Determination of Moisture in Rubber Stoppers: Effect of Karl Fischer Oven Temperatures

Abstract

Moisture released from rubber stoppers of pharmaceutical products may adversely affect product quality during storage. The objective of the current study was to identify an appropriate method to quantify free moisture in processed stoppers. The moisture content in stoppers is commonly determined by the Karl Fischer (KF) method. However, for the FM257/2 stoppers from Helvoet, our results suggest that the KF assay results are always lower than that from the gravimetric method and increase with the KF oven temperatures used. The systematic study presented in this manuscript shows that, although moisture results vary with respect to KF oven temperatures, reproducible results are obtained at fixed temperatures. Therefore, the observed variation can not be explained by the release of volatile chemicals from this rubberaffecting KF reagents. Furthermore, by extrapolating moisture results obtained with different thicknesses of rubber slabs to zero thickness, it was found that the diffusion barrier is also not a major source for the variation. It is hypothesized that the moisture in rubber stoppers can be free or bound. The KF method measures both free and bound moisture. As higher KF oven temperatures are used, more bound moisture is released and determined by the KF method. By deducting the bound moisture (measured by the KF method for samples dried at 100°C for one week) from the sample moisture, the amount of free moisture (which is releasable) can be estimated. A KF oven temperature at 250°C is recommended based on the accuracy and precision of the results. This method was validated by showing consistency with the gravimetric method for stoppers undergoing desorption at 25°C and 0% relative humidity (equilibrated with P₂O₅). An example is also presented to show the application of this method.