Efficient Resolution of Enantiomers by Coupling Preferential Crystallization and Dissolution. Part 2: A Parametric Simulation Study to Identify Suitable Process Conditions

Abstract

For pairs of enantiomers crystallizing as a conglomerate, several process strategies can be used to resolve them by preferential crystallization (PC). Usually, a main limitation is the nucleation of the counter enantiomer, which restricts productivities. The performance of PC can be strongly increased, when crystallization and selective dissolution are combined by coupling two crystallizers via the liquid phase. In doing so, one crystallizer contains a saturated racemic suspension, while the other is in a supersaturated state and initially seeded with pure enantiomer. The crystallization of the seeds in the corresponding tank leads to a transient undersaturation in the other tank and, thus, to a selective dissolution from the racemate. Due to the exchange of solution, crystallization is accelerated, while the solid racemate is purified. The process described, has been investigated in detail using a well-established population balance model, which was shown to be in good agreement with experimental results presented recently in ref 1. A parametric study was done, which revealed regions, in which the process can be operated at high productivity, yielding both enantiomers in pure form. The achieved understanding of the influence of the investigated process parameters on the performance can help to further improve and optimize the process.

Effect of additives on the preferential crystallization of L-asparagine monohydrate

“…Many researchers have tried to circumvent this problem, for instance by using coupled batch crystallizers -crystallizing the preferred enantiomer in one crystallizer and the counter enantiomer in another crystallizer, with exchange of solution between the two crystallizers [13], coupled batch crystallizers with seeding of the preferred enantiomer in one crystallizer and allowing nucleation of the counter enantiomer in another crystallizer maintained at a different temperature [14,15], coupled batch crystallizers with a membrane between the crystallizers to prevent transport of crystals from one crystallizer to another [16], and racemization of the solute species to equalize the concentrations of the preferred and counter enantiomer [17,18], Another way to circumvent the crystallization of the counter enantiomer is to use tailor made additives to inhibit the nucleation and growth of the counter enantiomer. This will be convenient if the scale of the resolution is such that a fully batch system is most suitable and crystallization or recycling of the counter enantiomer is not required.…”

Stereoselective Crystallization as a Basis for Single‐Enantiomer Drug Production

“…An intelligent, worthwhile modification of the two‐tank circuit is the approach proposed in , . The method is based on the property of the conglomerate of any nonracemic composition, described in Sect.…”

Modeling and Simulation Studies of a Novel Coupled Plug Flow Crystallizer for the Continuous Separation of Conglomerate-Forming Enantiomers

“…However, this can become increasingly difficult if the supersaturation level of the counter enantiomer is high in the crystallizer. This problem can be alleviated by a liquid phase exchange between two coupled crystallizers where both the enantiomers are crystallized separately [13][14][15]. Moreover, when chiral compound can be racemized in solution, a further alleviation of the supersaturation of the counter enantiomer can be obtained.…”

“…This novel configuration involves two PFCs coupled through solid free liquid phase exchange and the crystallization of the enantiomers takes place in two crystallizers separately. A population balance model [14,34,35] of the process has been developed and simulation results for the model compound D-/L-threonine are compared with the widely used coupled batch and coupled MSMPR-type crystallizers. Effect of various operating conditions such as amount and location of liquid exchange and seed mass has been presented as well.…”