Analysis of elemental
impurities (heavy metals) in
pharmaceutical materials
Epsilon 3XLE
Introduction
This data sheet shows that the Epsilon 3XLE – an energy
dispersive X-ray fluorescence spectrometer – is very well
capable of analyzing heavy metals in pharmaceutical
materials.
Application background
One of the most common product safety related analytical
tests is the quantification of heavy metals or inorganics in all
materials within a pharmaceutical product. This normally
includes the toxic heavy metals such as As, Hg and Pb and
catalysts such as Pd and Pt. Throughout the manufacturing
processes there are many potential sources of contamination.
Therefore, in addition to measuring the starting materials it is
essential to measure all finished products and in some cases
intermediates, to demonstrates compliancy with the various
regulations.
Instrumentation
Measurements were performed using Epsilon 3XLE, an EDXRF
spectrometer, equipped with a 50 kV silver anode tube, 6
filters, a helium purge facility, a high-resolution Silicon Drift
Detector, a spinner and a 10-position removable sample
changer.
Standards
A common excipient material (pharmaceutical grade
cellulose) was chosen as a base material. In-house standards
were prepared using ultra-pure commercially available
organo-metallic standards representing 7 heavy-metals. The
materials were chosen to represent a large area of the
periodic table ranging from medium to heavy transition
metals (Cr to Pt). Standard chemical techniques were
employed to dope the cellulose and produce a set of
standards. Standard concentrations were confirmed by
ICP-MS.
Sample preparation and measurement conditions
Loose powder samples, weighing approximately 2500 mg
were placed directly into disposable P1 sample cups with 6 μm
polypropylene film, Figure 1. All samples were tapped lightly
to remove air voids and measured directly. All analyses were
performed in an air atmosphere. The measurement conditions
for the various heavy-metals in a cellulose matrix are listed in
Table 1.
Table 1. Measurement conditions
Elements
kV
µA
Measurement
time (s)
Medium
Filter
Cr
20
300
600
Air
Al-thick
Ni, As, Pt, Se
50
140
600
Air
Ag
Ru, Pd
50
300
600
Air
Cu-thick
Figure 1. An example
of a disposable P1 cup
being filled with a
pharmaceutical
powder sample
Figure 2. Typical spectrum obtained of cellulose exicpient materials using
50kV, 300 μA and a Ag filter
Calibration results and detection limits
Examples of calibration curves are shown in Figures 3 - 5. A summary of the calibration results for all analyzed elements
is shown in Table 2. The root mean square (RMS) error
listed in Table 2 is a measure of the difference between the
calculated concentration and the chemical concentration and
is therefore a measure of the accuracy of the method.
Lower limits of detection determined using this method (LLD,
3σ) are listed in Table 3.
Table 2. Calibration results
4
8
12
16
As concentration (µg/g)
20
RMS
(µg/g)
Correlation
As
0 –22.7
0.1
0.9999
Cr
0 –20.7
0.1
0.9999
Ni
–132.6
0.6
0.9999
Pd
0 –20.6
0.5
0.9986
0
Pt
– 21.3
0.2
0.9999
Ru
0 –21.1
0.4
0.9995
Se
5.8
0.9858
0
0
– 84.7
Table 3. Detection limit using application method settings
Element
Figure 3. Calibration plot for As in loose cellulose powders
Concentration
range (µg/g)
LLD
As
(µg/g)
Cr
(µg/g)
Ni
(µg/g)
Pd
(µg/g)
Pt
(µg/g)
Ru
(µg/g)
Se
(µg/g)
0.2
0.4
0.3
0.9
0.3
0.7
0.2
Corrected intensity
Precision
To demonstrate the analytical precision of the analysis
one cellulose sample was measured 20 times. Average
concentrations and related RMS values are presented in Table 4.
Table 4. Results of the precision test (20 repeated measurements of a
cellulose sample)
Element
4
8
12
16
Pd concentration (µg/g)
20
As
(µg/g)
Cr
(µg/g)
Average
concentration
5.43
4.78
RMS
0.1
0.1
Ni
(µg/g)
Pd
(µg/g)
Pt
(µg/g)
Ru
(µg/g)
Se
(µg/g)
33.38
4.96
5.05
5.18
11.56
0.3
0.4
0.1
0.3
0.1
Figure 4. Calibration plot for Pd in loose cellulose powders
Corrected intensity
Summary
The results from this study clearly demonstrate that the
Epsilon 3XLE EDXRF spectrometer is well suited for the
analyses of pharmaceutical materials including
excipients, API’s and finished products.
4
8
12
16
Pt concentration (µg/g)
20
The repeatability results illustrate the stability and
robustness of the Epsilon 3XLE. Good results are
demonstrated for the regressions and lower limits of
detection. High detector resolution and powerful
software correction models contribute to this result.
Furthermore, the compact size and low weight of the
spectrometer makes it an ideal system for investigations
and testing of heavy metals in pharmaceuticals.
Figure 5. Calibration plot for Pt in loose cellulose powders
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Corrected intensity
Compound