Application of preferential crystallization to resolve racemic compounds in a hybrid process

Abstract

The application of preferential crystallization is at present limited to conglomerate forming systems, which cover only a minor part of chiral substances. In this paper, a hybrid process is proposed that extends the applicability of the preferential crystallization principle to the more common racemic compound forming systems. It comprises a preliminary (e.g., chromatographic) enantiomeric enrichment step and preferential crystallization to finally produce the desired pure enantiomer(s). The applicability of preferential crystallization to racemic compounds is demonstrated on the example of mandelic acid as a model system. Direct monitoring of the separation progress is performed using combined online polarimetry and online density measurements. A cyclic crystallization process, which provides alternating the pure mandelic acid enantiomer and the racemic compound, is feasible and allows the resolution of rac-mandelic acid as part of the proposed hybrid approach.

Ternary phase diagram of ketamine ((R,S)-2-(2-chlorophenyl)-2methylaminocyclohexanone) in ethanol and preliminary studies aiming at Enantioselective Crystallization of S-ketamine

“…The SMB technology was a breakthrough in increasing the productivity of chromatographic separations; however, a significative decrease in productivity can still be observed as the level of purification increases. For this reason, some authors have been pursuing the use of hybrid processes, combining SMB chromatography and crystallization in order to obtain an increase in productivity (Lim et al, 1995;Lorenz et al, 2001;Bléhaut et al, 2001;Gedicke, 2005;Lorenz et al, 2006). The general concept of the hybrid process is based on using chromatography as a prepurification stage, followed by a crystallization step to achieve the final purification.…”

An Autobiography of Ronald W. Rousseau

“…Such enrichment works because it moves the system composition from a region of a phase diagram where thermodynamics drives production of crystals of a racemate compound to a region where pure enantiomer can be crystallized. This has been done using a chromatographic technique to adjust the solution composition and allow preferential crystallization of a pure enantiomer (46). Encarnación suggested that the enrichment could be done by converting one enantiomer into the other with a reaction enhanced by an enzyme in a reactive crystallization process.…”

Efficient separation of enantiomers by preferential crystallization in two coupled vessels

“…The experimental procedure for mandelic acid has been chosen according to Lorenz et al 23 The solution used for the crystallization experiment was prepared according to the solubility data of RS-mandelic acid at 408C. 25 Initial masses of substance and water and experimental conditions were summarized in Table 2.…”

“…After generating an enantiomeric excess for example by a partially selective synthesis or by a chromatographic and a following evaporation step, the state A in Figure 2b located within the three-phase region can be reached. 22,23 As it is also depicted in Figure 2b seeding with crystals of the enantiomer E 1 initializes the crystallization of merely this enantiomer and the mother liquor composition tends towards point Z. Up to a certain time pure E 1 can be gained until the spontaneous nucleation of the racemic compound (rac) will occur and the trajectory will be attracted to the eutectic point E. The same considerations are valid for the crystallization of E 2 in the right-hand side three-phase region after seeding the enantiomerically enriched solution with E 2 .…”

“…More details about the batchwise and cyclic preferential crystallization of compound forming systems in a single vessel were presented recently. 22,23 Coupled Batchwise Preferential Crystallization. The degree of supersaturation is the driving force for crystallization.…”