Pfizer, Inc, PGRD, Parenteral Center of Emphasis, Groton, Connecticut 06340; University of Connecticut, School of Pharmacy, Department of Pharmaceutical Sciences, Storrs, Connecticut 06269.
J Pharm Sci. 2011 Apr;100(4):1362-76. doi: 10.1002/jps.22357. Epub 2010 Oct 1.
The freezing process is a source of product instability in many freeze-dried pharmaceuticals. During freezing, the solute is concentrated in the interstitial spaces between ice crystals, and phase separation may occur, with likely negative stability implications. Phase separation may involve crystallization but may also occur in completely amorphous systems even though there is little direct evidence to support this speculation in protein formulation applications. Previous work in our laboratory focused on the application of a novel Raman mapping technique to the study of amorphous phase separation in freeze-dried polymer systems. We report here the application of a similar Raman mapping technique to frozen systems, using a low-temperature stage. We study the impact of nucleation temperature and thermal history on phase separation using a model 1:1 polyvinylpyrrolidone:dextran phase separating system. Although cooling rate and nucleation temperature had a small effect on the extent of phase separation, it was clear that the large latent heat of crystallization controls the thermal history and propensity for phase separation in practical applications. The results suggest that phase separation can be somewhat controlled by minimizing fill depth and controlling nucleation temperature.
冷冻过程是许多冷冻干燥药物产品不稳定的一个来源。在冷冻过程中，溶质在冰晶之间的间隙中浓缩，可能会发生相分离，这可能对稳定性产生负面影响。相分离可能涉及结晶，但即使在完全无定形系统中也可能发生，尽管在蛋白质配方应用中几乎没有直接证据支持这种推测。我们实验室以前的工作集中于应用一种新型的拉曼映射技术来研究冷冻干燥聚合物系统中的无定形相分离。我们在这里报告了使用低温台将类似的拉曼映射技术应用于冷冻系统的情况。我们使用模型 1:1 聚乙烯吡咯烷酮：葡聚糖相分离系统研究了成核温度和热历史对相分离的影响。尽管冷却速率和成核温度对相分离的程度有一定的影响，但很明显，结晶的大潜热控制着实际应用中的热历史和相分离的倾向。结果表明，通过最小化填充深度和控制成核温度，可以在一定程度上控制相分离。
