No abstract

The purpose of this study was to develop a novel simulation program to accurately predict the maximum product temperature and the primary drying time in lyophilization using the predictive model for dry layer resistance, which is the resistance of dried cake against water vapor flow. Ten percent sucrose aqueous solution was selected as a model formulation. It was demonstrated that the deviations between the predicted and measured maximum product temperature were attributed to the error of dry layer resistance at a given drying condition, which was different from the measured dry layer resistance in a preliminary lyophilization run for the simulation program. However, when the predictive model of dry layer resistance was used for the simulation program, the model remarkably enhanced the accuracy of the simulation program to predict the maximum product temperature and primary drying time under various operating conditions. Furthermore, the primary drying condition required for minimized drying at a close collapse temperature was successfully discovered through one preliminary run. Therefore, it is expected that the developed simulation program is useful for designing the lyophilization cycle without a trial and error approach.Key words simulation; dry layer mass transfer resistance; maximum product temperature; primary drying time Lyophilization is widely employed in pharmaceutical industries to enhance the stability of drug products for parenteral injection. The lyophilization cycle mainly consists of three steps: freezing, primary drying, and secondary drying. Generally, the primary drying process is carried out through sublimation, and requires up to a few days. In order to maximize the sublimation rate in primary drying, it is important that the vial heat transfer rate is as high as possible, resulting in a minimized primary drying time and high product temperature. However, the maximum product temperature has to be kept below the collapse temperature, where a lyophilized cake loses macroscopic structure and collapses, to ensure the elegant appearance of the lyophilized cake and its stability. Hence, enormous efforts have been spent to minimize the primary drying time without the collapse of lyophilized cakes by adjusting the shelf temperature and chamber pressure in pharmaceutical development.In order to minimize the trial and error experiments, the mathematical model for the prediction of the optimized product temperature is thought to be useful. The mathematical model expressed by heat and mass transfer has been investigated for the expression of the sublimation phenomenon by many researchers. [1][2][3][4][5] In the heat and mass transfer model, two parameters, heat transfer coefficient and dry layer resistance, are important for estimating the product temperature during primary drying. The heat transfer coefficient for the estimation of the heat transfer rate depends on the lyophilizer and the glass vial container and its stopper, and is experimentally determined by a water sublimation test. [6][7][8] The ...

No abstract

This work presents the design and evaluation of a fully wireless, multi-point temperature sensor system as a Process Analytical Technology (PAT) for lyophilization. Each sensor contains seven sensing elements which measure the product temperature at various positions of the contents of a glass vial. The sensor performance was studied by freeze drying experiments with sensor placement in both center and edge of full shelf of 6R glass vials with 4 ml fill volume. Product temperature profile and primary drying time measured at the bottom center position in the glass vial by the wireless sensor as well as the primary drying time are in close comparison with the thermocouple data. The drying times during primary drying were determined at the top, higher middle, lower middle and bottom positions which are 3.26 mm apart vertically in the vial by the wireless sensor based on the temperature profile measured at different positions. For a center vial, the drying time from the start of primary drying to each layer was measured at 3.9, 9.3, 14.2, and 21 h respectively, allowing to track the sublimation interface during primary drying phase. In addition, sublimation rate at each layer was calculated based on the drying time and theoretical weight loss of ice in the product. The sublimation rate at the beginning of the primary drying was similar to the sublimation rate by gravimetric method. Furthermore, the vial heat transfer coefficient (Kv) was also calculated based on the sublimation rate. Thus, allowing the use of the multi-point wireless sensor to rapidly monitor the sublimation rate and Kv for every batch as continuous process verification. Similar tests were also conducted with 3% w/v mannitol solutions and the results were consistent demonstrating potential for real-time monitoring, process verification and cycle optimization for pharmaceutical lyophilization.