Influence of pH, Buffering Capacity, Ionic Strength, Bile Salts, and Model Drugs on Micellization Behaviour of Salcaprozate Sodium in Physiological Range pH Buffers

Salcaprozate sodium (SNAC) is an FDA GRAS-listed permeation enhancer used in oral semaglutide and vitamin B12 formulations. Although its rapid and reversible membrane-perturbing effects are well recognised, it's in vivo performance is highly variable. Since effective membrane fluidisation requires permeation enhancers to remain as monomers, the critical micelle concentration (CMC) is a key determinant of efficacy. This study investigated the micellization behaviour of SNAC under physiologically relevant conditions. The CMC of SNAC was determined across physiologically relevant pH buffers using complementary techniques, including conductometry, tensiometry, microvolume UV/Visible spectroscopy, and fluorescence spectroscopy. The effects of electrolytes, bile salts, and selected coadministered drugs on SNAC micellization were evaluated. SNAC did not form micelles under gastric conditions due to increased protonation and low solubility. In contrast, SNAC micellized at intestinal pH 6.8 with a CMC of 6.26 ± 0.38 mM. Physiological factors strongly influenced micellization, particularly under intestinal conditions. The presence of electrolytes significantly reduced the CMC to 3.36 ± 0.03 mM, due to reduced electrostatic repulsion and a counter-ion effect. Bile salts showed a biphasic effect, increasing the CMC at low concentrations and promoting mixed micellization at higher concentrations. Coadministered drugs, including aspirin, metformin, nimesulide, ciprofloxacin, and semaglutide, significantly altered SNAC CMC values. Semaglutide showed a non-monotonic effect, decreasing the CMC at low concentrations but increasing it at higher concentrations due to oligomerisation. These findings provide mechanistic insights into SNAC micellization under physiologically relevant conditions and offer a rational basis for optimising SNAC-based oral drug delivery systems.