CHARACTERIZATION, EXPERIMENTAL DATA AND CONTROL OF THE ICE MORPHOLOGY DURING VIAL FREEZE-DRYING OF PHARMACEUTICAL PROTEINS

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In pharmaceutical freeze-drying processes, the freezing step is a key-step because it fixes the morphology of the frozen material and, by the way, the final morphology of the freeze-dried material. It is the most difficult step to control due to the stochastic nature of nucleation processus and, besides, it could be a damaging step with respect to the biological activity loss of pharmaceutical proteins. In this review, we have analyzed published experimental data on ice morphology and sublimation rates obtained with some standard formulations used to stabilize pharmaceutical proteins during freeze-drying. Firstly, we analyzed data on ice crystals size morphology obtained by direct optical microscopy in cold chamber for different vial configurations and freezing parameters, namely: type of vials (moulded or tubing), height of filling, vial size, shelf loading temperature. It proved that the ice crystals sizes distributions depended not only on the freezing rates (well known result) but also on the vial size and type and also on the filling height. This behaviour was explained by the decrease of the super cooling effects which generally led to large and non homogenous ice crystals sizes distributions. Moreover, it was confirmed that adequate annealing treatments could homogenize and increase notably the mean ice crystals sizes. Secondly, an ultrasound system has been designed and investigated to control the ice nucleation in vial configurations for standard formulations (mannitol, BSA, sucrose). It proved that during super cooling, the nucleation temperatures of the sample could be controlled at selected and predetermined values. It was experimentally confirmed that the primary drying rates during freeze-drying were accelerated due to significant homogenization of the ice morphology by the ultrasound controlled nucleation.