Determination of Mass- and Heat Transfer Coefficients for Computer Modelling of Pharmaceutical Freeze-Drying

Abstract: This thesis work deals with the determination of mass- and heat transfer coefficients for pharmaceutical vial freeze-drying and the one-dimensional steady state computer modelling of primary drying. The overall heat transfer coefficient K_V for the vial/freeze-dryer system was successfully determined using a gravimetric method. The overall resistance to mass transfer R_p was successfully determined for a 3% sucrose solution using a heat conduction model. The pressure rise test with the manometric temperature algorithm was also investigated as an alternative method to monitor product temperature and determine transfer parameters without success. A novel approach using an aluminum vial holder was evaluated as a method to increase temperature homogeneity during primary drying. When using the vial holder, vials situated at the center and edge of the freeze-dryer shelf did not differ in freeze-drying behaviour. It could also be shown that the vial holder increased heat transfer above 10 Pa, and decreased heat transfer below 2 Pa. However, additional investigation is required to fully understand the vial holder's effect on heat- and mass transfer parameters. MATLAB was used to simulate primary drying of 3% sucrose solution at 10 Pa and -20 degree C based on determined K_V and R_p values. A one-dimensional steady state model based on governing mass- and heat transfer equations was used. When simulating primary drying of a full freeze-dryer shelf, the drying time was overestimated by 14%. Simulation of three vials placed in the vial holder instead underestimated the drying time with 9%. Predicted product temperatures were accurate for the first hours of primary drying, after which the accuracy significantly decreased. This is partly believed to be due to the phenomenon of microcollapse in the dry cake.