The Study of Amorphous Phase Separation in a Model Polymer Phase-Separating System Using Raman Microscopy and a Low-Temperature Stage: Effect of Cooling Rate and Nucleation Temperature

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. (c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:1362-1376, 2011