Surface Analysis Exposes Counterfeit Medicines

Author: Ceram Research Limited

This work by Ceram is licensed under a Creative Commons AttributionNonCommercial-ShareAlike 3.0 Unported License

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Introduction
Surface Analysis is assisting the pharmaceutical industry in a number of ways, including for example the optimisation and acceleration of new product development, evaluation of product and packaging stability, rapid identification of trace contamination and quality assessment of new manufacturing processes. And it is certain that Surface Analysis can illuminate much more about processes, and even origins, in this sophisticated marketplace – including by helping detect counterfeits. Developments at the forefront of Surface Analysis technology are so powerful that it is enabling an independent UK research centre to materially assist pharmaceutical companies in their battle against counterfeit drugs. Not only does this technology – the latest in X-ray Photoelectron Spectroscopy (XPS) and Time-ofFlight Secondary Ion Mass Spectrometry(ToFSIMS) in particular – afford a means of analysing the composition of various pharmaceuticals, recent work has also shown that it can even determine differences in the manufacturing processes involved, enabling the identification of previously undetectable chemical copies. Traditionally, one thinks of Surface Analysis as being concerned principally with the physical properties of surfaces – flatness, roughness, colour, reflectivity and so on. The state-of-the art in this area is ‘3D non-contact profiling’, where white light interferometry techniques allow examination of ‘microfeatures’. Areas from a few square microns up to the centimetre scale can be analysed with nanometre resolution.

Figure 1: Crystallite contamination discovered in a drug formulation. ToFSIMS imaging was used and a polymer additive identified, enabling the problem to be resolved.

Beyond Bulk Analysis
However Surface Analysis also now looks at chemical composition – and the leading edge technology here is Secondary Ion Mass Spectrometry (SIMS) which examines the chemical composition of surfaces and sub-surfaces, using a depth profiling technique to look at how this varies below the surface, to a depth of several microns using continuous bombardment. In fact, the word ‘surface’ is now almost misleading – the technology can now look at the chemical composition of small samples of all kinds of solids, by examining ions emitted from the surface. These techniques do not displace conventional chemical analysis. If somebody needs to discover whether a tablet is a genuine paracetamol tablet – or just a piece of chalk in fancy packaging – then bulk analysis (for example, Liquid Chromatography Mass Spectrometry) could be utilised. But if the counterfeit is more subtle, then bulk analysis may fail. It could be, for example, that the chemical composition appears correct, but the active drug distribution is incorrect. This is not just a matter of protecting patents, but in also protecting patients, for whom the counterfeit drug may not work effectively.

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Just because a drug contains the same ingredients as the genuine article, does not mean that it will react in the same way or have the same effect on the user – there are factors such as trace contaminants or distribution of the active components within the tablet – which could for example, change the rate of absorption and constitute a potential hazard to the user. Counterfeiting is a major problem not only for the pharmaceutical industry itself, but for the health of the world population in general. If people are taking pharmaceuticals other than those which have been fully tested and are properly licensed, there are obvious dangers, which in some cases could be extremely serious.

Costly Counterfeits
Counterfeiting was first recognised by the World Health Organisation (WHO) in 1985, which currently estimates that sales of counterfeit drugs worldwide may amount to 10% of the global supply, and sales could reach a staggering $75 billion by the year 2010. In 2006, the trade in the USA alone (with one of the most stringent pharmaceutical control regimes) was estimated at more than $30 billion. The pharmaceutical industry as a whole needs to be able to detect counterfeits, to protect its own reputation as well as its commercial interests. Many pharmaceutical companies now regularly turn to Surface Analysis techniques – not only for the detection of fakes, but for routine detailed analysis as part of a long-term quality assurance process.

Figure 2: ToFSIMS spectra of a yellowed tablet, enabling the cause of discolouration to be identified and corrected

For example, Ceram has recently been involved in analysing the appearance of crystallite contamination in a drug formulation after storage; discovering the cause of tablet yellowing with age (by investigating the leaching from packaging to product in long-term storage); mapping active drug distribution in controlled-release products (including medical devices such as ‘stents’ with active drug coatings); analysing trace cross-contamination between production lines, and so on. As pharmaceutical technology is continually moving forward, research is constantly exposing new techniques for analysis and monitoring. One pharmaceutical manufacturer approached Ceram with an unusual problem – to which, at the time, nobody knew the answer – but it was thought that Surface Analysis might indicate a way forward. The question posed by the drug manufacturer was: “Suppose we have encountered a counterfeit medicine, in tablet form, whose chemical composition appears to be correct but whose method of manufacture is different from the path licensed for the drug. Is it possible to detect that difference using Surface Analysis techniques?”

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We should note here that drug manufacture by other than the licensed process is just as much of an infringement as using the wrong ingredients – and because such manufacture is not properly authorised, health hazards could potentially arise. What the manufacturer wanted to investigate was the way that tablets are formed. Here it was using a technique called ‘direct compression’ – the active pharmaceutical ingredient (API) and other excipients are pressed together in a specific ratio to give the correct dosage. Another common method is ‘wet granulation’ where granules are formed in a wet process (requiring subsequent drying) before compression. Samples of tablets were prepared by the two different methods and offered for analysis.

Surface Analysis Technology
The primary analysis techniques used in the trial were X-ray Photoelectron Spectroscopy (XPS) and Time-of-Flight Secondary Ion Mass Spectrometry (ToFSIMS). Both are high-vacuum technologies. To carefully sectioned in a controlled atmosphere to expose an inner surface. The Principal Technologies Spectral ToFSIMS provides detailed molecular information from the outer 1-2nm of a surface, whilst spectral XPS provides quantified elemental and oxidation-state information from the outer 5-8nm with a sensitivity of 0.1%. Both techniques can be utilised in imaging mode. Using soft X-rays to dislodge photoelectrons from the surface of the target material, whose characteristic energies can then be detected, XPS can probe the surface of a material and determine the elements present, their concentrations and the chemical states of the elements found. This non-destructive quantitative testing method can detect elements down to 0.1At% concentration (Atomic percent: the ratio of atoms of a particular element to all atoms in a given volume). Every element can be detected (except hydrogen and helium) with a sampling depth of typically 5-8nm. ToFSIMS uses a primary focused ion beam to bring about a collision cascade, causing secondary ions to be emitted from the surface of the target material. The ‘time of flight’ of these ions to the detector is related to their mass. This gives information regarding elements, functional groups, polymer groups and molecules. Unlike XPS, the technique is not quantitative, but does provide more detailed structural information, particularly for organic and polymeric components. With very low primary ion doses, samples can be analysed with effectively no damage to the surface under examination, with a sampling depth of 1-2nm and detection sensitivity in the parts-per-million to parts-per-billion range. Because the ion beam can be ‘rastered’ across the surface under examination to produce a colourcoded chemical map, then full spectra can be obtained for every pixel point within the image.

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Distribution of Pressing Lubricant
The initial study indicated that the distribution of ‘lubricant’ might well be a parameter which could help identify the manufacturing process. Lubricants of some sort are used in most tablet formulations (to assist in the pressing process) and the most common of these is magnesium stearate. This is readily detectable by both XPS and ToFSIMS. It was postulated that the distribution of lubricant may be different in tablets produced by the two manufacturing processes – in wet granulation, the lubricant is added prior to compression and coats the surface of the granule (i.e. extra granular) but direct compression mixes the lubricant powder directly with the other ingredients, and it could be that the lubricant is more evenly distributed across the tablet as a result.
Figure 3: Cross-section of the tablet whose manufacturing process was being deduced. (Left) the optical image by conventional microscopy, and (right) images generated in the ToFSIMS investigation.

In the event, when comparisons were drawn, changes in the surface composition and distribution became clearly identifiable. (See Figure 3 images) By pinpointing key indicators such as these a complex model was produced, which proved very effective at differentiating between tablets produced using direct compression or wet granulation techniques. These are non-trivial results – it so happens that most pharmaceuticals are administered in tablet form, and of these, a considerable number are produced using magnesium stearate as the pressing lubricant. It is evident that this technique could shed light on the manufacturing processes involved in the production of many of them. What this study has shown, however, is that Surface Analysis technology is able to probe into the method of manufacture of tabletted preparations, even where a bulk chemical analysis can find no differences between the genuine and the copy. It is certain that Surface Analysis can discover even more about the nature and origins of counterfeit pharmaceuticals, to say nothing of helping to ensure the purity and quality of genuine ones. Ceram remains at the forefront of this research.

Figure 4: ToFSIMS image showing the distribution of active ingredients in blue and the lubricant in yellow/green. Also seen are other species coloured red. The surface examined is a cross-section revealed by cleanly cutting the tablet in half like a bun, the area represented is 500 microns square.

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About Ceram
Ceram is an independent expert in innovation, sustainability and quality assurance of materials. With a long history in the ceramics industry, Ceram has diversified into other materials and other markets including aerospace and defence, medical and healthcare, minerals, electronics and energy and environment. Partnership is central to how we do business; we work with our clients to understand their needs so that we can help them overcome materials challenges, develop new products, processes and technologies and gain real, tangible results. Headquartered in Staffordshire, UK, Ceram has approved laboratories around the world.

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