Sonofragmentation of molecular crystals: Observations and Modeling

The need for new production methods of active pharmaceutical ingredients (APIs) with a specific crystal size distribution is acute for improved drug delivery by aerosolization, injection or ingestion, for control of bioavailability, and for economy of preparation. "Sonocrystallization" (i.e., the use of ultrasound for the crystallization of APIs) is under very active investigation for its ability to influence particle size and size distribution, reduce metastable zone-width, induction time, and supersaturation levels required for nucleation, improve reproducibility of crystallization, control of polymorphism, and reduce or eliminate the need for seed crystals or other foreign materials. We will review the potential mechanisms for the breakage of molecular crystals under high-intensity ultrasound and relate our experimental and modeling studies of the sonocrystallization and fragmentation of acetylsalicylic acid (aspirin) crystals as a model API. Surprisingly, kinetics experiments rule out particle-particle collisions as a viable mechanism for sonofragmentation. Direct particle-shockwave interactions are the primary mechanism of sonofragmentation of molecular crystals.