Microfluidic Extractive Crystallization for Spherical Drug/Drug-Excipient Microparticle Production

Abstract

Granulation is a common manufacturing step for pharmaceutical drug products, which improves powder flowability, compactibility, and ensures tablet content uniformity. Granules of uniform content can conventionally be challenging to obtain due to powder segregation and mixing issues prior to granulation. Spherical crystallization—a method where drug crystals are directly formed into spherical granules—is a promising way to overcome issues with mixing and form granules with uniform content. However, a common challenge of existing quasi emulsion solvent diffusion or solvent extraction methods for spherical crystallization involving miscible solvents in stirred batch vessels is the coarse control over particles sizes, as they are sensitive to multiple scale-up factors (mixing efficiency, impeller and vessel geometry, inlet configuration). This limits the method in terms of content uniformity, which in turn limits the extent to which granules with tunable dissolution profiles can be created. Here, we propose a method for the formation of monodisperse drug-excipient microparticles with tunable release profiles via microfluidic spherical extractive crystallization using drug and excipient-loaded ethyl acetate-in-water emulsions. Monodisperse droplets are generated using microfluidics, and droplet saturation via solvent extraction leads to eventual and direct monodisperse spherical particle formation within minutes. We demonstrate this method using ethyl acetate droplets loaded with naproxen or naproxen and ethyl cellulose, as a hydrophobic drug and drug-excipient model system, respectively, and obtained monodisperse spherical microparticles in both cases. Lastly, preliminary investigations of in vitro drug release from a range of microparticles made from droplets containing different naproxen–ethyl cellulose ratios displayed clear differences in the release profiles. When coupled with microfluidic droplet generators that operate at high volumetric throughputs, this method has the potential to be applied in continuous manufacturing platforms for the production of monodisperse spherical drug particles or drug-excipient composites with excellent content uniformity and tunable release profiles at a kilogram per day scale throughput.