Annealing to optimize the primary drying rate, reduce freezing-induced drying rate heterogeneity, and determine T-g ' in pharmaceutical lyophilization

In a companion paper we show that the freezing of samples in vials by shelf -ramp freezing results in significant primary drying rate heterogeneity bec ause of a dependence of the ice crystal size on the nucleation temperature during freezing. (1)The purpose of this study was to test the hypothesis th at post-freezing annealing, in which the product is held at a predetermined temperature for a specified duration, can reduce freezing-induced heteroge neity in sublimation rates. In addition, we test the impact of annealing on primary drying rates. Finally, we use the kinetics of relaxations during a nnealing to provide a simple measurement of T-g', the glass transition temp erature of the maximally freeze-concentrated amorphous phase, under conditi ons and time scales most appropriate for industrial lyophilization cycles. Aqueous solutions of hydroxyethyl starch (HES), sucrose, and HES:sucrose we re either frozen by placement on a shelf while the temperature was reduced ("shelf-ramp frozen") or by immersion into liquid nitrogen. Samples were th en annealed for various durations over a range of temperatures and partiall y lyophilized to determine the primary drying rate. The morphology of fully dried liquid nitrogen-frozen samples was examined using scanning electron microscopy. Annealing reduced primary drying rate heterogeneity for shelf-r amp frozen samples, and resulted in up to 3.5-fold increases in the primary drying rate. These effects were due to increased ice crystal sizes, simpli fied amorphous structures, and larger and more numerous holes on the cake s urface of annealed samples. Annealed HES samples dissolved slightly faster than their unannealed counterparts. Annealing below T-g' did not result in increased drying rates. We present a simple new annealing-lyophilization me thod of T-g' determination that exploits this phenomenon. It can be carried out with a balance and a freeze-dryer, and has the additional advantage th at a large number of candidate formulations can be evaluated simultaneously . (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J P harm Sci 90:872-887, 2001.