Characterization of a Multistage Continuous MSMPR Crystallization Process assisted by Image Analysis of Elongated Crystals

This work demonstrates how quantitative image analysis can assist in the characterization of continuous crystallization processes and in the proper selection of mathematical models for the early assessment of crystal quality. An active pharmaceutical ingredient presenting an elongated crystal habit has been crystallized using two stirred tank crystallizers in series. Using image analysis of the crystallization magma, the sources of crystal breakage in the crystallization cascade have been identified and the impact on crystal habit has been evaluated quantitatively. As it is expected for particles presenting high aspect ratios, crystal breakage preferentially occurs in the smallest plane, perpendicular to the largest dimension. This phenomenon is hardly avoidable in downstream production, but it can be accounted with a design approach based on the real crystal dimensions. The kinetic rate equations for nucleation and crystal growth have been determined based on crystal width, from which a model for the accurate prediction of this dimension has been applied. The predicted crystal size distribution is consistent through a moderate degree of crystal breakage during downstream processing.