Periodic wet milling as a solution to size-based separation of crystal products from biocatalyst for continuous reactive crystallization

Abstract Combining the synthesis and crystallization of a compound into a single step may be beneficial for certain processes. Motivations range from process intensification to improving reaction network yield by shifting an equilibrium or protecting an intermediate, as is the case in the biocatalytic synthesis of beta-lactam antibiotics. Adapting such a reactive crystallization process to continuous manufacturing faces a challenge: the continuous separation of crystals from biocatalyst carriers. In this study, a size-based method for this separation problem is proposed. Separation is performed using a filter placed on the reactive crystallization vessel outlet. The primary factors for filter design are carrier and crystal size dictated by the separation condition Lcrystal