Self-emulsifying drug delivery systems (SEDDS) are widely utilized to enhance oral drug absorption; however, limited epithelial permeability remains a major barrier, particularly for hydrophilic drugs and macromolecules. Medium-chain fatty acids are promising permeation enhancers (PEs) due to their transient effects on epithelial barriers. In this study, caprylic acid (C8) and capric acid (C10) were systematically evaluated as PEs in SEDDS, with emphasis on the influence of ionization state and mode of presentation within the formulation. SEDDS were modified by incorporating C8 or C10 either as free acids (SEDDS-C8/C10@Acid), as dispersed sodium salts (SEDDS-C8/C10@Salt), or by external addition of sodium salts after emulsification (SEDDS-C8/C10@extSalt). SEDDS-C8/C10@Acid significantly enhanced cellular internalization in Caco-2, HEK, and HeLa cells, achieving up to a 2.5-fold increase compared with unmodified SEDDS. In contrast, salt-based systems showed approximately 1.5-fold lower cellular association than acid formulations, while exhibiting improved cellular tolerability. Permeation studies revealed pronounced epithelial permeation across Caco-2 monolayers for salt-modified SEDDS, with lucifer yellow permeation increasing up to 7-fold for both C8 and C10 systems. Consistently, mucus interaction studies demonstrated enhanced diffusion for salt-based formulations. Differences between C8- and C10-containing systems were minor, indicating that alkyl chain length was less influential than ionization state and formulation format. Overall, incorporation of the free acid PE primarily enhanced cellular association via increased membrane partitioning, whereas incorporation of the corresponding sodium salt more effectively promoted mucus diffusion and epithelial permeation. These findings identify ionization state and formulation-dependent presentation as key design parameters for permeation-enhancing lipid-based drug delivery systems.
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