Sono-crystallisation has been used to enhance crystalline product quality particularly in terms of purity, particle size and size distribution. In this work, the effect of impurities and ultrasound on crystallisation processes (nucleation temperature, yield) and crystal properties (crystal size distribution determined by Focused Beam Reflectance Measurement (FBRM), crystal habit, filtration rate and impurity content in the crystal product by Liquid Chromatography-Mass Spectroscopy (LC-MS)) were investigated in bulk suspension crystallisation experiments with and without the use of ultrasound. The results demonstrate that ultrasonic intervention has a significant effect on both crystallisation and product crystal properties. It increases the nucleation rate resulting in smaller particles and a narrower Particle Size Distribution (PSD), the yield has been shown to be increase as has the product purity. The effect of ultrasound is to reduce the level acetanilide impurity incorporated during growth from a 2 mol% solution of the selected impurity from 0.85 mol% to 0.35 mol% and likewise ultrasound reduces the uptake of metacetamol from 1.88 mol% to 1.52 mol%.

We have previously demonstrated product purity enhancement during the crystallization of paracetamol in a low intensity ultrasound field. In order to elucidate the underlying mechanisms of sonocrystallization, the applied ultrasonic interventions were characterized by measurements of cavitation bubble number, size and size distribution with a Mettler FBRM probe. Ultrasonic intensity measurements were conducted using a needle hydrophone. The solvents selected for study; water, ethanol and isoamyl alcohol show significant differences in behavior. This data provides an insight into the relationship between solvent properties and cavitation bubble activity under the same applied ultrasonic energy. Substantially more cavitation bubbles form in the organic solvents compared with water, this is consistent with the lower surface tension and higher vapor pressure of the organic solvents. The difference in bubble size distributions between ethanol and isoamyl alcohol is significant. In ethanol most bubbles remain below 30μm whereas in isoamyl alcohol they tend towards 1mm in size. Detection, quantification and measurement of cavitation bubbles in crystallization solvents contributes further evidence that acoustic cavitation is a key component in sonocrystallization. The industrial driver is to incorporate this understanding into both pharmaceutical process and equipment design to improve the product quality, reduce waste and improve access to medicines.