Merck & Company, Inc., Merck Research Laboratories, West Point, Pennsylvania, USA.
J Pharm Sci. 2012 Mar;101(3):1050-62. doi: 10.1002/jps.22815. Epub 2011 Nov 23.
Freezing and thawing of vaccines containing aluminum adjuvants can lead to formation of aggregates and loss in vaccine potency. We sought to understand whether and to what extent the freeze-thaw damage to aluminum adjuvants would differ based on suspension state (flocculation and settlement) at the time of freezing. As flocculation and settlement characteristics of aluminum adjuvants are driven largely by the electrostatic charges on the adjuvant particles, which, in turn, are strongly influenced by the pH of the suspension, we conducted freeze-thaw studies on both Adjuphos and Alhydrogel™ samples at three pH levels (4, 6.5, and 7.2) in buffer solutions with 9% sucrose. Significantly less aggregation occurred in the buffered sucrose solutions at the pH furthest from the aluminum adjuvant point of zero charge during slow freezing at -20°C. The freezing-induced aggregation for the samples with 9% sucrose at each pH was minimal during fast freezing at -70°C and -115°C. Suspensions that were flocculated and settled to a greater extent experienced the most freeze-thaw aggregation, whereas suspensions that were frozen before significant flocculation and settlement occurred showed little or no aggregation. Because pH of formulation can affect flocculation and settling time, it indirectly affects the extent of freeze-thaw aggregation.
含有铝佐剂的疫苗的冷冻和解冻会导致聚集物的形成和疫苗效力的丧失。我们试图了解在冷冻时的悬浮状态（絮凝和沉降）是否以及在何种程度上会导致铝佐剂的冷冻-解冻损伤不同。由于铝佐剂的絮凝和沉降特性主要取决于佐剂颗粒上的静电荷，而静电荷又强烈受到悬浮液 pH 的影响，因此我们在缓冲液中分别在三个 pH 值（4、6.5 和 7.2）和 9%蔗糖下对 Adjuphos 和 Alhydrogel™样品进行了冷冻-解冻研究。在缓慢冷冻至-20°C 时，远离铝佐剂零电荷点的 pH 值的缓冲蔗糖溶液中，聚集的情况明显较少。在-70°C 和-115°C 下快速冷冻时，每个 pH 值的 9%蔗糖样品的冷冻诱导聚集最小。经历更多冷冻-解冻聚集的絮凝和沉降程度较大的悬浮液，而在发生明显絮凝和沉降之前冷冻的悬浮液则几乎没有或没有聚集。由于配方的 pH 值会影响絮凝和沉降时间，因此它会间接影响冷冻-解冻聚集的程度。
