*3.5. Influence of Crystallization Temperature*

In Exp. 6 the crystallization temperature was reduced to Tcrys = 20 ◦C. To guarantee an approximately constant supersaturation of 1.23, the saturation temperature was adjusted to 24.6 ◦C. Figure 10 depicts the steady-state results of Exp. 6 together with the respective results of Exp. 4 (Tcrys = 30 ◦C, Tsat = 35 ◦C) for the same volumetric flowrate (12 L/h).

As seen in Figure 10a, an influence of the crystallization temperature on the product crystal size was not observed. At the lower crystallization temperature, the standard deviation decreases by almost 15%, hence, the selectivity of the size classifying effect is improved. Since the crystal growth rate decreases with the crystallization temperature, the crystal growth and the standard deviation show the same correlation as in the previous section. This correlation leads to the assumption that the crystal growth counteracts the size-classifying effect and thus its selectivity. The influences of the crystallization temperature on productivity and yield are depicted in Figure 10b,c. As expected, a lower crystallization temperature leads to both lower productivity and yield. The observed decreases of productivity and yield are in good agreement with the studied correlation between crystal growth kinetics (dotted lines) and crystallization temperature [19].

**Figure 10.** Mean steady-state crystal size distributions, q3, with their respective mean values and standard deviations (**a**), productivities, Pr (**b**), and yields, Y (**c**), for two different crystallization temperatures, Tcrys = 20 and 30 ◦C, at the same supersaturation and volumetric flowrate. The dotted lines (**b**) indicate the change with respect to the central point at Tcrys = 30 ◦C, assuming the withdrawn product mass is proportional to the growth rate [19]. Given results are from crystallizer C2 for Exps. 4, 6.

#### **4. Conclusions**

In the present experimental parameter study, seven experiments were performed to investigate the continuous fluidized bed crystallization at twice 0.5 L scale for racemate resolution at its steady-state. Each experiment was conducted for 8 hours to ensure constant conditions. As verified, after a relatively short operation time (approximately 2 hours), the utilized pilot plant reaches a cyclic steady-state, where product crystals with constant crystal size distribution and productivity can be periodically withdrawn. The reproducibility of the steady-state results was proven and sensitivities of the utilized pilot plant on the steady-state results were identified. In particular, it was observed that changes of the high-speed disperser slightly effect the steady-state results in terms of productivity and product crystal size distribution. Nevertheless, the steady-state results were shown in the present study to have exceptionally good reproducibility.

It was proven that the steady-state product crystal size mainly depends on the volumetric flowrate, and thus can be easily adjusted (in this work between 260 and 330 μm). All products, withdrawn at steady-state, have a narrow crystal size distribution (standard deviation <60 μm) and a low fines content. Thus, the size classifying effect of the conically shaped tubular crystallizers and its selectivity is verified. Productivity and yield increase with supersaturation, whereby it was shown that the continuous racemate resolution is limited by a certain maximal and minimal supersaturation. At too low supersaturation, the seed crystals grow insufficiently and are mainly discharged at the top of the crystallizer. At too high supersaturation, the respective counter-enantiomer nucleates and, thus, contaminates the resolution product. Furthermore, the limitations regarding the supersaturation are not fixed values and also depend on the volumetric flowrate. In particular, the nucleation probability increases with higher supersaturation and lower volumetric flowrates. A decrease of productivity was observed at lower supersaturation and higher volumetric flowrates, and thus, higher fluid velocities. These observed correlations enhance the expectation that the location and width of the operation window and, thus, the process performance, are tunable via geometrical aspects of the conically shaped tubular crystallizer [20].

The utilized pilot plant enables continuous racemate resolution with enantiomer purities above 97% and productivities up to 40 g/L/h for each enantiomer, which is far above productivities documented by other studies [14,21]. Since the process was not optimized at all, productivities higher than 40 g/L/h are to be expected. Thus, the coupled fluidized bed crystallization was proven to be an excellent technology for continuous enantioseparation, which facilitates high purities and the robust production of both enantiomers simultaneously.

**Author Contributions:** Conceptualization, H.L. and A.S.-M.; methodology, E.T. and J.G.; investigation, formal analysis, validation, data curation and visualization, J.G.; writing—original draft preparation, E.T. and J.G.; writing—review and editing, E.T., H.L. and A.S.-M.; supervision, H.L. and A.S.-M.; project administration and funding acquisition, A.S.-M. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by Deutsche Forschungsgemeinschaft (DFG) within the Research Program SPP 1679 "Dynamische Simulation vernetzter Feststoffprozesse".

**Acknowledgments:** The authors thank Jacqueline Kaufmann and Stefanie Leuchtenberg for their analytical support as well as Detlef Franz, Klaus-Dieter Stoll, Stefan Hildebrandt and Steve Haltenhof for their technical support.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
