This investigation compares in vitro release, ex vivo release and permeation, and in vivo ocular pharmacokinetics to render biologically informed evaluations of ophthalmic semi-solid drug products containing dexamethasone (hydrophobic) and tobramycin (hydrophilic). Both drugs were formulated with three petrolatum matrices (IGI® 320 A, IGI® 386, or Spectrum®) with distinct rheological character and benchmarked against the reference listed drug, Tobradex®. Temperature-sweep rheology revealed that IGI® 386 most closely reproduced the viscoelastic profile of the reference product. USP Apparatus I release testing with surfactant-free medium provided maximal discrimination for dexamethasone (Tobradex® > IGI® 320 A > IGI® 386 > Spectrum®), and rank-order release rates correlated strongly with ex vivo corneal permeation and in vivo corneal exposure. In contrast, tobramycin required a polysorbate-containing medium to resolve formulation differences in vitro, yet those differences did not persist ex vivo or in vivo, consistent with its rapid dissolution and diffusion, which attenuate matrix effects. The data demonstrate that drug solubility dictates the choice of biorelevant release conditions in petrolatum-based ophthalmic ointments: surfactant-free media capture formulation-dependent release for hydrophobic actives, whereas hydrophilic actives may yield artifactual discrimination when surfactant is present. However, formulations indistinguishable in vitro were typically similar in their in vivo ocular pharmacokinetics. By integrating tiered models, the framework enhances understanding of critical quality attributes, supports regulatory decision-making, and may help reduce reliance on animal studies, thereby expediting the development of therapeutically equivalent generic ophthalmic ointments.
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