Impact of vacuum-induced surface freezing on inter- and intra-vial heterogeneity

This paper aims to study the impact of freezing on both within-batch (inter-vial) and within- product (intra-vial) heterogeneity. This analysis has been carried out using two freezing protocols, the conventional shelf-ramped method and the Vacuum Induced Surface Freezing, and placebo formulations containing both crystallizing (mannitol) and amorphous (lactose and sucrose) excipients. The freezing conditions (i.e., the temperature of freezing, the temperature and time of the equilibration phase, and the filling volume) were found to have a dramatic impact on both the within-batch and the within-product homogeneity. Overall, we observed that the control of freezing can effectively minimize the variability in product characteristics, and moisture content, within the same batch. In addition to more uniform production, the control of freezing was found to be fundamental to achieve a more uniform product than that produced by the shelf-ramped freezing method. The influence of the freezing protocol on the crystallization process of mannitol was also investigated, showing that the temperature of freezing plays a key role in the formation of the mannitol polymorphs.