Figueiredo Alexandra, Fernandes Tânia, Costa Isabel Margarida, Gonçalves Luísa, Brito José
Instituto Superior de Ciências da Saúde Egas Moniz (ISCSEM), Campus Universitário-Quinta da Granja, 2829-511, Monte de Caparica, Portugal; Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Campus Universitário-Quinta da Granja, 2829-511, Monte de Caparica, Portugal; PhD student at Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Rua de Jorge Viterbo Ferreira, n°228, 4050-313 Porto, Portugal.
Instituto Superior de Ciências da Saúde Egas Moniz (ISCSEM), Campus Universitário-Quinta da Granja, 2829-511, Monte de Caparica, Portugal; Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Campus Universitário-Quinta da Granja, 2829-511, Monte de Caparica, Portugal.
J Pharm Biomed Anal. 2016 Apr 15;122:52-8. doi: 10.1016/j.jpba.2016.01.028. Epub 2016 Jan 21.
The aim of this study was to investigate the feasibility of Wavelength Dispersive X-ray Fluorescence (WDXRF) spectrometry for the measurement of As, Cd, Cr, Cu, Hg, Ir, Mn, Mo, Ni, Os, Pb, Pd, Pt, Rh, Ru and V impurities in pharmaceuticals and dietary supplements, in view of the requirements by EMA and USP for the measurement of elemental impurities in drug products and according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH guidelines). For that purpose, a 4 kW WDXRF spectrometer (S4 Pioneer, Bruker AXS) was used after system calibration. The linearity of the method was demonstrated by correlation coefficients in excess of 0.9 and by appropriate test of lack of fit, except for Cd, Hg, Pd, V and As, which were excluded from analysis. The calculated limits of detection and quantification were in the ranges 0.6-5.4 μg/g and 1.7-16.4 μg/g meeting defined acceptance criteria, except for Pb. The accuracy of the method, determined by the percent recovery (R) of known amounts of each element added to a selected drug, at 3 different concentration levels, was in the acceptance range 70-150% except for Os and Pt, in which case R was marginally outside that range. The repeatability of the method, assessed as the % residual standard deviation (%RSD) of 3 replicate measurements at 3 concentration levels, produced %RSD values lower than 20%, as required. These results show that the WDXRF method complies with the validation requirements defined by the European Pharmacopeia for Cu, Cr, Ir, Mn, Mo, Ni, Os, and Pt, and by the United States Pharmacopeia for Ir, Ni, Os and Pt. Therefore, it may be an alternative to the compendial analytical procedures recommended for such elements. The novelty of the present work is the application of WDXRF to final medicines and not only to active pharmaceutical ingredients and/or excipients.
本研究的目的是，鉴于欧洲药品管理局（EMA）和美国药典（USP）对药品中元素杂质测量的要求，并根据人用药品注册技术要求国际协调会（ICH指南），研究波长色散X射线荧光光谱法（WDXRF）用于测量药品和膳食补充剂中砷、镉、铬、铜、汞、铱、锰、钼、镍、锇、铅、钯、铂、铑、钌和钒杂质的可行性。为此，在系统校准后使用了一台4千瓦的WDXRF光谱仪（S4 Pioneer，布鲁克AXS）。除镉、汞、钯、钒和砷被排除在分析之外，该方法的线性通过超过0.9的相关系数和适当的失拟检验得以证明。计算得出的检测限和定量限范围分别为0.6 - 5.4 μg/g和1.7 - 16.4 μg/g，符合既定的验收标准，但铅除外。该方法的准确性通过向一种选定药物中添加已知量的每种元素在3个不同浓度水平下的回收率（R）来确定，除锇和铂外，回收率在70 - 150%的验收范围内，而锇和铂的回收率略超出该范围。该方法的重复性通过在3个浓度水平下3次重复测量的%残余标准偏差（%RSD）进行评估，产生的%RSD值低于规定的20%。这些结果表明，WDXRF方法符合欧洲药典对铜、铬、铱、锰、钼、镍、锇和铂的验证要求，以及美国药典对铱、镍、锇和铂的验证要求。因此，它可能是推荐用于此类元素的药典分析程序的替代方法。本研究的新颖之处在于将WDXRF应用于成品药，而不仅仅是活性药物成分和/或辅料。
