Possible mechanisms for the breakage of molecular crystals under high-intensity ultrasound were investigated using acetylsalicylic acid (aspirin) crystals as a model compound for active pharmaceutical ingredients. Surprisingly, kinetics experiments ruled out particle-particle collisions as a viable mechanism for sonofragmentation. Two other possible mechanisms (particle-horn and particle-wall collisions) were dismissed on the basis of decoupling experiments. Direct particle-shock wave interactions are therefore indicated as the primary mechanism of sonofragmentation of molecular crystals.