Determination of the Crystal Growth Rate of Paracetamol As a Function of Solvent Composition

Abstract

Growth kinetics, growth mechanisms, and the effect of solvent composition for the antisolvent crystallization of paracetamol in methanol–water mixtures have been determined by means of isothermal seeded batch experiments at constant solvent composition. A numerical model incorporating the population balance equation based on antisolvent free solubility was fitted to the desupersaturation data, and growth rate parameters are evaluated. An attenuated total reflectance–Fourier transform infrared (ATR-FTIR) probe was employed to measure online solute concentration and focused beam reflectance measurement (FBRM) was utilized to ensure negligible nucleation occurred. The model is validated by the final particle size distributions (PSDs) and online solute concentration measurements. Crystal growth rate was found to decrease with increasing water mass fractions up to a mass fraction of 0.68 where an increase is observed. A method has been introduced linking the effect of solvent composition with the growth mechanism and the growth rates. Utilizing the growth mechanism it has been postulated that a combination of the solubility gradient, viscosity, selective adsorption, and surface roughening are responsible for the reduction in growth rates with solvent composition. Furthermore, the effects of seed mass, size and initial supersaturation on the crystal growth rates were investigated to demonstrate the efficacy of the model at predicting these various phenomena.