Continuous Preferential Crystallization of Chiral Molecules in Single and Coupled Mixed-Suspension Mixed-Product-Removal Crystallizers

Abstract

In several industrial fields, the existence of chiral molecules causes challenges when only one enantiomer is the desired active ingredient in the final product. The separation of pairs of enantiomers can be achieved with different techniques. Once these enantiomers crystallize as conglomerates, preferential crystallization (PC) is a very attractive alternative. So far, various batchwise operating strategies have been developed and applied successfully. Very likely, however, it can be more beneficial to use PC in a continuous manner, since continuous processes can often outrun their batch counterpart in terms of productivity, product quality, and process complexity. In this contribution, chiral separation is investigated and performed in a continuous manner adapting the concept of mixed-suspension mixed-product-removal (MSMPR) to the requirements of preferential crystallization. Continuous PC could be realized successfully in two different experimental setups involving only one MSMPR crystallizer and two MSMPR crystallizers coupled via an exchange of their liquid phases. For the model system d-/l-threonine/water, this first experimental demonstration of the concept proves that the process can continuously separate enantiomers with purities >99%. The agreement of the experimental results with results of process simulation indicates the strength and usefulness of a previously published mathematical model.

Diastereomeric salt crystallization of chiral moleculesvia sequential coupled‐Batch operation

“…Traditionally, this may have been difficult to implement industrially in the pharmaceutical industry which has almost exclusively utilized standard batch equipment. However, the past decade has seen a significant uptake of crystallizer technologies for use in next generation continuous pharmaceutical platforms with ability to separate enantiomers in a continuous manner as well as access to a wider ranges of particle sizes, improved polymorph control, and increased purity …”

Particle Size Distributions and Performance of Preferential Crystallization of L‐Asparagine·H2O with Tailor‐Made Additives

“…A major objective in the process is to prevent the spontaneous crystallization of the counter‐enantiomer. Many processes have been suggested to minimize or mitigate the effect of counter‐enantiomer crystallization . A recent review of stereoselective crystallization has given a helpful overview of the topic and a summary of useful methods .…”

Stereoselective Crystallization as a Basis for Single‐Enantiomer Drug Production

“…To get closer to industrial technology, preferential crystallization of each enantiomer is performed in parallel using two crystallizers that are connected via the liquid phase. This group includes the so‐called auto‐seeded polythermic programmed preferential crystallization (AS3PC) , as well as some other modifications, listed in .…”