Moisture Control and Degradation Management

Dr. Jean Daou - Research & Development Manager, Aptar CSP Technologies.

Introduction

Often expressed in terms of relative humidity, water vapor can be a major source of contamination affecting product performance across various industries. Prescription and over-the-counter (OTC) drugs, probiotics and nutraceuticals, medical devices, cosmetics, electronics, and even food products face challenges associated with moisture exposure and require regulation of relative humidity to assure quality, stability, and efficacy.

Humidity mitigation is application-specific and is a critical component of extending shelf life and/or maintaining quality. In fruit and vegetable applications humidity must be fairly high, while potatoes and dry cereals require low humidity.^1,2 Moisture can cause increased corrosion reactions in electrical components and metal-based equipment, which can lead to changes in the chemical composition of the exposed material and ultimately, to structural deterioration,³ and products utilizing water-free chemicals can be rendered unusable if not properly protected from moisture.⁴

Controlling humidity in healthcare settings is both highly complicated and mission-critical. For some medical devices, such as blood glucose monitoring systems, even trace amounts of water can cause deterioration of the device’s active components.⁵

Moisture can also accelerate the physical and chemical deterioration of products through microbial growth, nutrient deterioration, and texture loss.^6-8 In the pharmaceutical industry, various high-value drug products, such as dry powder inhalers, oral solid dose drugs, orally disintegrating tablets, oral thin films, and biologic products, can be particularly moisture-sensitive. Understandably, such drugs are typically housed in packaging solutions that actively protect against humidity and other pollutants, thereby avoiding degradation or stability challenges.^9,10

Mitigating Degradation Risk Due to Moisture

Moisture control is fundamental to protecting products against degradation and ensuring quality, potency, and efficacy. To mitigate the risk of degradation from moisture, companies leverage a range of adsorbent technologies in their packaging, choosing the material source best adapted to specific target applications. This paper will focus on pharmaceutical applications specifically.

Due to its demonstrated effectiveness and ease of use, the most common method for delivering moisture control is leveraging adsorbents. Anhydrous salts,⁴ clays,^11,12 silica gel,^11,13 activated carbon,^14-16 metal-organic frameworks (MOFs)¹⁷ and zeolites are widely used for their significant water adsorption capacities (0.17 g/g to 0.45 g/g), and their ability to trap water molecules already at trace levels in the atmosphere.^18-24 The manner and extent of moisture control needed varies by application, with differing technologies utilized to achieve the desired relative humidity.

The following section reviews common materials for water adsorption, which can be divided into two categories: non-porous and porous.

a) Non-porous adsorbents

Anhydrous salts are accepted as the most commonly used materials for removing water from a solvent. Since the affinity of water for the salt is extremely high, the water molecules leave the solvent to bind to the salt. Schenk et. al showed that sodium sulfate (Na₂SO₄ ) was a weak drying agent in comparison to magnesium sulfate (MgSO₄ ), which possesses stronger drying properties.²⁵ Burfield et. al highlighted the significant water amount decrease in benzene solvent after using calcium chloride salt (CaCl₂).⁵ Sodium carbonate (Na₂CO₃ ) is another option for solvent drying, but its efficiency seems to be lower. Phosphorus pentoxide could reduce the water content in dioxane solvent more than by ten, while other salts are ineffective in comparison with benzene.⁴ For all these salts, it is important to take into account the nature of the solvent, the amount of added desiccant, the presence of stirring, etc. For air drying applications, the efficiency of hydride salts such as calcium hydride (CaH₂) or lithium aluminum hydride (LiAlH₄ ) was also proven with results showing 50% less water in Dichloromethane after 24 hours.⁴ These inorganic components oxidize to reduce water and a basic environment is formed with the release of dihydrogen. The water molecule is thus eliminated, however, caution is required with these compounds since the reaction is exothermic and the dihydrogen is very flammable.

b) Porous Adsorbents

Silica gel, one of the most used and studied adsorbents for water, is a porous silica-based material made of SiO₂ units containing silanol groups all over the surface responsible for its hydrophilic behavior. Water uptake for silica gel is generally between 0.25 g/g and 0.40 g/g, depending on the humidity conditions of the measurements.^11,13 The water uptake is dependent on the relative humidity present in the atmosphere, with water adsorption capacity increasing as the humidity rate increases.^11,13 Several works have tried to improve its water adsorption properties; one of the possibilities is by impregnation of the silica gel pores with hygroscopic salts.¹¹ Jia et al. studied silica gel impregnated with lithium chloride. They showed water adsorption capacities increased by a factor of 2 or 3 (~0.60 g/g to 0.70 g/g) in comparison with the parent silica gel at the same relative humidity (~0.25 g/g to 0.35 g/g).¹³ Similarly, Bu et al. showed that silica gel impregnated with calcium chloride could improve the water uptake up to six times in comparison to the parent silica gel.²⁶

Carbon-based materials, often called activated carbons, are also used for water adsorption. These materials are generally obtained after calcination or pyrolysis of carbon-based sources such as coconut shell, pine wood, sugar cane bagasse, etc.^27,28 Since several carbon sources exist in addition to totally different calcination or pyrolysis process parameters, the textural properties are wide, with porous volume ranging from ~0.24 cm3g.-1²⁸ to 1.40 cm3.g-1.²⁷ The carbon atoms mainly present in the structure of activated carbons confer hydrophobic character to the material. This is the reason why water adsorption is mostly performed on functionalized activated carbons. In this case, the porosity and the oxygen, nitrogen, and sulfur of functional groups at the surface act as a driving force for the capture of water molecules. Consequently, their performances are impacted by several factors, such as the concentration and the type of functional groups, as well as their distribution on the surface, the pore size distribution, and the link between pores.¹⁴

Generally, these materials show relatively low adsorption capacity at reduced pressures below 40% RH. A significant increase in adsorption capacity is observed between 40% and 100% relative humidity, depending mainly on the pore sizes and structures. Mesoporous and macroporous activated carbons show substantial adsorption at a high rate of humidity,¹⁵ while microporous materials adsorb significant amounts of water at a lower rate of humidity.¹⁶ In their review, Liu et al. report water adsorption capacities ranging between approximately 22 Wt.% to 60 Wt.%, depending on the source of carbon, the pore size, and functional groups.¹⁴ Activated carbons present interesting water adsorption capacities that could be better than anhydrous salts or silica gel. However, this solution can be expensive, as many parameters have to be managed in order to obtain an adapted water-sensitive material.

Clay minerals exist as natural or synthetic inorganic materials. They are characterized by a layered structure composed of tetrahedral (T) and octahedral (O) sheets of various compositions.¹¹ They present a high surface, either external or internal, and an accessible microporous volume useful for adsorption, ion exchange, or grafting. Guest molecules, such as water, can be occluded in the interlayer space. Depending on the composition of the layers, charge-compensating cations can be found in the interlayer space. Ng et al. indicate that clays can adsorb water in the range between 0.25 g/g to 0.48 g/g.¹¹ The water adsorption capacity of clay minerals depends on the size of the charge-compensating cation and the rate of humidity in the atmosphere. Hatch et al. studied the water adsorption of kaolinite, illite, and montmorillonite clays over a wide range of relative humidities.¹² Kaolinite showed a minimal water uptake of 4 Wt.% until 50% Relative Humidity (RH), which increases at 10 Wt.% above 60% RH. Illite clay contains 11 Wt.% of water at 50% RH and approximately 17 Wt.% at 80% RH, while montmorillonite showed 16 Wt.% and 26 Wt.% of adsorbed water at 50% and 80% RH, respectively. In conclusion, water adsorption isotherms of different clay minerals indicate that a high rate of humidity in the atmosphere is required to induce a significant water uptake.¹¹ This implies that traces of water cannot be easily trapped, which can be problematic for some targeted applications.

Metal-organic frameworks (MOFs) are hybrid organic-inorganic compounds, also called coordination polymers. They are crystalline and porous materials where metal cations are coordinated to each other by organic molecules (linkers) to form mono-, bi-, or three-dimensional crystal structures (Figure 1). Due to the variety of ligands and metallic cations, it is possible to adjust the size of the pores, leading to remarkable textural properties. Their surfaces and pore volumes are much greater than those of zeolites, for example. Their structures and large available microporous volume make them very relevant materials in the field of energy,²⁹ for gas storage/gas separation,³⁰ catalysis,^31,32 and for water adsorption.¹⁷ Today, MOFs are probably the most efficient materials for moisture adsorption due to their high available microporous volume, with water adsorption capacities that can reach ~1.2 g/g depending on the humidity conditions. However, their synthesis is complex and very expensive. Their potential for industrial applications is attracting resources in the field of research, but considerable work is still necessary before they can be easily used worldwide.

Zeolites are microporous crystalline aluminosilicates resulting from the juxtaposition of silicon [SiO4]4- and sometimes aluminum [AlO4]5- tetrahedra linked to each other by the sharing of an oxygen atom as displayed in Figure 2. The arrangement of all tetrahedra in the three directions of space generates a regular three-dimensional framework that forms a uniform network of cages, cavities, and/or channels with shapes and diameters that vary depending on the zeolite framework.

According to their pore opening and pore size distribution (see Figure 1), zeolites are microporous materials with a narrow pore size distribution, a significant porous volume, and good thermal and mechanical stabilities.^11,33-36 Consequently, they show very interesting properties in a wide range of applications, such as molecular decontamination and gas separation, by acting as molecular sieves.

The physical and chemical properties of zeolites are greatly influenced by the Si/Al ratio of their framework and by the nature of the charge-compensating cations. Thus, zeolites are generally categorized depending on their Si/Al ratio: low silica content (1 < Si/Al < 2), medium silica content (2 < Si/Al < 10), and high silica content (10 < Si/Al < ∞). Low Si/Al ratios resulting in a high aluminum content implies that the framework behaves as hydrophilic materials, thus water and polar molecules will have a strong affinity for this kind of zeolite. Zeolites such as LTA and FAU-type are highly hydrophilic and proved to be extremely efficient for water removal and water storage.¹¹ Bradley et al. showed that using 20 Wt.% of 3A zeolite (potassium as a major cation) in tetrahydrofuran solvent (THF) could reduce the residual water from 107.8 ppm to 4.1 ppm after 72 hours of contact, while a reduction from 224.9 ppm to 0.9 ppm was observed for toluene with 10% m/v after 24 hours.⁵ Burfield et al. showed, that after a period of 7 days, the water content decreased from 100 ppm to 0.06 ppm in Benzene solvent containing 5 Wt.% of 4A zeolite (sodium as a major cation).⁴ Several studies mentioned the use of gravimetric or volumetric methods to measure the water adsorption capacities of LTA and FAU-type zeolites. Significant stored amounts were observed, ranging globally from 0.18 g/g to 0.449 g/g.^18-24

Although the adsorption capacities of zeolites are lower than those of MOF materials, zeolites present the significant advantage of being able to adsorb water at very low concentrations, even at trace levels.^11,31,32 This ability to trap these few molecules present in the atmosphere with a relatively easy, reversible step, at a low cost, makes zeolites excellent candidates for such applications.

Next-Generation Active Material Science Solutions

While consideration must be given to the varied performances of the adsorbent materials outlined above – especially their effectiveness in protecting a given product – one potentially problematic issue is that these nanoporous materials are often deployed in powder form.

However, innovations in active material science technology have enabled the development of a new class of highly engineered polymer compounds that fully integrate moisture adsorption or other active properties into a product’s packaging or even the device itself. These compounds can be custom-engineered to adsorb all moisture in the environment surrounding the product or control relative humidity in packaging headspace.

Aptar CSP’s 3-Phase Activ-Polymer™ platform technology (Figure 3) employs nanoporous materials or other organic mineral materials as fillers in composite materials to improve their physical properties and/or moisture adsorption. The proprietary technology is delivered in a unique formulation comprised of a base majority polymer that provides the structure, a channeling agent, and active porous particles. It fully integrates into traditional packaging or device designs as a desiccant solution, preserving a drug product’s performance and limiting pollution problems associated with the spreading of nanoporous material otherwise deployed in a powder form.

Data Review: Water Adsorption Properties of Advanced Active Polymer Material

Prior to testing the water adsorption properties of the advanced active polymer composite materials, the associated nanoporous engineered material powders were analyzed at different temperatures and humidity conditions.

As expected from the water adsorption kinetics curves of the nanoporous powder displayed in Figure 4, all samples showed water adsorption capacity. However, there are some differences in the adsorption capacity (210-450mg of H₂O/g of porous materials) relative to the time needed to reach saturation and the impact the humidity rate had on the effectiveness of some of the adsorbent materials (TEST SAMPLES 2 and 3). TEST SAMPLE 1 material adsorbs all the moisture independently from the humidity rate, while TEST SAMPLE 2 and 3 materials can control the moisture content by adjusting their moisture adsorbing capacities depending on the humidity present in the environment.

Figure 5 shows the moisture adsorption curve at 22°C and 80% RH of one of the advanced active polymer’s extruded pellets (polymers + adsorbent) containing 55 Wt.% of TEST SAMPLE 1 adsorbent, deployed as an advanced active polymer vial solution. The adsorbent material present is able to reach 100% moisture adsorption capacity despite the presence of polymers (no pores blocking). The adsorption kinetics can be adjusted depending on the thickness of the composite materials and/or the nature of the polymers (not shown here).

Conclusion

Sensitive drug products often face moisture-driven stability challenges that can delay time to market or even prevent a drug from making it through the approval process due to an inability to meet stability requirements. While there are many adsorbent materials available, achieving the microclimate specificity a drug product may need and delivering that solution with a flexible form factor to meet a manufacturer’s needs presents a bigger challenge. Sophisticated R&D strategies must combine the advantages of interdisciplinary research, where materials and organic chemistry (synthesis, shaping, and characterization of the obtained materials), thermodynamic/dynamic (adsorption, kinetics, etc.), and computational chemistry synergize to devise the most promising adsorbents for challenging targeted adsorption scenarios. The identified adsorbents then can be used to build bespoke, innovative, and fully integrated active packaging-based solutions that can address the specific moisture challenges a product is facing, and deliver the precise microclimate needed to prevent product degradation and enhance stability, ultimately expediting time to market. This technology is currently used to protect highly sensitive drug treatments by actively adsorbing moisture inside the packaging and/or controlling the internal atmosphere of the packaging to improve stability and extend shelf life.

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Publication Detail

This article appeared in Tablets and Capsules Magazine 

Vol. 22, No. 1

Jan/Feb

Pages: 8-13

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