The separation conglomerate forming chiral molecules is investigated in continuous processes combining crystallization, milling and a racemization reaction in solution. Two process configurations that increase enantiomeric purity starting from racemic mixtures are presented and assessed with respect to attainable enantiopurities, achievable yields and productivities. The two processes differ in their feeding strategy: one is fed with a supersaturated solution of racemic composition and one is fed with a racemic mixture of solids. The two cases are studied using a consistent mathematical model based on population balance equations. A parameteric analysis on the key operating parameters of the processes is conducted and operating regions leading to high enantiomeric purity are identified. By combining the crystallization/mill/reaction process with appropriate filtration and solvent removal units, as well as recycle operations, we show that full enantiomeric purity at 100% yield is theoretically attainable for the solution-fed process, while it is unattainable for the solid-fed process variant. * Note that thalidomide enantiomers are known to rapidly racemize in vivo 1 , so that administering only the desired enantiomer would still likely have led to teratogenic effects. Nonetheless, thalidomide has seen a renaissance as a drug to manage certain types of cancer in recent years. 2

Continuous crystallization processes achieving the complete resolution of racemic feed mixtures of conglomerate forming substances are presented. The processes considered rely on the principles of preferential crystallization or attrition-enhanced deracemization (Viedma ripening). A single mechanistic population balance model is shown to describe both operating modes. For the case of isothermal Viedma ripening, a shortcut method is introduced that allows the rapid and computationally efficient design of processes using a single or multiple ripening stages. The achievable productivity and enantiomeric purity are determined for all process variants in a wide range of operating conditions and Pareto optimal operating points are identified. Since our results are obtained with a consistent set of kinetics for all operating modes, an unbiased comparison is enabled. It is shown that the productivity of the ripening process can be improved by using cascades of multiple crystallizers, but that the preferential crystallization process still achieves higher productivity at full enantiomeric purity.

The continuous crystallization of L-glutamic acid from water is studied in a single stage mixed suspension mixed product removal crystallizer that is coupled to a milling loop. We show that the stable β polymorph can be obtained in the presence of milling at operating conditions that would lead to the metastable α polymorph without milling. The effect is first shown through a series of experiments carried out at different residence times, feed concentrations and in the absence/presence of milling. The experimental observations are rationalized through the use of a population balance equation model. We conclude that the observed effects result from fines generation and the corresponding increase in crystal surface area. Using the model, we obtain a map of polymorphic outcomes and process productivity in dependence of operating conditions. It is shown that the combined milling/crystallization process exhibits higher productivity and an enlarged region of operating conditions where the stable polymorph of L-glutamic acid can be reliably obtained in comparison to a conventional crystallization process.