基于原位原子力显微镜的巴洛沙韦酯单晶溶解机制研究

Dissolution Mechanism of Baloxavir Marboxil Single Crystal Based on In-Situ AFM

本文使用原位原子力显微镜(in-situ AFM),在近分子尺度探究了抗流感药物巴洛沙韦酯晶型Form I晶体最大暴露晶面在水中的溶解行为。该晶体最大暴露晶面为(020)面,溶解前呈现出层状台阶和螺旋位错的微观形貌特征。原位原子力显微镜测试表明该晶面在水中主要以台阶后退溶解机制和蚀坑扩展溶解机制溶解。台阶后退溶解机制主要发生在留存有生长台阶的晶面处,通过层状台阶逐步后退推进溶解。蚀坑扩展溶解机制中,蚀坑具有规则蚀坑和倒螺旋位错型蚀坑两种形态。倒螺旋位错型蚀坑与螺旋位错处的缺陷溶解启动相关;规则四边形蚀坑则主要出现在较为平整光滑的完美晶面处,其原因在于该特征晶面仅能通过自发蚀坑成核来推进溶解过程。通过规则四边形蚀坑溶解机制溶解时,该晶面还存在溶解蚀坑临界尺寸现象,即只有超过一定尺寸的蚀坑才能推进溶解。

The dissolution behavior of the largest exposed crystal face of Baloxavir marboxil Form I crystal,an anti-influenza drug,was investigated by in-situ atomic force microscopy(AFM)at near molecular scale in water.The largest exposed crystal surface is the(020)face,the microstructure features of layered steps and spiral dislocations appear before dissolution.The in-situ AFM tests show that there are two main dissolution mechanisms:step retreat and pit expansion dissolution.The step retreat dissolution mechanism mainly occurs at the crystal faces where growth steps remain,and the dissolution is promoted by gradual retreat of layered steps.There are two forms of pits in pit expansion dissolution mechanism:regular pits and inverted spiral dislocation pits.The formation of inverted spiral dislocation pits is related to the defect initiated-dissolution at the spiral dislocation sites;the regular quadrilateral pits mainly appear at the relatively smooth and perfect crystal faces,because this characteristic crystal surface can only promote the dissolution process through spontaneous pitting nucleation.When the crystal face is dissolved by the regular pit dissolution mechanism,the critical size of the pit-dissolution exists,meaning only pits above a certain size can promote dissolution.