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WO2016019909A1 - 一种抗癌化合物的新晶型及其制备方法和用途 - Google Patents

一种抗癌化合物的新晶型及其制备方法和用途 Download PDF

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WO2016019909A1
WO2016019909A1 PCT/CN2015/086408 CN2015086408W WO2016019909A1 WO 2016019909 A1 WO2016019909 A1 WO 2016019909A1 CN 2015086408 W CN2015086408 W CN 2015086408W WO 2016019909 A1 WO2016019909 A1 WO 2016019909A1
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crystalline form
preparation
crystal form
lung cancer
compound
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French (fr)
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杨宝海
熊龙
余俊
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
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Jiangsu Hansoh Pharmaceutical Co Ltd
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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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings

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  • the invention relates to the field of medicinal chemical industry, in particular to an anticancer compound (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl Crystal form of 1-dimethylphosphonooxy-4-yl]pyridin-2-amine and preparation method thereof.
  • Lung cancer is the most common primary malignant tumor of the lung and is usually classified into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Lung cancer is the cancer with the highest morbidity and mortality. Non-small cell lung cancer accounts for 80% to 85% of the total number of lung cancers, and its mortality rate is as high as 80% to 90%. According to the statistics of the World Health Organization (WHO), there were 1,332,132 new cases of lung cancer in 2002, accounting for 12.4% of the total number of new cancer cases, ranking first, the third time announced by the Ministry of Health of China on April 29, 2008. The main results of the national death cause survey show that the mortality rate of lung cancer in China has increased by 465% in the past 30 years. At present, lung cancer has replaced liver cancer as the cause of death in the first malignant tumor in China, accounting for 22.7% of malignant tumor deaths.
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • the 5-year survival rate of lung cancer in developed countries is about 10% to 15%, which is lower in China. If the advanced NSCLC is not treated, the median survival time is about 4 to 5 months, and the 1-year survival rate is less than 10%.
  • the standard first-line chemotherapy regimen of advanced NSCLC is equivalent to the best supportive treatment, which can effectively prolong the median survival time and increase the 1-year survival period. Survival rate.
  • the current efficacy of chemotherapy seems to reach a platform, its objective efficiency is about 30%, the median survival time is 8 to 9 months, and the 1-year survival rate is 30% to 40%. Therefore, finding more effective and safe treatments has become a hot spot in current lung cancer research.
  • Tumor molecular targeted therapy is a treatment for other biological pathways.
  • NSCLC's targeted therapeutic drugs mainly include epidermal growth factor receptor (EGFR) family inhibitors, angiogenesis inhibitors, multi-target inhibitors, signal transduction inhibitors, and apoptosis inducers.
  • EGFR epidermal growth factor receptor
  • CSCO Clinical Oncology Collaborative Professional Committee
  • XALKORI provides us with a new path to explore future drug development and cancer treatment,” University of Colorado, Denver Cancer Research The heads of Professor Paul Bunn and the chief physician of James Dudley pointed out.
  • XALKORI is the first new drug to treat lung cancer approved by the FDA for more than 6 years, representing a shift in the treatment of non-small cell lung cancer. We are moving from a monolithic treatment regime to a treatment model through biomarker decision-making.”
  • the biomarker ALK fusion gene test result of the patient's tumor is positive to improve the possibility of responding to the treatment. This first test for lung cancer treatment allows researchers to observe good results in pre-screened patient populations.
  • ALK positive rate in non-small cell lung cancer is approximately 3-5%, meaning that there are approximately 650 to 11,000 ALK-positive non-small cell lung cancer patients in the United States each year.
  • NSCLC non-small cell lung cancer
  • Drug crystal research and solid-state drug development are of paramount importance in the pharmaceutical industry.
  • Drug molecules usually have different solid forms, including salts, polycrystals, eutectic, amorphous, hydrates and solvates; different crystal forms of the same drug molecule, in crystal structure, stability, manufacturability and bioavailability
  • any drug development requires a comprehensive system of polymorphic screening to find as many crystal forms as possible, and then use various solid-state methods to conduct in-depth research on these crystal forms to find the most suitable crystal form.
  • the crystalline XRPD pattern also exhibits a diffraction peak at 2 ⁇ ( ⁇ 0.2°) of 19.47, 20.06, 20.83, 22.43, 24.26, 26.18, 29.74.
  • the crystalline XRPD pattern is shown in Figure 1.
  • the crystal form of the present invention was subjected to thermogravimetric analysis (TGA) to show that the sample was kept constant from room temperature to 220 ° C, indicating that the sample contained no crystal water or an adsorption solvent. Then the sample began to lose weight. The sample weight loss was severe at around 260 °C, and the weight loss slowed down at about 400 °C, and the weight loss to 700 °C was about 62%.
  • TGA thermogravimetric analysis
  • the crystal form of the present invention exhibits an endothermic peak in the range of 180 ° C to 185 ° C by differential scanning calorimetry (DSC) and has a sharp absorption peak at 182 ⁇ 1 ° C.
  • It is also an object of the present invention to provide a process for preparing the crystalline form comprising dissolving a compound of formula I with an organic solvent, cooling and crystallization by stirring, and filtering to obtain a target crystalline form.
  • Another object of the present invention is to provide an alternative method of preparing the crystalline form comprising dissolving a compound of formula I with an organic solvent, adding an anti-solvent to agitate the crystal, and filtering to obtain a target crystalline form.
  • the drying temperature is 25 ° C or higher, preferably 70 ° C or higher, more preferably 80 ° C or higher.
  • the organic solvent is selected from the group consisting of acetonitrile, ethyl acetate and/or butyl acetate.
  • the anti-solvent is selected from the group consisting of isopropyl ether, n-heptane and/or n-hexane.
  • It is still another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form and a pharmaceutically acceptable carrier.
  • Another object of the present invention is to provide the use of the crystalline form or the pharmaceutical composition for the preparation of an antitumor drug
  • the crystal form provided by the invention has high purity, good stability, no hygroscopicity and high bioavailability, and is suitable for medical preparations.
  • Figure 1 is a (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphonooxylate of the present invention.
  • Figure 2 is a (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphonooxylate of the present invention.
  • Figure 3 is a (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphonooxylate of the present invention.
  • DSC Differential Scanning Thermogram
  • the present invention (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphine
  • the X-ray powder diffraction pattern of the acyloxy-4-yl]pyridin-2-amine crystal form did not change significantly under different temperature conditions, indicating that the crystal form did not change, indicating good thermal stability.
  • the wettability test was carried out according to the Guiding Principles for Drug Hygroscopicity Test (Chinese Pharmacopoeia 2010 Edition Part II Appendix XIX J). Take a dry stuffed glass weighing bottle (outer diameter 50mm, height 15mm), placed in a suitable 25 ° C ⁇ 1 ° C constant temperature dryer (lower ammonium chloride saturated solution) on the day before the test, accurately weighed Weight (m1); suitable for the crystal form of the present invention The amount is laid flat in the above weighing bottle. The thickness of the test sample is generally about 1 mm, and the weight is accurately weighed (m2); the weighing bottle is opened and placed under the above constant temperature and humidity conditions with the bottle cap. 24 hours; cover the weighing bottle cap and accurately weigh (m3).
  • Deliquescence absorbs enough water to form a liquid
  • Hygroscopicity 2% ⁇ X% ⁇ 15%;
  • the (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethyl group of the present invention was measured.
  • the weight gain percentage of the phosphinyloxy-4-yl]pyridin-2-amine crystal form compound was 0.02%, indicating that the crystal form of the present invention has no hygroscopicity and is hardly deliquescent under the influence of high humidity.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种抗癌化合物(R)-3-[1-(2,6-二氯-3-氟苯基)乙氧基]-5-[3-氟苯基-1-二甲基膦酰氧-4-基]吡啶-2-胺晶型及其制备方法，其结构式如式Ⅰ所示。本发明晶型性质稳定，纯度高，无引湿性，生物利用度高，适合药物制剂需求。

Description

一种抗癌化合物的新晶型及其制备方法和用途 技术领域
本发明涉及医药化工领域，具体涉及一种抗癌化合物(R)-3-[1-(2,6-二氯-3-氟苯基)乙氧基]-5-[3-氟苯基-1-二甲基膦酰氧-4-基]吡啶-2-胺的晶型及其制备方法。
背景技术
肺癌是最常见的肺部原发性恶性肿瘤，通常分为非小细胞肺癌(NSCLC)和小细胞肺癌(SCLC)。肺癌是发病率和死亡率最高的癌症，而非小细胞肺癌占肺癌总数的80％～85％，其死亡率高达80％～90％。根据世界卫生组织(WHO)的统计，2002年全球肺癌新发病例1332132例，占全部新发癌症病例总数的12.4％，居第一位，我国卫生部2008年4月29日公布的第三次全国死因调查主要结果显示过去30年我国肺癌死亡率上升了465％，目前肺癌已经取代肝癌成为我国首位恶性肿瘤死亡原因，占恶性肿瘤死亡的22.7％。
发达国家肺癌的5年生存率约10％～15％，在我国则更低。晚期NSCLC如果不治疗，中位生存期约4～5个月，1年生存率低于10％，晚期NSCLC的标准一线化疗方案相当于最佳支持治疗能有效延长中位生存期，提高1年生存率。但目前化疗的疗效似乎到达了一个平台，其客观有效率约30％，中位生存期8～9个月，1年生存率30％～40％。因此，寻找更为有效和安全的治疗手段成为当前肺癌研究的一个热点。肿瘤分子靶向治疗是针对其他生物学途径的治疗手段。目前，NSCLC的靶向治疗药物主要有表皮生长因子受体(EGFR)家族抑制剂、血管生成抑制剂、多靶点抑制剂、信号传导抑制剂、凋亡诱导剂等。中国抗癌协会临床肿瘤学协作专业委员会(CSCO)执行委员会主任委员、著名临床肿瘤专家马军教授指出说：“由于早期具有隐蔽性，大多数非小细胞肺癌患者发现时已是局部晚期或发生转移，超过半数的肺癌患者会错过手术机会。传统放化疗疗效有限，且伴随难以 忍受的药物毒副反应，通常放化疗失败的次数越多，后续治疗的效果越差。但靶向药物的出现，给征服肺癌提供了一种新可能。”
辉瑞公司于2011年8月26日宣布，该公司的XALKORI(crizotinib)胶囊获得美国食品药品管理局FDA批准，这是第一个对间变性淋巴瘤激酶(ALK)进行靶向治疗的药品，用于治疗通过FDA批准的检测方法诊断为ALK阳性的局部晚期或转移的非小细胞肺癌。XALKORI的疗效系基于客观缓解率(ORR)。XALKORI在获得FDA快速批准的同时，辉瑞正在进行上市后临床试验，旨在对XALKORI的临床疗效做进一步评估。根据FDA关于靶向治疗和伴随诊断的最新指导意见，辉瑞在临床试验中与FDA和雅培分子诊断业务部门进行了密切合作，确保XALKORI与雅培的诊断检测技术同时获得审评和批准。后者即雅培分子诊断业务部门的Vysis ALK Break Apart FISH(荧光原位杂交)探针试剂盒，用以发现ALK融合基因。XALKORI与雅培分子诊断业务部门的ALK FISH试剂盒同时获批，也标志着辉瑞的肿瘤药物或肿瘤治疗方案首次与诊断检测方案一起进行开发和获批。“通过真正了解NSCLC的驱动基因，如ALK，我们可以选择出最有可能对治疗反应的患者。XALKORI为我们提供了一条探索未来药物研发和癌症治疗的崭新道路，”科罗拉多大学丹佛分校癌症研究部门的负责人Paul Bunn教授和James Dudley主任医师指出。“XALKORI是6年多来FDA批准的第一个治疗肺癌的新药，代表了非小细胞肺癌治疗模式转变，我们正在从千篇一律的治疗方案转向通过生物标记物决策的治疗模式。”在XALKORI临床试验中，试验方案要求患者肿瘤的生物标记物ALK融合基因检测结果为阳性，以提高对治疗做出反应的可能性。首次用于肺癌治疗的这种检测方法可以使研究者在预先筛选的患者人群中观察到良好的治疗效果。初步的流行病学研究表明，在非小细胞肺癌中ALK阳性率大约为3-5％，意味着每年在美国大约有6 500到11 000名ALK阳性的非小细胞肺癌患者。通过XALKORI注册临床试验的靶向治疗，在晚期ALK阳性非小细胞肺癌患者中，客观缓解率为50到61％。
专家预测2008-2013年期内，中国非小细胞肺癌(NSCLC)治疗市场将增长一倍以上，从3.07亿美元至6.48亿美元。结直肠癌病例治 疗的增加将加速这种增长。城市化和人口老龄化将导致2008-2018年期间，中国非小细胞肺癌发病病例增长47％，从36.15万到53.13万。最明显的增长将发生在城市，在这里未来十年的非小细胞肺癌发病病例将增加72％，与此相反，农村地区只有8％的增长。吉非替尼(阿斯利康的易瑞沙)，埃罗替尼(罗氏的特罗凯)，和内皮抑素(江苏先声药业的恩度)等靶向治疗日趋普及，和新靶向治疗药物的推出——贝伐单抗(罗氏的阿瓦斯丁)和cetuximab(默克的爱必妥)——是2008-2013年期间推动中国非小细胞肺癌市场的主要力量。跨国公司中国非小细胞肺癌治疗的市场份额将从2008年的34％上升到2013年的47％。这一增长将主要由靶向药物的引入增加而驱动。由于低价竞争激烈，跨国公司的化疗药物将失去在中国的市场。因此，作为Crizotinib的“me too”药物，式Ⅰ化合物将会有广阔的市场潜力。
药物晶型研究和药物固态研发在制药业具有举足轻重的意义。药物分子通常有不同的固体形态，包括盐类，多晶，共晶，无定形，水合物和溶剂合物；同一药物分子的不同晶型，在晶体结构，稳定性，可生产性和生物利用度等性质方面可能会有显著差异，从而直接影响药物的疗效以及可开发性。因此，任何一个药品研发，都需要进行全面系统的多晶型筛选，找到尽可能多的晶型，然后使用各种固态方法对这些晶型进行深入的研究，从而找到最适合开发的晶型。
发明内容
本发明的目的在于提供一种式Ⅰ化合物的晶型，所述晶型XRPD图谱在2θ(±0.2°)为6.63、7.64、10.38、11.38、12.07、13.23、15.48、16.90处显示有衍射峰，
Figure PCTCN2015086408-appb-000001
优选的，所述晶型XRPD图谱还在2θ(±0.2°)为19.47、20.06、20.83、22.43、24.26、26.18、29.74处显示有衍射峰。
特别优选的，所述晶型XRPD图谱如图1所示。
本发明晶型经热重分析(TGA)，显示样品自室温至220℃保持恒重，说明样品不含结晶水或吸附溶剂。随后样品开始失重，至260℃左右样品失重剧烈，在约400℃失重有所减缓，至700℃失重约62％。
本发明晶型经差式扫描量热分析(DSC)，显示在180℃～185℃范围内吸热峰，且在182±1℃处有尖锐的吸收峰。
本发明的目的还在于提供一种制备所述晶型的方法，包括用有机溶剂溶解式Ⅰ化合物，搅拌冷却析晶，过滤得目标晶型。
本发明的另一目的还在于提供一种替代的制备所述晶型的方法，包括用有机溶剂溶解式Ⅰ化合物，加入反溶剂搅拌析晶，过滤得目标晶型。
进一步的，上述制备过程中，析晶过滤后还包括干燥步骤，干燥温度在25℃以上，优选在70℃以上，更优选在80℃以上。
优选的，所述有机溶剂选自乙腈、乙酸乙酯和/或乙酸丁酯。
优选的，所述反溶剂选自异丙醚、正庚烷和/或正己烷。
本发明的另一目的还在于提供一种药物组合物，包含治疗有效量的所述晶型和药学上可接受的载体。
本发明的另一目的还在于提供所述晶型或所述药物组合物在制备抗肿瘤药物中的用途
本发明所提供的晶型纯度高，稳定性好，无引湿性，生物利用度高，适合医药制剂需要。
附图说明
图1是本发明(R)-3-[1-(2,6-二氯-3-氟苯基)乙氧基]-5-[3-氟苯基-1-二甲基膦酰氧-4-基]吡啶-2-胺晶型的XRPD图谱。
图2是本发明(R)-3-[1-(2,6-二氯-3-氟苯基)乙氧基]-5-[3-氟苯基-1-二甲基膦酰氧-4-基]吡啶-2-胺晶型的热重分析图(TGA)。
图3是本发明(R)-3-[1-(2,6-二氯-3-氟苯基)乙氧基]-5-[3-氟苯基-1-二甲基膦酰氧-4-基]吡啶-2-胺晶型的差示扫描热分析图(DSC)。
具体实施方式
实施例1
将式Ⅰ化合物粗品5.0g投入乙腈70ml中，70℃水浴搅拌溶解，然后自然冷却搅拌析晶2h。过滤，25℃真空干燥得到目标晶型3.1g，经检测，其XRPD图谱如图1所示。
实施例2
将式Ⅰ化合物粗品5.0g投入乙酸乙酯100ml中，65℃水浴搅拌溶解，然后自然冷却搅拌析晶2h。过滤，25℃真空干燥得到目标晶型3.5g，经检测，其XRPD图谱基本与图1吻合，所有特征峰均在误差范围内。
实施例3
将式Ⅰ化合物粗品5.0g投入乙酸乙酯175ml中，60℃水浴搅拌溶解，然后加入异丙醚搅拌析晶2h。过滤，25℃真空干燥得到目标晶型4.3g，经检测，其XRPD图谱基本与图1吻合，所有特征峰均在误差范围内。
实施例4
将式Ⅰ化合物粗品5.0g投入乙酸乙酯175ml中，60℃水浴搅拌溶解，然后加入正庚烷搅拌析晶2h。过滤，25℃真空干燥得到目标晶型4.7g，经检测，其XRPD图谱基本与图1吻合，所有特征峰均在误差范围内。
实施例5
将式Ⅰ化合物粗品5.0g投入丙酮42ml中，60℃水浴搅拌溶解，然后自然冷却搅拌析晶2h。过滤，80℃真空干燥18小时以上得到目标晶型4.2g。经检测，其XRPD图谱基本与图1吻合，所有特征峰均在误差范围内。
实验例一、热稳定性研究
取适量本发明晶型，分别置于不同温度条件下，18小时后取样，检测其X-射线粉末衍射，结果如表1所示：
表1
Figure PCTCN2015086408-appb-000002
Figure PCTCN2015086408-appb-000003
由上表可知，本发明(R)-3-[1-(2,6-二氯-3-氟苯基)乙氧基]-5-[3-氟苯基-1-二甲基膦酰氧-4-基]吡啶-2-胺晶型在不同温度条件下，其X-射线粉末衍射图谱无明显变化，表明晶型未发生变化，显示热稳定性良好。
实验例二、影响因素试验
取适量本发明晶型，分别置于高温60℃、高湿RH92.5％、强光4500lx条件下，于第0、5、10天取样，检测样品的干燥失重、最大单杂、总杂、异构体和含量情况，检测结果如表2。
表2
Figure PCTCN2015086408-appb-000004
实验例三、加速试验
取适量本发明晶型，置于温度为40℃±2℃、相对湿度75％±5％的条件下，放置6个月。分别于第0、1、2、3、6月取样，检测样品的干燥失重、最大单杂、总杂、异构体和含量情况，检测结果如表3。
表3
Figure PCTCN2015086408-appb-000005
Figure PCTCN2015086408-appb-000006
实验例四、长期试验
取适量本发明晶型，置于温度为30℃±2℃、相对湿度65％±5％的条件下，放置24个月。分别于第0、3、6、9、12、18、24月取样，检测样品的干燥失重、最大单杂、总杂、异构体和含量情况，检测结果如表4。
表4
Figure PCTCN2015086408-appb-000007
由表2-4可知，本发明的(R)-3-[1-(2,6-二氯-3-氟苯基)乙氧基]-5-[3-氟苯基-1-二甲基膦酰氧-4-基]吡啶-2-胺晶型化合物在高温、高湿、强光以及加速6个月、长期24个月试验中，其各项检测指标均无明显变化，表明样品质量稳定可控，稳定性良好，方便存储和运输，非常适合作为原料制备用于药物制剂。
实验例五、引湿性
根据《药物引湿性试验指导原则》(中国药典2010版二部附录ⅪⅩ J)进行引湿性试验。取干燥的具塞玻璃称量瓶(外径为50mm，高为15mm)，于试验前一天置于适宜的25℃±1℃恒温干燥器(下部放置氯化铵饱和溶液)内，精密称定重量(m1)；取供本发明晶型适 量，平铺于上述称量瓶中，供试品的厚度一般约为1mm，精密称定重量(m2)；将称量瓶敞口，并与瓶盖同置于上述恒温恒湿条件下放置24小时；盖好称量瓶盖子，精密称重(m3)。
Figure PCTCN2015086408-appb-000008
引湿性试验判断标准如下：
潮解：   吸收足量水分形成液体
极易引湿性：         X％≥15％；
有引湿性：           2％≤X％＜15％；
略有引湿性：         0.2％≤X％＜2％；
无或几乎无引湿性：   X％＜0.2％。
按照以上方法，测得本发明的(R)-3-[1-(2,6-二氯-3-氟苯基)乙氧基]-5-[3-氟苯基-1-二甲基膦酰氧-4-基]吡啶-2-胺晶型化合物的增重百分率为0.02％，表明本发明晶型无引湿性，几乎不受高湿度影响而潮解。
实验例六、溶解性
按中国药典2010年版二部凡例试验。称取研成细粉的本发明晶型，置于25℃±2℃一定容量的溶剂中，每隔5分钟强力振摇30秒；观察30分钟内的溶解情况，如看不见溶质颗粒时，即视为完全溶解。结果见表5。
表5
溶剂 样品重量(g) 溶剂用量(ml) 溶解现象 结论
甲醇 0.1 0.2 完全溶解 易溶
丙酮 0.1 4.0 完全溶解 略溶
0.1mol/L盐酸 0.1 2.4 完全溶解 溶解
由表5可知，本发明的(R)-3-[1-(2,6-二氯-3-氟苯基)乙氧基]-5-[3-氟苯基-1-二甲基膦酰氧-4-基]吡啶-2-胺晶型化合物具有高溶解度，表明其具有高生物利用度。

Claims (10)

  1. 式Ⅰ化合物的晶型，其特征在于，所述晶型XRPD图谱在2θ(±0.2°)为6.63、7.64、10.38、11.38、12.07、13.23、15.48、16.90处显示有衍射峰，
    Figure PCTCN2015086408-appb-100001
  2. 根据权利要求1所述的晶型，其特征在于，所述晶型XRPD图谱还在2θ(±0.2°)为19.47、20.06、20.83、22.43、24.26、26.18、29.74处显示有衍射峰。
  3. 根据权利要求1所述的晶型，其特征在于，所述晶型XRPD图谱如图1所示。
  4. 制备权利要求1-3任意一项所述晶型的方法，包括用有机溶剂溶解式Ⅰ化合物，搅拌冷却析晶，过滤得目标晶型。
  5. 制备权利要求1-3任意一项所述晶型的方法，包括用有机溶剂溶解式Ⅰ化合物，加入反溶剂搅拌析晶，过滤得目标晶型。
  6. 根据权利要求4或5任意一项所述的制备方法，其特征在于，过滤后还包括干燥步骤，优选的，干燥温度在20℃以上，优选在70℃以上，更优选在80℃以上。
  7. 根据权利要求4或5任意一项所述的制备方法，其特征在于，所述有机溶剂选自乙腈、乙酸乙酯和/或乙酸丁酯。
  8. 根据权利要求5所述的制备方法，其特征在于，所述反溶剂选 自异丙醚、正庚烷和/或正己烷。
  9. 一种药物组合物，包含治疗有效量的权利要求1-3任意一项所述的晶型和药学上可接受的载体。
  10. 权利要求1-3任意一项所述晶型或权利要求9所述药物组合物在制备抗肿瘤药物中的用途，优选的，所述肿瘤为肺癌。
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