Comparison of ice fog methods and monitoring of controlled nucleation success after freeze-drying

Improving freeze-drying processes regarding drying time and batch homogeneity is subject of ongoing research work. In this context, controlled nucleation raised great expectations. However, practically we face some challenges, e.g. how to non-destructively monitor successfully performed controlled nucleation. The question if different controlled nucleation methods lead to comparable products, as not every method can easily be implemented in lab and production scale equipment, is also of high interest. Additionally, the optimal nucleation temperature for controlled nucleation is an open question. In our study, we addressed these challenges. We successfully evaluated frequency modulated spectroscopy as a fast and non-destructive method to monitor controlled nucleation success and batch homogeneity. We found that the better homogeneity generated by controlled nucleation during the freezing step did not sustain in the dried product. Lyophilizates produced by three different ice fog methods for controlled nucleation were characterized by comparable specific surface areas but differed in residual moisture content. To investigate the impact of the ice nucleation temperature (T-N) on the resulting specific surface area, we performed controlled nucleation at - 3 degrees C and -10 degrees C. We concluded that T-N is not the only specific surface area determining factor and a high TN does not necessarily lead to larger pores but poses a higher risk of not-nucleating vials.