Amorphous Solid Dispersions in Non-Oral Drug Delivery: A Critical Review Bridging Mechanistic Advantages and Gaps in Translational Evidence

Abstract Background Non-oral drug delivery routes, including cutaneous, transdermal, pulmonary, ophthalmic, parenteral, vaginal, and rectal administration, are essential for both local and systemic therapies but impose route-specific constraints on drug dissolution, retention, permeation, clearance, and exposure. Amorphous solid dispersions (ASDs),extensively investigated for oral delivery, may improve the performance of poorly water-soluble drugs by stabilizing high-energy amorphous states, increasing apparent solubility, and promoting transient supersaturation. However, their translation into non-oral dosage forms remains fragmented and largely preclinical. Objective This review critically examines the potential, limitations, and translational challenges of ASDs for non-oral drug delivery, with emphasis on the physicochemical, biopharmaceutical, pharmaceutical, and route-dependent determinants governing their performance. Scope Key aspects discussed include drug–polymer interactions, molecular mobility, phase behavior, water uptake, crystallization, interactions with secondary pharmaceutical bases, and route-specific pharmacokinetic/pharmacodynamic relationships. Current evidence is examined across dermal, transdermal, pulmonary, ophthalmic, vaginal, rectal, and parenteral delivery systems. Parenteral administration is considered a special case encompassing sterile suspensions, reconstitutable systems, microneedles, implants, and depot-forming formulations. Recent technological advances, patent and industrial landscapes, and the potential extension of ASD principles to peptides, proteins, biologics, and other complex molecular entities are also addressed. ASDs are further positioned in relation to alternative and complementary solubility-enhancing technologies, including nanoparticles, nanocrystals, cocrystals, cyclodextrins, micelles, lipid-based systems, emulsions, solvents, and cosolvents. Conclusions ASDs off er a promising but still underdeveloped strategy for improving non-oral delivery of poorly soluble drugs. Their successful translation will depend not only on achieving and maintaining favorable amorphousstates and supersaturation, but also on converting these physicochemical advantages into route-specific drug exposure, therapeutic benefit, formulation stability, manufacturability, and clinically meaningful outcomes.