Identification of Counterfeit Tablets and Authentication of Medicines in the International Wholesaling Supply Chain Using Near-infrared Spectroscopy

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

The School of Pharmacy

29/39 Brunswick Square, London.

sulaf.assi@pharmacy.ac.uk

Introduction : Counterfeit Medicines

Identity Active ingredient

SourceClass

Objective

To authenticate counterfeit tablets in the International wholesaler supply chain using near-infrared spectroscopy

FOSS 6500 NIR spectrometer equipped with (a) a Rapid Content Analyser (RCA) and (b) a Smart Probe.

Experimental (Materials)

Experimental (Procedure)

MethodSpectra measurement Sample positionLight variationDistance variation

Spectra treatmentSoftware (Vision, Unscrambler,

Microsoft Excel, Matlab)Pre-treatment methods (SNV, MSC, D1,

D2)Treatment methods (CWS, MDWS,

MDPCS, SIMCA, PCA)

Results and Discussion (Spectrum Quality)

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

The RCA has better spectral quality especially beyond 2200 nm.

Results and Discussion (Instrumental Noise/Pre-treatment method)

Standard deviation of 12 spectra of Protium tablets using the listed pre-treatment methods over the maxima wavelengths.

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

Results and Discussion (Optimum Number of Spectra)

Diagrammatic representation of 95 % frequency circles for a bi-variate normal distribution used in PCA plots

Results and Discussion (Optimum Identification Method) Of the methods applied correlation in wavelength space (CWS) and principal

component analysis (PCA) were the best two methods.

CWS map of the nine products: Lipitor, Plavix, Nexium, Singulair, Zyprexa, Protium, Seroquel, Risperdal and Effexor respectively.

PCA scores plot of the SNV-D2 spectra of the nine products measured by the RCA.

Obtain a batch of the product under test from an authenticated source to act as the authentic product for comparison purposes.

Measure 10 tablets using the RCA from the test batch measuring each tablet once on each side and take the mean SNV, second derivative spectrum. Do the same for 10 tablets from the authentic batch.

Compare the two spectra by CWS and report as a pass if the value is ≥ 0.95 and confirm by PCA.

If the value is < 0.95, examine the spectrum for obvious reasons for a failure. If the tablet was not blister packaged, remove the water regions from the mean spectra (1476-1516 nm and 1918-2089 nm) and re-compare. If the test product still fails, use PCA if a sufficient number of batches of the authentic product are available.

If the test product still fails, report it as non-authenticated.Report the results as failed or passed with the CWS value and

copies of the spectra of the authentic and test products.

Standard Operating Procedure

SNV-D2 NIR spectra of Bayer’s Ciprobay 250 mg tablet from Lebanon (blue), Bayer’s Ciproxin 500 mg from the UK (red) and Bayer’s Ciproxin 750 mg from the UK (green) which are completely superimposed.

Application (Korean and Lebanese samples)

Authentic batches (red) and counterfeit batches (blue) of Viagra Tablets 100 mg with the 95% and 99% equal frequency ellipses for the authentic batches.

Application (Wholesaler product authentication) 8 out of 104 batches obtained from the wholesaler failed having a CWS

value of less than 0.95.The wholesaler either did not buy the batch or did further analysis.

NIR spectra of authentic Plavix Tablets 75 mg (blue) and test tablets (red) which turned out to be Plavix Tablets 75 mg (r = 0.997)

NIR spectra of authentic Plavix Tablets 75 mg (blue) and test tablets (red) which turned out to be counterfeit Plavix Tablets 75 mg (r = 0.712).

Application (Wholesaler product authentication)

NIR spectra of authentic rosiglitazone 4 mg (blue) and test tablets rosiglitazone 4 mg which turned out to be counterfeit (red).

When the water regions (1476-1516 nm and 1918-2089 nm) were removed the CWS value dropped from 0.919 to 0.898, so the product still failed.

NIR spectra of authentic Dosan 4 mg (blue) and test tablets Dosan 4 mg which turned out to be authentic (red).

When the water regions (1476-1516 nm and 1918-2089 nm) were removed the CWS value stayed the same: 0.998.

Application (Wholesaler product authentication)

NIR average spectra of 10 authentic Atorlip 40 mg tablets (blue) and 10 test tablets Atorlip 40 mg (red).

r=0.953

NIR average spectra of 10 authentic Atorlip 40 mg tablets (blue) and 1 test tablet Atorlip 40 mg (red).

r= 0.886

In some cases one tablet fails while the average of the whole batch passes and this confirms the need for the use of at least 10 tablets from a single batch.

Application (BBC samples)

NIR spectra of authentic Viagra 100 mg (blue) and test tablet Viagra 100 mg which turned out to be counterfeit (red).

r= 0.95

PCA scores plot of the SNV-D2 NIR spectra of a calibration set of authentic (red) and counterfeit (blue) Viagra 100 mg tablets and a validation set of authentic Viagra 100 mg tablet B.No. 6098203U (green) and counterfeit Viagra 100 mg tablet 1 (magenta) and tablet 2 (cyan).

This Viagra tablet is one example how CWS failed to identify a counterfeit and PCA was able to spot it.

Application (BBC samples)

SNV-D2 NIR spectra of Reductil 15 mg standard B.No. 3300680 (blue) and Reductil 15 mg sample B.No. 311799D (red) capsule contents.

r= 0.503

PCA scores plot of the SNV-D2 NIR spectra of authentic Reductil 10 mg (blue) and 15 mg (red) standards and authentic reductil sample 10 mg (green) and counterfeit reductil sample 15 mg (magenta) with the 95% and 99% equal frequency ellipses around the authentic batches

Acknowledgement

FOSS NIRSystem for the FOSS 6500 instrument.

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

Lebanese National Council for Scientific Research for their Scholarship.