Water Content Determination of Rubber Stoppers Utilized for Sealing Lyophilized Pharmaceutical Products: Assessment of Two Karl Fischer Titration Methods.

摘要

In the pharmaceutical industry, the success of a new drug product is strongly impacted by the stability of the drug formulation. For many formulations, stability is governed by the drug product's water content, thus the ability to regulate this content determines the viability as a commercial product. Through lyophilization, the water content of a drug product may be controlled at the time of manufacture. However, over the product shelf life, additional water may be added or removed due to factors such as the storage environment and the drug's container/closure system, typically a vial, stopper, and cap. The water present in the rubber stopper may interact with the vial contents, potentially influencing the drug product's stability. Consequently, a formulation scientist must establish test methods capable of determining the initial and potentially subsequently changing moisture content for not only the lyophilized cake, but also the stopper.;Current literature describes two main analytical methods for measurement of the water content of rubber stoppers: a gravimetric method and a Karl Fischer (KF) titration method with oven. A third less common test method is the Karl Fischer titration method with tetrahydrofuran (THF) extraction. The results presented in this thesis thus describe the evaluation of the KF titration method utilizing an oven and the KF titration method utilizing a THF solvent extraction. The critical parameters of each test method were examined, and the advantages and disadvantages of these analytical methods were identified. Ultimately, it was concluded the drug product manufacturer must determine, based on knowledge of the drug product integrity and available manufacturing processes, the extent to which the water content of the rubber stoppers must be quantified, as well as define the test method to be employed to perform this moisture content measurement.