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30 September 2020 Tablets & Capsules Water migration also occurs when a sample has a different water activity than the environmental rela- tive humidity (RH) in which it is stored. If the sample has water activity of 0.5 and is stored in a controlled environment with an RH of 80 percent, the sample will absorb water until reaching equilibrium and a water activity of 0.8. If a sample with water activity of 0.8 is stored in a controlled environment with an RH of 50 percent, it will expel water until reaching equilibrium and a water activity of 0.5. A sample's actual water activ- ity values can therefore contain useful information about the sample's most-recent history, such as the protective- ness of packaging, intermediate opening and closing, and storage conditions. The speed at which water activity equilibrates depends on the difference in water activity between the materials, the ability of water molecules to diffuse within the mate- rials, the available surface area for moisture migration, the amount of moisture that needs to migrate, and the moisture barrier properties of the packaging [13]. Table 1 shows the water activity inside different packaging types after storage for 6 months at 40°C and 75 percent RH. As indicated by the difference between 0.75 A w in polyvinyl chloride compared to 0.2 A w in polychlorotri- fluoroethylene, water activity inside packaging is highly dependent on the packaging material's moisture vapor transmission rate (MVTR) [14]. The MVTR of packaging can be used to predict a product's speed of water uptake and set shelf-life and storage conditions. Moisture content The loss on drying (LOD) and Karl-Fisher (KF) meth- ods are two commonly used methods of measuring mois- ture content. LOD is a gravimetric method involving the heating of a known quantity of material until all free water is evaporated. For lactose, for example, this method includes 2 hours of heating at 80°C [15]. By weighing the sample before and after drying, you can determine the amount of free moisture in the sample. The KF method uses titration to measure the total amount of water in a sample. The method is based on the fundamental reaction involving the reduction of iodine by sulfur dioxide in the presence of water. The sample is titrated with an iodine-containing KF solution. When water is present in the system, all added iodine is consumed. When no water remains, excess free iodine is detected by two platinum electrodes immersed in the solution [16]. You calculate the amount of water in the sample from the amount of KF solution added before the excess iodine appeared. For excipients such as lactose, you can use the LOD and KF values to calculate the amount of crystal water in a material. The difference between the total amount of water measured by KF and the total amount of free water measured by LOD provides the amount of crystal water in the sample, as shown in Figure 3. Packaging material Moisture vapor trans- mission rate Water activity in packaging after 6 months Open >100 0.75 Polyvinyl chloride 3.06 0.75 High-density polyethylene 1.25 0.6 Polyvinylidene chloride 0.83 0.4 Polychlorotrifluoroethylene 0.14 0.2 Table 1 Water activity inside different types of packaging after 6 months of storage (40°C and 75 percent RH) Figure 2 Relative reaction rates as a function of water activity (adapted from [11, 12]) Relative reaction rate Water activity 0 0.25 0.5 0.75 1 Lipid oxidation Nonenzymatic browning Hydrolytic reactions Enzymatic activity Molds Yeasts Bacteria Figure 3 Using Karl-Fischer titration, which determines total moisture content, and loss on drying, which targets only free water, to determine the amount of crystal water in a sample (%w/w) % Crystal water Free water Karl-Fischer Loss on drying

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