Implementation of MSMPR Crystallization to Avoid Liquid–Liquid Phase Separation

The presence of metastable liquid–liquid phase separation (LLPS) near the solid–liquid equilibrium (SLE) is a common challenge encountered in the development of small-molecule crystallization. This phenomenon is generally undesired as it can negatively impact control over the purity and morphology of the product and limit the ability to measure crystallization kinetics. Using a continuous mixed-suspension, mixed-product-removal (MSMPR) crystallizer, a crystallization process was designed to avoid system compositions in which the metastable LLPS is present. The MSMPR crystallizer was operated under feed solute concentrations that were observed to lead to LLPS in analogous batch processing. A range of MSMPR operating conditions was explored and demonstrated to avoid LLPS both during the dynamic start-up and at a steady state. A population balance model was generated to estimate crystallization kinetics and develop predictions of operating yields. Analysis is provided for the trends of MSMPR yields and relative supersaturations (RSSs) at a steady state as a function of key process parameters.