Optimization-Based Process Synthesis for Integrated Crystallizer-Wet Mill System for Improved Crystal Shape Control

The simultaneous control of crystal size and shape is particularly important in fine chemical and pharmaceutical crystallization. These two quantities not only influence significantly the dissolution rate and bioavailability of final drug products, but also contribute to the manufacturability and efficiency of downstream operations. The manipulation of crystal shape, however, is difficult since it requires the decoupled growth rate control of individual crystal faces. The supersaturation and solvent system dependency of these rates are often not strong enough to enable impactful crystal shape control through temperature and/or solvent composition variation. The aim of this work is to analyse and evaluate the control possibilities of bivariate size distribution (which by definition involves crystal size and shape information) of high-aspect ratio crystals in an integrated crystallizer-external wet mill system. The crystallizer is modelled by primary and secondary nucleation, crystal growth and dissolution along the length and width axes, whereas in the wet mill - in addition to the aforementioned sub-processes - fragmentation and attrition are also considered. The advanced hydrodynamic description enables the direct implication of stirrer revolution speed in the model. The generated system of hyperbolic partial differential and ordinary differential equations is solved by the fully discretized high-resolution finite volume method, involving graphical processing unit acceleration, which brings significant - generally two orders of magnitude - speed-up. The dynamic optimization of wet-mill rotation speed, crystallizer temperature and recirculation flowrate revealed that the target bivariate crystal size distribution can be achieved much better with the integrated system than manipulating only the temperature profile of the batch crystallizer.