In pharmaceutical products, water plays a key role in the quality, stability, and safety of products, as excessive or insufficient moisture in the product or its environment can cause quality deterioration or lead to instability. An excess of moisture can trigger unwanted chemical reactions during storage, resulting in the formation of degradation products that reduce the efficacy and safety of the drug. Low humidity can also lead to issues, often drying and cracking of tablets. Although water exists in various forms, it is the free water that causes the most problems, as it participates in chemical reactions. The availability of free water is determined by measuring water activity (aw), which represents the ratio between the partial vapor pressure of water in the product and the saturated vapor pressure at the same temperature. To assess total water content in a product, both free and bound water, Karl Fischer (KF) titration is used. As part of the master's thesis, we developed and validated methods for determining aw and water content using KF titration on film-coated tablets. During aw method development, we examined various influencing factors and established optimal measurement conditions. Based on the results of the development of the aw method, measurements were performed on whole tablets at 15-30 % relative humidity. During the development of the aw method, it was found that a small change in tablet amount does not significantly affect the measured values and that grinding with a mill is a more suitable sample preparation method than crushing with a mortar. Consequently, milling was also applied for the determination of water content. For proper KF titration, the mass of tablet powder was optimized, an appropriate solvent was selected, and suitable humidity conditions were established for the sample preparation. Both developed methods were confirmed to be accurate, precise, robust, and linear. KF titration was shown to be sufficiently sensitive for reliable quantitative determination of water content. After comparing the correlation data between aw and water content, it was demonstrated using the GAB and BET models that their relationship is good and enables reliable prediction of drug product stability. It can be concluded that the method for determining aw is more suitable, efficient, and faster in everyday routine testing of drug products compared to the KF method. At the same time, aw is a more informative method, as it reflects the actual availability of free water in the product that influences drug product stability.
|
