Ultrasound Assisted Crystallization of Paracetamol: Crystal Size Distribution and Polymorph Control

Antisolvent crystallization of paracetamol was conducted using ultrasound. The effect of various ultrasonic frequencies and power on the mean crystal size, crystal size distribution, induction time, and type of polymorph obtained was studied. Multibubble sonoluminescence intensity was used to correlate the crystallization results with cavitation activity. Results showed that under optimum conditions ultrasound can significantly (i) reduce the mean crystal size from 170 to 13 μm, (ii) lower the induction time from 360 to 30 s, and (iii) narrow the size distribution. A close association between cavitation activity and rate of nucleation was observed. In addition, crystallization under sonication led to the formation of not only monoclinic polymorph (form I) but also orthorhombic polymorph (form II) of paracetamol, which is otherwise difficult to obtain in the absence of ultrasound.