The effects of supersaturation, temperature, agitation and seed surface area on the secondary nucleation of paracetamol in ethanol solutions

This work details the estimation of the secondary nucleation kinetics of paracetamol in ethanol solutions for cooling crystallisation processes, by means of isothermal under-seeded batch experiments. A numerical model, incorporating the population balance equation and the method of moments has been developed to describe the seeding process for a typical cooling crystallisation process, accounting for the primary and secondary nucleation and subsequent crystal growth. Primary nucleation and growth kinetics have been previously evaluated from induction time experiments and isothermal seeded batch experiments, respectively, allowing the secondary nucleation rate to be evaluated for a wide range of experimental conditions. The experimental technique involved the utilisation of two in-situ Process Analytical Techniques (PAT), a Focused Beam Reflectance Measurement (FBRM®) utilised to qualitatively indicate the occurrence of secondary nucleation and an Attenuated Total Reflectance — Fourier Transform Infrared (ATR-FTIR) probe employed for the online monitoring of solute concentration. Initial Particle Size Distributions (PSD) were used in conjunction with desupersaturation profiles to determine the secondary nucleation rate as a function of supersaturation, temperature and crystal surface area. Furthermore, the effects of agitation rate on the secondary nucleation rate were also investigated. Experimental data were compared to the model simulation, with the accuracy of the estimated secondary nucleation kinetics validated by means of the final product PSD and solute concentration.

► Secondary nucleation kinetics of paracetamol evaluated from isothermal under-seeded batch experiments.
► Two in-situ Process Analytical Techniques (PAT) employed to track the crystallisation process.
► Initial PSD's and desupersaturation profile employed to determine the secondary nucleation rate.
► Effect of temperature, supersaturation, seed surface area, agitation rate investigated.
► Population balance model developed to describe the seeding process.