药学学报, 2021, 56(11): 3153-3158
引用本文:
房政钰, 邢逞, 邢文慧, 王雪, 龚宁波*, 吕扬. 伊马替尼草酸盐多晶型的制备、表征、转化规律及溶解性能研究[J]. 药学学报, 2021, 56(11): 3153-3158.
FANG Zheng-yu, XING Cheng, XING Wen-hui, WANG Xue, GONG Ning-bo*, LÜ Yang. Preparation, characterization, transformation and solubility of imatinib-oxalate salt polymorphs[J]. Acta Pharmaceutica Sinica, 2021, 56(11): 3153-3158.

伊马替尼草酸盐多晶型的制备、表征、转化规律及溶解性能研究
房政钰, 邢逞, 邢文慧, 王雪, 龚宁波*, 吕扬
北京协和医学院、中国医学科学院药物研究所, 晶型药物研究北京市重点实验室, 北京 100050
摘要:
制备获得伊马替尼-草酸新盐型的3种晶型 (I、II和III) 和1种无定形 (IV),利用粉末X射线衍射法、差示扫描量热法、热重分析法和红外光谱法对新盐多晶型进行表征,研究4种盐型间的转化规律,使用高效液相色谱法考察晶型II的溶解性。结果表明,在室温下晶型II稳定而晶型I、III及无定形IV不稳定。在室温下晶型I可向晶型II转化;在相对湿度90%时晶型I、II及无定形IV均可转化为晶型III,在70 ℃下晶型III可转化为无定形IV。伊马替尼与草酸成盐后可显著提高伊马替尼的溶解度,在pH 6.8缓冲溶液和纯水中晶型II的平衡溶解度相较于伊马替尼原料药分别提高4.1和21.2倍。该研究为伊马替尼新盐型的开发和质量控制提供指导。
关键词:    伊马替尼            表征      转化规律      溶解度     
Preparation, characterization, transformation and solubility of imatinib-oxalate salt polymorphs
FANG Zheng-yu, XING Cheng, XING Wen-hui, WANG Xue, GONG Ning-bo*, LÜ Yang
Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
The three polymorphs (I, II, III) and one amorphous (IV) form of imatinib-oxalate new salt were prepared and characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis and infrared spectroscopy, and transformation rules among the four salts were analyzed. The solubility of polymorph II was investigated by high performance liquid chromatography. The results show that polymorph II was stable but polymorph I, III and amorphous IV were unstable at room temperature. Polymorph I transformed into polymorph II at room temperature. At relative humidity 90%, polymorph I, II and amorphous IV transformed into polymorph III, but polymorph III transformed into amorphous IV at 70 ℃. The solubility of imatinib was significantly improved after being salted with oxalic acid, and the equilibrium solubility of polymorph II in pH 6.8 buffer solution and pure water was increased by 4.1 and 21.2 fold, respectively, as compared to bulk drug. This research provides guidance for the development and quality control of a new salt form of imatinib.
Key words:    imatinib    salt    characterization    transformation    solubility   
收稿日期: 2021-07-10
DOI: 10.16438/j.0513-4870.2021-1026
基金项目: 国家重点研发计划(2016YFC1000901);中国医学科学院医学与健康科技创新工程项目(2017-I2M-1-010,2020-I2M-1-003);天然/有效活性小分子高效获取鉴定的技术集成体系构建及应用(2018ZX09711001-001);国家科技重大专项-重大新药创制(2018ZX09711001-010,2018ZX09711001-003-022).
通讯作者: 龚宁波,Tel:86-10-63030566,E-mail:gnb@imm.ac.cn
Email: gnb@imm.ac.cn
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