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WO2022000265A1 - Cocristaux d'axitinib et d'acide glutarique, et leur procédé de préparation - Google Patents

Cocristaux d'axitinib et d'acide glutarique, et leur procédé de préparation Download PDF

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Publication number
WO2022000265A1
WO2022000265A1 PCT/CN2020/099269 CN2020099269W WO2022000265A1 WO 2022000265 A1 WO2022000265 A1 WO 2022000265A1 CN 2020099269 W CN2020099269 W CN 2020099269W WO 2022000265 A1 WO2022000265 A1 WO 2022000265A1
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axitinib
glutaric acid
crystal
preparation
solvents
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PCT/CN2020/099269
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English (en)
Chinese (zh)
Inventor
陈嘉媚
任伯颖
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天津理工大学
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Priority to PCT/CN2020/099269 priority Critical patent/WO2022000265A1/fr
Publication of WO2022000265A1 publication Critical patent/WO2022000265A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to the technical field of medicinal chemistry, in particular to a co-crystal of axitinib and glutaric acid and a preparation method thereof.
  • Pharmaceutically active ingredients usually exist in crystalline forms such as polymorphs, hydrates, solvates, salts, co-crystals, and the like.
  • crystalline forms such as polymorphs, hydrates, solvates, salts, co-crystals, and the like.
  • different crystalline forms have different physicochemical properties. Therefore, in the pharmaceutical industry, it is of great significance to obtain suitable crystalline forms of drugs.
  • Drugs exist in the form of co-crystals, which have significant advantages in improving the stability, solubility and processability of active pharmaceutical ingredients. Therefore, drug co-crystals are an effective means to improve the physicochemical properties of active pharmaceutical ingredients.
  • Axitinib N-methyl-2-[[3-[(1E)-2-(2-pyridyl)vinyl]-1H-indazol-6-yl]sulfanyl ] benzamide, its chemical structural formula is:
  • Axitinib is a second-generation VEGFR inhibitor that selectively inhibits the activities of vascular endothelial growth factor VEGF-1, VEGF-2, and VEGF-3 receptors to exert anti-cancer effects.
  • the drug was developed by Pfizer under the trade name It was approved by the FDA on January 27, 2012 for the treatment of early-stage to advanced kidney cancer, and was approved by the EMA in September of the same year for marketing in Europe. Currently, the drug is used to treat advanced renal cell carcinoma in several countries. Pfizer has built a strict crystal form patent barrier for axitinib.
  • Patent US20060094763 discloses crystal forms I, II, III, IV, VI, VII, VIII and other crystal forms of axitinib; patent CN 103626739 discloses crystal forms XXV, XVI, XLI, IX of axitinib , XII, XV and other crystal forms.
  • the axitinib used in China is imported, which is expensive and unbearable for ordinary patients, which limits its clinical application.
  • axitinib is a BCS class II drug with poor water solubility, limiting its oral bioavailability. Therefore, in order to break through the crystal form patent of the original pharmaceutical company and improve its dissolution properties, we carried out a co-crystal study of axitinib.
  • One of the objects of the present invention is to provide a co-crystal of axitinib and glutaric acid; the second of the objects of the present invention is to provide a preparation method of this co-crystal of axitinib and glutaric acid; The third is to provide the application of this co-crystal of axitinib and glutaric acid.
  • the invention provides a co-crystal of axitinib and glutaric acid.
  • the molar ratio of axitinib to glutaric acid is 1:1; the X-ray powder diffraction pattern of this co-crystal measured by Cu K ⁇ radiation is 7.7 ⁇ 0.2°, 12.8 ⁇ There are characteristic peaks at 0.2°, 14.1 ⁇ 0.2°, 15.4 ⁇ 0.2°, 17.3 ⁇ 0.2°, 19.2 ⁇ 0.2°, 21.4 ⁇ 0.2°, and 25.5 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the co-crystal of axitinib and glutaric acid also has diffraction angles 2 ⁇ of 16.1 ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.2 ⁇ 0.2°, 20.1 ⁇ 0.2°, 22.1 ⁇ 0.2
  • diffraction angles 2 ⁇ 16.1 ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.2 ⁇ 0.2°, 20.1 ⁇ 0.2°, 22.1 ⁇ 0.2
  • °, 22.7 ⁇ 0.2°, 23.2 ⁇ 0.2°, 24.1 ⁇ 0.2°, and 24.7 ⁇ 0.2° have characteristic peaks.
  • the present invention provides a preparation method of the co-crystal of axitinib and glutaric acid.
  • a preparation method of axitinib and glutaric acid co-crystal comprising the following steps: feeding axitinib and glutaric acid according to a molar ratio of 1:1, adding an appropriate amount of solvent, and then stirring or grinding to obtain a co-crystal.
  • the solvent is at least one of alcohol solvents, ester solvents, ketone solvents, ether solvents, nitrile solvents, and alkane solvents.
  • alcohol solvents include but are not limited to methanol, ethanol, isopropanol
  • ester solvents include but are not limited to methyl acetate, ethyl acetate, isopropyl acetate, ethyl formate
  • ketone solvents include but are not limited to acetone
  • Ether-based solvents include but are not limited to diethyl ether, isopropyl ether, and tetrahydrofuran
  • nitrile-based solvents include but are not limited to acetonitrile
  • alkane-based solvents include but are not limited to n-hexane, n-heptane, and cyclohexane
  • the solvent is selected from methanol , one or more of
  • the ratio of the total mass of axitinib and glutaric acid to the amount of solvent during stirring is 1 g: (2-20) mL; when grinding, axitinib and glutaric acid are The ratio of the total mass of the solvent to the amount of the solvent is 1 g: (20-200) uL.
  • the preparation method of this co-crystal is as follows: feeding axitinib and glutaric acid in a molar ratio of 1:1, adding a solvent, stirring, filtering, and drying the obtained solid product , to obtain a eutectic.
  • the preparation method of the co-crystal is as follows: feeding axitinib and glutaric acid in a molar ratio of 1:1, adding a solvent and grinding to obtain a co-crystal.
  • the ratio of the total mass of axitinib and glutaric acid to the amount of solvent used during stirring is 1 g: (4-20) mL.
  • the ratio of the total mass of axitinib and glutaric acid to the amount of solvent used during grinding is 1 g: (100-200) uL.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the co-crystal of axitinib and glutaric acid and a pharmaceutically acceptable excipient.
  • pharmaceutically acceptable excipients refer to pharmaceutically acceptable materials, mixtures or vehicles that are related to the consistency of dosage forms or pharmaceutical compositions. Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form chosen. Furthermore, pharmaceutically acceptable excipients can be selected based on their particular function in the composition.
  • the pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents Agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste-masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants , preservatives, stabilizers, surfactants and buffers.
  • excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents Agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste-masking agents, colorants, anti-caking agents, humectants
  • the invention also provides the application of the co-crystal of axitinib and glutaric acid in the preparation of a medicament for preventing and/or treating cancer and other angioproliferative diseases.
  • the present invention converts axitinib into a new co-crystal of axitinib and glutaric acid for the first time, and the co-crystal of axitinib and glutaric acid has a faster dissolution rate and larger
  • the apparent solubility of axitinib provides a material basis for improving the oral bioavailability of axitinib.
  • the preparation method of the co-crystal of axitinib and glutaric acid disclosed by the invention has simple process, easy control of the crystallization process, good reproducibility, and is suitable for industrial production.
  • the co-crystal of axitinib and glutaric acid of the present invention has broad application prospects in the preparation of medicines for preventing and/or treating cancer and other vascular proliferation diseases.
  • Fig. 1 is the X-ray powder diffraction pattern of axitinib and glutaric acid co-crystal
  • Figure 2 is a differential scanning calorimetry analysis diagram of axitinib and glutaric acid co-crystal
  • Fig. 3 is the thermogravimetric analysis diagram of axitinib and glutaric acid co-crystal
  • Fig. 4 is the Fourier transform infrared spectrum of axitinib and glutaric acid co-crystal
  • Fig. 5 is the hydrogen nuclear magnetic resonance spectrum of co-crystal of Axitinib and glutaric acid
  • Fig. 6 is the powder dissolution curve diagram of axitinib crystal form IV, axitinib and glutaric acid co-crystal;
  • Figure 7 is a graph showing the characteristic dissolution curves of axitinib crystal form IV and axitinib co-crystal with glutaric acid.
  • axitinib 38.6 mg of axitinib and 13.2 mg of glutaric acid were weighed, and 1 mL of isopropyl ether was added to obtain a suspension. The suspension was stirred at room temperature for 24 h, filtered, and the obtained white solid was dried at 40 °C to obtain axitinib. A solid sample of the co-crystal of nitric acid and glutaric acid.
  • the co-crystal of axitinib and glutaric acid provided by the invention is analyzed by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric (TG) analysis, Fourier transform infrared spectroscopy (FTIR), hydrogen nuclear magnetic resonance (HNMR) and other methods.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TG thermogravimetric
  • FTIR Fourier transform infrared spectroscopy
  • HNMR hydrogen nuclear magnetic resonance
  • X-ray powder diffraction analysis was carried out on the solid sample of the co-crystal of Axitinib and glutaric acid prepared in Example 1, using a diffractometer of Rigaku Mini Flex 600 of Japan Rigaku Co., Ltd., Cu K ⁇ rays, and a voltage of 40 thousand volts, the current is 15 mA, the step size is 0.01°, the scanning speed is 20°/min, the scanning range is 5.0-40.0°, and the test temperature is room temperature.
  • the analysis results are shown in the X-ray powder diffraction (XRPD) diagram of FIG. 1 , and the X-ray powder diffraction data are shown in Table 1.
  • Example 2 Based on the same X-ray powder diffraction test method as in Example 1, the X-ray powder diffraction data of the solid sample of the co-crystal of axitinib and glutaric acid prepared in Example 2 are shown in Table 2.
  • Example 3 Based on the same X-ray powder diffraction test method as in Example 1, the X-ray powder diffraction data of the solid sample of the co-crystal of axitinib and glutaric acid prepared in Example 3 are shown in Table 3.
  • crystalline materials can be characterized by X-ray diffraction techniques, but the X-ray diffraction pattern will generally vary with the testing conditions of the instrument.
  • the relative intensities of X-ray diffraction patterns may vary with experimental conditions, so the relative intensity order of X-ray diffraction peaks cannot be used as the sole or decisive factor for the characterization of crystalline substances.
  • the peak angle is usually allowed to have an error of ⁇ 0.2°. Due to the influence of experimental factors such as sample height and test temperature, the overall peak angle will be shifted, and a certain shift is usually allowed.
  • the X-ray diffraction pattern of the co-crystal of axitinib and glutaric acid described in the present invention does not have to be completely consistent with the X-ray diffraction pattern in this example.
  • the cases where the characteristic peaks in the same or similar are all within the scope of the present invention.
  • Those skilled in the art can compare the spectrum listed in the present invention with the spectrum of an unknown substance to confirm that the unknown substance is or is not the co-crystal of axitinib and glutaric acid according to the present invention.
  • the solid sample of axitinib and glutaric acid co-crystal obtained in Example 1 was subjected to differential scanning calorimetry analysis, which was detected by a DSC 214 differential calorimeter of Germany NETZSCH Scientific Instruments Co., Ltd., and the atmosphere was nitrogen. , and the heating rate was 10 °C/min.
  • the analysis results are shown in the differential scanning calorimetry (DSC) analysis chart of FIG. 2 .
  • the DSC curve showed that no obvious endothermic or exothermic phenomenon was found in the co-crystal of axitinib and glutaric acid before thermal decomposition.
  • Thermogravimetric analysis was carried out on the solid sample of the co-crystal of Axitinib and glutaric acid prepared in Example 1, using a TG209F3 thermogravimetric analyzer from German NETZSCH Scientific Instruments Co., Ltd., the atmosphere was nitrogen, and the heating rate was 10 °C /min.
  • the analysis results are shown in the thermogravimetric (TG) analysis chart of FIG. 3 .
  • the TG curve shows that the co-crystal of axitinib and glutaric acid is heated to around 170°C and begins to decompose, and there is no weight loss before this temperature. During the heating process from 170°C to 500°C, there is a multi-stage weight loss phenomenon.
  • Example 2 The co-crystal sample of axitinib and glutaric acid prepared in Example 1 was analyzed by infrared spectroscopy, which was detected by ALPHA II Fourier transform infrared spectrometer of Bruker Company, and the detection range was 4000-500 cm -1 . See Figure 4 of the Fourier Transform Infrared (FTIR) spectrum.
  • FTIR Fourier Transform Infrared
  • the characteristic peak positions of its infrared spectrum are (cm -1 ): 3247, 2973, 2938, 2905, 2884, 2361, 2340, 2322, 2206, 2188, 2126, 2111, 1994, 1963, 1700 , 1640, 1557, 1458, 1434, 1337, 1267, 1236, 1150, 1085, 1065, 1052, 1020, 960, 861, 803, 754, 729, 702, 655, 608, 591, 515.
  • Example 1 The Axitinib and glutaric acid co-crystal samples prepared in Example 1 were subjected to 1H NMR spectrum analysis, and were detected by an Avance III 400M NMR spectrometer from Bruker, Germany. The analysis results were shown in the 1H NMR spectrum of accompanying drawing 5. ( 1 HNMR) spectrum.
  • Axitinib and glutaric acid co-crystal were prepared by the method provided in Example 1 of the present invention; Axitinib crystal form IV was purchased from Shanghai Shengde Pharmaceutical Technology Co., Ltd., with a purity of 99%.
  • Powder dissolution test method Axitinib and glutaric acid co-crystal and axitinib crystal form IV were ground and passed through 100 and 200 mesh sieves, respectively, and the particle size of the powder was controlled to be 75-150 ⁇ m.
  • Dissolution medium 0.01N hydrochloric acid solution
  • Dissolution temperature 37 ⁇ 0.5°C
  • Sampling time 0.5, 1, 2, 5, 10, 20, 40, 60, 120, 240 minutes;
  • Chromatographic column Inertsil ODS C18 column (4.6mm ⁇ 150mm, 5 ⁇ m);
  • UV detection wavelength 330nm
  • Injection volume 5 ⁇ L.
  • Characteristic dissolution test method The powder samples were ground and passed through 100-mesh and 200-mesh sieves, respectively, and the particle size of the powder was controlled at 75-150 ⁇ m. Weigh 100 mg of the powder and press it for 10 s at a pressure of 1 MPa to make a round tablet with a diameter of 5 mm, seal one side with solid wax and expose the other side, and place it in 500 mL of dissolution medium. Add 1 mL of solution, filter through a 0.45 ⁇ m microporous membrane, monitor the concentration of the solution at each time point with high performance liquid chromatography, and finally obtain the characteristic dissolution curve of each sample.
  • Dissolution medium 0.01N hydrochloric acid solution
  • Dissolution temperature 37 ⁇ 0.5°C
  • Chromatographic column Inertsil ODS C18 column (4.6mm ⁇ 150mm, 5 ⁇ m);
  • UV detection wavelength 330nm
  • Injection volume 20 ⁇ L.
  • the co-crystal of axitinib and glutaric acid provided by the invention can be used for preparing medicines for preventing and/or treating cancer and other vascular proliferation diseases, and has broad application prospects.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des cocristaux d'axitinib et d'acide glutarique, et leur procédé de préparation. Dans les cocristaux d'axitinib et d'acide glutarique, le rapport molaire entre l'axitinib et l'acide glutarique est de 1 : 1. Le procédé de préparation des co-cristaux d'axitinib et d'acide glutarique a une technologie simple, un procédé de cristallisation facile à commander et une bonne reproductibilité, et est approprié pour une production industrielle. Les co-cristaux d'axitinib et d'acide glutarique, par comparaison avec l'axitinib, ont une solubilité apparente supérieure et une vitesse de dissolution plus rapide, et facilitent l'amélioration de la biodisponibilité orale d'axitinib.
PCT/CN2020/099269 2020-06-30 2020-06-30 Cocristaux d'axitinib et d'acide glutarique, et leur procédé de préparation WO2022000265A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113943271A (zh) * 2020-07-15 2022-01-18 鲁南制药集团股份有限公司 一种阿昔替尼晶型及其制备方法
CN114685434A (zh) * 2020-12-28 2022-07-01 鲁南制药集团股份有限公司 一种阿昔替尼与戊二酸共晶

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CN110283052A (zh) * 2019-07-19 2019-09-27 黄泳华 由白藜芦醇与蛋白激酶抑制剂构成的共晶复合物以及含有该共晶复合物的组合物

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113943271A (zh) * 2020-07-15 2022-01-18 鲁南制药集团股份有限公司 一种阿昔替尼晶型及其制备方法
CN113943271B (zh) * 2020-07-15 2023-11-14 鲁南制药集团股份有限公司 一种阿昔替尼晶型及其制备方法
CN114685434A (zh) * 2020-12-28 2022-07-01 鲁南制药集团股份有限公司 一种阿昔替尼与戊二酸共晶
CN114685434B (zh) * 2020-12-28 2023-06-16 鲁南制药集团股份有限公司 一种阿昔替尼与戊二酸共晶

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