Towards Deracemization in the Absence of Grinding through Crystal Transformation, Ripening, and Racemization

Abstract

New insights into the obscure mechanisms of solid-state deracemization phenomena are obtained by crystal ripening experiments that, contrary to standard techniques, exclude attrition enhancement (grinding). The results point out that small particles and an initial size imbalance between the two enantiomeric crystal populations can intensify the rate of solid-state enantiomeric enrichment even in the absence of intermediate actions (e.g. grinding or thermal cycling). On this ground, a new process that creates such initial conditions is designed and exemplified for the proteinogenic glutamic acid. As a first step, racemic compound solvate (DL-glutamic acid monohydrate) crystals are completely converted to small-sized conglomerate anhydrate crystals, in the presence of larger seeds of a single chirality. After the transformation is complete and the racemization catalyst is added, the suspension contains an equal number of small-sized conglomerate crystals of both enantiomers together with the larger seeds of the preferred enantiomer. Over time, the large crystals of the preferred enantiomer tend to grow at the expense of smaller ones, which dissolve. This, combined with the fast racemization, leads to enantiomeric enrichment. The possible occurrence of enantioselective agglomeration between small and seed crystals speeds up this process by removing small crystals of the preferred enantiomer. Since most amino acids and several other pharmaceutical compounds are known to form metastable racemic hydrate crystals, it is expected that this new method is readily applicable to a variety of compounds. In addition, the process provides a technically simpler and more scalable route to enantiomeric enrichment compared to attrition-enhanced deracemization and its applicability extends to the wider pool of compounds that crystallize as racemic crystals.

Coupling Viedma Ripening with Racemic Crystal Transformations: Mechanism of Deracemization

“…In this study, we extend the cluster model typically used to describe Viedma ripening, to cover the very recently reported cases 30,31 in which a racemic crystal transformation takes place concurrently with deracemization. Even though here we focus on racemic crystal…”

“…When both breakage and agglomeration are excluded, the seeds of the preferred enantiomer maintain a large size, while the counter enantiomer is formed exclusively as clusters in the nucleation process. Consequently, after the complete dissolution of the racemic crystals and the depletion of the supersaturation, the system will contain a size imbalance between the enantiomers 31 . As a result, the clusters of the counter enantiomer dissolve and the large crystals of the preferred enantiomer grow leading to a single chirality.…”

“…In cases where the racemic compound is a solvate (e.g. DL-glutamic acid monohydrate 31 ), the solubility difference with the racemic conglomerate could be very high in a different solvent, where the solvated compound would be highly unstable, leading to extreme values for R 60 . In these cases, dissolution of the racemic compound solvate would also decrease the solvent fraction influencing further the relative solubility during the deracemization process 61 .…”

“…individual crystals contain both enantiomers in equal amounts), although for some compounds both crystal forms can appear depending on the crystallization conditions. Recently, it was shown that the combination of a solvent-mediated metastable racemic crystal transformation to conglomerate coupled with Viedma ripening can still lead to full deracemization, despite the presence of the racemic compound: crystal transformation-enhanced deracemization 30,31 . Remarkably, the rate of deracemization is also considerably faster when the transformation is included.…”

Intensified deracemization via rapid microwave-assisted temperature cycling

“…salicylaldehyde). 8 However, at such elevated temperatures, parallel to the racemization reaction, decomposition reactions can occur, depleting part of the reagent during the process. In particular, dehydration of glutamic acid into pyroglutamic acid has been observed in acidic media at temperatures >70°C.…”