A Robust, Automated Karl Fischer Titration System

Karl Fischer titration is one of the few assay techniques recognized by the US Food and Drug Administration for the determination of residual moisture in lyophilized pharmaceutical products (1). Because the iodine–water reaction is specific and quantitative, this technique provides high accuracy and precision. However, conventional Karl Fischer titration is not considered a high-throughput assay and requires significant manual intervention. This test can present a challenge when many samples must be analyzed in a short time. Furthermore, most lyophilized products are hygroscopic and must be processed promptly after removal from the primary container.

The few off-the-shelf automated setups offered by Karl Fischer titrator vendors use a carousel onto which several samples, preweighed in individual containers, can be loaded. The titration is performed directly in these containers as the carousel rotates each sample through the titration station. Unfortunately, no satisfactory means has been devised for sealing the samples from the environment while they await analysis. Hence, hygroscopic lyophilizates cannot be processed on these types of automated titrators.