Navigating Surfactant Selection in In Vitro Dissolution Testing: Mechanistic Insights and Practical Strategies

In vitro dissolution testing is central to pharmaceutical development, yet it is increasingly challenged by poorly soluble drugs, which account for over 40% of marketed products and up to 90% of new chemical entities, for which dissolution often limits absorption. Surfactants are widely incorporated into dissolution media to achieve sink conditions and improve the discriminatory powder of dissolution methods, but inappropriate surfactant selection or concentration can alter drug release mechanisms, mask formulation differences, and reduce biopredictive performance. This review examines the mechanisms of surfactant action, including wetting enhancement, micellar solubilization, and drug-surfactant interactions, together with the physicochemical properties of anionic, cationic, non-ionic, and zwitterionic surfactant relevant to dissolution testing. Building on these principles, we discuss practical considerations for surfactant selection, concentration optimization, analytical compatibility, surfactant quality and source variability, formulation-specific considerations for enabled drug delivery systems, integration with physiologically based biopharmaceutics modeling, and evolving regulatory expectations. Together, these provide a practical framework for developing robust, reproducible, and discriminating dissolution methods that better reflect in vivo performance and support decision-making across drug development.