During the operation of a high-speed shear wet granulator, the rotation of the granulation components leads to the emergence of the phenomenon of particle breakage, which results in changes in particle size. To simulate the breakage process of pharmaceutical powder particle agglomerates in a granulator, a Hertz−Mindlin with bonding contact model was designed in this study. The effects of impeller speed, chopper speed, and granulation time on particle breakage were then studied. The results show that the agglomerates formed by the powder particles are not only sheared and collided by the chopper at high speed but also squeezed by the impeller, which causes the powder particles to break. In this paper, 20 sets of case simulations were conducted, and it was found that the impeller significantly affected the fragmentation rate of particles. Increasing the speed of the impeller increases the particle breakage rate and reduces the mean particle size.