Tackling Moisture Challenges in Solid Dosage Manufacturing

Armin Gerhardt, associate professor of Pharmaceutical Science, Concordia University Wisconsin School of Pharmacy, discusses the effects of moisture on product quality and how to achieve good control of moisture during pharmaceutical manufacturing operations.
PharmTech: What are the different sources of moisture in a solid dosage form? 
Gerhardt: The most common sources of water in a solid dosage form are 
atmospheric moisture vapor; the manufacturing process; and the excipients. Many pharmaceutical facilities are located in geographical locations where periods of high heat and relative humidity are found. With atmospheric moisture vapor, it is possible for exposed solid-phase materials to sorb gas-phase water on their surface or within the particles. While the manufacturing and storage environment may be tightly controlled, there can be disruptions due to mechanical or human factors; for instance, a maintenance event of the air-handling system, or an operator error, that produces a temporary surge in atmospheric water content. 
During the manufacturing process, the most obvious sources of water increase are when liquid-phase water is added during a granulation or coating unit operation. While both these operations are associated with a subsequent drying step, it is important to conduct an accurate water content assessment of the product. Granulation samples taken from the drying unit operation need to ensure the sample particle size distribution is identical to the bulk material. 
Riffling or cone and quartering are two options for preparing samples of appropriate size, but pouring from a container frequently enriches the sample with larger particles, thus producing an inaccurate moisture assay result. Milling, an operation carried out to increase solid particle surface area, also increases the potential for sorption to occur. The kinetics of sorption can be quite rapid; a few minutes of uncontrolled exposure may produce significant increases of moisture. Also hold times between unit operations may increase the quantity of moisture sorption. 
Excipients are a potential source of moisture. Many pharmaceutical materials arrive with various quantities of water distributed in them. Polymeric materials are prime examples: microcrystalline cellulose typically has 4.5-5.0% water content, hard-gelatin capsules typically have 13-16% water content, and this water may equilibrate within the dosage form and influence processing and performance.
PharmTech: What are the effects of moisture on the physical and chemical properties of a drug product and the manufacturing process?
Gerhardt: Moisture content of the powder blend during compression is crucial to this unit operation and to product stability; however, moisture has 
opposite effects in these two facets. During compression, it is generally preferred to have a relatively higher moisture content so that higher tablet hardness can be produced at lower compression force. There is a limit though, because higher moisture content tends to produce two detrimental results: 
A reduction in powder flow rate increases moisture, which then increases powder particle adhesion, leading to erratic tablet weight uniformity
An increase in sticking defects, which can be particularly challenging with embossed compression tooling because there are more pockets where powder may adhere. 
Regarding chemical stability, a relatively lower moisture content is preferred to reduce the extent of drug degradation and make it more difficult for microbial growth to occur. Effervescent tablets, for example, are extremely sensitive to moisture content. The chemical reaction between the organic acid and inorganic base is autocatalytic and it yields gaseous carbon dioxide and water. A very low moisture content is, therefore, required to prevent the 
reaction from starting, but once started, the water produced by it further promotes the reaction until the components are exhausted. 
One further caution with effervescent tablets is that the high salt content necessary to achieve effervescence may be a health challenge to those on a restricted salt diet. The challenge during the development phase is to balance the contrasting water preferences of processing and stability, and define a moisture range where reasonable tablet hardness, weight uniformity, and chemical stability are achieved, and this part requires considerable effort and data generation.
PharmTech: How do you achieve good control of moisture during the manufacturing of solid dosage forms?
Gerhardt: Start with the principles of quality by design. Select excipients after a thorough review of their properties, including moisture level and impurities. Characterize the drug substance for its potential to sorb moisture and sensitivity to degradation. The drug substance need not decompose by hydrolysis to be sensitive to moisture. Water can move within a dosage form from one material to another. Rather than forming an even distribution across all surfaces or within particles, water may accumulate in microscopic pockets. And when it does, the solid-phase material at its periphery may become more mobile as the glass transition temperature in these zones is lowered, which may then lead to increased chemical reactivity and drug degradation. 
Anticipate the risks of all activities, equipment, and processes. Build on prior experience of all products and unit operations. Consider not just what happens 
within the confines of the manufacturing facility, but expand the scope to include excipient vendor activities/upgrades/modifications and equipment vendor expertise. Probe the technical service personnel of equipment vendors for their perspective on recent challenges and solutions that others within our industry have generated. Be particularly sensitive to queries from regulators as they have an inside perspective of all the companies within our industry. While they can not divulge the source or details of these questions, it is reasonable to infer another firm had challenges that spurred the question, and it may provide an opportunity to be proactive prior to having a similar challenge.
PharmTech: What about the packaging of the drug product? What materials are typically used for moisture-sensitive formulations?
Gerhardt: Typically the unit dose container-closure systems are the most 
challenging for stability. Composites with a layer of aluminum foil are routinely considered a very robust option for moisture-sensitive drug products. 
A quick survey of the over-the-counter effervescent products in a community pharmacy can be helpful during the development process. Data are available to compare the moisture vapor transmission rate of a wide range of materials. In addition, the seal between layers is an important consideration because this aspect is a frequent source for barrier failure. Also with unit-dose materials, the shape of the cavity containing the tablet or capsule is a factor. During the process of heating the flat sheet stock to form the cavities, there is significant stretching and thinning of the polymeric material. The thickness reduction can be as much as 50% or more where there are bends, and it is these thin portions where the most risk occurs for moisture ingress. With multiple dosage unit containers, comparison of the moisture vapor transmission rate for packaging resins is recommended. The head space and the quantity of potential moisture that could be added to the drug product needs inclusion, hence the requirement for controlling air quality during packaging. One additional option is to include a desiccant packet or canister. 
During early stages of development, it should be a top priority to initiate stability studies using a range of potential container-closure systems. Data from 12-, 18-, 24-month, or longer storage at the final storage temperature/relative humidity combination are very valuable.

Article Details

Pharmaceutical Technology
Vol. 40, No. 5
Pages: 34

Citation:
When referring to this article, please cite it as A. Siew, "Tackling Moisture Challenges in Solid Dosage Manufacturing," Sidebar to "A QbD Method Development Approach for a Generic pMDI" Pharmaceutical Technology 40 (5) 2016.