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WO2016165650A1 - 奥拉帕尼与尿素的共晶及其制备方法 - Google Patents

奥拉帕尼与尿素的共晶及其制备方法 Download PDF

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WO2016165650A1
WO2016165650A1 PCT/CN2016/079430 CN2016079430W WO2016165650A1 WO 2016165650 A1 WO2016165650 A1 WO 2016165650A1 CN 2016079430 W CN2016079430 W CN 2016079430W WO 2016165650 A1 WO2016165650 A1 WO 2016165650A1
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eutectic
crystal form
urea
ray powder
powder diffraction
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陈敏华
张炎锋
刘凯
张晓宇
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Crystal Pharmatech Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/02—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of urea, its salts, complexes or addition compounds
    • 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 invention relates to a eutectic of olaparib and urea, a preparation method and use thereof.
  • Olaparib was first developed by the British biotechnology company KuDOS Pharmaceuticals Co., Ltd. In 2005, after the acquisition of KuDOS, AstraZeneca continued to develop Olapani for the treatment of ovarian cancer. On December 19, 2014, Olapani was approved by the FDA in the United States. It is the first FDA-approved targeted drug for ovarian cancer patients with BRCA mutations. It is suitable for patients who have previously undergone chemotherapy. It has been shown in preclinical models that olaparib is the first oral poly ADP ribose polymerase (PARP) inhibitor that utilizes defects in the DNA repair pathway to preferentially kill cancer cells.
  • PARP poly ADP ribose polymerase
  • olapanib 4-[3-(4-cyclopropanecarbonyl-piperazine 1-carbonyl)-4-fluoro-benzyl]-2H-pyridazin-1-one, which has the structure of formula (I) Shown as follows:
  • KuDOS Korean Pharmaceutical Co., Ltd. discloses the free base form A of olaparib in patent CN101528714B, and the free base form L of olaparib is disclosed in CN101821242B.
  • the solubility of the free base crystal form listed in Olapani is low, and it is necessary to find a crystal form with high solubility to improve the absorption efficiency of the drug.
  • a eutectic is a crystal containing two molecules in the same crystal structure. The role between the two molecules is non- Covalent bonds (such as hydrogen bonds, ⁇ - ⁇ conjugates, halogen bonds, etc.).
  • the formation of drug eutectic does not destroy the covalent bond of the active ingredient of the drug, and has the opportunity to improve the crystallization and physicochemical properties of the drug itself, such as bioavailability (Pharmaceut. Res. 23 (8), 2006, pp. 1888-1897). .), Stability and Process Developability (Int. J. Pham. 320, 2006, pp. 114-123.), a new choice for pharmaceutical solid formulations.
  • the eutectic stability provided by the invention is good, and the wettability is low. Compared with the crystal form in the prior art, the solubility is improved, which is beneficial to improving the bioavailability of the drug, and is important for improving the efficacy and safety of the drug.
  • the technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a eutectic of olrapani and urea with high solubility and good stability.
  • the eutectic of olrapani and urea provided by the present invention has the structural formula shown in formula (II).
  • the eutectic provided by the present invention is named as eutectic crystal form A, and its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 17.4° ⁇ 0.2°, 20.7° ⁇ 0.2°, and 10.5° ⁇ 0.2°.
  • the eutectic crystal form A provided by the present invention has an X-ray powder diffraction pattern having one or more of 2theta values of 21.1° ⁇ 0.2°, 24.6° ⁇ 0.2°, and 12.2° ⁇ 0.2°. Characteristic peaks.
  • the eutectic crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 21.1° ⁇ 0.2°, 24.6° ⁇ 0.2°, and 12.2° ⁇ 0.2°.
  • the present invention provides a eutectic crystal form A having an X-ray powder diffraction pattern at a 2theta value.
  • a eutectic crystal form A having an X-ray powder diffraction pattern at a 2theta value.
  • 9.2° ⁇ 0.2°, 15.0° ⁇ 0.2°, and 23.4° ⁇ 0.2° have characteristic peaks.
  • the eutectic crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 9.2° ⁇ 0.2°, 15.0° ⁇ 0.2°, and 23.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of eutectic crystal form A is substantially as shown in FIG. Further, a total of 26 diffraction peaks were shown in the X-ray powder diffraction pattern, and the positions and relative peak intensities of these diffraction peaks are shown in Table 1 or Table 2, in which the peak position was varied within a range of 0.2°.
  • a total of 34 diffraction peaks are shown in the X-ray powder diffraction pattern of the eutectic crystal form A.
  • the positions of the diffraction peaks and the relative peak intensities are shown in Table 3, wherein the peak position is 0.2. ° range changes.
  • the eutectic crystal form A shows an endothermic heat peak at 170 ⁇ 2 ° C in a spectrum measured by differential scanning calorimetry.
  • the eutectic crystal form A is shown by thermogravimetric analysis as being heated to 120 ⁇ 2 ° C with a weight loss gradient of about 1.8%.
  • the eutectic crystal form A can be obtained by reacting olaparib and urea in one or more solvent systems of alcohols, ketones, alkyl nitriles, and cyclic ethers.
  • the alcohol solvent is preferably ethanol
  • the ketone solvent is preferably acetone
  • the alkyl nitrile solvent is preferably acetonitrile or a cyclic ether solvent, preferably tetrahydrofuran or 1,4-dioxane.
  • Another object of the present invention is to provide a method for preparing eutectic of olrapani and urea, which comprises olaparib and urea in one of alcohols, ketones, alkylnitrile and cyclic ethers.
  • the reaction is carried out in a plurality of solvent systems, and is obtained by a crystallization method including, but not limited to, volatilization, stirring or cooling.
  • the alcohol solvent is preferably ethanol
  • the ketone solvent is preferably acetone
  • the mixed system containing olrapani, urea and solvent is subjected to multiple heating and constant temperature cooling operations, and solid precipitation, filtration, washing and drying are carried out to obtain the eutectic crystal of the present invention.
  • the solvent is ethanol or acetone or a combination of the two.
  • the olaparib free base is the original It is dissolved in the solvent, and urea is added to obtain the mixed system containing olaparib, urea and a solvent.
  • the heating constant temperature cooling operation refers to heating the system to a set higher temperature than room temperature, then thermostating for a set time, and finally cooling to a lower temperature set below room temperature.
  • the set higher temperature may be, for example, 40 to 80 ° C, preferably 50 to 70 ° C, more preferably 55 to 65 ° C, and a specific higher temperature value is about 60 ° C.
  • the set lower temperature may be, for example, -5 to 18 ° C, preferably -5 to 10 ° C, more preferably -5 to 5 ° C, and most preferably 0 to 5 ° C.
  • the rate of heating may be from 0.5 to 3 ° C/min, preferably from 1 to 2 ° C/min.
  • the rate of temperature drop may be from 0.1 to 1 ° C/min, preferably from 0.3 to 0.6 ° C/min.
  • the constant temperature period is preferably 5 hours or longer, more preferably 8 hours or longer, further preferably 9 hours or longer, more preferably 9 to 12 hours, specifically, for example, 10 hours.
  • the number of times of the heating constant temperature cooling operation is preferably 2 to 4 times, and most preferably 3 times.
  • the higher temperature is 40 to 80 ° C
  • the lower temperature is -5 to 18 ° C
  • the constant temperature is 5 hours or longer.
  • the higher temperature is 55 to 65 ° C
  • the lower temperature is 0 to 5 ° C
  • the constant temperature is 9 to 11 hours.
  • Another object of the present invention is to provide a pharmaceutical composition comprising a co-crystal of olaparib and urea, and at least one pharmaceutically acceptable excipient, and a method of using the same for treating cancer.
  • a method of treating cancer includes administering to a cancer patient an effective amount of the pharmaceutical composition.
  • the cancer includes, but is not limited to, melanoma, pancreatic cancer, ovarian cancer, breast cancer, lymphoma, lung cancer, and the like.
  • the olapani and urea provided by the invention have good eutectic stability and low hygroscopicity, and no special drying conditions are needed in the preparation process, which simplifies the preparation and post-treatment process of the medicine, and is easy for industrial production. Moreover, the moisture content remains basically unchanged under different humidity conditions, which is convenient for long-term storage of medicines and has strong economic value.
  • the eutectic ratio of olaparib and urea provided by the present invention is free crystal form disclosed in patent CN101528714B
  • the higher solubility of A is beneficial to improve the absorption efficiency of the drug and improve the bioavailability of the drug, which is of great significance for improving the efficacy and safety of the drug.
  • Figure 1 is an XRPD pattern of eutectic crystal form A
  • Figure 3 is a TGA diagram of eutectic crystal form A
  • Figure 4 is a DVS diagram of eutectic crystal form A
  • Figure 5 is a DVS diagram of the free base crystal form A in the patent CN101528714B;
  • Figure 6 is a 1 H NMR chart of eutectic crystal form A.
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer; the powder of olaparib is obtained by a commercially available method.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q200.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • Preparation method of co-crystal of olaparib and urea 101.9 mg of olaparib free base dissolved in 3.0 mL of ethanol 98.7mg of urea was added, heated to 60 ° C at a heating rate of 1.0 ° C / min, stirred at 60 ° C for 600 min, then cooled to 5 ° C at a cooling rate of 0.37 ° C / min, repeating the above heating and cooling process three times, the reaction is over After filtration, the resulting solid was washed with ethanol and dried.
  • olaparib free base (amorphous) was dissolved in 0.6 mL of acetone, and 10.8 mg of urea was added to add After heating at a heating rate of 1.0 ° C / min to 60 ° C, stirring at 60 ° C for 600 min, cooling (cooling rate 0.37 ° C / min) to 5 ° C, repeat the above heating and cooling process three times, after the reaction is filtered, the resulting solid is washed with ethanol Dry, cool to room temperature and collect solids.
  • the solid obtained in this example was identical to the crystal form obtained in Example 1, and was a eutectic crystal form A, and its X-ray powder diffraction data is shown in Table 3.
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the eutectic crystal form A prepared by the present invention and the free base crystal form A of CN101528714B were respectively prepared into a saturated solution by using SGF (simulated artificial gastric juice) of pH 1.8 and pH 6.5 FaSSIF (artificial intestinal juice under fasting state) for 1 hour. After 4 hours, the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The experimental results are shown in Table 4.
  • the urea eutectic crystal form A of the present invention has higher solubility than the patent free base crystal form A after 4 hours; it is placed in FaSSIF for 4 hours.
  • the urea eutectic crystal form A of the present invention has a higher solubility.

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Abstract

公开了奥拉帕尼和尿素的共晶及其制备方法。具体的，公开了共晶晶型A，该晶型其X射线粉末衍射图在2theta值为17.4°±0.2°、20.7°±0.2°、10.5°±0.2°处具有特征峰。公开的的共晶与现有奥拉帕尼游离碱晶型比稳定性更好，引湿性更低，溶解度更高。

Description

奥拉帕尼与尿素的共晶及其制备方法 技术领域
本发明涉及一种奥拉帕尼与尿素的共晶及其制备方法和用途。
背景技术
奥拉帕尼(Olaparib)首先由英国生物技术公司KuDOS(库多斯)药物有限公司研发，2005年阿斯利康将KuDOS公司收购后，继续开发奥拉帕尼，用于治疗卵巢癌。2014年12月19日奥拉帕尼在美国获得FDA批准上市，是FDA批准的首款专门用于BRCA突变的卵巢癌患者的靶向药物，适用于先前经历过化疗治疗的患者。在临床前模型中已被证明，奥拉帕尼是一种首创口服多聚ADP核糖聚合酶(PARP)抑制剂，能够利用DNA修复途径的缺陷，优先杀死癌细胞。奥拉帕尼的化学名称为4-[3-(4-环丙烷羰基-哌嗪1-羰基)-4-氟-苄基]-2H-酞嗪1-酮，其结构如式(I)所示：
Figure PCTCN2016079430-appb-000001
KuDOS(库多斯)药物有限公司在专利CN101528714B中公开了奥拉帕尼的游离碱晶型A，在CN101821242B中公开了奥拉帕尼的游离碱晶型L。除此之外，尚无其他公开奥拉帕尼的晶型专利。但是奥拉帕尼上市的游离碱晶型溶解度低，有必要寻找溶解度高的晶型，以提高药物吸收效率。
基于此，本发明的发明人开发出了一种奥拉帕尼的共晶，解决了游离碱晶型溶解度低的难题。共晶是同一晶体结构中含有两种分子的晶体。两种分子之间的作用为非 共价键(比如氢键，π-π共轭，卤键等)。药物共晶的形成不会破坏药物活性成分的共价键，且有机会改善药物本身的结晶性能及物化性质，比如生物利用度(Pharmaceut.Res.23(8)，2006，pp.1888-1897.)，稳定性和工艺可开发性(Int.J.Pham.320，2006，pp.114-123.)，成为药物固体制剂的一个新选择。
本发明提供的共晶稳定性好，引湿性低，相比现有技术中的晶型，溶解度提高，有利于提高药物的生物利用度，对于药物疗效及安全性的提高具有重要意义。
发明内容
本发明所要解决的技术问题是克服现有技术的不足，提供一种溶解度高、稳定性好的奥拉帕尼与尿素的共晶。
优选地，本发明所提供的奥拉帕尼与尿素的共晶，其结构式如式(II)所示，
Figure PCTCN2016079430-appb-000002
具体的，本发明提供的共晶命名为共晶晶型A，其X射线粉末衍射图在2theta值为17.4°±0.2°、20.7°±0.2°、10.5°±0.2°处具有特征峰。
更进一步的，本发明提供的共晶晶型A，其X射线粉末衍射图还在2theta值为21.1°±0.2°、24.6°±0.2°、12.2°±0.2°中的一处或多处具有特征峰。
优选的，本发明提供的共晶晶型A，其X射线粉末衍射图在2theta值为21.1°±0.2°、24.6°±0.2°、12.2°±0.2°中处均有特征峰。
更进一步的，本发明提供的共晶晶型A，其其X射线粉末衍射图还在2theta值为 9.2°±0.2°、15.0°±0.2°、23.4°±0.2°中的一处或多处具有特征峰。
优选的，本发明提供的共晶晶型A，其X射线粉末衍射图在2theta值为9.2°±0.2°、15.0°±0.2°、23.4°±0.2°处均有特征峰。
根据本发明的一个具体且优选的方面，共晶晶型A的X射线粉末衍射图基本如图1所示。进一步的，该X射线粉末衍射图中共显示了26个衍射峰，这些衍射峰的位置以及相对峰强度如表1或表2所示，其中，峰位置在0.2°范围内变化。
根据本发明的又一个具体的方面，共晶晶型A的X射线粉末衍射图中共显示了34个衍射峰，这些衍射峰的位置以及相对峰强度如表3所示，其中，峰位置在0.2°范围内变化。
优选的，所述共晶晶型A以差示扫描量热测定的图谱中显示在170±2℃开始出吸热热峰。
优选的，所述共晶晶型A以热重分析测定的图谱中显示在加热至120±2℃，具有约1.8％的重量损失梯度。
根据本发明，共晶晶型A可通过将奥拉帕尼和尿素在醇类、酮类、烷基腈、环醚类中的一种或多种溶剂体系中反应制得。其中醇类溶剂优选乙醇，酮类溶剂优选丙酮，烷基腈类溶剂优选乙腈、环醚类溶剂优选四氢呋喃、1，4-二氧六环。
本发明的另一个目的是提供一种奥拉帕尼与尿素的共晶的制备方法，其包括将奥拉帕尼和尿素在醇类、酮类、烷基腈、环醚类中的一种或多种溶剂体系中反应，通过包括但不限于挥发、搅拌或降温等析晶方法得到。
更进一步的，所述醇类溶剂优选乙醇，所述酮类溶剂优选丙酮。
根据本发明的一个具体且优选方面，将含奥拉帕尼、尿素和溶剂的混合体系进行多次加热恒温降温操作，有固体析出，过滤，洗涤，干燥，即得本发明所述共晶晶型A。其中优选的，溶剂为乙醇或丙酮或二者的组合。优选的，以奥拉帕尼游离碱为原 料，将其溶解于所述溶剂中，再加入尿素获得所述含奥拉帕尼、尿素和溶剂的混合体系。所述的加热恒温降温操作是指先将体系加热至一设定的高于室温的较高温度，然后恒温一设定时间，最后降温至一设定的低于室温的较低温度。所述设定的较高温度可以为例如40～80℃，优选为50～70℃，更优选为55～65℃，一个具体的较高温度值为60℃左右。所述设定的较低温度可以为例如-5～18℃，优选为-5～10℃，更优选为-5～5℃，最优选为0～5℃。所述加热的速率可以为0.5～3℃/min，优选1～2℃/min。所述降温的速率可以为0.1～1℃/min，优选0.3～0.6℃/min。所述恒温时间优选为5小时以上，更优选为8小时以上，进一步优选为9小时以上，更优选为9～12小时，具体例如10小时。所述的加热恒温降温操作的次数优选为2次～4次，最优选为3次。
根据本发明的一个具体优选实施方案，较高温度为40～80℃，较低温度为-5～18℃，恒温的时间为5小时以上。在进一步的优选方案中，较高温度为55～65℃，较低温度为0～5℃，恒温的时间为9～11小时。
本发明的另一个目的是提供一种药用组合物和利用其治疗癌症的方法，药用组合物包含奥拉帕尼与尿素的共晶，以及至少一种药学上可接受的赋形剂。治疗癌症的方法包括将向癌症患者施加有效量的所述药物组合物。
根据本发明，所述癌症包括但不限于黑色素瘤、胰腺癌、卵巢癌、乳腺癌、淋巴瘤、肺癌等。
本发明的有益效果为：
本发明提供的奥拉帕尼与尿素的共晶稳定性好，且具有较低的引湿性，在制备过程中无需特殊的干燥条件，简化了药品的制备与后处理工艺，易于工业化生产。并且，在不同湿度条件下水分含量基本保持不变，便于药品的长期贮存，具有很强的经济价值。
本发明提供的奥拉帕尼与尿素的共晶比专利CN101528714B中公开的游离碱晶型 A溶解度更高，有利于提高药物吸收效率，提高药物的生物利用度，对于药物疗效及安全性的提高具有重要意义。
附图说明
图1为共晶晶型A的XRPD图；
图2为共晶晶型A的DSC图；
图3为共晶晶型A的TGA图；
图4为共晶晶型A的DVS图；
图5为专利CN101528714B中游离碱晶型A的DVS图；
图6为共晶晶型A的1H NMR图。
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施；所述的奥拉帕尼的粉末通过市售的方法获得。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu，Kα
Kα1
Figure PCTCN2016079430-appb-000003
：1.540598；Kα2
Figure PCTCN2016079430-appb-000004
：1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q200上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min；
保护气体：氮气。
本发明所述的热重分析(TGA)图在TA Q5000上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min；
保护气体：氮气。
实施例1
奥拉帕尼与尿素共晶晶型A的制备：
将10.0mg奥拉帕尼游离碱(无定形)溶于0.6mL乙醇中，加入11.8mg尿素，以加热速率1.0℃/min加热至60℃后，在60℃下搅拌600min，然后以0.37℃/min的降温速率降温至5℃，重复上述加热降温过程三次，反应结束后，过滤，所得的固体用乙醇洗涤，干燥，收集固体。经检测，本实施例得到的固体为共晶晶型A，其XRPD图如图1，其X射线粉末衍射数据如表1所示。其DSC图如图2，其TGA图如图3，其1H NMR图如图6。
上述方法制备得到的奥拉帕尼与尿素的共晶产品，其1H NMR鉴定数据如下：
1H NMR(400MHz，DMSO)δ12.57(s，1H)，8.26(d，J＝7.8Hz，1H)，7.97(d，J＝7.9Hz，1H)，7.89(t，J＝6.9Hz，1H)，7.83(t，J＝7.5Hz，1H)，7.44(dd，J＝8.2，5.3Hz，1H)，7.37 (d，J＝5.5Hz，1H)，7.24(t，J＝9.1Hz，1H)，4.33(s，2H)，3.59(t，J＝60.4Hz，6H)，3.26-3.08(m，2H)，1.97(s，1H)，0.73(t，J＝7.0Hz，4H)。
表1
2theta d间隔 强度％
6.66 13.26 7.31
9.21 9.60 1.89
10.50 8.42 3.50
12.20 7.25 3.96
13.34 6.64 1.29
15.00 5.90 2.17
17.41 5.09 22.35
18.51 4.79 1.72
18.66 4.75 1.24
20.10 4.42 1.96
20.67 4.30 9.65
21.10 4.21 2.38
22.23 4.00 100.00
22.29 3.99 50.88
23.45 3.79 1.95
24.56 3.62 4.74
25.18 3.53 1.45
26.24 3.39 0.82
26.90 3.31 0.53
29.58 3.02 2.83
30.30 2.95 1.17
31.68 2.82 0.27
32.94 2.72 0.54
33.69 2.66 0.52
35.51 2.53 1.80
37.06 2.42 1.08
实施例2
奥拉帕尼与尿素的共晶的制备方法：101.9mg的奥拉帕尼游离碱溶于3.0mL的乙醇 中，加入98.7mg的尿素，以加热速率1.0℃/min加热至60℃后，在60℃下搅拌600min，然后以降温速率0.37℃/min降温至5℃，重复上述加热降温过程三次，反应结束后过滤，所得的固体用乙醇洗涤，干燥。
经检测，本实施例得到固体为晶型A，其X射线粉末衍射数据如表2所示。
表2
2theta d间隔 强度％
3.19 27.69 3.95
6.66 13.28 17.03
9.21 9.60 14.41
10.48 8.44 23.01
12.20 7.25 16.21
13.34 6.64 4.44
14.99 5.91 11.75
17.41 5.09 80.90
18.49 4.80 13.15
18.65 4.76 8.79
19.54 4.54 3.32
20.11 4.42 7.32
20.66 4.30 50.82
21.08 4.21 20.78
23.43 3.80 10.94
24.18 3.68 4.12
24.56 3.62 20.51
25.15 3.54 10.06
26.23 3.40 6.73
26.92 3.31 2.25
27.65 3.23 4.14
29.56 3.02 12.32
30.26 2.95 9.71
32.94 2.72 2.59
33.69 2.66 3.30
37.04 2.43 8.81
实施例3
奥拉帕尼与尿素共晶的制备：
将10.0mg奥拉帕尼游离碱(无定形)溶于0.6mL丙酮中，加入10.8mg尿素，以加 热速率1.0℃/min加热至60℃后，在60℃下搅拌600min，降温(降温速率0.37℃/min)至5℃，重复上述加热降温过程三次，反应结束后过滤，所得的固体用乙醇洗涤，干燥，冷却至室温，收集固体。
经检测，本实施例得到固体与实施例1所得晶型一致，为共晶晶型A，其X射线粉末衍射数据如表3所示。
表3
2theta d间隔 强度％
6.66 13.27 20.43
9.21 9.61 5.31
10.50 8.42 11.34
12.21 7.25 12.27
13.35 6.63 4.90
15.00 5.91 9.33
17.42 5.09 70.03
17.99 4.93 8.66
18.50 4.80 5.88
19.57 4.54 17.94
20.14 4.41 17.07
20.69 4.29 40.92
20.95 4.24 21.27
22.24 4.00 100.00
23.45 3.79 35.47
24.20 3.68 11.50
24.61 3.62 40.84
25.06 3.55 19.08
25.83 3.45 8.99
26.25 3.40 21.52
26.92 3.31 2.58
27.65 3.23 1.87
28.46 3.14 8.85
29.32 3.05 25.61
29.57 3.02 10.60
30.30 2.95 5.67
30.66 2.92 2.26
31.68 2.82 3.65
32.89 2.72 4.79
33.72 2.66 3.40
34.17 2.62 3.16
35.52 2.53 6.99
37.10 2.42 7.77
38.25 2.35 2.84
实施例4
共晶晶型A和专利CN101528714B中游离碱晶型A引湿性对比研究：
分别取10mg本发明的共晶晶型A与专利CN101528714B中游离碱晶型A进行动态水分吸附(DVS)测试，然后取样测XRPD。结果如表4，共晶晶型A的DVS图如图4所示，专利CN101528714B中游离碱晶型A的DVS如图5所示。
结果表明，在25℃，80％和95％相对湿度条件下，本发明的共晶晶型A的增重均比专利CN101528714B中的游离碱晶型A低，表明本发明的共晶晶型A引湿性更低。
表4
Figure PCTCN2016079430-appb-000005
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录XIX J药物引湿性试验指导原则)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
实施例5
共晶晶型A和专利CN101528714B中游离碱晶型A溶解度对比研究：
将本发明制备得到的共晶晶型A和CN101528714B中游离碱晶型A分别用pH 1.8的SGF(模拟人工胃液)，pH6.5FaSSIF(空腹状态下人工肠液)配制成饱和溶液，在1个小时和4个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。实验结果如表4所示。
表4
Figure PCTCN2016079430-appb-000006
通过上述对比结果可以看出，在SGF中放置1个小时后，4个小时后本发明的尿素共晶晶型A与专利游离碱晶型A相比，溶解度更高；在FaSSIF中放置4小时后本发明的尿素共晶晶型A溶解度更高。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (17)

  1. 一种式(I)化合物与尿素的共晶。
    Figure PCTCN2016079430-appb-100001
  2. 根据权利要求1所述的共晶，其特征在于：所述共晶的结构式如式(II)所示。
    Figure PCTCN2016079430-appb-100002
  3. 根据权利要求1或2所述的共晶，包括共晶晶型A，其特征在于：所述共晶晶型A的X射线粉末衍射图在2theta值为17.4°±0.2°、20.7°±0.2°、10.5°±0.2°处具有特征峰。
  4. 根据权利要求3所述的共晶，其特征在于：所述共晶晶型A的X射线粉末衍射图还在2theta值为21.1°±0.2°、24.6°±0.2°、12.2°±0.2°中的一处或多处具有特征峰。
  5. 根据权利要求4所述的共晶，其特征在于：所述共晶晶型A的X射线粉末衍射图在2theta值为21.1°±0.2°、24.6°±0.2°、12.2°±0.2°处均具有特征峰。
  6. 根据权利要求3至5中任一项权利要求所述的共晶，其特征在于：所述共晶晶型A的X射线粉末衍射图还在2theta值为9.2°±0.2°、15.0°±0.2°、23.4°±0.2°中的一处或多处具有特征峰。
  7. 根据权利要求6所述的共晶，其特征在于：所述共晶晶型A的X射线粉末衍射图在2theta值为9.2°±0.2°、15.0°±0.2°、23.4°±0.2°处均具有特征峰。
  8. 一种如权利要求1至7中任一项权利要求所述的共晶的制备方法，其特征在于：将奥拉帕尼和尿素在醇类、酮类、烷基腈、环醚类中的一种或多种溶剂体系中反应，通过挥发、搅拌或降温析晶得到。
  9. 根据权利要求8所述的制备方法，其特征在于，所述醇类溶剂包括乙醇，所述酮类溶剂包括丙酮。
  10. 一种如权利要求1至7中任一项权利要求所述的共晶的制备方法，其特征在于：将含奥拉帕尼、尿素和溶剂的混合体系进行多次加热恒温降温操作，有固体析出，过滤，洗涤，干燥，即得共晶晶型A，所述的加热恒温降温操作是指先将体系加热至一设定的高于室温的较高温度，然后恒温一设定时间，最后降温至一设定的低于室温的较低温度。
  11. 根据权利要求10所述的制备方法，其特征在于：所述溶剂为乙醇或丙酮或二者的组合。
  12. 根据权利要求10所述的制备方法，其特征在于：所述较高温度为40～80℃，所述较低温度为-5～18℃，所述恒温的时间为5小时以上。
  13. 根据权利要求12所述的制备方法，其特征在于：所述较高温度为55～65℃，所述较低温度为0～5℃，所述恒温的时间为9～11小时。
  14. 根据权利要求10至13中任意一项权利要求所述的制备方法，其特征在于：所述的加热恒温降温操作的次数为2次，3次或4次。
  15. 一种药用组合物，其特征在于：所述药用组合物包含权利要求1至7中任意一项所述的共晶及药学上可接受的赋形剂。
  16. 一种治疗癌症的方法，其特征在于：包括向癌症患者施用有效量的权利要求15所述的药物组合物。
  17. 如权利要求1至7中任意一项所述的共晶在制备治疗癌症药物制剂中的应用。
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