Journal of Pharmaceutical and Biomedical Analysis
Reliable low-cost capillary electrophoresis device for drug quality control and counterfeit medicines
Introduction
A counterfeit medicine is a medicine that is deliberately and fraudulently mislabelled with respect to identity and/or source [1], [2], [3]. Both branded and generic products can be concerned by the counterfeiting. Counterfeits may include products (i) with correct ingredients/components, (ii) with wrong ingredients/components, (iii) without active ingredients, (iv) with incorrect amounts of active ingredients or (v) with fake packaging [1], [3]. The consequences of counterfeiting are mainly observed among patients, the medicines end-user's supposed to be the beneficiaries. They are exposed to risk of consuming such counterfeit products, i.e., therapeutic failure or drug resistance [4]. Some extreme cases can lead to death. Dramatic examples are reported in Panama and Nigeria. In 2006, more than 100 patients have been killed in Panama by medicines manufactured with counterfeit glycerine; in 2008, about 100 babies died because of absorbing a false paracetamol syrup [3], [5]. The proportion of counterfeit medicines is dramatically increasing these days [6], [7], [8], [9], in particular in some African countries pharmaceutical wholesalers where it was reported up to 80% of counterfeiting [10]. Unfortunately consumers and prescribers are unable to assess the quality, safety and efficacy of medical products.
Considerable efforts are deployed in order to truly fight and prevent trade in counterfeit medical products [1], [3], [7], [10], [11], [12], [13]. One of them is based on the dissemination of information useful for assessing technologies aimed at preventing, deterring, or detecting counterfeit medicinal products. This is somewhat paradoxical in particular for poor/emerging countries since such practices require adequate/large infrastructure or facilities, i.e. well equipped laboratory that is very often lacking or simply not functioning. Unfortunately, lack/insufficient of such facilities reduces the capacity of the Regulatory Agencies to react rapidly and adequately based on scientific considerations, thus leading to ineffective control. Several analytical methods, including near infrared spectroscopy, Raman spectroscopy, refractometry, colorimetry, X-ray powder diffraction analysis, nuclear magnetic resonance [14], [15], [16], [17], [18], [19], [20], [21], [22] and separations techniques such as liquid chromatography (LC), thin layer chromatography, gas chromatography and capillary electrophoresis (CE) [23], [24], [25], [26], [27], [28], [29], [30] are used to analyse pharmaceutical substances, taking into account their variety of structure and chemical properties such as polarity and acidity. These methods need straightforward sample preparation and rapidity to support decisions in pharmaceutical fields, i.e., batch release or rejection, etc. However, for most of these techniques, financial expenses are not affordable to allow an easy implementation for a regular, systematic and wide-spread (or extended) control. Furthermore, the apparatus maintenance is one of the crucial issues allowing a long-term use of an analytical device in emerging countries.
Last 20 years, CE has gained importance for its ability to analyze several compounds with good selectivity [27], [28]. Several aspects can largely contribute to the CE implementation in poor/emerging countries: simple, reliable and (cost-)efficient drug control methods, financial expenses, i.e., solvent and reference material consumption [31], water is often the solvent of choice, ease of operation (no need of complex solvent gradients [32]). Finally, several generic conditions have been reported for separating molecules. In this context, the University of Applied Sciences Western Switzerland, College of Engineering and Architecture of Fribourg (UAS-WS-FR) has developed in collaboration with the School of Pharmaceutical Sciences, University of Geneva-Lausanne and the Geneva University Hospital (HUG) a low cost analytical device, based on capillary electrophoresis (CE), with the aim to use it for educational purpose in developing and transitional countries. Three prototypes were built, the first one, within the period 2006–2007, where the mechanical and electronical issues were assessed, including an original detection device built on the basis of diode technology. The second, within the period 2007–2008, for the software and ergonomic optimisations and the third one (2009), was used for the development of methods of drugs analysis, selected toward a list submitted by African partners located in Mali, where it is now located. In the method development stage, in collaboration with the Institute of Pharmacie, University of Liège, a particular attention was paid to the robustness of the system in order to anticipate the problems that can be encountered when dealing with analytical methods in Africa as well as the quantitative aspects of quality controls of drugs.
In this paper, the analytical performance and the ability of the developed low-cost CE equipment for quantification is presented. A complete validation study with minimal requirement in regards to calibration purposes, were performed on representative drugs with different physico-chemical properties: quinine (QUN), furosemide (FUR) and the combination trimethoprime (TMP)/sulfamethoxazol (SMX) (see chemical structures in Fig. 1). These medicines represent one of the most targeted pharmacological groups by counterfeiting namely the antimalarial (21% of counterfeiting), diuretic (9%) and anti-effective (12%) drugs, respectively [35]. A strategy based on the total error of measurement was applied [33], [34] and completed with a method comparison in order to evaluate the performance of the low-cost CE equipment to another one commonly available on the market.
Section snippets
Instrumentation
Experiments for method development and validation of QUN were performed on an Agilent HP3DCE system (Hewlett-Packard, Waldbronn, Germany) equipped with an on-column diode-array detector, an autosampler, a high-velocity air-cooled capillary cartridge, a power supply able to deliver up to 30 kV and an external pressure system. A CE ChemStation software version Rev. A.10.02 was used to control the CE instrument, to acquire and to handle the data. Separations were performed in bare fused-silica
CE method development
In this study, CE methods were developed for identification of counterfeit drugs, with a focus on the determination of the presence of the active ingredient and the possibility to rapidly decipher regarding the correct amount of the active ingredient. Thus, several aspects needed to be taken into account: (i) simple and generic methods, in order to analyze a high number of compounds and make easier the method selection for each analyte with basic chemistry knowledge; (ii) low cost methods,
Conclusion
Drug counterfeits is a major public health issue in some poor and emerging countries. In order to fight this problem a robust and low cost analytical device was developed. Three methods were developed for the quantitative analysis of active substances present in pharmaceutical formulations subjected to be counterfeited and selected according to their therapeutic uses. For these methods, among the counterion tested, Tris+ gave the best results. Suitable parameter values were obtained allowing
Acknowledgements
A research grant from the Belgium National Fund for Scientific Research (FRS-FNRS) to E. Rozet is gratefully acknowledged as well as the research grant from the Belgian Coopération Universitaire au Développement (CUD, R.D. Marini) and Walloon Project PPP (Convention OPTIMAL DS No. 917007, R.D. Marini). Research grant from University of applied sciences of western Switzerland (Fribourg) Projet d’institut iTIN, Sagex No. 11480/19870 were received for the low-cost CE device development (C.
References (47)
- et al.
Quality assessment of Internet pharmaceutical products using traditional and non-traditional analytical techniques
Int. J. Pharm.
(2005) - et al.
Analysis of illegally manufactured formulations of tadalafil (Cialis®) by 1H NMR, 2D DOSY 1H NMR and Raman spectroscopy
J. Pharm. Biomed. Anal.
(2008) - et al.
Detection of counterfeit Viagra® with Raman spectroscopy
J. Pharm. Biomed. Anal.
(2008) - et al.
Use of refractometry and colorimetry as field methods to rapidly assess antimalarial drug quality
J. Pharm. Biomed. Anal.
(2007) - et al.
The usefulness of simple X-ray powder diffraction analysis for counterfeit control—the Viagra® example
J. Pharm. Biomed. Anal.
(2007) - et al.
Detection of Lipitor® counterfeits: a comparison of NIR and Raman spectroscopy in combination with chemometrics
J. Pharm. Biomed. Anal.
(2008) - et al.
NIR spectrometry for counterfeit drug detection. A feasibility study
Anal. Chim. Acta
(2005) - et al.
Quality assessment of Internet pharmaceutical products using traditional and non-traditional analytical techniques
Int. J. Pharm.
(2005) - et al.
Near-infrared chemical imaging (NIR-CI) for counterfeit drug identification. A four stage concept with a novel approach of data processing (Linear Image Signature)
J. Pharm. Biomed. Anal.
(2010) - et al.
Challenging near infrared spectroscopy discriminating ability for counterfeit pharmaceuticals detection
Anal. Chim. Acta
(2010)
Determination of 19 antiretroviral agents in pharmaceuticals or suspected products with two methods using high-performance liquid chromatography
J. Chromatogr. B
Development and validation of an improved HPLC method for the control of potentially counterfeit isometamidium products
J. Pharm. Biomed. Anal.
High-performance liquid chromatography analysis of anti-inflammatory pharmaceuticals with ultraviolet and electrospray-mass spectrometry detection in suspected counterfeit homeopathic medicinal products
J. Pharm. Biomed. Anal.
Development and validation of a capillary electrophoresis method within a pharmaceutical quality control environment and comparison with high-performance liquid chromatography
J. Chromatogr. A
Collaborative study on a liquid chromatographic method for the determination of R-timolol and other related substances in S-timolol maleate
Anal. Chim. Acta
Harmonization of strategies for the validation of quantitative analytical procedures. A SFTP Proposal—Part 1
J. Pharm. Biomed. Anal.
Determination of homologues of quaternary ammonium surfactants by capillary electrophoresis using indirect UV detection
J. Chromatogr. A
Nonaqueous capillary electrophoresis method for the enantiomeric purity determination of S-timolol using heptakis(2,3-di-O-methyl-6-O-sulfo)-β-cyclodextrin: validation using the accuracy profile strategy and estimation of uncertainty
J. Chromatogr. A
LC method for the determination of R-timolol in S-timolol maleate: validation of its ability to quantify and uncertainty assessment
Talanta
Critical analysis of several analytical method validation strategies in the framework of the fit for purpose concept
J. Chromatogr. A
Using total error as decision criterion in analytical method transfer
Chemometr. Intell. Lab. Syst.
Counterfeit Medical Products, Report by the Secretariat, Executive Board, 124th Session
Counterfeit Drugs—Guidelines for the Development of Measures to Combat Counterfeit Drugs
Cited by (67)
Capillary electrophoresis as a simple and low-cost analytical tool for use in money-constrained situations
2023, TrAC - Trends in Analytical ChemistryAuthentication of medicinal herb Wikstroemia indica using novel DNA markers derived from the chloroplast genome sequences
2021, Journal of Applied Research on Medicinal and Aromatic PlantsLow-cost and open-source strategies for chemical separations
2021, Journal of Chromatography ACost-effective capillary electrophoresis with contactless conductivity detection for quality control of beta-lactam antibiotics
2019, Journal of Chromatography A
- 1
FNRS-FRS Post-doctoral researcher.