The flow of carrier particles, coated with active drug particles, is studied in a prototype dry powder inhaler. A novel, multiscale approach consisting of a discrete element model (DEM) to describe the particles coupled with a dynamic large eddy simulation (LES) model to describe the dynamic nature of the flow is applied. The model consists of three different scales: the micro-scale, the meso-scale, and the macro-scale. At the micro-scale, the interactions of the small active drug particles with larger carrier particles, with the wall, with the air flow, and with each other is thoroughly studied using discrete element modeling and detailed computational fluid dynamics (CFD), i.e., resolving the flow structures around the particles. This has led to the development of coarse-grained models, describing the interaction of the small active drug particles at the larger scales. At the meso-scale the larger carrier particles, and all of their interactions are modeled individually using DEM and CFD-LES. Collisions are modeled using a visco-elastic model to describe the local deformation at each point of particle-particle contact in conjunction with a model to account for cohesion. At the macro-scale, simulations of a complete prototype inhaler are carried out. By combining the relevant information of each of the scales, simulations of the inhalation of one dose from a prototype inhaler using a patient relevant air flow profile show that fines leave the inhaler faster than the carrier particles. The results also show that collisions are not important for particle-particle momentum exchange initially but become more important as the particles accelerate. It is shown that for the studied prototype inhaler the total release efficiency of the fine particles is between 10 and 30%, depending on the Hamaker constant, using typical settings for the properties of both particles. The results are also used to study regions of recirculation, where carrier particles can become trapped, and regions where fines adhere to the wall of the device. (c) 2016 American Institute of Chemical Engineers AIChE J, 63: 501-516, 2017