethylene, normal heptane, isooctane.
A kind of solvent can be used in the solvent, and the mixture of two kinds or more of solvent also can be used, such as solvent is water, different
The mixture of the mixture of propyl ether, isopropyl ether and ether, isopropyl ether and n-hexane.
In a more preferred embodiment, the solvent is methyl tertiary butyl ether(MTBE) or isopropyl ether or cyclopentyl-methyl ether.
In preferred embodiments, logical sequence is cut down to be added in solvent for Buddhist nun's mesylate solid in step A and is configured to concentration
For the suspension of 0.01~0.05g/ml；Match it is furthermore preferred that cutting down to be added in solvent for Buddhist nun's mesylate solid by logical sequence in step A
The suspension that concentration is 0.02~0.04g/ml is made.
In preferred embodiments, the purified water in step B and the volume ratio of the solvent in step A are 1:100~1:
300；It is furthermore preferred that the purified water in step B and the volume ratio of the solvent in step A are 1:150~1:200.
In preferred embodiments, the additional amount of crystal seed is that logical sequence cuts down 0.1%~1% (w/w) for Buddhist nun's mesylate solid
(such as it is 0.01:10 or 1:10 that crystal seed and logical sequence, which are cut down for the mass ratio of Buddhist nun's mesylate solid), preferably 0.1%~0.5% (w/
w)。
In preferred embodiments, after purified water being added dropwise in step B, 10~30h is stirred at 20~30 DEG C of Yu Wendu, preferably
Stirring rate be 200~500r/min, more preferably 300r/min.
The present invention also provides the preparation methods that the logical sequence described in another kind cuts down the crystal form for Buddhist nun's mesylate, including following step
It is rapid:
Step A1: it logical sequence is cut down to be added in mixed solution for Buddhist nun's mesylate solid is configured to suspension；
Crystal seed is added in B1: Xiang Shangshu suspension liquid system of step, stirs 10~15h at Yu Wendu 30-50 DEG C, filters later
Magma is obtained, drying is cut down to constant weight to get the logical sequence for the crystal form of Buddhist nun's mesylate.
In above-mentioned preparation method of the invention, two kinds of solvents are can be used in the mixed solution, also can be used more
The mixture of kind solvent, such as the mixture of water and ethers, the mixture of water and alkanes.
In preferred embodiments, it is that logical sequence cuts down solid shape for Buddhist nun's mesylate that the logical sequence, which is cut down for Buddhist nun's mesylate solid,
Formula, preferably amorphous forms.
In preferred embodiments, the mixed solution is that organic solvent and water mix reach solution according to a certain percentage
Stratification state, it is preferred that the volume ratio of the organic solvent and water be 100:1~300:1, more preferable volume ratio be 150:1~
200:1.The organic solvent is selected from one of ethers, aromatic or alkanes or a variety of；Preferably, the ethers
Selected from one of ether, isopropyl ether, methyl tertiary butyl ether(MTBE), propyl ether, methyl phenyl ethers anisole or a variety of, the aromatic is selected from first
One or both of benzene, dimethylbenzene, the alkanes are selected from one or both of pentane, n-hexane.Described has
Solvent is a kind of mixture of the solvent of solvent or two kinds or more, such as organic solvent is isopropyl ether, isopropyl ether and ether
Mixture, or the mixture for isopropyl ether and n-hexane.
In a more preferred embodiment, the organic solvent is isopropyl ether or ether or methyl phenyl ethers anisole.
In preferred embodiments, the suspension concentration is 0.01~0.05g/ml, preferably 0.02~0.04g/ml.
In preferred embodiments, the additional amount of the crystal seed is that logical sequence is cut down for the 0.1%~1% of Buddhist nun's mesylate solid
(w/w), preferably 0.1%~0.5% (w/w).
In preferred embodiments, logical sequence is added in step A1 into mixed solution to cut down for after Buddhist nun's mesylate solid, matches
It is set to the suspension that concentration is 0.01~0.05g/ml, it is furthermore preferred that cutting down logical sequence for the addition of Buddhist nun's mesylate solid in step A1
The suspension that concentration is 0.02~0.04g/ml is configured into mixed solution；Wherein the mixed solution is organic solvent and water
According to a certain percentage mix after reach solution stratification state, it is preferred that the volume ratio of the organic solvent and water be 100:1~
300:1, more preferable volume are 150:1~200:1.
In preferred embodiments, in step B1 the additional amount of crystal seed be logical sequence cut down 0.1% for Buddhist nun's mesylate solid~
1% (w/w), such as it is 0.01:10 or 1:10 that crystal seed and logical sequence, which cut down the mass ratio for Buddhist nun's mesylate solid, preferably 0.1%~
0.5% (w/w).
In preferred embodiments, after crystal seed being added in step B1,10~15h is stirred at 30~50 DEG C of Yu Wendu, it is excellent
The stirring rate of choosing is 200~500r/min, more preferably 300r/min.
Embodiment
The present invention is further elaborated below by embodiment, purpose be only that more fully understand it is of the invention interior
Hold.
Logical sequence cuts down the preparation and characterization of the crystal form for Buddhist nun's mesylate:
(1) X-ray powder diffraction XRPD
Logical sequence is acquired on PANalytacal EmpyreanX powder diffraction analysis instrument using transmission mode to cut down for Buddhist nun's methanesulfonic acid
The XRPD map of the crystal form of salt.Scan 2 θ ranges be 3.5 °~40 ° (Cu K α transmitter, wavelength are), sweep current
For 40mA, scanning voltage 40KV, continuous transmission scan is carried out using Absolute scan at room temperature, step-length is 0.013 °,
Residence time is 50s.
(2) differential scanning calorimetric analysis (DSC)
The DSC of the crystal form for Buddhist nun's mesylate is cut down using the differential scanning calorimetry instrument acquisition logical sequence of METTLER TOLEDO
Map.Range of measuring temp is 35 DEG C~300 DEG C, and heating rate is 10 DEG C/min；Nitrogen is flowed in test process with 50ml/min
Amount is purged.
(3) thermogravimetric analysis (TGA)
The TGA of the crystal form for Buddhist nun's mesylate is cut down using the thermogravimetric analysis instrument acquisition logical sequence of METTLER TOLEDO.Test
Temperature range is 35 DEG C~300 DEG C；Heating rate is 10 DEG C/min；Nitrogen is blown in test process with 20ml/min flow
It sweeps.
(4) Karl_Fischer method determination of moisture
The water content of the crystal form for Buddhist nun's mesylate is cut down using ten thousand logical 787KF Titrino measurement logical sequences.
Test method: taking crystalline solid form sample about 0.1g, accurately weighed, is added in the reaction cup balanced, automatic drip
It is fixed, 2 moisture are measured in parallel, are averaged；It is calculated as follows: calculation formula:
Wherein in formula: A is taken the volume of Xiu Shi test solution, unit ml by test sample titration consumption；F is that every 1ml takes Xiu Shi
Test solution is equivalent to the weight of water, unit mg；W is the sample weighting amount of test sample, unit mg.
Embodiment 1
10g logical sequence is added into 400ml methyl tertiary butyl ether(MTBE) to cut down for Buddhist nun's mesylate solid, mixing speed 300r/min,
4ml purified water is added dropwise, 12h is stirred at 25 DEG C, filters gained magma, is dry under -0.1Mpa in temperature 45 C, vacuum degree
15h cuts down to get logical sequence for the crystal form of Buddhist nun's mesylate, purity 99.4%, and crystallization process yield is 91.0%.
Logical sequence obtained is cut down and carries out XRPD analysis for the crystal form of Buddhist nun's mesylate, X-ray powder diffraction is in the angle of diffraction
2 θ=5.6,8.0,11.2,12.6,16.1,17.2,17.8,18.1,18.9,19.6,19.8,20.2,20.7,21.8,22.1,
22.2,22.9,23.5,23.8,24.3,25.1,25.6,26.3,27.0,28.3,28.8,29.4,30.0,30.8,31.6 degree
There is characteristic peak at place.
Logical sequence obtained is cut down and carries out dsc analysis for the crystal form of Buddhist nun's mesylate, analyzes it in 108.1 DEG C and 159.0 DEG C
There is highly endothermic peak at place.
Logical sequence obtained is cut down and carries out TGA analysis for the crystal form of Buddhist nun's mesylate, analyzing its moisture weight loss is 6.23%.
Show that its water content is about 7.10% using Karl_Fischer method moisture determination.
Logical sequence obtained is cut down and is used in embodiment 2-8 use as crystal seed for the crystal form of Buddhist nun's mesylate.
Embodiment 2
10g logical sequence is added into 400ml methyl tertiary butyl ether(MTBE) to cut down for Buddhist nun's mesylate solid, mixing speed 300r/min,
0.1g crystal seed is added, 4ml purified water is added dropwise, 10h is stirred at 20 DEG C, filters gained magma, be in temperature 45 C, vacuum degree-
Dry 10h cuts down to get logical sequence for the crystal form of Buddhist nun's mesylate, purity 99.6% under 0.1Mpa, and crystallization process yield is
90.0%.
Logical sequence obtained is cut down and carries out XRPD analysis for the crystal form of Buddhist nun's mesylate, gained XRPD map is as shown in Figure 1, phase
The data of pass are as shown in table 1.
Logical sequence obtained is cut down and carries out dsc analysis for the crystal form of Buddhist nun's mesylate, as shown in Fig. 2, its at 108.1 DEG C and
There is highly endothermic peak at 159.0 DEG C.
Logical sequence obtained is cut down and carries out TGA analysis for the crystal form of Buddhist nun's mesylate, as shown in Fig. 2, its moisture weight loss is
6.23%.Show that its water content is about 6.98% using Karl_Fischer method determination of moisture.
Embodiment 3
10g logical sequence is added into 200ml methyl tertiary butyl ether(MTBE) to cut down for Buddhist nun's mesylate solid, mixing speed 200r/min,
0.01g crystal seed is added, 1.33ml purified water is added dropwise, 28 DEG C of stirring 28h filter gained magma, in temperature 50 C, vacuum degree
It cuts down for 10h dry under -0.1Mpa to get logical sequence for the crystal form of Buddhist nun's mesylate, purity 99.8%, crystallization process yield is
92.5%.
Logical sequence obtained is cut down and carries out XRPD analysis for the crystal form of Buddhist nun's mesylate, X-ray powder diffraction is in the angle of diffraction
2 θ=5.6,8.0,11.2,12.6,16.1,17.2,17.8,18.1,18.9,19.6,19.8,20.2,20.7,21.8,22.1,
22.2,22.9,23.5,23.8,24.3,25.1,25.6,26.3,27.0,28.3,28.8,29.4,30.0,30.8,31.6 degree
There is characteristic peak at place.
Logical sequence obtained is cut down and carries out dsc analysis for the crystal form of Buddhist nun's mesylate, analyzes it in 107.2 DEG C and 159.5 DEG C
There is highly endothermic peak at place.
Logical sequence obtained is cut down and carries out TGA analysis for the crystal form of Buddhist nun's mesylate, analyzing its moisture weight loss is 6.12%.
Show that its water content is about 6.79% using Karl_Fischer method moisture determination.
Embodiment 4
10g logical sequence is added into 1000ml isopropyl ether to cut down for Buddhist nun's mesylate solid, mixing speed 300r/min, is added
0.05g crystal seed is added dropwise 3.5ml purified water, keeps the temperature 20 DEG C of stirring 18h, filters gained magma, in temperature 45 C, vacuum degree for-
Dry 10h cuts down to get logical sequence for the crystal form of Buddhist nun's mesylate, purity 99.3% under 0.1Mpa, and crystallization process yield is
88.4%.
Logical sequence obtained is cut down and carries out XRPD analysis for the crystal form of Buddhist nun's mesylate, X-ray powder diffraction is in the angle of diffraction
2 θ=5.6,8.0,11.3,12.7,16.1,17.2,17.8,18.1,18.8,19.6,19.7,20.2,20.5,21.8,22.1,
22.2,22.9,23.5,23.8,24.3,25.0,25.5,26.3,27.0,28.3,28.7,29.4,30.0,30.8,31.6 degree
There is characteristic peak at place.
Logical sequence obtained is cut down and carries out dsc analysis for the crystal form of Buddhist nun's mesylate, analyzes it in 108.1 DEG C and 159.0 DEG C
There is highly endothermic peak at place.
Logical sequence obtained is cut down and carries out TGA analysis for the crystal form of Buddhist nun's mesylate, analyzing its moisture weight loss is 5.78%.
Show that its water content is about 6.73% using Karl_Fischer method moisture determination.
Embodiment 5
10g logical sequence is added into 400ml cyclopentyl-methyl ether to cut down for Buddhist nun's mesylate solid, mixing speed 500r/min,
0.05g crystal seed is added, 2.5ml purified water is added dropwise, keeps the temperature 25 DEG C of stirring 20h, filters gained magma, 55 DEG C of Yu Wendu, vacuum
Degree be under -0.1Mpa dry 10h to get logical sequence cut down for the crystal form of Buddhist nun's mesylate, purity 99.2%, crystallization process yield
It is 91.8%.
Logical sequence obtained is cut down and carries out XRPD analysis for the crystal form of Buddhist nun's mesylate, X-ray powder diffraction is in the angle of diffraction
2 θ=5.6,8.0,11.3,12.6,16.1,17.2,17.8,18.1,18.8,19.6,19.8,20.2,20.6,21.8,22.1,
22.2,22.9,23.5,23.8,24.3,25.1,25.5,26.3,27.0,28.3,28.8,29.4,30.0,30.8,31.6 degree
There is characteristic peak at place.
Logical sequence obtained is cut down and carries out dsc analysis for the crystal form of Buddhist nun's mesylate, analyzes it in 108.4 DEG C and 159.8 DEG C
There is highly endothermic peak at place.
Logical sequence obtained is cut down and carries out TGA analysis for the crystal form of Buddhist nun's mesylate, analyzing its moisture weight loss is 5.75%.
Show that its water content is about 6.63% using Karl_Fischer method moisture determination.
Embodiment 6
Logical sequence is cut down and is added in the saturated aqueous solution of 300mL isopropyl ether for Buddhist nun's mesylate solid 10g, it is brilliant that 0.1g is added
Kind, 40 DEG C of stirring 10h.Gained magma is filtered, and obtained wet crystal product is done in the case where 30 DEG C, vacuum degree is -0.1Mpa
Dry 15h obtains crystalline solid 9.25g.Purity is 98.79%, yield 92.5%.
Logical sequence obtained is cut down and carries out XRPD analysis for the crystal form of Buddhist nun's mesylate, X-ray powder diffraction is in the angle of diffraction
2 θ=5.6,8.0,11.3,12.6,16.1,17.2,17.8,18.1,18.8,19.6,19.8,20.2,20.6,21.8,22.1,
22.2,22.9,23.5,23.8,24.3,25.1,25.5,26.3,27.0,28.3,28.8,29.4,30.0,30.8,31.6 degree
There is characteristic peak at place.
Logical sequence obtained is cut down and carries out dsc analysis for the crystal form of Buddhist nun's mesylate, analyzes it in 108.1 DEG C and 159.0 DEG C
There is highly endothermic peak at place.
Logical sequence obtained is cut down and carries out TGA analysis for the crystal form of Buddhist nun's mesylate, analyzing its moisture weight loss is 6.23%.
Show that its water content is about 7.1% using Karl_Fischer method moisture determination.
Embodiment 7
Logical sequence is cut down and is added in the saturated aqueous solution of 30mL ether for Buddhist nun's mesylate solid 1.0g, 0.01g crystal seed is added,
30 DEG C of stirring 10h.Filter gained magma, and by obtained wet crystal product 40 DEG C, vacuum degree be≤- 0.07Mpa under do
Dry 10h obtains crystalline solid 0.92g.Purity is 98.3%, yield 92%.
Logical sequence obtained is cut down and carries out XRPD analysis for the crystal form of Buddhist nun's mesylate, X-ray powder diffraction is in the angle of diffraction
2 θ=5.6,8.0,11.3,12.6,16.1,17.2,17.8,18.1,18.9,19.6,19.8,20.2,20.7,21.8,22.1,
22.2,22.9,23.5,23.8,24.2,25.1,25.6,26.3,27.0,28.3,28.8,29.4,30.0,30.8,31.6 degree
There is characteristic peak at place.
Logical sequence obtained is cut down and carries out dsc analysis for the crystal form of Buddhist nun's mesylate, analyzes it in 107.0 DEG C and 159.0 DEG C
There is highly endothermic peak at place.
Logical sequence obtained is cut down and carries out TGA analysis for the crystal form of Buddhist nun's mesylate, analyzing its moisture weight loss is 6.19%.
Show that its water content is about 6.98% using Karl_Fischer method moisture determination.
Embodiment 8
Logical sequence is cut down and is added in the saturated aqueous solution of 30mL methyl phenyl ethers anisole for Buddhist nun's mesylate solid 1.0g, it is brilliant that 0.01g is added
Kind, 48 DEG C of stirring 12h.Filter gained magma, and by obtained wet crystal product 40 DEG C, vacuum degree be≤- 0.07Mpa under
Dry 10h, obtains crystalline solid 0.935g.Purity is 98.8%, yield 93.5%.
Logical sequence obtained is cut down and carries out XRPD analysis for the crystal form of Buddhist nun's mesylate, X-ray powder diffraction is in the angle of diffraction
2 θ=5.6,8.0,11.2,12.6,16.1,17.2,17.8,18.1,18.9,19.7,19.8,20.2,20.7,21.8,22.1,
22.2,22.9,23.5,23.8,24.3,25.2,25.6,26.3,27.0,28.3,28.8,29.4,30.0,30.8,31.6 degree
There is characteristic peak at place.
Logical sequence obtained is cut down and carries out dsc analysis for the crystal form of Buddhist nun's mesylate, analyzes it in 107.6 DEG C and 159.3 DEG C
There is highly endothermic peak at place.
Logical sequence obtained is cut down and carries out TGA analysis for the crystal form of Buddhist nun's mesylate, analyzing its moisture weight loss is 6.25%.
Show that its water content is about 6.95% using Karl_Fischer method moisture determination.
Testing experiment example:
1, stability of the crystal form under the acceleration environment of illumination, high temperature and high humidity
Crystal form of the invention is stored 30 days under illumination condition, hot conditions and super-humid conditions, to crystal form of the invention
Chemical stability studied.
Inspection method: high performance liquid chromatography (Chinese Pharmacopoeia version general rule 0512 in 2015)
Instrument: high performance liquid chromatograph is equipped with UV detector (Sample Room controllable temperature), electronic balance (d=0.01mg, d
=0.001mg)
Test reagent: potassium dihydrogen phosphate (AR grades)；Methanol (HPLC grades)
Chromatographic condition:
Chromatographic column: Shimadzu Inertsil ODS-3,4.6mm × 250mm, 5 μm；
Detection wavelength: 240nm；Column temperature: 40 DEG C；Flow velocity: 1.0ml/min；Sample volume: 20 μ l；Sample Room: 4 DEG C
Mobile phase A: 10mmol/L potassium dihydrogen phosphate (takes potassium dihydrogen phosphate 1.36g, is dissolved in water and is diluted to
1000ml)
Mobile phase B: methanol
Elution requirement: gradient elution.
Test example 1-1 thimble test
Logical sequence prepared by embodiment 6 is cut down and is placed in the vial of sealing clean for the crystal form of Buddhist nun's mesylate, is then divided
It is not placed in 40 DEG C of thermostatic drying chambers, samples within 30 days, according to above-mentioned inspection method checked for impurities content, purity result and according to card
Er Feixiufa measures water content, and as shown in table 2, XRPD map is as shown in Figure 3:
The logical sequence of 2 embodiment 6 of table preparation cuts down the high-temperature stability data for the crystal form of Buddhist nun's mesylate
| Time | Impurity number | It is total miscellaneous | Moisture | Purity |
| 0 day | 7 | 1.21% | 7.1% | 98.79% |
| 30 days | 7 | 1.21% | 7.0% | 98.79% |
Under above-mentioned hot conditions, as seen from Figure 3,0 day and 30 days X-ray powder diffraction pattern is almost the same.
From table 2 and Fig. 3 it can be concluded that, embodiment 6 prepare logical sequence cut down for Buddhist nun's mesylate crystal form under the high temperature conditions
Without significant change, crystal form does not change for purity and moisture content, that is, has heat-resisting quantity.
Test example 1-2 high humidity stability test
Logical sequence prepared by embodiment 6 is cut down and is shared equally respectively for the crystal form of Buddhist nun's mesylate into open culture dish, thickness≤
5mm is placed in (25 ± 2 DEG C) at room temperature, in the constant incubator that relative humidity RH is 92.5% and relative humidity is 75%, in 30
Its sampling measures water content such as 3 institute of table according to above-mentioned inspection method checked for impurities content, purity result and according to Karl_Fischer method
Show, XRPD is as shown in Figure 3:
The logical sequence of 3 embodiment 6 of table preparation cuts down the high humility stability data for the crystal form of Buddhist nun's mesylate
| Time | Impurity number | It is total miscellaneous | Moisture | Purity |
| 0 day | 7 | 1.21 | 7.1% | 98.79% |
| RH75%30 days | 7 | 1.23 | 7.0% | 98.77% |
| RH92.5%30 days | 7 | 1.22 | 7.0% | 98.78% |
Under above-mentioned super-humid conditions, as seen from Figure 3, the X of 0 day and 30 days relative humidity RH75% and RH92.5% are penetrated
Line powder diffraction spectrum is almost the same.
From table 3 and Fig. 3 it can be concluded that, embodiment 6 prepare logical sequence cut down for Buddhist nun's mesylate crystal form under conditions of high humidity
For purity without significant change, moisture is almost unchanged, and crystal form does not change, that is, has resistance to height moist.
The test of test example 1-3 light durability
Logical sequence prepared by embodiment 6 is cut down and is placed in the vial of sealing clean for the crystal form of Buddhist nun's mesylate, is then set
It is illumination under 4500lx ± 500lx light in luminous intensity, was sampled in 30 days, according to above-mentioned inspection method checked for impurities content, purity
As a result and as shown in table 4 according to Karl_Fischer method measurement water content, XRPD is as shown in Figure 3.
The logical sequence of 4 embodiment 6 of table preparation cuts down the light durability data for the crystal form of Buddhist nun's mesylate
| Time | Impurity number | It is total miscellaneous | Moisture | Purity |
| 0 day | 7 | 1.21 | 7.1% | 98.79% |
| 30 days | 8 | 1.29 | 6.9% | 98.71% |
Under above-mentioned illumination condition, as seen from Figure 3, the X-ray powder diffraction pattern under the conditions of 0 day and illumination in 30 days
It is almost the same.
It can be concluded that, logical sequence prepared by embodiment 6 cuts down the crystal form for Buddhist nun's mesylate under illumination condition from table 4 and Fig. 3
For purity without significant change, moisture is almost unchanged, and crystal form does not change, that is, has light resistance.
2, the physical stability of crystal form
Crystal form of the invention is milled into fine powder, is sieved with 500 μm and 250 μm of screens.
Mill as can be seen from Figure 4 sieving after crystal form X-ray powder diffraction peak with mill be sieved before it is almost the same.
Claims (15)
1. a kind of logical sequence is cut down for the crystal form of Buddhist nun's mesylate, it is characterised in that the X-ray powder diffraction figure of the crystal form is included in
About 16.1 ± 0.2 °, 17.8 ± 0.2 °, 18.8 ± 0.2 °, 25.0 ± 0.2 °, the peak at 25.4 ± 0.2 ° of the angle of diffraction (2 θ).
2. logical sequence according to claim 1 is cut down for the crystal form of Buddhist nun's mesylate, it is characterised in that the X-ray powder of the crystal form
Last diffraction pattern is included in about 8.0 ± 0.2 °, and 11.2 ± 0.2 °, 12.6 ± 0.2 °, 16.1 ± 0.2 °, 17.8 ± 0.2 °, 18.8 ±
0.2 °, 19.7 ± 0.2 °, 20.2 ± 0.2 °, 22.9 ± 0.2 °, 23.7 ± 0.2 °, 24.2 ± 0.2 °, 25.0 ± 0.2 °, 25.4 ±
0.2 °, 27.0 ± 0.2 ° and 28.3 ± 0.2 the angle of diffraction (2 θ) at peak；
Preferably, the X-ray powder diffraction figure of the crystal form is included in about 8.0 ± 0.2 °, and 11.2 ± 0.2 °, 12.6 ±
0.2 °, 16.1 ± 0.2 °, 17.2 ± 0.2 °, 17.8 ± 0.2 °, 18.1 ± 0.2 °, 18.8 ± 0.2 °, 19.7 ± 0.2 °, 20.2 ±
0.2 °, 20.6 ± 0.2 °, 21.9 ± 0.2 °, 22.1 ± 0.2 °, 22.9 ± 0.2 °, 23.3 ± 0.2 °, 23.7 ± 0.2 °, 24.2 ±
0.2 °, 25.0 ± 0.2 °, 25.4 ± 0.2 °, 26.3 ± 0.2 °, 27.0 ± 0.2 °, 28.3 ± 0.2 °, 28.8 ± 0.2 ° and 29.4
Peak at ± 0.2 ° of the angle of diffraction (2 θ)；
Preferably, the X-ray powder diffraction figure of the crystal form is as shown in Figure 1.
3. logical sequence according to claim 1 or 2 is cut down for the crystal form of Buddhist nun's mesylate, it is characterised in that the differential of the crystal form is swept
The temperature for retouching the endothermic peak of calorimetry respectively may be about 108.1 ± 2 DEG C and 159.0 ± 2 DEG C.
4. logical sequence according to claim 1-3 is cut down for the crystal form of Buddhist nun's mesylate, it is characterised in that the crystal form
Water content be 5%~8%.
5. the preparation method that the described in any item logical sequences of claim 1-4 cut down the crystal form for Buddhist nun's mesylate, it is characterised in that including
Following steps:
Step A: it logical sequence is cut down to be added in solvent for Buddhist nun's mesylate solid is configured to suspension；
Step B: crystal seed being added into suspension, and purified water is added dropwise, stirs 10~30h at 20~30 DEG C of Yu Wendu, filters later
Magma is obtained, drying is cut down to constant weight to get the logical sequence for the crystal form of Buddhist nun's mesylate；
Preferably, the solvent is selected from one of water, alcohols, ketone, alkanes, ethers or a variety of.
6. the preparation method that logical sequence according to claim 5 cuts down the crystal form for Buddhist nun's mesylate, it is characterised in that described is molten
Agent is selected from one of water, ethers or alkanes or a variety of；Preferably, the ethers is selected from ether, isopropyl ether, methyl- tert fourth
One of base ether, cyclopentyl-methyl ether are a variety of, and the alkanes are in n-hexane, hexamethylene, normal heptane, isooctane
One or more.
7. the preparation method that logical sequence according to claim 5 or 6 cuts down the crystal form for Buddhist nun's mesylate, it is characterised in that described outstanding
Supernatant liquid concentration is 0.01~0.05g/ml, preferably 0.02~0.04g/ml；The stirring rate is 200~500r/min,
Preferably 300r/min.
8. cutting down the preparation method of the crystal form for Buddhist nun's mesylate according to the described in any item logical sequences of claim 5-7, it is characterised in that
The volume ratio of the purified water and solvent is 1:100~1:300, preferably 1:150~1:200；The addition of the crystal seed
Amount is that logical sequence is cut down for the 0.1%~1% of Buddhist nun's mesylate solid, preferably 0.1%~0.5%；The mixing time be 15~
20h。
9. the preparation method that the described in any item logical sequences of claim 1-4 cut down the crystal form for Buddhist nun's mesylate, it is characterised in that including
Following steps:
Step A1: it logical sequence is cut down to be added in mixed solution for Buddhist nun's mesylate solid is configured to suspension；
Crystal seed is added in B1: Xiang Shangshu suspension liquid system of step, stirs 10~15h at Yu Wendu 30-50 DEG C, filters later brilliant
Slurries, drying are cut down to constant weight to get the logical sequence for the crystal form of Buddhist nun's mesylate.
10. the preparation method that logical sequence according to claim 9 cuts down the crystal form for Buddhist nun's mesylate, it is characterised in that described is mixed
Closing solution is that organic solvent and water mix reach solution stratification state according to a certain percentage, it is preferred that the organic solvent and water
Volume ratio be 100:1~300:1, more preferable volume ratio be 150:1~200:1.
11. cutting down the preparation method of the crystal form for Buddhist nun's mesylate according to the described in any item logical sequences of claim 9-10, feature exists
In the mixed solution be that organic solvent and water mix, wherein the organic solvent be selected from ethers, aromatic or
One of alkanes are a variety of；Preferably, the ethers is selected from ether, isopropyl ether, methyl tertiary butyl ether(MTBE), propyl ether, benzene first
One of ether is a variety of, and the aromatic is selected from one or both of toluene, dimethylbenzene, and the alkanes are selected from
One or both of pentane, n-hexane.
12. cutting down the preparation method of the crystal form for Buddhist nun's mesylate according to the described in any item logical sequences of claim 9-11, feature exists
In the step A1 logical sequence cut down be added in mixed solution for Buddhist nun's mesylate solid be configured to suspension concentration be 0.01~
0.05g/ml, preferably 0.02~0.04g/ml.
13. cutting down the preparation method of the crystal form for Buddhist nun's mesylate according to the described in any item logical sequences of claim 9-12, feature exists
The additional amount of crystal seed is that logical sequence cuts down 0.1%~1% (w/w) for Buddhist nun's mesylate solid in the step B1, preferably
0.1%~0.5% (w/w), the whipping temp are 30-50 DEG C, and the mixing time is 10-15h.
14. a kind of pharmaceutical composition, cut down it includes the described in any item logical sequences of claim 1-4 for the crystal form of Buddhist nun's mesylate, with
And one or more pharmaceutically acceptable carriers.
It is being prepared for the crystal form of Buddhist nun's mesylate for treating invasion, differentiation 15. the described in any item logical sequences of claim 1-4 are cut down
Purposes in the drug of type thyroid cancer.
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| WO2022022367A1 (en) * | 2020-07-28 | 2022-02-03 | 药源药物化学（上海）有限公司 | Method for preparing high-purity crystal |
| CN114174264A (en) * | 2020-04-24 | 2022-03-11 | 成都苑东生物制药股份有限公司 | Crystal form XI of varlitinib mesylate and preparation method thereof |
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