(486b) Accurate Temperature Prediction of the Freeze-Dried Cake during Secondary Drying Process in a Laboratory Scale Lyophilizer

Freeze drying is a widely used process that improves the stability of the pharmaceutical products. Conventional freeze-drying consists of two sequential steps: (1) primary drying where ice sublimates from the product to leave behind a porous cake (10-30 hr) and (2) secondary drying where the remaining bound water is removed from the porous cake (2-10 hr). Currently, there is a lack of robust models for secondary drying with comparable accuracy and flexibility as primary drying. To alleviate this issue, we investigated secondary drying using a lab-scale lyophilizer and developed an accurate heat transfer models of this process. Experiments involved lyophilizing various sugars (e.g., sucrose and mannitol) under different operating conditions to determine the effects they have on energy transfer during secondary drying. The overall heat transfer coefficient at the bottom of the vial was determined by using a heat flux sensor to measure the slope of heat flux versus temperature difference between the shelf and the cake. Experimental results show that the heat transfer coefficient is significantly different when compared to the primary drying process, and that the vial’s thermal properties play a large role in the heat transfer. Lastly, we develop three theoretical models to describe the heat transfer in the vial based on solving the heat equation with bound water desorption, using published desorption kinetic parameters and equilibrium moisture content data. The models describe the temperature and moisture content in the lyophilized cake with varying degrees of complexity depending on the application of interest. Simulation results are validated by comparison of temperature predictions with experimental data for shelf temperatures 15^oC ≤ T_sh ≤ 35^oC. These models have great potential for the precise estimation of the cake temperature and drying time compared to trial-and-error approaches. It is expected that our models will aid in understanding and optimizing secondary drying for the lyophilized product.