Annealing to optimize the primary drying rate, reduce freezing-induced drying rate heterogeneity, and determine Tg′ in pharmaceutical lyophilization
✍ Scribed by James A. Searles; John F. Carpenter; Theodore W. Randolph
- Publisher
- John Wiley and Sons
- Year
- 2001
- Tongue
- English
- Weight
- 278 KB
- Volume
- 90
- Category
- Article
- ISSN
- 0022-3549
- DOI
- 10.1002/jps.1040
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✦ Synopsis
In a companion paper we show that the freezing of samples in vials by shelframp freezing results in signi®cant primary drying rate heterogeneity because 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 that post-freezing annealing, in which the product is held at a predetermined temperature for a speci®ed duration, can reduce freezing-induced heterogeneity in sublimation rates. In addition, we test the impact of annealing on primary drying rates. Finally, we use the kinetics of relaxations during annealing to provide a simple measurement of T g H , the glass transition temperature of the maximally freeze-concentrated amorphous phase, under conditions and time scales most appropriate for industrial lyophilization cycles. Aqueous solutions of hydroxyethyl starch (HES), sucrose, and HES:sucrose were either frozen by placement on a shelf while the temperature was reduced (``shelf-ramp frozen'') or by immersion into liquid nitrogen. Samples were then annealed for various durations over a range of temperatures and partially 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 shelframp 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®ed amorphous structures, and larger and more numerous holes on the cake surface of annealed samples. Annealed HES samples dissolved slightly faster than their unannealed counterparts. Annealing below T g H did not result in increased drying rates. We present a simple new annealing± lyophilization method of T g H determination that exploits this phenomenon. It can be carried out with a balance and a freeze-dryer, and has the additional advantage that a large number of candidate formulations can be evaluated simultaneously. ß 2001 Wiley-