International Journal of Pharmaceutics 587 (2020) 119702

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International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Review

The silent development of counterfeit medications in developing countries – T

A systematic review of detection technologies
⁎
Anmole S. Bolla, Ashwani R. Patel, Ronny Priefer
Massachusetts College of Pharmacy and Health Sciences University, Boston 02115, USA

A R T I C LE I N FO A B S T R A C T

Keywords: Drug counterfeiting detection is very important for the safety of patients around the world. Counterfeit phar-
Counterfeit detection maceutical products can be referred to the production and distribution of mislabeled medications in which the
Pharmaceutical medications identity, authenticity, and/or effectiveness is altered. Drugs are often counterfeited to reduce manufacture costs,
Technologies while still marketing it at as an authentic product. Increased incidence of drug counterfeiting is most noticeable
Developing countries
in developing countries, which may not have the resources to supply counterfeit detection devices at a large
scale. It is important to consider the direct problems that it may cause and to propose options for controlling and
reducing the prevalence of counterfeit medications. Certain counterfeit detection devices have been successfully
used for qualitative and quantitative assessment to differentiate counterfeit medications from the reference
product. Different technologies are needed to identify the chemical properties of a questioned drug product,
which can then be used to determine its authenticity. This review examines the implications of counterfeit
medications and the current technological approaches that are able to detect counterfeited pharmaceuticals.

1. Introduction
In the past decade there has been an increase in incidence of
counterfeit medications in the market. Counterfeit pharmaceutical
products can be referred to as the production and distribution of frau-
dulent mislabeled medications in relation to the products identity, au-
thenticity, and/or effectiveness (Swaminath, 2008). This issue is rarely
seen in developed countries but has become especially concerning in
developing nations. This prevalence is due to a lack of law enforcement
as well as inadequate regulations of pharmaceuticals and the facilities
in which the medications are made. In the developing nations, the
overall prevalence of falsified medication is estimated to be approxi-
mately 14%, with antimalarial and antibiotics being mainly affected. In
Africa almost 60% of the medications are substandard, which can lead
to patients having subtherapeutic effects, indicative of the weighted
morbidity and mortality rates that these countries currently have
(Torloni et al., 2016). Overall, this has a global cost of an estimated $32
billion annually (Ozawa et al., 2018).
The numerous falsified medications have led to life-threatening
implications among populations including increased risk of prolonged
illness, poor outcomes to treatment, adverse drug reactions, and mor-
tality. An incentive for the counterfeit producers may be that they can
supply pharmaceuticals at a reduced cost. As American Association of
Retired Persons (AARP) claims, a major concern elderly have is whether
they would be able to afford their prescriptions (Nsimba, 2009). Al-
though this is seen as an issue in the United States, this is an even
greater concern in developing countries. This may be due to the in-
creased poverty rates in these countries and the inability of the popu-
lation to afford more than the necessities. Therefore, there are in-
centives for purchasing medications at discounted rates, which have not
had proper inspections on the authenticity of these pharmaceutical
products.
Organizations such as World Health Organization (WHO) have been
working on this issue for decades and in 2006 launched the
International Medical Products Anti-Counterfeiting Taskforce
(IMPACT). Members of international organizations, enforcement
agencies, industry, and nongovernmental organizations all work to-
gether in combatting the pharmaceutical counterfeit problem in dif-
ferent countries (World Health Organization, 2011). This work entails
tackling the increased criminal networks and internet sources in which
counterfeit medications are gaining popularity. The worldwide sales of
illegal medications are estimated to reach $75 billion in 2020, a 90%
increase in the past 5 years (World Health Organization, 2011). Due to
the different regulations and laws of different countries, IMPACT has
not been able to stop the counterfeit pharmaceutics from entering the
market.

⁎
Corresponding author.
E-mail address: ronny.priefer@mcphs.edu (R. Priefer).

https://doi.org/10.1016/j.ijpharm.2020.119702
Received 16 June 2020; Received in revised form 23 July 2020; Accepted 24 July 2020
Available online 28 July 2020
0378-5173/ © 2020 Elsevier B.V. All rights reserved.
A.S. Bolla, et al.
As this issue is a major public health concern, countries such as USA
have increased its surveillance of pharmaceuticals and created stan-
dards such as Good Manufacturing Practice (GMP) requirements to
ensure the pharmaceuticals arriving from other countries are authentic.
In some developing countries the emergence of counterfeit medications
is not well publicized. There is a sense that this information is being
kept quiet to avoid defaming a company’s products as well as to
minimize public fear (Cockburn et al., 2005). If the general population
was made aware of the severity of the issue, they may distrust all
medications and not adhere to their current medication therapies that
are not compromised (Cockburn et al., 2005). This may also lead to
other implications such as patient’s overall distrust in the health care
system and therefore, they may try to self-treat instead of seeking
treatment in well-established hospitals in their local area. This would
thus lead to a greater probability that patients turn to the internet to
attain medications.
According to a Pfizer sponsored study based on European countries,
getting a medication from an illicit source leads to a greater risk of
attaining a counterfeit rather than the intended medication (Porter,
2008). Many of the drugs sold through illicit sources are “lifestyle”
drugs such as for hypertension or ones that patients may be too em-
barrassed to see a doctor, such as for erectile dysfunction (Porter,
2008). Another publication in the New England Journal of Medicine
reported that in Singapore many non-diabetic patients were hospita-
lized with symptoms of severe hypoglycemia as a result of counterfeit
sexual enhancement drugs (Jackson et al., 2010). These patients were
receiving a drug laced with glyburide, a diabetic medication, and in-
cluded “inconsistent doses of active pharmaceutical ingredients (from
0% to > 200% of labelled dose), contaminants (including talcum
powder, commercial paint, and printer ink), and alternative ingredients
that are potentially hazardous” (Jackson et al., 2010). These medica-
tions were mixed with numerous other active ingredients ranging from
amphetamine to metronidazole, leaving uncertainty of possible drug-
drug interactions. These medications were obtained by individuals in
developed as well as developing nations by means other than the tra-
ditional clinic visit due to the cost of the medication and social stigma.
In a study, when more than 100 online pharmacies were identified and
assessed, approximately 94% had no verifiable pharmacist, 90% did not
require a prescription for prescription-only medications, 85% didn’t
have a physical location, and 79% had a website that violated in-
tellectual property (Jackson et al., 2010). This is seen as just one set of
cases in which patients have been hospitalized and possibly died due to
spurious medications, which the implications are far worse in the de-
veloping countries due to the limited resources they have.
In 2009, China was reported to counterfeit 600,000 antimalarial
tablets, which were intercepted by the Nigerian government (Lewis,
2009). These tablets, although they were produced and shipped from
China, were incorrectly labelled “Made in India”. When the residents of
China were themselves asked about their views of pharmaceuticals,
they were unsure whether what they were acquiring was fake or not. A
23-year-old inhabitant expressed his fears when he was prescribed
antibiotics for his kidney infection. As days went by his kidney infection
seemed to be progressively worsening. After 9 days he was called back
to his doctor, who informed him that his antibiotics could be fake
(Lewis, 2009). Another more recent study evaluated that around 28% of
the counterfeit medications are coming from China, with most of the
medications being adulterated are anti-infectives (Mackey et al., 2015).
It is now recognized as a danger globally to public health as seen in
reports compiled by public and private stakeholders that show the ex-
tent of production, distribution, and sales of substandard counterfeit
medications that continue to increase (Mackey et al., 2015). Further-
more, the Pharmaceutical Security Institute noted from 2005 to 2010
the diversion/theft of pharmaceuticals increased by 66% (Mackey et al.,
2015). However, during that same time, there was a 122% increase in
incidence of drug counterfeiting (Mackey et al., 2015). This indicates
that the theft of drugs is no longer as prevalent of an issue as is the
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International Journal of Pharmaceutics 587 (2020) 119702
international trade of the counterfeit drugs.
Counterfeit anti-malarial, antibiotics, and antivirals have a con-
sequential cost to public health as they can lead to resistance to med-
ications that are needed to mitigate diseases that would otherwise be
fatal to the population. Recently, treatment failure of infectious diseases
has been one of the major healthcare issues, especially in developing
countries, where respiratory tract infections have a mortality of 4 to 5
million people a year (Izadi et al.,). The most common respiratory tract
infection seen is pneumonia. Levofloxacin, because of its high oral
bioavailability and fast bactericidal activity, is the treatment of choice
for severe pneumonia (Izadi et al., 2019). Due to the poor quality that
has been seen of levofloxacin, the minimum required inhibitory con-
centration may not be achieved, thus leading to resistance. Likewise, in
recent years, drug resistance to HIV regimens is now being seen in
developing countries. Again, the resistance in part is due to inadequate
quality of the antivirals that are given to patients in these countries
(Suthar et al., 2019). Overall, resistance in medications such antivirals
and antibiotics can lead to increased mortality rates as well as limiting
treatment options.
Another problem in developing nations is postpartum hemorrhage
(PPH), known to be the leading cause of maternal mortality, represents
around 27% of all maternal deaths worldwide (Torloni et al., 2016).
Although oxytocin is the drug of choice in preventing PPH, in devel-
oping countries it is thought to be compromised due to poor manu-
facturing quality as well as inadequate transport, and storage (Torloni
et al., 2016).
The worldwide concern of counterfeit drugs has however resulted in
a rise of different methods in attempting to minimize the amount
reaching the market. These techniques range from spectroscopic and
chromatography approaches, to better tracking and labeling. Each have
their inherent strengths and weaknesses, in particular their practicality,
reliability, and cost. Some of the technologies that have been explored
are gas chromatography – mass spectrometry, high performance liquid
chromatography, liquid chromatography - mass spectrometry, etc. with
some showing promising results for monitoring counterfeit medica-
tions. Herein, is a report of approaches that are being explored to assist
in halting this significant healthcare risk by focusing on the identifi-
cation of the active agent.
2. Chromatography
Chromatography involves the use of separating the active in-
gredients from drug samples in order to quantify the amount of drug in
each sample (Deconinck et al., 2013). Chromatography separates a
given sample by applying the differences between the mobile and sta-
tionary phase. Initially, a sample of the questioned substance is dis-
solved in a fluid, often referred to as the mobile phase. The components
of the sample separate based on how the drug sample dissolves in the
mobile phase and the stationary phase (Chromatography, 2020). The
stationary phase can be divided into column, paper, and thin layer
chromatography. The higher the adsorption of a molecule to the sta-
tionary phase, the slower the drug components will move through the
column or along the TLC (Coskun, 2016). Conversely, the more soluble
a drug is in the mobile phase, the faster the molecule will move through
a column. Both factors will affect the adsorption rate of a drug and thus
the separation of the drug components. The different subsets of chro-
matography differ mainly in the mobile and stationary phases that is
used. For example, one subset of chromatography may use a normal-
phase chromatography where the mobile phase is non-polar, and the
stationary phase is polar. In contrast, some methods of chromatography
also use reverse-phase, where the mobile phase is polar, and the sta-
tionary phase is non-polar. Such changes in the phases allow for dif-
ferent drug affinity to the stationary phase, leading to different ad-
sorption rates (HPLC Separation Modes, 2020).
A.S. Bolla, et al.
2.1. Thin layer chromatography (TLC)
One of the most common devices that are used to detect counterfeit
drugs is through the use of thin layer chromatography (TLC) by German
Pharma Health Fund (GPHF) Minilab (The GPHF-Minilab™, 2020).
There are four processes that are utilized within the device in order to
test the quality of a drug. These processes include a physical inspection
of solid dosage forms and packages, a sample tablet and capsule dis-
integration test to verify modified-release dosage forms, a quick check
of the fill and total weight, and a semiquantitative TLC chemical test in
order to check for the quantities of the active principal ingredient (API)
(The GPHF-Minilab™, 2020). This kit is advantageous to developing
countries since electricity supplementation is not mandatory as the
device is battery powered and can be operated with minimal amounts
of training. The portable device provides a versatile means of drug
analysis, particularly in antimalarial, antituberculotic, antiretroviral,
and antibiotic medications (Jähnke, 2004). Furthermore, this device
has the means of screening various medications that are on the World
Health Organization’s essential medication list (Kenyon et al., 1995).
As mentioned above, one of the main uses for the Minilab includes
the detection of antimalarial medications. Subsequently, the Tanzania
Food and Drugs Authority (TFDA) has implemented the use of the
MiniLab kits. The supplementation of this device in their counterfeit
detection programs was utilized to improve the capacity of the TFDA to
monitor the medications that was currently in the distribution chain
(Risha et al., 2008). Testing procedures were not labor intensive, as one
manufacturer sample test screening took less than two hours. This ra-
ther quick screening allowed the TFSA to increase the number of
questionable samples to be analyzed in a timely manner.
Another TLC that has seen use is the paper analytical device (PAD).
This was originally developed to help monitor Kenya’s pharmaceuticals
for the detection of spurious medications commonly seen in this de-
veloping nation (Paper Analytical Device Project, 2020). The PAD
contains a yeast-based biosensor to test for possible counterfeit medi-
cations. Special training is not required, as the user does not need
anything more than the drug sample and water. The drug is placed on
the PAD with the addition of a drop of water and the sample is ran
along the lanes. The lanes test for different chemical and functional
groups that produce a unique chemical fingerprint based on the che-
mical structure of the medication (Paper Analytical Device Project,
2020). PAD testing was attempted to screen the authenticity of many
first line anti-tuberculosis medications in low resource settings where
high-performance liquid chromatography (HPLC) may be too costly.
This test was also shown to detect unwanted binders and fillers, which
the more traditional chromatographic methods could not detect
(Weaver et al., 2013). The color barcode the PAD produced was easily
compared to an authentic sample and it was found that the sensitivity
and selectivity of the analysis was also adequate to identify counterfeit
drugs from their counterpart (Weaver et al., 2013) (Table 1).
The use of the Minilab and PAD has demonstrated to be an in-
expensive and allow for rapid testing. However, the main shortcoming
is that they can only provide an estimate of the drug content, of which
the reliability of detection depends on the personnel’s visual cap-
abilities (Risha et al., 2008). Low concentration formulations and
compounds with structural similarities to authenticate cannot be cer-
tain.
Table 1
Advantages/Disadvantages of Thin Layer Chromatography.
Advantages
• Inexpensive
• Disposable TLC plates
• Minimal training required due to ease of use
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International Journal of Pharmaceutics 587 (2020) 119702
2.2. High performance liquid chromatography (HPLC)
High Performance Liquid Chromatography (HPLC) is a versatile tool
for the detection of counterfeit medications, while maintaining high
levels of specificity and sensitivity. Due to these features, HPLC has
been utilized in testing for a wide variety of drugs. For example, one
study utilized HPLC for the determination of the five most commonly
used antimalarial agents: amodiaquine, proguanil, mefloquine, arte-
mether, and lumefantrine (Hoellein and Holzgrabe, 2014). Although
expensive, certain readily available and cheap chemicals, solvents, and
standard C-18 reversed-phase (RP) columns can be used. This would
reduce the costs of producing this tool in countries that lack the means
and resources (Hoellein and Holzgrabe, 2014) (Fig. 1).
Additionally, HPLC has been used in research studies to distinguish
whether a sample was amiodarone or dronedarone (El-Bagary et al.,
2015). Historically, amiodarone has been used as a counterfeit in place
of dronedarone due to its inexpensive manufacturing costs when com-
pared to dronedarone (El-Bagary et al., 2015; Khaykin and Shamiss,
2012). Although amiodarone is considered more efficacious than dro-
nedarone, it also has a larger adverse effect profile, which is often at-
tributed to increased treatment discontinuations and rates of mortality
(Kim et al., 2014). Although no HPLC methods are acknowledged in
major pharmacopeias for the qualitative and quantitative estimation of
dronedarone in pharmaceutical dosage forms, certain studies further
prove the robustness that is offered by HPLC (El-Bagary et al., 2015;
Tondepu et al., 2012). The HPLC methods for determining the quantity
of dronedarone and amiodarone in pharmaceutical products was
proven to be precise, accurate, and specific to favor its utilization in
drug concentration ranges of 5–80 μg/mL for both amiodarone and
dronedarone (El-Bagary et al., 2015).
Furthermore, the use of isocratic reverse-phase HPLC has also been
tested to separate and determine numerous anti-diabetic medications:
glipizide, gliclazide, repaglinide, glimepiride, and glibenclamide (also
known as glyburide). This process utilizes an Alltima C18 column with
an isocratic mobile phase of a methanol-phosphate buffer (Yao et al.,
2007). The stock solutions of these medications were prepared by dis-
solving the appropriate amounts of the sample in methanol to accu-
rately measure the comparison between the test and the reference
sample. The study concluded that HPLC was a valid tool to accurately
detect counterfeit medications in anti-diabetic medications.
Although there are countless examples in which HPLC can be used,
there are many limitations that prohibits its use in developing coun-
tries. Although there are variations of solvents and columns that can
make the technology more affordable, HPLC is a premium tool, which
may not be financially feasible for developing countries to sustain.
Table 2 below acknowledges the advantages and limitations that must
be considered before utilizing HPLC devices.
2.3. Liquid chromatography – mass spectrometry
Liquid Chromatography – Mass Spectrometry (LC-MS) is a combi-
nation of the ability to separate molecules through liquid chromato-
graphy and then identifying the compound through mass spectrometry
(Pitt, 2009). This is widely accepted as these two approaches comple-
ment each other when used concomitantly. The introduction of MS after
chromatographic separation provides for its high sensitivity and se-
lectivity (Pang et al., 2016). MS compliments the qualitative LC by
Disadvantages
• TLC solvent toxicities
• Accuracy is dependent on operator visual abilities
• Similar chemical structures can lead to similar distance inaccuracies
A.S. Bolla, et al.
Fig. 1. Schematic Representation of High-Performance Liquid Chromatography (Center and Properly Select Components, 2020).
Table 2
Advantages/Disadvantages of High-Performance Liquid Chromatography.
Advantages Disadvantages
• High sensitivity allows for accurate • Expensive
results • Requires higher level training
• Fast results are good for large product
testing
• Requires
operate
high power source to
• Versatility allows nearly any drug can be
tested and identified
providing the structural characteristics of an unknown sample, while
also satisfying the insufficiencies of the quantitative factor of LC
(Venhuis et al., 2011).
Phosphodiesterase (PDE) Inhibitors are examples where LC-MS was
utilized for the detection of impurities. One example of this was with
Aildenafil, an analog of sildenafil. It was discovered the Aildenafil was
detected in capsules of a dietary supplement product that was ad-
vertised as a libido enhancing agent (Zou et al., 2006). LC-MS was in-
cluded in a combination with other counterfeit detection devices such
as IR and NMR in order to adequately determine the contents of Ail-
denafil in each supplement sample. The ability to couple LC-MS with
other detection techniques is important since the companies that pro-
duce these counterfeit medications could alter the chemical structures
of their products. This would allow manufacturers to match the regis-
tered active ingredients based on a specific testing device. However,
with the use of multiple detection techniques, it becomes more difficult
to evade the detection when such techniques are coupled (Pitt, 2009).
In fact, it becomes quite disturbing when we realized exactly how
many different supplements include PDE inhibitors in order to make
their marketing claims more believable. One study used liquid chro-
matography-electrospray ionization tandem mass spectrometry, a tool
with a selective mass analysis capability of triple quadruple mass
spectrometry, to detect for synthetic phosphodiesterase inhibitors and
their analogs in pre-market samples. These samples were submitted to
the Health Sciences Authority of Singapore (HSA) for screening, which
multiple samples were positive for containing a form of a PDE inhibitor
within the dietary supplement (Gratz et al., 2004). Another research
study screened for PDE inhibitors from samples of different manu-
facturers that claimed their herbal product to have sexual enhancement
properties. LC-MS was used to determine that approximately 50% of the
herbal samples contained a PDE-5 inhibitor (JoVE Science Education
Database, 2020) (Table 3).
One of the leading disadvantages of implementing the coupling of
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International Journal of Pharmaceutics 587 (2020) 119702
Table 3
Advantages/Disadvantages of Liquid Chromatography – Mass Spectrometry.
Advantages Disadvantages
• High efficiency of LC separations • Development of
• High sensitivity and selectivity to provide ionization suppression
information about the structural
characteristics of a drug sample
• Portability
• Cost effective
LC with MS in metabolic profiling studies is the occurrence of ionization
suppression. This can occur when two or more chemical compounds
elute from a chromatographic column concurrently. During this un-
fortunate process, there is identification insufficiencies, of which may
prove difficult to resolve.
2.4. Gas chromatography – mass spectrometry (GC–MS)
Gas Chromatography - Mass Spectrometry (GC–MS) is an analytical
tool that has been used to detect and characterize counterfeit medica-
tions. This method is a special form of chromatography in which the
mobile phase is a gas (Gas Chromatography Mass Spectrometry, 2020).
Gas Chromatography is widely known as the method of choice for
measuring steroid samples (Deisingh, 2005). This is primarily because
this technique is useful for detecting low concentration of analytes,
such as estradiol or testosterone.
Furthermore, GC–MS was recently utilized to detect counterfeit
Viagra tablets in Hungary (Committee on Understanding the Global
Public Health Implications of Substandard, 2013). These counterfeit
tablets contained amphetamine, rather than the active ingredient of
sildenafil citrate. Besides a tainted pink hue to the tablets, there was no
other physical difference that was noticeable (Committee on
Understanding the Global Public Health Implications of Substandard,
2013). Additionally, methylphenidate has historically been detected by
GC – flame-ionized detection (FID) and GC–MS at the California Bureau
of Forensic Services Laboratory (Committee on Understanding the
Global Public Health Implications of Substandard, Falsified, 2013).
Doing so allowed technicians to find traces of oxycodone and dihy-
drocodeinone in methylphenidate tablets (Table 4).
One of the main advantages of GC–MS is the ability to detect vo-
latile impurities (Soltaninejad et al., 2007). In Tehran, Iran, GC–MS was
coupled with HPLC in order to detect altered buprenorphine vials.
Temgesic and Bungesic were considered some of the most illicit medi-
cations of abuse by opioid addicts in Tehran’s black market
A.S. Bolla, et al.
Table 4
Advantages/Disadvantages of Gas Chromatography – Mass Spectrometry.
Advantages Disadvantages
• Helpful for detecting inadequate • Expensive
amounts of organic solvents when • Requires trained chemists
used with FID • Not readily portable
• Accurate • Requires high power source
• High sensitivity for nonpolar
molecules such as steroid samples
• Not capable of directly analyzing
drugs that are nonvolatile, polar, or
thermally labile
(Sciencedirect.com., 2020). With the help of GC–MS along with HPLC,
researchers were able to detect acetyl codeine, pheniramine, and dia-
cetylmorphine, which are responsible for the euphoria that is attributed
to the opioid addicts' dependency (Sciencedirect.com., 2020).
3. Spectrophotometry
Spectrophotometry is a tool that measures the intensity of a light
source when it passes through a given sample solution. This is based off
the principle that each sample solution absorbs a portion of the light
source, of which can be determined through a certain range of wave-
lengths (HunterLab Horizons Blog, 2020). This allows the wavelength
measurement to serve as a means of determining how much of a che-
mical substance is in each sample (HunterLab Horizons Blog, 2020).
Quantitative analysis also provides a reliable pharmaceutical finger-
print of the dosage. Additionally, spectrophotometry does not need
extensive sample preparation, which allows for consistent and accurate
spectra measurements without the need to destroy the drug sample
(Sensing, 2020). The spectrophotometer will analyze the color and re-
flectance patterns of a drug sample and will compare the results to a
reference product (Sciencedirect.com., 2020). The most common
spectrophotometry technologies for pharmaceutical counterfeit detec-
tion are Ultraviolet, Raman spectroscopy, Nuclear magnetic resonance,
and Infrared.
3.1. Ultraviolet spectrophotometry
Ultraviolet–visible spectroscopy (UV–Vis) is a simple, rapid, and
low-cost method for analyzing counterfeit drug products (Lawson
et al.,). However, its lack of specificity and sensitivity due to its poor
resolution limits the amount of information that can be obtained,
making this approach not ideal (Lawson et al.,). Despite this hurdle, UV
has been utilized in various tests to detect counterfeit drug samples
when referred to the reference product. For example, conventional
solvent extraction through UV analysis, similar to the approach in the
British Pharmacopoeia, was conducted to validate the authenticity of
paracetamol tablets (Figueroa et al., 2014). The paracetamol tablets
were analyzed from various country sources, including Europe, Africa,
Asian, and the Caribbean Islands. It was shown that in certain countries
the paracetamol tablets contained insufficient levels of the active
pharmaceutical ingredient (Figueroa et al., 2014).
Another study analyzed the levels of Tylenol through UV spectro-
photometry by separating the ingredient’s UV peaks from the mixture of
peaks that are generated from the excipients or inactive ingredients of
the tablet (Salmon and Priefer, 2018). Initially, samples were crushed,
and the powder was dissolved in multiple solvents in order to be
measured. Although somewhat burdensome, UV analysis preparation
only requires solvent extraction, dilution, and filtration (Figueroa et al.,
2014).
Due to the hurdles mentioned previously, UV-analysis has produced
very few real-world successes. However, a recent patent describes the
incorporation of an ELECTRE TRI process to offset the uncertainty.
Sorting boundary conditions are determined by the ELECTRE TRI pro-
cess into the most relevant categories (Dégardin et al., 2017). Limiting
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International Journal of Pharmaceutics 587 (2020) 119702
Table 5
Advantages/Disadvantages of Ultraviolet Spectrophotometry.
Advantages Disadvantages
• Inexpensive • Low Sensitivity/Specificity
• Simple, rapid testing • Requires more research
• Sample preparation is required prior to drug
analysis leading to variable measures of absorbance
the interference that uncertainty produces in UV can allow for further
confidence in the approach, thus allowing a potential increase in the
use of UV spectrophotometry (Table 5).
3.2. Raman spectroscopy
Raman Spectroscopy is a non-destructive approach that can accu-
rately analyze medication samples. When combined with chemometric
techniques, it is a feasible tool for characterizing and distinguishing
counterfeit medications (Pool, 2020). Handheld Raman spectrometers
have been developed that directs a light source at the actual drug
sample. The light source is normally provided through a laser, however,
near infrared and ultraviolet can be used as well. The light interacts
with the vibrations that are released from the molecule, which will
result in a shift in energy of the photons (ThermoFisher., 2020). The
shift in energy is important because it provides the information about
the vibrational modes that are detected, of which is used to distinguish
the characteristics of the drug sample. The inelastic light scattering is
detected, which will display a specific spectrum that is attributed only
to a certain molecule, making it helpful to identify counterfeit drug
molecules (ThermoFisher., 2020).
One example of a Raman analyzer device is the Thermo Scientific™
TruScan™ RM Handheld Raman Analyzer, which is advertised to deliver
reliable identity of the drug through sealed packaged materials (Lawson
and Rodriguez, 2016). Additionally, there are Raman barcode devices
for counterfeit drug detection (Neuberger and Neusüß, 2015). This
approach is advantageous since it does not need to include every pos-
sible drug product in the spectral library prior to testing the questioned
drug sample. Comparing a pharmaceutical product spectrum from one
manufacturer may not display similar analytical outcomes when com-
pared to other manufacturers of the same drug product. This may be
due to different coatings and inactive excipients that different manu-
facturers may use. This is especially important for generic medications,
which may have multiple different manufacturers for the same drug
product. The study concluded with being able to predict the active
pharmaceutical ingredient in 18 different samples of the 9 counterfeit
drug samples (Neuberger and Neusüß, 2015). Another study utilized
the change in Raman signals of acetylsalicylic acid tablets placed in five
different environments to detect chemical changes due to inadequate
storage conditions (Putzig et al., 1994).
There are challenges in Raman spectroscopy that occur mainly in
the analysis of the spectra. Multiple spectra may be available due to the
multiple manufacturing sites of generic formulations of medications
(Pool, 2020). Additionally, portable Raman spectrometers are not
adapted for quantitative measurements of low-dose medications (Pool,
2020). This may be of concern for high potency medications, as its
sensitivity is lower when compared to other analytical tools. In those
cases, a more sensitive tool such as infrared spectroscopy should be
used along with Raman spectroscopy (Pool, 2020) (Table 6).
3.3. Infrared
Infrared (IR) Spectroscopy is the analysis of the absorption, emis-
sion, or reflection of infrared light by a molecule to identify a sample. In
this technique, the vibrational transitions of molecules are analyzed and
the molecular structure liquid, solid, or gas phases can be determined
A.S. Bolla, et al.
Table 6
Advantages/Disadvantages of Raman Spectroscopy.
Advantages
• Portable
• High specificity and sensitivity alone without other technological add-ons
• Special training to use device is not required
(Wang et al., 2020). For example, it is seen that stronger bonds and
lighter atoms within infrared allow the molecules to vibrate at higher
stretching frequencies. This technique can be used to detect counterfeit
medications by identifying the functional group of the components
from the samples. The most popular IR approaches are the dispersive
infrared spectrometer and the Fourier infrared spectrometer.
Infrared spectroscopy has been used for detecting counterfeit med-
ications in developing nations. Near infrared spectroscopy (NIR) is
being used in the pharmaceutical industry for quantifying active
pharmaceutical ingredients within a margin of 2.5% (Chen et al.,
2019). Some cases that have been evaluated include efavirenz and
isoniazid tablets, of which NIR was used for quality assurance testing.
Although NIR devices are historically known for their steep price, over
time the approach has become more affordable and may be suitable for
routine counterfeit drug testing in developing countries (Chen et al.,
2019). One study used a relatively inexpensive NIR device that was able
to adequately measure a prediction error of approximately 10%.
Another example of how NIR spectroscopy can be used is in de-
termining expired medications. In China, samples of Levofloxacin found
in local drug stores were tested using NIR for quality assurance. It was
found that NIR had a 97% sensitivity and 100% specificity of the 34
unexpired and 128 expired medications discovered
(Www2.chemistry.msu.edu, 2020). Expired medications are harmful to
patients. When a medication is dispensed beyond the expiration date,
the potency of the medication is diminished and can lead to sub-
therapeutic effects of the medication. The testing with NIR suggests that
along with determining the authenticity of the medication, it can also
provide additional information about expired medications. This can
help individuals of developing nations in adequately identifying the
quality of medications they purchase from pharmaceutical companies
prior to dispensing (Table 7).
3.4. Nuclear magnetic resonance spectroscopy
Nuclear Magnetic Resonance Spectroscopy (NMR) is another ana-
lytical technique to identify molecular structures and has found uses for
quality control of pharmaceuticals. In this method, the protons of the
nucleus generate a magnetic field and leads to resonance (Avomeen,
2020). The sample is placed in an external magnetic field and an
electromagnetic wave excites the nucleus of the atom. Each nucleus has
a characteristic spin that will generate its own magnetic field, which
produces a resonance signal (Assemat et al., 2019). Laboratories can
utilize NMR to test the purity of samples.
NMR is often done in a laboratory, which is costly and requires
cumbersome equipment (Ribeiro et al., 2018). There are benchtop
nuclear magnetic resonance spectrometers, which is more compact,
portable, and cheaper than its equivalent. However, they are of a lower
Table 7
Advantages/Disadvantages of Infrared spectroscopy.
Advantages
• Sample preparation is not required
• Portable
• Minimal training required
• Rapid results
• Newer devices more affordable
International Journal of Pharmaceutics 587 (2020) 119702
Disadvantages
• Multiple spectra must be implemented for each reference drug
• Raman spectrometers are not well adapted for quantitative measurement of low-dose
medications
magnetic field, which decreases the sensitivity. In developing nations
where resources are scarce, a benchtop NMR spectrometer may be more
beneficial than its analogue in detecting spurious drugs due to the
simplicity and cost of the device.
Currently, there are very little studies in the use of NMR for testing
falsified medications in developing nations. From a study on benchtop
NMR used for detecting counterfeit erectile dysfunction and anti-
malarial medications, it successfully detected the falsified medications
within 5 min (McEwen et al., 2012). Another example included a more
advanced NMR technique to test the authenticity of anabolic steroids.
The findings indicated three types of adulterations: absence of active
ingredient, adulteration with other substance, and concentrations
below the indicated value [61]. NMR is also used with liquid for-
mulations, as was tested with counterfeit corticosteroid creams and
ointments. In some formulations, water made it difficult to identify the
corticosteroid. Although the results included numerous large-sized
signals due to water interference, it was possible to determine the au-
thenticity through longer processing (Wang et al., 2020). These studies
prove the advantages that NMR spectroscopy offers in the detection of
counterfeit medications for various formulations (Table 8).
4. Conclusion
Various pharmaceutical counterfeit detecting technologies are ei-
ther being developed or are already on the market. These approaches
utilize different technologies based on factors such as cost, resource
utilization, sensitivity, specificity, and the ability to detect a medication
based on its chemical characteristics. While accuracy is a standard that
must be upheld, it is important to consider the resources that may be
needed in the application of these approaches. A costly, high powered
tool that requires highly trained technicians may be too burdensome for
developing countries. Resource scarcity and cost is a shared challenge
for most counterfeit technologies. Further advancements in counterfeit
technologies could potentially address the needs of developing coun-
tries. This will ultimately lead to a larger decline in counterfeit pro-
duction.
Additional research is required to overcome the current challenges.
It is essential for these devices to be accurate enough to adequately
screen for counterfeit medications. Using a medication with insufficient
quantities of the active ingredient can lead to disease progression and
therapeutic inadequacy. In contrast, a medication with a larger quantity
of the active pharmaceutical ingredient than advertised can lead to
toxicities. Furthermore, the wrong active ingredient can lead to un-
known implications to the patient. Tailoring devices based on countries’
needs also includes the medications that have a high incidence of
counterfeiting. For example, antimalarials are a large target for coun-
terfeiting in Tanzania, of which a device that is highly selective and
Disadvantages
• Multiple spectra must be implemented for each reference drug
• Spectrometers are not well adapted for quantitative measurement of low-dose medications
• Does not provide relative location of the functional group on molecule in a sample
6
A.S. Bolla, et al.
Table 8
Advantages/Disadvantages of Nuclear magnetic resonance spectroscopy.
Advantages
• Definite method in analyzing the identify, structure, concentration, and behavior of molecules
• Study of molecular interactions
• Benchtop is compact
• Can be used for various analysis other than pharmaceutical such as diagnostic
• Can create a library of data collected
sensitive for antimalarials should be considered when determining
which technological approach to proceed with. The implementation of
these country-specific considerations in addition to an accurate phar-
maceutical counterfeit detecting device has the potential of dramati-
cally increasing the safety of millions of people around the world.
Contributions
Anmole S. Bolla and Ashwani R. Patel were responsible for the
composition of the bulk of the manuscript including finding the refer-
enced articles. Additionally, Anmole and Ashwani were responsible for
creating any tables and figures within the manuscript. Ronny Priefer
developed the idea of the manuscript and mentored Anmole and
Ashwani throughout the writing and proofread process.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgements
The authors wish to thank the School of Pharmacy at the
Massachusetts College of Pharmacy and Health Sciences University for
financial support of this project.
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