Polymorph control by designed ultrasound application strategy: The role of molecular self-assembly

Molecular self-assembly plays a vital role in the nucleation process and sometimes determines the nucleation outcomes. In this study, ultrasound technology was applied to control polymorph nucleation. For the first time, different ultrasonic application methods based on the nucleation mechanisms have been proposed. For PZA-water and DHB-toluene systems that the molecular self-assembly in solution resembles the synthon in crystal structure, ultrasound pretreatment strategy was conducted to break the original molecular interactions to alter the nucleated form. When the solute molecular self-associates can’t give sufficient information to predict the nucleated polymorph like INA-ethanol system, the method of introducing continuous ultrasonic irradiation in the nucleation stage was applied. The induction of ultrasound during nucleation process can break the original interactions firstly by shear forces and accelerate the occurrence of nucleation to avoid the reorientation and rearrangement of solute molecules. These strategies were proved to be effective in polymorph control and have a degree of applicability.