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Advances in rapid drug detection technology
Accepted Manuscript Title: Advances in Rapid Drug Detection Technology Authors: Wen-Bo Zou, Li-Hui Yin, Shao-Hong Jin PII: DOI: Reference:
S0731-7085(17)31247-5 http://dx.doi.org/doi:10.1016/j.jpba.2017.08.016 PBA 11461
To appear in:
Journal of Pharmaceutical and Biomedical Analysis
Received date: Revised date: Accepted date:
16-5-2017 10-8-2017 10-8-2017
Please cite this article as: Wen-Bo Zou, Li-Hui Yin, Shao-Hong Jin, Advances in Rapid Drug Detection Technology, Journal of Pharmaceutical and Biomedical Analysishttp://dx.doi.org/10.1016/j.jpba.2017.08.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Advances in Rapid Drug Detection Technology Wen-Bo Zoua, Li-Hui Yina,* *, Shao-Hong Jina,* a National Institutes for Food and Drug Control * Corresponding author. Tel: +861067095258. E-mail address: [email protected] ** Corresponding author. Tel: +861053851547. E-mail address: [email protected]
In this review we focus on some rapid drug detection technology which has been reported lately for the qualification and quantification of SFFC drugs. In addition, new characteristics and trends of SFFC drugs were listed and the solution was discussed. Abstract:Spurious/Falsely-labeled/Falsified/Counterfeit (SFFC)drugs have become a major threat to public health, especially in rural areas of developing countries.The goal of this review is to provide an overview of rapid detection technologies for counterfeits recently reported, such as Near Infrared Spectroscopy, Near Infrared Chemical Imaging, Raman Spectroscopy, X-Ray Fluorescence, X-RayPowder Diffraction, Ion Mobility Spectrometry, Ion MobilityMass Spectrometry,Isotope Ratio Mass Spectrometry and visual analytical methods.The advantages of each of these detection methods are introduced. Examples of characterization of SFFC drugs using the detection technology mentioned are presented. In addition, new characteristics and trends of SFFC drugs are listed and the solution is discussed. Keywords: Counterfeits; SFFC Drug; Rapid Detection
1. Introduction The global situation of counterfeits and sub-standards has grown in recent years due to counterfeiting methods that are becoming more and more advanced and sophisticated. Because the counterfeit products look so similar to the genuine products, they not only deceive the medical doctors but also the pharmaceutical professionals. Some Spurious/Falsely-labeled/Falsified/Counterfeit (SFFC) products could meet the requirements of the official specifications, that is, they actually do contain the correct amount of the correct API. The World Health Organization (WHO) defines counterfeit drugs as those which are 1
deliberately mislabeled with respect to identity and/or source. Counterfeiting applies to both branded and generic products, with counterfeit products including drugs with the correct ingredients or with the wrong ingredients, without active pharmaceutical ingredient (API),with insufficient API, or with fake packaging [1].Although some SFFC drugs contain the correct API, good manufacturing practices (GMP) and other specifications are not followed through manufacturing, further adding to safety concerns. In other cases, the use of counterfeit drug products containing lower drug content is of particular concern for antibacterial agents because microbial resistance can develop from subtherapeutic dosing[2]. Current methods of detection for SFFC drugs include visual analysis and chemical analysis. Features incorporated in drugs and packaging can be used for visual analysis. Some companies have proposed the use of special inks and print technologies to imprint a unique design, number, or icon directly onto the product[3]. The U.S. Food and Drug Administration (FDA) developed and deployed a portable technology based on using multi-wavelength light sources to visually analyze counterfeit products[4]. Chemical analysis methods include colorimetric methods, liquid chromatography-mass spectrometry, near infrared spectroscopy, near infrared chemical imaging, mid-infrared spectroscopy, Raman spectroscopy, X-ray fluorescence, X-ray powder diffraction, Ion Mobility 2
Spectrometry, and Isotope Ratio Mass Spectrometry. However, some of these analytical methods are time-consuming or not specific. In this review, we focus on rapid drug detection technologies which have been reported recently for the qualification and quantification of SFFC drugs. Additionally, some new characteristics of SFFC drugs are discussed and several examples of handling such counterfeits are given. 2. Spectroscopy Methods 2.1 Near Infrared Spectroscopy Near-infrared spectroscopy (NIRS) is a fast and nondestructive technique that provides multi-constituent analysis of virtually any matrix. It covers the wavelength range adjacent to the mid infrared and extends up to the visible region. Although a number of NIR experiments were carried out in the early 1920s, it was not until the mid to late1960s that NIRS was practically used. In recent years, NIRS has gained wide acceptance within the pharmaceutical industry for raw material testing, product quality control and process monitoring[5].Because of its major advantages over other analytical techniques, namely, easy sample preparation without any pretreatments, and quick and noninvasive analysis, NIRS has been used as an anti-counterfeiting analytical method[6,7].Scafi and Pasquini[6]reported an investigation on the use of NIRS with the objective of identifying counterfeit drugs. They established a relatively simple protocol and employed chemometric 3
methods (Principal Component Analysis, PCA, and Soft Independence Modeling of Class Analogy, SIMCA). They evaluated the main drawbacks relating to the use of NIRS for drug identification, such as humidity alteration, sample position and sample face (for tablets). Furthermore, they proposed and evaluated a simple protocol to produce a robust model with known counterfeit drugs. Olsen et al. [8]used Prozac as a model drug to demonstrate the flexibility of NIRS in screening for counterfeit drugs in general. Vredenbregt et al. [7] described a fast screening method using NIRS for Viagra® tablets, counterfeits, and imitations of Viagra®. Among48 unknown samples that looked like Viagra® in shape, color, and inscription, the method they developed easily identified 44 samples as counterfeit tablets. In China, for the purpose of combating the SFFC drugs distributed in rural areas, the China Food and Drug Administration(CFDA) instructed the National Institutes for Food and Drug Control (NIFDC) to develop mobile labs to be used in the field for drug screening tests. A “fast drug identification system” which includes a NIR testing system installed in a mobile vehicle is being developed. Feng et al.[9]chose roxithromycin tablets and erythromycin ethylsuccinate tablets from different manufacturers as examples for construction of universal quantitative models(models that can be used to test a pharmaceutical product with the same API but from different manufacturers)for use in the NIR 4
prescreening system. The universal models have good specificity, linearity, accuracy, precision and robustness. Furthermore, they can be directly used in different FT-NIR spectrometers of the same brand without any special mathematical treatment. Researchers of traditional Chinese medicine (TCM) have shown interest in NIRS recent years. The technique can be applied in medicinal species identification, classification and origin analysis, and adulteration detection of TCM [10]. 2.2 Near Infrared Chemical Imaging Near-infrared chemical imaging(NIR-CI) combines classical spectroscopy with the ability to provide spatial information on the distribution of the components of a drug product [5,11,12]. Thus, NIR-CI has been successfully applied for drug identification [13,14] and quantification[15,16], for visualizing manufacturing problems and process effects on dissolution [17–19], and for estimating homogeneity[15,20–24]. Dubois et al. [25] and Wolff et al. [26]have used NIR-CI for the identification and characterization of counterfeit drug products. Puchert et al. [27] presented a new four-stage concept for the reliable identification of solid counterfeits which were very similar to the genuine products. They found that for counterfeit identification, NIR-CI turned out to be superior to single-point NIRS because it combines the capability of spectroscopy with the potential of visualization, thus 5
allowing local characterization of the chemical composition, domain structure, and chemical architecture. Lopes et al. [28] combined NIR-CI and classical least squares estimation to study the composition of counterfeit tablets of unknown origin. It was concluded that without knowing anything about the tablets and without destroying the tablets, NIR-CI and CLS were able to spatially identify and quantify the major compounds present in the set of counterfeit tablets under study. 2.3 Raman Spectroscopy Raman is a spectroscopic method that makes use of inelastically scattered light to obtain a spectroscopic “fingerprint” of the sample. It is then possible to identify the components and their relative concentrations based on peak location and intensity[29].Like NIRS, Raman spectroscopy has proven to be successful in portable units[30] for identification and counterfeit detection in the field[31,32]. Without any sample preparation, Raman is capable of performing noninvasive and nondestructive screening through the packaging, thus preserving suspect samples intact should further testing be necessary. As this instrumental technique has developed, portable Raman instruments have become more popular. Noonan et al. [29]explored a more universal approach for developing models that can classify multiple drugs of interest in the presence of three cutting agents, some of which are chemically very similar to the drugs of interest. Based on the models developed, they were able to successfully 6
cluster four drug surrogates: benzocaine, lidocaine, isoxsuprine, and norephedrine. They detailed the acquisition of the spectra using both homebuilt and rugged, handheld, commercial instruments, as well as preprocessing of the spectra needed before model development. Loethen et al. [33] reported an approach which was shown to be amenable to anti-counterfeit rapid screening of finished drug products in the broad class of anti-infectives, using only the Raman spectra of the APIs as the reference library. Zhao et al. [34]have developed a convenient and effective method for rapid, noninvasive screening of human serum albumin injection products using a portable Raman spectrometer. The method could be used as a universal screening means on different Raman spectrometers. Lawson and Rodriguez [35] introduced a novel algorithm to screen antibiotic and antiviral finished drug products (FDPs) using Raman spectroscopy. The algorithm described introduced a binary barcode comparison method to identify APIs in FDPs. The method was shown to correctly predict the declared API present in 18 different commercial samples and nine simulated counterfeit samples. 2.4 X-ray Fluorescence X-ray fluorescence (XRF) is a suitable technique for characterization of the presence of metals [36,37]. This technique has advantageous features including multielemental capability, good sensitivity,high precision, and short analysis times;it also is nondestructive. These 7
features make it suitable to be extended to a great variety of samples. Thus, XRF presents an excellent analytical methodology for determination of APIs, coating agents, and excipients such as calcium phosphate, titanium oxide and iron oxide (P, Ca, Ti and Fe),all of which can be detected directly by XRF on the surface of pharmaceutical formulations [38]. Ortizaet al. [38] obtained inorganic chemical fingerprints of several commercial samples (Viagra®, Cialis®,Lazar®, Libiden®, Maxfil®, Plenovit®, Potent 75®, Rigix®, V-50®,Vimax® and Pramil®) and counterfeit samples (Viagra® and Cialis®)from XRF data, and used chemometric methods PCA and HCA (Hierarchical Cluster Analysis) to classify the tablets investigated as authentic or counterfeit. Thus, XRF presented an excellent analytical methodology for semi-quantitative determination of API and excipients. 2.5 X-ray Diffraction Powder X-ray diffraction (PXRD) is commonly used in the pharmaceutical industry for polymorph identification of APIs, but not for final products. Maurin et al. [39] demonstrate results of analyses of authentic and counterfeit Viagra® showing differences in tablet coatings and their interiors. No prior preparation, apart from eventual coating removal, was applied. The results obtained for counterfeit samples of Viagra® showed that X-ray powder diffraction, especially when using 8
new, fast diffraction techniques, including multilayer mirrors and position-sensitive counters, is a method suitable for pharmaceutical market screening control for counterfeit drugs. Musumeci et al. [40] described an anticounterfeit method based on micro-X-ray diffraction (μ-XRD) in which a scanned X-ray beam can be used to read barcodes and patterns, with features as small as 0.30 mm, fabricated with compounds that can be read by X-ray diffraction but were invisible to the naked eye or optical microscopy. The method was demonstrated with barcodes and logos of FDA-approved compounds printed on various substrates, including commercial aspirin and ibuprofen tablets. Theμ-XRD method is nondestructive, automated, and user-friendly and can be used to certify the authenticity of drug tablets by mapping hidden patterns printed under the tablet coating and on packages. 2.6 Infrared Spectroscopy Anzanello et al. [41] proposed a method for selecting the most relevant subsets of attenuated total reflection Fourier transform infrared spectroscopy(ATR-FTIR) wavenumbers for clustering medicine samples into two groups: authentic or fraudulent. The method first applies a multivariate technique, PCA, to ATR-FTIR data, and two variable importance indices are derived from the parameters provided by PCA. 3. Chromatography Methods 9
HPLC can not only be used in laboratory but also in situ for rapid detection of SFFC drugs. Zhu et al.[42] developed a HPLC method for rapid determination of 12 hypoglycemic drugs within twenty minutes. A diode array detector and a C18 or C8 column were used. Only a few reference standards were needed for quantification by the method proposed. Marini et al. [43] reported the analytical and quantification performance of a newly-developed low-cost capillary electrophoresis(CE) instrument. In their work, a complete validation study was performed on selected drugs which represent pharmacological groups commonly targeted by counterfeiting, namely the antimalarial, diuretic and anti-infective drugs [44]. Although rapid separation techniques such as HPLC, GC, CE etc. are efficient and specific, sample preparation can be time consuming. Several sample preparation techniques are commonly used in GC, including purge and trap, solid phase extraction, solid phase microextraction, liquid phase microextraction, microwave assisted extraction, and ultrasonic-assisted extraction[45]. 4. Mass Spectrometry 4.1 Isotope Ratio Mass Spectrometry Elemental analysis-isotope ratio mass spectrometer (EA-IRMS) is the conventional instrument used for stable isotope amount ratio 10
measurements in bulk samples, and it has been widely used for authenticity studies to establish the provenance of food stuffs and beverages
[46].Carbon and nitrogen measurements provide information
on plant type or diet whereas hydrogen, oxygen and sulfur data have been shown to provide reliable environmental and geographical information [46-55]. Jasper et al. reported the use of IRMS for the authentication of APIs [56]; in this study, 20 blind samples of four APIs were selected and isotope amount ratios for C, N, O and/or H were measured. Benson et al.[57] and Carter et al.[58]summarized the use of isotope ratio data for the analysis of illicit drugs. Fernandez et al. [59] performed an extensive study for 139 batches of the antiviral drug Heptodin™. Since the API of the Heptodin™tablets, i.e. lamivudine (C8H11N3O3S) contains C, N and S, these elements were analyzed for isotope amount ratio measurements by multiple collector inductively coupled plasma mass spectrometry (MC-ICP-MS) and EA-IRMS. It was shown that the combination of two methods had great potential to detect counterfeit drugs. Furthermore, this approach could enable linking two counterfeit batches to a common source, or establishing a link between a suspect carrying a set of counterfeits and the laboratory responsible for the production of the counterfeit drug. 4.2 Ion Mobility Spectrometry and Ion Mobility Mass Spectrometry Ion Mobility Spectrometry (IMS) is an analytical technique that 11
separates gas-phase ions based on their ion mobility, which is related to molecular structure, size and shape, analogous to electrophoresis in the condensed phase. The technique has long been used for the detection of illegal or dangerous substances [60,61]. Initially, ion mobility spectrometers were used only in the field of physical chemistry and for plasma physics research. The development of the matrix-assisted laser desorption and ionization (MALDI) [62–64] and electrospray ionization (ESI) [65, 66] methods in the late 1980senabled the measurement of large biomolecules by MS. This also resulted in a major breakthrough in the field of ion mobility MS (IM-MS) in the 1990s [67–70].Gryniewicz et al. [71] found IMS a useful rapid screening approach to the analysis of herbal supplements for adulteration by sildenafil, vardenafil, tadalafil, andfive known sildenafil analogs. Mans et al. [72] expanded the scope of IMS for the detection of the acetildenafil family of analogs, along with previously untested sildenafil analogs and the recently approved avanafil; they showed that IMS could be used a rapid screening tool for the detection of acetildenafils, sildenafils and avanafil adulterants in herbal supplement matrices. Krueger[73] et al. used a high performance ion mobility spectrometer for the rapid analysis of nutritional supplements. Harris et al. [74] applied drift tube ion mobility spectrometry (DTIMS) coupled with laser ablation/desorption electrospray ionization (LADESI) to the fingerprinting of field-collected antimalarial pharmaceutical tablets. 12
The LADESI DTIMS platform provided distinct spectral features that were used for identification of the APIs. Ion Mobility Mass Spectrometry(IM-MS) is a powerful analytical technique that combines the benefits traditionally associated with IMS and MS[75]. IM-MS has been applied in determination of saccharides, peptides, lipids, proteins, nucleotides, and their respective metabolites. It can be used to enhance various areas of chemical and biophysical analysis [60,61]. Cuyckenset al. [76] focused on IM-MS, which was used to extract and identify the ions of metabolites of peptide drugs in the presence of an in vivo matrix, in combination with charge state filtration and various existing software tools. Blackburn et al. [77] introduced waveform ion mobility spectrometry(FAIMS) in the bioanalysis of dianicline in animal plasma. Although so far there are only a few reports on rapid detection of SFFC drugs by IM-MS, this powerful technique is likely to become popular in the future. 4.3 GC-MS GC-MS is a sensitive and efficient technique in identification and quantification of unknown residual solvents in drugs. Furthermore, it can be applied in the detection of adulteration of TCM. Zhu et al. [78,79] developed GC-MS methods to detect sedative, hypnotic, and non-steroidal anti-inflammatory drugs in supplements and TCM. 4.4 Other Mass Spectrometric detection techniques 13
Fernandez et al. [80] characterized counterfeit drugs by Desorption Electrospray Ionization(DESI) and direct analysis-in-real-time(DART) coupled to time-of-flight mass spectrometry. They demonstrated the usefulness of DART for the rapid screening of counterfeit drugs, screening several different counterfeits of the antimalarial drug artesunate. Some of these counterfeits contained other antimalarial drugs that are no longer effective; one counterfeit contained artesunate, but at only 20% of the expected amount. This has significant implications for malaria control, as use of low-dose artesunate may lead to development of artesunate resistance in the malaria parasite, and thus render artesunate ineffective. 5. Visual Analytical Methods Visual analytical methods mainly concern printing and packaging, including Radio Frequency Identification (RFID) tags, 2D codes, optical variable inks, digital watermarking, and holographic techniques. A handheld instrument is another option. Ranieri et al.[4] evaluated a new handheld instrument which enabled rapid comparison of packaging and product. The instrument showed very good accuracy in detecting counterfeit artesunate packaging and tablets, which were fraudulently labeled as manufactured by one company. Minimal training was required, and agreement between the trainer and two trainees was 100%.
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6. Conclusions With the growth of counterfeiting methods, SFFC drugs are regarded as a major threat to public health, especially in emerging countries. New characteristics and trends of SFFC drugs have shown increasing sophistication, including (i)products that comply with Pharmacopoeia (that is, the SFFC product can pass the specified tests for the authentic product), (ii)adulteration of chemical drugs into traditional Chinese herbal medicines, and (iii)using used authentic packing materials collected from hospitals. To deal with this complex and evolving situation, satisfactory results will not be achieved by using only a single detection technology. Counterfeit TIENAM®(Imipenem and Cilastatin sodium for injection,Merck Ltd.) was tested in the Mobile Lab of CFDA[81]. The packaging boxes, the upper sealing stickers, the bottles containing drugs,the rubber stoppers and the insert sheets were authentic by visual analysis. However, under the UV light and visual inspection, the lower part sealing stickers, plastic caps and the aluminum caps were counterfeit by comparison. Further tests were performed by NIR and HPLC-MS, which proved it was cefradine in the bottles labeled as TIENAM®. With this combination of detection technologies, the counterfeit TIENAM® filling in used packaging materials purchased from hospitals could be identified quickly and correctly. In another case, falsified 15
lamivudine/zidovudine/nevirapine (Zidolam-N®, Hetero,India)tablets discovered in Kenya were tested according to specifications and the results complied with the requirements. But when Yin et al. [82] measured the bromine concentration in Zidolam-N® using XRF, the result showed that the bromine concentration in falsified drugs was much higher than that in the authentic drugs. Thus, falsified Zidolam-N® can be rapidly identified using a handheld, portable XRF instrument. Features of some of the techniques mentioned above are listed in table 1. Spectroscopy methods, especially NIRS, are of great importance in the detection of SFFC drugs. After 10 years of implementation, Chinese drug regulatory agencies have gradually developed a rapid NIR drug-screening system, which has become a major platform for the domestic application of NIRS [83]. When suspect drugs have been identified by rapid initial screening, further analysis is performed by HPLC or LC-MS for validation(Figure 1). In general, databases are employed with all of the detection techniques presented in this review. Rapid analysis is achieved by comparison of test results to the relevant database. Widespread sharing and application of these databases will accelerate the implementation of rapid detection technologies.
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22
Sample Rapid Screening
Visual analytical Methods
Spectroscopy Methods
Genuine Product
Color Reaction
TLC
Suspected Counterfeit
Further Tests, Identification and Quantification by HPLC or LC-MS
SFFC Drug Fig.1.Rapid detection strategy of SFFC drug
23
Table 1 Features of Rapid Detection Technique Need
Reagent
reference
/Consu
standards
me
or not
material
No
No
No
Low
Yes
Yes
No
No
Low
Yes
Need Category
Testing Technique
Description
Characters
instrument or not
Holographic technique
A technique which enables three-dimensional
well
images (holograms) to be made. It involves
established
the use of a laser, interference, diffraction,
technique,
light intensity recording and suitable
simple
illumination of the recording. With the
research work;
assistance of a database, it can quickly
high
identify SFFCs.
investment
Need Cost
database or not
Visual Analytical
RFID technique is the wireless non-contact
Technologies
use of radio-frequency electromagnetic fields to transfer data, for the purposes of Radio frequency identification (RFID)
automatically identifying and tracking tags attached to objects. The frequencies usually used are low frequencies（125k~134.2K）,high frequencies（13.56Mhz），super high
very complicated research; high investment
frequencies and microwaves. The signals are automatically recorded.
24
high pressure, rapid, high performance, high sensitive, applying broadly, both
HPLC
By establishing the database of the retention
for
factors and UV spectraof analytes, to
quantitative
quantitatively and qualitatively determine the
and qualitative
target compounds and ingredients.
determination.
Yes
Yes
High
Yes
Yes
Yes
Yes
High
No
Complicated
Instrumental Analytical
Yes
research, high
Chromatography
investment.
Technologies
Instruments are available on the market. CE is a technique which uses a capillary tube Capillary electrophoresis technique
as a separating channel, and high voltage direct current field as motive power.CE has various types of separation. CE could both quantitatively and qualitatively determine the target compounds and ingredients rapidly.
high performance, rapid, low cost. Complicated research, high investment.
25
easy, rapid, high performance, Near-infrared spectroscopy is based on molecular overtone and combination vibrations of hydrogen groups such as OH, NH and CH with the region from about 800 nm to 2500 nm. The molecular overtone and combination bands seen in the near-IR are
Spectroscopy
Near-infrared
typically very broad, leading to complex
spectroscopy(NI
spectra; it can be difficult to assign specific
R)
features to specific chemical components. Chemometric methods are often employed to extract the desired chemical information. Eventually chemometric modules are establishedforrapid qualitative and quantitative measurement of the target compounds and ingredients.
accurate, low cost, nondestructive , do not need chemical reagents, environmental friendly, apply both
Yes
No
No
High
Yes
quantitative and qualitative determination. complicated research and high investment. Instruments are available on the market.
26
easy, rapid, high performance, accurate, low cost, nondestructive , do not need The mid-infrared, approximately 4000–400 cm−1 (2.5–25 μm) is used to study the Mid-Infrared
fundamental vibrations and associated
spectroscopy(M
rotational-vibrational structure. By using
IR)
attenuated total reflection (ATR) technique, Mid-IR could be used for rapid analysis of API and some products.
chemical reagents, environmental friendly, apply both
Yes
No
no
High
Yes
quantitative and qualitative determination. complicated research and high investment. Instruments are available on the market.
27
easy, rapid, high performance, accurate, low cost, nondestructive , do not need chemical Raman spectroscopy is a spectroscopic
reagents,
technique used to observe vibrational,
environmental
Raman
rotational, and other low-frequency modes in
friendly, apply
spectroscopy
the samples. Raman spectroscopy can
both
perform quantitative and qualitative analysis
quantitative
of APIs, excipients, and medicines.
and qualitative
Yes
No
No
High
Yes
determination. complicated research and high investment. Instruments are available on the market.
28
rapid and easy. Could determine
X Ray fluorescence technique
XRF identifies each element by using the
various
characteristic "secondary" (or fluorescent)
elements,
X-rays, and quantitatively determines the
accurate.
element content by the intensity of X-rays. It
Simple
canbe used for the elemental analysis by
research, low
establishing analytical module.
investment.
Yes
No
No
High
Yes
Yes
No
No
High
Yes
Instruments Other new
are available
techniques
on the market. rapid and easy, could detect
Ion mobility technique
Ion mobility spectrometry is an analytical
trace material.
technique for detection of trace molecular
complicated
species at atmospheric pressure or
research, high
approximately atmospheric pressure,
investment.
according to the ion migration in a drift tube.
Instruments are available on the market.
29
DART is an atmospheric pressure ion source Direct analysis
that instantaneously ionizes gases, liquids and
in real time
solids in open air under ambient conditions.
(DART) mass
Combined with mass spectrometry, it can
spectrometry
rapidly analyzechemical medicines and illegal adulterated materials.
Isotope analysis technique
Isotope analysis determines the percentage content of C, N and S, and the content of 13C, and 15N
simple and rapid. Do not need sample preparation.
Yes
No
Yes
High
Yes
Yes
No
Yes
High
No
Complicated research, high investment traceable, complicated research, high cost
30
S0731-7085(17)31247-5 http://dx.doi.org/doi:10.1016/j.jpba.2017.08.016 PBA 11461
To appear in:
Journal of Pharmaceutical and Biomedical Analysis
Received date: Revised date: Accepted date:
16-5-2017 10-8-2017 10-8-2017
Please cite this article as: Wen-Bo Zou, Li-Hui Yin, Shao-Hong Jin, Advances in Rapid Drug Detection Technology, Journal of Pharmaceutical and Biomedical Analysishttp://dx.doi.org/10.1016/j.jpba.2017.08.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Advances in Rapid Drug Detection Technology Wen-Bo Zoua, Li-Hui Yina,* *, Shao-Hong Jina,* a National Institutes for Food and Drug Control * Corresponding author. Tel: +861067095258. E-mail address: [email protected] ** Corresponding author. Tel: +861053851547. E-mail address: [email protected]
In this review we focus on some rapid drug detection technology which has been reported lately for the qualification and quantification of SFFC drugs. In addition, new characteristics and trends of SFFC drugs were listed and the solution was discussed. Abstract:Spurious/Falsely-labeled/Falsified/Counterfeit (SFFC)drugs have become a major threat to public health, especially in rural areas of developing countries.The goal of this review is to provide an overview of rapid detection technologies for counterfeits recently reported, such as Near Infrared Spectroscopy, Near Infrared Chemical Imaging, Raman Spectroscopy, X-Ray Fluorescence, X-RayPowder Diffraction, Ion Mobility Spectrometry, Ion MobilityMass Spectrometry,Isotope Ratio Mass Spectrometry and visual analytical methods.The advantages of each of these detection methods are introduced. Examples of characterization of SFFC drugs using the detection technology mentioned are presented. In addition, new characteristics and trends of SFFC drugs are listed and the solution is discussed. Keywords: Counterfeits; SFFC Drug; Rapid Detection
1. Introduction The global situation of counterfeits and sub-standards has grown in recent years due to counterfeiting methods that are becoming more and more advanced and sophisticated. Because the counterfeit products look so similar to the genuine products, they not only deceive the medical doctors but also the pharmaceutical professionals. Some Spurious/Falsely-labeled/Falsified/Counterfeit (SFFC) products could meet the requirements of the official specifications, that is, they actually do contain the correct amount of the correct API. The World Health Organization (WHO) defines counterfeit drugs as those which are 1
deliberately mislabeled with respect to identity and/or source. Counterfeiting applies to both branded and generic products, with counterfeit products including drugs with the correct ingredients or with the wrong ingredients, without active pharmaceutical ingredient (API),with insufficient API, or with fake packaging [1].Although some SFFC drugs contain the correct API, good manufacturing practices (GMP) and other specifications are not followed through manufacturing, further adding to safety concerns. In other cases, the use of counterfeit drug products containing lower drug content is of particular concern for antibacterial agents because microbial resistance can develop from subtherapeutic dosing[2]. Current methods of detection for SFFC drugs include visual analysis and chemical analysis. Features incorporated in drugs and packaging can be used for visual analysis. Some companies have proposed the use of special inks and print technologies to imprint a unique design, number, or icon directly onto the product[3]. The U.S. Food and Drug Administration (FDA) developed and deployed a portable technology based on using multi-wavelength light sources to visually analyze counterfeit products[4]. Chemical analysis methods include colorimetric methods, liquid chromatography-mass spectrometry, near infrared spectroscopy, near infrared chemical imaging, mid-infrared spectroscopy, Raman spectroscopy, X-ray fluorescence, X-ray powder diffraction, Ion Mobility 2
Spectrometry, and Isotope Ratio Mass Spectrometry. However, some of these analytical methods are time-consuming or not specific. In this review, we focus on rapid drug detection technologies which have been reported recently for the qualification and quantification of SFFC drugs. Additionally, some new characteristics of SFFC drugs are discussed and several examples of handling such counterfeits are given. 2. Spectroscopy Methods 2.1 Near Infrared Spectroscopy Near-infrared spectroscopy (NIRS) is a fast and nondestructive technique that provides multi-constituent analysis of virtually any matrix. It covers the wavelength range adjacent to the mid infrared and extends up to the visible region. Although a number of NIR experiments were carried out in the early 1920s, it was not until the mid to late1960s that NIRS was practically used. In recent years, NIRS has gained wide acceptance within the pharmaceutical industry for raw material testing, product quality control and process monitoring[5].Because of its major advantages over other analytical techniques, namely, easy sample preparation without any pretreatments, and quick and noninvasive analysis, NIRS has been used as an anti-counterfeiting analytical method[6,7].Scafi and Pasquini[6]reported an investigation on the use of NIRS with the objective of identifying counterfeit drugs. They established a relatively simple protocol and employed chemometric 3
methods (Principal Component Analysis, PCA, and Soft Independence Modeling of Class Analogy, SIMCA). They evaluated the main drawbacks relating to the use of NIRS for drug identification, such as humidity alteration, sample position and sample face (for tablets). Furthermore, they proposed and evaluated a simple protocol to produce a robust model with known counterfeit drugs. Olsen et al. [8]used Prozac as a model drug to demonstrate the flexibility of NIRS in screening for counterfeit drugs in general. Vredenbregt et al. [7] described a fast screening method using NIRS for Viagra® tablets, counterfeits, and imitations of Viagra®. Among48 unknown samples that looked like Viagra® in shape, color, and inscription, the method they developed easily identified 44 samples as counterfeit tablets. In China, for the purpose of combating the SFFC drugs distributed in rural areas, the China Food and Drug Administration(CFDA) instructed the National Institutes for Food and Drug Control (NIFDC) to develop mobile labs to be used in the field for drug screening tests. A “fast drug identification system” which includes a NIR testing system installed in a mobile vehicle is being developed. Feng et al.[9]chose roxithromycin tablets and erythromycin ethylsuccinate tablets from different manufacturers as examples for construction of universal quantitative models(models that can be used to test a pharmaceutical product with the same API but from different manufacturers)for use in the NIR 4
prescreening system. The universal models have good specificity, linearity, accuracy, precision and robustness. Furthermore, they can be directly used in different FT-NIR spectrometers of the same brand without any special mathematical treatment. Researchers of traditional Chinese medicine (TCM) have shown interest in NIRS recent years. The technique can be applied in medicinal species identification, classification and origin analysis, and adulteration detection of TCM [10]. 2.2 Near Infrared Chemical Imaging Near-infrared chemical imaging(NIR-CI) combines classical spectroscopy with the ability to provide spatial information on the distribution of the components of a drug product [5,11,12]. Thus, NIR-CI has been successfully applied for drug identification [13,14] and quantification[15,16], for visualizing manufacturing problems and process effects on dissolution [17–19], and for estimating homogeneity[15,20–24]. Dubois et al. [25] and Wolff et al. [26]have used NIR-CI for the identification and characterization of counterfeit drug products. Puchert et al. [27] presented a new four-stage concept for the reliable identification of solid counterfeits which were very similar to the genuine products. They found that for counterfeit identification, NIR-CI turned out to be superior to single-point NIRS because it combines the capability of spectroscopy with the potential of visualization, thus 5
allowing local characterization of the chemical composition, domain structure, and chemical architecture. Lopes et al. [28] combined NIR-CI and classical least squares estimation to study the composition of counterfeit tablets of unknown origin. It was concluded that without knowing anything about the tablets and without destroying the tablets, NIR-CI and CLS were able to spatially identify and quantify the major compounds present in the set of counterfeit tablets under study. 2.3 Raman Spectroscopy Raman is a spectroscopic method that makes use of inelastically scattered light to obtain a spectroscopic “fingerprint” of the sample. It is then possible to identify the components and their relative concentrations based on peak location and intensity[29].Like NIRS, Raman spectroscopy has proven to be successful in portable units[30] for identification and counterfeit detection in the field[31,32]. Without any sample preparation, Raman is capable of performing noninvasive and nondestructive screening through the packaging, thus preserving suspect samples intact should further testing be necessary. As this instrumental technique has developed, portable Raman instruments have become more popular. Noonan et al. [29]explored a more universal approach for developing models that can classify multiple drugs of interest in the presence of three cutting agents, some of which are chemically very similar to the drugs of interest. Based on the models developed, they were able to successfully 6
cluster four drug surrogates: benzocaine, lidocaine, isoxsuprine, and norephedrine. They detailed the acquisition of the spectra using both homebuilt and rugged, handheld, commercial instruments, as well as preprocessing of the spectra needed before model development. Loethen et al. [33] reported an approach which was shown to be amenable to anti-counterfeit rapid screening of finished drug products in the broad class of anti-infectives, using only the Raman spectra of the APIs as the reference library. Zhao et al. [34]have developed a convenient and effective method for rapid, noninvasive screening of human serum albumin injection products using a portable Raman spectrometer. The method could be used as a universal screening means on different Raman spectrometers. Lawson and Rodriguez [35] introduced a novel algorithm to screen antibiotic and antiviral finished drug products (FDPs) using Raman spectroscopy. The algorithm described introduced a binary barcode comparison method to identify APIs in FDPs. The method was shown to correctly predict the declared API present in 18 different commercial samples and nine simulated counterfeit samples. 2.4 X-ray Fluorescence X-ray fluorescence (XRF) is a suitable technique for characterization of the presence of metals [36,37]. This technique has advantageous features including multielemental capability, good sensitivity,high precision, and short analysis times;it also is nondestructive. These 7
features make it suitable to be extended to a great variety of samples. Thus, XRF presents an excellent analytical methodology for determination of APIs, coating agents, and excipients such as calcium phosphate, titanium oxide and iron oxide (P, Ca, Ti and Fe),all of which can be detected directly by XRF on the surface of pharmaceutical formulations [38]. Ortizaet al. [38] obtained inorganic chemical fingerprints of several commercial samples (Viagra®, Cialis®,Lazar®, Libiden®, Maxfil®, Plenovit®, Potent 75®, Rigix®, V-50®,Vimax® and Pramil®) and counterfeit samples (Viagra® and Cialis®)from XRF data, and used chemometric methods PCA and HCA (Hierarchical Cluster Analysis) to classify the tablets investigated as authentic or counterfeit. Thus, XRF presented an excellent analytical methodology for semi-quantitative determination of API and excipients. 2.5 X-ray Diffraction Powder X-ray diffraction (PXRD) is commonly used in the pharmaceutical industry for polymorph identification of APIs, but not for final products. Maurin et al. [39] demonstrate results of analyses of authentic and counterfeit Viagra® showing differences in tablet coatings and their interiors. No prior preparation, apart from eventual coating removal, was applied. The results obtained for counterfeit samples of Viagra® showed that X-ray powder diffraction, especially when using 8
new, fast diffraction techniques, including multilayer mirrors and position-sensitive counters, is a method suitable for pharmaceutical market screening control for counterfeit drugs. Musumeci et al. [40] described an anticounterfeit method based on micro-X-ray diffraction (μ-XRD) in which a scanned X-ray beam can be used to read barcodes and patterns, with features as small as 0.30 mm, fabricated with compounds that can be read by X-ray diffraction but were invisible to the naked eye or optical microscopy. The method was demonstrated with barcodes and logos of FDA-approved compounds printed on various substrates, including commercial aspirin and ibuprofen tablets. Theμ-XRD method is nondestructive, automated, and user-friendly and can be used to certify the authenticity of drug tablets by mapping hidden patterns printed under the tablet coating and on packages. 2.6 Infrared Spectroscopy Anzanello et al. [41] proposed a method for selecting the most relevant subsets of attenuated total reflection Fourier transform infrared spectroscopy(ATR-FTIR) wavenumbers for clustering medicine samples into two groups: authentic or fraudulent. The method first applies a multivariate technique, PCA, to ATR-FTIR data, and two variable importance indices are derived from the parameters provided by PCA. 3. Chromatography Methods 9
HPLC can not only be used in laboratory but also in situ for rapid detection of SFFC drugs. Zhu et al.[42] developed a HPLC method for rapid determination of 12 hypoglycemic drugs within twenty minutes. A diode array detector and a C18 or C8 column were used. Only a few reference standards were needed for quantification by the method proposed. Marini et al. [43] reported the analytical and quantification performance of a newly-developed low-cost capillary electrophoresis(CE) instrument. In their work, a complete validation study was performed on selected drugs which represent pharmacological groups commonly targeted by counterfeiting, namely the antimalarial, diuretic and anti-infective drugs [44]. Although rapid separation techniques such as HPLC, GC, CE etc. are efficient and specific, sample preparation can be time consuming. Several sample preparation techniques are commonly used in GC, including purge and trap, solid phase extraction, solid phase microextraction, liquid phase microextraction, microwave assisted extraction, and ultrasonic-assisted extraction[45]. 4. Mass Spectrometry 4.1 Isotope Ratio Mass Spectrometry Elemental analysis-isotope ratio mass spectrometer (EA-IRMS) is the conventional instrument used for stable isotope amount ratio 10
measurements in bulk samples, and it has been widely used for authenticity studies to establish the provenance of food stuffs and beverages
[46].Carbon and nitrogen measurements provide information
on plant type or diet whereas hydrogen, oxygen and sulfur data have been shown to provide reliable environmental and geographical information [46-55]. Jasper et al. reported the use of IRMS for the authentication of APIs [56]; in this study, 20 blind samples of four APIs were selected and isotope amount ratios for C, N, O and/or H were measured. Benson et al.[57] and Carter et al.[58]summarized the use of isotope ratio data for the analysis of illicit drugs. Fernandez et al. [59] performed an extensive study for 139 batches of the antiviral drug Heptodin™. Since the API of the Heptodin™tablets, i.e. lamivudine (C8H11N3O3S) contains C, N and S, these elements were analyzed for isotope amount ratio measurements by multiple collector inductively coupled plasma mass spectrometry (MC-ICP-MS) and EA-IRMS. It was shown that the combination of two methods had great potential to detect counterfeit drugs. Furthermore, this approach could enable linking two counterfeit batches to a common source, or establishing a link between a suspect carrying a set of counterfeits and the laboratory responsible for the production of the counterfeit drug. 4.2 Ion Mobility Spectrometry and Ion Mobility Mass Spectrometry Ion Mobility Spectrometry (IMS) is an analytical technique that 11
separates gas-phase ions based on their ion mobility, which is related to molecular structure, size and shape, analogous to electrophoresis in the condensed phase. The technique has long been used for the detection of illegal or dangerous substances [60,61]. Initially, ion mobility spectrometers were used only in the field of physical chemistry and for plasma physics research. The development of the matrix-assisted laser desorption and ionization (MALDI) [62–64] and electrospray ionization (ESI) [65, 66] methods in the late 1980senabled the measurement of large biomolecules by MS. This also resulted in a major breakthrough in the field of ion mobility MS (IM-MS) in the 1990s [67–70].Gryniewicz et al. [71] found IMS a useful rapid screening approach to the analysis of herbal supplements for adulteration by sildenafil, vardenafil, tadalafil, andfive known sildenafil analogs. Mans et al. [72] expanded the scope of IMS for the detection of the acetildenafil family of analogs, along with previously untested sildenafil analogs and the recently approved avanafil; they showed that IMS could be used a rapid screening tool for the detection of acetildenafils, sildenafils and avanafil adulterants in herbal supplement matrices. Krueger[73] et al. used a high performance ion mobility spectrometer for the rapid analysis of nutritional supplements. Harris et al. [74] applied drift tube ion mobility spectrometry (DTIMS) coupled with laser ablation/desorption electrospray ionization (LADESI) to the fingerprinting of field-collected antimalarial pharmaceutical tablets. 12
The LADESI DTIMS platform provided distinct spectral features that were used for identification of the APIs. Ion Mobility Mass Spectrometry(IM-MS) is a powerful analytical technique that combines the benefits traditionally associated with IMS and MS[75]. IM-MS has been applied in determination of saccharides, peptides, lipids, proteins, nucleotides, and their respective metabolites. It can be used to enhance various areas of chemical and biophysical analysis [60,61]. Cuyckenset al. [76] focused on IM-MS, which was used to extract and identify the ions of metabolites of peptide drugs in the presence of an in vivo matrix, in combination with charge state filtration and various existing software tools. Blackburn et al. [77] introduced waveform ion mobility spectrometry(FAIMS) in the bioanalysis of dianicline in animal plasma. Although so far there are only a few reports on rapid detection of SFFC drugs by IM-MS, this powerful technique is likely to become popular in the future. 4.3 GC-MS GC-MS is a sensitive and efficient technique in identification and quantification of unknown residual solvents in drugs. Furthermore, it can be applied in the detection of adulteration of TCM. Zhu et al. [78,79] developed GC-MS methods to detect sedative, hypnotic, and non-steroidal anti-inflammatory drugs in supplements and TCM. 4.4 Other Mass Spectrometric detection techniques 13
Fernandez et al. [80] characterized counterfeit drugs by Desorption Electrospray Ionization(DESI) and direct analysis-in-real-time(DART) coupled to time-of-flight mass spectrometry. They demonstrated the usefulness of DART for the rapid screening of counterfeit drugs, screening several different counterfeits of the antimalarial drug artesunate. Some of these counterfeits contained other antimalarial drugs that are no longer effective; one counterfeit contained artesunate, but at only 20% of the expected amount. This has significant implications for malaria control, as use of low-dose artesunate may lead to development of artesunate resistance in the malaria parasite, and thus render artesunate ineffective. 5. Visual Analytical Methods Visual analytical methods mainly concern printing and packaging, including Radio Frequency Identification (RFID) tags, 2D codes, optical variable inks, digital watermarking, and holographic techniques. A handheld instrument is another option. Ranieri et al.[4] evaluated a new handheld instrument which enabled rapid comparison of packaging and product. The instrument showed very good accuracy in detecting counterfeit artesunate packaging and tablets, which were fraudulently labeled as manufactured by one company. Minimal training was required, and agreement between the trainer and two trainees was 100%.
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6. Conclusions With the growth of counterfeiting methods, SFFC drugs are regarded as a major threat to public health, especially in emerging countries. New characteristics and trends of SFFC drugs have shown increasing sophistication, including (i)products that comply with Pharmacopoeia (that is, the SFFC product can pass the specified tests for the authentic product), (ii)adulteration of chemical drugs into traditional Chinese herbal medicines, and (iii)using used authentic packing materials collected from hospitals. To deal with this complex and evolving situation, satisfactory results will not be achieved by using only a single detection technology. Counterfeit TIENAM®(Imipenem and Cilastatin sodium for injection,Merck Ltd.) was tested in the Mobile Lab of CFDA[81]. The packaging boxes, the upper sealing stickers, the bottles containing drugs,the rubber stoppers and the insert sheets were authentic by visual analysis. However, under the UV light and visual inspection, the lower part sealing stickers, plastic caps and the aluminum caps were counterfeit by comparison. Further tests were performed by NIR and HPLC-MS, which proved it was cefradine in the bottles labeled as TIENAM®. With this combination of detection technologies, the counterfeit TIENAM® filling in used packaging materials purchased from hospitals could be identified quickly and correctly. In another case, falsified 15
lamivudine/zidovudine/nevirapine (Zidolam-N®, Hetero,India)tablets discovered in Kenya were tested according to specifications and the results complied with the requirements. But when Yin et al. [82] measured the bromine concentration in Zidolam-N® using XRF, the result showed that the bromine concentration in falsified drugs was much higher than that in the authentic drugs. Thus, falsified Zidolam-N® can be rapidly identified using a handheld, portable XRF instrument. Features of some of the techniques mentioned above are listed in table 1. Spectroscopy methods, especially NIRS, are of great importance in the detection of SFFC drugs. After 10 years of implementation, Chinese drug regulatory agencies have gradually developed a rapid NIR drug-screening system, which has become a major platform for the domestic application of NIRS [83]. When suspect drugs have been identified by rapid initial screening, further analysis is performed by HPLC or LC-MS for validation(Figure 1). In general, databases are employed with all of the detection techniques presented in this review. Rapid analysis is achieved by comparison of test results to the relevant database. Widespread sharing and application of these databases will accelerate the implementation of rapid detection technologies.
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22
Sample Rapid Screening
Visual analytical Methods
Spectroscopy Methods
Genuine Product
Color Reaction
TLC
Suspected Counterfeit
Further Tests, Identification and Quantification by HPLC or LC-MS
SFFC Drug Fig.1.Rapid detection strategy of SFFC drug
23
Table 1 Features of Rapid Detection Technique Need
Reagent
reference
/Consu
standards
me
or not
material
No
No
No
Low
Yes
Yes
No
No
Low
Yes
Need Category
Testing Technique
Description
Characters
instrument or not
Holographic technique
A technique which enables three-dimensional
well
images (holograms) to be made. It involves
established
the use of a laser, interference, diffraction,
technique,
light intensity recording and suitable
simple
illumination of the recording. With the
research work;
assistance of a database, it can quickly
high
identify SFFCs.
investment
Need Cost
database or not
Visual Analytical
RFID technique is the wireless non-contact
Technologies
use of radio-frequency electromagnetic fields to transfer data, for the purposes of Radio frequency identification (RFID)
automatically identifying and tracking tags attached to objects. The frequencies usually used are low frequencies（125k~134.2K）,high frequencies（13.56Mhz），super high
very complicated research; high investment
frequencies and microwaves. The signals are automatically recorded.
24
high pressure, rapid, high performance, high sensitive, applying broadly, both
HPLC
By establishing the database of the retention
for
factors and UV spectraof analytes, to
quantitative
quantitatively and qualitatively determine the
and qualitative
target compounds and ingredients.
determination.
Yes
Yes
High
Yes
Yes
Yes
Yes
High
No
Complicated
Instrumental Analytical
Yes
research, high
Chromatography
investment.
Technologies
Instruments are available on the market. CE is a technique which uses a capillary tube Capillary electrophoresis technique
as a separating channel, and high voltage direct current field as motive power.CE has various types of separation. CE could both quantitatively and qualitatively determine the target compounds and ingredients rapidly.
high performance, rapid, low cost. Complicated research, high investment.
25
easy, rapid, high performance, Near-infrared spectroscopy is based on molecular overtone and combination vibrations of hydrogen groups such as OH, NH and CH with the region from about 800 nm to 2500 nm. The molecular overtone and combination bands seen in the near-IR are
Spectroscopy
Near-infrared
typically very broad, leading to complex
spectroscopy(NI
spectra; it can be difficult to assign specific
R)
features to specific chemical components. Chemometric methods are often employed to extract the desired chemical information. Eventually chemometric modules are establishedforrapid qualitative and quantitative measurement of the target compounds and ingredients.
accurate, low cost, nondestructive , do not need chemical reagents, environmental friendly, apply both
Yes
No
No
High
Yes
quantitative and qualitative determination. complicated research and high investment. Instruments are available on the market.
26
easy, rapid, high performance, accurate, low cost, nondestructive , do not need The mid-infrared, approximately 4000–400 cm−1 (2.5–25 μm) is used to study the Mid-Infrared
fundamental vibrations and associated
spectroscopy(M
rotational-vibrational structure. By using
IR)
attenuated total reflection (ATR) technique, Mid-IR could be used for rapid analysis of API and some products.
chemical reagents, environmental friendly, apply both
Yes
No
no
High
Yes
quantitative and qualitative determination. complicated research and high investment. Instruments are available on the market.
27
easy, rapid, high performance, accurate, low cost, nondestructive , do not need chemical Raman spectroscopy is a spectroscopic
reagents,
technique used to observe vibrational,
environmental
Raman
rotational, and other low-frequency modes in
friendly, apply
spectroscopy
the samples. Raman spectroscopy can
both
perform quantitative and qualitative analysis
quantitative
of APIs, excipients, and medicines.
and qualitative
Yes
No
No
High
Yes
determination. complicated research and high investment. Instruments are available on the market.
28
rapid and easy. Could determine
X Ray fluorescence technique
XRF identifies each element by using the
various
characteristic "secondary" (or fluorescent)
elements,
X-rays, and quantitatively determines the
accurate.
element content by the intensity of X-rays. It
Simple
canbe used for the elemental analysis by
research, low
establishing analytical module.
investment.
Yes
No
No
High
Yes
Yes
No
No
High
Yes
Instruments Other new
are available
techniques
on the market. rapid and easy, could detect
Ion mobility technique
Ion mobility spectrometry is an analytical
trace material.
technique for detection of trace molecular
complicated
species at atmospheric pressure or
research, high
approximately atmospheric pressure,
investment.
according to the ion migration in a drift tube.
Instruments are available on the market.
29
DART is an atmospheric pressure ion source Direct analysis
that instantaneously ionizes gases, liquids and
in real time
solids in open air under ambient conditions.
(DART) mass
Combined with mass spectrometry, it can
spectrometry
rapidly analyzechemical medicines and illegal adulterated materials.
Isotope analysis technique
Isotope analysis determines the percentage content of C, N and S, and the content of 13C, and 15N
simple and rapid. Do not need sample preparation.
Yes
No
Yes
High
Yes
Yes
No
Yes
High
No
Complicated research, high investment traceable, complicated research, high cost
30