The counterfeit detective

We are a pharmaceutical tablet manufacturer that is increasingly concerned by counterfeit drugs. We have received tablets that we suspect are counterfeit, but examination of the bulk composition has shown no significant differences. Could surface analysis techniques be utilized to determine the difference between genuine products and copies?

The answer is yes if the route of manufacture is different. However, before going into specifics we should define counterfeit drugs, explain the background and why they are such a large problem.

The threat

Counterfeiting was first recognized by the World Health Organization in 1985 and the agency estimates that the sales of fraudulent drugs will reach $75 billion (€47.9 billion) by 2010.¹ Currently, counterfeit pharmaceuticals are believed to account for 10% of the global supply chain and this percentage rises to 70% in some developing countries. Even in the US, a country renowned for having some of the most stringent regulations for the pharmaceutical industry, the sale of counterfeit drugs was estimated at $32 billion (€20.4 billion) in 2006.

While the direct effect on pharmaceutical company profits is important, the most concerning aspect is the health risks. In the best case scenario the counterfeit drug performs as the genuine article with no side-effects, in the worst case scenario the counterfeit drug results in death.

Currently, counterfeit drugs can be split into several categories:

• products without active ingredients

• products with incorrect quantities of active ingredients

• products with the wrong ingredients

• products with the correct quantities of active ingredients but with fake packaging

• products with high levels of impurities and contaminants

• copies of the original product.

Counterfeit drugs with the wrong chemical composition or contaminants can be investigated by a range of techniques such as nuclear magnetic resonance, near infrared spectrometry, thin layer chromatography, desorption electrostatic ionization, Raman spectroscopy, X-ray diffraction and liquid chromatography–mass spectrometry. However, those that contain the correct ingredients in the correct amounts (i.e., copies of the original) are more difficult to identify while potentially being as deadly as those with the incorrect ingredients.

Justine Bentley

Regarding the initial question, we need to understand why drugs with the correct ingredients in the correct amounts are a problem.

At first, these drugs may not appear to have the same health concerns as other types of counterfeit drugs, but it is not just the profits of pharmaceutical companies that suffer because of the practice of copying originals. Just because a drug contains the same ingredients as a genuine drug doesn't mean it will react in the same way or, more precisely, have the same effects on the person taking it. Drugs are specially designed to release APIs at set times if the composition is correct, but if the distribution of the counterfeit is different then it will produce undesired effects.

Finding the method

In relation to the question, we will focus solely on solid dosage forms — tablets.

There are two main routes of manufacture for pharmaceutical tablets:

• Granulation — a process by which particles within a formulation are enlarged to facilitate the flow of properties in a particular drug. This can be done by using either a wet or dry granulation technique that uses mechanical pressure to create the desired effect.

• Direct compression — a process that does not require agglomeration of particles, instead active ingredients and excipients are pressed together in a specific ratio to give the correct dosage.

The main factors to be considered when determining a tablet manufacturing route are:

• flow properties

• uniformity of mix

• compression characteristics

• necessity for controlled release of drug

• Homogeneity of drug requirements

• particle strength needed

• handling conditions during manufacture and intake

• cost

• simplicity of process

• degradation of raw materials relating to time of manufacture

• drug loading requirements.

Counterfeiters usually use the cheapest and easiest route to manufacture drugs rather than the most effective and accurate one. Determining the route that has been used can prove which is a genuine drug and which is a counterfeit. This is where surface analysis can help.

Figure 1 ToFSIMS spectra of a pharmaceutical tablet.

So how do we distinguish the route of manufacture when the bulk composition is the same? The distribution of lubricant can be different depending on the route of manufacture. In granulation, the lubricant is added to granules prior to compression and coats the surface of the granule, whereas in direct compression the lubricant is more uniformly distributed. This difference enables surface analysis to determine the route of manufacture.

Technique fact file: ToFSIMS

Spotting the difference

Step 1: prepare the tablets. Tablets with identical ingredients were formed using granulation and direct compression. A series of fracture surfaces were exposed for analysis as the surfaces of many pharmaceutical tablets are treated, uniform and nonrepresentative of the bulk distribution. A scalpel was used in a controlled atmosphere to 'crack' the tablets, exposing a fresh noncontaminated bulk surface that was immediately analysed.

Step 2: identify the species present at the fracture surface. Spectral Time-of-Flight Secondary Ion Mass Spectrometry (ToFSIMS) was used to identify the diluent (i.e., is the tablet a calcium phosphate or cellulosic-based formulation), the API and the lubricant at the fracture surface for each tablet.

Figure 1 shows part of a general ToFSIMS spectrum of a cellulose-based diluent.

Step 3: quantify the species present at the fracture surface. Standard X-ray photoelectron spectroscopy was used to quantify the elements, as well as their oxidation states (i.e., the percentage of carbon as C-C bonds and C-O bonds), present at the fracture surface.

Step 4: determine the route of manufacture. Once the information from steps 1–3 is known, the route of manufacture can be determined. It is not as straightforward as comparing the composition, which we already know is the same. This method uses a more complex equation that takes into account the composition of the diluent, as well as the quantity of the lubricant at the fracture surface.

Step 5: further confirmation. If further confirmation is necessary, ToFSIMS can be used. ToFSIMS imaging provides colour-coded molecular maps of the fracture surface. As previously mentioned, the lubricant is distributed differently depending on the route of manufacture. By mapping the lubricant at the surface, differences between genuine and counterfeit drugs can be identified.

Figure 2 shows a ToFSIMS image of a generic pharmaceutical tablet where the outer case is coloured blue, the inner matrix is shown in green with the central core containing the active pharmaceutical ingredient in red.

Figure 2 ToFSIMS image of a cross section of a pharmaceutical tablet.

In conclusion, whilst surface analysis techniques can not directly identify a counterfeit tablet they can investigate the route of manufacture, which can lead to the identification of a counterfeit tablet when compared with a genuine product.

References

1 www.who.int/mediacentre/news/releases/2006/pr09/en/