The use of microtomographic imaging in the identification of counterfeit medicines
Graphical abstract
Introduction
The definition of a counterfeit medicine is subject to continuous discussion. Nevertheless, a falsified medicine is any medicinal product with a false representation of [1]:
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its identity, including its packaging and labeling, its name or its composition as regards any of the ingredients including excipients and the strength of those ingredients;
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its source, including its manufacturer, its country of manufacturing, its country of origin or its marketing authorization holder; or
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its history, including the records and documents relating to the distribution channels used.
The practice of drug counterfeiting is an important challenge due to the extremely rapid growth rate of this disturbing trend and its immense potential harmfulness [2], [3], [4]. In developed countries it is estimated that about 1% of drugs is falsified whereas in developing countries counterfeit drugs can constitute even 10–30% [5].
Among medicines purchased via the Internet, on average, half of them are falsified [6].
Fake drugs may not contain any active pharmaceutical ingredient (API), they may contain another API, the appropriate API but other excipients, or they can be faithful copies of original medicines with the same quantitative and qualitative composition [7].
According to World Health Organization (WHO) about 32% of counterfeit medicines do not contain API [5]. Thus, therapy with such medicines will be ineffective, which in many cases may be life-threatening, especially if anti-cancer drugs [8], antibiotics [9] or antimalarials [10] are falsified. It can be equally dangerous to use drugs that contain too little or too high doses of API [7].
Many techniques are used to identify counterfeit medicines, in particular chemical analysis. These methods are expected to have high sensitivity and resolution. Today chromatographic methods are mainly used: thin layer chromatography (TLC) [11], high performance liquid chromatography (HPLC) [12], spectroscopic methods: mass spectrometry (MS) [10] and its derivatives: liquid chromatography - mass spectrometry (LC-MS) [13], gas chromatography - mass spectrometry (GC-MS) [14] as well as Fourier transform infrared spectroscopy (FTIR) [15], Raman spectroscopy [16], nuclear magnetic resonance (NMR) spectroscopy [17] and X-ray diffraction (XRD) spectrometry [18]. Furthermore, other methods, based, among others, on the analysis of thermokinetic parameters [19], and immunochemical methods [20] are also used.
Chemical analysis methods evaluate the chemical composition of the drug and compare it with the reference - the genuine medicine. Due to the very high sensitivity of these methods even small differences in the chemical composition are detected and may be a parameter identifying the genuine/falsified drug. Nevertheless, according to WHO [5] up to 10% of counterfeit medicines can be exact copies of original medicines. They have exactly the same quantitative and qualitative composition in terms of both API and excipients. Thus, the identification of such a drug using chemical analysis methods can be very difficult or even impossible.
Therefore, the techniques of identifying counterfeit medicines based on image analysis and processing methods are becoming increasingly popular. They allow to identify a drug that is an exact chemical copy of the original medicine [21]. In addition, image analysis and processing methods can be applied not only to the dosage form itself (e.g., tablet, capsule, ointment) but also in relation to the packaging [22], [23].
The methods of image analysis and processing used to identify counterfeit medicines are based on the assessment of the colour, shape and size of the dosage form or packaging.
The image of the analysed drug can be acquired using, among others, conventional cameras [24] or a thermal imaging camera [19].
In the case of drug image analysis and processing based on images obtained with the use of cameras the main challenge is to achieve repeatable conditions of their acquisition. Even small changes in lighting, image acquisition parameters or the change of the lens significantly affect the possibility of detecting counterfeit drugs. In view of the above, it was proposed to use the methods of analysis and processing of images that are microtomographic cross-sections of drugs.
The aim of this study was to verify the effectiveness of using computed microtomography in the identification of counterfeit medicines.
Section snippets
Test tablets
The original and falsified 100-mg Viagra® tablets (Pfizer) were compared. 8 original Viagra® tablets (hereinafter referred to as T) and 8 fake tablets (hereinafter referred to as F1-F8) were tested. The original Viagra® tablets were purchased at a pharmacy in Poland. The serial numbers of the packages were verified with the manufacturer of the original drug - Pfizer®. Counterfeit medicines were purchased on the black market (via the Internet) in Poland (7 tablets) and in Bulgaria (1 tablet).
Results
The proposed methods of microtomographic image analysis and processing allow for the quantitative identification of the parameters of microtomographic images of the test tablets Fig. 2. These features include: mean image brightness, contrast and homogeneity (GLCM) as well as the measurement of the number of areas after decomposition (QTDECOMP). The quantitative identification of unique parameters of microtomographic images is the first stage in determining the range of variability of these
Discussion
Identification of counterfeit medicines is usually carried out using chemical analysis methods [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. Although these methods are characterized by relatively highly sensitivity and specificity they have a number of disadvantages. First of all, they do not allow for the identification of falsified products being an exact "chemical copy" of the original medicine. In addition, they usually involve destructive tests. Therefore, this may be a
Conclusions
The proposed method of microtomographic image analysis and processing enables to identify solid dosage forms with high sensitivity and specificity. The parameters that are characterized by the highest variability in the studied case, and therefore identify falsified products best, are: brightness, homogeneity and QTDECOMP. Microtomography as a new method for identifying counterfeit medicines is effective, which is also very important in relation to the original chemical copies, non-destructive,
Acknowledgments
This work was financially supported by the Medical University of Silesia, Poland (Grant number KNW-1-067/N/8/O).
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