In vitro dissolution testing of long-acting injectables: regulatory methods, mechanistic development, and In Vitro-In...

Long-acting injectables (LAIs) have become an important platform for drug delivery providing sustained drug exposure over weeks to months, creating an increasing need for predictive in vitro dissolution methods to support formulation development, quality control, and the establishment of meaningful in vitro-in vivo correlations (IVIVCs). However, standardized in vitro release methods and regulatory guidance covering the range of LAI formulations remain limited, and existing recommendations vary across formulation types and regulatory authorities. This review examines FDA-recommended dissolution methods, relevant guidance from other regulatory authorities, and formulation-specific methodologies reported in the literature, and evaluates their applicability to the development of IVIVCs for LAIs. The available evidence demonstrates that current compendial methods primarily serve as product-specific quality control tests. Successful biopharmaceutically relevant dissolution testing depends on reproducing the dominant release mechanisms of each formulation platform, including drug dissolution, partitioning, polymer degradation, phase inversion, and microstructural evolution. Recent scientific advances demonstrate a transition from empirical dissolution testing to mechanistically informed and biopredictive methodologies. Collectively, the available evidence suggests that predictive dissolution testing of LAIs should be formulation-specific and designed to reproduce the dominant release mechanisms under physiologically relevant conditions, thereby supporting formulation development, IVIVC establishment, and regulatory evaluation.