Surface-Induced Polymorphism as a Tool for Enhanced Dissolution: The Example of Phenytoin

Polymorphism and morphology can represent key factors tremendously limiting the bioavailability of active pharmaceutical ingredients (API), in particular, due to solubility issues. Within this work, the generation of a yet unknown surface-induced polymorph (SIP) of the model drug, 5,5-diphenylimidazolidin-2,4-dion (phenytoin), is demonstrated in thin films through altering the crystallization kinetics and the solvent type. Atomic force microscopy points toward the presence of large single-crystalline domains of the SIP, which is in contrast to samples comprising solely the bulk phase, where extended dendritic phenytoin networks are observed. Grazing incidence X-ray diffraction reveals unit cell dimensions of the SIP significantly different from those of the known bulk crystal structure of phenytoin. Moreover, the aqueous dissolution performance of the new polymorph is benchmarked against a pure bulk phase reference sample. Our results demonstrate that the SIP exhibits markedly advantageous drug release performance in terms of dissolution time. These findings suggest that thin-film growth of pharmaceutical systems in general should be explored, where poor aqueous dissolution represents a key limiting factor in pharmaceutical applications, and illustrate the experimental pathway for determining the physical properties of a pharmaceutically relevant SIP.