Reinvestigating the Preferential Enrichment of DL-Arginine Fumarate: New Thoughts on the Mechanism of This Far from Equilibrium Crystallization Phenomenon

Author:

De Saint Jores ClémentORCID,Brandel ClémentORCID,Vaccaro Marie,Gharbi Najla,Schmitz-Afonso IsabelleORCID,Cardinael PascalORCID,Tamura Rui,Coquerel GérardORCID

Abstract

Preferential enrichment (PE) is a crystallization process, starting from either a racemic of slightly enantio-enriched solution (ca. +5%) that results in a high enantiomeric excess in the liquid phase (>+90%ee) and a slight opposite excess in the deposited crystals (−2 to −5%ee). The mechanism(s) of this symmetry-breaking phenomenon is (are) still a matter of debate since it eludes rationalization by phase diagram formalism. In this publication, we thoroughly reinvestigate the PE phenomenon of arginine fumarate by using a new approach: the process is monitored by introducing isotopically labeled arginine enantiomers into the crystallization medium to better understand the mass exchanges during crystallization. These experiments are supported by chiral HPLC-MS/MS. This study permits re-evaluating the criteria that were thought mandatory to perform PE. In particular, we show that PE occurs by a continuous exchange between the solution and the crystals and does not require the occurrence of a solvent-mediated solid–solid phase transition.

Funder

French Ministry of Research

Publisher

MDPI AG

Subject

Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science

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