Control of Polymorphism in Continuous Crystallization via Mixed Suspension Mixed Product Removal Systems Cascade Design

Control of polymorphism of the enantiotropic p-aminobenzoic acid at either the alpha or beta polymorph while maintaining high yield was achieved by mixed suspension mixed product removal (MSMPR) cascade design. A systematic approach was developed to identify the operational window of the process variables, stage temperature and residence time, in which the stringent polymorph purity criterion (>95 wt %) and high yield were met. The comprehensive understanding of the polymorphism of the model compound, p-aminobenzoic acid, was the key for the identification of the operational window. On the basis of single-stage MSMPR experiments, three temperature regimesthermodynamic control, energy barrier control, and kinetic competitionwere identified, and the interplay between the crystallization kinetics and the thermodynamics in each regime was elucidated. Experimental studies also demonstrated the first polymorph specific MSMPR for enantiotropic systems. Single-stage MSMPRs at low temperature, e.g., 5 degrees C, were found to be beta polymorph-specific at steady states across multiple operating conditions. Two-stage MSMPR was designed to alter the polymorphism at the 5 degrees C stage from beta polymorph-specific to a polymorph-specific. The first stage temperature was selected in the thermodynamic control regime (30 degrees C) at which the steady state polymorphism was a-specific. Feeding continuously to the second stage, the a crystals generated at the first stage increased the total surface area and thereby the secondary nucleation and mass deposition rates of the a polymorph in the 5 degrees C stage. This in turn increased the a polymorph from 0 wt % to at least 75 wt %, proving that it is feasible to control the polymorphism via design of the MSMPR cascade.