Design considerations for SMEDDS: Rationalizing drug and excipient selection for enhanced oral delivery

The solubility of many newly discovered drug molecules remains a critical challenge in pharmaceutical development, as poor aqueous solubility limits their therapeutic effectiveness and bioavailability. Lipid-based formulations have emerged as an important strategy to overcome this limitation through approaches such as lipid solutions, emulsions, microemulsions, nanoemulsions, and micellar systems. Among these, self-microemulsifying drug delivery systems (SMEDDS) have attracted particular attention due to their ease of preparation, scalability, robust physical stability, and ability to enhance oral absorption of poorly soluble drugs. This review provides a comprehensive analysis of the rationale behind the selection of drugs and excipients for SMEDDS development, emphasizing the critical role of oils, surfactants, and co-surfactants in achieving optimal solubilization and self-emulsification. Methods such as solubility screening, spectrophotometric analysis, and construction of pseudo-ternary phase diagrams are discussed as essential tools in formulation design. Furthermore, the review highlights formulation considerations, evaluation strategies, and factors influencing successful clinical translation. Overall, this article synthesizes current knowledge to guide rational design of SMEDDS, thereby supporting the advancement of lipid-based drug delivery systems for poorly soluble therapeutic agents.