Abstract: 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.

Key words: Baloxavir marboxil, in-situ AFM, dissolution mechanism, drug crystal, step retreat dissolution, pit expansion dissolution