Pharmaceutical Application: Water Activity Measurement
This powerful but under-used quality parameter is gaining interest in the Pharmaceutical Industry with the release of the USP <922> Water Activity method.
Water activity is broadly used and accepted in the food industry to control both product safety and quality. While for the pharmaceutical industry water activity has been well established to have the same efficacy, it has not yet been accepted as integral to a drug release program. While USP <1112>, an informational chapter on the application of water activity in pharma, has been in publication since 2006, it did not include an SOP or any validation guidance. To eliminate this limitation, USP has developed USP <922> Water Activity as an official method for water activity measurement and this will hopefully further facilitate the implementation of water activity as an integral part of a pharmaceutical quality program.
Both USP <922> and USP <1112> highlight the potential applications for water activity. These include stability control, microbial risk prevention, optimized formulation, reduced caking and clumping, and moisture migration control, which all have significant product improvement advantages. The resulting key benefits are: Less consumer complaints, greater confidence, higher production output with consequently better products for the consumer, and greater profits for the manufacturer. Conclusively, water activity is a powerful, and often essential, quality parameter for pharmaceutical products.
USP <922> Water Activity
Introducing USP <922>, the first officially published method for determination of water activity in pharmaceuticals. It includes a brief theoretical background explanation, outlines the best practices for water activity measurement, and provides an overview of potential applications for water activity in pharmaceutical products.
In terms of suggested uses for water activity, USP <922> extends beyond the usage suggestions of USP <1112> to include:
- Selecting ingredient isolation and product manufacturing processes conditions in terms of maintaining aw below the critical threshold to obtain thermodynamic control of the desired solid form (e.g., hydrate versus anhydrate)
- Selecting excipients for which aw may impact their material flow, compression characteristics, hardness, and performance characteristics (e.g., disintegration and dissolution) of dosage forms
- Optimizing fluidized bed drying processes
- Reducing the degradation of active ingredients within product formulations (e.g., those susceptible to chemical hydrolysis)
- Establishing the level of protection to product formulations to moisture by primary packaging materials during their shelf life
- Optimizing the shelf-life stability of probiotics
- Providing a complementary method for monitoring changes in water content
- Controlling and monitoring physical, chemical, and microbial product stability
- Optimizing formulations to improve the antimicrobial effectiveness of preservative systems
- Reducing the susceptibility of formulations to microbial contamination
- Providing a tool to justify the reduction of microbial testing of nonsterile drug and dietary supplements formulations (see Application of Water Activity Determination to Nonsterile Pharmaceutical Products 1112)
Let’s take a look at each of these applications in turn.
Critical Water Activity for Crystalline Excipients
Excipients, among many functions, act as bulking agents and protect Active Pharmaceutical Ingredients (API) in pharmaceutical solid dosage products. Typically, the matrix of these excipients is either crystalline or amorphous. For crystalline excipients, the addition or loss of waters of hydration or deliquescence can result in undesirable changes in product quality such as modification of dissolution properties or reduction in the efficacy of the API. These changes are thermodynamically controlled processes and are therefore related to water activity.
Critical Water Activity for Amorphous Excipients
Amorphous excipients are typically low moisture and are in a meta-stable glassy state. Their ability to provide protection to the API depends on their remaining in the glassy state throughout the life of the product. A transition of the excipient matrix from the glassy state to the rubbery state, called a glass transition, will result in structural collapse, increased mobility, changes in dissolution, and increased susceptibility to caking and crystallization. Consequently, the product will not flow, compress, or tablet properly and dissolution may occur prematurely. A glass transition can be induced through either a change in temperature or a change in water activity.
Water Activity and Microbial Safety
Microorganisms require access to water of a sufficient energy to allow for movement of water into the cell. This water is critical for maintaining turgor pressure and normal metabolic activity. The energy of the water surrounding the microorganism is described by the water activity and for water to move into the microbe, the interior water activity of the organism must be lower than water activity of its surroundings. When a microorganism encounters an environment with a lower water activity than its internal water activity, water leaves the cell, thereby lowering the turgor pressure and causing metabolic activity to cease. Consequently, any efforts to provide control limits for the risk of microbial contamination, and an accompanying reduction in microbial limits testing, must be based on water activity measurements.
Water Activity and Degradation of Active Ingredients
The water activity of solid dosage pharmaceuticals will typically be less than 0.70 aw, indicating that microbial growth is not likely to occur. However, products in this range do not have unlimited shelf life. For these products in the 0.40-0.70 aw range, chemical degradation of the API is a strong candidate for the mode of failure because reactions rates are at a maximum. In general, as water activity increases so do reaction rates, but lipid oxidation is unique in that the reaction rate also increases at very low water activity. The most effective way to prevent these reactions from resulting in significant loss of the API is to process them to a low water activity where reactions will be at a minimum and then choose the appropriate excipient that will do the best job of maintaining that water activity.
Water Activity and Shelf-Life Stability
When chemical reactions rendering the API ineffective is the mode of failure, the time required for the reaction to have progressed to the point of unacceptability at a given water activity and temperature will be the product’s shelf life. If the rate constants for these reactions at several different storage conditions are determined, a predictive model can be used to estimate the time needed for the reaction to proceed to an unacceptable level under any storage conditions. To do this, the progress of the reaction will need to be tracked using some type of quantitative assessment.
Tracking Moisture Change with Water Activity
The water activity of an API can increase to unsafe levels is through moisture migration in multiple component pharmaceuticals such as capsules. If the components are at different water activities, water will move between the components, regardless of their moisture content. Water moves from high water activity (energy) to low water activity and not from high to low water concentration. Moisture will continue to move between the components until an equilibrium water activity is achieved. If the water activity of the API increases, it could possibly move to high enough levels to speed up degradation. To avoid this problem, the components must be designed to be the same water activity.
USP <922> Water Activity and Packaging Selection
Once the ideal water activity is identified, it is critical that the product stays at that water activity during transit and storage. Water activity changes can occur due to exposure to ambient room humidity. Placing the product in moisture barrier packaging will slow down the change in water activity. Determining the correct packaging to use to prevent undesirable changes in water activity is critical to ensuring the desired shelf life for any pharmaceutical product.