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
Many modern drug substances and products are susceptible to environmental humidity, and may physically or chemically degrade,
or lose potency and efficacy when exposed to atmospheric moisture. Although higher barrier packaging can combat this issue,
it is often cost-prohibitive compared with less expensive packaging solutions, such as high-density polyethylene (HDPE) bottles
and incorporating sorbents. 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=ERHA=ERHD
Figure 1: A typical bottle container system.
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Each component, i (i=D, 1, 2, 3,...) inside the bottle has its own sorption isotherm, Si(Φ) (Figure 1).
The water vapour transmission rate (WVTR) of the bottle is measured at some known humidity difference (ΔRH) between internal
and external environments: ΔRH=Φin –Φout
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.
