CN117886783A - Hydrate crystal form C of taxane compound and preparation method and application thereof - Google Patents
Hydrate crystal form C of taxane compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN117886783A CN117886783A CN202211225765.6A CN202211225765A CN117886783A CN 117886783 A CN117886783 A CN 117886783A CN 202211225765 A CN202211225765 A CN 202211225765A CN 117886783 A CN117886783 A CN 117886783A
- Authority
- CN
- China
- Prior art keywords
- hydrate
- taxane compound
- water
- taxane
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940123237 Taxane Drugs 0.000 title claims abstract description 40
- -1 taxane compound Chemical class 0.000 title claims abstract description 34
- 239000013078 crystal Substances 0.000 title abstract description 30
- 238000002360 preparation method Methods 0.000 title abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 201000007270 liver cancer Diseases 0.000 claims description 5
- 208000014018 liver neoplasm Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 239000003880 polar aprotic solvent Substances 0.000 claims description 5
- 239000003586 protic polar solvent Substances 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 230000001613 neoplastic effect Effects 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000004580 weight loss Effects 0.000 claims description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 4
- 238000012360 testing method Methods 0.000 description 12
- 238000012512 characterization method Methods 0.000 description 9
- 238000011156 evaluation Methods 0.000 description 8
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 241000700159 Rattus Species 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000002960 lipid emulsion Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910021421 monocrystalline silicon Inorganic materials 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000013097 stability assessment Methods 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Abstract
The invention relates to the field of compound crystal forms, in particular to a hydrate crystal form C of taxane compound, and a preparation method and application thereof. The hydrate crystal form C of the taxane compound has the advantages of high solubility in water, good solid-state physical and chemical stability and good bioavailability.
Description
Technical Field
The invention belongs to the technical field of preparation of pharmaceutical chemistry crystals, and particularly relates to a hydrate crystal form C of a taxane compound, and a preparation method and application of the hydrate crystal form C.
Background
Drug molecules typically have different solid forms including salts, polymorphs, co-crystals, amorphous, hydrates or solvates. Different crystal forms of the same drug molecule may have significant differences in crystal structure, stability, producibility, bioavailability and other properties, thereby affecting the efficacy and developability of the drug, and being stable and beneficial to the clinical application without changing the efficacy of the drug. Therefore, the selection of safe, effective and stable crystalline forms has become an important aspect in the development of new and imitated drugs.
{2aR- [2aα,4β,4aβ,6β,9α (αr, βs) 11α,12α,12aα,12bα ] } - β - { [ (1, 1-dimethylethoxy) carbonyl ] amino } - α -hydroxyphenylpropionic acid {6- [ (4-acetylphenyl) carbamoyloxy ] -12 b-acetoxy-12-benzoyloxy-2 a,3, 4a,5,6,9,10,11,12 a,12 b-dodecahydro-4, 11-dihydroxy-4 a,8, 13-tetramethyl-5-oxo-7, 11-methylene-1H-cyclosunflower penta [3,4] benzo [1,2-b ] oxabutan-9-yl } ester is a novel taxane drug molecule developed by Jiangsu Ji Beier pharmaceutical industry, trade mark, code: JJH201601, a compound disclosed and authorized in patent application number CN201810185012.4, has a molecular structure shown in the following figure:
the preliminary drug effect research results show that the drug effect of the nude mouse model is obviously improved, the toxic and side effects are obviously reduced, tumors can be eliminated (the tumor inhibition rate reaches more than 99 percent), no tumor recurrence is found in the observation period after drug withdrawal, the results are verified on lung cancer A549, liver cancer HepG2 and pancreatic cancer Panc-1 models, and the compound is expected to be widely applied to the clinical quality of related diseases at present in the administrative approval stage.
At present, there are no reports related to the JJH201601 crystal form.
Disclosure of Invention
The invention aims to provide a crystal form of taxane compound JJH201601 with high water solubility, good solid-state physicochemical stability and good bioavailability, and a preparation method and application thereof, which are suitable for large-scale production and clinic application.
In order to achieve the technical purpose, the invention provides the following technical scheme: a hydrate form C of a taxane compound having an X-ray powder diffraction pattern with diffraction peaks at least three of the following 2Θ angles: 6.356 °± 0.2,6.653 ° ± 0.2,7.970 ° ± 0.2,9.204 ° ±0.2, 11.284 ° ±0.2, 13.285 ° ±0.2; the taxane compound has the structure shown in formula I:
further, the X-ray powder diffraction pattern thereof has diffraction peaks at least at four of the following 2θ angles: 6.356 °± 0.2,6.653 ° ± 0.2,7.970 ° ± 0.2,9.204 ° ±0.2, 11.284 ° ±0.2, 13.285 ° ±0.2.
Further, the X-ray powder diffraction pattern thereof has diffraction peaks at least five of the following 2θ angles: 6.356 °± 0.2,6.653 ° ± 0.2,7.970 °± 0.2,9.204 ° ± 0.2,9.966 ° ±0.2, 11.284 °±0.2, 12.318 °±0.2, 13.052°±0.2, 13.285 °±0.2.
Further, the X-ray powder diffraction pattern thereof has diffraction peaks at least seven of the following 2θ angles: 6.356 °± 0.2,6.653 ° ± 0.2,7.970 °± 0.2,9.204 ° ± 0.2,9.966 ° ±0.2, 11.284 °±0.2, 12.318 °±0.2, 13.052°±0.2, 13.285 °±0.2.
Further, the hydrate form C of the taxane compound has a weight loss at 150 ℃.
Further, the molar ratio of taxane compound to crystallization water in the hydrate crystal form C is 1:0.5-2.
Further, the molar ratio of taxane compound to crystallization water in the hydrate form C is 1:0.5 or 1:1 or 1:1.5 or 1:2.
The application also discloses a preparation method of the hydrate crystal form C of the taxane compound, which comprises the steps of dissolving the taxane compound shown in the formula I in a mixture of a polar aprotic solvent and a polar protic solvent, heating and stirring, cooling to room temperature to obtain a solid, and airing the obtained solid to obtain the hydrate crystal form C.
Further, the polar aprotic solvent is acetonitrile or acetone, and the polar protic solvent is water;
still further, the mixture is a mixture of acetonitrile and water in a volume ratio of 1:4 or a mixture of acetone and water in a volume ratio of 1:4.
Further, the heating temperature is 40-55 ℃;
still further, the heating temperature is 50 ℃.
Also disclosed herein is a pharmaceutical composition comprising an effective amount of taxane compound hydrate form C as described above;
still further, pharmaceutically acceptable excipients are included.
The application also discloses application of the taxane compound hydrate crystal form C or the pharmaceutical composition in preparing medicaments for preventing and treating tumor diseases;
further, the neoplastic disease includes lung cancer, liver cancer and pancreatic cancer;
still further, the tumor diseases specifically include lung cancer A549, liver cancer HepG2 and pancreatic cancer Panc-1.
By adopting the technology, compared with the prior art, the invention has the remarkable advantages that:
1) The technical scheme of the invention takes the mixture of polar aprotic solvent and polar protic solvent as solvent to prepare taxane compound hydrate crystal form C under the heating condition, has the advantages of high solubility in water and good solid physical and chemical stability, especially improves the solubility in water to more than 1.7 mug/mL, is suitable for being applied to the production process of pharmaceutical preparations, and solves the inconvenience caused by lower water solubility of taxane compound in the prior art in the preparation and storage processes of the preparations;
2) Compared with the conventional taxane compound amorphous substance and other crystal forms, the taxane compound hydrate crystal form C has more excellent biological activity, and is more suitable for clinical use.
Drawings
FIG. 1 is an XRPD pattern for taxane hydrate form C of the present invention;
FIG. 2 is a TGA/DCS characterization of taxane compound hydrate form C of the present invention;
FIG. 3 is a graph showing the XRPD characterization results before and after the solubility test of taxane compound hydrate form C of the present invention;
FIG. 4 is a graph showing the XRPD characterization results before and after solid state stability testing of taxane compound hydrate form C of the present invention;
FIG. 5 is a graph showing the results of a wettability evaluation test for the hydrate form C of taxane compounds of the present invention;
fig. 6 is an XRPD characterization result before and after the hygroscopicity assessment test of taxane hydrate form C of the present invention.
Detailed Description
The above-described matters of the present invention will be described in further detail by way of examples, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and all techniques realized based on the above-described matters of the present invention are within the scope of the present invention.
XRPD assay method:
XRPD data of samples in the project were collected using a pamalytical X' Pert3 and Empyrean X-ray powder diffractometer.
Appropriate amounts of samples were plated uniformly on single crystal silicon sample trays and XRPD testing was performed using the following parameters:
TABLE 1 XRPD Experimental parameters
TGA and DSC measurement method:
TGA and DSC profiles were collected on a TAQ5000/Discovery 5500 thermogravimetric analyzer and a TAQ2000/Discovery 2500 differential scanning calorimeter, respectively, with the following test parameters:
TABLE 2 TGA and DSC test parameters
Example 1
The preparation method of the taxane compound hydrate crystal form C of the embodiment is implemented according to the following steps:
amorphous sample of compound JJH201601 is circularly heated and cooled in a mixed solvent of acetonitrile/water (1:4, v/v)(0.05 ℃/min) and suspending and stirring for 8 days, collecting a solid sample and wet-airing at room temperature to obtain the crystal form C. The XRPD pattern is shown in fig. 1, and specific diffraction peak data is shown in table 3. The test results are shown in FIG. 2, with endothermic peaks at 77.1℃ 173.7, 215.9 ℃ (peak temperature) for the samples.
TABLE 3 XRPD diffraction peak data
Example 2
The preparation method of the taxane compound hydrate crystal form C of the embodiment is implemented according to the following steps:
amorphous sample of compound JJH201601 was magnetically stirred in a dimethylsulfoxide/water (1:9, v/v) solvent system at room temperature for 7 days, and solid sample was collected and placed under room temperature wet to give form C. Its XRPD pattern is the same as that of figure 1, with endothermic peaks at 77.1 ℃, 173.7, 215.9 ℃ (peak temperature).
Example 3
The preparation method of the taxane compound hydrate crystal form C of the embodiment is implemented according to the following steps:
amorphous sample of compound JJH201601 was prepared by cyclic warming in acetone/water (1:4, v/v) solvent system in the presence of form C seed crystals to give form C. Its XRPD pattern is the same as that of figure 1, with endothermic peaks at 77.1 ℃, 173.7, 215.9 ℃ (peak temperature).
Example 4
Taxane hydrate form C lost weight by about 3.0% upon heating from room temperature to 150 ℃. The sample had endothermic peaks at 77.1 ℃, 173.7 ℃ and 215.9 ℃ (peak temperature), and the specific TGA/DCS characterization results are shown in figure 2. The molar ratio of the compound molecules to the water molecules in the hydrate is 1:1.5 according to the TGA/DCS characterization result.
Example 5
24 hour equilibrium solubility test of taxane hydrate form C:
about 2mg of the corresponding solid sample was weighed separately, placed in a 2-mL centrifuge tube, 1mL of pure water was added, and capped and sealed. After shaking for 24 hours at room temperature (25.+ -. 3 ℃ C.) using a shaking table (800 rpm), the solid-liquid separation was performed by centrifugation. The remaining solid samples were characterized by XRPD to observe changes in crystalline form, and the concentration of compound JJH201601 in the solution was analyzed by HPLC to characterize the solubility of the sample in water. The results of the evaluation are summarized in Table 4-1, and the solubility of the amorphous starting sample in water is much lower than that of form C. Also XRPD characterization results are shown in fig. 3, showing that form C did not undergo conversion after solubility testing.
TABLE 4-1 24 hour Balanced solubility evaluation in Water results summary table
Evaluation of crystalline forms | Solubility of | pH | Remaining solid crystalline forms |
Amorphous form | 0.82μg/mL | 7.7 | Amorphous form |
Crystal form C | 1.7μg/mL | 6.61 | Crystal form C |
Example 6
Solid state stability evaluation test of taxane hydrate form C:
and respectively weighing a proper amount of corresponding crystal form C solid samples, standing for one week under the conditions of 25 ℃/60%RH and 40 ℃/75%RH, and standing another group of crystal form C solid samples for 24 hours in a closed mode under the condition of 80 ℃. The samples after placement were subjected to XRPD and HPLC characterization to detect changes in crystalline form and chemical purity.
XRPD of the samples before and after the experiment are shown in fig. 4. The evaluation results show that:
form C showed no change in form or significant purity drop under all three stability experimental conditions (80 ℃/closed/24 h, 25 ℃/60% rh/1week, 40 ℃/75% rh/1 week), while the amorphous sample showed significant purity drop under all the above experimental conditions.
TABLE 4-2 solid State stability assessment results summary table
Example 7
Wettability evaluation test of taxane hydrate form C:
the hygroscopicity assessment was further carried out using a dynamic moisture sorption (DVS). The experimental results are shown in FIG. 5. The evaluation results show that: the moisture adsorption of form C sample was 5.87% at 25 ℃/80% rh. After DVS characterization, form C did not undergo a form transformation (as shown in fig. 6).
Example 8
And respectively weighing a proper amount of crystal form C and an amorphous sample, adding a small amount of water for injection, stirring uniformly, taking a proper amount of fat emulsion, and adding the fat emulsion into the mixture to prepare a 1.2mg/mL suspension.
The rats were taken and randomly divided into 2 groups of 6 rats each according to body weight, and 6mg/kg of the dose was administered. Intravenous injection of forms C and C, respectivelyBlood was collected at different time points after the amorphous suspension. Plasma samples were subjected to LC-MS/MS analysis after treatment with precipitated proteins for pharmacokinetic comparison studies in rats and data are presented in table 5. The results show that the main drug-substitution parameter C related to the in-vivo exposure max AUC (all over all) 0-t Group C is much larger than the amorphous group and exhibits better pharmacokinetic profile.
TABLE 5 pharmacokinetic test data
The above embodiments are only preferred embodiments of the present invention, and should not be construed as limiting the present invention, and the protection scope of the present invention should be defined by the claims, including the technical equivalents of the technical features in the claims, as the protection scope, that is, the equivalent replacement and improvement within the protection scope of the present invention.
Claims (10)
1. A hydrate form C of a taxane compound characterized by an X-ray powder diffraction pattern having diffraction peaks at least three of the following 2Θ angles: 6.356 °± 0.2,6.653 ° ± 0.2,7.970 ° ± 0.2,9.204 ° ±0.2, 11.284 ° ±0.2, 13.285 ° ±0.2; the taxane compound has the structure shown in formula I:
2. form C of the hydrate according to claim 1, characterized in that its X-ray powder diffraction pattern has diffraction peaks at least at four of the following 2Θ angles: 6.356 °± 0.2,6.653 ° ± 0.2,7.970 ° ± 0.2,9.204 ° ±0.2, 11.284 ° ±0.2, 13.285 ° ±0.2;
preferably, its X-ray powder diffraction pattern has diffraction peaks at least five of the following 2θ angles: 6.356 °± 0.2,6.653 ° ± 0.2,7.970 °± 0.2,9.204 ° ± 0.2,9.966 ° ±0.2, 11.284 °±0.2, 12.318 °±0.2, 13.052°±0.2, 13.285 °±0.2.
3. Form C of the hydrate according to claim 2, characterized in that its X-ray powder diffraction pattern has diffraction peaks at least seven of the following 2Θ angles: 6.356 °± 0.2,6.653 ° ± 0.2,7.970 °± 0.2,9.204 ° ± 0.2,9.966 ° ±0.2, 11.284 °±0.2, 12.318 °±0.2, 13.052°±0.2, 13.285 °±0.2.
4. Form C of the hydrate according to claim 1, characterized by a weight loss at 150 ℃.
5. The hydrate form C according to any one of claims 1-4, wherein the molar ratio of taxane compound to crystallization water in the hydrate form C is 1:0.5-2;
preferably, the molar ratio of taxane compound to water of crystallization in hydrate form C is 1:0.5 or 1:1 or 1:1.5 or 1:2.
6. A process for preparing crystalline form C of a hydrate of the taxane compound according to claim 1, wherein the taxane compound of formula I is dissolved in a mixture of a polar aprotic solvent and a polar protic solvent, heated and stirred, cooled to room temperature to obtain a solid, and the obtained solid is dried to obtain crystalline form C of the hydrate.
7. The method according to claim 6, wherein the polar aprotic solvent is acetonitrile, dimethyl sulfoxide or acetone, and the polar protic solvent is water;
preferably, the mixture is a mixture of acetonitrile and water in a volume ratio of 1:4 or a mixture of acetone and water in a volume ratio of 1:4.
8. The method of claim 6, wherein the heating temperature is 40-55 ℃;
preferably, the heating temperature is 50 ℃.
9. A pharmaceutical composition comprising an effective amount of taxane compound hydrate form C of any one of claims 1-5; preferably, the composition further comprises pharmaceutically acceptable auxiliary materials.
10. Use of the taxane compound hydrate form C of any one of claims 1-5 or the pharmaceutical composition of claim 9 in the manufacture of a medicament for the prevention and treatment of neoplastic disease;
preferably, the neoplastic disease includes lung cancer, liver cancer and pancreatic cancer;
still more preferably, the neoplastic disease specifically includes lung cancer A549, liver cancer HepG2 and pancreatic cancer Panc-1.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211225765.6A CN117886783A (en) | 2022-10-09 | 2022-10-09 | Hydrate crystal form C of taxane compound and preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211225765.6A CN117886783A (en) | 2022-10-09 | 2022-10-09 | Hydrate crystal form C of taxane compound and preparation method and application thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117886783A true CN117886783A (en) | 2024-04-16 |
Family
ID=90644626
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211225765.6A Pending CN117886783A (en) | 2022-10-09 | 2022-10-09 | Hydrate crystal form C of taxane compound and preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117886783A (en) |
-
2022
- 2022-10-09 CN CN202211225765.6A patent/CN117886783A/en active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2011095059A1 (en) | Polymorphs of dasatinib, preparation methods and pharmaceutical compositions thereof | |
JP2007302658A (en) | POLYMORPHIC FORM AND NEW CRYSTAL FORM AND AMORPHOUS FORM OF IMATINIB MESYLATE, AND METHOD FOR PREPARING FORMalpha | |
CN109195980B (en) | Novel crystal form of sodium-glucose cotransporter inhibitor drug, preparation method and application thereof | |
EP3176173B1 (en) | Crystalline free bases of c-met inhibitor or crystalline acid salts thereof, and preparation methods and uses thereof | |
CN112142679A (en) | Gefitinib and vanillic acid eutectic methanol solvate and preparation method thereof | |
CN111777595A (en) | Novel crystal form of cyclohexane carboxamide compound and preparation method thereof | |
EP3159349B1 (en) | Lobaplatin crystal, preparation method and pharmaceutical application | |
CN117412749A (en) | Tolebutinib salt and crystal form thereof, preparation method, pharmaceutical composition and application thereof | |
CN114605406A (en) | Crystal form of AMG510 compound and preparation method and application thereof | |
CN111868054A (en) | Furosetinib eutectic crystal, preparation method, composition and application thereof | |
WO2023193563A1 (en) | Crystal form a of thienopyridine compound, and preparation method therefor and pharmaceutical composition thereof | |
WO2014036865A1 (en) | Method for preparing fingolimod mucate and crystal thereof and application of fingolimod mucate and crystal thereof | |
CN110903239A (en) | Novel crystal form of lenvatinib mesylate and preparation method thereof | |
CN117886783A (en) | Hydrate crystal form C of taxane compound and preparation method and application thereof | |
CN111620879B (en) | PF-06651600 maleate, crystal form and preparation method thereof | |
JP2021532165A (en) | Addition salt of S1P1 receptor agonist and its crystalline form, and pharmaceutical composition | |
CN112125910A (en) | Alvatinib crystal form and preparation method thereof | |
CN113045554A (en) | Fexotinib crystal form and preparation method thereof | |
CN115427397A (en) | Crystal form of nitroxoline prodrug, pharmaceutical composition containing nitroxoline prodrug, and preparation method and application of nitroxoline prodrug | |
CN113121419A (en) | Acipimox-1, 2-di (4-pyridyl) ethylene eutectic crystal | |
CN112778290B (en) | Addition salt of S1P1 receptor agonist, crystal form and pharmaceutical composition thereof | |
CN115583952B (en) | Polycrystal of phosphodiesterase 5 inhibitor, preparation method and application thereof | |
CN116655700A (en) | Lobaplatin crystal and preparation method and application thereof | |
CN111848677B (en) | Crystal form of ALK kinase inhibitor compound, preparation method and application | |
CN107043405B (en) | Crystal form of polycyclic heterocyclic compound, preparation method, application and composition thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination |