Investigation of PEG Crystallization in Frozen PEG-Sucrose-Water Solutions. I. Characterization of the Nonequilibrium Behavior during Freeze-Thawing

Our objective was to characterize the nonequilibrium thermal behavior of frozen aqueous solutions containing PEG and sucrose. Aqueous solutions of (i) sucrose (10%, w/v) with different concentrations of PEG (1-20%, w/v), and (ii) PEG (10%, w/v) with different concentrations of sucrose (2-20%, w/v), were cooled to -70 degrees C at 5 degrees C/min and heated to 25 degrees C at 2 degrees C/min in a differential scanning calorimeter. Annealing was performed at temperatures ranging from -50 to -20 degrees C for 2 or 6 h. Similar experiments were also performed in the low-temperature stage of a powder X-ray diffractometer A limited number of additional DSC experiments were performed wherein the samples were cooled to -100 degrees C. In unannealed systems with a fixed sucrose concentration (10%, w/v), the T-g' decreased from -35 to -48 degrees C when PEG concentration was increased from 1% to 20% (w/v). On annealing at -25 degrees C, PEG crystallized. This was evident from the increase in T-g' and the appearance of a secondary melting endotherm in the DSC. Low-temperature XRD provided direct evidence of PEG crystallization. Annealing at temperatures <=-40 degrees C did not result in crystallization and a devitrification event was observed above the T-g'. In unannealed systems with a fixed PEG concentration (10%, w/v), the T-g' increased from -50 to -40 degrees C when sucrose concentration was increased from 5% to 50%, w/v. As the annealing time increased (at -25 degrees C), the T-g' approached that of a sucrose water system, reflecting progressive PEG crystallization. A second glass transition at similar to -65 degrees C was evident in unannealed systems [10%, w/v sucrose and 10 (or 20%), w/v PEG] cooled to -100 degrees C. Investigation of the nonequilibrium behavior of frozen PEG-sucrose-water ternary system revealed phase separation in the freeze-concentrate. Annealing facilitated PEG crystallization. (C) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:2609-2619, 2010