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.

The resolution of enantiomers can be achieved by preferential crystallization as soon as they crystallize as a conglomerate. However, several successive and alternate crystallizations of each enantiomer as well as seeds of both enantiomers are required for this process to be efficient. The performance can be increased by using two tanks coupled via the liquid phase. In one subcooled tank, the crystallization of a single enantiomer is carried out by enantioselective seeding, while a suspension of racemic mixture in equilibrium at the saturation temperature with the liquid phase is present in a second tank. Over the course of the crystallization, the concentration of the seeded enantiomer decreases. Because of the liquid exchange, the crystallizing enantiomer becomes undersaturated in the second tank, leading to its selective dissolution. Crystallization and dissolution continue simultaneously in both tanks until the solid phase in the second tank becomes enantiopure. At this point, both suspensions can be filtrated, and each tank yields a pure enantiomer. The proof of principle has been successfully given for the resolution of DL-threonine. Besides reducing the number of steps needed to access both pure enantiomers, this process was found to be more productive than conventional alternatives of resolution by preferential crystallization. ■ INTRODUCTIONWhen a chiral molecule cannot be synthetized from a molecule of the chiral pool, a 50/50 mixture of both enantiomers is often obtained. In this case, the target enantiomer has to be separated from its antipode in a second step. Because of their mirror symmetry, most of their properties are identical, and dedicated resolution techniques are required. If the enantiomers form a conglomerate, their resolution by preferential crystallization is possible. 1 A supersaturated racemic solution eventually gives birth to nuclei of both enantiomers at the same time, leading to a racemic solid. However, if enantiopure seeds are introduced into the solution prior to nucleation, these seeds grow. The solid phase remains in the state of single chirality until the nucleation phenomenon occurs. Up to this point, the racemic mixture can be resolved yielding an enantiopure product. The mass of recovered enantiopure solid is however quite small as compared to the initial mixture (the yield of a single crystallization step is often about 10%). This can be improved by recycling the liquid phase, to selectively crystallize the antipode after the addition of racemic mixture and new seeding. Preferential crystallization therefore consists of successive and alternate crystallization steps of the enantiomers. The application of preferential crystallization requires a good knowledge of the thermodynamic and kinetic properties of the target molecules and involves a significant amount of manual handling. 2 The technology is time and cost consuming and can be difficult to apply for nonspecialists.During the past decade, a new variant of preferential crystallization has been developed. 3 Instead of c...

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.

Preferential crystallization is a cost efficient method to provide pure enantiomers from a racemic mixture of a conglomerate forming system. Exploiting small amounts of pure crystals of both enantiomers, several batch or continuous processes were developed, capable of providing both species. However, an intermediate production step has to be used when pure enantiomers are not available. In such cases, partially selective synthesis, chromatography, or crystallization processes utilizing chiral auxiliaries have to be used to provide the initial seed material. Recently, it was shown that a coupled Preferential Crystallization-selective Dissolution process (CPCD) in two coupled crystallizers can be applied if at least one pure enantiomer is available to produce both antipodes within one batch. The corresponding process is carried out in one reactor (crystallization tank) by seeding a racemic supersaturated solution with the available enantiomer at a certain temperature. The second reactor (dissolution tank) contains a saturated racemic suspension at a higher temperature. Both reactors are coupled via the fluid phase, allowing for a selective dissolution of the preferentially crystallizing enantiomer from the solid racemic feed provided in the dissolution vessel. The dissolution and crystallization processes continue until the solid racemic material is completely resolved and becomes enantiopure. At this point, both enantiomers can be harvested in their pure crystalline form. For a specific pharmaceutically relevant case study, a rational process design and the applied empirical optimization procedure will be described. The achieved productivities after optimization show the great potential of this approach also for industrial applications. Also, a strategy to control this process based on inline turbidity measurement will be presented.

For the design of crystallization processes, the specific substances have to be characterized in terms of their thermodynamic properties but also with respect to the corresponding crystallization kinetics. In an accompanying theoretical study, a short-cut-method was suggested and demonstrated for the quantification of different kinetic mechanisms, i.e. growth, dissolution and nucleation. Here, this method will be utilized for the estimation of parameters comprised in kinetic sub-models for three different substances. The experimental procedures as well as the data analysis will be discussed and the quality of the parameter estimates will be evaluated by comparing predictions of a population balance model using the identified parameters with the results of corresponding validation experiments. AbstractFor the design of crystallization processes, the specific substances have to be characterized in terms of their thermodynamic properties but also with respect to the corresponding crystallization kinetics. In an accompanying theoretical study, a shortcut-method was suggested and demonstrated for the quantification of different kinetic mechanisms, i.e. growth, dissolution and nucleation. Here, this method will be utilized for the estimation of parameters comprised in kinetic sub-models for three different substances. The experimental procedures as well as the data analysis will be discussed and the quality of the parameter estimates will be evaluated by comparing predictions of a population balance model using the identified parameters with the results of corresponding validation experiments.

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