Continuous-flow, well-mixed, microfluidic crystallization device for screening of polymorphs, morphology, and crystallization kinetics at controlled supersaturation

Abstract

Screening of crystal polymorphs and morphology and measurement of crystallization kinetics in a controlled supersaturated environment is crucial for the development of crystallization processes for pharmaceuticals, agrochemicals, semiconductors, catalysts, and other specialty chemicals. Most of the current tools including microtiter plates and droplet-based microfluidic devices suffer from depleting supersaturation in small compartments due to nucleation and growth of crystals. Such variation in supersaturation not only affects the outcome but also leads to impediments during the scale-up of the crystallizer. Here we develop an innovative technique using H-shaped and cyclone mixer designs to study crystallization at constant supersaturation maintained by a continuous flow of solution. While the H-shaped design can be used to screen crystals with slower kinetics, the cyclone mixer is better suited for crystals with faster kinetics. The polymorphs and morphology of o-aminobenzoic acid (o-ABA) at different supersaturations are analyzed using the cyclone mixer design and compared with the microtiter plate. While the polymorphs and morphology of o-ABA are affected by depleting supersaturation in a microtiter plate, the cyclone mixer design consistently screened stable and metastable polymorphs. These novel devices will also play an important role in supporting the FDA's initiative to spur innovation in continuous manufacturing for the advancements in drug development.