WO2021213453A1 - 一种甲磺酸仑伐替尼晶型xi及其制备方法 - Google Patents

一种甲磺酸仑伐替尼晶型xi及其制备方法 Download PDF

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WO2021213453A1
WO2021213453A1 PCT/CN2021/088827 CN2021088827W WO2021213453A1 WO 2021213453 A1 WO2021213453 A1 WO 2021213453A1 CN 2021088827 W CN2021088827 W CN 2021088827W WO 2021213453 A1 WO2021213453 A1 WO 2021213453A1
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crystal form
lenvatinib mesylate
ethyl acetate
purified water
lenvatinib
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PCT/CN2021/088827
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English (en)
French (fr)
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谷慧科
先小超
丁哲
王颖
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成都苑东生物制药股份有限公司
四川青木制药有限公司
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Priority to CN202180004022.3A priority Critical patent/CN114174264B/zh
Priority to JP2022529815A priority patent/JP7466642B2/ja
Priority to KR1020227041200A priority patent/KR102581450B1/ko
Publication of WO2021213453A1 publication Critical patent/WO2021213453A1/zh

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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
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the application relates to the field of drug crystal forms, and in particular to a crystal form of lenvatinib mesylate and a preparation method thereof.
  • Lenvatinib chemical name: 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, its structural formula is as follows (I) as shown in the formula.
  • Lenvatinib is a thyroid cancer and liver cancer drug developed by Japan Eisai Co., Ltd.
  • Lenvatinib is an oral multi-receptor tyrosine kinase (RTK) inhibitor with a novel binding mode to its receptor.
  • RTK oral multi-receptor tyrosine kinase
  • VEGF vascular endothelial growth factor
  • Patent CN100569753C, CN101337931B, CN101337932B and CN101337933B disclose crystal forms A, B, C, F, I of lenvatinib mesylate.
  • the non-crystal form B will transform into crystal form C or a mixed crystal with crystal form C under different humidity conditions
  • the crystal form I will also transform into crystal form C or a mixed crystal with crystal form C under different humidity conditions. Therefore, Form B and Form I are not very stable.
  • the purpose of the present invention is to provide a crystal form of lenvatinib mesylate, which solves the problem that the crystal form stability of lenvatinib mesylate in the prior art is not stable, the product quality is unstable, the preparation process is cumbersome, and the scale cannot be scaled. Issues such as chemical production.
  • a crystal form XI of Lenvatinib mesylate its X-ray powder diffraction pattern includes about 5.73° ⁇ 0.2°, 8.03° ⁇ 0.2°, 11.45° ⁇ 0.2°, 12.75° ⁇ 0.2°, 16.15° ⁇ 0.2 °, 17.24° ⁇ 0.2°, 18.16° ⁇ 0.2°, 19.69° ⁇ 0.2°, 20.68° ⁇ 0.2°, 22.15 ⁇ 0.2°, 22.96 ⁇ 0.2°, 23.76 ⁇ 0.2°, 24.32 ⁇ 0.2°, 25.13 ⁇ 0.2° , 26.32 ⁇ 0.2°, 27.00 ⁇ 0.2°, 28.87 ⁇ 0.2°, 29.51 ⁇ 0.2°, 34.90 ⁇ 0.2° diffraction angle (2 ⁇ ).
  • the X-ray powder diffraction pattern of the crystal form XI is basically as shown in FIG. 1.
  • the temperature of the endothermic peak of the differential scanning calorimetry (DSC) of the crystalline form XI is 114.05 ⁇ 5°C and 158.56 ⁇ 5°C, respectively.
  • thermogravimetric analysis (TGA) of the crystalline form XI loses about 6.94% in the range of 30-140°C.
  • the moisture content of the crystalline form XI is 6.5%.
  • the crystal form XI is lenvatinib mesylate dihydrate containing 2 crystal waters.
  • the present invention also provides a preparation method of lenvatinib mesylate crystal form XI, which comprises the following steps:
  • step (3) After the suspension of step (2) is uniformly dispersed, add a certain amount of crystal form XI seed crystals, stir at a temperature of 15-40°C for 4-24 hours, and dry with suction to obtain a solid powder.
  • Lenvatinib Sulfonate Form XI After the suspension of step (2) is uniformly dispersed, add a certain amount of crystal form XI seed crystals, stir at a temperature of 15-40°C for 4-24 hours, and dry with suction to obtain a solid powder. Lenvatinib Sulfonate Form XI.
  • a certain volume ratio of ethyl acetate and purified water is 100 mL: (2-10) mL; further preferably, a certain volume ratio of ethyl acetate and purified water is 100 mL: (2- 5) mL; most preferably 100 mL: 3 mL.
  • the mass-volume ratio of lenvatinib mesylate to ethyl acetate in the mixed solvent of step (1) is 1 g: (10-30) mL; further preferably, methanesulfonic acid
  • the mass-volume ratio of lenvatinib to ethyl acetate in the mixed solvent of step (1) is 1 g: (15-25) mL; most preferably, 1 g: 20 mL.
  • a certain amount of crystal form XI seed crystals are 0-10% by mass of the dosage of lenvatinib mesylate; further preferably, a certain amount of crystal form XI seed crystals are formaldehyde
  • the mass fraction of lenvatinib sulfonate is 2-6%; most preferably 5%.
  • the reaction temperature is 20-30°C; preferably 20-25°C; most preferably 25°C.
  • the stirring time is 6-12h; preferably 6-10h; most preferably 8h.
  • the preparation method of lenvatinib mesylate crystal form XI includes the following steps:
  • step (3) After the suspension of step (2) is uniformly dispersed, the crystal form XI seed crystals are added, and the amount is 5% by mass of the lenvatinib mesylate. Stir at 25°C for 8 hours, and pump The solid powder is obtained by filtration and drying, and the crystal form XI of lenvatinib mesylate is obtained.
  • the lenvatinib mesylate crystal form XI of the present invention has good solubility, good pharmacokinetic characteristics and good stability, and is suitable for preparing pharmaceutical preparations.
  • the lenvatinib mesylate crystal form XI of the present invention can keep the crystal form stable under the conditions of high temperature, high humidity and light.
  • the lenvatinib mesylate crystal form XI of the present invention has good fluidity, good compressibility, high bulk density, low hygroscopicity, and uniform particle size distribution.
  • the lenvatinib mesylate crystal form XI of the present invention has high purity, is not an organic solvate, has no residual risk of organic solvents, and has high safety.
  • the preparation method of lenvatinib mesylate crystalline form XI of the present invention can avoid the use of acetic acid, and the obtained product has high purity, low impurities, high yield, mild process conditions, simple and easy recovery of the solvent system, simple operation and stability Good, it can produce kilogram-level products stably, which is conducive to large-scale industrial production.
  • X-ray powder diffraction (XRD) measurement described in this application is collected by using the Haoyuan DX-2700B powder diffractometer in Dandong, Liaoning, and the specific parameters are as follows:
  • the differential scanning calorimetry (DSC) measurement described in this application is collected by METTLER TOLEDO model DSC-1, the heating rate is 10°C/min, the temperature range is 25-250°C, and the nitrogen purge rate during the test It is 60mL/min.
  • thermogravimetric analysis (TGA) measurement described in this application is collected by METTLER TOLEDO model TGA-2, the heating rate is 10°C/min, the temperature range is 30-250°C, and the nitrogen purge rate during the test is 20mL /min.
  • the dynamic vapor adsorption analysis (DVS) described in this application is collected by TA model Q5000SA, the equilibrium temperature is 25°C, and the specific test parameters are shown in the following table.
  • the moisture described in this application is measured using a Metrohm (Metrohm) model 870KF Titrino plus Kafir moisture meter.
  • UV detector (wavelength 252nm and 205nm)
  • Running time starting from the solvent peak, it is about 2.7 times the retention time of the lenvatinib peak
  • Test solution Take 12.5mg of this product, accurately weigh it, add a solvent to dissolve and dilute to make a solution containing about 0.5mg per 1mL, as the test solution
  • the obtained lenvatinib mesylate crystal form XI was subjected to X-ray powder determination using Cu-ka rays.
  • the obtained XRD spectrum is shown in Figure 1, and the relevant data is shown in Table 2:
  • the error of the 2 ⁇ diffraction angle is ⁇ 0.2°.
  • the obtained crystal form XI of Lenvatinib mesylate was analyzed by DSC. As shown in Figure 2, it has endothermic peaks at 114.05 ⁇ 5°C and 158.56 ⁇ 5°C.
  • the moisture content of the obtained lenvatinib mesylate crystal form XI was measured, and the moisture content was 6.5%.
  • the obtained lenvatinib mesylate crystalline form XI was subjected to ethyl acetate solvent residue determination, and the ethyl acetate solvent residue was 0.068%.
  • the crystal form XI is lenvatinib mesylate dihydrate (theoretical water content 6.44%) containing two crystal waters.
  • Test Example 1 Hygroscopicity test of Lenvatinib mesylate crystal form XI
  • the lenvatinib mesylate crystal form XI prepared in Example 1 was subjected to DVS analysis, as shown in FIG. 4. It can be seen from Figure 4 that the weight loss is about 0.33% in the relative humidity range of 0-40%, indicating that the crystal form is relatively stable, even if the relative humidity drops to 0%, the crystal water will not be lost; the crystal form is at a relative humidity of 40-80% Within the range, the moisture absorption and weight gain are about 0.25%, indicating that the moisture absorption of the crystal form is very small, even if the relative humidity is as high as 80%, the moisture absorption and weight gain are still very small.
  • Example 11 The samples of lenvatinib mesylate crystal form XI prepared in Example 11 were placed under different storage conditions, and the crystal form and impurity stability of the samples were investigated. The samples were taken for 30 days and the purity was tested according to the provided HPLC detection method. As shown in Table 3, the XRD spectrum is shown in Figure 5.
  • the lenvatinib mesylate crystal form XI prepared in Example 11 is stable under high temperature, high humidity, and light conditions, and has good high temperature resistance, high humidity resistance, and light resistance.
  • Test Example 3 Fluidity test of lenvatinib mesylate crystal form XI powder
  • Compression coefficient (%) 100% (tap density-bulk density)/tap density, the larger the compression coefficient, the worse the fluidity of the powder, which is not conducive to the uniform mixing of the powder and affects the tablet die or capsule filling , Which ultimately affects the quality, content uniformity, hardness and disintegration and dissolution of the preparation product.
  • Test Example 4 Pharmacokinetic test of Lenvatinib mesylate crystal form XI in rats
  • Test drug Lenvatinib mesylate crystal form XI prepared in Example 12.
  • test drug was formulated into a uniform suspension of 1.25 mg/kg with corn oil, it was immediately orally administered to the rat at a volume of 4 mL/kg, and was administered before and after 15min, 30min, 1h, 2h, 3h, After 4h, 5h, 6h, 7h, 8h, 24h, 0.1 mL of jugular blood was collected, placed in an EDTA-K2 tube, centrifuged at 3000r/min for 10min, separated from plasma, and stored in a refrigerator at -80°C.
  • the blood drug concentration in each blood sample is analyzed and determined autonomously, and the parameters of the test substance (the time to reach the maximum plasma concentration Tmax, the maximum plasma concentration Cmax, AUClast) are calculated. Based on the obtained parameters, the average value and standard deviation are calculated, and the specific results are shown in Table 5.
  • crystal form XI of the present invention has better absorption in animals, which is beneficial to improve the bioavailability of the drug, thereby enhancing the therapeutic effect of the drug.
  • the lenvatinib mesylate crystal form XI prepared in Example 12 was made into capsules and then added 900ml pH4.0 medium, stirred at 37°C (rotating speed 75r/min), paddle method, at 10min, 15min, 20min, 30min , 45min, 60min, 90min and 120min to take the solution, use ultraviolet-spectrophotometry, measure the absorbance at the wavelength of 250nm, calculate the dissolution of each grain.
  • the experimental results are shown in Table 6 below.

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Abstract

一种甲磺酸仑伐替尼晶型XI及其制备方法,甲磺酸仓伐替尼晶型XI的X射线粉末衍射图如图1所示。甲磺酸仑伐替尼晶型XI有很好的溶解度、较好的药代动力学特性和良好的稳定性，甲磺酸仑伐替尼晶型XI的制备方法工艺条件温和,溶剂体系简单易回收,操作简便,稳定性好。

Description

一种甲磺酸仑伐替尼晶型XI及其制备方法 技术领域
本申请涉及药物晶型领域，具体涉及一种甲磺酸仑伐替尼晶型及其制备方法。
背景技术
仑伐替尼(Lenvatinib)，化学名为：4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺，其结构式如(I)式所示。
Figure PCTCN2021088827-appb-000001
仑伐替尼是由日本卫材株式会社研发的一种甲状腺癌和肝癌药物。仑伐替尼是一种口服多受体酪氨酸激酶(RTK)抑制剂，其与其受体具有新颖的结合模式，除抑制参与肿瘤增殖的其他促血管生成和致癌信号通路相关RTK外，还能够选择性抑制血管内皮生长因子(VEGF)受体的激酶活性。2015年02月13日获得FDA批准，用于放射性碘难治性局部复发或转移的进展性分化型甲状腺癌患者的治疗，之后在欧盟和日本相继获批上市，2018年09月05日获得中国药监局批准，用于治疗既往未接受过全身系统治疗的不可切除的肝癌患者。
专利CN100569753C、CN101337931B、CN101337932B和CN101337933B公开了甲磺酸仑伐替尼的晶型A、B、C、F、I。其中无水晶型B在不同湿度条件下会转变为晶型C或与晶型C的混晶，晶型I在不同湿度条件下亦会转变为晶型C或与晶型C的混晶，因此晶型B和晶型I不太稳定。
综合以上可知，本领域仍需提供一种稳定性好、产品质量更优、制备工艺简便且适于工业化生产的甲磺酸仑伐替尼的晶型及其制备方法。
发明内容
本发明的目的在于提供一种甲磺酸仑伐替尼的晶型，解决现有技术中甲磺酸仑伐替尼的晶型稳定性不好、产品质量不稳定，制备工艺繁琐，不能规模化生产等问题。
为了解决上述的技术问题，本发明的技术方案如下：
一种甲磺酸仑伐替尼晶型XI，其X射线粉末衍射图包括在约5.73°±0.2°，8.03°±0.2°，11.45°±0.2°，12.75°±0.2°，16.15°±0.2°，17.24°±0.2°，18.16°±0.2°，19.69°±0.2°，20.68°±0.2°，22.15±0.2°，22.96±0.2°，23.76±0.2°，24.32±0.2°，25.13±0.2°，26.32±0.2°，27.00±0.2°，28.87±0.2°，29.51±0.2°，34.90±0.2°的衍射角(2θ)处的峰。
优选地，所述的晶型XI的X射线粉末衍射图基本如图1所示。
优选地，所述的晶型XI的差示扫描量热法(DSC)的吸热峰的温度分别为114.05±5℃和158.56±5℃。
优选地，所述的晶型XI的热重分析法(TGA)在30-140℃范围内失重约6.94％。
优选地，所述的晶型XI水分含量为6.5％。
优选地，所述的晶型XI为含有2个结晶水的甲磺酸仑伐替尼二水合物。
本发明还提供所述的甲磺酸仑伐替尼晶型XI的制备方法，包括以下步骤：
(1)将乙酸乙酯和纯化水在室温下以一定体积比搅拌混合均匀；
(2)将甲磺酸仑伐替尼加至步骤(1)的混合溶剂中；
(3)待步骤(2)的混悬液分散均匀后，加入一定量晶型XI的晶种，于温度15-40℃下搅拌4-24h，抽滤干燥得固体粉末，即得所述甲磺酸仑伐替尼晶型XI。
优选地，在步骤(1)中，乙酸乙酯和纯化水的一定体积比为100mL：(2-10)mL；进一步优选地，乙酸乙酯和纯化水的一定体积比为100mL：(2-5)mL；最优选为100mL：3mL。
优选地，在步骤(2)中，甲磺酸仑伐替尼与步骤(1)混合溶剂中的乙酸乙酯的质量体积比为1g：(10-30)mL；进一步优选地，甲磺酸仑伐替尼与步骤(1)混合溶剂中的乙酸乙酯的质量体积比为1g：(15-25)mL；最优选为1g：20mL。
优选地，在步骤(3)中，一定量晶型XI的晶种为甲磺酸仑伐替尼投料量的0-10％质量分数；进一步优选地，一定量晶型XI的晶种为甲磺酸仑伐替尼投料2-6％质量分数；最优选为5％。
优选地，反应温度为20-30℃；优选为20-25℃；最优选为25℃。
优选地，搅拌时间为6-12h；优选6-10h；最优选为8h。
进一步优选地，所述的甲磺酸仑伐替尼晶型XI的制备方法，包括以下步骤：
(1)将乙酸乙酯和纯化水在室温下搅拌混合均匀，其中乙酸乙酯和纯化水的体积比为100mL：3mL；
(2)将甲磺酸仑伐替尼加至步骤(1)的混合溶剂中，甲磺酸仑伐替尼与乙酸乙酯的质量体积比为1g：20mL；
(3)待步骤(2)的混悬液分散均匀后，加入晶型XI的晶种，其用量为甲磺酸仑伐替尼投料量的5％质量分数，于25℃下搅拌8h，抽滤干燥得固体粉末，即得所述甲磺酸仑伐替尼晶型XI。
采用本发明制备的甲磺酸仑伐替尼晶型XI具有以下优势：
1、本发明的甲磺酸仑伐替尼晶型XI有很好的溶解度、较好的药代动力学特性和良好的稳定性，适合制备药物制剂。
2、本发明的甲磺酸仑伐替尼晶型XI在放置高温、高湿、光照条件下能够保持晶型稳定。
3、本发明的甲磺酸仑伐替尼晶型XI流动性好，可压缩性好，堆密度大，吸湿性低，粒度分布均匀。
4、本发明的甲磺酸仑伐替尼晶型XI纯度高，不是有机溶剂化物，无有机溶剂残留风险，安全性高。
5、本发明的甲磺酸仑伐替尼晶型XI的制备方法可以避免使用醋酸，所得产品纯度高，杂质低，收率高，工艺条件温和，溶剂体系简单易回收，操作简便，稳定性好，可稳定的制备公斤级的产品，有利于大规模产业化生产。
附图说明
图1实施例1甲磺酸仑伐替尼晶型XI的XRD图谱
图2实施例1甲磺酸仑伐替尼晶型XI的DSC图谱
图3实施例1甲磺酸仑伐替尼晶型XI的TGA图谱
图4实施例1甲磺酸仑伐替尼晶型XI的DVS图谱
图5实施例11甲磺酸仑伐替尼晶型XI在不同放置条件下XRD对比图谱
具体实施方式
以下将结合实施例对本申请作进一步的详细描述，本申请的实施例仅用于说明本申请的技术方案，并非限制本申请的实质和范围。
本申请中所用到的缩写的解释如下：
XRD：X射线粉末衍射
本申请所述的X射线粉末衍射(XRD)的测定是采用辽宁丹东浩元DX-2700B粉末衍射仪进行采集，具体参数如下表：
Figure PCTCN2021088827-appb-000002
DSC：差式扫描量热仪
本申请所述的差式扫描量热(DSC)的测定是采用METTLER TOLEDO型号DSC-1进行采集，升温速率为10℃/min，温度范围为25-250℃，测试过程中的氮气吹扫速率是60mL/min。
TGA：热重分析仪
本申请所述的热重分析(TGA)的测定是采用METTLER TOLEDO型号TGA-2进行采集，升温速率为10℃/min，温度范围为30-250℃，测试过程中的氮气吹扫速率是20mL/min。
DVS：动态蒸气吸附分析仪
本申请所述的动态蒸气吸附分析(DVS)的测定是采用TA型号Q5000SA进行采集，平衡温度是25℃，具体的测试参数如下表所示。
Figure PCTCN2021088827-appb-000003
Figure PCTCN2021088827-appb-000004
KF：卡氏水分测定仪
本申请所述的水分采用Metrohm(瑞士万通)型号870KF Titrino plus的卡氏水分仪进行测定。
GC：气相色谱仪
本申请所述的溶剂残留采用安捷伦公司型号7890B的气相色谱仪进行测定，具体参数如下表所示。
平衡温度 110℃ 检测器温度 250℃
定量环 120℃ 空气流量 400mL/min
传输线 130℃ 氢气流量 30mL/min
平衡时间 30miN 辅助气流量 25mL/min
GC循环时间 42min 载气(氮气)流量 1.5mL/min
顶空瓶 20mL 进样口温度 180℃
分流比 1:1 进样/运行时间 0.5/34min
HPLC：高效液相色谱
HPLC谱图的测定采用安捷伦Agilent1260DAD型液相色谱仪进行。本申请中，甲磺酸仑伐替尼HPLC纯度用以下方法进行：
(1)以十八烷基硅烷键合硅胶为填充剂的色谱柱
(2)检测器：紫外检测器(波长252nm和205nm)
(3)流速：每分钟1mL
(4)运行时间：从溶剂峰开始计时，约为仑伐替尼峰保留时间的2.7倍
(5)供试品溶液：取本品12.5mg，精密称定，加溶剂溶解稀释制成每1mL约含0.5mg的溶液，作为供试品溶液
(6)进样量：10μl，通过自动积分法测定供试品溶液，按峰面积计算供试 品中仑伐替尼的纯度。
溶剂筛选实验
为了发现甲磺酸仑伐替尼的新晶型，发明人通过将一定量的甲磺酸仑伐替尼混悬于反应溶剂中，于25℃下搅拌6-8h，抽滤干燥的方法筛选新晶型。
在筛选反应溶剂时惊喜地发现，当反应溶剂为乙酸乙酯和水的混合溶剂时，能得到一种新的甲磺酸仑伐替尼晶型XI，结果如下表1所示。
表1不同溶剂体系制备晶型XI的实验结果
溶剂体系 晶型
甲醇 晶型A
乙醇 晶型A
丙酮 晶型A
乙腈 晶型A
乙酸乙酯 晶型C
乙醇和水 晶型A
丙酮和水 晶型A
乙酸乙酯：水＝100mL：15mL 胶状物
乙酸乙酯：水＝100mL：10mL 晶型XI
乙酸乙酯：水＝100mL：5mL 晶型XI
乙酸乙酯：水＝100mL：3mL 晶型XI
乙酸乙酯：水＝100mL：2mL 晶型XI
乙酸乙酯：水＝100mL：1mL 溶剂化物
由上表1可知，当使用纯的有机溶剂作为反应溶剂时，如甲醇、乙醇、丙酮等，所得产品为晶型A或晶型C；当使用其他混合溶剂作为反应溶剂时，如乙醇和水的混合溶剂时，所得产品为晶型A；由表1可以看出当乙酸乙酯和水的体积比为100mL：(2-10)mL才能制备得到晶型XI，其效果最好，方法最稳定。
实施例1：甲磺酸仑伐替尼晶型XI的制备
将200mL乙酸乙酯和10mL纯化水在室温下搅拌混合均匀，然后将10.0g甲磺酸仑伐替尼加至乙酸乙酯与纯化水的混合溶剂中，待混悬液分散均匀后，于 25℃搅拌24h，抽滤干燥得固体粉末9.1g。收率91.0％，纯度为99.73％。
1H-NMR数据如下：
1H NMR(400MHz,d 6-DMSO)δ9.00(d,J＝6.5Hz,1H),8.72(s,1H),8.36(d,J＝9.1Hz,1H),8.09(s,1H),7.95(d,J＝24.3Hz,2H),7.68(s,1H),7.66(d,J＝2.8Hz,1H),7.37(dd,J＝9.1,2.8Hz,1H),7.28(d,J＝2.4Hz,1H),6.97(d,J＝6.6Hz,1H),4.10(s,3H),2.58(m,1H),2.40(s,3H),0.64-0.70(m,2H),0.56–0.30(m,2H).
对所获得的甲磺酸仑伐替尼晶型XI使用Cu-ka射线进行X射线粉末测定，所得XRD谱图如图1所示，相关的数据如表2所示：
表2
Figure PCTCN2021088827-appb-000005
Figure PCTCN2021088827-appb-000006
其中，2θ衍射角的误差为±0.2°。
对所获得的甲磺酸仑伐替尼晶型XI进行DSC分析，如图2所示，其在114.05±5℃和158.56±5℃有吸热峰。
对所获得的甲磺酸仑伐替尼晶型XI进行TGA分析，如图3所示，其在30-140℃范围内失重约6.94％。
对所获得的甲磺酸仑伐替尼晶型XI进行水分测定，其水分含量为6.5％。
对所获得的甲磺酸仑伐替尼晶型XI进行乙酸乙酯溶剂残留测定，其乙酸乙酯溶剂残留为0.068％。
结合TGA失重量、水分以及溶残数据可知，晶型XI为含有2个结晶水的甲磺酸仑伐替尼二水合物(理论含水量6.44％)。
实施例2：甲磺酸仑伐替尼晶型XI的制备
将200mL乙酸乙酯和4mL纯化水在室温下搅拌混合均匀，然后将10.0g甲磺酸仑伐替尼加至乙酸乙酯与纯化水的混合溶剂中，待混悬液分散均匀后，加入0.3g晶型XI的晶种，然后于25℃搅拌8h，抽滤干燥得固体粉末9.2g。收率92.0％，纯度为99.77％，其XRD数据与实施例1数据基本保持一致。
实施例3：甲磺酸仑伐替尼晶型XI的制备
将2000mL乙酸乙酯和60mL纯化水在室温下搅拌混合均匀，然后将100.0g甲磺酸仑伐替尼加至乙酸乙酯与纯化水的混合溶剂中，待混悬液分散均匀后，加入5.0g晶型XI的晶种，然后于25℃搅拌8h，抽滤干燥得固体粉末93.0g。收率93.0％，纯度为99.76％，其XRD数据与实施例1数据基本保持一致。
实施例4：甲磺酸仑伐替尼晶型XI的制备
将200mL乙酸乙酯和20mL纯化水在室温下搅拌混合均匀，然后将10.0g甲磺酸仑伐替尼加至乙酸乙酯与纯化水的混合溶剂中，待混悬液分散均匀后，加入1.0g晶型XI的晶种，然后于20℃搅拌8h，抽滤干燥得固体粉末9.2g。收率92.0％，纯度为99.75％，其XRD数据与实施例1数据基本保持一致。
实施例5：甲磺酸仑伐替尼晶型XI的制备
将100mL乙酸乙酯和2mL纯化水在室温下搅拌混合均匀，然后将10.0g甲磺酸仑伐替尼加至乙酸乙酯与纯化水的混合溶剂中，待混悬液分散均匀后，加入0.5g晶型XI的晶种，然后于15℃搅拌8h，抽滤干燥得固体粉末9.3g。收率93.0％，纯度为99.73％，其XRD数据与实施例1数据基本保持一致。
实施例6：甲磺酸仑伐替尼晶型XI的制备
将100mL乙酸乙酯和10mL纯化水在室温下搅拌混合均匀，然后将10.0g甲磺酸仑伐替尼加至乙酸乙酯与纯化水的混合溶剂中，待混悬液分散均匀后，加入0.5g晶型XI的晶种，然后于30℃搅拌8h，抽滤干燥得固体粉末9.1g。收率91.0％，纯度为99.71％，其XRD数据与实施例1数据基本保持一致。
实施例7：甲磺酸仑伐替尼晶型XI的制备
将300mL乙酸乙酯和6mL纯化水在室温下搅拌混合均匀，然后将10.0g甲磺酸仑伐替尼加至乙酸乙酯与纯化水的混合溶剂中，待混悬液分散均匀后，加入0.2g晶型XI的晶种，然后于40℃搅拌4h，抽滤干燥得固体粉末9.0g。收率90.0％，纯度为99.69％，其XRD数据与实施例1数据基本保持一致。
实施例8：甲磺酸仑伐替尼晶型XI的制备
将300mL乙酸乙酯和30mL纯化水在室温下搅拌混合均匀，然后将10.0g甲磺酸仑伐替尼加至乙酸乙酯与纯化水的混合溶剂中，待混悬液分散均匀后，加入0.6g晶型XI的晶种，然后于25℃搅拌8h，抽滤干燥得固体粉末9.1g。收率91.0％，纯度为99.76％，其XRD数据与实施例1数据基本保持一致。
实施例9：甲磺酸仑伐替尼晶型XI的制备
将150mL乙酸乙酯和3mL纯化水在室温下搅拌混合均匀，然后将10.0g甲磺酸仑伐替尼加至乙酸乙酯与纯化水的混合溶剂中，待混悬液分散均匀后，加入0.5g晶型XI的晶种，然后于25℃搅拌6h，抽滤干燥得固体粉末9.2g。收率92.0％，纯度为99.72％，其XRD数据与实施例1数据基本保持一致。
实施例10：甲磺酸仑伐替尼晶型XI的制备
将250mL乙酸乙酯和5mL纯化水在室温下搅拌混合均匀，然后将10.0g甲 磺酸仑伐替尼加至乙酸乙酯与纯化水的混合溶剂中，待混悬液分散均匀后，加入0.5g晶型XI的晶种，然后于25℃搅拌12h，抽滤干燥得固体粉末9.1g。收率91.0％，纯度为99.73％，其XRD数据与实施例1数据基本保持一致。
实施例11：甲磺酸仑伐替尼晶型XI的制备
将5000mL乙酸乙酯和150mL纯化水在室温下搅拌混合均匀，然后将250.0g甲磺酸仑伐替尼加至乙酸乙酯与纯化水的混合溶剂中，待混悬液分散均匀后，加入12.50g晶型XI的晶种，然后于25℃搅拌8h，抽滤干燥得固体粉末232.8g。收率93.1％，纯度为99.78％，其XRD数据与实施例1数据基本保持一致。
实施例12：甲磺酸仑伐替尼晶型XI的制备
将30L乙酸乙酯和750mL纯化水在室温下搅拌混合均匀，然后将1.5kg甲磺酸仑伐替尼加至乙酸乙酯与纯化水的混合溶剂中，保持25℃搅拌10h，抽滤干燥得固体粉末1.4kg。收率93.3％，纯度为99.95％，其XRD数据与实施例1数据基本保持一致。
试验例1：甲磺酸仑伐替尼晶型XI吸湿性试验
将实施例1制备所得的甲磺酸仑伐替尼晶型XI进行DVS分析，如图4所示。由图4可知，其在相对湿度0-40％范围内失重约0.33％，说明该晶型比较稳定即使相对湿度降至0％依然不会失去结晶水；该晶型在相对湿度40-80％范围内吸湿增重约0.25％，说明该晶型的吸湿性很小，即使相对湿度高达80％其吸湿增重依然很小。
试验例2：甲磺酸仑伐替尼晶型XI稳定性试验
将实施例11制备的甲磺酸仑伐替尼晶型XI样品分别放置于不同的储存条件下，考察样品的晶型和杂质稳定性，30天取样，按照提供的HPLC检测方法检测纯度，结果如表3所示，XRD谱图如图5所示。
表3实施例11制备的甲磺酸仑伐替尼晶型XI的稳定性试验数据
Figure PCTCN2021088827-appb-000007
Figure PCTCN2021088827-appb-000008
在上述条件下，由图5可以看出，实施例11制备的甲磺酸仑伐替尼晶型XI，0天和30天XRD谱图基本一致，晶型未发生变化。
在上述条件下，由表3的数据可知，实施例11制备的甲磺酸仑伐替尼晶型XI在高温60℃、高湿92.5％、高湿75％以及光照条件下纯度未发生明显变化。
综上所述，实施例11制备的甲磺酸仑伐替尼晶型XI在高温、高湿、光照条件下均能保持稳定，有较好的耐高温性、耐高湿性、耐光性。
试验例3：甲磺酸仑伐替尼晶型XI粉体流动性试验
将实施例12制备所得的甲磺酸仑伐替尼晶型XI与参考专利CN100569753C制备的晶型C进行粉体流动性测试，测试结果如下表4所示。
表4晶型XI与晶型C的粉体流动性数据
晶型 松密度(g/mL) 振实密度(g/mL) 压缩系数(％)
XI 0.2225 0.3290 32.4
C 0.1940 0.3458 43.9
根据《制剂技术百科全书》第2版第1卷“固体材料的流动性”所述，材料在振实密度实验中压得越紧，流动性越差，压缩系数可以用来评价粉体流动性，压缩系数(％)＝100％(振实密度-松密度)/振实密度，压缩系数越大，粉体流动性越差，越不利于粉体的均匀混合进而影响压片冲模或者胶囊填充，最终影响制剂产品的质量、含量均匀度、硬度和崩解溶出。从表4可知，晶型C的压缩系数明显高于晶型XI的压缩系数，从而表明晶型XI流动性明显优于晶型C，更有利于进行后续的制剂生产工艺。
试验例4：甲磺酸仑伐替尼晶型XI大鼠的药代动力学试验
1、试验目的
考察相同给药剂量下，大鼠单次口服给予甲磺酸仑伐替尼晶型XI后，血浆中仑伐替尼浓度水平及其药代动力学特征。
2、材料和方法
2.1、受试药物：实施例12制备得到的甲磺酸仑伐替尼晶型XI。
2.2、试验动物
SD大鼠3只，雄性，体重220-240g，由成都恩斯维尔生物科技有限公司代购于湖南斯莱克景达实验动物有限公司，许可证号：SCXK(湘)2019-0004。
2.3、试验方法
受试药物用玉米油配制成1.25mg/kg均匀的混悬液后，立即按4mL/kg的体积口服给予大鼠，并在给药前及给药后15min、30min、1h、2h、3h、4h、5h、6h、7h、8h、24h颈静脉取血0.1mL，置于EDTA-K2管中，3000r/min，离心10min，分离血浆，-80℃冰箱冷冻保存。
2.4、LC/MS/MS生物样品分析：
取50μL血浆与5μL工作液或空白稀释液混匀，加入150μL含内标乙腈沉淀剂，旋涡震荡2min，12000r/min离心10min，取上清2μL与200μL纯水：乙腈(1:1)混匀后，以3μL体积进样分析。
3、试验结果：
采血全部结束后，自主分析测定各血样中的血药浓度，并计算受试物的参数(达到最大血浆浓度的时间Tmax、最大血浆浓度Cmax、AUClast)。基于得到的参数，计算其平均值和标准偏差，具体结果见表5。
表5晶型XI的药代动力学试验数据
Figure PCTCN2021088827-appb-000009
由表5可知，本发明晶型XI达到最大血浆浓度的时间为4.00±1.73h，最大血浆浓度为2290±216ng/mL，AUC last为22852±2840h*ng/mL。表明晶型XI在动物体内有较好的吸收，有利于提高药物的生物利用度，从而提升药物的治疗效果。
试验例5：甲磺酸仑伐替尼晶型XI的溶出试验
将实施例12制备所得的甲磺酸仑伐替尼晶型XI制作成胶囊后加入900ml pH4.0的介质，37℃搅拌(转速75r/min)，桨法，于10min，15min，20min，30min，45min，60min，90min和120min取溶液，采用紫外-分光光度法，在250nm波长处测定吸光度，计算每粒溶出量。实验结果如下表6所示。
表6 pH4.0介质中晶型XI的溶出试验数据
Figure PCTCN2021088827-appb-000010
从上表数据可知，晶型XI在pH4.0介质中(该介质具有最好的区分度)在120min基本溶出完成，表明晶型XI溶出度较好，有较好的生物利用度。
对于本领域的普通技术人员而言明显的是，在不偏离本申请精神或者范围的情况下，可对本申请化合物及其制备方法进行的多种修饰和变化，因此，本申请的保护范围涵盖了对本申请进行的各种修饰和变化，只要所述修饰或变化处于权利要求和其等同实施方式所涵盖的范围内。

Claims (20)

  1. 一种甲磺酸仑伐替尼晶型XI，其特征在于，所述的晶型的X射线粉末衍射图包括在约5.73°±0.2°，8.03°±0.2°，11.45°±0.2°，12.75°±0.2°，16.15°±0.2°，17.24°±0.2°，18.16°±0.2°，19.69°±0.2°，20.68°±0.2°，22.15±0.2°，22.96±0.2°，23.76±0.2°，24.32±0.2°，25.13±0.2°，26.32±0.2°，27.00±0.2°，28.87±0.2°，29.51±0.2°，34.90±0.2°的衍射角(2θ)处的峰。
  2. 根据权利要求1所述的甲磺酸仑伐替尼晶型XI，其特征在于，所述的晶型的X射线粉末衍射图基本如图1所示。
  3. 根据权利要求1或2所述的甲磺酸仑伐替尼晶型XI，其特征在于，所述晶型的差示扫描量热法的吸热峰的温度分别为114.05±5℃和158.56±5℃。
  4. 权利要求1-3任一项所述的甲磺酸仑伐替尼晶型XI的制备方法，其特征在于，包括以下步骤：
    (1)将乙酸乙酯和纯化水在室温下以一定体积比搅拌混合均匀；
    (2)将甲磺酸仑伐替尼加至步骤(1)的混合溶剂中；
    (3)待步骤(2)的混悬液分散均匀后，加入一定量晶型XI的晶种，于温度15-40℃下搅拌4-24h，抽滤干燥得固体粉末，即得所述甲磺酸仑伐替尼晶型XI。
  5. 根据权利要求4所述的甲磺酸仑伐替尼晶型XI的制备方法，其特征在于，步骤(1)中，乙酸乙酯和纯化水的一定体积比为100mL：(2-10)mL。
  6. 根据权利要求4所述的甲磺酸仑伐替尼晶型XI的制备方法，其特征在于，步骤(1)中，乙酸乙酯和纯化水的一定体积比为100mL：(2-5)mL。
  7. 根据权利要求4所述的甲磺酸仑伐替尼晶型XI的制备方法，其特征在于，步骤(1)中，乙酸乙酯和纯化水的一定体积比为100mL：3mL。
  8. 根据权利要求4所述的甲磺酸仑伐替尼晶型XI的制备方法，其特征在于，步骤(2)中，甲磺酸仑伐替尼与步骤(1)混合溶剂中的乙酸乙酯的质量体积比为1g：(10-30)mL。
  9. 根据权利要求4所述的甲磺酸仑伐替尼晶型XI的制备方法，其特征在于，步骤(2)中，甲磺酸仑伐替尼与步骤(1)混合溶剂中的乙酸乙酯的质量体积比为1g：(15-25)mL。
  10. 根据权利要求4所述的甲磺酸仑伐替尼晶型XI的制备方法，其特征在于，步骤(2)中，甲磺酸仑伐替尼与步骤(1)混合溶剂中的乙酸乙酯的质量体积比为 1g：20mL。
  11. 根据权利要求4所述的甲磺酸仑伐替尼晶型XI的制备方法，其特征在于，步骤(3)中，一定量晶型XI的晶种为甲磺酸仑伐替尼投料量的0-10％质量分数。
  12. 根据权利要求4所述的甲磺酸仑伐替尼晶型XI的制备方法，其特征在于，步骤(3)中，一定量晶型XI的晶种为甲磺酸仑伐替尼投料2-6％质量分数。
  13. 根据权利要求4所述的甲磺酸仑伐替尼晶型XI的制备方法，其特征在于，步骤(3)中，一定量晶型XI的晶种为甲磺酸仑伐替尼投料5％质量分数。
  14. 根据权利要求4所述的甲磺酸仑伐替尼晶型XI的制备方法，其特征在于，反应温度为20-30℃，搅拌时间为6-12h。
  15. 根据权利要求4所述的甲磺酸仑伐替尼晶型XI的制备方法，其特征在于，反应温度为20-25℃，搅拌时间为6-10h。
  16. 根据权利要求4所述的甲磺酸仑伐替尼晶型XI的制备方法，其特征在于，反应温度为25℃，搅拌时间为8h。
  17. 根据权利要求4所述的甲磺酸仑伐替尼晶型XI的制备方法，其特征在于，包括以下步骤：
    (1)将乙酸乙酯和纯化水在室温下搅拌混合均匀，其中乙酸乙酯和纯化水的体积比为100mL：3mL；
    (2)将甲磺酸仑伐替尼加至步骤(1)的混合溶剂中，甲磺酸仑伐替尼与乙酸乙酯的质量体积比为1g：20mL；
    (3)待步骤(2)的混悬液分散均匀后，加入晶型XI的晶种，其用量为甲磺酸仑伐替尼投料量的5％质量分数，于25℃下搅拌8h，抽滤干燥得固体粉末，即得所述甲磺酸仑伐替尼晶型XI。
  18. 根据权利要求4所述的制备方法，其特征在于，包括以下步骤：
    将200mL乙酸乙酯和20mL纯化水在室温下搅拌混合均匀，然后将10.0g甲磺酸仑伐替尼加至乙酸乙酯与纯化水的混合溶剂中，待混悬液分散均匀后，加入1.0g晶型XI的晶种，然后于20℃搅拌8h，抽滤干燥得固体粉末9.2g，收率92.0％，纯度为99.75％。
  19. 根据权利要求4所述的制备方法，其特征在于，包括以下步骤：
    将5000mL乙酸乙酯和150mL纯化水在室温下搅拌混合均匀，然后将250.0g 甲磺酸仑伐替尼加至乙酸乙酯与纯化水的混合溶剂中，待混悬液分散均匀后，加入12.5g晶型XI的晶种，然后于25℃搅拌8h，抽滤干燥得固体粉末甲磺酸仑伐替尼晶型XI 232.8g，收率93.1％，纯度为99.78％。
  20. 根据权利要求4所述的制备方法，其特征在于，包括以下步骤：
    将30L乙酸乙酯和750mL纯化水在室温下搅拌混合均匀，然后将1.5kg甲磺酸仑伐替尼加至乙酸乙酯与纯化水的混合溶剂中，保持25℃搅拌10h，抽滤干燥得固体粉末1.4kg，收率93.3％，纯度为99.95％。
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