Applications of temperature modulated differential scanning calorimetry in freeze-drying process development

The purpose of the present study was to investigate the potential of Temperature Modulated Differential Scanning Calorimetry (TMDSC) as an analytical tool in freeze-drying process development. After developing an adequate calibration method, the frequency dependence of low temperature transitions in model solutions was probed in an effort to support physical interpretations of the events that are observed in concentrated solutions. This information is useful both for the understanding of macroscopic collapse in vials and microscopically observed collapse during freeze-drying. Using sucrose solutions as the model system, a low temperature transition was found to possess frequency dependent characteristics consistent with a glass transition. A slightly higher temperature transition was found to possess frequency characteristics consistent with a melting event. Quasi-isothermal heat capacity data for sucrose solutions demonstrated kinetically limited ice crystallization in the glass transition region.;A TMDSC method was used to determine the apparent partial derivative of the rate of ice crystallization as a function of temperature for model solutes. As further evidence for the interpretation of the higher temperature thermal event, a peak in the ice crystallization rate was observed at temperatures consistent with the warming curves. A novel approach to determining the limit of detectable ice crystallization, Tc,lim, in frozen systems was developed by locating an apparent minimum in the partial derivative of the ice crystallization rate. An advantage of the method is that the collapse temperature can be estimated even if the glass transition is not detected during warming.;Finally, the frequency dependence of the glass transition was used to determine the fragility of model systems of non-crystallizing solutes in water. Using a closed system model the microscopically measured collapse temperature was predicted from determinations of the reduced collapse temperature and the fragility parameter.