Design and Optimization of a Combined Cooling/Antisolvent Crystallization Process

Design and optimization are important steps during the development of crystallization processes. The combined cooling/antisolvent crystallization of acetylsalicylic acid (ASA) in ethanol−water mixtures is studied by means of experiments and population balance modeling. Model-based approaches require accurate kinetics and thermodynamic data, which are obtained in this work using in situ process monitoring techniques such as attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy and focused beam reflectance measurement (FBRM). Solubility is measured in situ as a function of temperature and solvent composition using a multivariate calibration model for the ATR-FTIR. Nucleation and growth kinetics are determined based on crystallization experiments by a combination of a population balance model and an integral parameter estimation technique. The model is finally used to calculate optimal cooling and antisolvent addition profiles of the combined cooling/antisolvent crystallization process using a multiobjective optimization approach which optimizes the process with respect to product properties, that is, particle size distribution, and performance, that is, process time. It was found that the solubility exhibits a maximum at 17 wt% water and that the growth rate correlates well with the solubility. No effect of the solvent composition on the nucleation rate could be identified. The optimized trajectories for cooling and antisolvent could greatly reduce the number of nuclei formed as shown through modeling and experiments. The study shows that combining cooling and antisolvent crystallization allows both improving productivity and reducing the formation of fines, and illustrates how process analytical tools and population balance modeling also are effective in crystallization processes where temperature and solvent composition change.