Arif Budiman, Lisa Efriani Puluhulawa, Faradila Ratu Cindana Mo’o, Nurain Thomas, Melvern Theodorik S. Biu, Febrina Amelia Saputri, Siti Farah Rahmawati, Diah Lia Aulifa, Salma Amaliah, Agus Rusdin
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. Aims 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. Copyright © 2024. Published by Elsevier B.V.
Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, Indonesia; Department of Pharmacy, Faculty of Sport and Health, Universitas Negeri Gorontalo, Gorontalo, Indonesia; Departement of Pharmacy, Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia; Department of Pharmacology and Clinical Pharmacy, Institut Teknologi Bandung, Bandung, Indonesia; Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, Indonesia
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