Experimental Determination of the Key Heat Transfer Mechanisms in Pharmaceutical Freeze Drying

Abstract

Freeze-drying is often used in manufacture of pharmaceuticals to remove a solvent in such a way that the sensitive molecular structure of the active substance of a drug is least disturbed, and to provide a sterile powder that can be quickly and completely rehydrated. In this work heat transfer rates in a laboratory-scale freeze-dryer have been measured to investigate the contribution of different heat transfer modes. Pure water was partially dried under low-pressure conditions and sublimation rates were determined gravimetrically. The heat transfer rates were observed to be independent of the separation distance between a product vial and a dryer shelf and linearly dependent on the pressure in the free molecular limit. However, under higher pressures the heat transfer rates were independent of pressure and inversely proportional to the separation distance. Previous heat transfer studies in conventional freeze-drying cycles have attributed a dominant portion of the total heat transfer to radiation, the rest to conduction, whereas the convection has been found insignificant. While the measurements revealed the significance of the radiative and gas conduction components, the convective component was found to be comparable to the gas conduction contribution at pressures greater than 100mTorr. The current investigation suggests that the convective component of the heat transfer cannot be ignored at typical laboratory-scale freeze-drying conditions.

How Vial Geometry Variability Influences Heat Transfer and Product Temperature During Freeze-Drying

“…Possible hypotheses include: (i) differences in the shelf surface finish that could induce differences in the gas-shelf heat transfer through the accommodation coefficient 8 (Equation 6-7) as well as (ii) differences in the gas convection conditions, a mechanism responsible for a small part of the pressure-dependent heat transfer. 22 These results suggest that small differences between devices might become more apparent at high pressures. When considering only vials not exposed to edge effect a cycle designed with low operating pressure (below 10 Pa) could therefore be more suitable for safe scale-up.…”

“…The variability of the experimental distributions is completely explained by the geometrical variability at low pressures (i.e., 4, 6 Pa), whereas at higher pressures, the experimental coefficient of variation appears to be slightly higher than the one calculated based on vial geometry. It is thus possible that other sources of variability should be taken into consideration, for example convection in the drying chamber could play a role if higher pressures are considered 22. These considerations can guide the selection of the container as a function of the variability of the vial dimensions.…”

Evaluation of spin freezing versus conventional freezing as part of a continuous pharmaceutical freeze-drying concept for unit doses

“…The convective heat transfer became then more efficient, leading to a faster sublimation (Ganguly et al, 2013).…”

Impact of Microscale and Pilot-Scale Freeze-Drying on Protein Secondary Structures: Sucrose Formulations of Lysozyme and Catalase

“…Because of the distance of the shelf center from the PS freeze‐dryer Plexiglas door, it was anticipated that there would be reduced radiative heat transfer. The curved vial bottom shape provides little direct contact between vial and shelf, but the gas‐filled gap may have influenced the heat transfer characteristics depending on the chamber pressure . In the MS approach, the silver heating stage was utilized as a shelf but no space was available in which to place surrounding dummy samples.…”