Combining anti-solvent and cooling crystallization: Effect of solvent composition on yield and meta stable zone width

Combined cooling and anti-solvent crystallization (CCAC) of paracetamol was carried out from a water–isopropanol (IPA) mixture. Seeded and unseeded runs were performed in a 150 ml vessel with linear cooling rates varying from 0.028 to 2.0 K/min, and linear anti-solvent feed rates in the range from 0.88 to 5.0 g/min. The dynamic solvent composition is shown to have a substantial effect on the crystallization kinetics, and the meta stable zone width (MSZW). Existing models from the literature which predict the behavior of the MSZW have been applied to the CCAC process for the unseeded runs. The crystal growth rate was strongly influenced by the solvent composition. Hence, the performance of the crystallization process was increased substantially by first precipitating paracetamol by adding anti-solvent until a solvent composition was reached which caused a high growth rate. Subsequent cooling resulted in higher growth rates. This could be applied in industrial batch crystallization to decrease the required batch time, thus improving performance.