Evaluation of manometric temperature measurement as a method of monitoring product temperature during lyophilization.

The objective of this study was to evaluate manometric temperature measurement as a non-invasive method of monitoring product temperature during the primary drying phase of lyophilization. This method is based on analysis of the transient response of the chamber pressure when the flow of water vapor from the chamber to the condenser is momentarily interrupted. Manometric temperature measurements (MTM) were compared to product temperature data measured by thermocouples during the lyophilization of water, mannitol, lactose and potassium chloride solutions. The transient pressure response was mathematically modeled by assuming that four mechanisms contribute to the pressure rise: 1) direct sublimation of ice through the dried product layer at a constant temperature, 2) an increase in the temperature at the sublimation interface due to equilibration of the temperature gradient across the frozen layer, 3) an increase in the ice temperature due to continued heating of the frozen matrix during the measurement, and 4) leaks in the chamber. Experimental transient pressure response data were fitted to an equation consisting of the sum of these terms containing three variables corresponding to the vapor pressure of ice, product resistance to vapor flow, and the vial heat transfer coefficient. Excellent fit between the mathematical model and the experimental data was observed, and the value of the variables was calculated from the measured transient pressure response by a least squares method. The product temperature measured by MTM, which measures the temperature at the sublimation interface, was compared with product temperature measured by thermocouples placed in the bottom center of the vials. Manometrically measured temperatures were consistently lower than the thermocouple measurements by about 2 degrees C, this difference being largely accounted for by the temperature gradient across the frozen layer. The resistance of the dried product to mass transfer calculated from MTM was found to agree reasonably well with values measured by a direct vial technique. Product resistance was observed to increase with increasing solute concentration, and to increase continuously as the depth of the dried product layer increases for mannitol and potassium chloride. For lactose, product resistance increases continuously with thickness up to the onset of collapse, at which point the product resistance becomes essentially independent of depth. Scanning electron microscopy was used to explain this observation based on changes in morphology of the solid. The vial heat transfer coefficients obtained from regression analysis were on the order of 10(-3)-10(-4) cal.sec-1. degrees C-1; however, the scatter in the vial heat transfer coefficient data prevents the method from being used for accurate measurement of the vial heat transfer coefficient. The results of the study show that the manometric method shows promise as a process development tool and as an alternative method of in-process product temperature measurement during primary drying.