Solid Self-Emulsifying Drug Delivery Systems: From Liquid-to-Solid Transformation to Predictive Performance, Biopharmaceutical Risk, and Quality-by-Design

Poor aqueous solubility remains a major challenge in the oral delivery of many active pharmaceutical ingredients, particularly those with dissolution-limited absorption. Solid self-emulsifying drug delivery systems (S-SEDDS) have emerged as promising lipid-based formulations that combine the solubilization advantages of liquid self-emulsifying drug delivery systems with the handling, stability, and manufacturing benefits of solid dosage forms. Despite substantial progress in formulation development, the relationship between solidification strategy, carrier properties, preservation of self-emulsification performance, and in vivo drug absorption remains insufficiently understood. This review critically examines the principles of S-SEDDS formulation, including excipients selection, formulation optimization, and major solidification approaches such as adsorption onto porous carriers, spray drying, freeze drying, melt granulation, hot-melt extrusion, and emerging additive manufacturing technologies. Key characterization parameters, including drug loading, flow properties, solid-state behavior, re dispersibility, droplet size, dissolution, precipitation tendency, lipid digestion, and stability, are discussed in relation to their relevance to product performance. Particular emphasis is placed on the interactions among formulation composition, solidification-induced structural changes, gastrointestinal dilution and digestion, and maintenance of drug solubilization. The review also evaluates applications of S-SEDDS in improving oral delivery of poorly water-soluble drugs and examines limitations in biopharmaceutical prediction, scale-up, excipients selection, and translation from laboratory findings to clinical performance. Finally, an integrated formulation-to-performance framework is proposed to connect material attributes, process parameters, critical quality attributes, and bio relevant performance endpoints. This perspective aims to identify evidence gaps and guide the rational development of robust, scalable, and clinically relevant S-SEDDS formulations.