Drug formulation is one of the key factors for generic drug developers in reproducing and improving upon the efficacy of the brand-name reference listed drug (RLD). For this study, we applied correlative imaging to study the microstructures of sustained release pellets in RLD and generic ibuprofen drug products. Dual energy X-ray tomography  was used to reveal primary structures (sugar core, coating, and void space) and FIB-SEM to study secondary structures (API particles and microporosity matrix). Cross section imaging using FIB-SEM and a proprietary sample preparation protocol revealed microstructural differences of four generic samples, which are linked to an explanation of the differences in their release performance and failure to meet a pharmacopeia performance guidelines. In particular, differences in the tightness of the microporosity matrix was correlated with the release performance of the sustained release pellets. This study demonstrated that FIB-SEM cross sectioning and 3D imaging as important methodologies to study micro and nano-scale structural features resulting from different drug formulations and manufacturing conditions.