Control of crystal size distribution in batch protein crystallization by integrating a gapped Kenics static mixer to flexibly produce seed crystals

Abstract

Seeding is often used in crystallization to control the quality of crystalline products. The conventional approach to obtaining seed crystals typically involves milling, which may not be suitable for protein crystallization due to possible protein denaturation. We propose a novel method for generating protein seed crystals by using a gapped Kenics tubular crystallizer (gKTC). Small and non-agglomerated seed crystals are generated in the gKTC for the model protein lysozyme. Different seeding policies can be implemented by adjusting the transfer of crystals from the gKTC to a batch crystallizer, which offers flexible control over the crystal size distribution (CSD) of the batch product. This flexibility is demonstrated through an open-loop control strategy in which an optimal seeding policy to obtain a flat-top CSD is derived from a model, which is then implemented experimentally. The obtained CSD is close to the specified one, which cannot be achieved well with conventional batch crystallization.