Abstract

Counterfeit and illegal pharmaceutical products are an increasing worldwide problem and constitute a major challenge for analytical laboratories to detect and characterize them. Spectroscopic techniques such as infrared spectroscopy and Raman spectroscopy have always been the first methods of choice to detect counterfeits and illegal preparations, but due to the evolution in the seized products and the necessity of risk assessment, chromatographic methods are becoming more important in this domain. This review intends to give a general overview of the techniques described in literature to characterize counterfeit and illegal pharmaceutical preparations, focusing on the role of chromatographic techniques with different detection tools.

Introduction

Counterfeiting of medicinal products is a problem that has existed for centuries. During the first century, Pedanius Dioscorides, a Greek physician, warned about the dangers of adulterated drugs (1). Since then, many crises of falsification of medicines have been documented (2). Most of these crises implicated falsified herbal medicines and resulted in many lethal accidents, due to toxicity and/or a lack of efficacy of the adulterated drugs.

In modern times, the counterfeiting of drugs has been a growing problem for several years, especially since the extension of the internet. It is estimated that counterfeit drugs represent 7% of the worldwide pharmaceutical market (3, 4). Africa, Southeast Asia and many countries in Latin America are the most affected areas, where the World Health Organization (WHO) estimates that more than 30% of the medicines on sale are counterfeited (5). The industrialized countries (United States, European Union, Australia, Canada, Japan and New Zealand) have approximately 1% of their pharmaceutical market affected, despite effective regulatory systems and market controls.

According to data of the Pharmaceutical Security Institute (PSI), the international trade of counterfeit medicines is in permanent growth (6). Figure 1 shows the total number of reports of counterfeiting over the past nine years, revealing a permanent increase in the number of cases. Many factors may explain this growth: the lack of effective enforcement agencies in developing countries and the lack of a harmonized legal framework to define pharmaceutical crime and the penalties to apply. There is more evidence that the trade in counterfeit drugs is linked to international organized crime, because the trade of counterfeit drugs is more lucrative than the trade in narcotics and the criminal penalties for pharmaceutical counterfeiting are less severe (7, 8). The growth concerning the counterfeiting of medicines is also shown by the evolution of the number of cases opened by the office of criminal investigations of the Food and Drug Administration (FDA) (Figure 2) (9).

Figure 1.

Total number of reports of counterfeiting, illegal diversion and theft incidents for nine consecutive years (6).

Figure 1.

Total number of reports of counterfeiting, illegal diversion and theft incidents for nine consecutive years (6).

Figure 2.

Counterfeit drug cases opened by the FDA's office of criminal investigation per fiscal year.

Figure 2.

Counterfeit drug cases opened by the FDA's office of criminal investigation per fiscal year.

The WHO first cited the counterfeiting of medicines in 1985 at a conference of experts on the rational use of drugs in Nairobi. In 1988, a World Health Assembly Resolution (41.16) recommended to “initiate programmes for the prevention and detection of export, import and smuggling of falsely labelled, spurious, counterfeited or substandard pharmaceutical preparations” (10). This led to the launch of many international initiatives, among which the International Medicinal Products Anti-Counterfeiting Taskforce (IMPACT), started by the WHO in 2006. In parallel, the major pharmaceutical companies established the PSI in 2002. On the European level, the European Alliance for Access to Safe Medicines (EAASM) was created (11). This is a pan-European patient safety initiative committed to promoting the exclusion of counterfeit and substandard medicines from the supply chain. The European Parliament and the Council of Europe recently created an amendment to the European directive 2001/83/EC (12) on the community code relating to medicinal products for human use, describing the policy of the European Union towards counterfeit and substandard medicines. On the 26th of October, 2011, Europe launched the Medicrime convention, which was held in Moscow, Russia. Medicrime is the first international instrument for the criminalization of counterfeiting medical products and similar crimes to protect public health (13).

The WHO (14) defines a counterfeit drug as, “one which is deliberately and fraudulently mislabelled with respect to identity and/or source. Counterfeiting can apply to both branded and generic products and counterfeit products may include products with the correct ingredients or with the wrong ingredients, without the active pharmaceutical ingredients (APIs), with insufficient active ingredient or with fake packaging.” The WHO also defines a substandard medicine [also called an out of specification (OOS) product] as, “a genuine medicine produced by manufacturers authorized by the National Medical Regulatory Authority which do not meet the quality specifications set for them by national standards”. By definition, the latter group of medicines should not be present on the market. If they are, a problem has occurred with the controls of the legitimate supply chain or there have been unscrupulous activities and reselling of medicines to be destroyed (10).

The European parliament recently adopted a definition of falsified medicines, that is, a compromise between the definitions of counterfeit and substandard medicines of the WHO: “A falsified medicinal product is any medicinal product with a false representation of: (a) its identity, including its packaging and labelling, name, composition in respect of any of its components including excipients and strength; and/or (b) its source, including the manufacturer, country of manufacturing, country of origin, marketing authorization holder; and/or (c) its history, including the records and documents relating to the distribution channels used” (15).

U.S. law defines counterfeit drugs “as these sold under a product name without proper authorization. Counterfeiting can apply to both brand name and generic products, where the identity of the source is deliberately and fraudulently mislabelled in a way that suggests it is the authentic approved product. Counterfeit products may include products without the active ingredient, with an insufficient quantity of the active ingredient, with the wrong active ingredient, or with fake packaging” (4).

Due to the fact that the previously mentioned definitions are quite general and not always adapted to the situation encountered on the European and other markets of the industrialized world, the Dutch National Institute for Public Health and the Environment (RIVM) proposed a classification (Table I) distinguishing counterfeits, the appearance of which corresponds to that of the genuine product, and imitations, the appearance of which does not (16). Most of these imitations originate from Asian countries, which do not recognize European and American patents and represent the majority of illegal pharmaceutical preparations analyzed in the Official Medicines Control Laboratories (OMCL) recognised by the European Directorate For Quality of Medicines (EDQM).

Table I

Definitions of the RIVM Classes (13)

Primary category Subcategory Inclusion and exclusion criteria 
 Professional Appearance in conformity with genuine medicine 
  Content of correct API within 90–110% of declared value 
  No other APIs; not genuine medicine 
 Non-professional Appearance in conformity with genuine medicine 
  Content of correct API outside 90–110% of declared value 
  No other APIs 
Counterfeit Mixed Appearance in conformity with genuine medicine 
  Contains correct API and another known API 
 Fraudulent Appearance in conformity with genuine medicine 
  Contains a different, known, API. 
 Analog Appearance in conformity with genuine medicine 
  Contains other, unapproved API 
 Placebo Appearance in conformity with genuine medicine 
  Does not contain APIs 
 Professional Appearance not in conformity with genuine medicine 
  Content of correct API within 90–110% of declared value 
  No other APIs 
 Non-professional Appearance not in conformity with genuine medicine 
  Content of declared API outside 90–110% of declared value 
  No other APIs 
Imitation Mixed Appearance not in conformity with genuine medicine 
  Contains declared API and another API 
 Fraudulent Appearance not in conformity with genuine medicine 
  Contains an undeclared API 
 Analog Appearance not in conformity with genuine medicine 
  Contains other, unapproved API 
 Placebo Appearance not in conformity with genuine medicine 
  Does not contain APIs 
Primary category Subcategory Inclusion and exclusion criteria 
 Professional Appearance in conformity with genuine medicine 
  Content of correct API within 90–110% of declared value 
  No other APIs; not genuine medicine 
 Non-professional Appearance in conformity with genuine medicine 
  Content of correct API outside 90–110% of declared value 
  No other APIs 
Counterfeit Mixed Appearance in conformity with genuine medicine 
  Contains correct API and another known API 
 Fraudulent Appearance in conformity with genuine medicine 
  Contains a different, known, API. 
 Analog Appearance in conformity with genuine medicine 
  Contains other, unapproved API 
 Placebo Appearance in conformity with genuine medicine 
  Does not contain APIs 
 Professional Appearance not in conformity with genuine medicine 
  Content of correct API within 90–110% of declared value 
  No other APIs 
 Non-professional Appearance not in conformity with genuine medicine 
  Content of declared API outside 90–110% of declared value 
  No other APIs 
Imitation Mixed Appearance not in conformity with genuine medicine 
  Contains declared API and another API 
 Fraudulent Appearance not in conformity with genuine medicine 
  Contains an undeclared API 
 Analog Appearance not in conformity with genuine medicine 
  Contains other, unapproved API 
 Placebo Appearance not in conformity with genuine medicine 
  Does not contain APIs 

A recent study funded by Pfizer estimates the West European illicit trade of medicines at Euro10.5 billion. This study states that one out of five Europeans has bought a prescription-only medicine from an illegal source. Most of these bought their medicines on the internet. According to a WHO estimation, more than 50% of the medicines bought from websites disclosing their identity are counterfeited (17, 18).

Even if pharmaceutical counterfeiting is a global problem, the categories of adulterated drugs and the associated risks vary according to the region under consideration.

In developing countries, the anti-infective drugs are the most counterfeited (19). This represents a serious public health problem, because most of the population buy their medicines in the street at low prices. These products are often counterfeited or substandard medicines with low or no therapeutic activity. When treating diseases associated with high untreated mortality rates such as malaria, pneumonia, meningitis, AIDS, typhoid and tuberculosis with inefficient drugs, mortality and morbidity increase. Moreover, the use of subtherapeutic amounts of active ingredients increases the risk of developing microbial resistance. In this case, even genuine drugs could become inefficient (10).

In industrialized countries, the primary counterfeited therapeutic categories are lifestyle drugs (weight loss drugs and potency enhancement drugs). The risks associated with these drugs are mostly due to the presence of toxic compounds or impurities, too high amounts of active ingredients, the presence of unexpected active ingredients or new unknown designer molecules and wrong, missing or inadequate information concerning the use of the drug (20). Other categories such as antineoplastic drugs or cardiovascular counterfeited drugs have also been detected (21). The fact that counterfeit medicines may enter the legal supply chain represents a major risk for public health. Moreover, in addition to potential adverse effects, the patients may lose trust in medicines, even if they are sold in pharmacies, and so damage their trust in the health care systems, the health care professional, the pharmaceutical industry and the drug regulatory authorities (22).

Another problem in addition to counterfeiting is the adulteration of herbal products. In developed countries, people buy herbal alternatives for the treatment of obesity or erectile dysfunction disorders via the internet, believing that there is no risk for their health. However, several studies detected synthetic drugs as adulterants in herbal formulations, representing huge risks for public health (23, 24). When purchasing counterfeit drugs, the patient can be held partially responsible for the health risk he or she is willing to take, but this is not the case for adulterated herbal remedies. These products are fraudulently labeled and there is no way for the patient to know that he or she is taking preparations representing high risks for his health.

The national and international authorities have to be supported with data about falsified samples from laboratory analysis. Therefore, several laboratories throughout the world have specialized in the detection and analysis of counterfeit medicines. More knowledge about these samples can lead to a better fight against counterfeiting and a growing awareness of the risks by the patients.

Several reviews have already been published in the domain of counterfeit medicines and illegal pharmaceutical preparations. Most of them focus on a specific technique; e.g., nuclear magnetic resonance (NMR) (25), or on a specific type of counterfeited products, e.g., PDE-5 inhibitors (26). A few more general reviews have been published (4, 27), in which the different techniques that could be applied in the analysis of counterfeit medicines were discussed, together with some applications. This review intends to provide an updated overview of the techniques and approaches used in the detection and characterization of counterfeit medicines and illegal pharmaceutical preparations, with a focus on the role of chromatography and the chromatographic approaches described in literature. No reviews have been published in this domain focussing on chromatography. Chromatographic and hyphenated techniques have great potential in the analysis and characterization of counterfeit medicines and illegal pharmaceutical preparations, because they allow not only the detection and quantification of active ingredients, but can also provide a complete image of the composition of the sample. These characteristics have made chromatography the number one technique for risk evaluations of illegal preparations.

Analytical Approaches

The fight against the counterfeiting of medicines has resulted in numerous articles in which several analytical techniques have been used for the detection of counterfeit medicines. These techniques are separated in two primary groups: chromatographic and spectroscopic techniques.

Spectroscopic approaches: A brief overview

Spectroscopic techniques are often preferred to chromatography for the identification of counterfeit drugs because they are fast, need less (or no) sample preparation and some are nondestructive. Fourier-transformed infrared spectroscopy (FT-IR) (28–31), near infrared spectroscopy (NIR) (30, 32–36), Raman spectroscopy (30, 33, 37–41), X-ray diffraction (XRD) (42), colorimetry (43–47) and NMR (38, 48, 49) have demonstrated their usefulness to detect counterfeit or adulterated drugs. FT-IR and NMR are often used in the structural elucidation of active compounds or novel analogs found in illegal pharmaceutical preparations (25, 28, 29, 38, 48, 50–74). In most cases, these techniques are used in combination with liquid chromatography with mass spectrometry detection (LC–MS; described later). On the contrary, NIR is more often used in the detection and screening of counterfeit medicines. This is shown for example by Vredenbregt et al. (32), who described a method for the screening of Viagra tablets (genuine, counterfeit and imitations) that is able to check the homogeneity of a batch, detect counterfeit tablets and imitations and reveal the presence of sildenafil citrate in the tablets. Another example was given by Been et al. (33), who related the NIR spectra of counterfeit medicines to their chemical profiles and thus discriminate between counterfeits and genuine medicines, but also between different categories of counterfeit medicines. Dowell et al. (34) could discriminate between genuine and counterfeit artesunate tablets based on their NIR spectra; da Silva Fernandes et al. (35) used NIR to detect glibenclamide adulteration in tablets in a nondestructive way. A final example was given by Storme-Paris et al. (36), who used NIR spectra and chemometrics to discriminate between authentic samples, suspicious samples (samples with the same batch number as the counterfeits, withdrawn as a precaution) and counterfeit or imitation samples. Raman spectroscopy was also used in the discrimination between counterfeit and genuine tablets (30, 33, 37, 38). This discrimination is based on the presence of different excipients that could also be identified with Raman spectroscopy, as described by Trefi et al. (38). Been et al. (33) and Dégardin et al. (40) related the Raman spectra to the chemical profiles of counterfeit medicines and were able to discriminate genuine medicines from counterfeits and to differentiate between different categories of counterfeit medicines. Raman spectroscopy could also be used in portable devices to detect counterfeit medicines. An example of this for artesunate tablets was given by Ricci et al. (41). Another approach, which is becoming more popular, is the combination of different spectroscopic techniques for the detection and characterization of potential counterfeited samples. An example of a general approach in which two techniques are used in combination is given by De Peinder et al. (75), who used NIR and Raman spectroscopy to discriminate between genuine and counterfeit tablets of Lipitor. Sacré et al. (30) analyzed a group of counterfeit, imitated and genuine samples of both Viagra and Cialis with FT-IR, NIR and Raman spectroscopy and showed that the data was complementary. In that way, they were able to combine different spectra into one data set and treat it as a whole using chemometrics. The combination of different spectra improved the classification and predictive properties of the models, compared to those calculated based on only one type of spectrum (76). The combination of these techniques in the fight against counterfeit medicines is promising, because the quality of the counterfeit tablets is increasing (30, 76). Recently, the use of Raman microscopy was also described for the discrimination between counterfeit and genuine products (39, 77).

Even if NMR spectroscopy is often used in combination with MS and FT-IR for structural elucidation, NMR is also able to reveal differences in the composition of tablets. As an example, Holzgrabe and Malet-Martino (25) used NMR to reveal differences in composition between genuine and counterfeit tablets of Viagra. Nyadong et al. (49) applied NMR for the characterization of 14 different artesunate preparations, representative for the informal Asian market. The results revealed that only five preparations contained the active ingredient. NMR is a very valuable technique in counterfeit detection and analysis, although it has some disadvantages. First, it necessitates expensive equipment; it also needs experienced scientists to operate it and to interpret the data, especially in the analysis of unknown samples.

X-ray powder diffraction (XRPD), although quite expensive and not present in a common laboratory for the quality control of medicines, has showed its usefulness. Maurin et al. (42) showed that XRPD allows a fast screening of tablets that is able to discriminate between counterfeit and genuine products and to reveal differences in coating and product composition. Ortiz et al. (78) recently presented an application of X-ray fluorescence spectrometry for the chemical profiling of sildenafil and tadalafil tablets. Based on these chemical profiles, the authors were able to check the quality of the tablets and to detect suspicious samples.

Colorimetry is less often used in the detection of counterfeits, but it can be useful to screen for the presence of an active ingredient and to quantitate it (43, 45–47), even if chromatographic methods seem more appropriate in this case. Also, the detection of counterfeit tablets based on colorimetric measurements of the tablets' coatings or the secondary packaging has been described (44). In conclusion, many spectroscopic methods can be used for counterfeit detection, but some necessitate expensive and sophisticated equipment. In general, spectroscopic techniques are used for the detection of suspicious samples and they have some disadvantages, especially in the detection of impurities and the quantification of active ingredients, because they are often approaches for the whole sample. Therefore, next to the classical techniques like infrared, chromatographic approaches are interesting, because chromatography is a standard technique present in almost all laboratories for medicinal control.

Chromatographic Approaches

Chromatographic techniques have been extensively used in the detection and characterization of counterfeit medicines and illegal pharmaceutical preparations. In the majority of published papers, chromatographic techniques were used for the separation of active ingredients in the samples, to quantify them, to isolate the active ingredients or to detect or identify with mass spectrometry, for example. In some papers, and especially in papers concerning the counterfeit or falsification of traditional Chinese herbal medicines, the use of chromatographic fingerprints is often described.

Different chromatographic techniques have been described for the analysis of counterfeit medicines and illegal pharmaceutical preparations.

Thin-layer chromatography

Thin-layer chromatography (TLC) is a technique with the advantages that it is easy to implement and cheap. The principle of using TLC in counterfeit analysis is quite simple: the presence/identity of the active substance in a counterfeit or imitation sample is confirmed by comparing the results with a standard solution that is also applied to a TLC silica plate.

TLC has been used for the identification of essential drugs such as acetylsalicylic acid, paracetamol, ibuprofen, dexamethasone, prednisolone and hydrocortisone in preparations and betamethasone, metamizol and hydrocortisone acetate (79). TLC combined with ultraviolet (UV) detection and microcrystal tests was used for the detection and identification of phentermine (Ionamin) adulteration. The results showed that the counterfeit capsules contained only caffeine and phenylpropanolamine (80). More recently, Hu et al. (81) developed a fast chemical identification system consisting of two chemical color reactions and two TLC systems for the characterization of counterfeit or suspected macrolide antibiotic preparations. The system is able to distinguish 14-membered and 16-membered macrolides based on the color reactions. The TLC systems (one for each group) are then used to identify the concerned macrolide. Another application was described by Moriyasu et al. (82, 83) using TLC for the identification of sildenafil adulteration in health foods. TLC was applied to commercial health food products. After the identification of sildenafil, high-performance liquid chromatography–diode array detection (HPLC–DAD) revealed doses ranging from 25 to 45 mg of sildenafil citrate per tablet or bottle, corresponding to the therapeutic doses and thus constituting an important health risk. Also, Singh et al. and Reddy et al. (83, 84) developed a high-performance thin-layer chromatography (HPTLC) method for the identification and quantification of sildenafil in herbal formulations. Shewiyo et al. (85, 86) developed and validated normal-phase HPTLC methods with densitometric detection for the quality control and counterfeit detection of co-trimoxazole tablets and fixed-dose combination tablets of lamivudine, stavudine and nevirapine.

In the counterfeiting of herbal medicines, in which incorrect and cheap herbs are sold instead of the medicinal plant, TLC can also be applied . An example was described by Wu (87) for the identification of the counterfeit of a traditional herbal medicine called Curculigo Orchiode. For this purpose TLC and UV spectrometry were applied along with the classical morphology and histology tests.

Recently, TLC played an important role in a basic quality control test performed on anti-malarian drugs in the Amazon basin countries. Together with other basic tests, TLC showed an improvement in the quality of these kinds of medicines in these countries over the years, starting from the beginning of the quality control program (88). This is a good example of how basic quality testing, without very sophisticated techniques, can lead to an improvement in the quality of medicines sold and the withdrawal of counterfeit and/or substandard medicines from the market.

Liquid chromatography

LC is often used in the analysis and characterization of counterfeit medicines and illegal pharmaceutical preparations. LC, in combination with different detectors, is used in this domain for several purposes. The first is as a method for target analysis (the presence of one or more known compounds) and as a quantification method. LC in combination with MS is often used in screening of counterfeit samples, identification of ingredients and structural elucidation. Another application of LC is the use of chromatographic fingerprints, in analogy with the fingerprints obtained with spectroscopic techniques like infrared. Chromatographic fingerprints are often described in the quality control of herbal products, and especially in the determination between the necessary plants and those sold as counterfeits or falsifications.

Liquid chromatography–ultraviolet spectroscopy

LC with UV or DAD is still an important technique in the quality control of medicines and the characterization of illegal pharmaceutical preparations. The advantages of the technique are its low cost and its easiness to apply and to interpret. HPLC–UV/DAD more often belongs to the standard equipment of a medicine control laboratory and is therefore available in the majority of laboratories.

In literature, several methods are described for the analysis of active ingredients in illegal preparations and for impurities and not registered analogs. HPLC–UV/DAD has extensively been used in the detection of counterfeited, imitation and adulterated samples containing PDE-5 inhibitors. Nagaraju et al. (89) described a method that was able to separate and quantify sildenafil and its impurities. In a chromatographic run of 15 min, they were able to determine sildenafil and its process related impurities, both in bulk products and in pharmaceutical formulations. Park and Ahn (90) screened 105 counterfeit samples, seized in Korea, for the presence of sildenafil and tadalafil using HPLC–UV. The results showed that 73 of the 105 samples contained sildenafil in doses ranging from 4.3 to 453.2 mg per tablet. Seven samples contained tadalafil in doses from 2.2 to 40.4 mg per tablet. The proportion of cases having more than 100 mg sildenafil was 50%, and 78% had more than 20 mg of tadalafil. The presence of amounts higher than the maximal allowed therapeutic dose is worrying and represents a huge risk to the patients. Recently, the authors' group developed and validated an ultra high-performance liquid chromatography (UHPLC)–DAD method for the quantification of the three registered PDE-5 inhibitors (sildenafil, tadalafil and vardenafil) and seven of the most occurring analogs and impurities in counterfeit and imitation samples seized in Belgium. The method was applied in routine analysis after confirmation and identification with LC–MS (91). The same approach was followed by Gratz et al. (92), who developed an HPLC–UV method for the quantification of registered PDE-5 inhibitors after their presence was confirmed with LC–MS. This group screened 40 botanical products, from which half were tested positive for PDE-5 inhibitors. The majority of the positive samples contained therapeutic doses of the active ingredients. Tomic et al. (93) conducted an HPLC–UV analysis on a group of erectile dysfunction drugs seized by the Zagreb city police in Croatia. The results showed that even if all samples contained the correct active substance, more than 50% of the samples failed the content limits of 95–105%, raising the suspicion of counterfeiting. De Orsi et al. (94) developed an HPLC–DAD method for the determination of PDE-5 inhibitors, testosterone and local anesthetics in cosmetic creams sold as promising remedies for male erectile dysfunction and female genital stimulation. The results showed that in the majority of the analyzed creams, one or more of these substances, which are prohibited in cosmetics, was present. In India, HPLC–DAD was used in a screening of Indian aphrodisiac ayurvedic/herbal healthcare products for adulteration with PDE-5 inhibitors (95). In the study, 85 samples of this product, well known on the regular market in India, were analyzed and only one was tested positive for adulteration with sildenafil in a therapeutic dose. These results showed the initiation of the clandestine activity with a traditional Indian product. The previous two studies (94, 95) clearly show an advantage of using HPLC over spectroscopic methods, i.e., the application to different kinds of matrices such as tablets, creams and herbal products. Zou et al. (96) applied HPLC–DAD to the screening of pre-market capsules and pre-mixed bulk powder for the presence of PDE-5 inhibitors and their analogs. Six out of seven samples were tested positive for non-approved analogs of sildenafil.

Also, HPLC–UV has been applied for the characterization of other types of molecules/preparations. For example, Amin et al. (97) used HPLC–UV in a quality control study of sulphadoxine-pyrimethamine and amodiaquine products in Kenya. These products are life saving medicines, used in the prevention and treatment of malaria, and the presence of counterfeit and substandard medicines on the market constitutes a huge health risk. The results of the tests showed that approximately one third of the preparations failed the limits of 93–107% set by the United States Pharmacopeia (USP) (98). Gaudiano et al. (99) applied HPLC–DAD for the quality control of antimalarial tablets purchased on the informal market of Goma (Democratic Republic of Congo). The results showed not only that the tablets contained only 88.6% of the indicated amount of quinine, but also that many impurities were present in amounts higher than the reference samples and the samples purchased on the Italian market. Debrus et al. (100) proposed an HPLC–DAD method for the screening of 19 anti-malaria drugs in pharmaceutical preparations. The method was validated and intended for the use in developing countries, where the anti-malaria drugs are important on the black markets as substandard or counterfeit drugs.

A validated HPLC–DAD method was proposed for the simultaneous screening of some antibiotics often present in counterfeit and substandard medicines by Gaudiano et al. (101). Shad et al. (102) proposed an HPLC–UV method for the characterization of potential counterfeit isometamidium products. Isometamidium is a product used in the prophylaxis of veterinary trypanosomiasis.

Another important problem, especially in the Western world, are the dietary supplements sold for weight control and presumed to be 100% natural and from herbal origin, although adulteration with different kinds of synthetic drugs has been discovered. HPLC–UV has been extensively used for these cases. Kim et al. (103) developed and validated an LC–DAD method, applicable to routine drug adulteration screening of dietary supplements for anti-diabetes and anti-obesity drugs. This kind of screening is very important, especially in the Western world, where adulterated dietary supplements purchased via the internet are one of the major groups of seized and analyzed preparations. Dietary supplements adulterated with sibutramine and its analogs are frequently encountered. Stypulkowska et al. (104) proposed a strategy for the characterization of such adulterated supplements, in which the presence of a chemical is first tested with XRPD, followed by an identification of sibutramine and/or its analogs with XRPD and/or LC–time-of-flight (TOF)-MS. LC–UV is used to quantify sibutramine and/or its analogs when their presence and identity is confirmed. Other examples of applications are given by Almeida et al. (105, 106), who proposed HPLC–UV methods for the confirmation and quantification of amfepramone, fenproporex, diazepam and mazindol as adulterants in herbal preparations. Mikami et al. (107) proposed an HPLC–UV method for the screening of benzodiazepines in herbal slimming products. Benzodiazepines are often used to mask the side effects of anorexics. Recently, the authors' group developed and validated a UHPLC–DAD method for the simultaneous quantification of nine chemical compounds (sibutramine, modafinil, metformine, orlistat, diethylpropion, ephedrine, norephedrine, caffeine and theophyllin), often encountered in adulterated herbal dietary supplements with slimming as indication (108). Liu et al. (109) described an HPLC–DAD method that, in combination with a GC–MS method, is able to screen herbal dietary supplements for adulteration with 266 pharmaceuticals.

Liquid chromatography–mass spectroscopy

LC–MS is the method of choice when dealing with counterfeit and illegal pharmaceutical preparations. The method not only allows target analysis, but also screening of unknown preparations for the presence of chemical drug compounds. Furthermore, when an unknown compound is encountered, LC–MS in combination with other techniques like IR and NMR, allows identification and/or structural elucidation. The latter is very important because the companies producing counterfeit medicines and imitations are modifying the chemical structures of the registered active substances, creating non-tested analogs to avoid patent laws.

In both domains, LC–MS as screening method and for structural elucidation, numerous papers have been published.

In the group of the PDE inhibitors, a lot of non-registered analogs and impurities have been detected. The majority have been detected and identified using LC–MS, generally combined with NMR and IR techniques (28, 29, 50–74). An overview of the different analogs detected over the years was recently given by Venhuis and de Kaste (26), therefore these applications will not be discussed in detail here. In addition to the use of LC–MS in the structural elucidation of analogs and impurities, several screening methods have been described for the detection and identification of PDE-5 inhibitors, analogs and impurities (92, 96, 110–112).

Even if the highest numbers of papers using LC–MS for screening and structural elucidation in the domain of counterfeiting medicines address the PDE-5 inhibitors, other counterfeited medicines can also be analyzed with LC–MS. Amin et al. (97) used LC–MS in the quality control and detection of counterfeit and substandard sulphadoxine-pyrimethamine and amiodiaquine products. Li et al. (113) performed the structural elucidation of dapoxetine, a selective serotonin reuptake inhibitor, present as adulterant in a health supplement for sexual performance enhancement. Recently, Dorlo et al. (114) applied LC–MS, combined with FT-IR and NIR, for the detection of counterfeit miltefosine capsules, used to treat a fatal parasitic disease in resource-poor countries. Dai et al. (115) developed a UHPLC–MS method for the qualitative detection of alpha-glucosidase inhibitors in potential counterfeit products sold to treat diabetes.

A group of medicines often encountered as adulterants in herbal slimming preparations are the anti-obesity drugs like sibutramine and analogs, but also other anorexics and diuretics, antidepressants and laxative molecules (116). LC–MS has been applied both for screening and for identification purposes. Kim et al. (103) and Stypulkowska et al. (104) applied LC–MS for the screening of herbal dietary supplements for the presence of sibutramine and its analogs. Venhuis et al. (117) applied LC–MS for the identification of rimonabant and sibutramine and their analogs in counterfeit Acomplia and imitation products, whereas Wang et al. (118) used LC–MS to perform a survey of 22 herbal weight reducing preparations for the presence of sibutramine and its analogs, phenolphthalein, fenfluramine and orlistat. Out of the 22 samples, 10 were positive for sibutramine, three for phenolphtaleine and two for N-mono-desmethyl sibutramine.

Bogusz et al. (119) developed an LC–MS-MS method to screen herbal remedies for the presence of synthetic adulterants. The proposed method was able to screen for adulterants of different clinical groups comprising analgesic drugs, antibiotics, antidiabetic drugs, antiepileptic drugs, aphrodisiacs, hormones and anabolic drugs, psychotropic drugs and weight reducing compounds. A similar approach was followed by Chen et al. (120), who developed a LC–linear ion trap (QTRAP)-MS method to screen botanical health supplements for the presence of blood pressure and lipid lowering agents, sedative drugs, anti-diabetic drugs, weight reducing agents and aphrodisiac drugs. De Carvalho et al. (121) recently reviewed all compounds found as adulterants in slimming phytotherapeutic formulations in addition to their analytical approaches. The majority of the different groups of adulterants that can be screened for with LC–MS includes anorexics, diuretics, benzodiazepines, antidepressants, analgesics and hypoglycemics. Another application was given by Hall et al. (122), who applied LC–MS for the characterization of artesunate tablets purchased in different Asian countries; 23 of 34 samples did not contain artesunate; 10 of the 11 that did contained artesunate in the correct dose. From the 23 samples not containing artesunate, eight contained erythromycin and five contained paracetamol.

Chromatographic fingerprinting

Chromatographic fingerprinting is a technique that is extensively described in the domain of plant analysis and is specific for authentic species recognition of traditional herbal medicines. A fingerprint can be defined as a characteristic profile reflecting the (complex) chemical composition of the analyzed sample and can be obtained by spectroscopic, chromatographic and electrophoretic techniques (123, 124). Spectroscopic fingerprints are very interesting and widely used for the identification of bulk materials. Pharmacopoeias use infrared spectra to compare the fingerprint regions of the spectra obtained from a sample with reference spectra, identifying a bulk product as the drug compound under concern (98, 125, 126). As described previously, infrared spectroscopy and other spectroscopic techniques have proven to be very valuable in the analysis and discrimination of counterfeit medicines. Nevertheless, a disadvantage of spectroscopic fingerprints is that the fingerprint is influenced by all compounds of the samples, because it is an analysis of the whole sample.

Therefore, fingerprints based on separation techniques like chromatography and electrophoresis are very interesting. By spreading the information about the chemical composition of the sample over time, the individual compounds and their underlying information can be revealed (123, 124). Chromatographic fingerprinting is mostly used in plant analysis for several purposes: for classification of plants, especially to differentiate related species, for which the minor differences in composition can largely affect the public health (128–130); for stability testing and quality control (130, 131); and to predict pharmacological activities or to identify potential active compounds (132–136). The first application is interesting in the detection and characterization of counterfeit samples. Also, counterfeiting is occurring in herbal medicines, selling non–standardized plants, related plants or even totally different plants, with huge health risks as a consequence.

Even if TLC (136–147) and GC–MS (148–159) (essentially for essential oils) are techniques that proved their usefulness in the identification of plants and discrimination between species, the literature is more often turning to LC combined with different detectors to differentiate between plants and fight counterfeits. The advantages of HPLC are its easiness to operate, its fully automatable character and its high resolution, selectivity and sensitivity. For herbal fingerprinting, many papers have been published using detectors such as UV absorbance (160–174), ELSD (162, 170), chemiluminescence and mass spectrometry (160, 164, 166, 169, 175, 176).

Despite the potential of chromatographic fingerprints in the classification, identification and discrimination of herbs and traditional medicines, only few publications were published using them in the domain of counterfeit medicines. Dumarey et al. (177) used chromatographic fingerprints or impurity profiles to distinguish four clusters of paracetamol preparations based on their synthesis pathways. In fact, paracetamol can be synthesised in different ways, and each synthesis pathway has its own impurity profile. This approach can both be used for detecting patent infringements and for counterfeit identification, because both synthesis pathways and the amounts of impurities can differ between genuine and counterfeit/imitation medicines. Schneider and Wessjohann compared the impurity profiles of Orlistat pharmaceutical products (178). The impurity profiles, recorded both with LC–UV and LC–MS-MS, showed a clear difference between the original product (Xenical) and two generic (legal) products (Figure 3). Even if the major impurity was the same for the three products, the generic products contained 17 and 14 different impurities above the detection limit, respectively, compared to four in the original product. All impurities were well within quality limits, so no problem is to be expected with the generic products, but this study shows that impurity profiles or fingerprints can be used to discriminate between original and generic products. Because the discrimination between original and generic is often more difficult than the discrimination between counterfeit and genuine, the approach will also be valuable in the detection and discrimination of counterfeit or imitation products of Xenical. Indeed, generic products have to meet the same quality requirements as the original products, whereas counterfeits and imitations often do not meet those requirements. These two studies illustrate the possibilities and the potential of chromatographic fingerprints in counterfeit detection. The authors' group conducted a feasibility study for the use of such fingerprints for the discrimination between genuine and counterfeit medicines. Two case studies were studied: one for a set of 73 counterfeit and imitation and nine genuine samples of Viagra and one for a set of 44 counterfeit and imitation and five genuine samples of Cialis (179). The fingerprints were recorded using HPLC–UV with methods adapted from those published in Pharmeuropa (180, 181). The fingerprints or impurity profiles showed clear differences between the genuine and counterfeit/imitation samples, as shown in Figure 4. The results showed, as could be already concluded from the studies described by Dumarey et al. and Schneider and Wessjohann (177, 178), that it is possible to discriminate counterfeits and genuine medicines based on chromatographic fingerprints or impurity profiles.

Figure 3.

HPLC–UV chromatograms of samples of tetrahydrolipstatin drugs: Roche (Xenical) (A); Ranbaxy (Cobese) (B); KRKA (Orsoten) (C) [reprinted with permission from Schneider and Wessjohann (178)].

Figure 3.

HPLC–UV chromatograms of samples of tetrahydrolipstatin drugs: Roche (Xenical) (A); Ranbaxy (Cobese) (B); KRKA (Orsoten) (C) [reprinted with permission from Schneider and Wessjohann (178)].

Figure 4.

Impurity profiles: counterfeit tablet of Viagra (A); genuine tablet of Viagra (B); colored imitation tablet of Cialis (C); genuine tablet of Cialis (D) [reprinted with permission from Sacré et al. 179)].

Figure 4.

Impurity profiles: counterfeit tablet of Viagra (A); genuine tablet of Viagra (B); colored imitation tablet of Cialis (C); genuine tablet of Cialis (D) [reprinted with permission from Sacré et al. 179)].

A disadvantage of the chromatographic fingerprint approach is the difficulty to extract the information from the data. In general, chemometrics are necessary to handle the amounts of data generated, especially for large sample sets. When recording chromatographic fingerprints or impurity profiles, retention time shifts can occur under the influence of column aging, temperature changes and mobile phase changes. These shifts influence the data analysis and interpretation, and therefore, the chromatograms should be aligned or warped. Different alignments or warping techniques exist (124, 179, 182, 183). The most popular technique is correlation optimized warping (COW) (124, 182, 183). In addition to the problem of data pretreatment, chromatographic techniques applied for fingerprinting generate large amounts of data, which causes the problem of interpretability. Again, chemometric approaches are necessary to interpret the data and to differentiate different samples as genuine and counterfeit. In chromatographic fingerprinting; more specifically, in the discrimination between samples, principal component analysis (PCA), partial least squares (PLS) and clustering techniques are often used (124, 179). Only few papers have used modeling techniques to predict the nature of a sample based on its chromatographic fingerprint. For modeling, basic techniques such as k-nearest neighbors (k-NN) and soft independent modeling by class analogy (SIMCA), seem to work perfectly for the discrimination between counterfeit and genuine samples (179, 184). The authors' group recently showed that some more advanced chemometrics can be valuable in the discrimination of genuine and counterfeit samples based on chromatographic fingerprints and can be more specific in the differentiation between the different classes/groups of counterfeit samples (184).

Gas Chromatography

Gas chromatography (GC) techniques have been used in the detection and characterization of counterfeit medicines. GC has been used to confirm the identity of essential oils and the presence of residual solvents, volatile constituents (especially in the quality control of herbal medicines) and unknown compounds or analogs (185). Two examples of the latter are the detection of amphetamine instead of sildenafil citrate with GC–MS in counterfeited tablets of Viagra in Hungary (4, 186) and the detection of oxycodone and dihydrocodeinone in counterfeit Ritalin with GC–flame ionization detection (FID) and GC–MS (187). Newton et al. and Reepmeyer and Woodruff (2, 57) used chemical derivatization and GC–MS to differentiate the four different possible structures of piperidenafil. To resolve the structure, the presence of the piperidine moiety was confirmed with acid hydrolysis of the sulphonamide bond, followed by analysis of the amine and the sulfonic acid by GC–MS. The same approach was used to elucidate structures of nor-acetildenafil (2, 57) and aildenafil (188). Liu et al. (109) proposed a GC–MS screening method, which, in combination with LC–DAD, was able to screen for 266 pharmaceuticals present as adulterations in herbal preparations. Among these pharmaceuticals are the important groups of anorexics, anxioletics, antidepressants and diuretics, often found in so-called natural slimming products. A German group analyzed 42 products of anabolic steroids from the illegal German market with GC–MS and found that 15 of these products did not contain the compounds that were labeled (189). This is an example of the performance of GC–MS for the analysis of steroids. In fact, this is the major application of GC–MS in the analysis of illegal pharmaceutical preparations in medicine control laboratories.

Lin et al. (190) used GC–MS in a study about the counterfeiting of musk, a highly valued ingredient in Chinese traditional medicines, and found that no muscone, the compound believed to be the active ingredient, was present in products seized by customs or in Musk-Tiger Bone plaster preparations. On the contrary, muscone was clearly present in the preparations purchased in Chinese medicine stores.

In Iran, GC–MS and HPLC were used in the analysis of counterfeit preparations of buprenorphine, the active ingredient of Temgesic and Bungesic, some of the most popular drugs of abuse by the young opioid-addicted population in Iran. Researchers revealed the presence of diacetylmorphine, acetylcodeine and pheniramine instead of buprenorphine in the majority of the samples originating from the black market (191). In Jordan, GC–MS was applied in the screening of seized counterfeit Captagon tablets (fenethylline), a popular drug of abuse in the Middle East. The results revealed the presence of amphetamine and methamphetamine, responsible for the stimulant effect experienced by the abuser, but also other different compounds like anti-malarial drugs, antibiotics and sympaticomimetica. The presence of these compounds in these preparations represents huge health risks, especially because they are often present in combination with fenethylline and the interactions between these drugs are unknown (192). Lee et al. (193) used impurity profiles, recorded with GC–FID and GC–MS, of illicit methamphetamine seized in Japan and Korea as chemical fingerprints to cluster samples with the same possible origin. The study revealed similarities between samples seized in different regions of Japan and Korea, showing the international nature of the trade in methamphetamine.

The analysis of organic volatile impurities is a useful tool in the quality control of bulk pharmaceuticals and also allows the detection of counterfeit drugs and tracing of their source. Static headspace analysis in combination with GC–MS is often used in the detection of organic volatile impurities, e.g., residual solvents (194–199). This approach has been used successfully in the detection of counterfeit sulfamethazine, ranitidine hydrochloride and doxycycline hyclate (200). In each case, the different sources could be distinguished based on the profiles of the organic volatile impurities present. Recently, the authors' group conducted a study in which a group of counterfeit and imitation Viagra and Cialis samples were tested for their residual solvent contents (201). The content was compared to the residual solvent contents of the genuine products and revealed a clear difference between genuine and counterfeit/imitation samples. In the non-genuine samples, more residual solvents were present and in higher doses, often in amounts exceeding the limits set by the International Committee for Harmonization guidelines for residual solvents (202) and the Pharmacopoeias (98, 125, 126).

Electrophoretic Approaches

Electrophoresis is another separation technique that has been described for some applications in the analysis of counterfeit medicines, substandard medicines and adulterated herbal preparations. Capillary electrophoresis (CE) has some advantages such as high resolution power (selectivity), short analysis time and the low consumption of chemicals and samples. Marini et al. (203) developed and validated methods for a prototype of a portable CE device based on capillary zone electrophoresis (CZE) for the quantification of some important anti-malarial drugs for quality control and counterfeit detection. The idea was to apply this device and the corresponding methods as quality control devices in some African regions where counterfeiting is reaching high proportions. Recently, Amin et al. (204) proposed a CE method for the quality control of fixed dose combination tablets of artesunate and amodiaquine. The authors considered the advantages of CE (long lifetime, low price of capillaries, low volumes and simplicity) over HPLC in the fight against low quality medicines in developing countries. Recently, Lamalle et al. (205) proposed a micellar electrokinetic chromatography (MEKC) method to detect and quantify 15 anti-malarial drugs in pharmaceutical preparations. The method was applied to four pharmaceutical preparations purchased on the African market. The results showed that all preparations contained the correct ingredients, although three of the four did not meet the 95–105% content limits set by the Pharmacopoeias and two of them contained the active ingredients in a dose inferior to 90% of the one claimed on the package.

Another domain in which CE has been applied was in the determination of adulterants in herbal preparations. The most frequently used techniques are CZE and MEKC. CZE methods have been proposed for the determination of anorexics (206, 207), amphetamines (206, 208), benzodiazepines (207) and some other frequently found adulterants (206, 207, 209). MEKC methods have been proposed for benzodiazepines (210, 211, 212) and nortriptyline, sulpiride and pyridoxine (211). The use of CE in the domain of counterfeit medicines is not often described in literature, nor is CE–MS, which could have potential as a confirmation method for adulterants.

Discussion and Conclusion

The idea of this review was to provide a general overview of the role chromatography currently plays in the detection, analysis/characterization and risk assessment of illegal and counterfeited pharmaceutical preparations. In literature, spectroscopic techniques, particularly NIR and Raman spectroscopy, are still very popular in the detection of counterfeited and illegal preparations. The spectroscopic methods surely have many advantages, especially for the detection of counterfeit medicines, in which the spectrum of a sample can be compared to that of the genuine product. However, in the analysis of illegal pharmaceutical preparations, like imitated medicines or adulterated dietary supplements, these methods have the disadvantage of being a whole sample approach. For the detection of a chemical compound in a matrix, especially in an herbal matrix with spectroscopy, the compound should be present in a considerable dose and no masking effects from matrix compounds should occur. If this is not the case, it is possible to classify a sample as legal and safe based on the spectroscopic results alone, especially when the sample is not sent to a laboratory, but screened with a portable device by the customs. Furthermore, in the case of adulterated dietary supplements, it is not unthinkable that illicit producers add components to the matrix to mask the synthetic compounds from detection with spectroscopy.

These disadvantages of the spectroscopic techniques can be solved by applying separation methods such as chromatography, in which the synthetic compounds are first extracted from the matrix and then separated on the TLC plate, chromatographic column or capillary, depending on the chosen technique. After separation, the components are separately detected, identified and quantified if necessary. When an unknown component is detected, MS and spectroscopic techniques (FT-IR or NMR) can be applied for structural elucidation.

Another field in which separation methods and chromatography are preferred over spectroscopic methods is the field of health sciences. In this domain, it is not enough to divide samples into counterfeit and genuine; they should also be evaluated for the risk they represent to the patient or to the public health. In this case, chromatographic fingerprinting can be of interest, because it not only allows identifying and quantifying the active ingredients and detecting counterfeit products, but also provides a complete image of the product. Many impurities in the fingerprint, mean that it is a counterfeit of low quality, and thus, potentially dangerous. Additionally, a chromatographic fingerprint can reveal the presence of a chemical substance (concentration >0.1%) in a dietary supplement presumed to be of herbal origin.

In conclusion, all techniques, spectroscopic and chromatographic, have their uses in the detection and analysis of illegal pharmaceutical preparations, depending on the purpose of the study. For simple counterfeit detections spectroscopic methods are very useful, but they have some disadvantages in the detection of adulterations and the evaluation of the risk for public health. Separation techniques have the advantage to allow a complete analysis of the sample: detection/identification of active substances, classification as counterfeit, imitation or genuine and risk evaluation. The disadvantages are the limited possibilities for miniaturization and application in portable devices.

In general, it can be concluded that authorities, health practitioners and patients should be vigilant. Despite the initiatives concerning tampering, holograms and other means to protect the legal supply chain, the presence of counterfeited products cannot entirely be excluded. Furthermore, patients should be aware that buying medicines or dietary supplements via the internet or from an illegal source can seriously endanger their health.

Unfortunately, the literature discussing or reporting incidents of counterfeit medicines, imitations or adulterated dietary supplements only show the tip of the iceberg. Therefore, the development of efficient analytical methods for detection, characterization and risk evaluation should continue; their use and necessity will not diminish in the near future. Analytical results concerning these products are necessary to support health authorities in their decisions and prevention campaigns, and also as part of legal dossiers for pharmaceutical crime.

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