Stable Isotope Profiling of Internet-Sourced Viagra® and 'generic- Viagra' Tablets

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Conference: European Geosciences Union General Assembly 2013
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Abstract
Viagra® manufactured by Pfizer was the first prescription drug for the treatment of erectile dysfunction (ED), a condition that is estimated to affect 1 in 10 men at some stage in their lives (1). Viagra® contains the active pharmaceutical ingredient (API) sildenafil, as the citrate salt. Sildenafil, along with Tadalafil and Vardenafil belong to a class of drugs known as phosphodiesterase type 5 (PDE5) inhibitors. Since its first production in 1998, Viagra® has generated well in excess of 10 billion US dollars in sales (2) and with Pfizers' patent extended to April 2020 (3) it still remains the only sildenafil-based treatment option for sufferers of ED in the US. There are no legal 'generic-Viagra' formulations available in the US. However, formulations containing sildenafil citrate as API are widely available over the internet and often sold as 'generic Viagra'. These cheaper alternatives are often manufactured under less than ideal conditions with little or no QA/QC procedures in place. The World Health Organisation recognised the scale of the problem in its 2010 bulletin "Growing threat from counterfeit medicines" (4) and quotes a Dutch study cited in the International Journal of Clinical Practice in which from a cohort of 370 seized Viagra® samples, only 10 were genuine. We sourced a variety of tablets sold for the treatment of ED which claimed to have sildenafil citrate as API. Viagra®, 'generic-Viagra', Kamagra, Silagra and Filagra tablets were ordered via the internet and supplied from both UK-based pharmacies as well as overseas suppliers (Hong Kong, India, Vanuata). In this small-scale pilot study, we present results from bulk 2H/18O and 13C/15N stable isotope analysis performed on crushed tablets from 23 samples of internet-sourced tablets sold for the treatment of ED and purported to contain sildenafil citrate as API. References 1. www.healthcare.org.uk 2. www.moneynews.com 3. US Patent & trademark office (www.uspto.gov) 4. WHO bulletin 2010; 88:247-248
Stable Isotope Profiling of
Internet Sourced Viagra® and
generic- Viagra Tablets
H.F.Kemp1 and W.Meier-Augenstein1,2
1Stable Isotope Forensic Lab, James Huon Instute, Dundee, DD2 5DA, UK
2Environmental & Forensic Science Group, Robert Gordon University, Aberdeen AB10 1FR, UK
Email: [email protected]on.ac.uk
Introducon
Viagra® manufactured by Pfizer was the
first prescripon drug for the treatment of
erecle dysfuncon (ED), a condion that is
esmated to affect 1 in 10 men at some
stage in their lives (1). Viagra® contains the
acve pharmaceucal ingredient (API)
sildenafil, as the citrate salt.
Since its first producon in 1998, Viagra®
has generated well in excess of $10 billion
US dollars in sales (2) and with Pfizers’
patent extended to April 2020 (3) it sll
remains the only sildenafil-based treatment
opon for sufferers of ED in the US. There
are no legal generic-Viagra formulaons
available in the US. However, formulaons
containing sildenafil citrate as API are
widely available over the internet and oen
sold as ‘generic Viagra’. These cheaper
alternaves are oen manufactured under
less than ideal condions with lile or no
QA/QC procedures in place.
The World Health Organisaon recognised
the scale of the problem in its 2010 bullen
“Growing threat from counterfeit
medicines” (4) and quotes a Dutch study
cited in the Internaonal Journal of Clinical
Pracce in which from a cohort of 370
seized Viagra samples, only 10 were
genuine. In a more recent study (5),
Campbell et al., analysed 22 samples of
Viagra sourced from the internet and found
only 4 to be authenc, based on the %API.
During September 2012, we sourced a
variety of tablets sold for the treatment of
ED which claimed to have sildenafil citrate
as API. Viagra®, generic-Viagra, Kamagra,
Silagra and Filagra tablets were ordered via
the internet and supplied from both
UK/European-based pharmacies as well as
overseas suppliers (Hong Kong, India,
Vanuata).
In this small-scale pilot study, we present
results from bulk 2H/18O and 13C/15N stable
isotope analysis performed on crushed
tablets from 23 samples of
internet-sourced tablets sold for the
treatment of ED and purported to contain
sildenafil citrate as API.
References
1. www.healthcare.org.uk; 2. www.moneynews.com; 3. US Patent &
trademark office (www.uspto.gov); 4. WHO bullen 2010;88:247-248; 5.
Campbell et al., Viagra (sildenafil citrate) ordered via the internet is
rarely genuine. J.Sex Med. Aug 2012 9, (S4), p248; 6. NicDaéid et al.,
Using isotopic fraconaon to link precursor to product in the synthesis
of (±)-mephedrone. A new tool for combang ‘legal high’ drugs; Anal.
Chem. 2012 84, 8691-8696; DOI: 10.1021/ac3019069.
Conclusions
The technique of mul-variant stable isotope analysis shows the potenal to be able to
disnguish between different tablets sold as Pfizer-branded Viagra® and generic Viagra.
Further work is required in the first instance to a) authencate samples sold as branded Pfizer
Viagra®, b) fully chemically characterise the 23 tablets analysed for their stable isotope profile in
this study and c) expand the database.
Results
Materials & Methods
Figure 4: Principal
Component Plot with
first and second
component explaining
48% and 39%,
respecvely of all
variability in the data.
Samples believed to be
authenc Pfizer
products are circled in
violet.
Table 1: List of products ordered via the internet during September 2012. All products claimed to have sildenafil
citrate as acve pharmaceucal ingredient (API) and were sold for the treatment of erecle dysfuncon.
Tablet preparaon
One tablet from each foil-sealed packet was selected and any outer tablet-coang removed using a scalpel blade (Figure 2).
Each tablet was ground to a fine powder using an agate pestle & mortar. Powdered tablets were placed into glass vials
(Figure 3) and stored under vacuum in sealed desiccators over phosphorus pentoxide before being weighed into either
silver capsules or n capsules prior to 2H/18O, 13C/15N analysis respecvely.
Bulk 2H, 18O, 15N and 13C isotope analysis
Stable isotope analysis of powdered tablet samples by Connuous Flow – Isotope Rao Mass Spectrometry (CF-IRMS) was
carried out as described elsewhere (NicDaéid et al., 2012).
Principal Component Analysis (PCA) of data obtained from bulk 2H, 18O, 13C and 15N stable isotope analysis of all powdered
tablets splits the sample cohort into 5 disnct clusters (Figure 4).
PCA shows products V1-V6-WP form two disnct groups, V1-V5 in one group and V6-WP alone in a second group. All six
products were sold as branded Pfizer Viagra®. Products V1-V5 were ordered from UK/European-based online pharmacies
and required the compleon of an online pro-forma consultaon. Samples V1-V5 were supplied in Pfizer-branded sealed
boxes complete with paent informaon leaflets. Product V6-WP was supplied from a PO Box in Hong Kong and arrived
as a single foil sachet in a jiffy bag without any documentaon. In addion, differences were noted with regards to
posioning of batch No. and expiry date on the reverse of the blister packs between product V6-WP and products V1-V5
(whose blister packs were all of consistent appearance).
No significant difference was observed between branded Pfizer Viagra® samples V1-V5 believed to be authenc (see
above) despite different API content (V1-V4: 50mg API and V5: 100mg API).
The ght clustering of the 9 Kamagra tablets K1 and K2A-H, the 5 “authenc” Pfizer products V1-V5, and the 4 Filagraxxx
products F2-F5 indicated a relavely low degree of inter- and intra-batch variability within these 3 different products.
Lab-assigned
Identifier
Product sold as Batch No.
Tablet colour &
shape
API strength
V1
Pfizer Viagra
A216901U
blue diamond
50mg
V2
Pfizer Viagra
A246105U
blue diamond
50mg
V3 Pfizer Viagra A246105U blue diamond 50mg
V4
Pfizer Viagra
B111483547
blue diamond
50mg
V5 Pfizer Viagra B101483652 blue diamond 100mg
V6-WP
Pfizer Viagra
B314833021
blue diamond
100mg
S1-WP Silagra-100 DP1144 lilac teardrop 100mg
F1
Filagra-50
F-123003
blue diamond
50mg
F2-O
Filagraxxx-100 'fruit chew'
F-144001
orange diamond
100mg
F3-P
Filagraxxx-100 'fruit chew'
F-144001
pink diamond
100mg
F4-LY Filagraxxx-100 'fruit chew' F-144001 light yellow diamond 100mg
F5-DY
Filagraxxx-100 'fruit chew'
F-144001
dark yellow diamond
100mg
K1-WP
Kamagra-100 Gold
AK0591K
turquoise diamond
100mg
K2-(A-H)
Kamagra-100 Gold
AK0172C
turquoise diamond
100mg
C1-WP Cenforce-50 T-02501L11 light blue diamond 50mg
C2-BP Cenforce-Professional T-09502D12 light blue diamond 100mg (sublingual)
Tablet Summary (see Table 1)
16 products were ordered. With the excepon of
our product reference K2, 1 tablet per product
was analysed. Product K2 was supplied as 8
sachets of 4 tablets; 1 tablet from each of the 8
foil-sachets were analysed (K2A-H). Tablets
V1-V5, S1 & K1 were supplied in proprietary
packaging (sealed boxes; Figure 1) with paent
informaon leaflets whereas the remaining were
received simply as a foil sachet in jiffy
bags/cardboard envelopes (V6-WP, C1-C2, F1-F5,
K2) with lile or no documentaon.
Figure 1 Figure 2 Figure 3
This research hasn't been cited in any other publications.
  • US Patent & trademark office (www.uspto.gov)
    www.healthcare.org.uk; 2. www.moneynews.com; 3. US Patent & trademark office (www.uspto.gov); 4. WHO bulletin 2010;88:247-248; 5.
  • Article
    Several recent deaths in the U.K. have been attributed to "legal high" drugs and in particular to (±)-4-methylmethcathinone ((±)-mephedrone). Recent literature has begun to focus on the chemical analysis of mephedrone and related substituted cathinones and methcathinones; however, no studies involving the application of stable isotope analysis to these compounds has yet emerged. Such studies have, for example, the potential to provide information linking the final products to a particular precursor by the manufacturer. In this study, the use of stable isotope profiling was explored to provide a possible connection between product and precursor chemicals. Six samples each of mephedrone were prepared using precursor chemicals from two different manufacturers, providing 12 samples in total. Synthesis was via a stable intermediate.