Determination of ice interface temperature, sublimation rate and the dried product resistance, and its application in the assessment of microcollapse using through-vial impedance spectroscopy.

Through-vial impedance spectroscopy (TVIS) is a new approach for characterizing product attributes during freeze-drying process development. In this study, a pair of copper foil electrodes was attached to the external surface of a Type I glass tubing vial, of nominal capacity 10 mL and containing 3.5 g of an aqueous solution of 5%w/v lactose, and the impedance spectrum of the vial and contents recorded during a lyophilization cycle. The cycle included a temperature ramp in the primary drying stage in order to induce a collapse event in the dry layer. Using the peak in the dielectric loss spectrum, associated with the dielectric relaxation of ice, methods were developed to predict the sublimation rate and the ice interface temperature at the sublimation front, from which the dry layer resistance was then calculated. A four-fold increase in sublimation rate and a reduction in the dry layer resistance wereobserved once the ice interface temperature reached -33 °C, which coincides with the onset of the glass transition (as determined by DSC) and the time point at which micro-collapse occurred (as evidenced by SEM images at the end of the cycle). This work suggests a prospective application of impedance measurements in driving process efficiencies by operating the dryer at the highest achievable temperature (i.e. the collapse temperature) whilst avoiding macro-collapse.