Abstract
Griseofulvin (GSF) is an antifungal drug that has been clinically used for six decades. Here, we present a rich polymorphism of GSF crystallizing from GSF dispersions with polyethylene glycol (PEG), including five true polymorphs (Forms I-V) and one inclusion complex (IC). Two new polymorphs were reported for the first time, denoted Forms IV and V. Single-crystal structures of new polymorphs and a GSF-PEG IC were determined by X-ray crystallography using single crystals cultivated by microdroplet melt crystallization. A comprehensive solid form landscape of GSF is established to describe phase conversions between polymorphs. Enhancement in molecular mobility by PEG is suggested to be the reason for the nucleation of two new polymorphs, while the small geographic radius of PEG is attributed to the formation of a GSF-PEG IC increasing the density and lowering the Gibbs free energy of the system. This work expands our understanding of the complicated crystallization behavior of GSF in dispersions with PEG and emphasizes the importance of polymorphism control during the manufacturing and storage of PEG-based solid dispersions to achieve reproducible and consistent pharmaceutical performance. The results also suggest that polymer addition is an alternative strategy that cannot be neglected in polymorphism screening.