Supercooled liquid state facilitates recrystallization-mediated gelation of amorphous cinnarizine

Abstract

Amorphization is an effective strategy for enhancing the solubility of poorly water-soluble drugs. However, its benefits can be compromised by gelation-a counterintuitive phenomenon that leads to decreased dissolution behavior compared to the crystalline counterpart. In this study, we found that amorphous cinnarizine (CIN) exhibits a pronounced gelation tendency at higher pH, temperature, and ionic strength. We propose that the gelation process is initiated by CIN’s transition into a supercooled liquid state above its glass transition temperature (Tg). This state is characterized by high viscosity but sufficient molecular mobility, which collectively facilitates rapid recrystallization and subsequent gel network formation. This study elucidates the underlying mechanism and offers a perspective for preventing gelation in low-Tg amorphous drugs.