Figure 1 ToFSIMS spectra of drug samples.
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We are currently experiencing a problem with one of our tablet lines. While the tablets appear white immediately after manufacture,
after a time many of the tablets begin to take on a yellowish appearance. Could this be an issue that surface analysis could
help resolve? Discolouration issues present a very visible problem and can cost companies a great deal of money, regardless of whether the
product (in this case a particular tablet formulation) itself is functionally affected or not.
But while the problem may be visible, the cause often isn't. The reason for this is that discolouration is almost always an
issue that relates to surface conditions and not simply to bulk composition. Tiny variations in the outer nanometres of a
particular tablet can be to blame for changes in appearance.
These variations are sometimes caused by contaminants that have penetrated the manufacturing process or, in other instances,
by packaging treatments that lead to unforeseen chemical interactions. Occasionally, the chemical composition of the product
surface reacts with the surrounding light and air, resulting in molecular conversion and possible changes in colouration.
Figure 2 Generation of secondary ions.
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All three of these scenarios are very different, but, as the resulting effects are confined to the surface of the products,
any attempt to troubleshoot a solution using bulk analysis is likely to prove inconclusive, as it will not have the required
sensitivity to discern the chemistry of interest and relevance. With this in mind, surface analysis could not only help you
and your company, but also be the only conclusive solution.
However, to say "surface analysis can help" is casting too broad a net, as there are numerous techniques encompassed by this
description. For this particular product phenomenon I would initially recommend a programme of Time of Flight Secondary Ion
Mass Spectrometry (ToFSIMS).
Other than its extreme analytical accuracy, the reason ToFSIMS is so suited to this scenario is that it is essentially nondestructive.
As surface reactions could be the root of the discolouration, analysis techniques that alter or affect the sample's surface
structure may also produce inaccurate data, or data that are true of lab conditions, but not manufacturing conditions. ToFSIMS
provides an important and highly accurate troubleshooting solution.
So, which of the causes mentioned is the most likely scenario? It is impossible for me to say without access to the sample,
but, given the time delay in the discolouration, I would favour some sort of reaction to light being the most likely cause.
It is a more common issue than you might imagine, and one that we regularly see in the CSMA labs. A recent example of this
may help to demonstrate.
A pharmaceutical sample submitted for ToFSIMS analysis displayed significant discolouration after manufacture. To assess the
possible effects of light on the tablet formulation in question, a test was devised that analysed the following sample types:
- Pristine drug reference (control sample).
- Tablet prior to light exposure.
- Tablet exposed to light (Figure 1).
In the tablet exposed to light, ToFSIMS showed that selective degradation of the drug molecule had taken place where the acetic
acid group (—CH2COOH) was converted to an aldehyde group (—COH). This resulted in the formation of a new molecule (Mdeg) with a mass of 30
less than the pristine drug reference (Mdrug), where M=molecular mass. As a consequence of this conversion (the actual process
is caused by the interaction between the carbonyl group (C=O) and the 'aromatic ring'), a shift in the light absorption from
the ultraviolet region of the electromagnetic spectrum had taken place (at least partially) into the blue region of the visible
spectrum. This results in an outward appearance of yellowish discolouration.
