Polymorphism of racemic (±)-Mefloquine free base: The role of enantiomeric recognition in polymorph assemblies

• Published in: Journal of molecular structure 2025-03, Vol.1325, p.141043, Article 141043
• Main Authors: Vasconcelos, Stéphano A., Tenorio, Juan C., Gurgel, João V. M., Benevides, Cauê C., Nazario, Carlos E. D., Carvalho Jr, Paulo S.
• Format: Article
• Language: English
• Subjects: Chirality; Mefloquine; Pharmaceutical; Polymorphism
• ISSN: 0022-2860
• DOI: 10.1016/j.molstruc.2024.141043

•Polymorphism of the antimalarial drug mefloquine free base have been characterized.•The polymorphs exhibit distinct racemic motifs, due to OH⋅⋅⋅N H-bonds between molecules.•The differences between the polymorphs structure shows that the enantiomer are recognized at different forms.•The polymorphs exhibit a slight energy difference, suggesting a monotropic relationship. The interplay between chiral recognition and crystal packing forces dictates the polymorphism of racemic compounds. Herein, a second polymorph of racemic Mefloquine free base (Mf) has been identified and characterized. The attempt to obtain new salt produced the second polymorphs from Mf-II of the compound and its crystal structure was determined by single-crystal X-ray diffraction. Analyzing the Mf polymorph structures reveals that the molecules interact with each other via OH⋅⋅⋅N hydrogen bonds, but their crystal organizations differ in the enantiomer's distribution. While a Mf polymorph shows the assembly of homochiral chains, the second phase packs from the racemic chains of enantiomers. The physicochemical properties and relative stability of the Mf-I and Mf-II have been investigated by PXRD, DSC/TGA, and solubility methods. The polymorphs exhibit a slight energy difference, suggesting a monotropic relationship. This further highlights the possibility of simultaneous crystallization. Our results highlight the importance of chiral enantiomer recognition in the polymorphic occurrence of racemic molecules.