Unveiling Supramolecular Structures Formed by Menthol and Xanthan Gum in Oleic Acid-Based Microemulsions

Microemulsions (MEs) are delivery systems that can enhance the rate of drug dissolution due to their supramolecular structure. However, adding drugs, such as menthol, and thickness agents, like xanthan gum (XG), can significantly modify these nanoscaled architectures. This study aimed to understand the mechanistic basis of supramolecular structural modifications in oleic acid-based MEs induced by XG and menthol addition. A multitechnique approach combining electron microscopy, dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), rheology, and texture analysis was employed to characterize formulations containing concentration ranges of menthol (0.1-1.0%w/w) and XG (0.1-0.5%w/w). This complementary analytical strategy enabled the detection of structural changes across different length scales. Our findings revealed that menthol addition leads to droplet diameter modulation (DLS: 127-157 nm; SAXS: 108-136 nm), suggesting drug entrapment within the oil phase. XG addition produces a distinctive interconnected "pearl-necklace" supramolecular architecture without significant droplet size changes (DLS: 102-111 nm; SAXS: 102 nm). Crucially, rheological and textural analyses detected physical property modifications not identified by light scattering techniques, with XG dramatically influencing consistency, firmness, and adhesiveness, while menthol enhanced adhesive properties. These structure-function correlations showed that rational ME design can be achieved through controlled excipient addition. Collectively, the nanoscaled pearl-necklace architecture and enhanced adhesive properties suggest promising applications for sustained topical drug delivery, warranting future investigation of skin permeation kinetics and therapeutic efficacy in dermatological formulations.