WO2014015760A1 - 卡巴他赛的结晶形式及其制备方法 - Google Patents
卡巴他赛的结晶形式及其制备方法 Download PDFInfo
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- WO2014015760A1 WO2014015760A1 PCT/CN2013/079575 CN2013079575W WO2014015760A1 WO 2014015760 A1 WO2014015760 A1 WO 2014015760A1 CN 2013079575 W CN2013079575 W CN 2013079575W WO 2014015760 A1 WO2014015760 A1 WO 2014015760A1
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- cabazitaxel
- preparation
- carbon atoms
- ester compound
- filter cake
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- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 title claims abstract description 145
- 229960001573 cabazitaxel Drugs 0.000 title claims abstract description 128
- 239000013078 crystal Substances 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- -1 ester compound Chemical class 0.000 claims abstract description 39
- 239000002904 solvent Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 125000004432 carbon atom Chemical group C* 0.000 claims description 31
- 239000012065 filter cake Substances 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 30
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 22
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 17
- 238000002425 crystallisation Methods 0.000 claims description 16
- 230000008025 crystallization Effects 0.000 claims description 16
- 239000012046 mixed solvent Substances 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 9
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 2
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 claims description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 2
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims 6
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims 3
- 239000002246 antineoplastic agent Substances 0.000 claims 3
- 229940041181 antineoplastic drug Drugs 0.000 claims 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 150000001298 alcohols Chemical class 0.000 claims 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 claims 1
- 229960001701 chloroform Drugs 0.000 claims 1
- 239000012141 concentrate Substances 0.000 claims 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 229960003750 ethyl chloride Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 13
- 229940079593 drug Drugs 0.000 abstract description 12
- 206010060862 Prostate cancer Diseases 0.000 abstract description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 abstract description 5
- 239000002552 dosage form Substances 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 239000008213 purified water Substances 0.000 description 12
- 238000000967 suction filtration Methods 0.000 description 10
- 238000002411 thermogravimetry Methods 0.000 description 10
- 238000002329 infrared spectrum Methods 0.000 description 9
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000013112 stability test Methods 0.000 description 5
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- IXADHCVQNVXURI-UHFFFAOYSA-N 1,1-dichlorodecane Chemical compound CCCCCCCCCC(Cl)Cl IXADHCVQNVXURI-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102000029749 Microtubule Human genes 0.000 description 3
- 108091022875 Microtubule Proteins 0.000 description 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- MROCJMGDEKINLD-UHFFFAOYSA-N dichlorosilane Chemical compound Cl[SiH2]Cl MROCJMGDEKINLD-UHFFFAOYSA-N 0.000 description 3
- 229960003668 docetaxel Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 210000004688 microtubule Anatomy 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000002834 transmittance Methods 0.000 description 3
- KHPNGCXABLTQFJ-UHFFFAOYSA-N 1,1,1-trichlorodecane Chemical compound CCCCCCCCCC(Cl)(Cl)Cl KHPNGCXABLTQFJ-UHFFFAOYSA-N 0.000 description 2
- RGUFZILIVUBHAE-UHFFFAOYSA-N 2-(2-decoxy-2-oxoethyl)-2-hydroxybutanedioic acid Chemical compound CCCCCCCCCCOC(=O)CC(O)(C(O)=O)CC(O)=O RGUFZILIVUBHAE-UHFFFAOYSA-N 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 2
- 229930182558 Sterol Natural products 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000013522 chelant Substances 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- GBAOZECSOKXKEL-UHFFFAOYSA-N copper yttrium Chemical compound [Cu].[Y] GBAOZECSOKXKEL-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 150000003432 sterols Chemical class 0.000 description 2
- 235000003702 sterols Nutrition 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- PGIBJVOPLXHHGS-UHFFFAOYSA-N Di-n-decyl phthalate Chemical compound CCCCCCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCCCCC PGIBJVOPLXHHGS-UHFFFAOYSA-N 0.000 description 1
- 206010062904 Hormone-refractory prostate cancer Diseases 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001946 anti-microtubular Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- XAKXZZPEUKNHMA-UHFFFAOYSA-N decyl decanoate Chemical compound CCCCCCCCCCOC(=O)CCCCCCCCC XAKXZZPEUKNHMA-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000016507 interphase Effects 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 230000035773 mitosis phase Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to the field of medicinal chemistry, and in particular to a novel crystalline form of cabazitaxel and a process for the preparation thereof.
- Cabazitaxel English name Cabazitaxel, chemical name 4-acetoxy-2 ⁇ -benzoyloxy-5 ⁇ , 20-epoxy-1-hydroxy-7 ⁇ , 10 ⁇ -dioxine (2-R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, -9-oxo-11-taxane-13 ⁇ -alcohol, is by Sanofi, France
- the structure is as shown in Formula I:
- cabazitaxel The anticancer mechanism and characteristics of cabazitaxel are similar to docetaxel and belong to anti-microtubule drugs.
- Cabazitaxel combines with tubulin to facilitate its assembly into microtubules, while preventing the disassembly of these assembled microtubules, stabilizing microtubules, and thereby inhibiting cell mitosis and interphase cellular functions.
- Cabazitaxel is a drug of choice for patients with advanced prostate cancer who are ineffective or even exacerbated with docetaxel and are the first choice for the treatment of advanced, anti-steroidal prostate cancer.
- Cabazitaxel injection for prednisone Combination therapy has previously received patients with metastatic hormone-refractory prostate cancer (mHRPC) treated with docetaxel.
- mHRPC metastatic hormone-refractory prostate cancer
- Crystal form is one of the important factors affecting the quality of the drug, the efficacy and the processing properties of the formulation.
- Polymorphism refers to the same compound. By controlling the different formation conditions, two or more molecular spatial arrangements can be formed to produce different solid crystals.
- Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same compound have the same chemical composition, but different microscopic crystal structures, which leads to differences in their appearance, physical and chemical properties and biological activities. These characteristics directly affect the processing properties of the drug and affect the stability, solubility and bioavailability of the drug, which in turn affects the quality, safety, effectiveness and application of the drug. Therefore, in the development of drugs, the polymorphic problem of drugs should be fully considered.
- Patent WO2005/028462 identifies and characterizes the crystalline form A of cabazitaxel, namely 4-acetoxy-2 ⁇ -benzoyloxy-5 ⁇ , 20-ring. (2R,3S)-3-tert-butoxycarbonylamino-2 of oxy-1-hydroxy-7 ⁇ , 10 ⁇ -dimethoxy- 9-oxo-11-taxane-13 ⁇ -alcohol Form of the acetoxy complex of -hydroxy-3-phenylpropionate.
- Patent WO 2009/115655 identifies and characterizes the anhydrate form of cabazitaxel C, D, E, F, the form of the ethanolate B, D, E, the ethanol/water isocyanate F, the hydrate form C and the second Hydrate Form (3. SUMMARY OF THE INVENTION
- the present invention studies, discovers, and provides three crystal forms of cabazitaxel by means of crystallography, namely, the ester form of cabazitaxel form J, the hydrate form of cabazitaxel form G, and kappa. He is the crystal type I.
- the present invention can be used, for example, to study and characterize new crystalline forms of cabazitaxel using the internationally recognized X-ray powder diffraction method (XRPD).
- XRPD X-ray powder diffraction method
- an ester form J of cabazitaxel which in one embodiment may have the following characteristics: 7.9, 8.5, 10.1 in an X-ray powder diffraction pattern of about 2 ⁇ .
- the corresponding peak intensities are 100.0, 7.9, 21.6, 14.1
- the X-ray powder diffraction pattern thereof is as shown in Fig. 1.
- the present invention also employs infrared spectroscopy (IR) to study and characterize the new crystalline form of cabazitaxel.
- IR infrared spectroscopy
- Instrument BRUKER TENSOR27 Fourier transform mid-infrared spectrometer (Brook, Germany).
- Determination method KBr tableting method, spectral range O cm-L ⁇ OO cm- 1 , resolution A cm.
- the present invention provides an ester form of cabazitaxel form J, and its infrared spectrum can be as Figure 2 shows.
- Form J can also be characterized using other analytical techniques well known in the art.
- the chelate form form of cabazitaxel J has a thermogravimetric analysis (TGA) pattern as shown in Fig. 3.
- TGA thermogravimetric analysis
- DSC differential scanning calorimetry
- a hydrate form G of cabazitaxel which in one embodiment may have the following characteristics: 4.5, 8.5, 8.9 in an X-ray powder diffraction pattern of about 2 Torr. There are peaks at positions 11.1, 12.4, 13.9, 15. 4, 17.7 and 19.3. Preferably, the corresponding peak intensities are 19.0, 42.1, 100, 36.5, 9.2, 26.5,
- the X-ray powder diffraction pattern thereof is as shown in Fig. 5.
- the infrared spectrum of the hydrated form crystal form of cabazitaxel can be as shown in FIG. 6, and the thermogravimetric analysis (TGA) pattern can be as shown in FIG.
- the method (DSC) chart can be as shown in Figure 8.
- the present invention also provides a crystalline form I of cabazitaxel, which, in one embodiment, has the following characteristics: 7.4, 7.8, 8.9, 10.1 of about 2 ⁇ in the X-ray powder diffraction pattern.
- a crystalline form I of cabazitaxel which, in one embodiment, has the following characteristics: 7.4, 7.8, 8.9, 10.1 of about 2 ⁇ in the X-ray powder diffraction pattern.
- the corresponding peak intensities are 20.1, 100, 13.1, 11.5, 44.2, 10.7, 10.2, 17.7, 24.4 and 16.4.
- the X-ray powder diffraction pattern thereof is as shown
- the infrared spectrum of Cabazitaxel Form I can be as shown in Figure 10.
- the X-ray powder diffraction pattern may be 2 ⁇ A slight change, the value may differ by about 1 unit, or about 0.8 units, or about 0.5 units, or about 0.3 units, or about 0.1 units, so the value given cannot be considered absolute.
- the method for preparing the ester form of the cabazitaxel form of the present invention is as follows: the cabazitaxel is dissolved in an ester compound having 1 to 6 carbon atoms, and crystallized from the solution. Thereby obtaining the ester form form of cabazitaxel].
- the ester form J of cabazitaxel is prepared by dissolving cabazitaxel in an ester compound having 1 to 6 carbon atoms, concentrating, crystallizing, suction filtration, and drying the filter cake. .
- the concentration is concentrated to be viscous or has a proper amount of crystals precipitated, and then crystallized at a low temperature, suction filtration, and the filter cake is dried by heating.
- the amount of the ester compound having 1 to 6 carbon atoms is based on g/mL, preferably kappa. He played 1 to 50 times. That is, 1 to 50 mL of an ester compound having 1 to 6 carbon atoms is added per lg of cabazitaxel. More preferably, it is 20 to 30 times.
- the ester compound having 1 to 6 carbon atoms is decyl citrate, acetic acid.
- the hydrate form G of the cabazitaxel provided by the present invention is prepared by dissolving cabazitaxel in a halogenated alkane having 1 to 5 carbon atoms or having 1 to 4 carbon atoms.
- a halogenated alkane having 1 to 5 carbon atoms or having 1 to 4 carbon atoms In the alcohol compound, water is added, or cabazitaxel is dissolved in a mixed solvent of a halogenated alkane having a carbon number of 1 to 5 and water or a mixed solvent of an alcohol compound having 1 to 4 carbon atoms and water. Crystallization from the solution to obtain the hydrate form G of cabazitaxel.
- the method for dissolving cabazitaxel in a mixed solvent of a paraffin having a carbon number of 1 to 5 and water or a mixed solvent of an alcohol compound having 1 to 4 carbon atoms and water is: first, the number of carbon atoms is A 1 to 5 halogenated alkane or an alcohol compound having 1 to 4 carbon atoms is mixed with water, and then cabazitaxel is dissolved in the above mixed solvent.
- the hydrate form G of Cabazitaxel is prepared by dissolving cabazitaxel in a halogenated alkane having 1 to 5 carbon atoms or an alcohol compound having 1 to 4 carbon atoms, and adding water. , or to dissolve cabazitaxel in a mixed solvent of a paraffin having 1 to 5 carbon atoms or a mixed solvent of an alcohol compound having 1 to 4 carbon atoms and water, followed by crystallization, suction filtration, filter cake Dry is available.
- the crystallization is a low temperature crystallization, and the filter cake is dried to be heated and dried.
- the halogenated alkane having 1 to 5 carbon atoms or the alcohol having 1 to 4 carbon atoms The amount of the compound, based on g/mL, is preferably from 5 to 40 times that of cabazitaxel. That is, each lg of cabazitaxel is added with 5 to 40 mL of a halogenated alkane having 1 to 5 carbon atoms or an alcohol compound having 1 to 4 carbon atoms. More preferably, it is 8 to 20 times.
- the amount of water is in the range of g/mL, preferably 10 to 40 times that of cabazitaxel. That is, 10 to 40 mL of water is added per lg of cabazitaxel. More preferably, it is 20 to 30 times.
- the halogenated alkane having 1 to 5 carbon atoms is preferably dichlorodecane or trichlorodecane.
- the hydrate form of the cabazitaxel form G in the preparation method, is preferably decyl alcohol, ethanol, propanol or isopropanol. More preferably, it is decyl alcohol or ethanol.
- the present invention provides a method for preparing Cabazitaxel Form I by dissolving cabazitaxel in dichlorosilane, adding cyclohexane, or dissolving cabazitaxel in dichlorodecane.
- a mixed solvent with cyclohexane it is crystallized from the solution to obtain Cabazitaxel Form I.
- the cabazitaxel is dissolved in a mixed solvent of dichloromethane and cyclohexane, i.e., dichloromethane is first mixed with cyclohexane, and then cabazitaxel is dissolved in the mixed solvent.
- the crystal form I of cabazitaxel is prepared by dissolving cabazitaxel in dichlorosilane, adding cyclohexane, or dissolving cabazitaxel in a mixed solvent of dichlorosilane and cyclohexane. , crystallization, suction filtration, filter cake drying.
- the crystallization is a low temperature crystallization, and the filter cake is dried to be heated and dried.
- the amount of the dichloromethane is in the range of g/mL, preferably from 1 to 50 times that of cabazitaxel. That is, 1 to 50 mL of methylene chloride is added per lg of cabazitaxel. More preferably, it is 5 to 20 times.
- the cyclohexane in the preparation of the Cabazitaxel Form I, is used in an amount of from 2 to 100 times, preferably in g/mL, preferably from cabazitaxel. That is, 2 to 100 mL of cyclohexane is added per lg of cabazitaxel. More preferably, it is 10 to 40 times.
- the hydrate form of the cabazitaxel form of the cabazitaxel form and the preparation form of the hydrate form of the cabazitaxel form I are both subjected to low temperature crystallization, suction filtration, The filter cake is dried by heating.
- the temperature of the low temperature crystallization is preferably -20 to 35 °C. More preferably -10 ⁇ 10
- the temperature at which the filter cake is heated and dried is preferably from 30 to 100 °C. More preferably, it is 50 to 60 °C.
- the new crystal form of cabazitaxel according to the present invention has good stability and good solubility in common solvents, and is convenient for storage and preparation of a formulation dosage form, and thus can be used for preparing a medicament for treating prostate cancer.
- FIG. 1 is a view showing an X-ray powder diffraction pattern of a crystalline form J of an etoposide of cabazitaxel provided in Example 1 of the present invention, which is obtained by irradiation with copper yttrium.
- the ordinate indicates the diffraction intensity expressed in counts per second (cps), and the abscissa indicates the diffraction angle expressed in degrees 2 ⁇ ;
- Example 2 is an infrared spectrum diagram of the crystal form J of the cabazitaxel ethyl acetate compound provided in Example 1 of the present invention, wherein the ordinate is the light transmittance (T), the unit is the percentage (%); the abscissa is the wave number, the unit Is cm;
- FIG. 3 is a thermogravimetric analysis (TGA) diagram of the ethyl form of the ethyl acetate compound of the cabazitaxel provided in Example 1 of the present invention, the ordinate is the weight (mg), the unit is the percentage (%); Temperature, in units. C ;
- DSC differential scanning calorimetry
- Fig. 5 is a view showing an X-ray powder diffraction pattern of the form of the form of the cabazitaxel hydrate form G provided in Example 3 of the present invention, which is obtained by irradiation with copper ⁇ rays.
- the ordinate indicates the diffraction intensity expressed in counts per second (cps), and the abscissa indicates the diffraction angle expressed in degrees 2 ⁇ ;
- Figure 6 is a view showing the infrared spectrum of the crystal form G of the cabazitaxel hydrate form provided in Example 3 of the present invention, wherein the ordinate is the light transmittance (T), the unit is the percentage (%); the abscissa is the wave number, and the unit is cm;
- FIG. 7 is a thermogravimetric analysis (TGA) diagram of the form G of the cabazitaxel hydrate form provided in Example 3 of the present invention, the ordinate is the weight (mg), the unit is the percentage (%); the abscissa is the temperature, the unit for. C ;
- Figure 8 is a differential scanning calorimetry (DSC) chart of the form G of the cabazitaxel hydrate form provided in Example 3 of the present invention, wherein the ordinate is the heat flow rate in units of card/second; the abscissa is temperature, and the unit is . C ;
- Figure 9 is a graph showing the X-ray powder diffraction pattern of Cabazitaxel Form I provided in Example 6 of the present invention, which was obtained by irradiation with copper yttrium. In the X-ray powder diffraction pattern, the ordinate indicates the diffraction intensity expressed in counts per second (cps), and the abscissa indicates the diffraction angle expressed in degrees 2 ⁇ ;
- Figure 10 is a graph showing the infrared spectrum of the Cabazitaxel crystal form I provided in Example 6 of the present invention.
- the ordinate is the light transmittance (T) in units of percentage (%); the abscissa is the wave number in cm -1 .
- BEST MODE FOR CARRYING OUT THE INVENTION disclose test data of a new crystalline form of cabazitaxel and a preparation method thereof, and a new crystal form of cabazitaxel in improving solubility and improving stability. Those skilled in the art can learn from the contents of this document and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
- the method of the present invention has been described by the preferred embodiments, and it is obvious that those skilled in the art can change and adapt and combine the methods described herein to implement and apply the techniques of the present invention without departing from the scope of the present invention. .
- Example 2 10 g of cabazitaxel was added to 300 mL of decyl decanoate to dissolve, and concentrated to a small amount of crystals, which was crystallized at -20 ° C overnight, suction filtered, and the filter cake was vacuum dried at a temperature of 100 ° C to obtain 9.0 g of kappa. He is a J-type crystal of the bismuth citrate ester form. The purity of HPLC was 99.78%, and the residue of decyl citrate was determined by GC to be 85400 ppm.
- Example 3 10 g of cabazitaxel was added to 300 mL of decyl decanoate to dissolve, and concentrated to a small amount of crystals, which was crystallized at -20 ° C overnight, suction filtered, and the filter cake was vacuum dried at a temperature of 100 ° C to obtain 9.0 g of kappa. He is a J-type crystal of the bismuth citrate ester form. The purity
- cabazitaxel 5 g was added to 250 mL of ethyl acetate to dissolve by heating, and concentrated to a small amount of crystals, which was crystallized at -20 ° C overnight, suction filtered, and the filter cake was vacuum dried at a temperature of 100 ° C to obtain 4.4 g of cabazid.
- the ethyl acetate compound forms a J-type crystal.
- the purity of HPLC was > 99.73%, and the residual ethyl acetate was determined by GC to be 94286 ppm.
- cabazitaxel 20 g was dissolved in 200 mL of dichloromethane, and then crystallized by adding 500 mL of cyclohexane, and crystallized at 0 to 5 ° C overnight, suction filtration, and the filter cake was vacuum dried at a temperature of 50 to 60 ° C to obtain 17g cabazitaxel type I crystal.
- the purity of HPLC was >99.84%, and the X-ray powder diffraction pattern and infrared spectrum were shown in Fig. 9 and Fig. 10, respectively.
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Abstract
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Priority Applications (8)
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CA2870569A CA2870569A1 (en) | 2012-07-25 | 2013-07-18 | Crystal form of cabazitaxel and preparation method thereof |
IN1962MUN2014 IN2014MN01962A (zh) | 2012-07-25 | 2013-07-18 | |
US14/399,513 US9353076B2 (en) | 2012-07-25 | 2013-07-18 | Crystal form of cabazitaxel and preparation method thereof |
EP13822828.3A EP2835369B1 (en) | 2012-07-25 | 2013-07-18 | Crystal form of cabazitaxel and preparation method thereof |
CA2909500A CA2909500C (en) | 2012-07-25 | 2013-07-18 | Crystal form of cabazitaxel and preparation method thereof |
AU2013295924A AU2013295924B2 (en) | 2012-07-25 | 2013-07-18 | Crystal form of cabazitaxel and preparation method thereof |
JP2015514346A JP6329135B2 (ja) | 2012-07-25 | 2013-07-18 | カバジタキセルの結晶形態を有する結晶、その調製方法およびその使用 |
AU2016200343A AU2016200343B2 (en) | 2012-07-25 | 2016-01-21 | Crystal form of cabazitaxel and preparation method thereof |
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CN201210259595.3A CN102746258B (zh) | 2012-07-25 | 2012-07-25 | 卡巴他赛的结晶形式及其制备方法 |
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Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2014514306A (ja) | 2011-04-12 | 2014-06-19 | プラス・ケミカルス・エスアー | 固体形態のカバジタキセル及びその製造方法 |
US9394266B2 (en) | 2012-03-08 | 2016-07-19 | IVAX International GmbH | Solid state forms of cabazitaxel and processes for preparation thereof |
CN102746258B (zh) * | 2012-07-25 | 2015-02-04 | 重庆泰濠制药有限公司 | 卡巴他赛的结晶形式及其制备方法 |
CN103804323A (zh) * | 2012-11-14 | 2014-05-21 | 上海希迈医药科技有限公司 | 一种卡巴他赛溶剂化物及其制备方法和应用 |
CN103819428B (zh) * | 2012-11-19 | 2016-01-13 | 齐鲁制药有限公司 | 7β,10β-二甲氧基多西紫杉醇的溶剂化物的晶型及其制备方法 |
CN103058960B (zh) * | 2012-12-12 | 2014-12-10 | 江苏奥赛康药业股份有限公司 | 卡巴他赛多晶型形式及其制备方法 |
KR101429543B1 (ko) | 2012-12-13 | 2014-08-14 | 주식회사 삼양바이오팜 | 카바지탁셀의 신규 결정형 및 그 제조방법 |
CN103044364B (zh) * | 2013-01-07 | 2016-01-20 | 重庆泰濠制药有限公司 | 一种卡巴他赛无定形晶及其制备方法 |
WO2014128728A2 (en) * | 2013-02-25 | 2014-08-28 | Laurus Labs Private Limited | Solid forms of cabazitaxel and processes for preparation thereof |
CN103450119B (zh) * | 2013-09-24 | 2015-06-17 | 天津炜捷制药有限公司 | 一种卡巴他赛晶型w及其制备方法 |
EP2865674A1 (en) * | 2013-10-23 | 2015-04-29 | INDENA S.p.A. | Crystalline solvate forms of Cabazitaxel |
CN105461665A (zh) * | 2014-08-21 | 2016-04-06 | 中国医学科学院药物研究所 | 卡巴他赛晶n6型物质及制备方法和其组合物与用途 |
CN105461664A (zh) * | 2014-08-21 | 2016-04-06 | 中国医学科学院药物研究所 | 卡巴他赛晶n5型物质及制备方法和其组合物与用途 |
WO2017123760A1 (en) | 2016-01-15 | 2017-07-20 | Qun Sun | Compositions and formulations including cabazitaxel and human serum albumin |
EP3509569A1 (en) * | 2016-09-07 | 2019-07-17 | Cadila Healthcare Limited | Sterile injectable compositions comprising drug micelles |
WO2019204738A1 (en) | 2018-04-20 | 2019-10-24 | Zhuhai Beihai Biotech Co., Ltd. | Formulations and compositions of cabazitaxel |
CN113429369B (zh) * | 2021-07-23 | 2022-12-02 | 无锡紫杉药业有限公司 | 一种高效的卡巴他赛纯化方法 |
Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005028462A1 (fr) | 2003-09-19 | 2005-03-31 | Aventis Pharma S.A. | Solvat acetonique du dimethoxy docetaxel et son procede de preparation |
WO2009115655A2 (fr) | 2008-01-17 | 2009-09-24 | Aventis Pharma S.A. | Formes cristallines du dimethoxy docetaxel et leurs procedes de preparation |
CN102060815A (zh) * | 2010-12-24 | 2011-05-18 | 重庆泰濠制药有限公司 | 一种紫杉烷类化合物的制备方法 |
CN102336726A (zh) * | 2011-09-30 | 2012-02-01 | 重庆泰濠制药有限公司 | 一种卡巴他赛的制备方法 |
CN102482243A (zh) * | 2009-05-29 | 2012-05-30 | 伊佛潭有限公司 | 一种(2R,3S)-3-叔丁氧基羰基氨基-2-羟基-3-苯基丙酸-4-乙酰氧基-2α-苯甲酰氧基-5β,20-环氧-1,7β,10β-三羟基-9-氧-紫杉-11-烯-13α-基酯溶剂 |
CN102503913A (zh) * | 2011-10-20 | 2012-06-20 | 江苏红豆杉生物科技有限公司 | 直接用于x射线单晶衍射分析的二甲氧基紫杉烷类化合物单晶晶体的制备方法 |
CN102746258A (zh) * | 2012-07-25 | 2012-10-24 | 重庆泰濠制药有限公司 | 卡巴他赛的结晶形式及其制备方法 |
CN102898406A (zh) * | 2012-11-02 | 2013-01-30 | 上海金和生物技术有限公司 | 一种卡巴他赛晶体及其制备方法 |
WO2013034979A2 (en) * | 2011-09-09 | 2013-03-14 | Scinopharm Taiwan, Ltd. | Crystalline forms of cabazitaxel |
WO2013080217A2 (en) * | 2011-11-28 | 2013-06-06 | Fresenius Kabi Oncology Ltd. | Crystalline forms of carbazitaxel and process for preparation thereof |
WO2013088335A1 (en) * | 2011-12-13 | 2013-06-20 | Aventis Pharma S.A. | Crystalline form of cabazitaxel and process for preparing the same |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MXPA02006660A (es) * | 2000-01-07 | 2002-12-13 | Transform Pharmaceuticals Inc | Formacion, identificacion y analisis de diversas formas solidas de alto rendimiento. |
CN101525321B (zh) * | 2008-03-06 | 2012-03-07 | 上海希迪制药有限公司 | 多烯紫杉醇倍半水结晶体及其制备方法 |
JP2014514306A (ja) | 2011-04-12 | 2014-06-19 | プラス・ケミカルス・エスアー | 固体形態のカバジタキセル及びその製造方法 |
SG10201508986RA (en) * | 2011-09-30 | 2015-11-27 | Life Technologies Corp | Methods and systems for image analysis identification |
WO2013065070A1 (en) * | 2011-11-01 | 2013-05-10 | Fresenius Kabi Encology Ltd. | Amorphous form of cabazitaxel and process for its preparation |
US9394266B2 (en) * | 2012-03-08 | 2016-07-19 | IVAX International GmbH | Solid state forms of cabazitaxel and processes for preparation thereof |
CN104583189A (zh) * | 2012-07-31 | 2015-04-29 | 永信药品工业股份有限公司 | 非晶型的卡巴利他索 |
CN103058960B (zh) | 2012-12-12 | 2014-12-10 | 江苏奥赛康药业股份有限公司 | 卡巴他赛多晶型形式及其制备方法 |
-
2012
- 2012-07-25 CN CN201210259595.3A patent/CN102746258B/zh active Active
-
2013
- 2013-07-18 JP JP2015514346A patent/JP6329135B2/ja active Active
- 2013-07-18 WO PCT/CN2013/079575 patent/WO2014015760A1/zh active Application Filing
- 2013-07-18 EP EP16162975.3A patent/EP3067348A1/en not_active Withdrawn
- 2013-07-18 AU AU2013295924A patent/AU2013295924B2/en active Active
- 2013-07-18 CA CA2870569A patent/CA2870569A1/en not_active Abandoned
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- 2013-07-18 CA CA2909500A patent/CA2909500C/en active Active
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- 2013-07-18 EP EP13822828.3A patent/EP2835369B1/en active Active
-
2016
- 2016-01-21 AU AU2016200343A patent/AU2016200343B2/en active Active
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005028462A1 (fr) | 2003-09-19 | 2005-03-31 | Aventis Pharma S.A. | Solvat acetonique du dimethoxy docetaxel et son procede de preparation |
WO2009115655A2 (fr) | 2008-01-17 | 2009-09-24 | Aventis Pharma S.A. | Formes cristallines du dimethoxy docetaxel et leurs procedes de preparation |
CN101918385A (zh) * | 2008-01-17 | 2010-12-15 | 安万特医药股份有限公司 | 二甲氧基多西紫杉醇的结晶形式及其制备方法 |
CN102482243A (zh) * | 2009-05-29 | 2012-05-30 | 伊佛潭有限公司 | 一种(2R,3S)-3-叔丁氧基羰基氨基-2-羟基-3-苯基丙酸-4-乙酰氧基-2α-苯甲酰氧基-5β,20-环氧-1,7β,10β-三羟基-9-氧-紫杉-11-烯-13α-基酯溶剂 |
CN102060815A (zh) * | 2010-12-24 | 2011-05-18 | 重庆泰濠制药有限公司 | 一种紫杉烷类化合物的制备方法 |
WO2013034979A2 (en) * | 2011-09-09 | 2013-03-14 | Scinopharm Taiwan, Ltd. | Crystalline forms of cabazitaxel |
CN102336726A (zh) * | 2011-09-30 | 2012-02-01 | 重庆泰濠制药有限公司 | 一种卡巴他赛的制备方法 |
CN102503913A (zh) * | 2011-10-20 | 2012-06-20 | 江苏红豆杉生物科技有限公司 | 直接用于x射线单晶衍射分析的二甲氧基紫杉烷类化合物单晶晶体的制备方法 |
WO2013080217A2 (en) * | 2011-11-28 | 2013-06-06 | Fresenius Kabi Oncology Ltd. | Crystalline forms of carbazitaxel and process for preparation thereof |
WO2013088335A1 (en) * | 2011-12-13 | 2013-06-20 | Aventis Pharma S.A. | Crystalline form of cabazitaxel and process for preparing the same |
CN102746258A (zh) * | 2012-07-25 | 2012-10-24 | 重庆泰濠制药有限公司 | 卡巴他赛的结晶形式及其制备方法 |
CN102898406A (zh) * | 2012-11-02 | 2013-01-30 | 上海金和生物技术有限公司 | 一种卡巴他赛晶体及其制备方法 |
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JP2015518012A (ja) | 2015-06-25 |
US9353076B2 (en) | 2016-05-31 |
AU2016200343B2 (en) | 2017-03-30 |
CA2870569A1 (en) | 2014-01-30 |
IN2014MN01962A (zh) | 2015-07-10 |
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EP2835369A4 (en) | 2015-12-02 |
AU2016200343A1 (en) | 2016-02-11 |
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