Aim <p>It was the aim of this study to compare two different dry reverse micelle (RM) preparation methods for the incorporation of hydrophilic drugs into oral self-emulsifying drug delivery systems (SEDDS).</p> Methods <p>Cationic ethacridine lactate, anionic fluorescein sodium salt and the antibiotic peptide bacitracin were solubilized in RM containing sodium docusate, soy phosphatidylcholine and sorbitan monooleate in highly lipophilic oils such as squalane. In the dry addition (DA) method, drugs were directly added to empty RM in their powder form. In the organic solvent-aided (OS) method, drugs were pre-dissolved in ethanol or 2-propanol, which were then evaporated to form loaded dry RM.</p> Results <p>RM with sorbitan monooleate prepared via the DA method yielded up to 2.7-fold higher solubility only for bacitracin compared to the OS method. In contrast, OS-RM with sodium docusate and soy phosphatidylcholine exhibited significantly higher drug solubilities, achieving up to 109-fold, 44-fold and 97-fold increase for ethacridine, fluorescein and bacitracin, respectively. For all model drugs, the logD_{lipophilic phase/water} was highest for RM comprising sorbitan monooleate, with a slight increase for OS-RM. This was consistent with the release profiles from SEDDS, showing an enhanced retention when loaded with OS-RM. While DA-RM showed no significant difference in cellular uptake, it was 1.6-fold higher in OS-RM loaded squalane-based SEDDS.</p> Conclusion <p>The DA method is an easier approach for incorporating hydrophilic drugs into dry RM. However, the OS method presents a more promising alternative as it significantly enhanced the solubility and retention of these drugs in highly lipophilic formulations.</p> Graphical abstract <p></p>