Improved detection limits withX-ray fluorescence spectrometer

1st April 2013

Dirk Wissman looks at the monitoring of limits for heavy metaltraces in pharmaceutical products using an energy-dispersiveX-ray fluorescence spectrometer.

The analysis processes that are recommended in many pharmacopoeias for the determination of impurities sometime require complex sample preparation. They sometimes do not show very good reproducibility and have to be matched to the sample matrix. Energy-dispersive XRF conforms to the analysis processes described without the requirement of extensive sample preparation. Using optimised excitation and evaluation parameters, the technology provides detection limits sufficient for the analysis of most of the relevant elements.

The production of pharmaceutical products requires the analysis of a series of essential trace elements such as Fe, Cu, Zn, Cr, Se, Ca, Mg, Li, Co, Mo, I, Si, and Mn, as well as elements that are toxic in larger concentrations such as Cd, Mo, Pb, Hg, As, and Sn.

Aspects such as the bio-availability, toxicity, and quantity of the elements must be considered. The sources of such impurities can be production-related contamination from sieve and grinding processes, treatment with catalysts, and transportation in piping. Additional impurities may result from packing material and preservatives. It is also possible that the raw material, eg from plants, is already contaminated.

With regard to toxicity, the WHO Guidelines concerning maximum amounts adults can tolerate can be taken into account for some elements. Some example amounts are 3 mg Pb, 0.4­0.5 mg Cd and 0.3 mg Hg per week. In co-operation with the FAO (Food and Agriculture Organisation of the United Nations), analysis methods for the determination of heavy metals are being evaluated and the Codex Alimentarius is being published. The maximum tolerable metal and metalloid contents in food will be listed in this Codex Alimentarius.

The analysis process of heavy metals (the traditional purity test) is described in national and international pharmacopoeias. A heavy-metal-limit test is conducted before the release of pharmaceuticals for use. Various processes are permissible for this test ­ however, these have some disadvantages, depending on the method used. One permissible method is to mix12 ml of an aqueous 5­10 per cent pharmaceutical solution with 2 ml buffer (ph 3) and 1.2 ml thioacetamide reagent. After two minutes, the brown colour of this mixture is visually compared with the reaction of a control substance. This process cannot be used with some solutions such as organics and poorly water-soluble pharmaceutical solutions. Thioacetamide is suspected of being cancer causing. Other processes have other disadvantages, ie the reproducibility rates are sometimes not very good. The following fundamental principle applies in determining permissible heavy metal contents: the higher the pharmaceutical dosage, the stronger the purity requirements. When looking at the limits (that are to be complied with) in a few examples, the limits are as follows: 10 mg/kg of the agent caffeine, 3 mg/kg for the element As; 20 mg/kg of the adjuvant sodium stearyl fumarate, 10 mg/kg for Pb, and 3 mg/kg for As; 20 mg/kg of the raw material calcium carbonate, 3 mg/kg for As, 3 mg/kg for Pb and 0.5 mg/kg for Hg. Other methods can be used for testing of pharmaceuticals and pharmaceutical adjuvants, provided that these methods allow for clear determination of whether the material meets the requirements. Thus, the use of X-ray fluorescence analysis is described as analytical technique in the European Pharmacopoeia. It is necessary, however, to measure or calculate the mass absorption coefficients in the sample in addition to the net impulse rate.

The advantages of the optimised excitation of elements through polarisation and secondary targets in the SPECTRO X-LABi 2000 lie in the improvement of detection sensitivity for this application. In addition, analysis of the back-scattered spectrum from the sample allows for measurement of the mass absorption coefficient. Only through a combination of both advantages the requirement for the most precise analysis possible of traces is met.

Fig. 2a shows the spectra of two comparative samples, to which, in both cases, some trace elements with a concentration of 10 mg/kg were added. On one side, the illustration shows the sensitivity of the analysis system and, on the other, the influence of the matrix and its mass attenuation coefficient on the intensity of the fluorescence radiation. This influence can be corrected, however, using the determined mass attenuation coefficient. As described above, this occurs by viewing the back scattering of the sample. The corresponding measurement spectra during excitation with aZr secondary target are shown in Fig. 2b.

The obtainable detection limits (with different excitation conditions) for an organic matrix can be taken from the following table below.

An additional advantage in using XRF for this application lies in the simple sample preparation. Because the sample to be analysed is usually ground powder, for analysis a measuring cuvette just has to be filled with the powder. This sample continues to be analysed non-destructively and remains available for additional analyses. This sample can also be archived for a certain length of time.

Energy-dispersive X-ray fluorescence analysis conforms to the analysis processes described in the pharmacopoeias. The advantage, which is to optimise the excitation of the radiation by using polarisation and secondary targets, can be seen in the improved detection limits. In addition, analysis of the back scattering of the radiation provides a measurement of the mass absorption coefficient in order to correct the influence from varying matrix.

With energy-dispersive XRF, it is also possible to conduct an overview analysis of all elements from Na to U, in order to retrieve additional information about the sample. In addition, it involves simple sample preparation, elimination of the risk of contamination during analysis.

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Dirk Wissman is product manager XRF at SPECTRO Analytical Instruments GmbH & Co. KG, Kleve, Germany.





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