Optimization and characterization of small-molecule diffusion are important in the development of drug-delivery systems. For example, the delivery of local antibiotics is an important component of therapy for orthopedic devicerelated infections (ODRI). However, despite its wide use, the exact elution mechanism is not yet fully understood. In this study, we developed a quantitative, non-destructive, micro-CT technique to characterize 2D diffusion of small-molecules in a tissue-equivalent phantom. Our objective is to use a radio-opaque molecule (Iohexol; molecular weight (MW) 821 Da) as a surrogate for small-molecule antibiotics (e.g., Vancomycin; MW 1449 Da) to characterize diffusion from a finite, cylindrical-core carrier into an agar, tissue-equivalent, sink. A single-phase diffusion experiment was performed to validate our micro-CT imaging method. A two-part phantom consisted of an inner, cylindrical, agar core loaded with Iohexol as a drug-surrogate, directly communicating with an outer annulus of pure agar. The estimate of a single-phase diffusion coefficient for agar was derived from the analysis of 2D radial diffusion distance. We then applied the validated method to evaluate diffusion in two-phases, using calcium-sulphate matrices loaded with Iohexol eluting into an agar tissue-equivalent sink. Image acquisition was performed at regular intervals up to 25 days. Cumulative release amount was used to calculate diffusion coefficients in two-phase phantoms. Iohexol diffusion coefficient was 2.6 ×10-10 m2 s-1, 0.46 ×10-10 m2 s-1, 0.85 ×10-10 m2 s-1 through agar, Stimulan, and Plaster of Paris, respectively. This approach could be used to validate drug delivery in the development of new carrier structures and materials.