A Review of the Use of Process Analytical Technology for the Understanding and Optimization of Production Batch Crystallization Processes

Crystallization at production scale is typically a poorly understood unit operation, with little implementation of the first principles aspect of crystallization in its design, optimization, and control. Problems with production crystallizers include the following: (1) inconsistencies of batch-to-batch in terms of the size and number of crystals produced and (2) the purity profile (residual impurities in crystals, or wrong polymorph or chiral purity). This can have a significant impact both on product quality and downstream process unit operations including filtration, drying, milling, and product formulation. This contribution reviews typical problems encountered in production crystallization, with case studies, advice, and strategies to understand and avoid these problems through the use of in situ crystallization characterization tools.