Mechanistic Insights into Paracetamol Crystallization: Exploring Ultrasound and Hydrodynamic Cavitation with Quartz Crystal Microbalance Dissipation

Crystallization is a crucial process in the purification of active pharmaceutical ingredients (APIs). Achieving controlled and efficient crystal formation is vital in successful production for industrial applications. This study investigates the crystallization of paracetamol using a model system, focusing on two techniques: ultrasound cavitation (UC) and hydrodynamic cavitation (HC). The role of cavitation in enhancing crystallization is well-established by using ultrasound. However, the crystallization process utilizing HC, especially in the absence of an antisolvent, is not investigated. A detailed investigation is still necessary to understand the nucleation process at the molecular level. This work primarily focuses on forming paracetamol crystals in an aqueous medium without the need for an antisolvent in HC. To address the nucleation study at the molecular level, the quartz crystal microbalance with dissipation (QCM-D) technique was employed to explore the nucleation kinetics of paracetamol crystallization while the solution is cooling. QCM-D allowed for real-time monitoring of mass changes and viscoelastic properties on the sensor surface, providing valuable insights into the adsorption, growth, and dissolution kinetics of paracetamol crystals under the influence of both cavitation techniques. The study revealed distinct crystallization behaviors depending on the type and intensity of cavitation, shedding light on the underlying mechanisms and potential implications for pharmaceutical manufacturing and formulation. These findings indicate that high-quality crystals can be produced using HC without the need for an antisolvent. This work highlights the significant potential for improving the efficiency and control of paracetamol crystallization and plays an important role in scaling up the crystallization process using HC.