Double Salt Formation on Diastereoisomeric Crystallization of Mefloquine with Propionic and Succinic Acid Derivatives: A Structural Study of Chiral Nondiscrimination

Abstract

The diastereomeric resolution remains a challenging endeavor due to the intricate interplay of experimental parameters and the inherent variability of crystallization outcomes. Understanding of the enantiomer’s discrimination leading to the formation of the diastereomeric double salts was investigated for mefloquine (Mf), a racemic antimalarial drug. A series of nine diastereomeric double salts and their racemic counterparts were synthesized by combining racemic Mf with propionic and succinic acid derivatives. All materials were characterized by differential scanning calorimetry, thermogravimetry, and single-crystal X-ray diffraction. The salts were designed to exploit the NH⁺···COO^– H-bond to create the salts. This resulted in a diverse range of crystal packing arrangements. The complexity of the packing of the double salt structure includes a high Z’ parameter, hydration, conformational, and synthon multiplicity. In comparison to the pure racemic counterparts, the double salt structures exhibit isostructurality and/or isomorphism. From thermal behavior and solubility data, it is noticed that the pure racemate is still the most stable state, and double salts occur, in general, as an attempt to imitate or achieve the pure racemic structure.

Racemic and diastereoisomeric double salts of mefloquine were synthesized and their crystal structures elucidated. A comprehensive analysis of chiral recognition and molecular self-assembly in relation to varying molecular size and chirality is presented.