里托纳维尔回顾:融化结晶可以轻松找到晚出现的多态II,并意外发现新的多态III
Shuting Li1, Binbin Liu1, Ziqiao Chen1
1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Molecular pharmaceutics
|July 14, 2023
概括
在聚乙烯糖醇 (PEG) 的帮助下,融结晶有效地揭示了隐藏的药物多态,如Ritonavir (RIT) 形式II. 这种方法还发现了一种新的多态,Form III,对药物开发至关重要.
科学领域:
- 制药科学 制药科学
- 材料科学 材料科学 材料科学
- 晶体学 晶体学是指结晶学.
背景情况:
- 在早期药物开发中,识别稳定的药物多态是至关重要的.
- 里托纳维尔 (RIT) 形式II是一种热力学稳定的多态体,在上市后出现,造成了巨大的财务损失.
- 现有的选方法可能会错过动力阻碍或迟出现的多态体.
研究的目的:
- 研究融结晶作为一种揭示RIT多态的方法.
- 探索聚乙烯糖醇 (PEG) 在促进特定多态结晶中的作用.
- 发现和描述新的RIT多态及其结构.
主要方法:
- 在低超降温下进行Ritonavir (RIT) 的常规融化结晶.
- 用不同度的聚乙烯糖醇 (PEG) 进行结晶实验.
- 同步光X射线衍射用于确定新多态的单晶结构 (形式III).
主要成果:
- 融化结晶显示RIT形式II在低超冷却下,尽管核化概率低.
- 添加30-50%的PEG显著促进了II型结晶,提高了其可检测性.
- 一种新的多态体,RIT Form III,出乎意料地被发现,其晶体结构得到了解决 (P1,Z'=4).
- 热力学稳定性顺序:形式II>形式I>形式III,不同于溶解性顺序.
结论:
- 融结晶对于全面的药物多形态查至关重要.
- 添加PEG有助于检测动态受阻的多态,如RIT表格II.
- 发现Form III及其结构的确定凸显了融结晶和同步子分析的力量.
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