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WO2022000265A1 - 一种阿西替尼与戊二酸共晶及其制备方法 - Google Patents

一种阿西替尼与戊二酸共晶及其制备方法 Download PDF

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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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French (fr)
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陈嘉媚
任伯颖
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Tianjin University of Technology
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Tianjin University of Technology
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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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Abstract

本发明公开了一种阿西替尼与戊二酸共晶及其制备方法。这种阿西替尼与戊二酸共晶中，阿西替尼与戊二酸的摩尔比为1:1。这种阿西替尼与戊二酸共晶的制备方法工艺简单，结晶过程易于控制，重现性好，适用于工业化生产。该阿西替尼与戊二酸共晶较阿昔替尼具有较大的表观溶解度和较快的溶出速率，有利于提高阿昔替尼的口服生物利用度。

Description

一种阿西替尼与戊二酸共晶及其制备方法 技术领域
本发明涉及医药化学技术领域，特别是涉及一种阿西替尼与戊二酸共晶及其制备方法。
背景技术
药物活性成分通常以结晶形式存在，如多晶型、水合物、溶剂化物、盐和共晶等。对同一种药物活性成分而言，不同的结晶形式具有不同的理化性质。因此，在制药行业中，获得适宜的药物结晶形式具有重要意义。药物以共晶的形式存在，可在提高药物活性成分的稳定性、溶解性和加工性等方面具有显著的优势。所以，药物共晶是一种改善药物活性成分理化性质的有效手段。
阿西替尼(Axitinib)的化学名称为N-甲基-2-[[3-[(1E)-2-(2-吡啶基)乙烯基]-1H-吲唑-6-基]硫基]苯甲酰胺，其化学结构式为：
Figure PCTCN2020099269-appb-000001
阿西替尼是第二代VEGFR抑制剂，可以选择性抑制血管内皮生长因子VEGF-1、VEGF-2、VEGF-3受体活性发挥抗癌作用。该药由Pfizer公司研发，商品名为
Figure PCTCN2020099269-appb-000002
2012年1月27日获得FDA批准用于早期至晚期肾癌的治疗，同年9月获得EMA批准其在欧洲上市。目前，该药物在多个国家被用于治疗晚期肾细胞癌。Pfizer公司对阿昔替尼构筑了严密的晶型专利壁垒。包括专利US20060094763公开了阿昔替尼的晶型I、II、III、IV、VI、VII、VIII等多种晶型；专利CN 103626739公开了阿昔替尼的晶型XXV、XVI、XLI、IX、XII、XV等多种晶型。现在国内使用的阿昔替尼均为进口，价格昂贵，一般患者难以承受，使其临床应用受到限制。此外，阿西替尼是BCS II类药物，水溶性很差，限制了它的口服生物利用度。因此，为了突破原研药厂的晶型专利，并改善其溶出性质，我们开展了阿昔替尼的共晶研究。
发明内容
本发明的目的之一在于提供一种阿昔替尼与戊二酸共晶；本发明的目的之二在于提供这种阿昔替尼与戊二酸共晶的制备方法；本发明的目的之三在于提供这种阿昔替尼与戊二酸共 晶的应用。
本发明人经过大量的试验研究，尝试过将阿昔替尼与多种二元羧酸化合物的共晶筛选实验，包括丁二酸、戊二酸、己二酸、庚二酸等。最终成功发现了一种阿昔替尼与戊二酸的共晶，可以有效改善阿昔替尼的溶出性质，为提高阿昔替尼的口服生物利用度提供物质基础。
本发明所采取的技术方案是：
本发明提供了一种阿昔替尼与戊二酸共晶。
一种阿昔替尼与戊二酸共晶共晶，该共晶的结构式如式(Ⅰ)所示：
Figure PCTCN2020099269-appb-000003
这种共晶中，阿昔替尼与戊二酸的摩尔比为1:1；这种共晶以Cu Kα射线测得的X射线粉末衍射图谱在衍射角度2θ为7.7±0.2°、12.8±0.2°、14.1±0.2°、15.4±0.2°、17.3±0.2°、19.2±0.2°、21.4±0.2°、25.5±0.2°处具有特征峰。
优选的，这种阿昔替尼与戊二酸共晶的X射线粉末衍射图谱还在衍射角度2θ为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°、24.7±0.2°中的一处或多处具有特征峰。
本发明提供了这种阿昔替尼与戊二酸共晶的制备方法。
一种阿西替尼与戊二酸共晶的制备方法，包括如下步骤：将阿西替尼与戊二酸按照摩尔比1：1投料，加入适量溶剂，然后通过搅拌或研磨得到共晶。
优选的，这种共晶的制备方法中，溶剂为醇类溶剂、酯类溶剂、酮类溶剂、醚类溶剂、腈类溶剂、烷烃类溶剂中的至少一种。其中，醇类溶剂包括但不限于甲醇、乙醇、异丙醇；酯类溶剂包括但不限于乙酸甲酯、乙酸乙酯、乙酸异丙酯、甲酸乙酯；酮类溶剂包括但不限于丙酮；醚类溶剂包括但不限于乙醚、异丙醚、四氢呋喃；腈类溶剂包括但不限于乙腈；烷烃类溶剂包括但不限于正己烷、正庚烷、环己烷；进一步优选的，溶剂选自甲醇、乙醇、异丙醇、乙酸乙酯、乙腈、丙酮、异丙醚、四氢呋喃、正庚烷中的一种或多种。
优选的，这种共晶的制备方法中，搅拌时阿西替尼与戊二酸的总质量与溶剂的用量比为1g：(2～20)mL；研磨时阿西替尼与戊二酸的总质量与溶剂的用量比为1g：(20～200)uL。
在本发明一些优选的实施方式中，这种共晶的制备方法具体是：将阿西替尼与戊二酸按照摩尔比1：1投料，加入溶剂后搅拌，过滤，将所得的固体产物干燥，得到共晶。
在本发明另一些优选的实施方式中，这种共晶的制备方法具体是：将阿西替尼与戊二酸按照摩尔比1：1投料，加入溶剂后研磨，得到共晶。
优选的，这种共晶的制备方法中，搅拌时阿西替尼与戊二酸的总质量与溶剂的用量比为1g：(4～20)mL。
优选的，这种共晶的制备方法中，研磨时阿西替尼与戊二酸的总质量与溶剂的用量比为1g：(100～200)uL。
本发明提供了一种药物组合物，这种药物组合物，包括这种阿西替尼与戊二酸共晶和药学上可接受的赋形剂。
本发明中，药学上可接受的赋形剂是指与给药剂型或药物组合物一致性相关的药学上可接受的材料、混合物或溶媒。合适的药学上可接受的赋形剂会依所选具体剂型而不同。此外，可根据它们在组合物中的特定功能来选择药学上可接受的赋形剂。
优选的，药学上可接受的赋形剂包括以下类型的赋形剂：稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、造粒剂、包衣剂、润湿剂、溶剂、共溶剂、助悬剂、乳化剂、甜味剂、矫味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、塑化剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。
本发明还提供了这种阿西替尼与戊二酸共晶在制备预防和/或治疗癌症及其他血管增生类疾病的药物中的应用。
本发明的有益效果是：
本发明首次将阿昔替尼转化为一种全新的阿西替尼与戊二酸共晶，该阿西替尼与戊二酸共晶较阿昔替尼具有较快的溶出速率和较大的表观溶解度，为提高阿昔替尼的口服生物利用度提供物质基础。
本发明公开的阿西替尼与戊二酸共晶的制备方法工艺简单，结晶过程易于控制，重现性好，适用于工业化生产。
本发明这种阿西替尼与戊二酸共晶在制备预防和/或治疗癌症及其他血管增生类疾病的药物中具有广阔的应用前景。
附图说明
图1是阿西替尼与戊二酸共晶的X射线粉末衍射图；
图2是阿西替尼与戊二酸共晶的差示扫描量热分析图；
图3是阿西替尼与戊二酸共晶的热失重分析图；
图4是阿西替尼与戊二酸共晶的傅里叶变换红外谱图；
图5是阿西替尼与戊二酸共晶的核磁共振氢谱图；
图6是阿西替尼晶型IV、阿西替尼与戊二酸共晶的粉末溶出曲线图；
图7是阿西替尼晶型IV、阿西替尼与戊二酸共晶的特性溶出曲线图。
具体实施方式
以下通过具体的实施例对本发明的内容作进一步详细的说明。实施例中所用的原料如无特殊说明，均可从常规商业途径得到。
实施例1
称取386mg阿西替尼与132mg戊二酸，加入10mL正庚烷和50μL乙醇中得混悬液，将该混悬液置于室温搅拌4h，过滤，所得白色固体在40℃干燥，获得阿西替尼和戊二酸共晶的固体样品，产率为92.5％。
实施例2
称取38.6mg阿西替尼与13.2mg戊二酸，加入1mL正庚烷和10μL丙酮得混悬液，将该混悬液置于室温搅拌24h，过滤，所得白色固体在40℃干燥，获得阿西替尼和戊二酸共晶的固体样品。
实施例3
称取38.6mg阿西替尼与13.2mg戊二酸，加入1mL苯甲醚得混悬液，将该混悬液置于室温搅拌24h，过滤，所得白色固体在40℃干燥，获得阿西替尼和戊二酸共晶的固体样品。
实施例4
称取38.6mg阿西替尼与13.2mg戊二酸，加入1mL正庚烷和10μL乙醇得混悬液，将该混悬液置于室温搅拌4h，过滤，所得白色固体在40℃干燥，获得阿西替尼和戊二酸共晶的固体样品。
实施例5
称取38.6mg阿西替尼与13.2mg戊二酸，加入1mL正庚烷和10μL乙酸乙酯得混悬液，将该混悬液置于室温搅拌24h，过滤，所得白色固体在40℃干燥，获得阿西替尼和戊二酸共晶的固体样品。
实施例6
称取38.6mg阿西替尼与13.2mg戊二酸，加入1mL乙醚得混悬液，将该混悬液置于室温搅拌24h，过滤，所得白色固体在40℃干燥，获得阿西替尼和戊二酸共晶的固体样品。
实施例7
称取38.6mg阿西替尼与13.2mg戊二酸，加入1mL甲基叔丁基醚得混悬液，将该混悬液置于室温搅拌24h，过滤，所得白色固体在40℃干燥，获得阿西替尼和戊二酸共晶的固体样品。
实施例8
称取38.6mg阿西替尼与13.2mg戊二酸，加入1mL异丙醚得混悬液，将该混悬液置于室温搅拌24h，过滤，所得白色固体在40℃干燥，获得阿西替尼和戊二酸共晶的固体样品。
实施例9
称取154.4mg阿西替尼与52.8mg戊二酸，加入1mL正庚烷和10μL乙醇中得混悬液，将该混悬液置于室温搅拌24h，过滤，所得白色固体在40℃干燥，获得阿西替尼和戊二酸共晶的固体样品，产率为92.5％。
实施例10
称取38.6mg阿西替尼与13.2mg戊二酸，加入球磨罐中，然后加入10μL丙酮，在20Hz频率下研磨30min，所得白色固体在40℃干燥，获得阿西替尼与戊二酸共晶的固体样品。
实施例11
称取38.6mg阿西替尼与13.2mg戊二酸，加入球磨罐中，然后加入10μL乙酸甲酯，在20Hz频率下研磨30min，所得白色固体在40℃干燥，获得阿西替尼与戊二酸共晶的固体样品。
实施例12
称取38.6mg阿西替尼与13.2mg戊二酸，加入球磨罐中，然后加入10μL甲醇，在20Hz频率下研磨30min，所得白色固体在40℃干燥，获得阿西替尼与戊二酸共晶的固体样品。
实施例13
称取38.6mg阿西替尼与13.2mg戊二酸，加入球磨罐中，然后加入10μL乙腈，在20Hz频率下研磨30min，所得白色固体在40℃干燥，获得阿西替尼与戊二酸共晶的固体样品。
实施例14
称取38.6mg阿西替尼与13.2mg戊二酸，加入球磨罐中，然后加入10μL乙醚，在20Hz频率下研磨30min，所得白色固体在40℃干燥，获得阿西替尼与戊二酸共晶的固体样品。
实施例15
称取38.6mg阿西替尼与13.2mg戊二酸，加入球磨罐中，然后加入10μL异丙醚，在20Hz频率下研磨30min，所得白色固体在40℃干燥，获得阿西替尼与戊二酸共晶的固体样品。
实施例16
称取38.6mg阿西替尼与13.2mg戊二酸，加入球磨罐中，然后加入10μL正己烷，在20Hz频率下研磨30min，所得白色固体在40℃干燥，获得阿西替尼与戊二酸共晶的固体样品。
表征分析
本发明提供的一种阿西替尼与戊二酸共晶，通过X射线粉末衍射(XRPD)、差示扫描量热(DSC)分析、热失重(TG)分析、傅里叶变换红外光谱(FTIR)、核磁共振氢谱(HNMR)等方法表征。
对实施例1制得的阿西替尼与戊二酸共晶的固体样品进行X射线粉末衍射分析，其采用日本理学有限公司Rigaku Mini Flex 600型的衍射仪，Cu Kα射线，电压为40千伏，电流为15毫安，步长0.01°，扫描速度20°/min，扫描范围5.0～40.0°，测试温度为室温。其分析结果见附图1的X射线粉末衍射(XRPD)图，X射线粉末衍射数据如表1所示。
表1 实施例1的阿西替尼与戊二酸共晶X射线粉末衍射数据
Figure PCTCN2020099269-appb-000004
基于与实施例1相同的X射线粉末衍射测试方法，实施例2制得的阿西替尼与戊二酸共晶的固体样品的X射线粉末衍射数据如表2所示。
表2 实施例2的阿西替尼与戊二酸共晶X射线粉末衍射数据
Figure PCTCN2020099269-appb-000005
Figure PCTCN2020099269-appb-000006
基于与实施例1相同的X射线粉末衍射测试方法，实施例3制得的阿西替尼与戊二酸共晶的固体样品的X射线粉末衍射数据如表3所示。
表3 实施例3的阿西替尼与戊二酸共晶X射线粉末衍射数据
Figure PCTCN2020099269-appb-000007
本领域技术人员公知，结晶物质可以用X射线衍射技术表征，但是X射线衍射图通常会随着仪器的测试条件而有所改变。特别需要指出的是，X射线衍射图的相对强度可能随着实验条件的变化而变化，所以X射线衍射峰的相对强度顺序不能作为结晶物质表征的唯一或决定性因素。另外，峰角度通常允许有±0.2°的误差，由于样品高度、测试温度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明所述的阿西替尼与戊二酸共晶的X射线衍射图不必和本实施例中的X射线衍射图完全一致，任何具有和这个图谱中的特征峰相同或相似的情况均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知物质的图谱相比较，以证实未知物质是或不是本发明所述的阿西替尼与戊二酸共晶。
对实施例1制得的阿西替尼与戊二酸共晶的固体样品进行差示扫描量热分析，其采用德国耐驰科学仪器有限公司DSC 214型差示量热仪检测，气氛为氮气，升温速率为10℃/min。其分析结果见附图2的差示扫描量热(DSC)分析图。DSC曲线显示，阿西替尼与戊二酸共晶在热分解之前未发现明显的吸热或放热现象。
对实施例1制得的阿西替尼与戊二酸共晶的固体样品进行热失重分析，其采用德国耐驰科学仪器有限公司TG209F3型热重分析仪，气氛为氮气，升温速率为10℃/min。其分析结果见附图3的热失重(TG)分析图。TG曲线显示，阿西替尼与戊二酸共晶被加热至170℃附近开始分解，并且在此温度之前无重量损失。从170℃至500℃加热过程中呈现多阶失重现象。
对实施例1制得的阿西替尼与戊二酸共晶样品进行红外光谱分析，其采用Bruker公司的ALPHA II傅里叶变换红外光谱仪检测，检测范围为4000～500cm -1，其分析结果见附图4的傅里叶变换红外(FTIR)谱图。从图4中可以看出，其红外光谱特征峰位置为(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。
对实施例1制得的阿西替尼与戊二酸共晶样品进行核磁共振氢谱分析，采用德国Bruker公司Avance III 400M核磁共振波谱仪检测，其分析结果见附图5的核磁共振氢谱( 1HNMR)谱图。从图5中可以看出，阿西替尼的峰为： 1HNMR(400MHz,DMSO)δ13.38(s,1H),8.61(d,J＝4.0Hz,1H),8.43(d,J＝4.6Hz,1H),8.22(d,J＝8.5Hz,1H),7.96(d,J＝16.4Hz,1H),7.82(td,J＝7.7,1.7Hz,1H),7.67(d,J＝7.8Hz,1H),7.6(m,1H),7.50(dd,J＝7.3,1.6Hz,2H),7.30(m,J＝14.8,7.4,2.5Hz,3H),7.19(d,J＝8.5Hz,1H),7.10(m,1H),2.78(d,J＝4.6Hz,3H)。戊二酸的 峰为： 1HNMR(400MHz,d 6-DMSO)δ12.11(s,2H),2.24(t,J＝7.4Hz,4H),1.70(p,J＝7.4Hz,2H)。根据特征峰的积分结果可知，阿西替尼与戊二酸共晶中阿西替尼和戊二酸的化学计量比为1：1。
溶解性评价
将阿西替尼与戊二酸共晶与阿昔替尼的药用晶型IV的粉末溶出数据和特性溶出数据进行对比研究。
受试样品来源：阿西替尼与戊二酸共晶由本发明实施例1提供的方法制备；阿昔替尼晶型IV购买于上海升德医药科技有限公司，纯度99％。
粉末溶出实验方法：将阿西替尼与戊二酸共晶及阿昔替尼晶型IV研磨后分别过100和200目筛，控制粉末粒径在75～150μm。分别称量100mg阿西替尼晶型IV，134.2mg阿西替尼与戊二酸共晶，加入15mL溶出介质中，每隔一段时间取0.2mL溶液，经0.45μm微孔滤膜过滤，并稀释到适当倍数，用高效液相色谱监测各个时间点的溶液浓度，最终得到各样品的粉末溶出曲线。
粉末溶出条件：
溶出介质：0.01N的盐酸溶液；
搅拌速度：50转/分钟；
溶出温度：37±0.5℃；
取样时间：0.5，1，2，5，10，20，40，60，120，240分钟；
液相条件：
仪器：SHIMADZU LC-2030C 3D；
色谱柱：Inertsil ODS C18柱(4.6mm×150mm，5μm)；
紫外检测波长：330nm；
流动相：乙腈:0.03M pH 4.6乙酸钠-乙酸溶液＝40:60；
柱温：40℃；
流速：0.8mL/min；
进样量：5μL。
特性溶出实验方法：将粉末样品研磨后分别过100和200目筛，控制粉末粒径在75～150μm。分别称量100mg粉末以1MPa的压力压制10s，制成直径为5mm的圆形片剂，将一面用固体蜡封口，另一面暴露在外，置于500mL溶出介质中，每隔一段时间取样1mL，再补液1mL，经0.45μm微孔滤膜过滤，用高效液相色谱监测各个时间点的溶液浓度，最终得到各样品的特 性溶出曲线。
特性溶出条件：
溶出介质：0.01N的盐酸溶液；
搅拌速度：100转/分钟；
溶出温度：37±0.5℃；
取样时间：5，10，15，20，25，30分钟；
液相条件：
仪器：SHIMADZU LC-2030C 3D；
色谱柱：Inertsil ODS C18柱(4.6mm×150mm，5μm)；
紫外检测波长：330nm；
流动相：乙腈:0.03M pH 4.6乙酸钠-乙酸溶液＝40:60；
柱温：40℃；
流速：0.8mL/min；
进样量：20μL。
实验结果见附图6的粉末溶出曲线图和附图7的特性溶出曲线。如图6所示，阿昔替尼晶型IV和阿西替尼与戊二酸共晶的最大表观溶解度分别为276.1±40.54μg/mL和919.4±144.1μg/mL，共晶相比阿昔替尼晶型IV提高了3.3倍。如图7所示，阿昔替尼晶型IV和阿西替尼与戊二酸共晶在30分钟内的特性溶出速率分别为0.0098mg·cm -2·min -1和0.0579mg·cm -2·min -1，共晶比阿昔替尼晶型IV提高了5.9倍。
本发明提供的这种阿西替尼与戊二酸共晶可应用于制备预防和/或治疗癌症及其他血管增生类疾病的药物，具有广阔的应用前景。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (8)

  1. 一种阿西替尼与戊二酸共晶，其特征在于：所述共晶的结构式如式(Ⅰ)所示：
    Figure PCTCN2020099269-appb-100001
    所述共晶中，阿西替尼与戊二酸的摩尔比为1:1；所述共晶以Cu Kα射线测得的X射线粉末衍射图谱在衍射角度2θ为7.7±0.2°、12.8±0.2°、14.1±0.2°、15.4±0.2°、17.3±0.2°、19.2±0.2°、21.4±0.2°、25.5±0.2°处具有特征峰。
  2. 根据权利要求1所述的共晶，其特征在于：所述共晶以Cu Kα射线测得的X射线粉末衍射图谱在衍射角度2θ为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°、24.7±0.2°中的一处或多处具有特征峰。
  3. 一种权利要求1～2中任一项所述共晶的制备方法，其特征在于：包括如下步骤，将阿西替尼与戊二酸按照摩尔比1：1投料，加入适量溶剂，然后通过搅拌或研磨得到共晶。
  4. 根据权利要求3所述的制备方法，其特征在于：所述溶剂为醇类溶剂、酯类溶剂、酮类溶剂、醚类溶剂、腈类溶剂、烷烃类溶剂中的至少一种。
  5. 根据权利要求3所述的制备方法，其特征在于：所述搅拌时，阿西替尼与戊二酸的总质量与溶剂的用量比为1g：(4～20)mL。
  6. 根据权利要求3所述的制备方法，其特征在于：所述研磨时，阿西替尼与戊二酸的总质量与溶剂的用量比为1g：(100～200)uL。
  7. 一种药物组合物，其特征在于：包括权利要求1～2中任一项所述的阿西替尼与戊二酸共晶和药学上可接受的赋形剂。
  8. 权利要求1～2中任一项所述的阿西替尼与戊二酸共晶在制备预防和/或治疗癌症及其他血管增生类疾病的药物中的应用。
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