Microfluidic Methods for the Crystallization of Active Pharmaceutical Ingredients

Abstract

Emulsion-based crystallization to produce spherical crystalline agglomerates (SAs) holds great potential for the intensification of pharmaceutical manufacturing, as the spherical particles produced by this technique have superior downstream properties. However, current batch methods yield polydisperse SAs, and insights about the formation mechanism of individual SAs are hard to come by. This thesis presents the start-to-finish development of a continuous emulsion-based crystallizer to produce uniform SAs, a feat enabled by monodisperse emulsion generation in microfluidic devices. First, microfluidic droplet generation was coupled with thin-film evaporation to produce uniform SAs of glycine, a model API compound. On-line microscopic monitoring revealed the dynamics of SA formation. Next, the process was investigated through experiments and mathematical modeling to delineate segments of processing parameter space in which SAs of a desired morphology form. Finally, a prototype continuous thin-film evaporator is presented. This scalable setup can produce high quality SAs at industrially relevant rates.