Comparative evaluation of ternary amorphous solid dispersions: Identifying optimal excipient systems for enhancing...

The limited aqueous solubility of numerous active pharmaceutical ingredients (APIs) remains a major barrier to achieving optimal oral bioavailability, therapeutic efficacy, and clinical translation. Amorphous solid dispersion (ASD) systems have emerged as a leading strategy to overcome these biopharmaceutical limitations, with ternary ASDs offering greater formulation flexibility and performance enhancement through the synergistic inclusion of functional third components.

This review aims to systematically explore and critically analyze the formulation strategies, comparative outcomes, and molecular mechanisms underlying ternary ASDs-specifically Drug:Polymer:Polymer, Drug:Polymer:Surfactant, Drug:Polymer:Excipient, and Drug:Drug:Polymer systems-in improving solubility, dissolution, stability, and pharmacokinetic performance. A comprehensive literature search was conducted across Scopus, PubMed, and Web of Science databases for peer-reviewed articles published between 2015 and 2025, focusing on experimental studies evaluating ternary ASDs. Studies were selected based on relevance to solubility enhancement, dissolution profile, in vitro-in vivo correlation, and mechanistic insights at the molecular level. Ternary ASDs demonstrated superior performance over binary systems, particularly those incorporating surfactants, which exhibited the highest solubility enhancement (up to 810.81-fold). Polymer-polymer and polymer-excipient systems also improved dissolution and pharmacokinetic parameters, although with lower magnitude. Mechanistically, ternary ASDs work through micellization, hydrogen bonding, molecular dispersion, and recrystallization inhibition, which collectively maintain supersaturation and improve absorption and bioactivity. Ternary ASD systems represent a scientifically rational and pharmaceutically significant advancement for formulating poorly soluble drugs. Their ability to modulate solubility, dissolution, and pharmacological outcomes through molecular-level interactions underscores their transformative potential in drug delivery. Future research should focus on tailoring ternary components based on physicochemical drug properties and predictive modeling.