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N Tablets & Capsules March 2017 27 analytical techniques Elemental analysis by WD-XRF: A simplified approach Glenn Williams, Thanh Nguyen, and Nicole McNulty Rigaku Americas Using wavelength dispersive x-ray fluorescence (WD-XRF) to assess elemental impurities offers several advantages over other techniques. It eliminates the need to prepare a solution and is more suitable for use in a manufacturing setting. This article summarizes a study that illustrates the advantages of a direct method of solid analysis and discusses direct analysis of a cup of finished tablets without need for sample preparation. ew guidelines from the International Conference on Harmonization (ICH) call for the pharmaceutical indus- try to test its products for elemental impurities. The doc- ument, ICH Q3D "Elemental Impurities" [1] has been incorporated into an FDA Guidance [2] and General Chapters <232> and <233> from United States Pharmacopeia (USP) outline the impurity limits and sug- gest analytical procedures [3,4]. While these documents suggest methodologies and sample preparation procedures, they are not rigid because the variability of the materials and the range of elemental analytes require flexibility in conducting the tests. Even so, inductively coupled plasma (ICP) techniques have been the most widely used due to their high sensitivity. Both ICP mass spectroscopy (ICP-MS) and ICP opti- cal emission spectroscopy (ICP-OES) tend to be very sensitive (≤1 part per billion) for many elements, but they require digestion of the sample material into a solution [5-7]. For final product analyses of tablets and capsules, this would require materials to be ground and dissolved in very strong acids (in some cases highly toxic hydroflu- oric acid) with the addition of agitation or heat. In many cases, a microwave digestion apparatus is required [5]. Certain hard-to-digest samples may not dissolve com- pletely or the solutions that result may require dilution before undergoing final analysis. To prevent contamina- tion of the materials, these preparatory steps must often be performed in a cleanroom. In addition, ICP techniques require skilled operators and must often be closely moni- tored during analyses. As a result, these techniques are not commonly implemented in a manufacturing setting to conduct final product quality assurance/quality control (QA/QC). This article describes how wavelength dispersive x-ray fluorescence (WD-XRF) can be used to detect and quantify elemental impurities in compliance with ICH Q3D. It also discusses how WD-XRF—a direct technique that eliminates sample digestion—can analyze final products as unadulter- ated tablets in a nondestructive way. For simplicity, a cellu- lose matrix was used in the study described here. Different formulations, however, have shown similar results. WD-XRF has been implemented in QA/QC opera- tions in many industries, including steel and alloys, cement, plastics, glass, food, and oil production and refining, where it is accepted as a stable, reliable, and simple-to-operate technique. In basic terms, WD-XRF entails excitation of atoms in a solid or liquid sample in order to produce characteristic x-rays that are separated by wavelength dispersion and detected. The diagram in Figure 1 illustrates how fluorescent x- rays are generated. Because secondary fluorescent x-rays are characteristic of the atoms contained in the sample, they make it possible to identify the sample's con- stituents. Figure 2 shows the technique's specificity for

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