Polymorph selection by continuous crystallization in the presence of wet milling

Abstract

The polymorph selection in a continuous crystallization process combined with wet milling is investigated. To this end, a dimensionless population balance equation model accounting for secondary nucleation, crystal growth, and breakage is formulated and solved numerically. We show that a surprisingly small number of dimensionless parameter groups (combinations of kinetic parameters and operating conditions) is decisive in controlling the polymorphic outcome. Specifically, we show how the operating region where the stable polymorph is obtained can be enlarged by tuning the milling intensity, feed concentration, and residence time. We further rationalize the dependence of the mean size of the particles obtained, the fraction of solute recovered, and the productivity of such a process on the dimensionless variables. We showcase this for the model system l-glutamic acid crystallized from water and show that our analysis is in agreement with previously reported experimental studies. Summarizing, the analysis approach introduced here can be used to identify operating spaces for single-stage continuous crystallization processes where the right polymorph is reliably obtained and where size, solute recovery, and productivity are guaranteed to desired levels.