Mefloquine docusate-liposome interactions: spectroscopic and molecular dynamics insights into API-based organic salts

The conversion of active pharmaceutical ingredients (APIs) into organic salts has emerged as an effective strategy to modulate physicochemical and pharmacological properties, including solubility, stability, permeability, and drug release. Among their biological effects, interactions with biomembranes are particularly relevant, as they directly influence drug efficacy and bioavailability. Despite extensive studies on organic salts, investigations focusing on API-based salts and their membrane interactions remain limited. In this work, the organic salt mefloquine docusate ([MFLH][AOT]) was investigated as a model system to evaluate how counterion selection influences drug–membrane interactions. Using soybean asolectin (ASO) liposomes as simplified membrane models, we combined Fourier transform infrared spectroscopy (HATR-FTIR), hydrogen and phosphorus nuclear magnetic resonance ( 1 H NMR and 31 P NMR) spectroscopies, and molecular dynamics (MD) simulations to gain both experimental and molecular-level insights. The results indicate that [MFLH][AOT] interacts with membranes primarily through Coulombic interactions and hydrogen bonding involving lipid headgroups and interfacial regions, alongside hydrophobic contributions. Compared to isolated components, free mefloquine shows deeper membrane penetration, whereas the organic salt exhibits reduced interaction due to ion pairing and aggregate formation. MD simulations supported the structural stability of the liposomes over 6 μs and showed that AOT–MFL association modulates additive redistribution, penetration, and aggregation within the liposomal environment. These findings support the interpretation that [MFLH][AOT] behaves as a distinct supramolecular entity rather than as independent ions. This behavior has important implications for drug delivery, suggesting potential for controlled co-encapsulation and release in liposomal systems, as well as modulation of pharmacokinetic properties.