Control of Crystal Properties in a Mixed-Suspension Mixed-Product Removal Crystallizer: General Methods and the Effects of Secondary Nucleation

Continuous crystallization has gained growing interest in the pharmaceutical industry due to its high productivity and consistency of the product quality. Significant progress on the control of mixed-suspension mixed-product removal (MSMPR) product properties with the aspects of crystal size distribution, polymorphism, and crystal shape has been achieved. This review aims to summarize different property control methods and put forward new viewpoints on process control by applying a secondary nucleation mechanism. The review begins with a brief introduction to the characteristics and mechanisms of secondary nucleation, followed by an attempt to investigate the underlying phenomena involved in secondary nucleation. Then, the steady-state conditions of continuous crystallization from mathematical and mechanism analyses are discussed. Subsequently, the focus is on a variety of approaches that have been implemented in continuous crystallization processes to enable crystals to meet different critical quality attributes. Among them, by applying a secondary nucleation mechanism, new design strategies for crystal size and polymorph control in continuous crystallization are proposed. Furthermore, the possible relationship between the secondary nucleation threshold and crystal shape distribution is elaborated using a theoretical analysis and selecting supporting experimental evidence from the literature.