Rapid, Automated Measurement of Dynamic Size Distributions and Size-Dependent Growth Rates of Crystal Ensembles within Microfluidic Flow Cells

In-process monitoring of crystal sizes and extraction of crystal growth kinetics during crystallization, enabled by process analytical technologies, are crucial for the development of crystal size distribution (CSD) control strategies in pharmaceutical manufacturing. In this paper, we demonstrate a well-based microfluidic flow cell platform for rapid and direct measurements of evolving crystal sizes and size-dependent growth rates within crystal ensembles exposed to well-defined flow fields. We present detailed growth measurements of two high-aspect-ratio model drugs─celecoxib and glycine, where growing crystal ensembles are trapped in pseudo-static fashion within wells in a microfluidic flow cell under controlled laminar shear fields and observed via polarized microscopy over sustained time intervals. Time-varying CSDs are extracted via a novel image segmentation-based length detection algorithm, which then allow rapid estimation of shear and size-dependent growth rates through a simple optimization scheme. We also demonstrate discrimination between different regimes of crystal growth in the two model drugs. We envision the platform to be applicable both as a process development and analytics tool. The obtained growth kinetics data can be directly incorporated into computational fluid dynamics-coupled population balance models for improved accuracy in CSD prediction. The platform can also be retrofitted to crystallization vessels for rapid online measurements of evolving crystal sizes.