新晶型替格瑞洛的制备、表征及溶解性能研究

Preparation, Characterization and Improved Solubility of New Crystal Form of Ticagrelor

关键词:  替格瑞洛  溶解度  晶型

Key words:  ticagrelor  solubility  crystal form

摘要:

目的 探索制备替格瑞洛新晶型，优化制备工艺，同时进行表征和溶解特性研究。方法 采用溶剂介导将替格瑞洛晶型Ⅱ转晶成一种新的晶型，利用粉末X-射线衍射法、红外光谱法、差示扫描量热法，对新晶型替格瑞洛进行表征。测定替格瑞洛晶型Ⅱ和新晶型在模拟胃液(pH 1.2盐酸溶液)、模拟肠液(pH 6.8磷酸盐缓冲溶液)和30%乙醇/水溶液中溶解的平衡溶解度。结果 替格瑞洛新晶型的2θ值在5.49°，11.01°，12.48°，13.88°，16.86°，17.34°，18.21°，18.87°，19.34°，20.12°，21.29°，22.02°，22.68°，24.03°，25.44°，28.24°，31.03°处有特征吸收峰，明显区别于其他晶型。结论 在模拟胃液(pH 1.2盐酸溶液)和模拟肠液(pH 6.8磷酸盐缓冲溶液)中，替格瑞洛新晶型的平衡溶解度均约为替格瑞洛晶型Ⅱ的0.89倍；在30%乙醇水溶液中，替格瑞洛新晶型的平衡溶解度约为替格瑞洛晶型Ⅱ的1.75倍。

Abstract:

OBJECTIVE To explore the preparation of new crystal forms of ticagrelor, optimize the preparation process, meanwhile, conduct characterization and dissolution studies. METHODS Using solvent mediation of ticagrelor crystal form Ⅱ into a new crystal form. The new crystal form of ticagrelor was characterized by powder X-ray diffraction, infrared spectroscopy, and differential scanning calorimetry. The equilibrium solubility of ticagrelor crystal form Ⅱ and new crystal form in simulated gastric fluid(pH 1.2 hydrochloric acid solution), simulated intestinal fluid(pH 6.8 phosphate buffer solution) and 30% ethanol/water solution were determined. RESULTS The 2θ values of the new crystal form ticagrelor had characteristic absorption peaks at 5.49°, 11.01°, 12.48°, 13.88°, 16.86°, 17.34°, 18.21°, 18.87°, 19.34°, 20.12°, 21.29°, 22.02°, 22.68°, 24.03°, 25.44°, 28.24°, 31.03°, which were obviously different from other crystal forms. CONCLUSION In simulated gastric fluid (pH 1.2 hydrochloric acid solution) and simulated intestinal fluid(pH 6.8 phosphate buffer solution), the equilibrium solubility of ticagrelor new crystal form is about 0.89 times that of ticagrelor crystal form II; In 30 % ethanolwater solution, the equilibrium solubility of ticagrelor new crystal form is about 1.75 times that of ticagrelor crystal form II.