Liquid–liquid phase separation in pharmaceutical crystallization

Abstract Liquid–liquid phase separation (LLPS) during crystallization development of pharmaceuticals is being reported increasingly in recent years. It often causes quality issues such as failure of impurity reject and fragile morphology. In worst cases, crystallization cannot proceed at all after LLPS occurs. Many studies have been published on LLPS during crystallization and an analysis and synthesis of the current state-of-art is needed. In this review, recent advances in LLPS research will be summarized, including brief theoretical interpretations of LLPS, characteristics in phase diagrams and measurement methods for representative model systems, strategies to suppress LLPS, crystallization development in the presence of LLPS and options when direct crystallization fails due to LLPS. This review aims to provide a framework to deal with the occurrence of LLPS during crystallization development.