Amorphous solid dispersions (ASDs) are commonly developed to increase the apparent solubility and dissolution of poorly water-soluble drugs, yet formulation success cannot be defined by amorphization or physical stability alone. Polymer selection, drug loading, molecular interactions, moisture exposure, hydrated-state phase behavior, precipitation, downstream dosage-form composition, and absorptive flux can alter stability and performance in different directions. This systematic review examines ASDs as formulations occupying a multidimensional stability–performance trade space. The aim is to distinguish evidence supporting physical stabilization, supersaturation generation, dissolution, absorption-relevant drug availability, and translational performance from assumptions that these outcomes necessarily improve together. Peer-reviewed literature published from 2017 through 2024 was systematically screened using predefined eligibility, evidence-extraction, and quality-appraisal criteria. Evidence was separated by analytical level, including molecular and polymer attributes, physical stability, hydrated-state phase behavior, dissolution and supersaturation, dosage-form effects, and biopharmaceutic translation. Selection arithmetic was maintained in the review ledger without substituting reference-list size for included-evidence counts. The literature demonstrates no universal correspondence between maximal ASD stability and maximal pharmaceutical performance. Polymer–drug interactions may suppress crystallization yet retard release, while in other systems persistent interactions stabilize supersaturation. Drug loading can produce abrupt transitions from congruent release toward phase-separated or drug-rich surface states. Moisture, process history, nanoscale heterogeneity, downstream tableting excipients, dissolution conditions, and absorption sinks further modify apparent performance. These findings support a state-dependent interpretation in which storage stability, hydration behavior, supersaturation, precipitation, and absorption-relevant drug availability are related but analytically non-equivalent endpoints. ASD development is more appropriately treated as selection within a conditional stability–performance trade space than as optimization of a single stability or dissolution metric. Formulation decisions require explicit separation of stored-state stability, hydrated-state transformations, release mechanisms, and downstream biopharmaceutic relevance.
IJPRAS
