WO2015000165A1 - 二甲氧基多西紫杉醇一丙酮化物的稳定转化物及其结晶形式、以及它们的制备方法 - Google Patents
二甲氧基多西紫杉醇一丙酮化物的稳定转化物及其结晶形式、以及它们的制备方法 Download PDFInfo
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- WO2015000165A1 WO2015000165A1 PCT/CN2013/078847 CN2013078847W WO2015000165A1 WO 2015000165 A1 WO2015000165 A1 WO 2015000165A1 CN 2013078847 W CN2013078847 W CN 2013078847W WO 2015000165 A1 WO2015000165 A1 WO 2015000165A1
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- acetonate
- dimethoxy docetaxel
- docetaxel
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- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 229960003668 docetaxel Drugs 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 30
- -1 dimethoxy docetaxel Chemical compound 0.000 title claims abstract description 23
- 230000009466 transformation Effects 0.000 title claims abstract 6
- 239000013078 crystal Substances 0.000 claims description 53
- 239000000047 product Substances 0.000 claims description 25
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 18
- 238000001228 spectrum Methods 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 12
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- 238000004458 analytical method Methods 0.000 claims description 7
- 239000002274 desiccant Substances 0.000 claims description 6
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 5
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 3
- 239000012084 conversion product Substances 0.000 claims 6
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 65
- 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 description 44
- 229960001573 cabazitaxel Drugs 0.000 description 41
- 239000003814 drug Substances 0.000 description 18
- 229940079593 drug Drugs 0.000 description 17
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 12
- 239000008186 active pharmaceutical agent Substances 0.000 description 10
- 229940088679 drug related substance Drugs 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 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 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 4
- 230000008859 change Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 229940025735 jevtana Drugs 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- BWLBGMIXKSTLSX-UHFFFAOYSA-N 2-hydroxyisobutyric acid Chemical compound CC(C)(O)C(O)=O BWLBGMIXKSTLSX-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000000719 anti-leukaemic effect Effects 0.000 description 2
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 0 C*(CC1)CC2*1C2C* Chemical compound C*(CC1)CC2*1C2C* 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- JXGFNOAMBPABCK-JVXKREHESA-N cabazitaxel acetone Chemical compound CC(C)=O.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 JXGFNOAMBPABCK-JVXKREHESA-N 0.000 description 1
- 229960002504 capsaicin Drugs 0.000 description 1
- 235000017663 capsaicin Nutrition 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000001225 nuclear magnetic resonance method Methods 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 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
Definitions
- the present invention relates to the field of medicinal chemistry, and in particular to a stable transformant of dimethoxy docetaxel monoacetonate, dimethoxy docetaxel-acetonate
- Solid drugs are classified as crystalline and amorphous (amorphous).
- the basic unit constituting the crystal of the drug is a crystal lattice in which the drug molecules are arranged in a certain regular pattern; and the amorphous form is that the molecules are arranged in an disorderly manner without a clear crystal lattice.
- a crystalline solvent molecule is included in the drug crystal, it is called a solvate, and when the solvent is water (i.e., contains crystal water), it is generally called a hydrate.
- the solid drug may have a different crystal form, or there may be a crystalline form and an amorphous form, or the presence of an unsolvate and a solvate, or no or water of crystallization, it is referred to as a polymorphism in the drug.
- the different crystal forms of the drug are caused by the difference in the arrangement of the molecules in the crystal lattice.
- the drugs with polymorphism may have different chemical and physical properties, such as different melting points, due to different lattice energies. , chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure and density, etc.
- Polymorphic drugs may have an influence on the preparation of the drug substance and the preparation, the stability of the drug substance and the preparation, the dissolution rate of the preparation, and the bioavailability due to the difference in physical and chemical properties between the different crystal forms.
- different apparent solubility results in different dissolution rates of the formulation and may result in different bioavailability
- different optical and mechanical properties, density, etc. may affect the preparation process of the formulation
- different chemical reactivity may lead to drug stability difference. Differences in drug dissolution, bioavailability, stability, etc., may affect the quality controllability, safety, and effectiveness of the drug.
- Powder X-ray diffraction is a commonly used method for studying and distinguishing different crystal forms. This method can be used not only for the qualitative differentiation of different crystal forms, but And after establishing the quantitative relationship between the characteristic diffraction peak and the different crystal form content, powder X-ray diffraction (XPRD) can also be used for quantitative control of different crystal form ratios.
- XPRD powder X-ray diffraction
- Dimethoxy docetaxel chemical name: 4-acetoxy-2 ⁇ -benzoyloxy-5 ⁇ , 20-epoxy-1-hydroxy-7 ⁇ , 10 ⁇ -dimethoxy-9-oxo Taxane-11-ene-13 ⁇ -based
- 3-phenylproplonate also commonly referred to as 7B, 1 OB-dimethoxy docetaxel, or cabazitaxel (hereinafter referred to as "Kappa", CAS No.: 183133-96- 2)
- Kappa CAS No.: 183133-96- 2
- Cabazitaxel can be prepared by the international application WO 9630355 or the international application WO 9925704, however the product obtained according to the method of these applications is not a crystalline substance.
- a drug has a plurality of crystal forms
- some crystal forms may not be easily formed or obtained, and only a part of the crystal form can be formed during the production and preparation of the drug substance and its preparation. Therefore, the focus of research and development should be on the crystal forms that may be formed during the preparation of the drug substance, the preparation of the drug, and the storage of the drug and the preparation.
- the effects of polymorphism on the stability of the drug substance and formulation, on the dissolution and bioavailability of the formulation, and on the preparation process of the drug substance and preparation should be considered in the development process.
- the preparation of the above crystal forms 8, C, D, E and F has a number of disadvantages, including preparation procedures It is cumbersome, for example, the preparation of crystalless C, D, E; or the preparation conditions are harsh, for example, the crystalless type B and E need to be treated at a temperature of 100 ° C or higher for a long time. It is known that the melting point or decomposition point of these two crystal forms of cabazitaxel is about 150 ° C. Long-term high temperature treatment tends to cause decomposition of the product, eventually leading to an increase in impurities and a decrease in purity.
- the preparation of heteronuclear crystals of the same crystal form, including cabazitaxel ethanolate or ethanol/water isocyanate is more complicated, and must be prepared without crystal form, and then can be prepared on the basis of the latter.
- the stability of crystalline materials is significantly better than the corresponding amorphous materials.
- Kappastat has a high molecular weight, a complex structure, and a large number of polar groups in the molecule. Therefore, the drug substance in the form of crystal has the advantages of long effective period and better quality.
- the active ingredient of capsaicin in Shangyu in June 2010 is crystal form A prepared by using cabazitaxel-acetonate.
- the generic name is Cabazitaxel. Trade name: JEVTANA), that is, a preparation prepared from the crystal form A.
- one of the objects of the present invention is to provide a stable transformant of dimethoxy docetaxel-acetonate.
- Another object of the present invention is to provide a crystalline form of a dimethoxy docetaxel-acetonate stable transformant.
- a further object of the present invention is to provide a stable transformant of dimethoxy docetaxel monoacetonate and a process for preparing the crystalline form thereof.
- the stable transformant of dimethoxy docetaxel monoacetonate has the following structural formula:
- the crystalline form of the dimethoxy docetaxel-acetonate stable transformant provided by the present invention is a crystalline form of dipentate docetaxel penta-one acetonide, designated as Form G, which is contained in X- Ray powder diffraction (XRPD) analysis of the spectrum by 2 ⁇
- XRPD X- Ray powder diffraction
- the diffraction angles of 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 11.1, 13.5 and 10.5 ⁇ 0.2° are shown. That is, the crystal form G was characterized by X-ray powder diffraction pattern to show characteristic peaks including 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 11.1, 13.5, and 15.0 ⁇ 0.2 ° 2 ⁇ .
- the crystal form G of the diacetate docetaxel penta-one acetonide provided by the present invention is more contained in 7.2, 7.4, 7.8, 8.1 represented by 2 ⁇ in the X-ray powder diffraction analysis chart. 8.8, 9.8, 10.2, 10.4, 11.1, 13.5, 14.3, 15.0 and 15.2 ⁇ 0.2° diffraction angle. Namely, the crystal form G was characterized by X-ray powder diffraction pattern to show characteristic peaks including 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 10.2, 10.4, 11.1, 13.5, 14.3, 15.0 and 15.2 ⁇ 0.2 ° 2 ⁇ .
- the crystal form G of the diacetate docetaxel pentaacetate provided by the present invention is more, and includes 7.2, 7.4, 7.8, 8.1 represented by 2 ⁇ in the X-ray powder diffraction analysis spectrum. Diffusion angles of 8.8, 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0 and 15.2 ⁇ 0.2°. That is, the crystal form G is characterized by X-ray powder diffraction pattern to include 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0, and 15.2 ⁇ 0.2 ° 2 ⁇ Characteristic peak.
- the crystal form G of the diacetate docetaxel pentaacetate provided by the present invention is more, and includes 7.2, 7.4, 7.8, 8.1 represented by 2 ⁇ in the X-ray powder diffraction analysis spectrum. 8.8, 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0, 15.2, 15.7, 16.3, 16.5, 17.1, 17.6, 17.9 ⁇ 0.2° diffraction angle.
- the crystallization of the Form G by X-ray powder diffraction pattern shows that it is located at 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0, 15.2, 15.7, 16.3, 16.5, 17.1, 17.6, 17.9 ⁇ 0.2 ° 2 ⁇ characteristic peak.
- crystal forms of the already disclosed cabazitaxel include crystal forms VIII, B, C, D, E and F, the specific data (characteristic peaks represented by the diffraction angle of 2 )) are: crystalline form ⁇ : disclosed for international application WO200480026128, but Specific values are not listed, only their XRPD maps are listed, see Figure 1 of which it is disclosed.
- Form ⁇ For the international application WO200980102389, the characteristic peaks are 7.3, 8.1, 9.8, 10.4, 11.1, 12.7, 13.1, 14.3, 15.4 and 15.9 ⁇ 0.2°.
- Form C disclosed for international application WO200980102389, with characteristic peaks of 4.3, 6.8, 7.4, 8.7, 10.1, 11.1, 11.9, 12.3, 12.6 and 13.1 ⁇ 0.2°.
- Form D disclosed for international application WO200980102389, with characteristic peaks of 3.9, 7.7, 7.8, 7.9, 8.6, 9.7, 10.6,
- Form E As disclosed in the international application WO200980102389, the characteristic peaks are 7.1, 8.1, 8.9, 10.2, 10.8, 12.5, 12.7 (extremely weak peaks, negligible), 13.2, 13.4 and 13.9 ⁇ 0.2°.
- Form F For the international application WO200980102389, the characteristic peaks are 4.4, 7.2, 8.2, 8.8, 9.6, 10.2, 10.9, 11.2, 12.1 and 12.3 ⁇ 0.2. .
- crystal forms C, D, and F have a characteristic peak of 2 ⁇ of 4.3, 3.9, and 4.4, respectively, which is significantly different from the crystalline form of the present invention; although crystal form A does not list specific data in the literature, it is from the map. It can also be clearly seen that there is no 2 ⁇ characteristic peak data below 8.5°; the characterization data of crystal forms B and E are relatively similar, and in the range of 0.2°, most of the data are consistent, including 7.3 and 7.1.
- the XRPD data of the present invention (characteristic peaks represented by the diffraction angle of 2 ⁇ ) are 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0, 15.2.
- the most significant difference from Forms B and E is the portion of the 2 ⁇ diffraction angle below 10, including 7.2, 7.4, 7.8, 8.1, 8.8, 9.8°, especially between 7 and 8 where dense fingerprint areas appear.
- the diffraction angles other than this are consistent with Forms B and E, including: 10.2, 10.4, 11.1, 12.6,
- the invention provides a method for preparing a stable transformant of dimethoxy docetaxel monoacetonate, comprising: dissolving dimethoxy docetaxel (carbataxel) monoacetonate under vacuum in the presence of a desiccant or In the absence of the condition, heat at 40 ⁇ 60 °C for 24 ⁇ 120 hours.
- the heating time is preferably 24 to 96 hours, more preferably 30 to 96 hours, and most preferably 48 to 96 hours.
- the preparation method of the dimethoxy docetaxel divalent acetone of the present invention comprises: dimethoxy-docetaxel (carbataxel)-acetonate under vacuum, drying Heat at 40 ⁇ 60 ° C for 24 hours in the presence or absence of the agent.
- the preparation method of the diacetate docetaxel penta acetonide comprises: dimethoxy docetaxel (carbataxel) monoacetonate Under vacuum conditions, in the presence or absence of a desiccant, heat at 40 to 60 ° for 48 to 96 hours.
- the heating temperature is preferably 55 °C. That is, in the preparation of diacetate docetaxel acetonide and dimethoxy docetaxel penta acetonate, the temperature may preferably be 55 °C.
- the desiccant may be selected from anhydrous calcium chloride or phosphorus pentoxide, preferably anhydrous calcium chloride.
- the heating can be stopped at any time, and the heating time can be accumulated to the above range. It is not necessary to be a vacuum condition for the intermittent heating stop, and it is preferred to maintain the vacuum condition.
- the present invention overcomes the shortcomings of the prior art cabazitaxel-acetonate instability, and a stable conversion of dimethoxy docetaxel (cabbataxel) monoacetonate can be found by simple treatment.
- the product prepared by the invention can last for a long time under relatively harsh conditions, the state does not change, and the product has good stability; and the existing cabazitaxel-acetonate continues under similar conditions. The conversion occurred in a very short time, indicating that it is very unstable.
- the preparation method of the invention is simple, and the stable product (especially one-fifth acetonide and its crystalline form) satisfying the pharmaceutical requirement can be obtained without preparing the crystal-free type; Long-term high temperature treatment minimizes the temperature-related impurities, ensuring product quality and thus contributing to patient health.
- the one-fifth of the acetonide of the present invention has higher stability than the above-mentioned cappastamine drug substance, and the quality of the preparation made of the drug substance is better, and the cost is indirectly lowered (yew Alkane anticancer drugs are extremely expensive, and the active feedstock contains less acetone and is therefore more safe.
- Figure 1 is an HNMR spectrum of an amorphous cabazitaxel bulk drug.
- Figure 2 is an H NMR spectrum of the cabazitaxel monoacetonate obtained in accordance with Example 1.
- Figure 3 shows the H NMR spectrum of cabazitaxel-acetonate treated under vacuum at 55 ° C for 24 hours with a acetone content of 3.2%, i.e. containing one-half of acetone.
- Figure 4 shows the H NMR spectrum of cabazitaxel-acetonate treated under vacuum at 55 ° C for 48 hours.
- the acetone content in the spectrum is 1.3%, i.e., contains one-fifth of acetone molecules.
- Figure 5 shows the H NMR spectrum of cabazitaxel-acetonate treated under vacuum at 55 ° C for 72 hours with an acetone content of 1.3%, i.e. still containing one-fifth of acetone molecules.
- Figure 6 shows the TGA spectrum of cabazitaxel-acetonate treated under vacuum at 55 ° C for 72 hours.
- the acetone content in the spectrum is 1.3%, which still contains one-fifth of acetone molecules.
- Figure 7 shows XPRD spectra of cabazitaxel-acetonate treated under vacuum at 55 °C for 72 hours.
- Figure 8 shows the H NMR spectrum of a kappataxel-acetonate treated under vacuum at 55 ° C for 96 hours.
- the acetone content in the spectrum was 1.3%, i.e., still contained one-fifth of acetone molecules.
- Figure 9 is a HPLC chart of the solution obtained in accordance with Example 4 after standing at 25 ° C for 6 months. detailed description
- tube pressure 45 kV
- 26 6 scanning range 5 ⁇ 50 ° step length 0.015 °
- X-ray powder diffraction experimental data Reflected at a diffraction angle of 2 ⁇ A theoretical discussion of X-ray powder diffraction patterns can be found in "X-ray diffraction procedures", ⁇ . P. Klug and L. E. Alexander, J. Wiley, New York (1974).
- the amorphous cabazitaxel material of the present invention is prepared by the method described in Chinese patent application CN 96192884, and the quality of the raw material is determined by HPLC: the content is >99%, and the single impurity is less than 0.15%. It was analyzed and analyzed to obtain an HNMR spectrum as shown in Fig. 1, and it was clearly observed that the moisture and the organic solvent were not contained in the spectrum.
- Example 1 of International Application WO2004800261208 2 mL of purified water was added to a solution of 500 mg of cabazitaxel in 4.8 mL of acetone, followed by seeding of a suspension of 5 mg of cabazitaxel in 0.05 mL of water and 0.05 mL of acetone. After the mixture was stirred for 16 hours, 3.6 mL of purified water was added, then stirred for 1 hour, filtered, and the filter cake was washed with a mixture of 1 mL of acetone and 1.3 mL of water.
- the product was dried under reduced pressure in a vacuum drying oven by an oil pump, and treated at 55 ° C for 24 hours to obtain a target product (ie, one-part acetone of cabazitaxel).
- NMR showed an acetone content of 3.2% (see Figure 3).
- the product was dried under reduced pressure in an air drying oven, and the treatment was continued at 55 ° C for 24 hours (ie, 48 hours in total) to obtain the target product (ie, One-fifth of the acetonide in cabazitaxel, in crystalline form, NMR showed an acetone content of 1.3% (see Figure 4).
- one-fifth of the effervescent of cabazitaxel was continuously dried in a vacuum drying oven with an oil pump, and the product was treated at 55 ° C for 24 h (i.e., total 72 h) without change, and the target product was still obtained.
- NMR showed an acetone content of 1.3% (see Figure 5);
- TGA showed an acetone content of 1.3% (see Figure 6);
- the structure of the one-fibrate acetonide of cabazitaxel according to the present invention can be determined by nuclear magnetic resonance and TGA, and the acetone contained in the molecule can be obtained by nuclear magnetic resonance method and TGA. Good qualitative and quantitative, and the two methods have a good correlation.
- the crystal form G of one-fifth of the effervescent of cabazitaxel is continuously dried in a vacuum drying oven by an oil pump, and the product is still unchanged after being treated at 55 ° C for 24 hours (ie, 96 hours in total), that is, The target product was still obtained, and NMR showed an acetone content of 1.3% (see Figure 8).
- the XPRD spectrum of the one-fibrous acetonate form G of cabazitaxel obtained by the third method is substantially the same as that of Fig. 7.
- the cabazitaxel monoacetonate obtained by the method of Example 1 was continuously placed in a vacuum drying oven, and vacuum was obtained by decompression with an oil pump in the presence of anhydrous calcium chloride, and then dried at 40 ° C for 120 hours to obtain a kappa.
- the cabazitaxel-acetonate obtained as in the method of Example 1 was continuously placed in a vacuum drying oven, and a vacuum was obtained by decompression with an oil pump in the presence of anhydrous calcium chloride, followed by drying at 60 ° C for 48 hours to obtain a kappa.
- Example 4 On the basis of the method disclosed in Example 1, there is no disclosure in the literature that others continue to react to obtain a stable conversion of cabazitaxel containing acetone. The inventors continued research and improvement on the basis of the prior art (lack of product stability), and eliminated a large number of interfering factors (which generate a large number of unstable transformants). After long-term and trial and error exploration, the inventors finally determined. this invention.
- Example 4 On the basis of the method disclosed in Example 1, there is no disclosure in the literature that others continue to react to obtain a stable conversion of cabazitaxel containing acetone. The inventors continued research and improvement on the basis of the prior art (lack of product stability), and eliminated a large number of interfering factors (which generate a large number of unstable transformants). After long-term and trial and error exploration, the inventors finally determined. this invention. Example 4
- the capsaid product of Cabazitaxel (trade name: JEVTANA) is a 60 mg/1.5 mL original solution: contains 60 mg of cabazitaxel-acetonate and 1.5 mL of polysorbate 80.
- a two-step dilution is required before administration to the patient. The first step is: Dilute the original solution to a 10 mg/mL mixed solution using 5.7 mL of 13% (w/w) aqueous ethanol solution; the second step is: The one-step dilution solution is transferred to 250 mL of 0.9% sodium chloride solution or 5% glucose solution for injection.
- the raw material drug product obtained in the second method of the third embodiment was prepared by using the polysorbate 80 as a solvent, and a solution having a concentration of 60 mg/1.5 mL was also smoothly prepared. After the solution was allowed to stand at 25 ° C for 6 months, HPLC showed that the product was very stable (see Figure 9), and the same two-step dilutions as JEVTANA were used to obtain the exact same product.
- the dimethoxy docetaxel (carbataxel) acetonide provided by the invention, and the corresponding crystalline form have higher stability, and use them as a raw material medicine to prepare a pharmaceutical preparation having anticancer and anti-leukemia effects, Facilitating the quality control of the product will make the preparation product have a longer effective period and better quality; at the same time, the active raw material contains less acetone and thus has higher safety.
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Abstract
提供二甲氧基多西紫杉醇一丙酮化物的稳定转化物,其结晶形式,以及它们的制备方法。所述稳定转化物及其结晶形式具有更高的稳定性,利用它们为原料制成的药物制剂具有更好的质量、更长有效期和更高安全性。
Description
二甲氧基多西紫杉醇一丙酮化物的稳定转化物 及其结晶形式、 以及它们的制备方法 技术领域
本发明涉及药物化学领域, 具体地, 涉及二甲氧基多西紫杉醇一 丙酮化物的稳定转化物,二甲氧基多西紫杉醇一丙酮化
的结晶形式, 以及它们的制备方法。 背景技术
固体药物有结晶型和非结晶型(无定形)之分。 构成药物结晶的 基本单元为晶格, 在晶格中药物分子以一定的规律排列; 而无定形是 分子以无序的方式排列, 不具有明确的晶格。 若药物结晶中包含结晶 溶剂分子, 就称为溶剂化物, 当该溶剂为水时 (即含有结晶水), 通 常称为水合物。 如果固体药物可存在不同的晶型, 或存在结晶型与无 定形, 或存在非溶剂化物与溶剂化物、 不含或含有结晶水等现象, 就 称为该药物存在多晶型现象。
药物的不同晶型是由分子在晶格中排列方式的不同所致,存在多 晶型现象的药物由于晶格能的不同,其不同晶型可具有不同的化学和 物理性质, 如不同的熔点、 化学反应性、 表观溶解度、 溶出速率、 光 学和机械性质、 蒸汽压和密度等。 多晶型药物由于不同晶型之间理化 性质的不同, 可能对原料药及制剂的制备, 原料药及制剂的稳定性, 制剂的溶出度及生物利用度等产生影响。比如不同的表观溶解度致使 制剂有不同的溶出度, 并可能导致生物利用度的不同; 不同的光学和 机械性质、 密度等可能影响制剂的制备工艺; 不同的化学反应性可导 致药品稳定性的差异。 药品溶出度、 生物利用度、 稳定性等的差异进 而可能影响药品的质量可控性、 安全性和有效性。
由于多晶型问题可能影响药品的安全有效性和质量可控性,应当 针对不同情况釆取相应的措施。 粉末 X -射线衍射是常用的研究和区 分不同晶型的有效方法, 该方法不仅可用于不同晶型的定性区分, 而
且在建立特征衍射峰与不同晶型含量之间的定量关系后, 粉末 X - 线衍射(XPRD )还可用于不同晶型比例的定量控制。
二甲氧基多西紫杉醇, 化学名为: 4-乙酰氧基 -2α-苯甲酰氧基 -5β,20-环氧 -1-羟基 -7β,10β-二甲氧基 -9-氧代紫杉 -11-烯 -13α-基
( 2R,3S ) -3-叔丁氧基羰基氨基 -2-羟基 -3-苯基丙酸酯 (4-acetoxy-
2a-benzoyloxy-5 , 20-epoxy- 1 -hydroxy-7 , 1 Οβ-dlmethoxy- 9-oxotax- l l-en-13a-yl ( 2R,3S ) -3-tert-butoxycarbonylamino-2-hydroxy-
3-phenylproplonate ), 通常也可以称为 7B, 1 OB-二甲氧基多西紫杉醇 ( dimethoxy docetaxel ), 或者卡巴他赛(本发明以下统称为 "卡巴他 赛", CAS号: 183133-96-2 ), 具有显著的抗癌和抗白血病功效, 研究 表明其即为存在上述多晶型现象的物质。
卡巴他赛以及相关结晶形式的制备可以根据以下申请中的具体 描述方法完成:
国际申请 WO 9630355或国际申请 WO 9925704可以制备得到卡 巴他赛, 然而根据这些申请中的方法获得的产物并不是晶体物质。
国际申请 WO 200480026128公开了第一种卡巴他赛晶体化合物 一一卡巴他赛一丙酮溶剂化物, 并进行了表征, 确定为晶型 A。
国际申请 WO 200980102389公开了卡巴他赛的乙醇化物、水合物 及无水合物的五种晶型, 分别是经由晶型 A制备出晶型 B、 C、 D、 E 和 F, 以及它们的制备方法, 并对其中部分晶型进行了表征。
然而, 一种药物虽然存在多种晶型, 但某些晶型可能不易形成或 得到, 仅有部分晶型在原料药及其制剂的生产制备过程中能够形成。 因此, 研发工作中重点应考虑那些在原料药制备、 制剂制备、 以及原 料药及制剂贮藏过程中可能形成的晶型。 对于存在多晶型现象的药 物, 研发过程中需要考虑多晶型对原料药及制剂稳定性、 对制剂溶出 及生物利用度的影响, 以及对原料药及制剂制备工艺的影响。
上述晶型8、 C、 D、 E和 F的制备存在诸多缺点, 包括制备程序
繁瑣, 例如无水晶型 C、 D、 E的制备; 或者制备条件苛刻, 例如无水 晶型 B和 E需要在 100°C或更高温度下进行长时间处理。 已知这几种晶 型的卡巴他赛的熔点或者分解点在 150°C左右, 长时间高温处理易引 起产品分解,最终导致杂质增多,纯度降低。而相同晶型的异核晶体, 包括卡巴他赛乙醇化物或者乙醇 /水异溶剂化物的制备更是复杂, 必 须先制备出无水晶型, 然后在后者的基础上才能制备出来。
一般情况下, 晶体物质的稳定性显著优于相应的无定型物质。 卡 巴他赛分子量较高, 结构复杂, 分子中具有较多的极性基团, 因而, 其以晶体形式存在的原料药具有有效期长、质量更佳的优点。 虽然已 经公开的卡巴他赛晶型较多, 然而, 于 2010年 6月上巿的卡巴他赛活 性成分为卡巴他赛一丙酮化物制备得到的晶型 A, 通用名为卡巴他赛 ( Cabazitaxel, 商品名: JEVTANA ), 即由该晶型 A制备的制剂。
然而, 研究表明: A晶型的卡巴他赛一丙酮化物稳定性较差, 分 子中的丙酮易分解,严重影响原料药的质量控制, 进而必定影响到其 制剂的有效性和安全性。 因而, 有必要找到更加合适的卡巴他赛, 即 二甲氧基多西紫杉醇一丙酮化物的稳定转化物,以及二甲氧基多西紫 杉醇一丙酮化物稳定转化物新的结晶形式。 发明内容
为了解决现有技术中存在的问题, 本发明的目的之一在于, 提供 二甲氧基多西紫杉醇一丙酮化物的稳定转化物。
本发明的另一目的在于,提供二甲氧基多西紫杉醇一丙酮化物稳 定转化物的结晶形式。
本发明的又一目的在于,提供二甲氧基多西紫杉醇一丙酮化物的 稳定转化物及其结晶形式的制备方法。
本发明提供的二甲氧基多西紫杉醇一丙酮化物的稳定转化物,结 构式如下:
其中, X=l/2或 1/5。
也就是说:
本发明提供的二甲氧基多西紫杉醇一丙酮化物的稳定转化物,可 以为二甲氧基多西紫杉醇(卡巴他赛)二分之一丙酮化物, 结构式如 下 (当 X=l/2时):
本发明提供的二甲氧基多西紫杉醇一丙酮化物的稳定转化物,也 可以为二甲氧基多西紫杉醇(卡巴他赛)五分之一丙酮化物, 结构式 如下 (当 X=l/5时):
本发明提供的二甲氧基多西紫杉醇一丙酮化物稳定转化物的结 晶形式, 为二甲氧基多西紫杉醇五分之一丙酮化物的结晶形式,命名 为晶型 G, 其包含在 X-射线粉末衍射(XRPD )分析谱图中由 2 Θ表
示的 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 11.1、 13.5和 15.0士 0.2°的衍射 角。 即, 晶型 G通过 X-射线粉末衍射图谱表征显示了包含 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 11.1、 13.5和 15.0士 0.2° 2 Θ的特征峰。
本发明提供的二甲氧基多西紫杉醇五分之一丙酮化物的晶型 G, 更多地,包含在 X-射线粉末衍射分析图谱图中由 2 Θ表示的 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 13.5、 14.3、 15.0 和 15.2 士 0.2°的衍射角。 即, 晶型 G通过 X-射线粉末衍射图谱表征显示了包含 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 13.5、 14.3、 15.0 和 15.2士 0.2° 2 Θ的特征峰。
本发明提供的二甲氧基多西紫杉醇五分之一丙酮化物的晶型 G, 更多地, 包含在 X-射线粉末衍射分析谱图中由 2 Θ表示的 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 12.6、 12.9、 13.5、 14.3、 15.0 和 15.2士 0.2° 的衍射角。 即, 晶型 G通过 X-射线粉末衍射图谱表征 显示了包含 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 12.6、 12.9、 13.5、 14.3、 15.0和 15.2士 0.2° 2 Θ的特征峰。
本发明提供的二甲氧基多西紫杉醇五分之一丙酮化物的晶型 G, 更多地, 包含在 X-射线粉末衍射分析谱图中由 2 Θ表示的 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 12.6、 12.9、 13.5、 14.3、 15.0、 15.2、 15.7、 16.3、 16.5、 17.1、 17.6、 17.9士 0.2°的衍射角。 即, 晶 型 G通过 X-射线粉末衍射图谱表征显示了位于 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 12.6、 12.9、 13.5、 14.3、 15.0、 15.2、 15.7、 16.3、 16.5、 17.1、 17.6、 17.9士 0.2° 2 Θ的特征峰。
已经公开的卡巴他赛的晶型包括晶型八、 B、 C、 D、 E和 F, 其具 体数据 (2 Θ衍射角表示的特征峰) 为: 晶型 Α : 为国际申请 WO200480026128公开, 但未列出具体的值, 仅列出了其 XRPD图谱, 参见其公开的附图 1。 晶型 Β: 为国际申请 WO200980102389公开, 特 征峰为 7.3、 8.1、 9.8、 10.4、 11.1、 12.7、 13.1、 14.3、 15.4和 15.9士 0.2°。
晶型 C: 为国际申请 WO200980102389公开, 特征峰为 4.3、 6.8、 7.4、 8.7、 10.1、 11.1、 11.9、 12.3、 12.6和 13.1士 0.2°。 晶型 D: 为国际申请 WO200980102389公开, 特征峰为 3.9、 7.7、 7.8、 7.9、 8.6、 9.7、 10.6、
10.8、 11.1和 12.3士 0.2°。 晶型 E: 为国际申请 WO200980102389公开, 特征峰为 7.1、 8.1、 8.9、 10.2、 10.8、 12.5、 12.7(极其微弱的峰, 可以 忽略)、 13.2、 13.4和 13.9士 0.2°。 晶型 F: 为国际申请 WO200980102389 公开, 特征峰为 4.4、 7.2、 8.2、 8.8、 9.6、 10.2、 10.9、 11.2、 12.1和 12.3士 0.2。。
通过比较, 晶型 C、 D和 F分别存在 4.3、 3.9和 4.4°的 2 Θ特征峰, 与本发明的结晶形式差异显著; 晶型 A虽然在文献中没有列出具体数 据,但从图谱上也可以明显看出不存在低于 8.5°的 2 Θ特征峰数据; 晶 型 B和 E的特征数据相对而言比较类似, 以士 0.2°的范围看, 绝大部分 数据一致, 包括 7.3与 7.1°、 8.1与 8.1°、 9.8与 10.2°、 11.1与 10.8°、 12.7 与 12.5°、 13.1与 13.2°、 14.3与 13.9° (每组前面为晶型 B的数据, 后面 为晶型 E的数据), 两种晶型只有两个特征峰不一样, 分别是晶型 B的 10.4、 15.4°, 晶型 E的 8.9、 13.4°, 因而差异不像前面的几种晶型一样 显著, 需要仔细辨认。
本发明的 XRPD数据(2 Θ衍射角表示的特征峰)为 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 12.6、 12.9、 13.5、 14.3、 15.0、 15.2。, 与晶型 B和 E最显著的区别是 2 Θ衍射角在 10以下的部分, 包括 7.2、 7.4、 7.8、 8.1、 8.8、 9.8°, 特别是在 7〜8之间出现密集的指紋区, 除此 之外的衍射角与晶型 B和 E比较一致, 包括: 10.2、 10.4、 11.1、 12.6、
12.9、 14.3°中的部分或多个。
本发明提供的二甲氧基多西紫杉醇一丙酮化物的稳定转化物的 制备方法, 包括: 将二甲氧基多西紫杉醇(卡巴他赛)一丙酮化物于 真空条件下, 在干燥剂存在或不存在的条件下, 40〜60°C加热 24〜120 小时。
其中, 所述加热时间优选 24〜96小时, 更优选 30〜96小时, 最优 选 48〜96小时。
当加热时间为 24小时时, 得到的是二甲氧基多西紫杉醇二分之 一丙酮化物。 也就是说, 本发明提供的二甲氧基多西紫杉醇二分之一 丙酮化物的制备方法, 包括: 将二甲氧基多西紫杉醇(卡巴他赛)一 丙酮化物于真空条件下, 在干燥剂存在或不存在的条件下, 40〜60°C 加热 24小时。
当加热时间为 48〜96小时时,得到的是二甲氧基多西紫杉醇五分 之一丙酮化物, 为结晶形式, 即上述晶型 G。 也就是说, 本发明提供 的二甲氧基多西紫杉醇五分之一丙酮化物(也就是晶型 G )的制备方 法, 包括: 将二甲氧基多西紫杉醇(卡巴他赛)一丙酮化物于真空条 件下, 在干燥剂存在或不存在的条件下, 40〜60° 加热48〜96小时。
上述制备方法中, 加热温度优选 55 °C。 即在二甲氧基多西紫杉 醇二分之一丙酮化物和二甲氧基多西紫杉醇五分之一丙酮化物的制 备过程中, 温度均可优选 55 °C。
上述制备方法中, 干燥剂可以选择无水氯化钙或五氧化二磷, 优 选无水氯化钙。
根据工作环境, 可以随时停止加热, 加热时间累计达到上述范围 即可。在停止加热的间歇可以不必为此真空条件,优选保持真空条件。
本发明克服了现有技术中卡巴他赛一丙酮化物不稳定的缺点,通 过简单的处理即能找到二甲氧基多西紫杉醇(卡巴他赛)一丙酮化物 的稳定转化物。本发明制备得到的产物, 能在较为苛刻的条件下持续 很长时间, 状态并不发生变化, 体现了产物较好的稳定性; 而现有的 卡巴他赛一丙酮化物在类似的条件下持续极短时间即发生了转换,说 明十分不稳定。
本发明制备方法简单,不需要制备出无水晶型就能得到满足药学 需要的稳定产物 (尤其是五分之一丙酮化物及其结晶形式); 不需要
长时间高温处理, 使与温度相关的杂质含量降至最低, 保证了产品质 量, 进而有利于患者健康。
本发明的五分之一丙酮化物与已经上巿的卡巴他赛原料药相比, 具有更高的稳定性, 以其为原料药制成的制剂的质量更佳, 使得成本 间接降低 (紫杉烷类抗癌药物价格极其昂贵), 而且活性原料中包含 的丙酮更少, 因而具有更高的安全性。 附图说明
图 1为无定形卡巴他赛原料药的 HNMR谱。
图 2为按照实施例 1得到的卡巴他赛一丙酮化物的 HNMR谱。 图 3为卡巴他赛一丙酮化物在真空、 55°C下处理 24小时的 HNMR 谱, 谱中丙酮含量为 3.2%, 即含有二分之一丙酮分子。
图 4为卡巴他赛一丙酮化物在真空、 55°C下处理 48小时的 HNMR 谱, 谱中丙酮含量为 1.3%, 即含有五分之一丙酮分子。
图 5为卡巴他赛一丙酮化物在真空、 55°C下处理 72小时的 HNMR 谱, 谱中丙酮含量为 1.3%, 即仍然含有五分之一丙酮分子。
图 6为卡巴他赛一丙酮化物在真空、 55°C下处理 72小时的 TGA 谱, 谱中丙酮含量为 1.3%, 即仍然含有五分之一丙酮分子。
图 7为卡巴他赛一丙酮化物在真空、 55°C下处理 72小时的 XPRD 谱。
图 8为卡巴他赛一丙酮化物在真空、 55°C下处理 96小时的 HNMR 谱, 谱中丙酮含量为 1.3%, 即仍然含有五分之一丙酮分子。
图 9为按照实施例 4得到的溶液于 25°C放置 6个月后测得的 HPLC图谱。 具体实施方式
以下通过各实施例进一步说明本发明的内容,但不应理解为对本 发明的限制。 在不背离本发明精神和实质的情况下, 对本发明方法、 步骤或条件所作的修改或替换, 均属于本发明的范围。
若未特别指明,本发明未描述的实验操作方法和条件均为本领域 的常规选择。
本发明釆用 BRUKER D8 ADVANCE X射线粉末衍射仪,测定条 件: CuKal 辐射( λ =1.5406Α ), 管压 45 kV, 2 6扫描范围 5〜50 ° , 步长 0.015 ° , X射线粉末衍射实验数据以 2 Θ衍射角体现。 X射线粉 末衍射图谱的理论探讨可见于 "X 射线衍射过程 (X-ray diffraction procedures)" , Η. P. Klug 和 L. E. Alexander, J. Wiley, New York (1974)。
本发明的无定形卡巴他赛原料参考中国专利申请 CN 96192884 所述的方法制备, 原料质量由 HPLC 确定: 含量 >99% , 单杂小于 0.15%。 对其进行检测分析, 得到如图 1所示的 HNMR谱, 谱中可以 清晰看出不含水分和有机溶剂。
实施例 1: 卡巴他赛一丙酮化物的制备
参考国际申请 WO200480026128中实施例 1公开的方法,将 2mL 纯净水加入到 500mg卡巴他赛在 4.8mL丙酮的溶液中,然后加入 5mg 卡巴他赛在 0.05mL水和 0.05mL丙酮的悬浮液种晶。 将混合物搅拌 16h后,加入 3.6mL纯净水,然后搅拌 lh,过滤,用 lmL丙酮和 1.3mL 水的混合液洗滤饼。 然后在真空干燥箱中, 以油泵减压干燥产品, 在 55 °C下 4h得到产品 460mg。 NMR显示丙酮含量为 7.3%(参见附图 2 ), 与国际申请 WO 200480026128保护的卡巴他赛一丙酮溶剂化物包含 的丙酮数据相当 (其测定的丙酮含量均值为 7%左右, 理论值为 6.5% )。
实施例 2: 卡巴他赛二分之一丙酮化物的制备
按照实施例 1的方法获得卡巴他赛一丙酮化物后,再在真空干燥箱 中以油泵减压干燥产品, 在 55 °C下处理 24h得到目标产品 (即卡巴他 赛二分之一丙酮化物), NMR显示丙酮含量为 3.2% (参见附图 3 )。
从本实施例也可以看出: 现有的卡巴他赛一丙酮化物在制备的条 件下处理一段时间即发生了转换, 说明其十分不稳定。
实施例 3: 卡巴他赛五分之一丙酮化物的制备
方法一:
按照实施例 2的方法获得卡巴他赛二分之一丙酮化物后,然后在真 空干燥箱中以油泵减压干燥产品,在 55 °C下继续处理 24h(即共计 48h ) 可以得到目标产品 (即卡巴他赛五分之一丙酮化物, 为结晶形式), NMR显示丙酮含量为 1.3% (参见附图 4 )。
方法二:
按照上述方法一获得的卡巴他赛五分之一丙酮化物, 其继续在真 空干燥箱中以油泵减压干燥产品, 在 55 °C处理 24h (即共计 72h )无变 化, 仍然得到目标产品。 NMR显示丙酮含量为 1.3% (参见附图 5 ); TGA显示丙酮含量为 1.3% (参见附图 6 ); XPRD: 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 12.6、 12.9、 13.5、 14.3、 15.0、 15.2、 15.7、 16.3、 16.5、 17.1、 17.6、 17.9士 0.2°的特征峰( 2 Θ ) (参见附图 7 )。
在图 7中, 主要的峰信息如下表所示:
11 12.662 6.98523 23.4
12 12.993 6.80843 21.3
13 13.515 6.54624 3.4
14 14.327 6.17728 13.1
15 15.008 5.89845 4.2
16 15.279 5.79448 4.5
17 15.797 5.60536 11.4
18 16.323 5.42614 8.8
19 16.518 5.36234 5.5
20 17.170 5.16021 9.2
21 17.606 5.03338 9.9
22 17.948 4.93826 3.7
23 18.157 4.88200 3.7
24 18.510 4.78949 18.0
25 18.798 4.71681 9.2
26 19.176 4.62466 1.9
27 19.791 4.48232 10.7
28 20.440 4.34142 5.7
29 21.082 4.21076 1.8
30 21.917 4.05213 8.3
31 22.609 3.92956 6.9
32 22.959 3.87054 2.9
33 24.005 3.70415 3.2
34 24.340 3.65401 3.8
35 24.832 3.58271 1.3
36 25.403 3.50342 5.2
37 26.198 3.39891 4.0 本发明所述的卡巴他赛五分之一丙酮化物的结构可以通过核磁 共振和 TGA确定,分子中所含的丙酮通过核磁共振方法和 TGA可以获
得良好的定性和定量, 而且这两种方法具有良好的相关性。
方法三:
按照上述方法二获得的卡巴他赛五分之一丙酮化物的晶型 G, 其 继续在真空干燥箱中以油泵减压干燥产品, 在 55 °C处理 24h (即共计 96h )仍无变化,即仍然得到目标产品, NMR显示丙酮含量为 1.3% (参 见附图 8 )。
用方法三得到的卡巴他赛五分之一丙酮化物晶型 G的 XPRD谱, 与图 7基本一致。
方法四:
将如实施例 1的方法获得的卡巴他赛一丙酮化物继续置于真空干 燥箱中, 在无水氯化钙存在下, 以油泵减压获得真空, 然后在 40°C干 燥 120h可以得到卡巴他赛五分之一丙酮化物 (为结晶形式, 即晶型 G ), 其 XPRD谱与图 7基本一致, HNMR图谱与图 4、 5和 8基本一致。 方法五:
将如实施例 1 的方法获得的卡巴他赛一丙酮化物继续置于真空 干燥箱中, 在无水氯化钙存在下, 以油泵减压获得真空, 然后在 60°C 干燥 48h可以得到卡巴他赛五分之一丙酮化物(为结晶形式, 即晶型 G ), 其 XPRD谱与图 Ί基本一致, HNMR图谱与图 4、 5和 8基本一 实施例 3说明:本发明制备得到的产物,能在较为苛刻的条件下, 持续很长时间, 但状态并不发生变化, 体现了较好的稳定性。
在实施例 1公开方法的基础上,并没有文献公开他人继续进行反 应从而得到卡巴他赛含丙酮的稳定转化物。 发明人在现有技术(得到 产品稳定性欠缺)的基础上进行继续研究和改进, 排除大量干扰因素 (其中会产生大量的不稳定的转化物),经过长期和反复试验的摸索, 最终确定了本发明。
实施例 4
卡巴他赛的上巿产品 (商品名: JEVTANA )为 60 mg/1.5 mL的 原始溶液: 包含 60 mg的卡巴他赛一丙酮化物及 1.5 mL的聚山梨醇 酯 80。 在给患者用药前需要经过两步稀释, 第一步为: 使用 5.7 mL 的 13% ( w/w ) 的乙醇水溶液将原始溶液稀释为 10 mg/mL的混合溶 液; 第二步为: 将第一步的稀释溶液以注射剂转移至 250 mL的 0.9% 的氯化钠溶液或 5%的葡萄糖溶液中待用。
将实施例 3方法二得到的原料药产品以聚山梨醇酯 80为溶剂, 也可以顺利地制备得到 60 mg/1.5 mL浓度的溶液。 该溶液于 25°C放 置 6个月后, HPLC显示产品非常稳定(见附图 9 ), 其分别经过与 JEVTANA相同的两步稀释后也能够顺利得到完全相同的相应产品。
波长 =230 nm, 附图 9相关信息如下表所示:
工业实用性
本发明提供的二甲氧基多西紫杉醇(卡巴他赛)丙酮化物, 以及 相应的结晶形式具有更高的稳定性,利用它们作为原料药制成具有抗 癌和抗白血病功效的药物制剂, 更便于产品的质量控制, 会使得制剂 产品有效期长、 质量更佳; 同时, 活性原料中包含的丙酮更少, 因而 具有更高的安全性。
Claims
1、 二甲氧基多西紫杉醇一丙酮化物的 , 结构式如下:
其中, X=l/2或 1/5。
2、 根据权利要求 1所述二甲氧基多西紫杉醇一丙酮化
, 其特征在于, 当 X=l/5时, 结构式如下:
'、 权利要求 2所述二甲氧基多西紫杉醇一丙酮化物的转化物的
'晶形: K , 其包含在 X-射线粉末衍射分析谱图中由 2 Θ表示的 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 11.1、 13.5和 15.0士 0.2°的衍射角。
4、 权利要求 2所述二甲氧基多西紫杉醇一丙酮化物的转化物的 结晶形式,其包含在 X-射线粉末衍射分析图谱图中由 2 Θ表示的 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 13.5、 14.3、 15.0和 15.2
5、 权利要求 2所述二甲氧基多西紫杉醇一丙酮化物的转化物的 结晶形式, 其包含在 X-射线粉末衍射分析谱图中由 2 Θ表示的 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 12.6、 12.9、 13.5、 14.3、 15.0和 15.2士 0.2°^ fe
6、 权利要求 1或 2所述二甲氧基多西紫杉醇一丙酮化物的转化 物的制备方法,包括: 将二甲氧基多西紫杉醇一丙酮化物于真空条件 下, 在干燥剂存在或不存在的条件下, 40〜60°C加热 24〜120小时。
7、 根据权利要求 6所述的制备方法, 其特征在于, 加热时间为 24〜96小时。
8、 根据权利要求 6或 7所述的制备方法, 其特征在于, 加热时 间为 24小时, 得到的二甲氧基多西紫杉醇一丙酮化物的转化物的结 构式如下:
9、 根据权利要求 6或 7所述的制备方法, 其特征在于, 加热时 间为 48〜96小时,得到的二甲氧基多西紫杉醇一丙酮化物的转化物的 结构式如下:
10、权利要求 3〜5任意一项所述二甲氧基多西紫杉醇一丙酮化物 转化物的结晶形式的制备方法, 包括: 将二甲氧基多西紫杉醇一丙酮 化物于真空条件下, 在干燥剂存在或不存在的条件下, 40〜60°C加热 48〜96小时。
11、根据权利要求 6〜10任意一项所述的制备方法, 其特征在于,
加热温度为 55 °C。
12、根据权利要求 6〜10任意一项所述的制备方法, 其特征在于, 所述干燥剂为: 无水氯化钙或五氧化二磷。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050065138A1 (en) * | 2003-09-19 | 2005-03-24 | Aventis Pharma S.A. | Acetone solvate of dimethoxy docetaxel and its process of preparation |
WO2009115655A2 (fr) * | 2008-01-17 | 2009-09-24 | Aventis Pharma S.A. | Formes cristallines du dimethoxy docetaxel et leurs procedes de preparation |
WO2013034979A2 (en) * | 2011-09-09 | 2013-03-14 | Scinopharm Taiwan, Ltd. | Crystalline forms of cabazitaxel |
CN103058960A (zh) * | 2012-12-12 | 2013-04-24 | 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 |
WO2013088335A1 (en) * | 2011-12-13 | 2013-06-20 | Aventis Pharma S.A. | Crystalline form of cabazitaxel and process for preparing the same |
-
2013
- 2013-07-04 WO PCT/CN2013/078847 patent/WO2015000165A1/zh active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050065138A1 (en) * | 2003-09-19 | 2005-03-24 | Aventis Pharma S.A. | Acetone solvate of dimethoxy docetaxel and its process of preparation |
WO2009115655A2 (fr) * | 2008-01-17 | 2009-09-24 | Aventis Pharma S.A. | Formes cristallines du dimethoxy docetaxel et leurs procedes de preparation |
WO2013034979A2 (en) * | 2011-09-09 | 2013-03-14 | Scinopharm Taiwan, Ltd. | Crystalline forms of cabazitaxel |
WO2013088335A1 (en) * | 2011-12-13 | 2013-06-20 | Aventis Pharma S.A. | Crystalline form of cabazitaxel and process for preparing the same |
CN103058960A (zh) * | 2012-12-12 | 2013-04-24 | 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 |
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