Enhancing the Crystal Production Rate and Reducing Polydispersity in Continuous Protein Crystallization

This article focuses on the modeling and control of a continuous crystallizer with a fines trap and a product classification unit employed to produce tetragonal hen-egg-white lysozyme crystals. A kinetic Monte Carlo model is initially developed to simulate the crystal nucleation, growth, and aggregation processes taking place in the crystallizer using experimentally determined rate expressions. Subsequently, the influence of varying (a) the flow rates of the streams to the fines trap and the product classification unit and (b) the corresponding cutoff sizes is studied, and as a result, an operating strategy that takes advantage of the aggregation, fines removal, and product classification units is proposed to simultaneously achieve a high production rate and a low polydispersity of the crystals produced by the crystallizer. Finally, a model predictive controller is designed using a reduced-order model, which manipulates the jacket temperature to lead to the production of crystals with the desired shape and size distributions.