Effect of Solution Volume and Agitation on Primary Nucleation of Griseofulvin in Methanol

Abstract

Nucleation, the first step of crystallization, is stochastic at small volumes and becomes increasingly deterministic with increasing volume. Translating crystallization processes from the lab to commercial scale remains challenging due to the stochastic nature of nucleation at smaller scales, differences between crystallizer designs, and inconsistencies that arise during scale-up. This study examines how solution volume and agitation affect nucleation kinetics in the crystallization of griseofulvin in methanol. Induction time experiments were conducted at 1 and 100 mL scales using Crystal16 and EasyMax setups, respectively. These results were compared to previously reported experiments conducted at a 20 mL scale using a setup of magnetically stirred solutions, where the induction time was determined through visual analysis of video recordings. GSF nucleated as stable Form I under all investigated conditions. There is a transition from stochastic nucleation observed at 1 and 20 mL scales to a more deterministic process at the 100 mL scale. The nucleation rate exhibits a correlation with differing energy dissipation and solution volume conditions.