Freezing and Annealing Phenomena in Lyophilization: Effects Upon Primary Drying Rate, Morphology, and Heterogeneity

Freezing and Annealing Phenomena in Lyophilization: Effects Upon Primary Drying Rate, Morphology, and Heterogeneity
Theodore W. Randolph, Ph.D.1 & James A. Searles, Ph.D.2, 1University of Colorado, Boulder, 2Eli Lilly & Co.
Freeze-drying, or lyophilization, is often employed for live virus vaccines and protein pharmaceuticals in order to ensure stability over a reasonable shelf-life [1, 2, 22]. Lyophilization is also employed for many small-molecule (non-proteinaceous) therapeutics [32]. The process entails freeze concentration of an aqueous solution and sublimation drying under vacuum, all in single-dose vials. Traditionally, lyophilization cycle design has been divided into three parts: 1) freezing, in which the liquid sample is cooled until pure crystalline ice forms from part of the liquid and the remainder of the sample is freeze-concentrated into a glassy state where the viscosity is too high to allow further crystallization; 2) primary drying, wherein the ice formed during the freezing is removed by sublimation under vacuum at low temperatures, leaving a highly porous structure in the remaining amorphous solute that is typically 30% water. This step is carried out at pressures of 10-4 to 10-5 atmospheres, and a product temperature of ?45 to ?20?C; and 3) secondary drying, wherein most of the remaining water is desorbed from the glass as the temperature of the sample is gradually increased while maintaining low pressures. Ideally, the final product is a dry, easily reconstituted cake with a high surface area (ca. 10 m2/g) [7].
As it is currently practiced, lyophilization is an expensive, batch process, making up as much as 50% of protein purification costs [5]. Much of the high cost of lyophilization can be ascribed to the length of time required for the primary drying step, which can require several days to complete. Clearly it would be economically advantageous if lyophilization process parameters could be adjusted so as to increase sublimation rates and shorten primary drying times.
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