A Study of the In-Vial Crystallization of Ice in Sucrose–Salt Solutions—An Application for Through-Vial Impedance Spectroscopy (TVIS)

Ice nucleation temperatures and associated ice growth rates are critical parameters in defining the initial ice morphology template, which governs dry layer resistance during sublimation and therefore impacts primary drying kinetics and overall process time. In this study, we developed a through-vial impedance spectroscopy (TVIS) method to determine both ice nucleation temperature and average ice growth rate, from which future estimation of average ice crystal size may be possible. Whereas previous TVIS applications were limited to solutions containing simple, uncharged solutes such as sugars, our adapted approach enables the analysis of conductive solutions (5% sucrose with 0%, 0.26%, and 0.55% NaCl), covering osmolarities below and above isotonicity. We established that the real part capacitance at low and high frequencies—either side of the dielectric relaxation of ice—provides the following: (i) a temperature-sensitive parameter for detecting the onset of ice formation, and (ii) a temperature-insensitive parameter for determining the end of the ice growth phase (unaffected by temperature changes in the frozen solution). This expanded capability demonstrates the potential of TVIS as a process analytical technology (PAT) for non-invasive, in situ monitoring of freezing dynamics in pharmaceutical freeze-drying.