Modeling Moisture Control

Desiccants help stabilize drugs, and may get them to market faster.

By David Vaczek
 
CSP Technologies (Auburn, AL) incorporates
desiccating materials into primary packages such as vials, blister packages, and its Power-Pak for edible films. (Editor’s note: The blister package shown features paper instead of tablets or capsules for demonstration purposes only; the paper is not part of the desiccating solution. The desiccation is achieved with the desiccating strip shown at the top of the blister.) Photo by Roni Ramos.

With an increasing number of drugs exhibiting high sensitivity to moisture and oxygen, desiccant manufacturers have offered an array of solutions to inhibit drug degradation and extend the shelf life of products.

Aggressive desiccation with packets and canisters is usually an option. However, solutions such as desiccant films, desiccating polymers, and special caps and inserts may influence providers’ primary packaging design.

CAREFUL CALCULATIONS

Desiccant providers often work closely with packaging engineers and formulation chemists in devising optimal desiccant and packaging solutions. Adrian Possumato, global manager, pharmaceutical market, Multisorb Technologies Inc. (Buffalo, NY), says that a number of highly sensitive molecules have been shelved in recent years because they could not be stabilized through reformulation or traditional packaging protection methods.

“Technologies in moisture and oxygen control are helping extend drug shelf life, improve brand quality, and, most importantly, enable the marketing of drug products that had previously been considered too unstable,” he says.

Companies employ modeling techniques to define the interrelation of the package, product, and desiccant, and predict equilibrium relative humidity (ERH) and drug product hydration over the course of the drug product’s shelf life.

John Hart, chemical engineer, Desiccare Inc. (Pomona, CA), says that there are software programs available to calculate RH levels for given ingredients and ingredient mixtures.

“Calculations are made by use of thermodynamic relations. Programs such as Excel Mathcad, Mathlab, and Mathematica are generally used,” Hart says.

In devising desiccant solutions, a multidisciplinary approach is often useful. “In many cases, we will proactively engage the formulation chemists and the packaging group. The packaging group may not understand the impact of desiccant options on a drug’s stability profile. The formulation group needs to know that it is providing for the stability they require and that they may not be able to reach through formulation changes alone,” says Possumato.

With its SimulSorb program, Multisorb defines the sorbent characteristics of a drug product and simulates the effect of packaging with varying amounts and types of desiccants. A desiccant solution is often recommended to achieve a required package headspace ERH and management of drug product hydration levels.

Modeling techniques analyze drug degradation rates by defining values for the ingress of moisture and oxygen. The package’s permeability is related to the sorbent properties of the drug. Engineers determine theoretical sorbent level requirements, then demonstrate their findings through proof-of-concept accelerated stability testing.

“We take the moisture-vapor transmission rates for the plastic resins and define the adsorption/desorption isotherms, or profiles, for the desiccant and drug product. Then you apply a math model to predict the desiccant’s action on the headspace RH and its action on the free moisture value in the tablets. We are showing what the RH headspace is and how hydrated the tablets are,” Possumato says.

StabilOx oxygen absorbers from Multisorb Technologies maintain an intermediate equilibrium relative humidity within sealed environments to protect the integrity of drug compositions.

PREDICTING RH

“By relating these integrals, we can tell the customer from day one through day 180 under accelerated conditions what the relative humidity will be inside the bottle and what the tablet moisture will be inside the tablets. Real-time stability modeling is also available. The chemist knows that if the tablets are kept at a certain moisture percentage, it will be a stable product. Then the manufacturer will perform stability testing to confirm our recommendation,” he says.

CSP Technologies (Auburn, AL) devised a desiccant solution for a manufacturer providing a cough medicine and breath-freshening product in edible films. Packaging was needed to provide chemical stability for the product as well as physical protection of the thin filmstrips.

“Very early in the project we engaged with the film manufacturer and the marketer to characterize the edible film’s sensitivity to moisture,” says Billy Abrams, vice president, business development, CSP Technologies.

The film product formulation originally presented was susceptible to overdrying.

“These dissolvable film products are very delicate. They stick together if there is too much humidity present or temperatures get too high. If they are overdried, they become brittle and crack,” Abrams says.

“We worked with the film provider to understand its compatibility with our desiccant plastic. In the commercialized package, the desiccant controls the relative humidity to prevent the fusing of the film, without over-drying the product,” Abrams says.

See Sidebar: Süd-Chemie Expands in United States

The solution, a two-shot injection-molded Power-Pak container featuring a molded inner liner, incorporates CSP’s Controlled Interactive Packaging technology. CIP polymers employ microscopic transmitting pathways to control absorption or release of substances to specified levels.

The company’s desiccated polymer technology is also used in packaging for glucose test strips. More recently, GlaxoSmithKline this year adopted the active packaging solution for Commit nicotine lozenges. The plastic is sealed to the inner wall of a flip-top child-resistant vial.

“We engaged GSK’s research and development and packaging teams to custom design a packaging system that would ensure product protection throughout shelf life and consumer use of the product,” says Abrams.

In some instances, desiccants support drug processing, such as when moisture is used in wet-process granulation. With the addition of a packaging desiccant solution, a chemist can utilize the required moisture content for granulation and tableting, for example, for product flowability, yet avoid degradation arising from the free moisture introduced into the tablets thereafter.

Generic companies have used desiccants in place of stabilizing additives to get around patents covering the ingredients and to launch to market faster. Since the first FDA-approved generic version of a brand name drug earns a 180-day exclusivity period as the only lower-cost alternative to the brand, millions of dollars are often at stake.

The sustained-release versions of Wellbutrin (bupropion hydrochloride) from GSK and partner Biovail Laboratories Inc. (Toronto) employ patent-protected organic acids to prevent moisture degradation. Some generic companies have used desiccants in place of the acids in developing stable formulations of Wellbutrin SR (twice daily) and Wellbutrin XL (once daily). Alleging patent infringement on its sustained-release technology, Biovail is challenging generic firms that have raced to file abbreviated new drug applications for a share of Wellbutrin XL’s $1.1 billion in sales. The drug loses patent August 28, 2006.

“With bupropion, without the organic-acid additives, you have rapid hydrolysis and rapid moisture-mediated oxidation occurring simultaneously. Generic companies have not had access to the stabilizing agents because they are patent protected. We have put companies into very aggressive desiccant solutions,” says Possumato.

Possumato notes that moisture provides the molecular mobility that creates the medium for degradation for all chemical pathways of drug product degradation, including moisture-mediated oxidation and isomerization as well as hydrolysis.

“In theory, if you completely dry the head space and remove all free moisture from the tablet, then all chemical pathways of degradation will stop. We can achieve a very low ERH in a lot of instances,” he says.

Süd-Chemie offers flat capsule configurations for use in blister packaging.

BUSTING OXYGEN

Oxygen absorbers may be used with products for which oxygen is the main pathway of degradation. In many iron oxide–based oxygen absorbers, silica gel pulls moisture out of the product to oxidize an iron powder.

Multisorb offers its Fresh Pax D– series product for controlling oxygen in packaging when there is little moisture present to initiate oxidation. Moisture is preloaded into a self-contained rust packet, requiring no external sources of moisture to facilitate oxygen removal.

Where moisture degradation is also an issue, the silica gel may be only partly hydrated, with enough moisture to kick-start the oxidation and maintain an acceptable RH level, says Possumato. “This is the case with our StabilOx product, where moisture that permeates the bottle continues the reaction,” he says.

The O-Buster from Desiccare similarly is an iron-based scavenger employing water along with salt to speed the reaction, says Hart. In the area of moisture control, Desiccare is phasing out its Dri-Mac canister and transitioning to an SPL canister. “The SPL canister body is made from HDPE with a sieve edge. The canister top is made from LDPE, with the top and bottom fritted to allow airflow through the canister,” says Hart.

PharmaKeep, by Süd-Chemie and Mitsubishi Gas Chemical Company, Inc. (Tokyo), is an organic-based oxygen-absorbing system that works without moisture. So it may be paired with a desiccant. “Most pharmaceutical applications require drugs to be packaged in low RH environments. In many cases, PharmaKeep is used in high-gas-barrier packaging that doesn’t allow moisture to enter,” says Mark Flores, marketing manager.

For moisture control in blister packages, Tekni-Plex Inc. (Somerville, NJ) has launched the Tekniflex Modified Atmosphere.

Blister (MAB). The product incorporates one or more of CSP Technologies’ Activ-Strip poly desiccant strips into the rib design of a two-or-three layer PCTFE laminate blister.

Active strips are affixed to the foil lidding stock, with thermoformed channels running from the strip to each blister cavity. The dust-free Activ-Strip does not come in contact with the product. Tekni-Plex said the high-barrier PCTFE laminate paired with the moisture-scavenging desiccant system maintains low relative humidity longer than cold-form foil blisters in accelerated stability testing.

Süd-Chemie is also developing an oxygen-absorbing blister film, says Flores.

Abrams notes that in addition to performing product stability evaluations, companies have to understand how moisture affects product during consumer use and reuse. “Control of relative humidity during consumer use is contingent on the seal integrity of the container and on the ability to control the relative humidity while they are in use,” he says.

“When we are involved early on at the package development stage, we can pretty much guarantee the control of relative humidity to the level required to maintain product stability. So pharmaceutical companies are not losing sales, and, with desiccant plastic packaging, you avoid the risk of consumers’ removing the desiccant,” Abrams adds.

 

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