Direct Growth of Microspheres on Amorphous Precursor Domains in Polymer-Controlled Crystallization of Indomethacin

Abstract

Polymer-controlled crystallization is becoming an increasingly important approach to achieve functional materials precipitated from the solution phase. Nevertheless, there exist multiple pathways under the control of yet unpredictable kinetic factors, which significantly hinder the mechanistic understanding. Herein, the mechanistic study of polymer-controlled precipitation of a typical drug compound, indomethacin, was performed. The presence of a nonionic additive poly(vinylpyrrolidone) induces the heterogeneous nucleation of networks of dumbbell-shaped crystalline microspheres on amorphous precursor domains, which is an emerging pathway in polymer-controlled crystallization. This pathway is also verified in the precipitation of l-histidine in the presence of poly(acrylic acid) in the current study. As a comparison, the presence of a cationic polymeric additive, branched polyethylenimine, promotes the formation of aggregates of amorphous nanoparticles and the subsequent crystallization of a spherical-shaped microsphere on each aggregate, a pathway in line with those in numerous studies of polymer-controlled crystallization of inorganic compounds. Our results suggest that the heterogeneous crystallization of microspheres on the amorphous precursor domains could be a specific pathway occurring in polymer-controlled precipitation of organic compounds mainly due to the fast kinetics of the precipitation process. In short, our study broadens our understanding of polymer-controlled crystallization of functional organic crystals.