Gas-filled packaging problems

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.

Technique fact file: XPS

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.

Analysis in practice

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.

Figure 1: 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.

The way forward

Using the techniques outlined previously provides a clear picture of the form of attack the drug surface has suffered. The amount of tests available to troubleshoot potential product lifespan problems is immense, but with our data a likely candidate can be identified and the correct form of further analysis can be selected. In the case of atmospheric related symptoms, this further analysis usually takes the form of residual gas analysis (RGA). This technique has recently been refined for pharmaceutical packaging gas analysis (PPGA) to allow intact pouches or blister packs to be studied. Similarly, modified RGA analysis can also be used to study entrained bubbles of contaminated gas to identify a likely contamination source.

Taking its routes from secondary ion mass spectrometry, PPGA enables the residual gas from sealed packaging or glass bubbles to be leaked in a controlled manner into the residual gas analyser (Figure 2).

Figure 2: Detail of fracture chamber and pumping arrangement.

The mechanism for in vacuo fracturing of samples is based on a modified ultra high vacuum (UHV) valve assembly where the central sealing spindle is replaced by a diamond-tipped shaft. This shaft is mechanically driven by rotation of the valve assembly, bringing the diamond tip into contact with the surface of the sample (Figure 3). Increasing the pressure on the tip causes rupturing of the sample with resultant release of the internal atmosphere into the evacuated chamber. An UHV leak valve is then used to bleed the gas into the main instrument chamber for mass spectral gas analysis.

Figure 3: Glass bubble trial sample mounted for fracturing.

Cost saving analysis

Returning to the specific query outlined at the beginning, the benefits of combining analytical techniques are two fold. By using the initial surface analysis techniques to identify the specific symptoms demonstrated by the drug, the field of potential causes is significantly narrowed.

In turn, appropriate further action can be taken more quickly and with less risk of wasted effort. From a business perspective, this means that lifespan issues are likely to be resolved faster, without the expenses of unnecessary extensive testing.

Figure 4: Mass spectrum from gas-filled packaging.

In effect, surface analysis provides the key to unlocking the correct door to a solution, and can make a big difference to profit lines and continued production.

Justine Bentley joined CSMA in 2005 as a Technical Sales Consultant. She promotes the features and benefits of surface analysis techniques to a range of sectors and disciplines, providing valuable advice on troubleshooting and on delivering analytical solutions for commercial applications, including successful product development and reverse engineering.

Questions?

If you have any questions for the experts at Surface Surgery then please send an email to clawrence@advanstar.com