Investigate the Effects of Sonication on the Nucleation of Acetaminophen and Design the Sonoseeding Approach for Crystal Size Modification

This study developed a sonoseeding strategy for controlling the crystal size of acetaminophen during cooling crystallization by introducing sonication into a supersaturated solution, thereby inducing nucleation. Based on the synthetic route of acetaminophen, crystallization behavior in both water and acetic acid aqueous solutions was investigated, along with the influence of a structurally related additive, p-aminophenol, on nucleation. To establish the sonoseeding approach, the solubility of acetaminophen in water and an aqueous solution of acetic acid, with and without the additive, was measured over a temperature range of 10–70 °C using a titration method. In parallel, the nucleation temperatures and metastable zone widths of acetaminophen were systematically determined during cooling crystallization under varying operating conditions. Results demonstrate that sonication effectively induces nucleation and significantly narrows the metastable zone width, particularly in aqueous solutions of acetic acid. Guided by the determined solubility and nucleation behavior, sonoseeding crystallization experiments were conducted at various supersaturation levels, allowing for the efficient control of acetaminophen crystal size, which ranged from 27 μm to 95 μm, with narrower particle size distributions compared to spontaneous nucleation. Furthermore, the recrystallized acetaminophen was confirmed as Form I using PXRD, DSC, and FTIR analysis. This study demonstrates that the sonoseeding approach is an efficient method for controlling crystal size during the crystallization of active pharmaceutical ingredients.