WO2023098848A1 - Osimertinib co-crystal, preparation method, and application as drug or in pharmaceutical formulation - Google Patents
Osimertinib co-crystal, preparation method, and application as drug or in pharmaceutical formulation Download PDFInfo
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- WO2023098848A1 WO2023098848A1 PCT/CN2022/136087 CN2022136087W WO2023098848A1 WO 2023098848 A1 WO2023098848 A1 WO 2023098848A1 CN 2022136087 W CN2022136087 W CN 2022136087W WO 2023098848 A1 WO2023098848 A1 WO 2023098848A1
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
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Definitions
- the present invention relates to a co-crystal formed by osimertinib, a preparation method thereof and its application as a medicine or in a pharmaceutical preparation for treating non-small cell lung cancer, especially for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC), Patients whose tumors have an epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation, and who treat metastatic EGFR T790M mutation-positive NSCLC whose disease follows EGFR tyrosine kinase inhibitor (TKI) therapy or later develop.
- EGFR epidermal growth factor receptor
- TKI tyrosine kinase inhibitor
- Non-small cell lung cancer is one of the most common malignant tumors in the world, and it has become the first cause of death from malignant tumors in urban population in my country.
- Non-small cell lung cancer includes squamous cell carcinoma (squamous cell carcinoma), adenocarcinoma, and large cell carcinoma. Compared with small cell carcinoma, its cancer cells grow and divide more slowly, and spread and metastasize relatively later.
- Non-small cell lung cancer accounts for about 80% of all lung cancers, and about 75% of the patients are in the advanced stage when they are discovered, and the 5-year survival rate is very low.
- Osimertinib mainly acts by binding to the Cys-797 residue, and for this site, AZD9291 will produce C797S mutation acquired drug resistance after an average of about 9.6 months of clinical use.
- the original research company adopted osimertinib mesylate for clinical research.
- mesylate has the problems of high toxicity, high hygroscopicity and high humidity and is easy to deliquesce, so it is not suitable for use in pharmaceuticals under selective conditions. Therefore, it is necessary to develop drugs with high bioavailability, low toxicity and longer drug resistance time.
- Drug co-crystallization technology refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bond or other non-covalent bonds. From a chemical point of view, the API molecule itself has not changed. Therefore, the original drug effect is still maintained, but the solubility, bioavailability, stability and other aspects of the co-crystal drug will be greatly improved, especially for the development of some oral pharmaceutical preparations.
- API active pharmaceutical ingredient
- CCF co-crystal former
- the co-crystals of the present invention may meet one or more objectives such as, but not limited to, improved solubility, stability and bioavailability and more permeability in pharmaceutical applications.
- the present invention relates to co-crystals of osimertinib and gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid.
- the active substance is selected from osimertinib
- the co-crystal precursor is selected from gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3 ,4-Dihydroxystyrene acid.
- Osimertinib active pharmaceutical ingredient API
- gallic acid citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid (co-crystal precursor) by When hydrogen-bonded together, the co-crystals of the present invention are formed. In some embodiments, other non-covalent bonds and covalent interactions may also exist in the co-crystal.
- One aspect of the invention contemplates osimertinib-based co-crystals that provide sufficient levels of bioavailability to be therapeutically effective in pharmaceutical applications and to maintain levels for a therapeutically effective period of time.
- the osimertinib co-crystal designed in the present invention has better solubility and stability, is convenient for storage and use; and can be directly used in the preparation of solid preparations, and has good powder properties.
- Figure 1 shows the X-ray powder diffraction (XRPD) pattern of osimertinib and gallic acid co-crystal.
- Figure 2 shows the X-ray powder diffraction (XRPD) pattern of osimertinib and citric acid co-crystal.
- Figure 3 shows the X-ray powder diffraction (XRPD) pattern of osimertinib and salicylic acid co-crystal.
- Figure 4 shows the X-ray powder diffraction (XRPD) pattern of the co-crystal of osimertinib and fumaric acid.
- Figure 5 shows the X-ray powder diffraction (XRPD) pattern of the co-crystal of osimertinib and 4-aminobenzoic acid.
- Figure 6 shows the X-ray powder diffraction (XRPD) pattern of the co-crystal of osimertinib and 3,4-dihydroxystyrene acid.
- Figure 7 shows the effect of osimertinib co-crystal on the viability of NCI-H1975 cells.
- Figure 8 shows the effect of osimertinib co-crystal on the viability of NCI-H1975/OSIR cells.
- the invention relates to a co-crystal of osimertinib and a preparation method thereof.
- the co-crystal contains osimertinib and the co-crystal precursors gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid.
- osimertinib and gallic acid are combined in a 1:1 ratio.
- the co-crystal has an XRPD pattern comprised of 5.620°, 8.600°, 14.280°, 15.879°, 17.341°, 18.739°, 20.180° and 24.400° (rounded to 5.6°, 8.6°, 14.3°, 15.9°, respectively , 17.3°, 18.7°, 20.2° and 24.4°) (corresponding to d-spacing) peaks at diffraction angles 2 ⁇ of ⁇ 0.2°.
- the co-crystal comprises an XRPD pattern at diffraction angles 2 ⁇ of 5.620°, 8.600°, 14.280°, 15.879°, 17.341°, 18.739°, 20.180°, and 24.400° ⁇ 0.1°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2 ⁇ of 5.620°, 8.600°, 14.280°, 15.879°, 17.341°, 18.739°, 20.180°, and 24.400° ⁇ 0.05°. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 1 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 1 .
- osimertinib and citric acid are combined in a 1:1 ratio.
- the co-crystal contained an X-ray diffraction pattern as shown in FIG. 2 .
- the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 2 .
- osimertinib and salicylic acid co-crystal are combined in a 1:1 ratio.
- the co-crystal has an XRPD pattern comprised of 5.700°, 12.560°, 15.040°, 18.220°, 18.739°, 19.381°, 19.918° and 25.040° (rounded to 5.7°, 12.6°, 15.0°, 18.2°, respectively , 18.7°, 19.4°, 19.9 and 25.0°) (corresponding to d-spacing) peaks at diffraction angles 2 ⁇ of ⁇ 0.2°.
- the co-crystal comprises an XRPD pattern at diffraction angles 2 ⁇ of 5.700°, 12.560°, 15.040°, 18.220°, 18.739°, 19.381°, 19.918° and 25.040° ⁇ 0.1°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2 ⁇ of 5.700°, 12.560°, 15.040°, 18.220°, 18.739°, 19.381°, 19.918° and 25.040° ⁇ 0.05°. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 3 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 3 .
- osimertinib and fumaric acid cocrystal are combined in a 1:1 ratio.
- the co-crystal has an XRPD pattern comprised of 5.019°, 10.001°, 11.398°, 13.282°, 13.619°, 15.120°, 15.939° and 18.221° (rounded to 5.0°, 10.0°, 11.4°, 13.3°, respectively , 13.6°, 15.1°, 15.9° and 18.2°) (corresponding to d-spacing) peaks at diffraction angles 2 ⁇ of ⁇ 0.2°.
- the co-crystal comprises an XRPD pattern at diffraction angles 2 ⁇ of 5.019°, 10.001°, 11.398°, 13.282°, 13.619°, 15.120°, 15.939°, and 18.221° ⁇ 0.1°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2 ⁇ of 5.019°, 10.001°, 11.398°, 13.282°, 13.619°, 15.120°, 15.939°, and 18.221° ⁇ 0.05°. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 4 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 4 .
- osimertinib and 4-aminobenzoic acid co-crystal are combined in a 1:1 ratio.
- the co-crystal has an XRPD pattern.
- the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 5 .
- the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 5 .
- the 2,2-di-n-propylacetamide and 3,4-dihydroxystyrene acid co-crystals are combined in a 1:1 ratio.
- the co-crystal has an XRPD pattern comprised of 5.660°, 7.358°, 9.261°, 9.900°, 11.321°, 11.779°, 12.418° and 14.241° (rounded to 5.7°, 7.4°, 9.3°, 9.9°, respectively , 11.3°, 11.8°, 12.4° and 14.2°) (corresponding to d-spacing) peaks at diffraction angles 2 ⁇ of ⁇ 0.2°.
- the co-crystal comprises an XRPD pattern at diffraction angles 2 ⁇ of 5.660°, 7.358°, 9.261°, 9.900°, 11.321°, 11.779°, 12.418°, and 14.241° ⁇ 0.1°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2 ⁇ of 5.660°, 7.358°, 9.261°, 9.900°, 11.321°, 11.779°, 12.418°, and 14.241° ⁇ 0.05°. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 6 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 6 .
- the co-crystal of the present invention comprises: gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid as co-formers; and Osimertinib, as co-former and active pharmaceutical ingredient (API).
- gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid and osimertinib are combined in a 1:1 ratio.
- the solid state of the co-crystal of the present invention is any crystalline polymorph or other mixture. Co-crystals can also be made in amorphous form, which can be combined with any crystalline form. In other embodiments, the solid state of the co-crystal is an amorphous form, different forms of the co-crystal of the present invention can be obtained by different crystallization processes, and the co-crystal can be made into an amorphous form using known techniques.
- co-crystals of the present invention can be prepared by methods comprising:
- the solvent used is selected from ethanol, acetonitrile; for the citric acid, the solvent used is selected from acetonitrile, ethanol, preferably acetonitrile; for the salicylic acid, the solvent used is selected from ethanol, acetonitrile, preferably Ethanol; for the fumaric acid, the solvent used is selected from water, ethanol; for the 4-aminobenzoic acid, the solvent used is selected from water, ethanol, preferably water; for the 3,4-dihydroxystyrene Acid, the solvent used is selected from acetonitrile, ethanol, preferably ethanol;
- step (b) adding osimertinib to dissolve or suspend in a solvent together with or after step (a);
- reaction time can be selected from 0.1-24 hours, during which the temperature described in (a) is kept and stirred;
- the specific conditions of the process can be adjusted, and the appropriate ratios are in the following molar ranges: 1:0.1-1:20, 1:0.2-1:20, 1:0.3-1:20, 1:0.3-1:20, 0.4-1:20, 1:0.5-1:20, 1:0.6-1:20, 1:0.7-1:20, 1:0.8-1:20, 1:0.9-1:20, 1:1- 1:20, 1:2-1:20, 1:3-1:20, 1:4-1:20, 1:5-1:20, 1:6-1:18, 1:7-1: 15. 1:8-1:13, 1:9-1:12 or 1:10-1:11.
- a suitable ratio is about 1:1 (molar).
- the period of time for pulping or stirring the mixture may be in the range of: 0.1-24 hours, 0.2-12 hours, 0.25-6 hours, 0.3-2 hours, 0.4-1 hours, or 0.5-1 hours Hour. In some embodiments, the time period for pulping or stirring the mixture may be about 0.5 hours.
- co-crystal compounds can be obtained by drying, filtering, centrifuging, pipetting, or combinations thereof. In some embodiments, co-crystal compounds can be obtained by centrifugation.
- osimertinib co-crystal The inhibitory effect of osimertinib co-crystal on the proliferation of NCI-H1975 cells and NCI-H1975/OSIR cells was detected by MTT method. As shown in Figures 7 and 8, osimertinib co-crystal can effectively enhance the effect on NCI-H1975 cells and NCI-H1975/OSIR cells, stronger than osimertinib itself, and osimertinib co-crystals have stronger lethality to the two types of cells.
- NCI-H1975 cells When the concentration of osimertinib reaches 20 ⁇ M, NCI-H1975 cells The survival rate is only about 30%, and the survival rate of NCI-H1975/OSIR cells is also lower than 50%, indicating that the osimertinib co-crystal enhances the anti-tumor effect of the drug and shows a strong anti-tumor effect.
- Osimertinib co-crystal inhibits non-small cell lung cancer in rats
- the rats were randomly divided into 3 groups, 20 in each group. 1 The 20 rats in the treatment group were given 50 mg/kg (calculated as osimertinib) osimertinib and osimertinib co-crystal by gavage for 14 days continuously. 2 The 20 rats in the model group were administered with normal saline (50mg/kg) for 14 days after successful modeling. 3 The 20 rats in the control group were not modeled, and were only administered intragastrically with normal saline (50 mg/kg) for 14 consecutive days. At the end of the treatment, the animals were sacrificed, the tumor tissues were dissected, and the tumor tissues of the three groups of rats were weighed and the tumor inhibition rates were calculated.
- the tumor weight and tumor volume in the model group and the treatment group increased significantly; compared with the model group, the tumor weight decreased and the tumor inhibition rate increased significantly in the treatment group. And in the treatment group, the tumor inhibition rate of osimertinib co-crystal was significantly higher than that of osimertinib group and osimertinib mesylate group.
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Abstract
Involved are an osimertinib co-crystal, a preparation method therefor, and an application thereof as a drug or in a pharmaceutical formulation, more particularly for treating non-small cell lung cancer. The co-crystal has good solubility, good stability and process developability and the like; and the preparation method is simple and low in cost, and has an important value for optimization and development of the drug in the future.
Description
本发明涉及奥希替尼形成的共晶体及其制备的方法以及它作为药物或在药物制剂中治疗非小细胞肺癌的应用,尤其适用于转移性非小细胞肺癌(NSCLC)患者的一线治疗,其肿瘤具有表皮生长因子受体(EGFR)外显子19缺失或外显子21 L858R突变,和治疗转移性EGFR T790M突变阳性NSCLC患者,其疾病在EGFR酪氨酸激酶抑制剂(TKI)治疗之后或之后发展。The present invention relates to a co-crystal formed by osimertinib, a preparation method thereof and its application as a medicine or in a pharmaceutical preparation for treating non-small cell lung cancer, especially for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC), Patients whose tumors have an epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation, and who treat metastatic EGFR T790M mutation-positive NSCLC whose disease follows EGFR tyrosine kinase inhibitor (TKI) therapy or later develop.
肺癌是世界上最常见的恶性肿瘤之一,已成为我国城市人口恶性肿瘤死亡原因的第1位。非小细胞型肺癌包括鳞状细胞癌(鳞癌)、腺癌、大细胞癌,与小细胞癌相比其癌细胞生长分裂较慢,扩散转移相对较晚。非小细胞肺癌约占所有肺癌的80%,约75%的患者发现时已处于中晚期,5年生存率很低。Lung cancer is one of the most common malignant tumors in the world, and it has become the first cause of death from malignant tumors in urban population in my country. Non-small cell lung cancer includes squamous cell carcinoma (squamous cell carcinoma), adenocarcinoma, and large cell carcinoma. Compared with small cell carcinoma, its cancer cells grow and divide more slowly, and spread and metastasize relatively later. Non-small cell lung cancer accounts for about 80% of all lung cancers, and about 75% of the patients are in the advanced stage when they are discovered, and the 5-year survival rate is very low.
服用吉非替尼(易瑞沙)、国产凯美纳,盐酸厄洛替尼(特罗凯)的患者耐药以后大部分的病人都会产生T790M突变,而这类病人就没有可以替代的药物了,病人几乎是没有了继续生存的可能。英国阿斯利康研发的针对非小细胞晚期肺癌新药Tagrisso(osimertinib),治疗晚期非小细胞肺癌(NSCLC)患者的口服药物的上市给这类患者带来了希望。Most patients who take gefitinib (Iressa), domestic conmana, and erlotinib hydrochloride (Tarceva) will develop T790M mutation after drug resistance, and there is no alternative drug for these patients The patient has almost no possibility of continued survival. The listing of Tagrisso (osimertinib), a new drug for advanced non-small cell lung cancer (NSCLC) developed by AstraZeneca in the United Kingdom, has brought hope to such patients.
瑞典阿斯利康有限公司在专利CN105348266B公开了游离碱或其盐的多种晶型(游离碱有晶型A、晶型B、晶型C、晶型D、晶型E、晶型F、晶型K;其甲磺酸盐有晶型A和晶型B)。其中,晶型D、晶型E和晶型F均为水合物,溶解度不高;另外,在可供选择的情况下,相对于其盐晶型,三个晶型都不利于提高药物的生物利用度及疗效。Sweden AstraZeneca Co., Ltd. discloses various crystal forms of free base or its salt in patent CN105348266B (free base has crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form Form K; its methanesulfonate has crystal form A and crystal form B). Among them, crystal form D, crystal form E, and crystal form F are all hydrates, and their solubility is not high; in addition, in the case of alternatives, compared with their salt crystal forms, the three crystal forms are not conducive to improving the biological properties of drugs. Utilization and efficacy.
奥希替尼主要是通过与Cys-797残基结合产生作用,而针对这个位点,AZD9291会在平均临床用药约9.6个月后产生C797S突变获得性耐药。原研公司采用了奥希替尼甲磺酸盐用于临床研究。然而甲磺酸盐存在毒性大、引湿性高且高湿度易潮解的问题,在有选择的情况下不适合用于成药。因而开发出生物利用度高、毒性小且产生耐药时间更长的药物十分必要。Osimertinib mainly acts by binding to the Cys-797 residue, and for this site, AZD9291 will produce C797S mutation acquired drug resistance after an average of about 9.6 months of clinical use. The original research company adopted osimertinib mesylate for clinical research. However, mesylate has the problems of high toxicity, high hygroscopicity and high humidity and is easy to deliquesce, so it is not suitable for use in pharmaceuticals under selective conditions. Therefore, it is necessary to develop drugs with high bioavailability, low toxicity and longer drug resistance time.
药物共结晶技术是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体,从化学角度讲,API分子本身未发生变化,因此还保持原有的药效,而共晶药物的溶解度,生物利用度,稳定性等方面却会有极大的改善,尤其对于一些口服药物制剂的发展有非常积极的作用。Drug co-crystallization technology refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bond or other non-covalent bonds. From a chemical point of view, the API molecule itself has not changed. Therefore, the original drug effect is still maintained, but the solubility, bioavailability, stability and other aspects of the co-crystal drug will be greatly improved, especially for the development of some oral pharmaceutical preparations.
因此,使用共晶技术改善奥希替尼药物的基础结构,而可以改善其性质,如溶解度,稳定性,渗透性和生物利用度。本发明中的一系列奥希替尼和没食子酸,柠檬酸,水杨酸,反丁烯二酸,4-氨基苯甲酸和3,4-二羟基苯乙烯酸作为共晶前体的共晶。本发明的共晶可以满足一个或多个目标目的,例如不限于提高溶解度,稳定性和生物利用度以及在药物应用中的更多的通透性。Therefore, improving the basic structure of osimertinib drug using co-crystal technology can improve its properties, such as solubility, stability, permeability, and bioavailability. A series of co-crystals of osimertinib and gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid as co-crystal precursors in the present invention . The co-crystals of the present invention may meet one or more objectives such as, but not limited to, improved solubility, stability and bioavailability and more permeability in pharmaceutical applications.
发明内容Contents of the invention
本发明涉及奥希替尼和没食子酸,柠檬酸,水杨酸,反丁烯二酸,4-氨基苯甲酸和3,4-二羟基苯乙烯酸的共晶体。The present invention relates to co-crystals of osimertinib and gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid.
在一些实施方案中,活性物质选自奥希替尼,在一些实施方案中,共晶前体选自没食子酸,柠檬酸,水杨酸,反丁烯二酸,4-氨基苯甲酸和3,4-二羟基苯乙烯酸。In some embodiments, the active substance is selected from osimertinib, and in some embodiments, the co-crystal precursor is selected from gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3 ,4-Dihydroxystyrene acid.
在奥希替尼(活性药物成分API)和没食子酸,柠檬酸,水杨酸,反丁烯二酸,4-氨基苯甲酸和3,4-二羟基苯乙烯酸(共晶前体)通过氢键结合在一起时,形成本发明的共晶。在一些实施方案中,其他非共价键和共价相互作用也可以存在于共晶中。In Osimertinib (active pharmaceutical ingredient API) and gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid (co-crystal precursor) by When hydrogen-bonded together, the co-crystals of the present invention are formed. In some embodiments, other non-covalent bonds and covalent interactions may also exist in the co-crystal.
本发明的一个方面设计提供足够水平的生物利用度的基于奥希替尼的共晶,其在药物应用中是在治疗上有效的并且维持水平,持续在治疗上有效的时间段。One aspect of the invention contemplates osimertinib-based co-crystals that provide sufficient levels of bioavailability to be therapeutically effective in pharmaceutical applications and to maintain levels for a therapeutically effective period of time.
本发明所设计的奥希替尼共晶体,相比较于奥希替尼具有更好溶解度和稳定性,方便存储和使用;并且可直接用于固体制剂的制备,具有良好的粉体学性质。Compared with osimertinib, the osimertinib co-crystal designed in the present invention has better solubility and stability, is convenient for storage and use; and can be directly used in the preparation of solid preparations, and has good powder properties.
图1显示了奥希替尼和没食子酸共晶体的X射线粉末衍射(XRPD)图谱。Figure 1 shows the X-ray powder diffraction (XRPD) pattern of osimertinib and gallic acid co-crystal.
图2显示了奥希替尼和柠檬酸共晶体的X射线粉末衍射(XRPD)图谱。Figure 2 shows the X-ray powder diffraction (XRPD) pattern of osimertinib and citric acid co-crystal.
图3显示了奥希替尼和水杨酸共晶体的X射线粉末衍射(XRPD)图谱。Figure 3 shows the X-ray powder diffraction (XRPD) pattern of osimertinib and salicylic acid co-crystal.
图4显示了奥希替尼和反丁烯二酸共晶体的X射线粉末衍射(XRPD)图谱。Figure 4 shows the X-ray powder diffraction (XRPD) pattern of the co-crystal of osimertinib and fumaric acid.
图5显示了奥希替尼和4-氨基苯甲酸共晶体的X射线粉末衍射(XRPD)图谱。Figure 5 shows the X-ray powder diffraction (XRPD) pattern of the co-crystal of osimertinib and 4-aminobenzoic acid.
图6显示了奥希替尼和3,4-二羟基苯乙烯酸共晶体的X射线粉末衍射(XRPD)图谱。Figure 6 shows the X-ray powder diffraction (XRPD) pattern of the co-crystal of osimertinib and 3,4-dihydroxystyrene acid.
图7显示了奥希替尼共晶体对NCI-H1975细胞存活率的影响。Figure 7 shows the effect of osimertinib co-crystal on the viability of NCI-H1975 cells.
图8显示了奥希替尼共晶体对NCI-H1975/OSIR细胞存活率的影响。本发明涉及奥希替尼的共晶及其制备方法。共晶包含奥希替尼和共晶前体没食子酸,柠檬酸,水杨酸,反丁烯二酸,4-氨基苯甲酸和3,4-二羟基苯乙烯酸。Figure 8 shows the effect of osimertinib co-crystal on the viability of NCI-H1975/OSIR cells. The invention relates to a co-crystal of osimertinib and a preparation method thereof. The co-crystal contains osimertinib and the co-crystal precursors gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid.
在一些实施方案中,奥希替尼和没食子酸以1:1的比例结合。共晶体具有XRPD图谱,所述XRPD图谱包含在5.620°,8.600°,14.280°,15.879°,17.341°,18.739°,20.180°和24.400°(分别四舍五入至5.6°,8.6°,14.3°,15.9°,17.3°,18.7°,20.2°和24.4°)(分别对应于
的d-间距)±0.2°的衍射角2θ处的峰。在一些实施方案中,共晶体包含在5.620°,8.600°,14.280°,15.879°,17.341°,18.739°,20.180°和24.400°±0.1°的衍射角2θ处的XRPD图谱。在一些实施方案中,共晶体包含在5.620°,8.600°,14.280°,15.879°,17.341°,18.739°,20.180°和24.400°±0.05°的衍射角2θ处的XRPD图谱。在一些实施方案中,共晶体包含如图1所示的X射线衍射图谱。在一些实施方案中,共晶体具有基本上类似于图1所示的X射线衍射图谱。
In some embodiments, osimertinib and gallic acid are combined in a 1:1 ratio. The co-crystal has an XRPD pattern comprised of 5.620°, 8.600°, 14.280°, 15.879°, 17.341°, 18.739°, 20.180° and 24.400° (rounded to 5.6°, 8.6°, 14.3°, 15.9°, respectively , 17.3°, 18.7°, 20.2° and 24.4°) (corresponding to d-spacing) peaks at diffraction angles 2θ of ±0.2°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 5.620°, 8.600°, 14.280°, 15.879°, 17.341°, 18.739°, 20.180°, and 24.400° ± 0.1°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 5.620°, 8.600°, 14.280°, 15.879°, 17.341°, 18.739°, 20.180°, and 24.400° ± 0.05°. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 1 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 1 .
在一些实施方案中,奥希替尼和柠檬酸以1:1的比例结合。共晶体包含如图2所示的X射线衍射图谱。在一些实施方案中,共晶体具有基本上类似于图2所示的X射线衍射图谱。In some embodiments, osimertinib and citric acid are combined in a 1:1 ratio. The co-crystal contained an X-ray diffraction pattern as shown in FIG. 2 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 2 .
在一些实施方案中,奥希替尼和水杨酸共晶体以1:1的比例结合。共晶体具有XRPD图谱,所述XRPD图谱包含在5.700°,12.560°,15.040°,18.220°,18.739°,19.381°,19.918°和25.040°(分别四舍五入至5.7°,12.6°,15.0°,18.2°,18.7°,19.4°,19.9和25.0°)(分别对应于
的d-间距)±0.2°的衍射角2θ处的峰。在一些实施方案中,共晶体包含在5.700°,12.560°,15.040°,18.220°,18.739°,19.381°,19.918°和25.040°±0.1°的衍射角2θ处的XRPD图谱。在一些实施方案中,共晶体包含在5.700°,12.560°,15.040°,18.220°,18.739°,19.381°,19.918°和25.040°±0.05°的衍射角2θ处的XRPD图谱。在一些实施方案中,共晶体包含如图3所示的X射线衍射图谱。在一些实施方案中,共晶体具有基本上 类似于图3所示的X射线衍射图谱。
In some embodiments, osimertinib and salicylic acid co-crystal are combined in a 1:1 ratio. The co-crystal has an XRPD pattern comprised of 5.700°, 12.560°, 15.040°, 18.220°, 18.739°, 19.381°, 19.918° and 25.040° (rounded to 5.7°, 12.6°, 15.0°, 18.2°, respectively , 18.7°, 19.4°, 19.9 and 25.0°) (corresponding to d-spacing) peaks at diffraction angles 2θ of ±0.2°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 5.700°, 12.560°, 15.040°, 18.220°, 18.739°, 19.381°, 19.918° and 25.040°±0.1°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 5.700°, 12.560°, 15.040°, 18.220°, 18.739°, 19.381°, 19.918° and 25.040° ± 0.05°. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 3 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 3 .
在一些实施方案中,奥希替尼和反丁烯二酸共晶体以1:1的比例结合。共晶体具有XRPD图谱,所述XRPD图谱包含在5.019°,10.001°,11.398°,13.282°,13.619°,15.120°,15.939°和18.221°(分别四舍五入至5.0°,10.0°,11.4°,13.3°,13.6°,15.1°,15.9°和18.2°)(分别对应于
的d-间距)±0.2°的衍射角2θ处的峰。在一些实施方案中,共晶体包含在5.019°,10.001°,11.398°,13.282°,13.619°,15.120°,15.939°和18.221°±0.1°的衍射角2θ处的XRPD图谱。在一些实施方案中,共晶体包含在5.019°,10.001°,11.398°,13.282°,13.619°,15.120°,15.939°和18.221°±0.05°的衍射角2θ处的XRPD图谱。在一些实施方案中,共晶体包含如图4所示的X射线衍射图谱。在一些实施方案中,共晶体具有基本上类似于图4所示的X射线衍射图谱。
In some embodiments, osimertinib and fumaric acid cocrystal are combined in a 1:1 ratio. The co-crystal has an XRPD pattern comprised of 5.019°, 10.001°, 11.398°, 13.282°, 13.619°, 15.120°, 15.939° and 18.221° (rounded to 5.0°, 10.0°, 11.4°, 13.3°, respectively , 13.6°, 15.1°, 15.9° and 18.2°) (corresponding to d-spacing) peaks at diffraction angles 2θ of ±0.2°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 5.019°, 10.001°, 11.398°, 13.282°, 13.619°, 15.120°, 15.939°, and 18.221° ± 0.1°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 5.019°, 10.001°, 11.398°, 13.282°, 13.619°, 15.120°, 15.939°, and 18.221° ± 0.05°. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 4 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 4 .
在一些实施方案中,奥希替尼和4-氨基苯甲酸共晶体以1:1的比例结合。共晶体具有XRPD图谱。在一些实施方案中,共晶体包含如图5所示的X射线衍射图谱。在一些实施方案中,共晶体具有基本上类似于图5所示的X射线衍射图谱。In some embodiments, osimertinib and 4-aminobenzoic acid co-crystal are combined in a 1:1 ratio. The co-crystal has an XRPD pattern. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 5 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 5 .
在一些实施方案中,2,2-二-正丙基乙酰胺和3,4-二羟基苯乙烯酸共晶体以1:1的比例结合。共晶体具有XRPD图谱,所述XRPD图谱包含在5.660°,7.358°,9.261°,9.900°,11.321°,11.779°,12.418°和14.241°(分别四舍五入至5.7°,7.4°,9.3°,9.9°,11.3°,11.8°,12.4°和14.2°)(分别对应于
的d-间距)±0.2°的衍射角2θ处的峰。在一些实施方案中,共晶体包含在5.660°,7.358°,9.261°,9.900°,11.321°,11.779°,12.418°和14.241°±0.1°的衍射角2θ处的XRPD图谱。在一些实施方案中,共晶体包含在5.660°,7.358°,9.261°,9.900°,11.321°,11.779°,12.418°和14.241°±0.05°的衍射角2θ处的XRPD图谱。在一些实施方案中,共晶体包含如图6所示的X射线衍射图谱。在一些实施方案中,共晶体具有基本上类似于图6所示的X射线衍射图谱。
In some embodiments, the 2,2-di-n-propylacetamide and 3,4-dihydroxystyrene acid co-crystals are combined in a 1:1 ratio. The co-crystal has an XRPD pattern comprised of 5.660°, 7.358°, 9.261°, 9.900°, 11.321°, 11.779°, 12.418° and 14.241° (rounded to 5.7°, 7.4°, 9.3°, 9.9°, respectively , 11.3°, 11.8°, 12.4° and 14.2°) (corresponding to d-spacing) peaks at diffraction angles 2θ of ±0.2°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 5.660°, 7.358°, 9.261°, 9.900°, 11.321°, 11.779°, 12.418°, and 14.241° ± 0.1°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 5.660°, 7.358°, 9.261°, 9.900°, 11.321°, 11.779°, 12.418°, and 14.241° ± 0.05°. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 6 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 6 .
本发明的共晶体包含:没食子酸,柠檬酸,水杨酸,反丁烯二酸,4-氨基苯甲酸和3,4-二羟基苯乙烯酸作为共晶前体(co-former);和奥希替尼,作为共晶前体(co-former)和活性药物成分(API)。The co-crystal of the present invention comprises: gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid as co-formers; and Osimertinib, as co-former and active pharmaceutical ingredient (API).
在一些实施方案中,没食子酸,柠檬酸,水杨酸,反丁烯二酸,4-氨基苯甲酸和3,4-二羟基苯乙烯酸和奥希替尼以1:1的比例结合。In some embodiments, gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid and osimertinib are combined in a 1:1 ratio.
本发明的共晶的固体状态是任何结晶多晶型或其他混合物。共晶还可以制成无定形形式,其可以与任何晶型组合。在其它实施方案中,共晶的固体状态是无定形形式,本发明共晶的不同形式可以通过不同的结晶过程获得,并且可以用已知技术将共晶制成无定形形式。The solid state of the co-crystal of the present invention is any crystalline polymorph or other mixture. Co-crystals can also be made in amorphous form, which can be combined with any crystalline form. In other embodiments, the solid state of the co-crystal is an amorphous form, different forms of the co-crystal of the present invention can be obtained by different crystallization processes, and the co-crystal can be made into an amorphous form using known techniques.
本发明的共晶体可以通过包括以下方法制备:The co-crystals of the present invention can be prepared by methods comprising:
(a)将所述没食子酸,柠檬酸,水杨酸,反丁烯二酸,4-氨基苯甲酸和3,4-二羟基苯乙烯酸分别溶解或混悬在溶剂中,可选将溶液或分散体加热至高于室温且低于所述溶液或分散体的沸点的温度;(a) The gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid are respectively dissolved or suspended in a solvent, and the solution can be optionally or the dispersion is heated to a temperature above room temperature and below the boiling point of said solution or dispersion;
优选地,对于所述没食子酸,所用溶剂选自乙醇、乙腈;对于所述柠檬酸,所用溶剂选自乙腈、乙醇,优选乙腈;对于所述水杨酸,所用溶剂选自乙醇、乙腈,优选乙醇;对于所述反丁烯二酸,所用溶剂选自水、乙醇;对于所述4-氨基苯甲酸,所用溶剂选自水、乙醇,优选水;对于所述3,4-二羟基苯乙烯酸,所用溶剂选自乙腈、乙醇,优选乙醇;Preferably, for the gallic acid, the solvent used is selected from ethanol, acetonitrile; for the citric acid, the solvent used is selected from acetonitrile, ethanol, preferably acetonitrile; for the salicylic acid, the solvent used is selected from ethanol, acetonitrile, preferably Ethanol; for the fumaric acid, the solvent used is selected from water, ethanol; for the 4-aminobenzoic acid, the solvent used is selected from water, ethanol, preferably water; for the 3,4-dihydroxystyrene Acid, the solvent used is selected from acetonitrile, ethanol, preferably ethanol;
(b)与步骤(a)一起或之后分别加入奥希替尼溶解或混悬在溶剂中;(b) adding osimertinib to dissolve or suspend in a solvent together with or after step (a);
(c)反应时间可选0.1-24个小时,期间保持上述(a)所述的温度并进行搅拌;(c) The reaction time can be selected from 0.1-24 hours, during which the temperature described in (a) is kept and stirred;
(d)将经步骤(a),(b),(c)的溶液或分散体冷却至环境温度或以下;(d) cooling the solution or dispersion of steps (a), (b), (c) to ambient temperature or below;
(e)可选地使部分或所有的所述溶剂蒸发;以及(e) optionally evaporating some or all of said solvent; and
(f)过滤出所得的共晶体。(f) The resulting co-crystals are filtered off.
在一些实施方案中,可以调整方法的具体条件,该适当的比例在下述的摩尔范围内:1:0.1-1:20、1:0.2-1:20、1:0.3-1:20、1:0.4-1:20、1:0.5-1:20、1:0.6-1:20、1:0.7-1:20、1:0.8-1:20、1:0.9-1:20、1:1-1:20、1:2-1:20、1:3-1:20、1:4-1:20、1:5-1:20、1:6-1:18、1:7-1:15、1:8-1:13、1:9-1:12或1:10-1:11。在一些实施方案中,适当比例为约1:1(摩尔)。在一些实施方案中,用于制浆或搅拌混合物的时间段可以在下述范围内:0.1-24小时、0.2-12小时、0.25-6小时、0.3-2小时、0.4-1小时或0.5-1小时。在一些实施方案中,用于制浆或搅拌混合物的时间段可以为约0.5小时。在一些实施方案中,共晶化合物可经干燥、过滤、离心、移液或它们的组合获得。在一些实施方案中,可以通过离心获得共晶化合物。In some embodiments, the specific conditions of the process can be adjusted, and the appropriate ratios are in the following molar ranges: 1:0.1-1:20, 1:0.2-1:20, 1:0.3-1:20, 1:0.3-1:20, 0.4-1:20, 1:0.5-1:20, 1:0.6-1:20, 1:0.7-1:20, 1:0.8-1:20, 1:0.9-1:20, 1:1- 1:20, 1:2-1:20, 1:3-1:20, 1:4-1:20, 1:5-1:20, 1:6-1:18, 1:7-1: 15. 1:8-1:13, 1:9-1:12 or 1:10-1:11. In some embodiments, a suitable ratio is about 1:1 (molar). In some embodiments, the period of time for pulping or stirring the mixture may be in the range of: 0.1-24 hours, 0.2-12 hours, 0.25-6 hours, 0.3-2 hours, 0.4-1 hours, or 0.5-1 hours Hour. In some embodiments, the time period for pulping or stirring the mixture may be about 0.5 hours. In some embodiments, co-crystal compounds can be obtained by drying, filtering, centrifuging, pipetting, or combinations thereof. In some embodiments, co-crystal compounds can be obtained by centrifugation.
实施例1Example 1
在25ml茄形瓶中加入51.1mg(0.3mmol)没食子酸和3ml乙醇,搅拌0.5小时溶解,加入50mg(0.1mmol)奥希替尼,加热至60℃,搅拌4小时后停止加热,冷却至室温,旋干溶剂,真空40℃干燥,得到共晶体粗品,经XRPD检测为无定形。Add 51.1mg (0.3mmol) gallic acid and 3ml ethanol to a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 50mg (0.1mmol) osimertinib, heat to 60°C, stop heating after stirring for 4 hours, and cool to room temperature , spin-dried the solvent, and dried under vacuum at 40°C to obtain the crude co-crystal, which was detected as amorphous by XRPD.
实施例2Example 2
在25ml茄形瓶中加入51.1mg(0.3mmol)没食子酸和3ml乙腈,搅拌0.5小时溶解,再加入50mg(0.1mmol)奥希替尼,加热至60℃,搅拌4小时后停止加热,冷却至室温,旋干溶剂,真空40℃干燥,得到共晶体粗品,经XRPD检测有特征峰。Add 51.1mg (0.3mmol) of gallic acid and 3ml of acetonitrile into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, then add 50mg (0.1mmol) of osimertinib, heat to 60°C, stop heating after stirring for 4 hours, and cool to At room temperature, the solvent was spin-dried and dried in vacuum at 40°C to obtain the crude co-crystal, which had characteristic peaks detected by XRPD.
实施例3Example 3
在25ml茄形瓶中加入34.07mg(0.2mmol)没食子酸和3ml乙醇,搅拌0.5小时溶解,再加入100mg(0.2mmol)奥希替尼,加热至60℃,搅拌6小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌3小时,过滤,得到晶体粗品,用乙醇和庚烷处理,真空40℃干燥,得到109.80mg共晶体。通过XRPD和HPLC检测,确定为无定形以及比例为1:1。Add 34.07mg (0.2mmol) of gallic acid and 3ml of ethanol into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, then add 100mg (0.2mmol) of osimertinib, heat to 60°C, stir for 6 hours, then naturally cool to room temperature, Then, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, and filtered to obtain a crude crystal, which was treated with ethanol and heptane, and dried under vacuum at 40°C to obtain 109.80 mg of co-crystal. It was determined to be amorphous and the ratio was 1:1 by XRPD and HPLC detection.
实施例4Example 4
在25ml茄形瓶中加入34.07mg(0.2mmol)没食子酸和3ml乙腈,搅拌0.5小时,再加入100mg(0.2mmol)奥希替尼,加热至60℃,搅拌6小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌3小时,过滤,得到晶体粗品,用乙腈和庚烷处理,真空40℃干燥,得到113.36mg共晶体。通过XRPD和HPLC检测,确定晶型以及比例为1:1。Add 34.07 mg (0.2 mmol) of gallic acid and 3 ml of acetonitrile into a 25 ml eggplant-shaped bottle, stir for 0.5 hour, then add 100 mg (0.2 mmol) of osimertinib, heat to 60 ° C, stir for 6 hours, and then naturally cool to room temperature. The reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with acetonitrile and heptane, and dried in vacuum at 40°C to obtain 113.36 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.
实施例5Example 5
在25ml茄形瓶中加入68.14mg(0.4mmol)没食子酸和5ml乙腈,搅拌0.5小时,再加入200mg(0.4mmol)奥希替尼,加热至60℃,搅拌6小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌3小时,过滤,得到晶体粗品,用乙腈和庚烷处理,真空40℃干燥,得到231.27mg共晶体。通过XRPD和HPLC检测,确定晶型以及比例为1:1。Add 68.14 mg (0.4 mmol) of gallic acid and 5 ml of acetonitrile into a 25 ml eggplant-shaped bottle, stir for 0.5 hour, then add 200 mg (0.4 mmol) of osimertinib, heat to 60 ° C, stir for 6 hours, then cool naturally to room temperature, then The reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with acetonitrile and heptane, and dried under vacuum at 40°C to obtain 231.27 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.
实施例6Example 6
在25ml茄形瓶中加入57.68mg柠檬酸(0.3mmol)和3ml乙腈,搅拌0.5小时溶解,加入50mg(0.1mmol)奥希替尼,加热至60℃,搅拌4小时后停止加热,冷却至室温,旋干溶剂,真空40℃干燥,得到共晶体粗品,经XRPD检测为无定形。Add 57.68mg of citric acid (0.3mmol) and 3ml of acetonitrile into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 50mg (0.1mmol) of osimertinib, heat to 60°C, stop heating after stirring for 4 hours, and cool to room temperature , spin-dried the solvent, and dried under vacuum at 40°C to obtain the crude co-crystal, which was detected as amorphous by XRPD.
实施例7Example 7
在25ml茄形瓶中加入38.45mg(0.2mmol)柠檬酸和3ml乙腈,加热至60℃,搅拌 0.5小时溶解,加入100mg(0.2mmol)奥希替尼,搅拌6小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌3小时,过滤,得到晶体粗品,用乙腈和庚烷处理,真空40℃干燥,得到77.85mg共晶体。通过XRPD和HPLC检测,确定为无定形以及比例为1:1。Add 38.45mg (0.2mmol) of citric acid and 3ml of acetonitrile into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours to dissolve, add 100mg (0.2mmol) of osimertinib, stir for 6 hours and then cool to room temperature naturally. The reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with acetonitrile and heptane, and dried under vacuum at 40°C to obtain 77.85 mg of co-crystals. It was determined to be amorphous and the ratio was 1:1 by XRPD and HPLC detection.
实施例8Example 8
在25ml茄形瓶中加入76.9mg(0.4mmol)柠檬酸和5ml乙腈,加热至60℃,搅拌0.5小时溶解,加入200mg(0.4mmol)奥希替尼,搅拌6小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌3小时,过滤,得到晶体粗品,用乙腈和庚烷处理,真空40℃干燥,得到180.57mg共晶体。通过XRPD和HPLC检测,确定为无定形以及比例为1:1。Add 76.9mg (0.4mmol) of citric acid and 5ml of acetonitrile into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours to dissolve, add 200mg (0.4mmol) of osimertinib, stir for 6 hours, then cool naturally to room temperature, then The reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with acetonitrile and heptane, and dried in vacuum at 40°C to obtain 180.57 mg of co-crystals. It was determined to be amorphous and the ratio was 1:1 by XRPD and HPLC detection.
实施例9Example 9
在25ml茄形瓶中加入41.47mg(0.3mmol)水杨酸和3ml乙醇,搅拌0.5小时,加入50mg(0.1mmol)奥希替尼,加热至60℃,搅拌4小时后停止加热,冷却至室温,旋干溶剂,真空40℃干燥,得到共晶体粗品,经XRPD检测为无定形。Add 41.47mg (0.3mmol) salicylic acid and 3ml ethanol to a 25ml eggplant-shaped bottle, stir for 0.5 hours, add 50mg (0.1mmol) osimertinib, heat to 60°C, stop heating after stirring for 4 hours, and cool to room temperature , spin-dried the solvent, and dried under vacuum at 40°C to obtain the crude co-crystal, which was detected as amorphous by XRPD.
实施例10Example 10
在25ml茄形瓶中加入27.65mg(0.2mmol)水杨酸和3ml乙醇,搅拌0.5小时溶解,加入100mg(0.2mmol)奥希替尼,加热至60℃,搅拌6小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌3小时,过滤,得到晶体粗品,用乙醇和庚烷处理,真空40℃干燥,得到113.14mg共晶体。通过XRPD和HPLC检测,确定晶型以及比例为1:1。Add 27.65mg (0.2mmol) of salicylic acid and 3ml of ethanol into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 100mg (0.2mmol) of osimertinib, heat to 60°C, stir for 6 hours and then naturally cool to room temperature, Then, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, and filtered to obtain a crude crystal, which was treated with ethanol and heptane, and dried under vacuum at 40°C to obtain 113.14 mg of co-crystal. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.
实施例11Example 11
在25ml茄形瓶中加入55.3mg(0.4mmol)水杨酸和5ml乙醇,搅拌0.5小时溶解,加入200mg(0.4mmol)奥希替尼,加热至60℃,搅拌6小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌3小时,过滤,得到晶体粗品,用乙醇和庚烷处理,真空40℃干燥,得到223.18mg共晶体。通过XRPD和HPLC检测,确定晶型以及比例为1:1。Add 55.3mg (0.4mmol) of salicylic acid and 5ml of ethanol into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 200mg (0.4mmol) of osimertinib, heat to 60°C, stir for 6 hours, then cool naturally to room temperature, Then, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, and filtered to obtain a crude crystal, which was treated with ethanol and heptane, and dried under vacuum at 40°C to obtain 223.18 mg of co-crystal. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.
实施例12Example 12
在25ml茄形瓶中加入34.82mg(0.3mmol)反丁烯二酸和3ml水,搅拌0.5小时,加入50mg(0.1mmol)奥希替尼,加热至60℃,搅拌4小时后停止加热,冷却至室温,旋干溶剂,真空40℃干燥,得到共晶体粗品,经XRPD检测有特征峰。Add 34.82mg (0.3mmol) fumaric acid and 3ml water into a 25ml eggplant-shaped bottle, stir for 0.5 hours, add 50mg (0.1mmol) osimertinib, heat to 60°C, stop heating after stirring for 4 hours, and cool After reaching room temperature, the solvent was spin-dried and dried in vacuum at 40°C to obtain the crude co-crystal, which had characteristic peaks detected by XRPD.
实施例13Example 13
在25ml茄形瓶中加入34.82mg(0.3mmol)反丁烯二酸和3ml乙醇,搅拌0.5小时,加入50mg(0.1mmol)奥希替尼,加热至60℃,搅拌4小时后停止加热,冷却至室温,旋干溶剂,真空40℃干燥,得到共晶体粗品,经XRPD检测有特征峰。Add 34.82mg (0.3mmol) fumaric acid and 3ml ethanol into a 25ml eggplant-shaped bottle, stir for 0.5 hours, add 50mg (0.1mmol) osimertinib, heat to 60°C, stop heating after stirring for 4 hours, and cool After reaching room temperature, the solvent was spin-dried and dried in vacuum at 40°C to obtain the crude co-crystal, which had characteristic peaks detected by XRPD.
实施例14Example 14
在25ml茄形瓶中加入23.21mg(0.2mmol)反丁烯二酸和3ml水,搅拌0.5小时溶解,加入100mg(0.2mmol)奥希替尼,加热至60℃,搅拌6小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌3小时,过滤,得到晶体粗品,用水和庚烷处理,真空40℃干燥,得到106.77mg共晶体。通过XRPD和HPLC检测,确定晶型以及比例为1:2。Add 23.21mg (0.2mmol) fumaric acid and 3ml water into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 100mg (0.2mmol) osimertinib, heat to 60°C, stir for 6 hours and then cool naturally to At room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with water and heptane, and dried in vacuum at 40°C to obtain 106.77 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:2.
实施例15Example 15
在25ml茄形瓶中加入46.42mg(0.4mmol)反丁烯二酸和3ml水,搅拌0.5小时溶解,加入100mg(0.2mmol)奥希替尼,加热至60℃,搅拌6小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌3小时,过滤,得到晶体粗品,用水和庚烷处理,真空40℃干燥,得到125.17mg共晶体。通过XRPD和HPLC检测,确定晶型以及比例为1:2。Add 46.42mg (0.4mmol) fumaric acid and 3ml water into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 100mg (0.2mmol) osimertinib, heat to 60°C, stir for 6 hours and then cool naturally to At room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with water and heptane, and dried in vacuum at 40°C to obtain 125.17 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:2.
实施例16Example 16
在25ml茄形瓶中加入92.84mg(0.8mmol)反丁烯二酸和6ml水,加热至60℃,搅 拌0.5小时溶解,加入200mg(0.4mmol)奥希替尼,搅拌6小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌3小时,过滤,得到晶体粗品,用水和庚烷处理,真空40℃干燥,得到220.86mg共晶体。通过XRPD和HPLC检测,确定晶型以及比例为1:2。Add 92.84mg (0.8mmol) of fumaric acid and 6ml of water into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours to dissolve, add 200mg (0.4mmol) of osimertinib, stir for 6 hours and then cool naturally to At room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with water and heptane, and dried in vacuum at 40°C to obtain 220.86 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:2.
实施例17Example 17
在25ml茄形瓶中加入46.42mg(0.4mmol)反丁烯二酸和6ml水,加热至60℃,搅拌0.5小时溶解,加入200mg(0.4mmol)奥希替尼,搅拌6小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌3小时,过滤,得到晶体粗品,用水和庚烷处理,真空40℃干燥,得到216.89mg共晶体。通过XRPD和HPLC检测,确定晶型以及比例为1:1。Add 46.42mg (0.4mmol) of fumaric acid and 6ml of water into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours to dissolve, add 200mg (0.4mmol) of osimertinib, stir for 6 hours and then cool naturally to At room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with water and heptane, and dried in vacuum at 40°C to obtain 216.89 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.
实施例18Example 18
在25ml茄形瓶中加入41.17mg(0.3mmol)4-氨基苯甲酸和3ml水,搅拌0.5小时,加入50mg(0.1mmol)奥希替尼,加热至60℃,搅拌4小时后停止加热,冷却至室温,旋干溶剂,真空40℃干燥,得到共晶体粗品,经XRPD检测为无定形。Add 41.17mg (0.3mmol) 4-aminobenzoic acid and 3ml water into a 25ml eggplant-shaped bottle, stir for 0.5 hours, add 50mg (0.1mmol) osimertinib, heat to 60°C, stop heating after stirring for 4 hours, and cool After reaching room temperature, the solvent was spin-dried, and dried in vacuum at 40°C to obtain a crude co-crystal, which was detected as amorphous by XRPD.
实施例19Example 19
在25ml茄形瓶中加入27.45mg(0.2mmol)4-氨基苯甲酸和3ml水,加热至60℃,搅拌0.5小时溶解,加入100mg(0.2mmol)奥希替尼,搅拌6小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌3小时,过滤,得到晶体粗品,用水和庚烷处理,真空40℃干燥,得到58.23mg共晶体。通过XRPD和HPLC检测,确定为无定形以及比例为1:1。Add 27.45mg (0.2mmol) of 4-aminobenzoic acid and 3ml of water into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours to dissolve, add 100mg (0.2mmol) osimertinib, stir for 6 hours and then cool naturally to At room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with water and heptane, and dried in vacuum at 40°C to obtain 58.23 mg of co-crystals. It was determined to be amorphous and the ratio was 1:1 by XRPD and HPLC detection.
实施例20Example 20
在25ml茄形瓶中加入54.9mg(0.4mmol)4-氨基苯甲酸和5ml水,加热至60℃,搅拌0.5小时溶解,加入200mg(0.4mmol)奥希替尼,搅拌6小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌3小时,过滤,得到晶体粗品,用水和庚烷处理,真空40℃干燥,得到167.93mg共晶体。通过XRPD和HPLC检测,确定为无定形以及比例为1:1。Add 54.9mg (0.4mmol) of 4-aminobenzoic acid and 5ml of water into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours to dissolve, add 200mg (0.4mmol) osimertinib, stir for 6 hours and then cool naturally to At room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with water and heptane, and dried in vacuum at 40°C to obtain 167.93 mg of co-crystals. It was determined to be amorphous and the ratio was 1:1 by XRPD and HPLC detection.
实施例21Example 21
在25ml茄形瓶中加入54.09mg(0.3mmol)3,4-二羟基苯乙烯酸和3ml乙腈,搅拌0.5小时,加入50mg(0.1mmol)奥希替尼,加热至60℃,搅拌4小时后停止加热,冷却至室温,旋干溶剂,真空40℃干燥,得到共晶体粗品,经XRPD检测有特征峰。Add 54.09mg (0.3mmol) of 3,4-dihydroxystyrene acid and 3ml of acetonitrile into a 25ml eggplant-shaped bottle, stir for 0.5 hours, add 50mg (0.1mmol) of osimertinib, heat to 60°C, and stir for 4 hours Heating was stopped, cooled to room temperature, the solvent was spin-dried, and dried in vacuum at 40°C to obtain a crude co-crystal, which had characteristic peaks detected by XRPD.
实施例22Example 22
在25ml茄形瓶中加入36.06mg(0.2mmol)3,4-二羟基苯乙烯酸和3ml乙腈,加热至60℃,搅拌0.5小时,加入100mg(0.2mmol)奥希替尼,搅拌6小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌3小时,过滤,得到晶体粗品,用乙腈和庚烷处理,真空40℃干燥,得到112.13mg共晶体。通过XRPD和HPLC检测,确定晶型以及比例为1:1。Add 36.06mg (0.2mmol) of 3,4-dihydroxystyrene acid and 3ml of acetonitrile into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours, add 100mg (0.2mmol) osimertinib, and stir for 6 hours Naturally cooled to room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with acetonitrile and heptane, and dried in vacuum at 40°C to obtain 112.13 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.
实施例23Example 23
在25ml茄形瓶中加入72.12mg(0.4mmol)3,4-二羟基苯乙烯酸和5ml乙腈,加热至60℃,搅拌0.5小时,加入200mg(0.4mmol)奥希替尼,搅拌6小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌3小时,过滤,得到晶体粗品,用乙腈和庚烷处理,真空40℃干燥,得到235.44mg共晶体。通过XRPD和HPLC检测,确定晶型以及比例为1:1。Add 72.12mg (0.4mmol) 3,4-dihydroxystyrene acid and 5ml acetonitrile into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours, add 200mg (0.4mmol) osimertinib, and stir for 6 hours Naturally cooled to room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with acetonitrile and heptane, and dried in vacuum at 40°C to obtain 235.44 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.
实施例24Example 24
通过MTT法检测奥希替尼共晶体对NCI-H1975细胞和NCI-H1975/OSIR细胞增殖的抑制作用,如图7和8所示,奥希替尼共晶体能有效的增强对NCI-H1975细胞和NCI-H1975/OSIR细胞抑制作用,强于奥希替尼本身,而奥希替尼共晶体对两种细胞的杀伤力更强, 以奥希替尼计浓度达到20μM时,NCI-H1975细胞存活率仅30%左右,NCI-H1975/OSIR细胞存活率也低于50%,表明奥希替尼共晶体增强了药物的抗肿瘤效应,显示较强的抗肿瘤作用。The inhibitory effect of osimertinib co-crystal on the proliferation of NCI-H1975 cells and NCI-H1975/OSIR cells was detected by MTT method. As shown in Figures 7 and 8, osimertinib co-crystal can effectively enhance the effect on NCI-H1975 cells and NCI-H1975/OSIR cells, stronger than osimertinib itself, and osimertinib co-crystals have stronger lethality to the two types of cells. When the concentration of osimertinib reaches 20 μM, NCI-H1975 cells The survival rate is only about 30%, and the survival rate of NCI-H1975/OSIR cells is also lower than 50%, indicating that the osimertinib co-crystal enhances the anti-tumor effect of the drug and shows a strong anti-tumor effect.
对比例1Comparative example 1
在25ml茄形瓶中加入39.38mg(0.3mmol)L-亮氨酸和3ml水,加热至60℃,搅拌0.5小时,加入50mg(0.1mmol)奥希替尼,搅拌4小时后自然冷却到室温,旋干溶剂,真空40℃干燥,得到粗品,经XRPD检测样品图谱与奥希替尼图谱重叠,未形成共晶体。Add 39.38mg (0.3mmol) of L-leucine and 3ml of water into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours, add 50mg (0.1mmol) of osimertinib, stir for 4 hours, then naturally cool to room temperature , spin to dry the solvent, and dry at 40°C in vacuum to obtain the crude product. The XRPD detection pattern of the sample overlapped with that of osimertinib, and no co-crystal was formed.
对比例2Comparative example 2
在25ml茄形瓶中加入27.65mg(0.2mmol)水杨酸和5ml乙醇,搅拌0.5小时溶解,加入200mg(0.4mmol)奥希替尼,加热至60℃,搅拌4小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌1小时,过滤,得到粗品,用乙醇和庚烷处理,真空40℃干燥,得到168.44mg样品。通过XRPD检测,经XRPD检测样品图谱与奥希替尼图谱重叠,未形成共晶体。Add 27.65mg (0.2mmol) of salicylic acid and 5ml of ethanol into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 200mg (0.4mmol) of osimertinib, heat to 60°C, stir for 4 hours and then naturally cool to room temperature. Then the reactant was ice-bathed to 0-5°C, stirred for 1 hour, filtered to obtain a crude product, treated with ethanol and heptane, and dried in vacuum at 40°C to obtain 168.44 mg of a sample. Through XRPD detection, the pattern of the sample detected by XRPD overlapped with the pattern of osimertinib, and no co-crystal was formed.
对比例3Comparative example 3
在25ml茄形瓶中加入51.1mg(0.3mmol)没食子酸和3ml甲苯,搅拌0.5小时溶解,加入50mg(0.1mmol)奥希替尼,加热至60℃,搅拌4小时后停止加热,冷却至室温,旋干溶剂,通过XRPD检测,经XRPD检测样品图谱与没食子酸图谱重叠,未形成共晶体。Add 51.1mg (0.3mmol) of gallic acid and 3ml of toluene into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 50mg (0.1mmol) of osimertinib, heat to 60°C, stop heating after stirring for 4 hours, and cool to room temperature , the solvent was spin-dried, and detected by XRPD, and the XRPD detection sample spectrum overlapped with the gallic acid spectrum, and no co-crystal was formed.
对比例4Comparative example 4
在25ml茄形瓶中加入76.9mg(0.4mmol)柠檬酸和5ml乙腈,室温(25℃)下反应,搅拌0.5小时溶解,加入200mg(0.4mmol)奥希替尼,搅拌6小时后自然冷却到室温,再将反应物冰浴至0-5℃,搅拌3小时,过滤,得到晶体粗品,用乙腈和庚烷处理,真空40℃干燥,得到186.22mg共晶体。通过XRPD检测,经XRPD检测样品图谱与奥希替尼图谱重叠,未形成共晶体。Add 76.9mg (0.4mmol) of citric acid and 5ml of acetonitrile in a 25ml eggplant-shaped bottle, react at room temperature (25°C), stir for 0.5 hours to dissolve, add 200mg (0.4mmol) Osimertinib, stir for 6 hours and then cool naturally to At room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with acetonitrile and heptane, and dried in vacuum at 40°C to obtain 186.22 mg of co-crystals. Through XRPD detection, the pattern of the sample detected by XRPD overlapped with the pattern of osimertinib, and no co-crystal was formed.
奥希替尼共晶体抑制大鼠非小细胞肺癌试验Osimertinib co-crystal inhibits non-small cell lung cancer in rats
取对数生长期人肺腺癌A549细胞悬液200μL(2×106细胞数)经背部穿刺,选取辐射后的裸大鼠,细胞悬液注射于右前肢腋下,以构建大鼠非小细胞肺癌模型,右腋皮下5d后出现一个长宽约为0.4cm×0.4cm的肿瘤即为成功造模。Take 200 μL (2×106 cells) of human lung adenocarcinoma A549 cell suspension in the logarithmic growth phase and undergo back puncture, select irradiated nude rats, and inject the cell suspension into the armpit of the right forelimb to construct rat non-small cell For the lung cancer model, a tumor with a length and width of about 0.4 cm × 0.4 cm after 5 days under the skin of the right armpit was considered as a successful model.
随机将大鼠分为3组,各20只。①治疗组20只大鼠分别用50mg/kg(以奥希替尼计)奥希替尼和奥希替尼共晶体连续进行14d灌胃。②模型组20只大鼠成功造模后连续进行14d的生理盐水(50mg/kg)灌胃。③对照组20只大鼠未实施造模,仅连续进行14d的生理盐水(50mg/kg)灌胃。治疗结束处死动物,剖取肿瘤组织,取三组大鼠的肿瘤组织称量质量并计算其抑瘤率。利用游标卡尺测量出移植瘤的短径(W)及长径(L),计算瘤体的体积:V=W2×L×0.52;抑瘤率(%)=(空白荷瘤组的平均肿瘤质量-各实验组的平均肿瘤质量)/空白荷瘤组的平均肿瘤质量×100%。The rats were randomly divided into 3 groups, 20 in each group. ①The 20 rats in the treatment group were given 50 mg/kg (calculated as osimertinib) osimertinib and osimertinib co-crystal by gavage for 14 days continuously. ②The 20 rats in the model group were administered with normal saline (50mg/kg) for 14 days after successful modeling. ③ The 20 rats in the control group were not modeled, and were only administered intragastrically with normal saline (50 mg/kg) for 14 consecutive days. At the end of the treatment, the animals were sacrificed, the tumor tissues were dissected, and the tumor tissues of the three groups of rats were weighed and the tumor inhibition rates were calculated. Use a vernier caliper to measure the short diameter (W) and long diameter (L) of the transplanted tumor, and calculate the volume of the tumor: V=W2×L×0.52; tumor inhibition rate (%)=(average tumor mass of the blank tumor-bearing group- Average tumor mass of each experimental group)/average tumor mass of blank tumor-bearing group×100%.
与对照组相比,模型组和治疗组和瘤体重量、瘤体体积显著增多;与模型组对比,治疗组瘤体质量下降,肿瘤抑制率升高明显。且治疗组中,奥希替尼共晶体的抑制肿瘤率明显高于奥希替尼组和甲磺酸奥希替尼组。Compared with the control group, the tumor weight and tumor volume in the model group and the treatment group increased significantly; compared with the model group, the tumor weight decreased and the tumor inhibition rate increased significantly in the treatment group. And in the treatment group, the tumor inhibition rate of osimertinib co-crystal was significantly higher than that of osimertinib group and osimertinib mesylate group.
溶解度测试Solubility test
溶解度测试数据如表1所示。Solubility test data are shown in Table 1.
表1Table 1
稳定性测试stability test
稳定性测试数据如表2~表3所示。Stability test data are shown in Table 2-Table 3.
表2Table 2
表3table 3
Claims (19)
- 共晶体,由奥希替尼作为活性物质与作为共晶前体的其他化合物形成;其中,所述共晶前体选自下述化合物类中的一种或多种:反丁烯二酸,4-氨基苯甲酸,没食子酸,3,4-二羟基苯乙烯酸,柠檬酸,水杨酸。A co-crystal formed by osimertinib as an active substance and other compounds as a co-crystal precursor; wherein the co-crystal precursor is selected from one or more of the following compound classes: fumaric acid, 4-Aminobenzoic acid, gallic acid, 3,4-dihydroxystyrene acid, citric acid, salicylic acid.
- 权利要求1的共晶体,其中所述的奥希替尼和所述共晶前体反丁烯二酸,4-氨基苯甲酸,没食子酸,3,4-二羟基苯乙烯酸,柠檬酸,水杨酸以1:1的比例结合。The co-crystal of claim 1, wherein said osimertinib and said co-crystal precursor fumaric acid, 4-aminobenzoic acid, gallic acid, 3,4-dihydroxystyrene acid, citric acid, Salicylic acid is combined in a 1:1 ratio.
- 权利要求1的共晶体,所述共晶体选自以下:The co-crystal of claim 1 selected from the group consisting of:包含以1:1比例结合的奥希替尼和反丁烯二酸的共晶体,Contains a co-crystal of osimertinib and fumaric acid combined in a 1:1 ratio,包含以1:1比例结合的奥希替尼和4-氨基苯甲酸的共晶体,Contains a co-crystal of osimertinib and 4-aminobenzoic acid combined in a 1:1 ratio,包含以1:1比例结合的奥希替尼和没食子酸的共晶体,Contains a co-crystal of osimertinib and gallic acid combined in a 1:1 ratio,包含以1:1比例结合的奥希替尼和3,4-二羟基苯乙烯酸的共晶体,Contains a co-crystal of osimertinib and 3,4-dihydroxystyrene acid combined in a 1:1 ratio,包含以1:1比例结合的奥希替尼和柠檬酸的共晶体,和A co-crystal comprising osimertinib and citric acid combined in a 1:1 ratio, and包含以1:1比例结合的奥希替尼和水杨酸的共晶体。Contains a co-crystal of osimertinib and salicylic acid combined in a 1:1 ratio.
- 权利要求1的共晶体,其包含以1:1比例结合的奥希替尼和反丁烯二酸的共晶体,具有包含在5.019°,10.001°,11.398°,13.282°,13.619°,15.120°,15.939°和18.221°±0.2°的衍射角2θ处的峰的X-射线衍射粉末衍射(XRPD)图谱。The co-crystal of claim 1, comprising a co-crystal of osimertinib and fumaric acid combined in a 1:1 ratio, having a range of , X-ray diffraction powder diffraction (XRPD) patterns of peaks at diffraction angles 2θ at 15.939° and 18.221°±0.2°.
- 权利要求1的共晶体,其包含以1:1比例结合的奥希替尼和4-氨基苯甲酸的共晶体,具有无定形的X-射线衍射粉末衍射(XRPD)图谱。The co-crystal of claim 1, comprising a co-crystal of osimertinib and 4-aminobenzoic acid combined in a 1:1 ratio, having an amorphous X-ray Diffraction Powder Diffraction (XRPD) pattern.
- 权利要求1的共晶体,其包含以1:1比例结合的奥希替尼和没食子酸的共晶体,具有包含在5.620°,8.600°,14.280°,15.879°,17.341°,18.739°,20.180°和24.400°±0.2°的衍射角2θ处的峰的X-射线衍射粉末衍射(XRPD)图谱。The co-crystal of claim 1, comprising a co-crystal of osimertinib and gallic acid combined in a 1:1 ratio, having a range of and the X-ray diffraction powder diffraction (XRPD) pattern of the peak at the diffraction angle 2θ of 24.400°±0.2°.
- 权利要求1的共晶体,其包含以1:1比例结合的奥希替尼和3,4-二羟基苯乙烯酸的共晶体,具有包含在5.660°,7.358°,9.261°,9.900°,11.321°,11.779°,12.418°和14.241°±0.2°的衍射角2θ处的峰的X-射线衍射粉末衍射(XRPD)图谱。The co-crystal of claim 1, which comprises a co-crystal of osimertinib and 3,4-dihydroxystyrene acid combined in a 1:1 ratio, having an °, 11.779 °, 12.418 ° and 14.241 ° ± 0.2 ° of diffraction angle 2θ of the peak X-ray diffraction powder diffraction (XRPD) pattern.
- 权利要求1的共晶体,其包含以1:1比例结合的奥希替尼和柠檬酸的共晶体,具有无定形的X-射线衍射粉末衍射(XRPD)图谱。The co-crystal of claim 1, comprising a co-crystal of osimertinib and citric acid combined in a 1:1 ratio, having an amorphous X-ray Diffraction Powder Diffraction (XRPD) pattern.
- 权利要求1的共晶体,其包含以1:1比例结合的奥希替尼和水杨酸的共晶体,具有包含在5.700°,12.560°,15.040°,18.220°,18.739°,19.381°,19.918°和25.040°±0.2°的衍射角2θ处的峰的X-射线衍射粉末衍射(XRPD)图谱。The co-crystal of claim 1 , comprising a co-crystal of osimertinib and salicylic acid combined in a 1:1 ratio, having a range of ° and 25.040 ° ± 0.2 ° of the peak of the diffraction angle 2θ of the X-ray diffraction powder diffraction (XRPD) pattern.
- 药物组合物,其包含权利要求1~9中任一项的共晶体化合物,任选地还包含制药学上允许的载体。A pharmaceutical composition comprising the co-crystal compound according to any one of claims 1-9, optionally further comprising a pharmaceutically acceptable carrier.
- 权利要求10的药物组合物,其中所述化合物以任何结晶多晶型或无定形形式或其混合物的固体状态存在。The pharmaceutical composition of claim 10, wherein said compound exists in the solid state of any crystalline polymorph or amorphous form or a mixture thereof.
- 一种用于制备根据权利要求11所述的共晶体的方法,包括下述步骤:A method for preparing the co-crystal according to claim 11, comprising the steps of:(a)将所述共晶前体没食子酸,柠檬酸,水杨酸,反丁烯二酸,4-氨基苯甲酸,3,4-二羟基苯乙烯酸分别溶解或混悬在溶剂中,可选将溶液或分散体加热至高于室温且低于所述溶液或分散体的沸点的温度;(a) respectively dissolving or suspending the co-crystal precursors gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid, and 3,4-dihydroxystyrene acid in a solvent, optionally heating the solution or dispersion to a temperature above room temperature and below the boiling point of said solution or dispersion;优选地,对于所述没食子酸,所用溶剂选自乙醇、乙腈;对于所述柠檬酸,所用溶剂选自乙腈、乙醇,优选乙腈;对于所述水杨酸,所用溶剂选自乙醇、乙腈,优选乙 醇;对于所述反丁烯二酸,所用溶剂选自水、乙醇;对于所述4-氨基苯甲酸,所用溶剂选自水、乙醇,优选水;对于所述3,4-二羟基苯乙烯酸,所用溶剂选自乙腈、乙醇,优选乙醇;Preferably, for the gallic acid, the solvent used is selected from ethanol, acetonitrile; for the citric acid, the solvent used is selected from acetonitrile, ethanol, preferably acetonitrile; for the salicylic acid, the solvent used is selected from ethanol, acetonitrile, preferably Ethanol; for the fumaric acid, the solvent used is selected from water, ethanol; for the 4-aminobenzoic acid, the solvent used is selected from water, ethanol, preferably water; for the 3,4-dihydroxystyrene Acid, the solvent used is selected from acetonitrile, ethanol, preferably ethanol;(b)与步骤(a)一起或之后分别加入奥希替尼溶解或混悬在溶剂中;(b) adding osimertinib to dissolve or suspend in a solvent together with or after step (a);(c)反应时间可选0.1-24个小时,期间保持上述(a)所述的温度并进行搅拌;(c) The reaction time can be selected from 0.1-24 hours, during which the temperature described in (a) is kept and stirred;(d)将经步骤(a),(b),(c)的溶液或分散体冷却至环境温度或以下;(d) cooling the solution or dispersion of steps (a), (b), (c) to ambient temperature or below;(e)可选地使部分或所有的所述溶剂蒸发;以及(e) optionally evaporating some or all of said solvent; and(f)过滤出所得的共晶体。(f) The resulting co-crystals are filtered off.
- 权利要求12所述的方法所制备的包含以1:1比例结合的奥希替尼和没食子酸的共晶体,并且具有如图1所示的XRPD图谱。The co-crystal comprising osimertinib and gallic acid combined at a ratio of 1:1 prepared by the method of claim 12 has an XRPD pattern as shown in FIG. 1 .
- 权利要求12所述的方法所制备的包含以1:1比例结合的奥希替尼和柠檬酸的共晶体,并且具有如图2所示的XRPD图谱。The co-crystal comprising osimertinib and citric acid combined at a ratio of 1:1 prepared by the method of claim 12 has an XRPD pattern as shown in FIG. 2 .
- 权利要求12所述的方法所制备的包含以1:1比例结合的奥希替尼和水杨酸的共晶体,并且具有如图3所示的XRPD图谱。The co-crystal comprising osimertinib and salicylic acid combined at a ratio of 1:1 prepared by the method of claim 12 has an XRPD pattern as shown in FIG. 3 .
- 权利要求12所述的方法所制备的包含以1:1比例结合的奥希替尼和反丁烯二酸的共晶体,并且具有如图4所示的XRPD图谱。The co-crystal comprising osimertinib and fumaric acid combined at a ratio of 1:1 prepared by the method of claim 12 has an XRPD pattern as shown in FIG. 4 .
- 权利要求12所述的方法所制备的包含以1:1比例结合的奥希替尼和4-氨基苯甲酸的共晶体,并且具有如图5所示的XRPD图谱。The co-crystal comprising osimertinib and 4-aminobenzoic acid combined at a ratio of 1:1 prepared by the method of claim 12 has an XRPD pattern as shown in FIG. 5 .
- 权利要求12所述的方法所制备的包含以1:1比例结合的奥希替尼和3,4-二羟基苯乙烯酸的共晶体,并且具有如图6所示的XRPD图谱。The co-crystal comprising osimertinib and 3,4-dihydroxystyrene acid combined at a ratio of 1:1 prepared by the method of claim 12 has an XRPD pattern as shown in FIG. 6 .
- 权利要求1-9任一项所述的共晶体或权利要求10-11任一项所述的药物组合物在制备药物中的应用,所述药物用于治疗非小细胞肺癌。Use of the co-crystal according to any one of claims 1-9 or the pharmaceutical composition according to any one of claims 10-11 in the preparation of medicines for treating non-small cell lung cancer.
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