Date of Award

Fall 2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Aeronautics and Astronautics

First Advisor

Alina Alexeenko

Committee Chair

Alina Alexeenko

Committee Member 1

Elizabeth M. Topp

Committee Member 2

John P. Sullivan

Committee Member 3

Steven L. Nail

Abstract

Freeze-drying is a low-pressure, low-temperature condensation pumping process widely used in the manufacture of bio-pharmaceuticals for removal of solvents by sublimation. The goal of the process is to provide a stable dosage form by removing the solvent in such a way that the sensitive molecular structure of the active substance is least disturbed. The vacuum environment presents unique challenges for understanding and controlling heat and mass transfer in the process. As a result, the design of equipment and associated processes has been largely empirical, slow and inefficient.^ A comprehensive simulation framework to predict both, process and equipment performance is critical to improve current practice. A part of the dissertation is aimed at performing coupled fluid-thermal analysis of low-pressure sublimation-condensation processes typical of freeze-drying technologies. Both, experimental and computational models are used to first understand the key heat transfer modes during the process. A modeling and computational framework, validated with experiments for analysis of sublimation, water-vapor flow and condensation in application to pharmaceutical freeze-drying is developed.^ Augmented with computational fluid dynamics modeling, the simulation framework presented here allows to predict for the first time, dynamic product/process conditions taking into consideration specifics of equipment design. Moreover, by applying the modeling framework to process design based on a design-space approach, it has demonstrated that there is a viable alternative to empiricism.

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