Modeling of freezing step during vial freeze-drying of pharmaceuticals—influence of nucleation temperature on primary drying rate

To optimize the primary drying step of freeze-drying processes, it is very important to control morphological parameters of the frozen matrix. A mathematical model that simulates temperature profiles during freezing process of standard pharmaceutical formulations was set up and the ice crystal mean sizes were semi-empirically estimated from the simulated thermal profiles. Then, water vapor mass transfer kinetics during sublimation step was estimated from ice phase morphological parameters. All these numerical data were compared with experimental data and a quite good agreement was observed, which confirmed the adequacy of the present model calculations. It was confirmed that, for a given formulation, the mass transfer parameters during freeze-drying were strongly dependent on morphological textural parameters, and consequently, on the nucleation temperatures that fix the ice phase morphology. The influence of freezing rates was also predicted from the simulations, proving that an increase of cooling rates led to slower primary drying rates. Copyright © 2010 Curtin University of Technology and John Wiley & Sons, Ltd.