Estimation of the nucleation kinetics for the anti-solvent crystallisation of paracetamol in methanol/water solutions

In this work the primary nucleation kinetics have been estimated for the anti-solvent crystallisation of paracetamol in methanol–water solutions from metastable zone widths (MSZW) and induction times at 25 °C. Laser back-scattering via a focused beam reflectance Measurement (FBRM®) is utilised to detect the onset of nucleation. The theoretical approach of Kubota was employed to estimate the nucleation kinetics, which accounts for the sensitivity of the nucleation detection technique. This approach is expanded in this work to analyse the induction time for an anti-solvent crystallisation process. Solvent composition is known to have a significant impact on the measured induction times and MSZW. The induction time in this paper was measured from 40% to 70% mass water and the MSZW is measured from 40% to 60% mass water. The primary focus of the paper was to gauge the extent of how solvent composition affects nucleation kinetics so that this effect may be incorporated into a population balance model. Furthermore, the effects of solvent composition on the estimated nucleation rates are investigated. The primary nucleation rates were found to decrease with dynamic solvent composition, with the extent of their reduction linked to the gradient of the solubility curve. Finally, both MSZW and induction time methods have been found to produce similar estimates for the nucleation parameters.

► Nucleation kinetics evaluated for anti-solvent crystallisation of paracetamol.
► Solvent composition found to have significant impact on kinetic parameters.
► Effect of solvent composition linked with the gradient of the solubility curve.
► Theory expanded to describe the induction time for anti-solvent crystallisation.
► Both MSZW and induction time found to produce similar kinetic estimates.