Experimental determination of the key heat transfer mechanisms in pharmaceutical freeze-drying



The study is aimed at quantifying the relative contribution of key heat transfer modes in lyophilization. Measurements of vial heat transfer rates in a laboratory-scale freeze-dryer were performed using pure water, which was partially sublimed under various conditions. The separation distance between the shelf and the vial was systematically varied, and sublimation rates were determined gravimetrically. The heat transfer rates were observed to be independent of separation distance between the vial and the shelf and linearly dependent on pressure in the free molecular flow limit, realized at low pressures (<50 mTorr). However, under higher pressures (>120 mTorr), heat transfer rates were independent of pressure and inversely proportional to 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 convection has been found to be insignificant. Although the measurements reported here confirm the significance of the radiative and gas conduction components, the convective component has been found to be comparable to the gas conduction contribution at pressures greater than 100 mTorr. The current investigation supports the conclusion that the convective component of the heat transfer cannot be ignored in typical laboratory-scale freeze-drying conditions. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1610–1625, 2013