**1. Introduction**

Recently, continuous crystallization has again become the focus of many research activities. Efforts have been made to develop design rules based on comparing it with the corresponding batch process [1,2] or to elucidate basic mechanisms, for example, the impurity incorporation and carryover [3]. Additionally, novel concepts, applying to example slug-flow [4], oscillatory baffled [5,6], Couette-Taylor [7,8] or fluidized bed crystallizers [9–12], as well as columns with static mixers [1] or coiled flow inverters [13], have been developed lately. These concepts exploiting tubular crystallizers in general are not superior nor applicable for every substance system or separation problem. They have specific benefits and drawbacks [1] compared to the well-known mixed-suspension, mixed-product removal (MSMPR) concept but have given new input to the topic of continuous crystallization and have widened the field of application for the food, agriculture, and pharmaceutical industries.

Fluidized bed crystallizers (FBCs) have recently been successfully exploited in wastewater treatment to recover phosphate [9,10], sulfates and magnesia [11], or boron [12] from diluted aqueous solutions. All of these studies aimed at a full conversion of the pollutant ions in the liquid phase to form a salt and utilized afterward the surface of fluidized, inert particles to collect the fine precipitate. FBCs can be also applied, however, for separations where the substance of interest has a similar or the same concentration as the impurity, as is the case for enantioseparations [14].

This process is then based on Preferential Crystallization, which is often applied as an efficient and inexpensive option for the production of pure enantiomers from the racemic, i.e., 50:50, mixture [2,15]. The classical variant is, nevertheless, an unstable process carried out in the metastable zone of the respective ternary substance system, consisting in this case of two enantiomers, D and L, dissolved in a solvent. Seeds of the desired enantiomer are utilized to selectively remove this species from the

liquid phase. Hence, the dissolved mass of the seeded component decreases while the mass fraction of the counter-enantiomer increases. Consequently, the supersaturation of the counter-enantiomer also increases in most cases, which forces this species to nucleate after a certain induction time. A complete separation with the maximum yield is, hence, only achievable if the process is interrupted at the right time shortly before the nucleation.

To increase robustness, productivity, and yield of the classical variant, two opposite Preferential Crystallizations can be carried out in two vessels only connected via a continuous liquid phase exchange [16]. In this way, the selective removal of the enantiomers in the respective crystallizer is counterbalanced and a racemic liquid phase composition maintained, which reduces the risk of nucleation.

The application of fluidized bed crystallizers together with the coupled Preferential Crystallization principle, as shown in Figure 1, provides two additional benefits. Firstly, the flow rate of the feed entering the columns from the bottom drags small crystals out of the process at the top. Hence, contamination of the product can be avoided to a certain extend even if the counter enantiomer nucleates since the nuclei follow the liquid flow. Secondly, a product classification can be achieved by a conical shape of the columns. Then the liquid velocity profile varies over the height of the crystallizers and only a specific crystal size is present at the product outlet. This process allows, hence, for a continuous production of pure enantiomers with a high productivity and a specific, adjustable product crystal size. In previous studies, the feasibility of steady-state operation of this process was shown without considering the process dynamics [17] and only based on the liquid phase composition for a specific operation point [14,17]. However, no systematic investigation also based on the periodically harvested product crystals has been conducted.

**Figure 1.** Principle scheme of a coupled Preferential Crystallization carried out in two fluidized bed crystallizers for the separation of the D- and L-enantiomer from the racemic (50:50) mixture provided in the feed tank (adapted from [2]).

In this work we, first, prove the achievability of steady-state operation on the example of D-/L-asparagine monohydrate based on the liquid phase composition as well as the periodically harvested product crystal size distribution. Furthermore, the required startup time to reach the steady-state will be estimated for different operation conditions and the high reproducibility of the results will be demonstrated. On this basis, consecutively the dependence of productivity, purity, and

yield on the process conditions, feed flow rate, supersaturation, and crystallization temperature, will be systematically studied.
