Can potentially costly problems with gas-filled packaging be solved with surface analysis? CSMA searches for the answer.

Our oral pharmaceutical product is packaged by a range of contract packaging companies. Adverse properties of the final packaged product from one particular company indicate that the product shelf life is shorter than it should be. It has been suggested that this could be related to gas filling issues. Is this anything that surface analysis could clarify?

This could certainly be the case — gas contamination and compositional errors are an increasingly common issue, particularly in the pharmaceutical industry where gas-filled packaging is frequently used. However, 'could' is no good when your product and, ultimately, your profits are suffering. Clarification is required.

The particular value of surface analysis in this scenario is in identifying the correct course of further investigation to avoid costly and unnecessary testing procedures.

Gas filling

Pharmaceutical packaging can be for powder, liquids, tablets, capsules, creams and gels, and is generally more sophisticated than packaging for other industry sectors.

High-barrier packaging, such as gas-filled packaging, maintains the atmosphere within the packaging, but this atmosphere must be modified to provide a long product shelf life. This is achieved in one of two ways: vacuum packing or gas flush packaging. It is the second method that concerns us.

Gas flush packaging reduces the amount of oxygen surrounding the drug to slow or eliminate the growth of aerobic life forms, which increase the rate of oxidation reactions. Often, the displaced oxygen is replaced with nitrogen, carbon dioxide or sometimes argon. The gas composition of an average blister-packed pharmaceutical product, for example, would contain less than 1% oxygen compared with the 21% typically found in air.

Spotting the symptoms

Pharmaceutical products that show signs of oxygen or moisture attack often indicate atmospheric issues in the packaging itself. Unfortunately, spotting these symptoms is not always straightforward, and without definitively identifying the root cause as being atmospherically related, the resolution remains unclear.

This is where surface analysis techniques can be invaluable. While some harmful effects caused by atmospheric issues can be observed visually, such as discolouration, most are much less obvious and can only be confirmed using extremely sensitive analytical equipment. As an example, one of the most common side-effects of atmospheric interference is a change in surface morphology. Differences in the surface contact area can interfere with engineered dissolution rates and affect the speed of absorption in vivo. Topographical changes at the surface of the pharmaceutical, or simply a change in roughness, can easily be demonstrated using noncontact surface profiling (3DP), where changes at the submicron level can be monitored.

Sometimes chemical changes at the drug surface occur because an unprotected pharmaceutical product undergoes surface chemistry oxidation or hydration. Once again, surface analysis techniques are the ideal identification tools; for example, x-ray photoelectron spectroscopy (XPS) offers quantified data on elemental and oxidation state changes within the top 5–8 nm of a surface. The technique not only enables the overall level of oxygen (as combined in oxygen-containing groups) at the surface to be measured, but can also differentiate between the form of the oxygen — such as whether it is present as an acid, carbonyl, ester or alcohol. Figure 1 shows XPS technology in action.

Whereas XPS provides quantified data, time-of-flight secondary ion mass spectrometry (ToFSIMS) provides detailed molecular information from the outer 1–2 nm, enabling unequivocal fingerprinting of drug molecular ions, excipients and any modified contaminants or modified species. One demonstrable example of the technique in practice is 'blooming'. Oxygen attack, caused by atmospheric issues in packaging, often results in 'blooms' occurring at the drug surface. By taking repeated measurements from the drug surface to the sample subsurface, ToFSIMS can differentiate between blooming caused by oxidation and a straightforward contamination of the external surface.

Additionally, scanning electron microscopy can be used to analyse the physical form of the 'bloom' crystals to identify how they formed. In the case of atmospheric problems, material at the drug surface is likely to have been dissolved and then slowly recrystalized because of water vapour ingress.