Implementation of Water-Activity Testing to Replace Karl Fischer Water Testing for Solid Oral-Dosage Forms

Feb 02, 2007

Most pharmacopeial monographs that have procedures for the measurement of water are based on the measurement of total water either by the Karl Fischer titration or by loss on drying. Karl Fischer titrations have dominated the measurement of water in pharmaceutical products for many years. Although the technique is reliable under carefully controlled conditions, it is subject to a variety of problems such as sample handling and side-reactions that cause erroneous results. Results commonly vary with changes in room relative humidity (RH). In addition, general models for describing the effect of water on physical, chemical, and microbiological characteristics recognize that different types of water may be present (1–3) and that the measurement of total water may not be the best approach for understanding the effects of water.

According to most common definitions, water can be present in at least three forms: free water, adsorbed water, and bound water. Free water is present in the void volume or in the pores. Free water can serve as a dispersing agent, as a solvent for crystalline compounds, or for microbiological growth. Adsorbed water is located on the surface of the material. Bound water is defined as the water of hydration bound to the product by strong H-bonds. Bound water relates to the monolayer of water molecules, whereas adsorbed water is present in the form of multilayers in the matrices. Water also may be present as a crystal hydrate that effectively is the same as bound water. An example of another type of water is structural water associated with hydrogen bonding between helices of polymer in a gel network (4). This explanation follows the theory of the BET isotherm describing vapor desorption or adsorption isotherms (3).

Figure 1: Water sorption isotherm.
When water interacts with solutes and surfaces, it is unavailable for other hydration interactions. The term water activity (aw) describes the (equilibrium) amount of water available for the hydration of materials. Water activity is unitless and a value of unity indicates pure water, whereas zero indicates the total absence of water molecules. Water activity is the effective mole fraction of water, defined as: a w = λ w x w = p /p0 in which λw is the activity coefficient of water, xw is the mole fraction of water in the aqueous fraction, p is the partial pressure of water above the material, and p0 is the partial pressure of pure water at the same temperature (i.e., the water activity is equal to the equilibrium relative humidity [ERH]), expressed as a fraction. The relationship between water activity and weight percent water is shown in a sorption isotherm (see Figure 1). Figure 1 also shows the hysteresis observed when the sorption isotherm depends on whether the water is added to the dry material or removed from the wet material. This hysteresis is caused by nonreversible structural changes and/or kinetic effects.