技术领域technical field
本发明涉及化学医药领域，特别是涉及奥拉帕尼的晶型I及其制备方法。The invention relates to the field of chemistry and medicine, in particular to the crystal form I of olaparib and a preparation method thereof.
背景技术Background technique
奥拉帕尼首先由英国生物技术公司KuDOS(库多斯)药物有限公司研发，被阿斯利康收购后，继续研发的一款治疗卵巢癌的药物。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。Olapani was first developed by the British biotechnology company KuDOS (Kudos) Pharmaceutical Co., Ltd. After being acquired by AstraZeneca, it continued to develop a drug for the treatment of ovarian cancer. On December 19, 2014, Olaparib was approved by the FDA for marketing in the United States. It is the first targeted drug approved by the FDA for ovarian cancer patients with BRCA mutations, and is suitable for patients who have previously undergone chemotherapy. It has been demonstrated in preclinical models that olaparib is a first-in-class oral poly ADP ribose polymerase (PARP) inhibitor that exploits defects in the DNA repair pathway to preferentially kill cancer cells.
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：The chemical name of olaparib is 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one, and its structure is as follows: I) Shown:
KuDOS(库多斯)药物有限公司在专利CN101528714B公开了奥拉帕尼的游离碱晶型A和一个溶剂合物晶型，在CN101821242B公开了奥拉帕尼的游离碱晶型L。尚无其他公司公开奥拉帕尼的晶型专利。KuDOS (Kudos) Pharmaceutical Co., Ltd. disclosed the free base crystal form A and a solvate crystal form of olaparib in patent CN101528714B, and disclosed the free base crystal form L of olaparib in CN101821242B. No other company has disclosed the patent of the crystal form of olaparib.
固体化学药物晶型不同，可造成其溶解度和稳定性不同，从而影响药物的吸收和生物利用度，并且会导致临床药效的差异。因此，有必要对式(I)化合物进行全面系统的多晶型筛选，选择最适合开发的晶型。Different crystal forms of solid chemical drugs can cause different solubility and stability, which will affect drug absorption and bioavailability, and lead to differences in clinical efficacy. Therefore, it is necessary to conduct a comprehensive and systematic polymorphic screening of the compound of formula (I) to select the most suitable crystal form for development.
本发明的发明人开发出了一种奥拉帕尼的新晶型，该新晶型稳定性更好，溶解度、引湿性符合药用要求，且制备方法所用溶剂无毒环保，对未来该药物的优化和开发具有重要价值，为药物固体制剂提供一个更好的选择。The inventors of the present invention have developed a new crystal form of olaparib. The new crystal form has better stability, solubility and hygroscopicity meet the requirements of medicine, and the solvent used in the preparation method is non-toxic and environmentally friendly. The optimization and development of is of great value, providing a better choice for pharmaceutical solid preparations.
发明内容Contents of the invention
本发明的一个目的是提供奥拉帕尼的一种新晶型，命名为晶型I。One object of the present invention is to provide a new crystal form of olaparib named as crystal form I.
具体的，本发明提供的晶型I，其特征在于，其X射线粉末衍射图在2theta值为6.4°±0.2°、12.7°±0.2°、15.1°±0.2°处具有特征峰。Specifically, the crystal form I provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 6.4°±0.2°, 12.7°±0.2°, and 15.1°±0.2°.
更进一步的，本发明提供的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为6.9°±0.2°、19.7°±0.2°、22.2°±0.2°处具有特征峰。Furthermore, the crystal form I provided by the present invention is also characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 6.9°±0.2°, 19.7°±0.2°, and 22.2°±0.2°.
更进一步的，本发明提供的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为17.7°±0.2°、20.2°±0.2°、21.0°±0.2°处具有特征峰。Furthermore, the crystal form I provided by the present invention is also characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 17.7°±0.2°, 20.2°±0.2°, and 21.0°±0.2°.
本发明提供的晶型I，其特征在于，其X射线粉末衍射图基本如图1所示。The crystal form I provided by the present invention is characterized in that its X-ray powder diffraction pattern is basically as shown in FIG. 1 .
本发明提供的晶型I，其特征在于，其差示扫描量热分析图基本如图2所示。The crystal form I provided by the present invention is characterized in that its differential scanning calorimetry diagram is basically as shown in FIG. 2 .
本发明提供的晶型I，其特征在于，其热重分析图基本如图3所示。The crystal form I provided by the present invention is characterized in that its thermogravimetric analysis diagram is basically as shown in FIG. 3 .
本发明的另一个目的是提供一种奥拉帕尼的晶型I的制备方法，其特征在于，将奥拉帕尼的固体置于纯水或含水溶剂中搅拌得到。Another object of the present invention is to provide a method for preparing the crystal form I of olaparib, which is characterized in that it is obtained by stirring the solid of olaparib in pure water or an aqueous solvent.
更进一步的，所述含水溶剂，包括含水体积不小于80％的混合溶剂。Furthermore, the aqueous solvent includes a mixed solvent with a water volume not less than 80%.
更进一步的，所述含水溶剂，其特征在于，包括醇类、酮类、醚类、烷烃类、芳香类溶剂。Furthermore, the water-containing solvent is characterized in that it includes alcohols, ketones, ethers, alkanes, and aromatic solvents.
本发明的另一个目的是提供一种药用组合物，包含有效量的奥拉帕尼的晶型I共晶，以及至少一种药学上可接受的赋形剂。Another object of the present invention is to provide a pharmaceutical composition, comprising an effective amount of the crystalline form I co-crystal of olaparib, and at least one pharmaceutically acceptable excipient.
更进一步的，本发明所述的药用组合物中，奥拉帕尼的晶型I可用于制备治疗癌症药物制剂中的用途。Furthermore, in the pharmaceutical composition of the present invention, the crystalline form I of olaparib can be used in the preparation of pharmaceutical preparations for treating cancer.
更进一步的，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。Furthermore, the cancer includes but not limited to melanoma, pancreatic cancer, ovarian cancer, breast cancer, lymphoma, and lung cancer.
本发明的有益效果为：The beneficial effects of the present invention are:
本发明提供的奥拉帕尼的晶型I稳定性比专利CN101528714B中的晶型A更好,在制备、储存以及制剂开发过程中都能够保持稳定，不会发生转晶，对该药物的开发意义巨大。The crystal form I of olaparib provided by the present invention is more stable than the crystal form A in the patent CN101528714B, and can remain stable during preparation, storage and formulation development without crystal transformation. It means a lot.
本发明提供的奥拉帕尼的晶型I的制备方法，工艺简单，所用溶剂无毒环保，对未来该药物的优化和开发具有重要价值，为药物固体制剂提供一个更好的选择。The preparation method of the crystal form I of olaparib provided by the present invention has a simple process, and the solvent used is non-toxic and environmentally friendly, which is of great value to the optimization and development of the drug in the future, and provides a better choice for the solid preparation of the drug.
附图说明Description of drawings
图1为晶型I的XRPD图Figure 1 is the XRPD pattern of Form I
图2为晶型I的DSC图Figure 2 is the DSC diagram of Form I
图3为晶型I的TGA图Figure 3 is the TGA diagram of Form I
具体实施方式detailed description
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。The following will further illustrate the present invention through specific examples, but it is not intended to limit the protection scope of the present invention. Those skilled in the art can make improvements to the preparation method and the equipment used within the scope of the claims, and these improvements should also be considered as the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention should be based on the appended claims.
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。In the following examples, the test methods are usually implemented under conventional conditions or conditions suggested by the manufacturer.
本发明中所用到的缩写的解释如下：The abbreviations used in the present invention are explained as follows:
XRPD：X射线粉末衍射XRPD: X-ray powder diffraction
DSC：差示扫描量热分析DSC: Differential Scanning Calorimetry
TGA：热重分析TGA: Thermal Gravimetric Analysis
本发明所述的X射线粉末衍射图在PanalyticalEmpyreanX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：The X-ray powder diffraction pattern described in the present invention is collected on a Panalytical Empyrean X-ray powder diffractometer. The method parameter of X-ray powder diffraction of the present invention is as follows:
X射线反射参数：Cu,KαX-ray reflection parameters: Cu, Kα
Kα1：1.540598；Kα2：1.544426Kα1 : 1.540598; Kα2 : 1.544426
Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50
电压：45仟伏特(kV)Voltage: 45 kilovolts (kV)
电流：40毫安培(mA)Current: 40 milliamps (mA)
扫描范围：自3.0至40.0度Scanning range: from 3.0 to 40.0 degrees
本发明所述的差示扫描量热分析(DSC)图在TAQ2000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：The differential scanning calorimetry (DSC) diagrams of the present invention were collected on TAQ2000. The method parameter of differential scanning calorimetry (DSC) of the present invention is as follows:
扫描速率：10℃/minScanning rate: 10°C/min
保护气体：氮气Protective gas: nitrogen
本发明所述的热重分析(TGA)图在TAQ5000上采集。本发明所述的热重分析(TGA)的方法参数如下：The thermogravimetric analysis (TGA) figure of the present invention is collected on TAQ5000. The method parameters of thermogravimetric analysis (TGA) of the present invention are as follows:
扫描速率：10℃/minScanning rate: 10°C/min
保护气体：氮气Protective gas: nitrogen
实施例1Example 1
奥拉帕尼晶型I的制备方法：The preparation method of olaparib crystal form I:
将10.0mg的奥拉帕尼游离碱溶解于1.0mL的纯水中，室温下搅拌7天，抽滤，干燥，收集固体，经检测，本实施例制备得到的晶型是晶型I。Dissolve 10.0 mg of olaparib free base in 1.0 mL of pure water, stir at room temperature for 7 days, filter with suction, dry, and collect the solid. After testing, the crystal form prepared in this example is crystal form I.
本实施例得到的晶型的X射线粉末衍射数据如表1所示。其XRPD图如图1，其DSC图如图2，其TGA图如图3。Table 1 shows the X-ray powder diffraction data of the crystal forms obtained in this example. Its XRPD diagram is shown in Figure 1, its DSC diagram is shown in Figure 2, and its TGA diagram is shown in Figure 3.
表1Table 1
实施例2Example 2
奥拉帕尼晶型I的制备方法：The preparation method of olaparib crystal form I:
将10.0mg专利CN101528714B中的奥拉帕尼晶型A加入到0.5mL的纯水中，再加入1.0mg晶型I的晶种，室温下搅拌72小时，抽滤，用纯水洗涤，干燥，收集固体，经检测，本实施例制备得到的晶型是晶型I。Add 10.0 mg of olaparib crystal form A in patent CN101528714B to 0.5 mL of pure water, then add 1.0 mg of crystal form I seed crystals, stir at room temperature for 72 hours, filter with suction, wash with pure water, and dry. The solid was collected, and it was detected that the crystalline form prepared in this example was crystalline form I.
本实施例得到的晶型I的X射线粉末衍射数据如表2所示。Table 2 shows the X-ray powder diffraction data of Form I obtained in this example.
表2Table 2
实施例3Example 3
奥拉帕尼晶型I和专利CN101528714B中晶型A的稳定性对比试验：Stability comparative test of olaparib crystal form I and crystal form A in patent CN101528714B:
分别取10.0mg专利CN101528714B中的晶型A和1.0mg实施例1中制备得到的晶型I于一个小瓶中，加入0.5mL纯水，制成悬浊液。在室温下搅拌72小时后，测试样品的XRPD，专利CN101528714B中的晶型A已经全部转化为本发明中的晶型I，结果如表3所示。Take 10.0 mg of the crystal form A in patent CN101528714B and 1.0 mg of the crystal form I prepared in Example 1 respectively in a vial, add 0.5 mL of pure water to make a suspension. After stirring at room temperature for 72 hours, the XRPD of the test sample showed that the crystal form A in the patent CN101528714B had been completely transformed into the crystal form I in the present invention, and the results are shown in Table 3.
表3table 3
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010211575.3ACN112010809A (en) | 2015-06-12 | 2015-06-12 | Crystal form I of olaparib and preparation method thereof |
| CN201510320070.XACN105439961A (en) | 2015-06-12 | 2015-06-12 | Crystal form I of olaparib and preparation method thereof |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510320070.XACN105439961A (en) | 2015-06-12 | 2015-06-12 | Crystal form I of olaparib and preparation method thereof |
| Application Number | Title | Priority Date | Filing Date |
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| CN202010211575.3ADivisionCN112010809A (en) | 2015-06-12 | 2015-06-12 | Crystal form I of olaparib and preparation method thereof |
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| CN105439961Atrue CN105439961A (en) | 2016-03-30 |
| Application Number | Title | Priority Date | Filing Date |
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| CN201510320070.XAPendingCN105439961A (en) | 2015-06-12 | 2015-06-12 | Crystal form I of olaparib and preparation method thereof |
| CN202010211575.3APendingCN112010809A (en) | 2015-06-12 | 2015-06-12 | Crystal form I of olaparib and preparation method thereof |
| Application Number | Title | Priority Date | Filing Date |
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| CN202010211575.3APendingCN112010809A (en) | 2015-06-12 | 2015-06-12 | Crystal form I of olaparib and preparation method thereof |
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| US10662178B2 (en) | 2018-01-31 | 2020-05-26 | Apotex Inc. | Crystalline form of Olaparib |
| US10703728B1 (en) | 2019-06-18 | 2020-07-07 | Scinopharm Taiwan, Ltd. | Crystalline form of olaparib and a process for preparing the same |
| CN111689905A (en)* | 2020-07-22 | 2020-09-22 | 天津理工大学 | Eutectic of olaparib and maleic acid and preparation method thereof |
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| US10138211B2 (en) | 2016-01-14 | 2018-11-27 | Scinopharm Taiwan, Ltd. | Crystalline forms of olaparib and manufacturing processes therefor |
| US10662178B2 (en) | 2018-01-31 | 2020-05-26 | Apotex Inc. | Crystalline form of Olaparib |
| US10703728B1 (en) | 2019-06-18 | 2020-07-07 | Scinopharm Taiwan, Ltd. | Crystalline form of olaparib and a process for preparing the same |
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| CN111995582B (en)* | 2020-07-09 | 2021-12-03 | 天津理工大学 | Eutectic of olaparib and urea and preparation method thereof |
| CN111689905A (en)* | 2020-07-22 | 2020-09-22 | 天津理工大学 | Eutectic of olaparib and maleic acid and preparation method thereof |
| CN111689905B (en)* | 2020-07-22 | 2021-12-03 | 天津理工大学 | Eutectic of olaparib and maleic acid and preparation method thereof |
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