Highly Selective, Kinetically Driven Polymorphic Selection in Microfluidic Emulsion-Based Crystallization and Formulation

Abstract

We present a simple, potentially generalizable method to create highly monodisperse spherical microparticles (SMs) of ∼200 μm size containing active pharmaceutical ingredient (API) crystals and a macromolecular excipient, with unprecedented, highly specific, and selective control over the morphology and polymorphic outcome. The basic idea and novelty of our method is to control polymorphic selection within evaporating emulsion drops containing API–excipient mixtures via the kinetics of two simultaneously occurring processes: liquid–liquid phase separation and supersaturation generation, both governed by solvent evaporation. We demonstrate our method using two model hydrophobic APIs: 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY) and carbamazepine (CBZ), formulated with ethyl cellulose (EC) as excipient. We dispense monodisperse oil-in-water (O/W) emulsions containing the API–excipient mixture on a flat substrate with a predispensed film of the continuous phase, which are subsequently subjected to evaporative crystallization. We are able to control the polymorphic selection by varying solvent evaporation rate, which can be simply tuned by the film thickness; thin (∼0.5 mm) and thick (∼2 mm) films lead to completely specific and different polymorphic outcomes for both model APIs: yellow (YT04) and orange (OP) for ROY, and form II and form III for CBZ respectively. Our method paves the way for simultaneous, bottom-up crystallization and formulation processes coupled with unprecedented polymorphic selection through process driven kinetics.