Developing processes for the production of active pharmaceutical ingredients (APIs) with a specific crystal size or polymorph distribution is critical for improved drug delivery by aerosolization, injection or ingestion, for control of bioavailability, and for economy of preparation. The use of ultrasound for the crystallization of APIs has attracted substantial recent attention due to (1) its influence on particle size and size distribution, (2) reduction of metastable zone-width, induction time, and supersaturation levels required for nucleation, (3) improved reproducibility of crystallization, (4) control of polymorphism, and (5) reduction or elimination of the need for seed crystals or other foreign materials. 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 (APIs). Surprisingly, kinetics experiments rule out particle-particle collisions as a viable mechanism for sonofragmentation. Two other possible mechanisms — particle-horn or particle-wall collisions — were dismissed based on decoupling experiments. Direct particleshockwave interactions are therefore indicated as the primary mechanism of sonofragmentation of molecular crystals.