目的 分析晶習對辛伐他汀氧化穩(wěn)定性的影響。方法 將辛伐他汀從不同極性的溶劑混合物中重結(jié)晶,制備辛伐他汀的不同晶習,使用電子順磁共振波譜儀(EPR)表征氧化穩(wěn)定性,采用密度泛函理論(DFT)方法計算分析氧化位點,使用多晶X射線衍射儀(PXRD)進行晶面檢測分析。結(jié)果 制備得到辛伐他汀I晶型的薄片狀和棒狀兩種晶習,EPR結(jié)果顯示棒狀晶習氧化穩(wěn)定性更好,DFT計算顯示辛伐他汀氧化位點在辛伐他汀六氫萘片段上,PXRD結(jié)果顯示薄片狀晶習比棒狀晶習暴露的氧化位點更多。辛伐他汀晶習不同導致各晶面占比不同,活潑氧化位點的暴露比例不同,活潑氧化位點暴露越多的晶習越不穩(wěn)定,而將活潑位點更多保護在晶體內(nèi)部的晶習更加穩(wěn)定。結(jié)論 開發(fā)了一種高效、無損的氧化穩(wěn)定性EPR檢測方法,為藥物晶習的相關(guān)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

國家自然科學基金資助項目(22103068);浙江省基礎(chǔ)公益研究計劃項目(LGC22B050010)