Scaling Up Temperature Cycling-Induced Deracemization by Suppressing Nonstereoselective Processes

Abstract

The scale-up of Temperature Cycling Induced Deracemization (TCID) of sodium bromate is feasible provided that two non-stereoselective processes are suppressed. Both nonstereoselective processes occur as a result of insufficient crystal breakage or attrition. In the absence of crystal breakage or attrition during the temperature cycles, large crystals emerge and the resulting small total crystal surface area is unable to sufficiently consume the supersaturation during cooling, resulting in non-stereoselective nucleation. This nonstereoselective process can be avoided by applying small temperature cycles involving small dissolving solid fractions. However, this leads to a slow deracemization rate. In addition, crystals undergo non-stereoselective agglomeration, which leads to the formation of large racemic agglomerates constructed of both chiral forms. To counteract their formation, secondary nucleation through crystal breakage was found to be a key requirement. At a large scale, a homogenizer was used to induce crystal breakage which, in combination with 2 temperature cycles, led to the removal of racemic agglomerates as well as a significant increase in the deracemization rate. Overusing the homogenizer, however, caused the enantiomeric excess increase to stop. Our experiments show the importance of secondary nucleation in TCID of sodium bromate. However, secondary nucleation is currently not incorporated in the TCID process models. In the presence of a sufficient amount of crystals at the highest temperature and careful use of the homogenizer, TCID leads to complete deracemization in volumes up to 1 L, demonstrating the potential to extend TCID to industrial applications.

On the Effect of Secondary Nucleation on Deracemization through Temperature Cycles

“…Hence, a threshold suspension density exists below which nonstereoselective secondary nucleation takes place in addition to stereoselective secondary nucleation. Such a threshold suspension density was also found for sodium bromate and is expected to be system‐dependent.…”

“…In turn, the amplitude of the thermal cycles dictates the solid mass that dissolves during each cycle and hence the mass of crystals remaining on partial dissolution. The theoretical fraction of solid mass after heating at a given T h can be quantified according to [Eq. ]: …”

“…Although TCID features simple steps in its realization, the key elements of the controlling mechanism of this relatively recent deracemization technique have not been completely established yet. Operating parameters such as the impact of solid mass involved in the thermal cycles,– the amount of catalyst, the cooling rate, the suspension volume, the initial enantiomeric excess, the amplitude of the sweeps, the racemization rate, and the use of additives as growth inhibitors have been studied previously. Moreover, several computational studies have attributed the observed chiral enrichment to the crystallization step occurring during the cooling stage.…”

“…While several studies have highlighted the importance of secondary nucleation in chiral crystallization as early as in the 1950s with the work of Havinga and later in the work of Kondepudi et al., there is still no clear evidence reported for the interplay between the generation of secondary nuclei and enantiomeric enrichment in deracemization processes involving thermal cycles. Experimental evidence of secondary nucleation taking place in the recrystallization step during TCID has been reported, as secondary nucleation was observed when extremely fast cooling was attained in a microwave apparatus and during stirrer‐induced secondary nucleation featuring intense stirring through a homogenizer . However, previous mechanistic studies on TCID have not considered the effects of secondary nucleation during the cooling/low‐temperature stage of the process.…”

Modeling and Simulation Studies of a Novel Coupled Plug Flow Crystallizer for the Continuous Separation of Conglomerate-Forming Enantiomers

“…Since then there has been many studies on this attrition enhanced ripening for chiral resolution [11,19,20]. In recent years, it has been further demonstrated that a complete deracemization of the solid phase can be achieved via a batch-wise combination of solution racemization and temperature cycling [21][22][23][24]. An industrially easy way to apply temperature cycling-enhanced deracemization was lately proposed where instead of applying temperature cycles, the suspension is circulated between two vessels-one kept at high temperature where partial dissolution of the suspension take place, while the other kept at low temperature to promote crystal growth [25].…”