The effect of sucrose, maltodextrin and skim milk on survival of L. bulgaricus after drying was studied. Survival could be improved from 0.01% for cells that were dried in the absence of protectants to 7.8% for cells dried in a mixture of sucrose and maltodextrin. Fourier transform infrared spectroscopy (FTIR) was used to study the effect of the protectants on the overall protein secondary structure and thermophysical properties of the dried cells. Sucrose, maltodextrin and skim milk were found to have minor effects on the membrane phase behavior and the overall protein secondary structure of the dried cells. FTIR was also used to show that the air-dried cell/protectant solutions formed a glassy state at ambient temperature. 1-Palmitoyl 2-oleoyl phosphatidyl choline (POPC) was used in order to determine if sucrose and maltodextrin have the ability to interact with phospholipids during drying. In addition, the glass transition temperature and strength of hydrogen bonds in the glassy state were studied using this model system. Studies using poly-L-lysine were done in order to determine if sucrose and maltodextrin are able to stabilize protein structure during drying. As expected, sucrose depressed the membrane phase transition temperature (Tm) of POPC in the dried state and prevented conformational changes of poly-L-lysine during drying. Maltodextrin, however, did not depress the Tm of dried POPC and was less effective in preventing conformational changes of poly-L-lysine during drying. We suggest that when cells are dried in the presence of sucrose and maltodextrin, sucrose functions by directly interacting with biomolecules, whereas maltodextrin functions as an osmotically inactive bulking compound causing spacing of the cells and strengthening of the glassy matrix.

Vial design features can play a significant role in heat transfer between the shelf and the product and, consequently, in the final quality of the freeze-dried product. Our objective was to investigate the impact of the variability of some geometrical dimensions of a set of tubing vials commonly used for pharmaceuticals production on the distribution of the vial heat transfer coefficients (K) and its potential consequence on product temperature. Sublimation tests were carried out using pure water and 8 combinations of chamber pressure (4-50 Pa) and shelf temperature (-40°C and 0°C) in 2 freeze-dryers. K values were individually determined for 100 vials located in the center of the shelf. Vial bottom curvature depth and contact area between the vial and the shelf were carefully measured for 120 vials and these data were used to calculate K distribution due to variability in vial geometry. At low pressures commonly used for sensitive products (below 10 Pa), the vial-shelf contact area appeared crucial for explaining K heterogeneity and was found to generate, in our study, a product temperature distribution of approximately 2°C during sublimation. Our approach provides quantitative guidelines for defining vial geometry tolerance specifications and product temperature safety margins.

In pharmaceutical freeze-drying, the position of the product container (vial) on the shelf of the equipment constitutes a major issue for the final product quality. Vials located at the shelf edges exhibit higher product temperature than vials located at the centre, which in turn often results in collapsed product. A physics-based model was developed to represent heat transfer phenomena and to study their variation with the distance from the periphery of the shelf. Radiation, conduction between solids, and conduction through low-pressure water vapour were considered. The modelling software package COMSOL Multiphysics was employed in representing these phenomena for a set of five vials located at the border of the shelf, close to the metallic guardrail. Model predictions of heat fluxes were validated against experimental measurements conducted over a broad range of shelf temperatures and chamber pressures representative for pharmaceutical freeze-drying. Conduction through low-pressure water vapour appeared as the dominant mechanism explaining the additional heat transfer to border vials compared to central ones. The developed model constitutes a powerful tool for studying heterogeneity in freeze-drying while reducing experimental costs. Highlights:• A 3D mathematical model of heat transfer in freeze-drying is proposed.• The role of several heat transfer mechanisms is explored.• Knudsen effect is considered for conduction inside low-pressure water vapour.• Radiation heat transfer is evaluated using the surface-to-surface model.• Atypical heat transfer is explained mainly by gas conduction rather than radiation.