A Review on Four-Dimensional Additive Manufacturing of Oral Solid Dosage Forms

Review Article

Abstract

Four-dimensional oral dosage forms utilize stimuli-responsive polymeric networks to execute post-fabrication conformational changes upon exposure to physiological triggers, including hydrational gradients, luminal pH transitions, localized enzymatic cleavage, and core physiological temperatures. These formulations modulate drug release kinetics via triggered surface area expansion, controlled matrix erosion, internal pore development, and spatial compartment exposure by coupling digital structural configuration with responsive polymer dynamics. Gastroretentive systems represent a primary therapeutic focus, utilizing shape-memory polymer architectures that preserve a compact geometry for oral administration and subsequently unfold or expand within gastric fluid beyond the diameter of the resting human pyloric orifice, resisting phase III migrating motor complex clearance. Similarly, site-directed colonic release, multi-active polypill isolation, and zero-order delivery kinetics are achieved by synchronizing structural kinetics with regional gastrointestinal transit. Translating four-dimensional oral architectures from concept to standard practice requires resolving significant engineering and regulatory hurdles, notably active ingredient thermodegradation during hot-melt processing, anisotropic mechanical stresses during layer-by-layer fusion, long-term shape-memory recovery drift under ambient storage conditions, and the lack of compendial quality assessment standards. This review discusses about the mechanisms, formulation variables, processing pathways, analytical characterization protocols, and regulatory pathways necessary to transition four-dimensional additive manufacturing into reliable oral drug delivery platforms