This paper numerically investigated the mechanisms of powder de-agglomeration on mechanical impaction, aiming to explain the experimental observations in our previous study (Adi et al., 2010). A numerical model based on a coupled computational fluid dynamics (CFD) and discrete element method (DEM) approach was developed to simulate the dispersion of drug mannitol agglomerates in the customised impaction throats containing one or two angles with different flow rates. Information in terms of particle-throat and particle-fluid interactions, number of fragments, fine particle fraction (FPF) and powder deposition was monitored over the whole process and quantitatively analysed. The results indicated that the breakage of the agglomerate was mainly attributed to the mechanical impaction and less affected by the shear effect from the flow-particle interaction. While the first impaction caused the major damage to the agglomerate, the second impaction in fact generated more fine particles with size less than 5. ?m, resulting much improved dispersion performance for the throats with two angles. Powder deposition, which is dependent on impaction velocity and angle and fragment size, was another important factor affecting the dispersion. The analysis of dispersion mechanisms indicated that de-agglomeration at different conditions can be characterised by the ratio of the particle-wall impaction energy and agglomerate strength.