目的 分析晶习对辛伐他汀氧化稳定性的影响。方法 将辛伐他汀从不同极性的溶剂混合物中重结晶,制备辛伐他汀的不同晶习,使用电子顺磁共振波谱仪(EPR)表征氧化稳定性,采用密度泛函理论(DFT)方法计算分析氧化位点,使用多晶X射线衍射仪(PXRD)进行晶面检测分析。结果 制备得到辛伐他汀I晶型的薄片状和棒状两种晶习,EPR结果显示棒状晶习氧化稳定性更好,DFT计算显示辛伐他汀氧化位点在辛伐他汀六氢萘片段上,PXRD结果显示薄片状晶习比棒状晶习暴露的氧化位点更多。辛伐他汀晶习不同导致各晶面占比不同,活泼氧化位点的暴露比例不同,活泼氧化位点暴露越多的晶习越不稳定,而将活泼位点更多保护在晶体内部的晶习更加稳定。结论 开发了一种高效、无损的氧化稳定性EPR检测方法,为药物晶习的相关研究提供了新思路和新方法。

Objective To study influence of crystal habit on the oxidative stability of simvastatin. Methods Different crystal habits of simvastatin were recrystallized from solvent mixtures with different polarities. The oxidation stability was characterized by electron paramagnetic resonance spectroscopy (EPR). The oxidation sites were calculated by density functional theory (DFT). The crystal planes were detected and analyzed by polycrystalline X-ray diffraction (PXRD). Results Lamellar and rodlike crystal habits of simvastatin I crystal form were prepared. EPR results showed that rodlike crystal habit have better oxidation stability. DFT calculation showed that the oxidation site of simvastatin was on the hexahydronaphthalene fragment of simvastatin. PXRD results showed that the lamellar crystal habit exposed more oxidation sites than the rodlike crystal habit. The proportion of exposed active oxidation sites in the two crystal habits was different. The more active oxidation sites were exposed, the more unstable the crystal habit was. Conclusion An efficient and nondestructive EPR method for measuring oxidation stability has been developed. This experiment provides a new idea and method for the related research of drug crystal habit.

R927

国家自然科学基金资助项目(22103068);浙江省基础公益研究计划项目(LGC22B050010)