Searles J A, Carpenter J F, Randolph T W
Center for Pharmaceutical Biotechnology and Department of Chemical Engineering, University of Colorado, Boulder, Colorado 80309, USA.
J Pharm Sci. 2001 Jul;90(7):872-87. doi: 10.1002/jps.1040.
In a companion paper we show that the freezing of samples in vials by shelf-ramp freezing results in significant 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 specified 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)', 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 shelf-ramp 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, simplified 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)' did not result in increased drying rates. We present a simple new annealing-lyophilization method 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 that a large number of candidate formulations can be evaluated simultaneously.
在一篇配套论文中，我们表明，由于冷冻过程中冰晶尺寸取决于成核温度，通过搁板梯度冷冻法在小瓶中冷冻样品会导致显著的一次干燥速率不均匀性。1 本研究的目的是检验以下假设：冷冻后退火，即将产品在预定温度下保持特定持续时间，可以减少冷冻引起的升华速率不均匀性。此外，我们还测试了退火对一次干燥速率的影响。最后，我们利用退火过程中的弛豫动力学，在最适合工业冻干循环的条件和时间尺度下，提供一种简单的方法来测量最大冷冻浓缩非晶相的玻璃化转变温度 T(g)'。羟乙基淀粉（HES）、蔗糖以及 HES:蔗糖的水溶液，要么通过在温度降低时放置在搁板上进行冷冻（“搁板梯度冷冻”），要么通过浸入液氮进行冷冻。然后将样品在一系列温度下进行不同持续时间的退火，并进行部分冻干以确定一次干燥速率。使用扫描电子显微镜检查完全干燥的液氮冷冻样品的形态。退火降低了搁板梯度冷冻样品的一次干燥速率不均匀性，并使一次干燥速率提高了高达 3.5 倍。这些效果归因于冰晶尺寸增大、非晶结构简化以及退火样品饼层表面上更大且更多的孔洞。退火后的 HES 样品溶解速度比未退火的样品略快。在 T(g)'以下进行退火不会导致干燥速率增加。我们提出了一种利用这一现象的简单的新的退火 - 冻干法来测定 T(g)'。它可以用天平和平板冻干机进行，并且还有一个额外的优点，即可以同时评估大量候选配方。
