药学学报, 2021, 56(2): 570-576
引用本文:
喻红梅, 房政钰, 邢逞, 胡堃, 龚宁波, 吕扬. 替格瑞洛新盐型的制备、表征及溶解性能研究[J]. 药学学报, 2021, 56(2): 570-576.
YU Hong-mei, FANG Zheng-yu, XING Cheng, HU Kun, GONG Ning-bo, L� Yang. Preparation, characterization and improved solubility of ticagrelor salts[J]. Acta Pharmaceutica Sinica, 2021, 56(2): 570-576.

替格瑞洛新盐型的制备、表征及溶解性能研究
喻红梅, 房政钰, 邢逞, 胡堃, 龚宁波, 吕扬
中国医学科学院、北京协和医学院药物研究所, 晶型药物研究北京市重点实验室, 北京 100050
摘要:
为改善替格瑞洛溶解性差的问题,采用悬浮液法和加液研磨法制备得到替格瑞洛-3,5-二硝基苯甲酸、替格瑞洛-吡嗪酰胺、替格瑞洛-D-脯氨酸、替格瑞洛-L-脯氨酸4种新盐型物质。利用粉末X-射线衍射法、红外光谱法、差示扫描量热法、核磁共振波谱法和元素分析技术对盐进行表征,分析各分子间盐键等作用力。使用高效液相色谱法测定原料药和盐在pH 1.2和pH 6.8缓冲溶液中的平衡溶解度。替格瑞洛与3,5-二硝基苯甲酸、吡嗪酰胺、D-脯氨酸、L-脯氨酸均以1:1比例成盐,除替格瑞洛-D-脯氨酸外,其余3种盐型物质在pH 1.2缓冲溶液中平衡溶解度均有所提高,其中,替格瑞洛-3,5-二硝基苯甲酸的溶解度与原料药相比提高了1.7倍。该成盐技术方法简单,能够有效提高替格瑞洛的溶解度。
关键词:          替格瑞洛      表征      平衡溶解度     
Preparation, characterization and improved solubility of ticagrelor salts
YU Hong-mei, FANG Zheng-yu, XING Cheng, HU Kun, GONG Ning-bo, L� 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:
Four salts of ticagrelor, ticagrelor-3,5-dinitrobenzoic acid, ticagrelor-pyrazinamide, ticagrelor-D-proline and ticagrelor-L-proline were prepared by solvent suspension and liquid-assisted grinding to improve the solubility of ticagrelor. The compounds were characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, nuclear magnetic resonance spectroscopy, elemental analysis, and the intermolecular salt-bonding forces were analyzed. The equilibrium solubility of salts and pure drug in hydrochloride buffer pH 1.2 and phosphate buffer pH 6.8 were measured by high-performance liquid chromatography. Ticagrelor was salted with 3,5-dinitrobenzoic acid, pyrazinamide, D-proline, L-proline all in a stoichiometric ratio of 1:1; with the exception of ticagrelor-D-proline, the solubility of the other three salts provided significantly improved solubility in hydrochloride buffer pH 1.2, and the equilibrium solubility of ticagrelor-3,5-dinitrobenzoic acid was increased by approximately 1.7 folds as compared to pure drug. Salt-forming technology is convenient and can improve the solubility of ticagrelor.
Key words:    salt    ticagrelor    characterization    equilibrium solubility   
收稿日期: 2020-09-09
DOI: 10.16438/j.0513-4870.2020-1470
基金项目: 国家重点研发计划(2016YFC1000900);中国医学科学院医学与健康科技创新工程项目(2017-I2M-1-010);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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