Shortcut Model for Describing Isothermal Batch Preferential Crystallization of Conglomerates and Estimating the Productivity

Abstract

Preferential crystallization (PC) is a powerful method to separate the enantiomers of chiral molecules that crystallize as conglomerates. The kinetically controlled separation method works in a typically narrow metastable zone. Currently, there are no simple models available that allow estimating the productivity of PC and, thus, the comparison with rivalling resolution techniques. In this Article, we suggest a simple shortcut model (SCM) capable of describing the main features of batch-wise operated PC using three ordinary differential equations originating from the mass balance of the target enantiomer and solvent in the liquid and solid phases. Compared to population balance models, the basis of the SCM is the assumption that the crystals for each enantiomer have the same size, which increases continuously from prespecified initial values. The goal of the model is to describe the initial period of the batch, during which the purity is within the specification required. It is accepted that after reaching this border, the precision of predictions can drop. This Article also illustrates a simple strategy how to parametrize the model based on a few experimental runs of PC. At first, for demonstration purposes, theoretical transients generated using the more rigorous PBE model is analyzed using SCM considering the separation of the enantiomers of dl -threonine. Subsequently, results of an experimental study with the enantiomers of asparagine monohydrate are presented to validate the shortcut model, which is seen as a new valuable tool to quantify more rapidly the productivity of PC and to further promote this elegant technique capable to resolve enantiomers of conglomerate forming chiral systems.

Immobilization of an amino acid racemase for application in crystallization‐based chiral resolutions of asparagine monohydrate

“…The efficiency of the enzymatic flow reactor with immobilized AAR was validated in steady state experiments at two different enantiomeric excesses, 100 and 4.5%. This last condition is expected during PC of asparagine enantiomers, according to our previous experiments [25]. A minimum residence time of only 1.1 min was needed to fully convert the substrate into the racemic mixture regardless of the initial ee.…”

“…Figure 1 shows a schematic process and setup of the desired combination. In our previous work, we developed a model to quickly assess productivity of preferential crystallization and reported PC experiments with asparagine monohydrate [25]. The goal of the present study is to provide an effective bioreactor that can be combined with preferential crystallization of asparagine enantiomers.…”

“…This is an essential parameter when combining preferential crystallization with racemization. We measured a maximum enantiomeric excess of 4.6 to 5.1% reached during isothermal preferential crystallization of asparagine monohydrate at 30 • C with saturation at 35, 37, and 40 • C [25]. To evaluate the effect of ee on the conversion in PBR, the packed column was fed with asparagine solutions with ee equal to 4.5% and 100% (excess of D-Asn).…”

Shortcut Model for Batch Preferential Crystallization Coupled with Racemization for Conglomerate-Forming Chiral Systems

“…In our previous study, we developed an SCM for the simulation of isothermal batch PC for the conglomerate-forming system. The model is based on quantifying in a simplified manner the “overall mass transfer” between the two phases, assuming a lumped kinetic mechanism for crystal growth and nucleation . It is briefly summarized below before being extended in Section to include various variants of coupling the process with racemization.…”

Crystallization Behavior and Crystallographic Properties ofdl-Arabinose anddl-Xylose Diastereomer Sugars

“…In order to design effective separation processes and ensure enantiomeric purity of the final product, it is essential to understand how enantiomers crystallize. In fact, while the two enantiomers of conglomerate systems might be separated by preferential crystallization from the same solution, additional unit operations might be required for efficient separation of enantiomeric pairs that form racemates or solid solutions. − …”