Effect of intermediate polarity molecule on phase transitions and bilayer structure in phospholipid membranes

Lipid-based formulations are widely utilized in various applications including food, cosmetics, and pharmaceuticals. The properties of these formulations can be influenced by changes in the external environment. As one example, dehydration can induce phase changes and alter the structural organization and molecular dynamic in the formulation, which potentially compromises the reversibility to a dispersed liquid crystalline state upon rehydration. A common strategy to prevent phase transitions and mitigate these effects involves the addition of small molecules with low vapor pressure. The protective effects of such additives will depend on their distribution within the lipid self-assembly structure. In this study, we investigate the effects of an intermediate polarity compound on phospholipid self-assembly in varying hydration conditions. As a model intermediate polarity compound, we use 1,2,3-trimethoxy propane (TMP), and we compare its effects with hydrophobic and hydrophilic compounds of similar molecular weight on the same lipid system. Lipid self-assembly structure and molecular dynamics were characterized using a multi-technique approach, including solid-state NMR, differential scanning calorimetry, and small- and wide-angle X-ray scattering. It is demonstrated that TMP influences lipid self-assembly at low water content while its effect becomes negligible at high water content. The observations can be rationalised based on the partitioning of TMP within the lamellar structure, where it behaves as a hydrophobic additive in dry conditions and as a hydrophilic additive in more hydrated conditions. The underlying principles of TMP's dual behavior highlight the potential of other intermediate polarity molecules in tailoring the properties of lipid-based formulations.