•Coupled CFD-DEM model built to predict the performance of common capsule DPIs.•Model predicts particle dynamics that affect powder aerosol characteristics.•Formulation and DPI design interplay affecting fine aerosol generation identified.•Model results correlate with experimental cascade impactor data.•Design modifications to optimize capsule DPI performance are proposed. Display omitted Capsule-based, single-dose dry powder inhalers (DPIs) are commonly-used devices to deliver medications to the lungs. This work evaluates the effect of the drug/excipient adhesive bonding and the DPI resistances on the aerosol performance using a combination of empirical multi-stage impactor data and a fully-coupled computational fluid dynamics (CFD) and discrete element method (DEM) model. Model-predicted quantities show that the primary modes of powder dispersion are a function of the device resistance. Lowering the device resistance increases its capacity to transport a wider range of particle size classes toward the outlet and generate more intense turbulence upstream therein. On the other hand, a higher device resistance increases the velocity of the tangential airflow along the device walls, which in turn increases the intensity of particle/device impaction. Correlating model data and experimental results shows that these differing powder dispersion mechanisms affect different formulations differently, with finer aerosols tending to result when pairing a lower resistance device with formulations that exhibit low API/excipient adhesion, or when pairing a high resistance device with more cohesive formulations.