Double Salts and Racemate in Mefloquine-Ibuprofen and Mefloquine-Ketoprofen Systems. A Structural and Thermochemical Analysis.

The formation of salts remains a highly sought-after yet unpredictable strategy for resolving chiral drugs. Using a drug-drug approach, we have investigated the crystallization behavior of Mefloquine (Mf), a racemic antimalarial drug, in combination with enantiopure (S)-ibuprofen and (S)-ketoprofen, as well as their racemic forms. Double salts and racemates have been obtained and characterized by single-crystal and powder X-ray diffraction, Hirshfeld surface analysis, thermal analysis (DSC and TGA), and solubility measurements. Structural analysis reveals that the formation of double salts often follows a pattern similar to the packing and supramolecular motifs found in the corresponding racemates. For the ketoprofen systems, the double salt and racemate have been found to be isostructural and isomorphic, whereas the ibuprofen systems display different architectures despite similar unit cells. Both double salts exhibited thermal stability and solubility profiles comparable to their racemic counterparts. On the other hand, the racemate with ketoprofen and the double salt with ibuprofen are the most soluble structures, suggesting that they are more stable systems than their counterparts. These findings support the view that double salt formation in such systems results from structural mimicry of racemates, emphasizing the challenges of predictable enantiomeric resolution and the importance of understanding structure-property relationships in chiral crystallization.