(125c) Implementation of Continuous Crystallization to Circumvent a Meta-Stable Liquid-Liquid Separation

High concentrations of complex organic solute may lead to meta-stable liquid-liquid separations due to solvent-solute interactions, even in otherwise miscible solvent systems. The formation of such non-ideal phases is generally undesirable in crystallization operations, as they tend to unevenly distribute the solute across the resulting liquids. Some of the potential side effects of this phenomenon are uncontrolled nucleation and growth, inadequate impurity purge, solvent entrainment, and morphological inconsistencies in the solids. Despite the inherent challenges that arise due to the formation of non-ideal phases, they have become increasingly common in pharmaceutical process development due to the current shift in the industry towards higher-complexity molecular structures and greater sustainability. The growing prevalence of these complex systems solicits the design and implementation of novel development tools that can assist process engineers in creating robust crystallization procedures. Traditional batch crystallization relies on modifications to the cooling curves, or overall solvent/anti-solvent composition to avoid meta-stable liquid-liquid separations; however, some chemical systems lack the flexibility required to incorporate these corrective measures, and the potential recourse may lead to unexpected consequences, such as polymorphic changes and slower crystallization kinetics. Using a Mixed Suspension Mixed Product Removal (MSMPR) continuous crystallizer, we captured a steady state equilibrium point in the saturation curve that avoids the formation of the undesired meta-stable phase for the purification of a commercially relevant small-molecule. The resulting continuous crystallization process circumvents original design limitations of the system, providing controlled recovery of the desired material without altering the original solvent/anti-solvent composition. In this talk, we will discuss and compare the different development challenges encountered when implementing the process in batch versus continuous mode. Additionally, we will outline the benefits of implementing continuous crystallization as a tool to obtain crystallization kinetic data, which can be incorporated with a 3D population balance and mass balance model to optimize conditions for yield and productivity.