Microfluidic approach to polymorph screening through antisolvent crystallization

Here we present a microfluidic platform comprised of 48 wells to screen for polymorphs of active pharmaceutical ingredients (API) through antisolvent crystallization. API solutions and anti-solvents are precisely metered in various volumetric ratios (range from 50 : 10 to 10 : 50), and mixed via diffusive mixing on-chip. Optical microscopy and Raman spectroscopy were used to analyze the resultant solids. The small volumes (37 nL) and the ability to screen a wide range of supersaturations through diffusive mixing make this platform especially useful for solid form development at discovery and early development stages in pharmaceutical industry. To validate this microfluidic approach, we conducted on-chip antisolvent crystallization using indomethacin. Solvent choice, supersaturation level, and antisolvent-to-solution ratio were found to affect the resulting crystal form of the solids prepared on chip. We modelled the representative time-dependent concentration profiles during the mixing of the antisolvent and API solutions. Combining this analysis with solubility data yielded spatiotemporal supersaturation profiles, which we correlated with solid formation as observed experimentally.