XRPD For The Identification of Counterfeit Drugs
Reprint. Original can be found here.
The patent disclosing methodology to study counterfeits with XRPD is accessible here.
Introduction
World Health Organization statistics indicate that 30% of medicines
supplied in developing countries are fake; in some Eastern European
countries the proportion is 10%. With reductions in trade barriers and
the emergence of an increasing number of internet pharmacies, this has
become a massive and growing global problem. The annual earnings
from counterfeit drugs are estimated to be between 20 and 50 billion
USD.
While the source of the counterfeiting problem must be addressed
with economic and regulatory measures, it is also important to look
at methods that aid discrimination of fake drugs from real ones. X-ray
powder diffraction (XRPD) has become a key analytical technique
in the pharmaceutical industry and is being used for the discovery,
development and manufacture of drugs. Here we will demonstrate
that XRPD also allows the effective, quick and reliable screening of
pharmaceutical tablets without removing them from their original
blister packing.
Experimental
X-ray diffraction measurements were carried out using an X’Pert PRO
MPD diffractometer equipped with a focusing mirror and motorized highthroughput stage. The blister cards were mounted on a metal frame and
the diffraction signals were measured in transmission mode using an
X’Celerator detector. For the commercial products investigated, the original,
intact blister cards were used as received, without any sample preparation.
Results
XRPD measurements of tablets through the blister
Figure 1 shows XRPD data from a single commercial tablet in an opaque
blister and the signal from the emptied blister. The presence of the
packaging material is evidenced mainly by an increased background and by
the two Bragg peaks at high angles. This shows that high quality diffraction
data can be obtained directly from the intact, blister-packed tablets.
In most cases the absorption factor from the blister card was found to be in
the range of only 2.5 – 3.5, with the highest value being 5.6.
Figure 1: XRPD scan
measured from a
commercial tablet
through a fully opaque
blister within 30 minutes.
The separately measured
emptied blister material
does not significantly
interfere with the
diffraction pattern from
the tablet. The two
intense peaks observed
around 2 Theta of 38˚ and
45˚ are attributed to the
aluminum foil.
Automated high-throughput scanning of whole blister cards
In order to demonstrate batch homogeneity testing, a whole (3 x 6) blister
card was measured in an automated way. The data obtained are given in
Figure 2. Measurement time for each tablet was just 10 minutes, allowing
the whole blister card to be scanned in 3 hours. Limiting scans to a preselected, narrower angular range in which most of the characteristic
diffraction signals should appear can decrease the time further.
Direct comparison of the results for the different tablets shows that a
few differ in some detail from the others. They exhibit additional or
more pronounced peaks that could be related to differences in preferred
orientation / particle statistics of one compound, or to differences in
composition. No efforts were made here to determine the exact reason for
these discrepancies.
Figure 2: Automated
XRPD scans of tablets in
a 3 x 6 blister card. The
patterns of a few tablets
differ from those of the
others in showing some
additional or significantly
more pronounced Bragg
peaks (marked with
circles). For the sake of
clarity, the scans were
offset relatively to each
other along the intensity
axis.
Detection of fake drugs or polymorphic changes of tablets in a blister pack
To simulate drugs in which tablets contain different or no API, and also to
simulate polymorphic changes during processing or storage, tablets with different
compositions were prepared in a blister packaging. Details are given in Table 1.
These samples contained 5% Indomethacin (IMC) as the API, and 95% excipient
(α-lactose monohydrate and magnesium stearate). Different polymorphs of IMC
were used, namely the α- and γ- forms. In addition, one set of tablets was entirely
placebo. The tablets were placed in an emptied commercial blister card that was
carefully re-closed. Figure 3 shows that the difference in crystal form and/or amount
of API is clearly visible through the absence or presence of various diffraction peaks,
mainly at diffraction angles below 25˚.
|
API
Indomethacin (IMC) |
Excipients
α-lactose monohydrate (98,5%)
Magnesium stearate (1.5) |
Tablet 1 |
5% α-IMC 0% γ-IMC |
95% |
Tablet 2 |
0% α-IMC 5% γ-IMC |
95% |
Tablet 3 |
0% α-IMC 0% γ-IMC |
100% |
Table 1: Composition of three different test tablets that were used for XRPD measurements
through a blister
Figure 3: Left: XRPD data measured from the test tablets (Table 1) through the blister package. The
main differences (marked by arrows) are seen at diffraction angles 2Theta below 25˚.
Right: Magnification of the experimental data in the angular range where differences are
most evident. The different API in the test tablets is clearly evidenced by the presence or
absence of peaks at the angular positions indicated by arrows.
Identification of counterfeit drugs
Figure 4 shows the diffraction patterns of an original Viagra tablet (Pfizer) and a
copy product. Both tablets contain 100 mg Sildenafil citrate, but the diffraction
patterns are clearly different showing the difference in crystallinity of the API
(related to the bioavailability) and differences in the composition of the rest of the
tablet (excipients).
Figure 4: Comparison of the diffraction patterns of an
original Viagra tablet (Pfizer) with a copy product.
Figure 5: Cluster analysis of
scans from original tablets and
counterfeit tablets of a product
(the green cluster contains the
scans from the original tablets)
Figure 5 shows the cluster analysis of different original and counterfeit tablets of
one product. The green cluster contains the original tablets whereas the other
clusters contain fake tablets from different sources.
Conclusions
It was shown that high quality XRPD data of intact pharmaceutical tablets can
be obtained without removing them from their original blister packaging. Such
measurements can readily be done even through fully opaque blister pack
material.
This method can be used to differentiate authentic drugs from counterfeit
products, e.g. by checking for the presence of the correct polymorphic form
or the comparison of the tablet fingerprint. In addition, non-invasive product
control after production or as a function of shelf-life and storage conditions is
possible, without needing to open the blister.