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Valere Logel is head of innovation at Clariant Healthcare Packaging.
Stephane Rault is product manager at Clariant Healthcare Packaging.
Aurelie Emond is head of development & marketing at Clariant Healthcare Packaging.
Kenneth C. Waterman, PhD, is president, FreeThinkTechnologies, Inc.
Mark Florez is product manager at Clariant Healthcare Packaging.
While cold-form, foil-foil (aluminumaluminum) blister packaging is considered the most moisture-protective packaging available, in fact, plastic containers such as bottles and tubes, when combined with desiccants, such as silica gel canisters and packets, will often provide lower internal relative humidity for long time periods.
Many solid drug and consumer products, especially tablets and capsules, show moisture sensitivity that can be quantified using specialized stability studies that encompass the moisture-modified Arrhenius equation combined with an isoconversion calculation (e.g., ASAPprime, FreeThink Technologies, Inc.). While cold-form, foil-foil (aluminum-aluminum) blister packaging is considered the most moisture-protective packaging available, in fact, plastic containers such as bottles and tubes, when combined with desiccants, such as silica gel canisters and packets, will often provide lower internal relative humidity for long time periods. This in turn can result in greater stabilization of the product and a longer assignable product shelf-life. Most health-related products have an expiration date (shelf-life) determined based on chemical and physical changes in product attributes over time. For regulated products such as pharmaceuticals (prescription or over the counter) and nutraceuticals (including vitamins), this stability-indicating change is most often either an increase in the level of degradation products or a decrease in potency of the active(s) due to chemical degradation. Less often, the shelf-life is limited by changes in dissolution properties for solid products, such as capsules and tablets. Whatever the shelf-life limiting attribute, changes are commonly affected by temperature, relative humidity (RH), and oxygen level. These attributes are in turn impacted by the initial drug product water content, the storage conditions, and the moisture and oxygen permeability of the packaging.
The Accelerated Stability Assessment Program (ASAP) involves a series of designed conditions of temperature and RH that samples are exposed to without packaging in order to build a stability model of a product. The data are first used to determine the failure times at each conditions (isoconversion times), then these times are fit to the moisture-modified Arrhenius equation to determine the explicit temperature and RH sensitivity (B-term). The design and analyses are conveniently carried out using commercial software (e.g., ASAPprime, FreeThink Technologies, Inc.). In this modeling, the RH sensitivity of products follows an exponential function (with the exponent B). From an ASAP model of a product’s degradation behavior, it is possible to accurately determine the product’s shelf-life at different storage (i.e., combination of temperature and RH) and packaging conditions. For products that have a significant moisture sensitivity (i.e., a high B term found from the ASAP study), protection from moisture by packaging is an effective method of increasing the stability.
For blister packaging, the most protective packaging is cold-form, aluminum-aluminum (alu-alu) blisters. In this case, the moisture permeability (moisture vapor transmission rate [MVTR]) is virtually zero. As such, foil-foil packaging is often considered the “gold-standard” for protection of moisture-sensitive products. Interestingly enough, using moisture-permeable bottles (e.g., those made from high-density polyethylene [HDPE] or multilayer bottles) can actually provide greater stabilization for moisture-sensitive products. The key to this is the use of desiccants. Such desiccants are available in various configurations, the most common of which are the automatable drop-in form canisters and packets (e.g., Sorb-it, Clariant), but can also include desiccant closures and protective systems such as tubes and desiccant stoppers.
To understand why this is the case, it is important to first understand how moisture distributes within a package, then how moisture transfer affects the RH inside the package over time. Moisture is held by solids to a different degree depending on the RH of the environment. Moisture sorption involves both water bound to the surface of solids (adsorption) and water within a matrix itself (absorption). This behavior is described by the moisture sorption isotherm of the product. Sorption isotherms are commonly measured using dynamic vapor sorption (DVS) instruments, which measure the weight gain/loss as a function of RH. With crystalline materials, virtually all the water is bound on the surface. The result is that relatively little water can sorb to these materials, even at high RH conditions. With amorphous materials, significantly more water can sorb within the solid matrix. Mixtures of materials, even processed into tablets, behave as a weighted average of the individual materials.
Inside a bottle or blister, the moisture in the headspace and the solids equilibrate relatively quickly (minutes for powders to hours for film-coated tablets). This equilibration means that the solids will gain or lose water to bring the RH of the solid (water activity) equal to the RH in the headspace. Because the solids typically hold far more moisture than the headspace, the RH of the solids will normally dominate where that equilibrium lies. The RH of the solids will depend on preparation and storage conditions prior to packaging. Most often, this RH will vary between approximately 20 and 50% RH. In many applications, companies set specifications for water content rather than water activity. Water content can be converted to water activity using the moisture sorption isotherm and correcting for any water of hydration.
Moisture will transfer into a package (assuming a higher RH external than internal) at a rate proportional to the difference in RH between the external and internal environments. This proportionality constant is called the moisture vapor transmission rate (MVTR). The MVTR of foil-foil blisters is low because water vapor only permeates through the seal layer and not through the metal substrate. This means that during a two-year period, the RH inside the foil-foil blister will remain almost unchanged.
In contrast, the MVTR of plastic bottles (such as those made from HDPE) is related to the wall thickness and overall surface area due to the permeable nature of plastics. For a given bottle size, an amount of water will enter and re-equilibrate between the headspace and the solids. This means that the greater the sorption capacity of the solids (based on the sorption isotherm and mass), the slower the RH will increase. As temperature increases, the MVTR also increases.
Figure 1 shows the RH as a function of time for a typical tablet product in alu-alu blisters, in 60-cc HDPE bottles (with heat induction seals), and with the bottles containing 2 g of silica gel desiccant, all stored at 30 °C/75% RH (International Council for Harmonisation Zone IVB conditions). As can be seen, the RH starts the same for the three packaging configurations, but in permeable bottles without a desiccant, RH increases over time, leading to lower stability of the tablets.
A desiccant is a material that can absorb a significant amount of moisture for its weight. The most common desiccant used commercially is silica gel, but molecular sieves and desiccants combined with activated carbon are also common. Typically, silica gel desiccants are provided with their moisture levels before insertion into packaging at a low value and comply with the new United States Pharmacopeia (USP) <670>. When a desiccant is added to a bottle containing solids, the moisture will transfer between the solids, the desiccant, and the headspace until all reach an equilibrium at the same RH (water activity). Because the RH of the desiccant is generally lower than the drug products, the drug products will lose water to the silica gel. This means that the solid will rapidly equilibrate to an RH below that for the solid that is directly packaged without the desiccant. As moisture transfers into the bottle with desiccant, the rate of RH increase will be buffered by the sorption capacity of the desiccant. As shown in the example in Figure 1, even after two years’ storage at 30 °C/75% RH, the internal RH in the bottle remains below that for the alu-alu blister. The ability of desiccants to remove water from the solid-dosage form is a unique benefit of using desiccants that cannot be matched even using impermeable alu-alu blisters.
From ASAP studies, it is possible to determine the explicit humidity sensitivity of a product, which can be combined with the knowledge of the RH as a function of time inside the package to determine the product’s shelf-life in any package with known permeability (MVTR). As an example, an ASAP analysis of thiamine (vitamin B1) in a multivitamin tablet showed that this active has about an average moisture sensitivity for loss of the active (B equals 0.036). As shown in Figure 1, the product’s estimated shelf-life (in this case for storage at 30 °C/75% RH) in HDPE bottles based on the RH curve discussed above is only 1.2 years. This improves to 1.7 years in alu-alu blisters. With 2 g of silica gel desiccant in the bottle, the shelf-life increases to 2.6 years. As a note, in polyvinyl chloride, PVC, blisters, the shelf-life is only 0.5 years (not shown). In this example, only with the desiccant is the shelf-life greater than two years.
For any specific product, it will be important to carry out an ASAP study to determine the product’s exact moisture sensitivity. In many cases, the greatest shelf-life will be achieved not with impermeable, alu-alu blister packaging, but rather with bottles or other types of packaging (e.g., tubes) containing desiccants.
Volume 40, Number 9
Supplement: APIs, Excipients, & Manufacturing 2017
When referring to this article, please cite it as K. Waterman et al., “Why Bottles with Desiccant Outperform Foil-Foil Blister Packaging," Pharmaceutical Technology 41 (9), Supplement, APIs, Excipients, & Manufacturing 2017.