Drug products subjected to degradation because of environmental stresses can be salvaged if proper packaging and protection is provided by sorbents. By the time the drug product is handed from the formulation chemists to the packaging engineers, mechanisms of degradation, such as hydrolysis, oxidation, dehydration, isomerization, racemization, elimination and photodegradation, are usually known. It is then up to the packaging engineers to plan a 'defence' against these degradation pathways.

In accordance with various regulatory guidelines, stability studies are required to prove that a drug will maintain its physical and chemical characteristics during a given time frame (expiration dating) to ensure the safety, identity, strength, quality and purity of the medicines. The International Conference on Harmonisation (ICH) has published a widely known guidance document regarding the outline of such stability studies.¹

Whether dealing with a new drug application for innovators or an abbreviated new drug application (ANDA) for generics, time is money and quickly bringing a quality product to market is key. This is particularly true for generic companies filing ANDAs for reference listed drugs, as they are in competition for the 180-day exclusivity provisions set forth by the Hatch-Waxman Amendments to the Federal Food, Drug and Cosmetics Act.²

Historically, basic calculations were made for products requiring a sorbent regarding sorbent selection for registration stability lots. A sorbent-ranging study was performed prior to this to determine whether or not the desiccant recommended and its quantity were correct. Performing these additional characterization tests, such as dissolution, assay and degradant monitoring, takes time and money.

Our goal was to eliminate sorbent-ranging studies or 'guesswork' by creating a predictive model of moisture permeation and adsorption to determine the appropriate sorbent and its amount to achieve shelf-life targets for given pharmaceutical formulations and dosage forms.

The scientific model

A pseudo-empirical modelling programme has been developed by Multisorb Technologies to mathematically predict the stability outcomes of testing. No model can truly replace empirical testing, but the programme decreases excessive testing, and demonstrates and predicts the effects of the selected packaging and its incorporated sorbents. The model predicts the internal conditions of a drug product package based on a given set of external conditions and selected input criteria. This modelling is based on the integration of internal and external equilibrium relative humidity (ERH) conditions with time, and the adsorption profiles/isotherms of the desiccant and drug product.

One of the assumptions necessary regarding the dynamics of permeation and adsorption was that, at any given time, the system inside a package is in a state of equilibrium: Φin=ERH₁=ERH₂=ERH₃=ERH_A=ERH_D

Figure 1: A typical bottle container system.

The water vapour transmission rate (WVTR) of the bottle is measured at some known humidity difference (ΔRH) between internal and external environments: ΔRH=Φ_in –Φ_out

A simplified picture of permeation and adsorption is considered:

• The RH outside the bottle is constant, as is the case with stability testing.
• Moisture permeation through container/package surface area is relatively slow, allowing for fairly rapid equilibration and an uniform ERH of all components.
• Quasi steady-state pattern of permeation through the bottle wall is present.
• Package WVTR is linearly scalable with ΔRH between separated environments, which is the case with many polymers including polyolefins.