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.
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