Resolution Control in a Continuous Preferential Crystallization Process

Preferential crystallization is a technique used to separate enantiomers and is usually performed in batch mode. For a continuously operated preferential crystallization process from a supersaturated racemic solution, however, nucleation and growth of the unwanted counter enantiomer eventually becomes inevitable, and a controlling measure should be taken. Through the use of polarimetry as an effective monitoring tool to detect the crystallization of the unwanted enantiomer, a novel strategy to eliminate the unwanted enantiomer crystals in a continuous cooling preferential crystallization process is presented. The strategy involves switching from the racemic feed solution to an enantiopure feed solution upon detection of the counter enantiomer crystals. This allows selective dissolution of the counter enantiomer crystals while the preferred enantiomer crystals continue to crystallize. After all of the counter enantiomer crystals are dissolved by decreasing the counter enantiomer solution concentration sufficiently below its solubility, the feed is switched back to the racemic solution. Through the use of this model-free controlling action the continuous process does not have to be terminated. Instead, this method rectifies the situation to the initial metastable steady state by using a portion of the produced enantiomer product. The process can therefore operate at higher supersaturations compared with existing processes for longer periods of time since the control action does not rely on the dissolution kinetics of the system but rather on the thermodynamics of the phase diagram. We show that this new approach is an effective and scalable control strategy for achieving enantiopure product in a continuous preferential crystallization process.