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

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.

Strategies for chiral separation: from racemate to enantiomer

“…Furthermore, with the addition of 10 mL 13 C 6 -labeled L-Arg enantiomer solution (0.1 wt% of the total DL-Arg), despite the completion of PE, 13 C 6 labeled molecules could still be found in the crystal phase. 198 These results showed that PE of DL-Arg$fumaric acid is only driven by the material exchange between the solution and crystals under high supersaturation, rather than polymorphic transition (Fig. 10c).…”

“…Thus, the crystal engineering strategy can impart Racs with unique intermolecular interactions, packing modes and polymorphism, leading to a different 194 (c) PE mechanism of the DL-Arg$fumaric acid cocrystal. 198 PE mechanism. In 2023, the recapture of a second-generation cocrystal, DL-Arg$fumaric acid, further raised doubts about the necessity of the polymorphic transformation.…”

“…Interestingly, more cocrystals of Racs such as DL-Phe$fumaric acid, DL-Arg$fumaric acid and DL-leucine$oxalic acid exhibited PE phenomena. 194,198 Hence, the crystal engineering strategy may enlarge the substrate scope of PE and contribute to its the exploration of its mechanism.…”

Chiral resolution methods for racemic pharmaceuticals based on cocrystal formation

“…Finally, enantioenriched domains must develop without facing an enormous energy cost or the presence of a solid solution in proximity to the racemic arrangement. 72…”

Phase Diagrams of Praziquantel and Vanillic Acid Cocrystals: Racemic Compound and Conglomerate System

“…While various resolution methods are available (chromatography and membrane separation), crystallization is an attractive technique due to the high degree of chiral discrimination achievable during molecular self-assembly. If there are few examples of enantiomeric separation based on crystallization applied to molecules forming stable racemic compounds, − in most cases, accessing a conglomerate is a prerequisite (i.e., the two enantiomers must crystallize in separate crystals, each being enantiopure). This is applicable to preferential crystallization (PC), an out-of-equilibrium stereoselective crystallization process occurring via seeding.…”