Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Pharm Res. 2013 Mar;30(3):826-35. doi: 10.1007/s11095-012-0923-1. Epub 2012 Nov 10.
To investigate the heating-induced dehydration and melting behavior of the trihydrate phase of the calcium salt of atorvastatin.
Multivariate curve resolution (MCR) was used to decompose a variable-temperature synchrotron X-ray powder diffraction (VT-XRPD) data matrix into diffraction patterns and concentration profiles of pure drug phases.
By means of the MCR-estimated diffraction patterns and concentration profiles, the trihydrate phase of the drug salt was found to dehydrate sequentially into two partially dehydrated hydrate structures upon heating from 25 to 110°C, with no associated breakage of the original crystal lattice. During heating from 110 to 140°C, the remaining water was lost from the solid drug salt, which instantly collapsed into a liquid crystalline phase. An isotropic melt was formed above 155°C. Thermogravimetric analysis, hot-stage polarized light microscopy, and hot-stage Raman spectroscopy combined with principal component analysis (PCA) was shown to provide consistent results.
This study demonstrates that MCR combined with VT-XRPD is a powerful tool for rapid interpretation of complex dehydration behavior of drug hydrates, and it is also the first report on a liquid crystalline phase of the calcium salt of atorvastatin.
研究阿托伐他汀钙三水合物的加热诱导脱水和熔融行为。
采用多元曲线分辨（MCR）技术，将变温同步辐射粉末 X 射线衍射（VT-XRPD）数据矩阵分解为纯药物相的衍射图谱和浓度分布。
通过 MCR 估计的衍射图谱和浓度分布，发现药物盐的三水合物在从 25°C 加热到 110°C 的过程中，依次脱水成两种部分脱水的水合物结构，而没有原始晶格的破坏。在从 110°C 加热到 140°C 的过程中，固体药物盐中的剩余水分被除去，固体盐瞬间坍塌成液晶相。在 155°C 以上形成各向同性熔体。热重分析、热台偏光显微镜和热台拉曼光谱结合主成分分析（PCA）的结果表明，这几种方法的结果一致。
本研究表明，MCR 结合 VT-XRPD 是快速解析药物水合物复杂脱水行为的有力工具，也是阿托伐他汀钙盐液晶相的首次报道。
