Modeling of Nucleation, Growth, Dissolution, and Disappearance of Paracetamol in Ethanol Solution for Unseeded Batch Cooling Crystallization with Temperature-Cycling Strategy

A population balance model (PBM) is developed for unseeded batch crystallization, with temperature-cycling strategies to control the crystal size distribution. The model is able to predict the evolution of crystal size distributions of crystallizing paracetamol from ethanol solutions considering the characteristics of primary nucleation, secondary nucleation, growth, dissolution, and disappearance of crystals. Process analytical technology (PAT) tools were employed to collect solute concentration data and crystal size distribution data. This model employs a boundary condition to describe the disappearance of crystals in temperature-cycling strategies where the temperature is increased and decreased repeatedly. As a result, the obtained model can describe the evolution of crystal size distribution when repetition of cooling and heating is carried out. Moreover, this model can be applied to investigate phenomena that are challenging to explain with experimental data alone, thereby we can gain insight and optimize the operation of the process.