Adulterated pharmaceutical chemicals in botanical dietary supplements: novel screening approaches
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Yan Liu
Abstract
The increased availability and use of botanical dietary supplements (BDS) has been accompanied by an increased frequency of adulteration of these products with pharmaceutical chemicals. These adulterated products are a worldwide problem, and their consumption poses health risks to consumers. The main focus of this paper is to highlight novel screening approaches utilized in the detection of adulterants in BDS marketed for different therapeutic purposes. We summarize spectroscopic methods involving near-infrared, infrared, Raman, and nuclear magnetic resonance spectroscopy as feasible and interesting in-field screening tools for the analysis of suspected products (adulterated or not) before being sent to a laboratory for deeper inspection. In addition, the new approaches based on chromatographic methods such as liquid chromatography-circular dichroism, liquid chromatography-mass spectrometry, thin layer chromatography-surface enhanced Raman spectroscopy, and thin layer chromatography-mass spectrometry are discussed and reviewed. Novel analysis strategies from targeted analysis to post-targeted and non-targeted analysis allowing simultaneous determination of the number of multiclass pharmaceuticals are discussed.
Introduction
Botanical dietary supplements (BDS) are also known as herbal-based pharmaceutical formulations and are widely used globally because of their claim to be entirely natural alternatives. There is a general perception that most BDS are safe with few side effects, and these long-term medications claim to have a slow curative effect (Jordan, Cunningham & Marles, 2012; Zhu et al., 2014b). In recent years, the consumption of dietary supplements has increased among consumers. Unscrupulous manufacturers and distributors deliberately adulterate BDS with pharmaceutical chemicals to develop an immediate pharmacological action or intensify the biological effects of dietary supplements (Calahan et al., 2016; Jordan, Cunningham & Marles, 2012). Sometimes, the products may also be added with multiple adulterants or analogs. In fact, dietary supplements illegally doped with pharmaceutical drugs or analogs carry further health risk because customers may be unaware of their content (Haneef et al., 2013; Moreira, Martini & de Carvalho, 2014; Rocha, Amaral & Oliveira, 2015; Sarker, 2014; Vaclavik, Krynitsky & Rader, 2014).
Several studies have shown the increasing frequency of adulteration of BDS via pharmaceutical drugs or analogs including phosphodiesterase type 5 (PDE-5) inhibitors (Jankovicsa et al., 2013; Lee et al., 2015; Mustazza et al., 2014; Song et al., 2014; Ulloa et al., 2015), weight loss agents (Li et al., 2014; Miao et al., 2016), anti-diabetic agents (Feng, Lei & Hu, 2014; Guo et al., 2014), antihypertensive agents (Li et al., 2015b; Zhu et al., 2014c), anti-inflammatory agents (Kim et al. 2015a; 2015b), and anabolic steroids (Aqai et al., 2013; Kim et al., 2014). Thus, as BDS consumption and market globalization has increased, there has been continuing and effective monitoring of possible adulterants in dietary supplements.
Several groups have developed and applied analytical techniques for the detection of a wide range of adulterants in dietary supplements. The laboratory-based analysis of pharmaceutical substances adulterated in BDS includes high performance liquid chromatography (HPLC) (Kim et al., 2015b), gas chromatography (GC) (Damiano et al., 2014), liquid chromatography-tandem mass spectrometry (LC-MS) (Choi et al., 2015; Moreira et al., 2016; Stojanovska et al., 2014; Zeng et al., 2015), and gas chromatography-tandem mass spectrometry (GC-MS) (Damiano et al., 2014; Kern et al., 2016; Khazan et al., 2014; Mokhtar et al., 2016). These are seemingly the preferred and established primarily tools for this analysis.
More recently, both approved drugs and their structurally similar analogs have been routinely identified in “natural” dietary supplements (Kern et al., 2016; Lee et al. 2015; 2016; Li et al., 2015b). In these analogs and/or isomers, minor modifications were made to the molecular structure (Sakamoto et al., 2016). This makes detection and qualitative analysis difficult. Therefore, the development and optimization of novel and existing laboratory analytical methods is essential to identify adulterated pharmaceutical chemicals.
Many novel analytical methods have been developed for this purpose, and this review overviews novel analytical approaches to analyze pharmaceutical adulterants in BDS. We summarize the spectroscopic methods involving near-infrared (NIR), infrared (IR), Raman, and nuclear magnetic resonance (NMR) spectroscopy. In addition, new chromatographic approaches including liquid chromatography-circular dichroism (LC-CD) and novel analytical strategies based on LC-MS and sophisticated analytical methods are included. Hyphenated techniques based on thin layer chromatography (TLC), TLC-surface enhanced Raman spectroscopy (TLC-SERS), and TLC-MS are discussed and reviewed in detail. Worldwide adulteration cases related to BDS are presented and cover many works.
Novel analytical approaches to detect adulteration in BDS
Spectroscopic methods
Spectroscopic methods are gaining an increasing interest in the detection of adulterated BDS because they are rapid, require little or no sample preparation, provide rich structural information, and can be possibly adapted for in-field screening (Rocha, Amaral & Oliveira, 2015; Rooney et al., 2015). Vibrational spectroscopic methods, when used in conjunction with chemometrics, can be harnessed to maximize the utilization of a dataset’s dimensionality and are efficient tools for the detection of a large variety of possible adulterants and structural elucidation of new adulterants in BDS (Rooney et al., 2015). More recently, handheld spectroscopic tools allow on-site analyses (Assi et al., 2015). These methods are summarized in Table 1.
Summary of spectroscopic methods used for analysis of adulterant pharmaceutical chemicals in botanical dietary supplements.
| Category type | Adulterants detected | Analytical methods | Reference | Data processing method |
|---|---|---|---|---|
| Weight loss | Sibutramine and phenolphthalein | IR, NIR, and Raman | Rooney et al. (2015) | PCA and PLS |
| Weight loss | Sibutramine | NIR | Yang et al. (2013) | SIMCA |
| Anti-diabetic | Metformin, gliclazide, glibenclamide, and glimepiride | NIR | Feng, Lei, and Hu (2014) | Improved RCCM with characteristic spectral band |
| Weight loss | Sibutramine | NIR | Da Silva et al. (2015) | PLS-DA, PLS, and MLR |
| Weight loss | Sibutramine | ATR-IR | Deconinck et al. (2014) | k-NN, PLS-DA, CART, and random forests |
| PDE-5 inhibitors | Sildenafil and tadalafil | Micro-Raman | Mao, Weng, and Yang (2012) | Wavelet denoising and similarity calculation |
| Stimulants | Dextromethorphan, 2-aminoindane, and lidocaine | NIR, ATR-IR, and Raman | Assi et al. (2015) | The instruments' inbuilt identification algorithms |
| Weight loss | Ephedrine and pseudoephedrine | IR | Miao et al. (2016) | SD and 2DCOS |
| Anti-diabetic, weight loss | Rosiglitazone maleate, phenformin hydrochloride, metformin hydrochloride, pioglitazone hydrochloride, and sibutramine hydrochloride | Raman | Zhang et al. (2013) | Compared with the reference substance spectrum |
| Weight loss | Sibutramin, mono-desmethylsibutramine, and di-desmethylsibutramine | Raman | Mao et al. (2015) | SD, DA, and PLS |
| Antipyretic | Aminopyrine | Raman | Zheng et al. (2014) | Compared with the reference substance spectrum |
| Dye | Rhodamine, methylene blue, malachite green, crystal violet, Rhodamine B, bromophenol blue, erythrosine B sodium salt, crocein scarlet 3B, and Auramine O | Raman | Li et al. (2015a) | Compared with the reference substance spectrum |
| Enhancement of sexual performance | Sildenafil analogs | NMR | Mustazza et al. (2014) | A list of key signals and interpretation of NMR chemical shifts |
| Enhancement of sexual performance | PDE-5 inhibitors, analogs, and other drugs | NMR | Gilard et al. (2015) | Spectral characteristics comparison |
| Weight loss | Sibutramine, phenolphthalein, sildenafil, orlistat, fluoxetine, and lorcaserine | NMR | Hachem et al. (2016) | Spectral signatures comparison |
Near-infrared spectroscopy
NIR is a powerful tool for adulterant drug identification because it is quick, non-destructive, and reagent-free. However, herbal medicines are complex, and thus the technique is limited in identifying adulteration due to the complexity of the matrix and a lack of selectivity.
There are NIR-based new approaches to overcome this challenge especially when NIR is used in conjunction with chemometric techniques such as soft independent modeling of class analogy (SIMCA), partial least squares-discriminant analysis (PLS-DA), and multiple linear regression (MLR). Wang, Feng, and Hu (2009) studied sildenafil citrate from 6200–5500 cm−1 combined with a reverse correlation coefficient method (RCCM) and detected sildenafil citrate illegally adulterated in herbal aphrodisiacs. Feng, Lei, and Hu (2014) improved RCCM threshold settings regarding the correlation coefficient between the tested sample and the reference substance with characteristic spectral region (6200–5500 cm−1). This process identified unknown samples by RCCM followed by confirmation of RCCM results using characteristic peak comparisons. The authors analyzed 174 batches of laboratory samples and 127 batches of herbal anti-diabetic medicines with satisfactory results.
Yang et al. (2013) integrated SIMCA and NIR spectroscopy for rapid and precise identification of BDS. The SIMCA method reduced the dimensions of the spectra and improved the calculation speed while also providing a useful and fast classification of high dimensional variations (Branden & Hubert, 2005). The authors analyzed 40 products and concluded that the method is a rapid and powerful tool for the early detection of adulterants in raw materials.
Da Silva et al. (2015) utilized a qualitative screening approach and a quantitative methodology based on multivariate calibration to evaluate potential adulteration of herbal medicines with sibutramine (SB). PLS-DA is a useful tool for classifying herbal medicine samples as adulterated or not adulterated with SB. In the quantitative approach, both PLS and MLR models can successfully quantify the content of SB with low root mean squares error of prediction. The authors suggested that it is possible to use green analytical alternatives to chromatographic approaches.
Infrared spectroscopy
IR is a fast, simple, and cost-effective technique that is already used regularly for the detection of adulterations. Besides conventional methods for IR analysis including the preparation of a film, a mull, or a pellet (inconvenient for BDS samples), attenuated total reflectance (ATR) is often used in combination with IR, which enables samples to be examined directly in their solid or liquid state without any further sample preparation steps. ATR-IR is therefore very interesting and another good choice for BDS samples.
Deconinck et al. (2014) applied ATR-IR spectra in conjunction with different basic chemometric tools, k-nearest neighbors (k-NN), PLS-DA, classification and regression trees (CART), and random forests for the detection of SB in adulterated BDS. They found that ATR-IR combined with k-NN could detect all adulterated dietary supplements in an external test set with a minimum of false positive results. The authors suggested that it is possible to use an initial screening technique for adulterated samples.
More recently, Rooney et al. (2015) demonstrated that ATR-IR spectroscopy was apt for the identification of the performance of three anorectic and laxative adulterants relative to Raman and NIR. Adulterated and unadulterated samples were spectrally separated during principal component analysis (PCA); semi-quantitative analysis of SB and phenolphthalein could be achieved via the PLS model with low errors. These examples were evaluated for lab-based instruments and are not designed for in-field use. Handheld spectroscopic methods are promising for in-field detection because these techniques are readily transferred from the lab to the field.
Assi et al. (2015) demonstrated three handheld spectroscopic methods (i.e. NIR, Raman, and ATR-IR) for the identification of “legal high” substances based on the instruments’ inbuilt identification algorithms and spectral libraries composed of pure substances and mixtures with caffeine. Most active ingredients in the Internet products were identified with one or two instruments. The study indicated the suitability of the three complementary techniques for rapid identification of “legal high” products.
In fact, due to the complexity of the analytical matrix, the characteristic peaks of adulterants in IR spectra would be partly or even completely embedded within the complex background especially when the amount of adulterants is low. Hence, it is considerably challenging to detect these adulterants merely by IR. Miao et al. (2016) employed two-dimensional correlation spectroscopy (2DCOS) combined with IR for the identification of low contents ephedrine (Ep) and pseudoephedrine (Ps) simultaneously adulterated in slimming herbal products. To highlight specific features and enhance resolution, a second derivative (SD) spectral pretreatment was used prior to 2DCOS analysis. In the asynchronous spectra, the simulated positive samples showed the characteristic peaks of Ep and Ps reference substances, and the limit of detection (LOD) was <1%. The method was used to analyze eight sliming herbal medicines. One sample contained peaks at 747, 1320, and 1364 cm−1 in the power spectrum, which corresponded to the characteristic peaks of Ep. Auto peaks at 767, 1308, 1335, 1375, and 1455 cm−1 were similar to the features of Ps. Additionally, cross peak at (749, 767), (1335, 1341), (1372, 1375), and (1455, 1495) cm−1 appeared in the asynchronous plot but were absent in the synchronous plot. This indicated that the sample was adulterated with Ep and Ps. Similarly, the cross peak in the synchronous spectrum of other samples disappeared in the asynchronous plot indicating that the sample was adulterated with Ep only. The study is presented in Figure 1, and it allowed for a simple, economical, and accurate methodology to identify other chemicals in illegally adulterated herbal products.
1D, SD, power spectrum (A), synchronous and asynchronous spectra (B) of Sample 6; 1D, SD, power spectrum (C), synchronous and asynchronous spectra (D) of Sample 7. Reprinted from Miao et al. (2016) with permission from John Wiley and Sons.
Raman spectroscopy
Raman spectroscopy is an attractive option for screening counterfeits. It is fast, non-destructive, and has little sample preparation (Li et al., 2014; Loethen et al., 2015; Neuberger & Neusüß, 2015). While it generates information-rich and unique spectra of analytes, the inherent lack of sensitivity and problems with fluorescence backgrounds in the complex matrix severely limit its utility in detecting adulterants (Mabbott et al. 2013; 2015; Rooney et al., 2015). Micro Raman spectroscopy using a microscope and SERS can reduce strong fluorescence and provide obvious Raman bands of adulterated samples by optimizing experimental parameters.
Mao, Weng, and Yang (2012) developed a micro-Raman spectroscopy method for screening sildenafil and tadalafil adulterated in healthcare products. Using a viewing microscope with 780 nm laser, 25 mm pinhole, and objective 50×, the suspect area of healthcare products was selected. This had a discernable crystal form or shape from the surrounding zone. In addition, wavelet de-noising combined with a similarity calculation was used to establish an automated approach for discrimination of adulterated healthcare products. Five of 10 analytical samples are adulterated with sildenafil, and two samples are adulterated with tadalafil. Confocal micro-Raman combined with a similarity calculation offered another powerful tool to screen adulterated healthcare products.
SERS utilizes the specificity of vibrational spectroscopy with ultra-high sensitivity at the molecular level. It has a major increase in sensitivity over conventional Raman. In recent decades, both gold (Au) and silver (Ag) nanoparticles (NPs) are used most frequently as nanomaterials for the fabrication of SERS-active nanosubstrates. Zhang et al. (2013) demonstrated the SERS method for the detection of five illegally added drugs in Chinese traditional patent medicine. Silver colloids prepared by a sodium citrate reaction were used as a SERS substrate. Two or three kinds of these chemicals could be simultaneously detected without any separation. Many efforts have been made to develop highly SERS-active metal NPs (i.e. Ag and Au) colloids (Izquierdo-Lorenzo, Sanchez-Cortes & Garcia-Ramos, 2011; Jiang et al., 2013; Sallum et al., 2014; Zhu et al., 2014a).
Zheng et al. (2014) combined the desirable features of both Au and Ag and prepared silver-coated gold NPs (Au@Ag NPs) exhibiting high sensitivity and Raman enhancement. They used the SERS-active substrates for rapid and direct identification and detection of trace synthetic antipyretic analgesic drugs in traditional Chinese medicines. The target analyte solution was mixed with Au@Ag NPs colloids in a centrifuge tube, and then the mixture was placed into a capillary glass fixed onto a glass slide and perturbed with a Raman spectrometer. The LOD of aminopyrine was 2.50 × 10−7m using the characteristic peak at 999 cm−1. Later, Mao et al. (2015) applied SERS coupled with chemometrics for rapid discrimination and detection of trace SB and its analogs. Clear discrimination between SB and its analogs were achieved based on SERS data, DA, and SD transformation. Meanwhile, PLS was used for quantitative analysis of the samples. The LOD for SIB, MDS and DDS was 5.00 × 10−8m, 5.00 × 10−7m, and 1.00 × 10−6m, respectively.
Conventional SERS substrates based on silicon, glass, and porous alumina are not efficient materials for sample collection due to their non-conformal, rigid, and brittle nature (Lee, Tian & Singamaneni, 2010). Li et al. (2015a) created a silver-NP-based SERS wiper for the detection of dye adulteration on the surface of medicinal herbs. A silver NP wiper (“Ag NPs wiper”) was created by trapping silver NPs in filter paper to form a SERS-active substrate that transferred the dye to a simple device before SERS detection. This reduced the difficulties associated with SERS analysis. The authors tested, evaluated, and optimized four types of Ag NPs wiper as well as two modes of wetting/wiping, three kinds of wetting reagents, and 16 combinations of wetting and wiping times. Nine dyes and simulated dye adulterants could be detected by the novel method without separation. The authors concluded that the method is a highly sensitive, convenient, and rapid platform for detecting trace levels of dyes on the surfaces of medicinal herbs. However, SERS is not a separation technique, and it does not always offer reliable differentiation of several components in a mixture. This will be discussed in detail in the Thin layer chromatography-surface enhanced Raman spectroscopy section.
Nuclear magnetic resonance spectroscopy
Structurally modified analogs require significant work for detection with much less structural elucidation. NMR is very powerful at identifying the structural features of synthetic compounds that have been published and reviewed (Haneef et al., 2013; Jankovicsa et al., 2013; Patel et al., 2014; Rocha, Amaral & Oliveira, 2015; Ulloa et al., 2015). Indeed, the chemical structures of most new adulterants in BDS could be elucidated by NMR (Gilard et al., 2015). NMR is an essential screening approach for high throughput analysis of complex mixtures such as BDS without identical reference materials.
To enhance the capacity of detecting new unknown analogs, Mustazza et al. (2014) presented a tool for analog identification and structural elucidation by analyzing NMR signals characteristic of 16 synthetic analogs. A list of key signals and interpretation of NMR chemical shifts were discussed to aid in the detection and identification of other analogs and indicate how to deal with structural elucidation of novel analogs. This study provides a novel attempt to analyze the structural analog series and could be enlarged to other analog series.
Later, Gilard et al. (2015) established the 1H NMR spectra of 150 BDS advertised for enhancing sexual performance. They completely analyzed their spectral signatures. The method clearly brought out structural differences between analogs and showed that 61% of those were adulterated with PDE-5 inhibitors or their structurally modified analogs. Some products contained higher amounts than the maximum recommended dose. The authors stated that 1H NMR in particular could be a first line method for BDS quality control.
Hachem et al. (2016) used proton NMR for the detection, identification and quantification of adulterants in weight loss BDS. SB, phenolphthalein, sildenafil, orlistat, fluoxetine, and lorcaserine were found in 164 samples. This demonstrated the efficiency of 1H NMR spectroscopy for the detection of tainted BDS.
Chromatographic and hyphenated techniques
Liquid chromatography and hyphenated techniques
Chromatographic techniques particularly HPLC and ultra-high performance liquid chromatography combined with diode array detector (Poplawska et al., 2014) or most often with mass spectrometry (MS) (Moreira et al., 2016) or high resolution MS (HRMS) (Guo et al., 2014; Li et al., 2014; Wang et al., 2015) or tandem MS (MS/MS) (Choi et al., 2015; Kim et al. 2014; 2015a; 2016; Zeng et al., 2015) detectors are key and primary tools for the analysis of pharmaceutical adulterants in BDS. For brevity, these will be omitted here. With advances in LC and related hyphenated techniques, LC-CD and novel data analytical strategies have been applied to the analysis of BDS adulterants.
Liquid chromatography-circular dichroism
CD spectroscopy capitalizes upon the preferential absorption of right-handed or left-handed circularly polarized light that arises from structural asymmetry within a chiral molecule. In general, CD can be observed for any chiral species (Bertucci et al., 2014; Stanley & Stalcup, 2011). Hence, CD is well suited for the analysis of many chiral components. The hyphenation of HPLC and CD detection allows one to determine the stereochemistry of the eluted fractions.
N-Octylnortadalafil (RR-OTDF) is an analog of tadalafil, and it contains two chiral centers in the 6R, 12aR configuration and is optically active. The three other stereoisomers are (6S, 12aR), (6R, 12aS), and (6S, 12aS) isomers. Thus, Sakamoto et al. (2016) synthesized RR-OTDF and its stereoisomers and successfully developed a LC-CD method for their simultaneous stereo separation. Compounds were chirally separated using a Chiralcel OD-RH column and isocratic elution within 20 min. They were detected by CD detection in a stop-flow mode. The authors used this method to analyze a dietary supplement and found 73 μg of RR-OTDF per tablet. They concluded that the method could identify stereoisomers in BDS.
Liquid chromatography-tandem mass spectrometry
Most researchers currently consider LC-MS to be the method of choice in detecting adulterants in BDS. A detailed description of these techniques can be found in several reports and comprehensive reviews (Haneef et al., 2013; Kim et al., 2016; Rocha, Amaral & Oliveira, 2015; Vaclavik, Krynitsky & Rader, 2014). The view only introduces some novel analytical strategies.
Johansson et al. (2014) assembled an effective general screening platform based on LC time-of-flight mass spectrometry (LC-QTOF-MS) and NMR to identify and quantify unknown pharmaceutical substances in suspected illegal products. The screening procedure for counterfeit/illegal medicines using LC-QTOF-MS and NMR for identification and quantification is presented in Figure 2. The hybrid MS technique can provide both accurate mass measurements and ion fragmentation information. This can be used to construct an in-house library and confirm known illegal adulterants and discover unknown ones in complex matrices. Thus, the accurate mass of peaks of interest was recorded and searched against an in-house database containing approximately 4200 substances including weight-loss substances and PDE-5 inhibitors. Also, an analytical strategy and screening procedure was outlined for identification and quantification. Unknown substances can often be identified and quantified simply and quickly without resorting to reference substances using LC-QTOF-MS.
Screening procedure for counterfeit/illegal medicines using LC-QTOF-MS and NMR for identification and quantification. Reprinted from Johansson et al. (2014) with permission from Elsevier.
However, the hybrid MS system – especially the HRMS technique – collects vast amounts of data from herbal medicine samples. There are currently too many illegal adulterants (Guo et al., 2014; Li et al., 2014; Wang et al., 2015). Consequently, it can be difficult to exclude matrix interferences. Detecting and confirming illegal adulterants by comparing mass data from suspected compounds to library spectra is difficult. In addition, many methods focus on a specific category of illegal adulterant. However, some samples can contain various categories such as theophylline, prednisone acetate, and dexamethasone acetate in antitussive herbal medicines. In these cases, the analytical methods for a single category cannot screen all illegal adulterants. Therefore, Wang et al. (2015) developed an integrated strategy by employing HPLC-HRMS and a mass spectral tree similarity filter (MTSF) technique. The workflow strategy for the detection, confirmation, and quantification of illegal adulterants is shown in Figure 3. This analytical method can rapidly collect high-resolution, high-accuracy, optionally multistage mass data for illegal adulterant standards to obtain a mass spectral tree library named “illegal adulterants”.
A workflow strategy for the detection, confirmation, and quantification of illegal adulterants by HPLC-HRMS and MTSF. Reprinted from Wang et al. (2015) with permission from John Wiley and Sons.
After a preliminary screening by retention time and high-resolution mass spectral data, the known illegal adulterants can be detected based on the similarity between its mass spectral tree and the illegal adulterants in the library. The mass spectral tree similarity filter technique has been applied to identify unknown samples based on a similarity score. In addition, the candidate structure of the unknown illegal adulterant was obtained based on its mass spectral tree information and the precise molecular weight. Thus, this technique deduced the structures of adulterants and reduced the workflow using conventional untargeted blind detection.
Thin layer chromatography and hyphenated techniques
BDS are complex, and appropriate separation should be performed before qualitative identification of adulterants. Thin layer chromatography (TLC) is another choice for the analytical chemist, and it has been widely used for the detection of adulteration in BDS (Ariburnu et al., 2012; Ulloa et al., 2015). The compounds separated on the TLC plate form spots that are usually detected with UV light, iodine vapor, or other visualization reagents. However, these methods are not sufficiently specific and sensitive to identify the nature of the separated compounds (Ariburnu et al., 2012; Ilbeigi & Tabrizchi, 2015). To overcome this limitation, SERS, MS, and other methods have been developed to identify compounds separated on TLC plates.
Thin layer chromatography-surface enhanced Raman spectroscopy
TLC coupled with SERS is an interesting technique for the analysis of BDS mixtures. Analytes and components of pharmaceutical matrices were separated by TLC, and SERS was then used for qualitative identification of trace substances on the TLC plate. The effective separation of TLC combined with the enhanced sensitivity of SERS makes the methodology much more amenable than other analytical techniques for on-site detection due to its simplicity, rapidity, and high sensitivity. The combination of these two techniques not only compensates for each technique’s inadequacies but also strengthens their advantages in complex analysis.
TLC-SERS was previously used for the detection of diterpenoic acids (Oriňák et al., 2008), natural dyes on art (Brosseau et al., 2009), substituted aromatic pollutants in water (Li et al., 2011), and structural analogs (Pozzi et al., 2013). The use of this technique for the analysis of adulterants in BDS is recent. Zhu et al. (2014b) proposed TLC-SERS for rapid on-site detection of antidiabetes chemicals used to adulterate BDS for diabetes. Under optimized conditions, phenformin hydrochloride (PHE), metformin hydrochloride (MET), rosiglitazone maleate (ROS), and pioglitazone hydrochloride (PIO) could be measured separately in TLC analysis with confirmation via their characteristic Raman fingerprint. The LODs were 0.2% for PHE, 0.18% for MET, 0.001% for ROS, and 0.016% for PIO. The method was applied to the analysis of 12 real samples. The characteristic Raman peaks were compared with a reference, and the authors concluded that four samples were doped with ROS and two samples were adulterated with PHE showing that the method would have good prospects for on-site qualitative screening of BDS for adulterants.
Based on the same principle and similar approaches, a TLC-SERS method was also applied to detect four antipertensive chemicals (Zhu et al., 2014c) and four heat-clearing chemicals adulterated in BDS (Chen et al., 2015). These structurally modified analogs, e.g. PIO and ROS, possess similar SERS signals and were difficult to accurately discriminate when they coexisted in the complex BDS system. Moreover, the SERS signals of PIO were almost fully covered by the ROS. These could give a false-negative result for PIO. In this case, the combination of a TLC-SERS method with 2DCOSwas applied to analyze highly overlapping phenomena by Li et al. (2015b). The laser exposure was optimized to obtain dynamic spectra for the 2D correlation analysis. The 2D correlation asynchronous spectrum gave outstanding performance in the improvement of spectral resolution because some weak or highly overlapped peaks gave distinct signs in the asynchronous spectra, but all spectra were absent in the 1D SERS, SD, and autopower spectra. Finally, two chemicals with similar structures were successfully differentiated from the complex BDS matrices.
Reference substances for adulterants are rarely available. Lv et al. (2015) described another novel analytical strategy for the detection of Ep and its analogs as trace adulterants in BDS. The work focused on the known analogs (Ep, Ps, methylephedrine, and norephedrine) and used their eight common Raman peaks to establish a reference-free detection model. This offered a simple, rapid, accurate, and reference-free methodology, and it can be used to detect and elucidate possible adulterants in BDS.
There is still a challenge in the sensitivity and stability of TLC-SERS. Dynamic SERS (DSERS) collects Raman signals during the SERS substrate transformation from the wet state to the dry state. It offers higher detection sensitivity compared to traditional SERS method (Liu et al., 2014; Yang et al. 2012; 2015). Currently, a new ultra-sensitive detection method named DSERS-TLC used for on-site detection of antitussive and antiasthmatic drugs adulterated in BDS was proposed by Fang et al. (2016); the schematic illustration is shown in Figure 4. Solvent played an important role in DSERS detection. The study found that 50% glycerol silver colloid served as the DSERS active substrate and resulted in about twice as much SERS enhancement as ultrapure water silver colloid. Furthermore, the SERS signals could last a rather long period of time at a rather high level because glycerol with its large viscosity could slow down the speed of volatilization. The method has been used to analyze 10 real samples and found one sample adulterated with benproperine phosphate. The authors concluded that the combined method with high sensitivity and stability would have good prospects for on-site and sensitive detection of adulterated BDS.
Schematic illustration of TLC-DSERS for on-site detection of antitussive and antiasthmatic drugs adulterated in BDS. Reprinted from Fang et al. (2016) with permission from Elsevier.
Nearly all reports above utilized traditional Lee-Meisel Ag NPs with hydrophilic analytes. However, the detection of hydrophobic analytes using this method is difficult, and the specificity must be improved. Zhu et al. (2016) synthesized a SERS-active non-aqueous silver sol, (AgNPs)-dimethylformamide sol and used it to test eight analytes including hydrophilic and hydrophobic substances with richer and more stable spectral features. This showed the benefits of structural analysis and analog discrimination as well as improvements in robustness. The non-aqueous AgNPs had great promise for applications in the detection of hydrophobic adulterant in BDS.
Thin layer chromatography-mass spectrometry
The coupling of TLC with mass spectrometry offers additional information that is complementary to chromatographic processes. It can improve specificity even with high matrix loads (Rani, Medhe & Srivastava, 2015). A drawback in using the mass spectrometer for TLC is that the mass spectrometer operates under vacuum, while TLC is prepared at ambient pressure. Recently, ambient mass spectrometryhas been shown to allow desorption, ionization, and characterization of analytes via mass spectrometry directly from their natural matrixes. It is an attractive alternative in adulteration problems.
De Carvalho et al. (2016) used paper spray ionization mass spectrometry (PS-MS) to identify and quantify cocaine and its adulterants (benzocaine, phenacetin, caffeine, and lidocaine). PS-MS involves directly loading the sample onto a triangular-shaped paper, which is wetted with a solvent and placed in front of the mass spectrometer inlet. The spray of the charged micro-droplets is formed by application (usually 3–5 kV) in the opposite side of the paper tip, and desolvation occurs without any sheath gas (Wang et al., 2010). The method resulted in higher sensitivity, selectivity, and speed than common TLC. It enhances the reliability of traditional and routine TLC analysis and eliminates false positives.
Other TLC-based hyphenated techniques
An alternative technique is the coupling of TLC and ion mobility spectrometry (IMS) developed by Ilbeigi and Tabrizchi (2015). The coupling scheme used a special solvent tank, horizontally mounted TLC strip, and a very small funnel directly below the TLC tip to collect the solvent and transfer it to a needle via a capillary tubing. The scratched TLC or its pieces can be directly introduced into the IMS without any need for time-consuming sample preparation procedures.
IMS had worse resolution than MS, but its resolution and speed are high enough to identify compounds already separated by TLC. The advantage of TLC-IMS is that both techniques work at atmospheric pressure, which makes coupling simpler. The method achieved acceptable separation for two component mixtures and could be used in the analysis of adulterants. Despite the apparent potential of this method, no reports describing the application of the TLC-IMS in the adulteration analysis are currently available. Table 2 summarizes analytical approaches based on chromatographic and hyphenated technique used for analysis of adulterant pharmaceutical chemicals in BDS.
Summary of chromatographic and hyphenated analytical approaches used for analysis of adulterant pharmaceutical chemicals in botanical dietary supplements.
| Category type | Adulterants detected | Analytical methods | Reference |
|---|---|---|---|
| Enhancement of sexual performance | N-Octylnortadalafil and its stereoisomers | LC-CD | Sakamoto et al. (2016) |
| Weight loss, enhancement of sexual performance, analgesic, and others | Approximately 4200 substances (sibutramine, orlistat, acetildenafil, aildenafil, aminotadalafil, carbodenafil, homosildenafil, hydroxyhomosildenafil, nor-acetildenafil, morphine, codeine, and others) | LC-QTOF-MS | Johansson et al. (2014) |
| Anti-fatigue, hypoglycemic, antitussive, hypnotic, and hormone | 63 illegal adulterants and their analogs (yohimbine, N-desethylvardenafil, hydroxyvardenafil, dimethyl sildenafil, N-desmethylsildenafil, hydroxyhomosildenafil, and others) | HPLC-HRMS | Wang et al. (2015) |
| Antidiabetes | Phenformin hydrochloride, metformin hydrochloride, rosiglitazonemaleate, and pioglitazone hydrochloride | TLC-SERS | Zhu et al. (2014b) |
| Antipertensive | Nicardipine hydrochloride, doxazosinmesylate, propranolol hydrochloride, and hydrochlorothiazide | TLC-SERS | Zhu et al. (2014c) |
| Antidiabetes | Rosiglitazone maleate and pioglitazone hydrochloride | TLC-SERS | Li et al. (2015b) |
| Weight loss | Ephedrine, pseudoephedrine, methylephedrine, and norephedrine | TLC-SERS | Lv et al. (2015) |
| Weight loss | Diphenhydramine hydrochloride, benproperine phosphate, and chlorphenamine maleate | TLC-DSERS | Fang et al. (2016) |
| Anesthetic | Caffeine, benzocaine, lidocaine, and phenacetin | TLC-PS-MS | De Carvalho et al. (2016) |
| Anesthetic | Morphinepapaverin and acridine-papaverine | TLC-IMS | Ilbeigi and Tabrizchi (2015) |
Conclusion
Adulteration of BDS is a major area of concern to both consumers and regulatory agencies. Manufacturers of adulterated BDS products may try everything possible to avoid detection including new adulterants or novel designer analogs. Therefore, the development and application of broad screening methods that keeps pace with these practices remains a continuing challenge. The novel analytical technique must be fast, specific, sensitive, simple, high-throughput, and preferably post-targeted and non-targeted. Currently, spectroscopic methods based on IR, NIR, and Raman spectroscopy combined with chemometrics techniques focus on an increasing interest in the analysis of numerous pharmaceutical adulterants in diverse product. It is a feasible and interesting on-field screening tool for the analysis of suspected products (adulterated or not). Chromatographic methods mostly use LC, TLC, and hyphened methods. With recent advancements in hyphenated techniques and sophisticated analytical methods, there are many new techniques such as LC-CD, LC-MS, TLC-(D) SERS, TLC-MS, and TLC-IMS for the detection and structural identification of adulterants from different pharmacological classes (including new/unknown analogs). The development of new and improved analytical methodologies for the identification and detection of known and unknown adulterants is critically important to protect public health and ensure the quality of dietary supplements.
Acknowledgments
This research was supported by the Ministry of Science and Technology of the People’s Republic of China (Grant no. 2012YQ180132), National Natural Science Foundation of China (Grant no. 81573598), and Science & Technology Commission of Shanghai Municipality (Grant no. 15142201300).
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Articles in the same Issue
- Urine oligosaccharide tests for the diagnosis of oligosaccharidoses
- Design of experiments in liquid chromatography (HPLC) analysis of pharmaceuticals: analytics, applications, implications and future prospects
- Adulterated pharmaceutical chemicals in botanical dietary supplements: novel screening approaches
