WO2015000165A1 - Produit de transformation stable du mono-acétonate de dimethoxy docetaxel et ses formes cristallines, et leurs procédés de préparation - Google Patents

Produit de transformation stable du mono-acétonate de dimethoxy docetaxel et ses formes cristallines, et leurs procédés de préparation Download PDF

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Publication number
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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preparation
acetonate
dimethoxy docetaxel
docetaxel
hours
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PCT/CN2013/078847
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Chinese (zh)
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王海勇
孙天宇
来庚
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北京新天宇科技开发有限公司
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Publication of WO2015000165A1 publication Critical patent/WO2015000165A1/fr

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    • 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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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un produit de transformation stable du mono-acétonate de diméthoxy docétaxel, ses formes cristallines, et leurs procédés de préparation. Le produit de transformation stable et ses formes cristallines présentent une plus grande stabilité, ainsi les préparations pharmaceutiques obtenues au moyen du produit de transformation stable et des formes cristallines comme matières premières sont dotées d'une meilleure qualité, d'une durée d'efficacité plus longue et d'une sécurité accrue.
PCT/CN2013/078847 2013-07-04 2013-07-04 Produit de transformation stable du mono-acétonate de dimethoxy docetaxel et ses formes cristallines, et leurs procédés de préparation WO2015000165A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
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 (fr) * 2011-09-09 2013-03-14 Scinopharm Taiwan, Ltd. Formes cristallines du 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 (fr) * 2011-12-13 2013-06-20 Aventis Pharma S.A. Forme cristalline de cabazitaxel et procédé pour préparer celle-ci

Patent Citations (5)

* Cited by examiner, † Cited by third party
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 (fr) * 2011-09-09 2013-03-14 Scinopharm Taiwan, Ltd. Formes cristallines du cabazitaxel
WO2013088335A1 (fr) * 2011-12-13 2013-06-20 Aventis Pharma S.A. Forme cristalline de cabazitaxel et procédé pour préparer celle-ci
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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