Optimal operation of batch enantiomer crystallization: From ternary diagrams to predictive control

Abstract

In this work, the modeling and control of batch crystallization for racemic compound forming systems is addressed in a systematic fashion. Specifically, a batch crystallization process is considered for which the initial solution has been preenriched in the desired enantiomer to enable crystallization of only the preferred enantiomer. A method for determining desired operating conditions (composition of the initial pre-enriched solution and temperature to which the mixture must be cooled for maximum yield) for the batch crystallizer based on a ternary diagram for the enantiomer mixture in a solvent is described. Subsequently, it is shown that the information obtained from the ternary diagram, such as the maximum yield attainable from the process due to thermodynamics, can be used to formulate constraints for an optimization-based control method to achieve desired product characteristics such as a desired yield. The proposed method is demonstrated for the batch crystallization of mandelic acid in a crystallizer with a fines trap that is seeded with crystals of the desired enantiomer. The process is controlled with an optimization-based controller to minimize the ratio of the mass of crystals obtained from nuclei to the mass obtained from seeds while maintaining the desired enantioseparation.

Inferring kinetic dissolution of NaCl in aqueous glycol solution using a low‐cost apparatus and population balance model

“…The resulting model based on PBE consists of a set of coupled integrodifferential equation (eg, the mass balance) and a hyperbolic partial differential equation (the PBE), often presenting sharp profiles. [45,46] In order to deal with those features, several specialized numerical methods are needed; for a detailed review, see Costa et al [47] The method of moments is widely used because it transforms the partial differential equations into a set of ordinary differential equations. The drawback is that it requires additional methods to reconstruct the PSD and it is not applicable in some situations, as in sizedependent growth or the disappearance of particles at a certain size.…”

Enabling Mechanical Separation of Enantiomers through Controlled Batchwise Concomitant Crystallization: Digital Design and Experimental Validation

“…2 Such is the case of Naproxen: the Senantiomer produces the desired anti-inflammatory response, whereas its mirror image Renantiomer causes liver poisoning. 3 There are a number of process techniques available to separate enantiomers, including deracemization [4][5][6] and chromatography [7][8][9] techniques. A common resolution technique used in industry in preferential crystallization (PC).…”

“…However, in the more serious case, the opposite enantiomer can induce a hazardous effect on the patient . Such is the case of Naproxen: the S- enantiomer produces the desired anti-inflammatory response, whereas its mirror image R- enantiomer causes liver poisoning …”