Residence time distribution characterization and proof-of-concept of a novel stacked 7-stage continuous crystallizer cascade with diaphragm-driven slurry transfer

Abstract

Process developers in the pharmaceutical industry lack readily deployable, standardized, off-the-shelf continuous crystallizers (<100 mL), abiding the low material requirements of early stage product development. This study evaluates a novel continuous tower crystallizer (TWC), hosting a series of seven vertically stacked mixed suspension mixed product removal crystallizers (MSMPRCs, 80 mL total volume) enabled by an innovative diaphragm driven slurry transfer, which eliminates known transfer line issues in MSMPRC cascades. Residence time distribution measurements using the model compound glycine demonstrate ideal mixing for both liquid (homogeneous) and solid (heterogeneous) phases (particle < 100 μm, slurry density < 22.8%). A comparison with the tank in series model reveals nonideal mixing for particles >300 μm. Finally, a proof-of-concept continuous antisolvent crystallization of glycine demonstrates the TWC’s capability to produce high-quality crystals continuously, proving its functional and robust operation.