S. Assi, R. Watt, A.C. Moffat

Identification of Counterfeit Medicines

Pharmaceutical Counterfeiting

Worldwide problem

Both brand and generic medicines

Leads to harm or even death

From The TimesSeptember 18, 2007

Fake world of the Viagra plotters

Robin Pagnamenta For tens of thousands of men the medicines offered by Ashish Halai and his gang appeared to be the answer to two of their most worrying and embarrassing health concerns: impotence and baldness. But the unsuspecting customers, buying what they thought were Viagra and Propecia, were victims of one of the most ambitious and elaborate of counterfeiting crimes. Halai and his associates were buying fake drugs from Chinese suppliers for as little as 25p a tablet and selling them for up to £20. Details of their vast network – stretching from Britain to Hong Kong, Dubai, the US and the Bahamas – emerged yesterday as justice finally caught up with the conmen. In the largest drug counterfeiting case in Britain, and after a trial lasting more than seven months, Halai, 33, was jailed at Kingston Crown Court for four and a half years as one of the key players in the plot.

From The TimesSeptember 18, 2007

Fake world of the Viagra plotters

Times Online

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Robin Pagnamenta For tens of thousands of men the medicines offered by Ashish Halai and his gang appeared to be the answer to two of their most worrying and embarrassing health concerns: impotence and baldness. But the unsuspecting customers, buying what they thought were Viagra and Propecia, were victims of one of the most ambitious and elaborate of counterfeiting crimes. Halai and his associateswere buying fake drugs from Chinese suppliers for as little as 25p a tablet and selling them for up to £20. Details of their vast network – stretching from Britain to Hong Kong, Dubai, the US and the Bahamas – emerged yesterday as justice finally caught up with the conmen. In the largest drug counterfeiting case in Britain, and after a trial lasting more than seven months, Halai, 33, was jailed at Kingston Crown Court for four and a half years as one of the key players in the plot.

Counterfeit Identification

The literature reveals various methods for identification of counterfeit medicines:

ColorimetricColorimetricChromatographicChromatographicMass SpectrometricMass SpectrometricHyphenated techniquesHyphenated techniquesThe German Pharma Health Fund (minilab)The German Pharma Health Fund (minilab)Isotopic characterizationIsotopic characterizationSpectroscopic TechniquesSpectroscopic Techniques

A Near-Infrared spectroscopic method was optimized for identification of counterfeit medicines

Experimental

The medicinal products mostly

counterfeited.

High market share.

Lifestyle Drugs.

Have a wide range of percentage,

color, active, and shapes.

Basis of Products Selection:

Nexium 20 mg Excipients

Glycerol monostearate 40-55

Hyprolose

Hypromellose

Iron oxide

Magnesium stearate

Synthetic paraffin

Macrogol

Crospovidone

Sodium stearyl fumarate

Sucrose

Maize starch

Talc

Titanium dioxide (E 171)

Triethyl citrate.

Protium 20 mg Excipients

Propylene glycol

Polysorbate 80

Sodium laurilsulfate

Triethyl citrate

Titanium dioxide E 171

Yellow ferric oxide E 172

Sodium carbonate

Mannitol

Crospovidone

Povidone K90

Calcium stearate

Hypromellose

Povidone K25

Procedure

MethodSample Position

Light Variation

Distance Variation

Blister effect

Spectra TreatmentSoftware

Vision 2.51

Unscrambler 7.5

Methods CWS

MDWS

MDPCS

SIMCA

PCA

Results and Discussion

Figure 1. Near-infrared spectra of 12 scans of (a) Nexium measured by the Smart probe, (b) Nexium measured by the RCA, (c) Protium measured by the Smart Probe and (d) Protium measured by the RCA

Number of peaks.Bandwidth (instrument resolution).Absorption intensity.Range.

Spectra Quality

Parameters for selection of best spectra quality:

The RCA possessed better wavelength range. Regarding the other parameters they were almost similar in both cases.

Optimum of Wavelength Range

RCA possessed less standard deviation over the full range from 1100 to 2500 nm

Fig. 2 Standard deviation of 12 spectra of Protium 20 mg using the Probe and the RCA

Instrumental and Peak Noise

Instrumental Root Mean Square Noise

(RMS)

Peak Root Mean Square Noise

USP method was appliedLower RMS noise was observed

in RCA

Product specificProbe in dark the least peak

RMS noise.

Data Pre-treatment and Treatment

SNV Second derivative was the best pre-treatment method yielding the least standard deviation at the spectra peaks maxima

CWS, MDWS, and PCA showed the highest identification and discrimination potential

Fig. 3 PCA score plots of the nine products measured with the Probe

Fig. 4 PCA score plots of the nine products measured with the RCA

PCA

Optimum Presentation Method

Presentation Method

Probe RCA

light Spacing to sample

0.1 cm

Position to sample

up

down0.15 cm

0.3 cm

0.6 cm

light

dark

Optimum Presentation Method

The Results were very closeBest identification as well as

discrimination was observed in RCA

RCA yielded best identification potential

Probe in dark yielded the best discrimination potential

The presentation methods applied were compared according to CWS and MDWS

MDWS CWS

Method Precision and Repeatability

Replication of spectra

The mean of different number of spectra was taken (from 2 to 12).

Four measurements were enough to get a representative spectrum.

However, for some statistical procedures up to 20 spectra is needed

to get representative data of the sample.

Blister Effect on Product Identification (1)

Tablets were measured with and without their blister as such:

Without their blister In their closed blister

In their blister openedIn their opened blisterClosed with ceramic

Blister Effect on Product Identification (2)

The four sets were compared utilising CWS and MDWS. However, none of the latter three cases could be identified as the intact tablet.

Better quality spectra was observed with the RCA Better quality spectra was observed with the RCA over the range 1100-2500 nm.over the range 1100-2500 nm.

Preprocessing data is best done through SNV Preprocessing data is best done through SNV second derivative and processing through CWS, second derivative and processing through CWS, MDWS, and PCA. MDWS, and PCA.

The optimum presentation method is with the sample The optimum presentation method is with the sample in direct contact with the RCA.in direct contact with the RCA.

Based on the aim of this work

The optimum number of replicates is four.The optimum number of replicates is four.

Application

CWS was applied to the identification of commercial products from different sources

Sources

Turkey Australia FranceIndia

-0.30

-0.20

-0.10

0.00

0.10

0.20

0.30

1100.00 1300.00 1500.00 1700.00 1900.00 2100.00 2300.00

Wavelength/nm

SN

V-D

2

Actonel 35 mgUKStd B.No.410433

Actonel 35 mgTestsample#58B.No. 407444

Actonel 35 mgTestsample#59B.No. 405728

Turkish samples (1)

Fig. 5 SNV Second derivative near-infrared spectra of Actonel 35 mg standard and test samples .

r2 (sample 58)= 0.9990

r2 (sample 59) = 0.9995

Turkish samples (2)

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

1100.001300.001500.001700.001900.002100.002300.00

Wavelength/nm

SN

V D

2

Co-Diovan160/25 mgTestsample#55B.No. K0019

Co-Diovan160/25 mg UKStd B.No. S0030

Fig. 6 SNV Second derivative near-infrared spectra of Co-Diovan 160/25 mg standard and test samples

r2 (sample 55)= 0.9962

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

1100.00 1300.00 1500.00 1700.00 1900.00 2100.00 2300.00

Wavelength/nm

SNV

D2

Clopivas 75 mgtestsample 84B.No. X69659

Clopivas 75 mgstandardsampleB.No. D70733

Fig. 7 SNV Second derivative near-infrared spectra of Clopivas 75 mg standard and test samples

Indian Sample

r2 (sample 84)= 0.9962

Australian Sample

-0.2

-0.1

0

0.1

0.2

1100.00 1300.00 1500.00 1700.00 1900.00 2100.00 2300.00

Wavelength/nm

SN

V D

2

Plavix 75 mgUK standardB.No. BK385

Plavis 75 mgtest sample #G61A B.No.627871

Fig. 8 SNV Second derivative near-infrared spectra of Plavix 75 mg standard and test samples

r2 (sample G61A)= 0.9910

French Samples

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

1100.00 1300.00 1500.00 1700.00 1900.00 2100.00 2300.00

Wavelength/nm

SNV

D2

Plavix 75 mgUK standardB.No. BK385

Plavix 75 mgtest sample #29 B.No. 1811

Plavix 75 mgtest sampleG62A B.No.1753

Fig. 9 SNV Second derivative near-infrared spectra of Plavix 75 mg standard and test samples

r2 (sample G62A)= 0.7364 r2 (sample 29) = 0.9931

CONCLUSION

The Optimum identification method for counterfeit tablet identification is done by measuring the tablet on the RCA.

The optimum chemometric procedure is CWS.

References

WHO Counterfeit Medicines: www.who.int/mediacentre/factsheets/fs275/en/print.html. Anil K.Deisingh,The Analyst ,2005,130,271.

Acknowledgement

The School of Pharmacy for the Overseas Student Research (ORS) Award.

FOSS COMPANY for the FOSS NIR 6500.

Thank You Thank You For Your For Your AttentionAttention