Karl-Fischer titration (KFT)
Karl-Fischer titration (KFT) is the primary technique for the determination of residual moisture in lyophilized drug products.
KFT is based on a technique developed by Karl Fischer, a German chemist in the 18th century. It is performed by adding a solution containing iodine and sulfur oxide of known concentrations to the lyophilized product. In presence of a base and an alcohol, the Karl Fischer reaction occurs under the consumption of water and iodine in a 1:1 molar ratio. When all water molecules are consumed, the excess iodine is quantified by a detector electrode, allowing for a calculation of the water content.
KFT is an extremely accurate technique for residual moisture determination and in general not influenced by the excipients in the freeze-dried drug product.
Compared to the orthogonal technique of headspace moisture analysis [HMA], KFT does not rely on reference standards for quantification. Thus, method development is reduced to a minimum. However, KFT is a destructive technique.