This paper investigated the behaviour of agglomerate–agglomerate collision based on a combined computational ﬂuid dynamics (CFD) and discrete element method (DEM) approach, aiming to develop better understanding of the underlying the mechanisms of loose drug agglomerates aerosolisation in DPIs. The collision between two mannitol agglomerates in a T-shape pipe was simulated. The effects of key variables such as agglomerate strength, air ﬂow rate and collision angle were investigated. The aero- solisation performance was characterised with the size distribution of fragments and ﬁne particle fraction (FPF) which was the mass fraction of the fragments with size less than 5 μm. The results showed that the collision between agglomerates has a signiﬁcant effect on aerosolisation process. For a given agglomerate, there was a threshold velocity, above which would increase aerosolisation and otherwise would decrease. The analyses of airﬂow ﬁeld and the agglomerate properties indicated that the aerosolisation per- formance was determined by two competitive factors, i.e. interparticle cohesion and total collision energy. An index to character of aerosolisation efﬁciency was provided based on the ratio of total collision energy and agglomerate strength. This index could be used to help design the high-dose DPI for the different drug agglomerates varied in strength.