Designs of continuous-flow pharmaceutical crystallizers: developments and practice

Abstract

Crystallization is an effective, low-cost purification & formulation process widely applied to pharmaceuticals and fine chemicals. This review describes recent advances in research on lab-scale solution-based continuous crystallization, including (1) a 5-step general design procedure; (2) key design/operational parameters; (3) process intensification strategies; and (4) a case study. The continuous crystallizers reviewed include mixed-suspension mixed-product removal, fluidized beds, oscillatory baffled flow, and tubular laminar/segmented/slug-flow crystallizers. Their corresponding design and operational considerations are summarized in terms of general parameters (e.g., residence time), and crystallizer-specific parameters and strategies (e.g., mixing strategies). In-line nucleation and crystal modification methods are categorized, including use of micromixers, wet milling, ultrasonication, temperature cycling, and recycling selection (filtration, sedimentation). Throughout the article, links are drawn with extensive existing knowledge of batch crystallizers, to facilitate the understanding and design of continuous crystallizers.