Experimental investigation of inhomogeneities of primary drying during lyophilization: Impact of the vials packing density

Abstract

Inhomogeneous lyophilization (different drying rates at different locations of the lyophilizer), usually called edge-vial-effect, is a known but still not fully understood problem in freeze drying. The edge-vial-effect is a phenomenon in which vials positioned at the shelf edges and corners tend to dry more quickly compared to central vials. For example, in a recent study of Assegehegn et al. (2020) the authors observed that for all combinations of shelf temperature and chamber pressure studied, the highest product temperature, sublimation rate, and overall vial heat transfer coefficient are observed in front edge vials, whereas the lowest values are observed in center vials. This observation is usually explained by an additional heating from the chamber walls. However, the higher sublimation rates in the edge vials exist also at shelf temperatures higher than room temperatures, when one would expect cooling from the walls and subsequently lower sublimation rates in the edge vials. Another, less known source of inhomogeneous drying is the impact of the packing density of vials on the shelves that was identified by Placek et al. (1999). The key idea is that with increasing number of competitive vials (i.e. the vials surrounding a monitored vial) the amount of heat coming from the shelf and available for sublimation in the monitored vial is decreasing. In other words, a smaller packing density of vials leads to a faster drying. Carefully designed sublimation experiments with different patterns and combinations of active vials (filled with water and open for sublimation) and inactive vials (empty vials without stopper) proved significant impact of the packing density and its contribution to the total sublimation rate. Quantification of the experiments at the different shelf temperatures shows that the total sublimation rate in both, corner vials and central vials, increases with temperature. Also, the contribution of the packing density to the total sublimation rate increases with the shelf temperature. On the other hand, the impact of radiation and conduction from the lyophilizer walls and door decreases with increasing temperature until it starts to show the opposite trend. For the shelf temperature of 25 °C (i.e. higher than the ambient room temperature of 20 °C), the edge vials are cooled from the walls and therefore, the contribution of radiation for drying temperature of 25 °C is negative. It is expected that combination of the radiation cage (Ehlers et al., 2021) and specifically designed experiments employing inactive vials in the central part of the shelves can significantly reduce (or almost eliminate) inhomogeneous drying rates during lyophilization.