Recent progress in supersaturation-based SNEDDS: Formulation, mechanism, and biopharmaceutical performance

• Supersaturation-based SNEDDS generate a supersaturated state in the gastrointestinal tract, enhancing the thermodynamic activity and driving force for drug absorption. • Supersaturation-based SNEDDS are classified into supersaturable and supersaturated systems, distinguished by when and how supersaturation is generated. • The supersaturated state in the GIT is metastable, requiring precipitation inhibitors to maintain drug solubility and prevent premature crystallization. • Polymers or copolymers such as HPMC K4M and PVP K30 are common precipitation inhibitors used in supersaturation-based SNEDDS. These inhibitors act via steric hindrance, hydrogen bonding, or viscosity enhancement and require careful screening for optimal compatibility and performance. • Supersaturation-based SNEDDS demonstrate superior drug absorption and bioavailability not only over pure drug or commercial products, but also compared to conventional SNEDDS. This review highlights supersaturation-based SNEDDS (self-nanoemulsifying drug delivery systems), focusing on formulation strategies, supersaturation generation, stabilization mechanisms, and their impact on drug release, permeation, and bioavailability. The discussion is based on articles from reputable databases published between 2020 and 2025. Supersaturation-based SNEDDS are classified into supersaturable and supersaturated types, differing in the onset of supersaturation and approaches to precipitation inhibition. Widely developed for BCS Class II and IV drugs, these systems increase thermodynamic activity and enhance drug absorption in the gastrointestinal tract. Although metastable and prone to precipitation, precipitation inhibitors (PIs) such as HPMC or PVP can stabilize the supersaturated state, suppressing nucleation and crystal growth . Proper screening is essential to identify the most suitable PIs for each formulation. Supersaturable and supersaturated SNEDDS have improved drug release and intestinal permeation, enhancing bioavailability compared to pure drugs, conventional SNEDDS, or marketed formulations.