Title

Critical engineering and chemical problems in freeze drying process design

Date of Completion

January 2003

Keywords

Chemistry, Pharmaceutical

Degree

Ph.D.

Abstract

Choice of the target product temperature (Ttarget) and determination of the shelf temperature necessary to achieve the Ttarget in primary drying are the two critical factors for freeze drying process optimization. The target product temperature chosen in primary drying is dependent upon the “chemical” aspects of the formulation, which includes the Tg and Teu of the formulation and the stability of the labile drug, i.e., protein denaturation or unfolding. ^ Protein unfolding during cold denaturation in high viscosity systems, in which sucrose was used to enhance the system viscosity, was used as a model in a study of the protein unfolding kinetics. It was found that the stabilization effect of sugars and/or polyols on protein cold denaturation is much larger than on thermal denaturation, which can be counteracted by using of denaturants, thus allowing us to maintain a relatively constant protein cold denaturation temperature during our kinetic studies. The unfolding kinetics were investigated at various viscosities by both tryptophan fluorescence emission spectroscopy and high sensitivity modulated DSC methods. It was demonstrated that protein unfolding kinetics is highly coupled with system viscosity in high viscosity systems. The data suggest that it is not necessary to freeze dry protein formulations at temperature below Tg to avoid protein unfolding. ^ Manometric temperature measurement (MTM) was evaluated as a method to achieve the optimum shelf temperature to achieve the Ttarget, to determine drying end points and to evaluate residual moisture in real-time. It was found that the product temperature (Tp) measured by MTM needs sufficient ice sublimation area and the MTM yields a temperature close to the lowest product temperature in a product temperature heterogeneous system. The accuracy of MTM product dry layer resistance is improved if the temperature gradient across the ice from bottom to the sublimation interface (ΔT) is evaluated from the pressure rise data and the thermal shields are used during freeze drying. The extent of primary drying can be monitored by calculation of the amount of ice remaining using MTM data. However, MTM yields product temperatures which are too low at the later stage of primary drying when high concentrations of amorphous materials are freeze dried, a result of water vapor resorption by amorphous dry product during MTM valve closure. ^ It was demonstrated that Manometric Temperature Measurement (MTM) and an “Expert System” for good practices in freeze drying allow development of an optimized freeze drying process during a single laboratory freeze drying experiment, a procedure we denote the “smart freeze dryer” procedure. ^