Bromine and iodine determination in active pharmaceutical ingredients by ICP-MS† Aline L. H. Muller, ab Paola A. Mello, ab Marcia F. Mesko, c Fabio A. Duarte, d Valderi L. Dressler, ab Edson I. Muller ab and Erico M. M. Flores * ab Received 19th July 2012, Accepted 31st August 2012 DOI: 10.1039/c2ja30212h A method based on microwave-induced combustion (MIC) was applied for digestion of active pharmaceutical ingredients (APIs) and subsequent determination of bromine and iodine by inductively coupled plasma mass spectrometry (ICP-MS). Ten APIs including amoxicillin, atenolol, clavulanic acid, clonazepan, diltiazem, haloperidol, imipramine, nimesulide, propranolol and sodium diclofenac were decomposed by MIC. Combustion of 500 mg of each API was possible in less than 30 s using 20 bars of oxygen as initial pressure. A single and diluted solution (50 mmol L 1 (NH 4 ) 2 CO 3 ) was used for the absorption of both analytes and a reflux step of 5 min was applied to improve analyte recoveries. Final digests were suitable to Br and I determination by ICP-MS. Accuracy was evaluated using certified reference materials and agreement better than 95 and 97% for Br and I was obtained, respectively. Results were also compared with those obtained by ion chromatography (IC). The carbon content in digests obtained after decomposition was lower than 500 mg L 1 avoiding interferences in the determination step for both techniques. With the use of MIC, up to eight samples could be processed simultaneously and only diluted solutions are required, minimizing reagent consumption and waste generation. The limits of detection for Br and I by ICP-MS were 0.02 and 0.001 mgg 1 , respectively, that were considered suitable for the determination of these elements in the investigated active pharmaceutical ingredients. Introduction Synthesis of pharmaceutical products frequently involves the use of reactive compounds and formation of intermediates and by- products. Low-levels of reagents or by-products may be present in the final active pharmaceutical ingredients (APIs) as residual impurities. Such chemically reactive impurities may have unwanted toxicities, including genotoxicity and carcinogenicity, and hence the potential impact on product quality and risk profile requires consideration and management. 1,2 According to the International Conference on Harmonisation (ICH) of Europe, Japan and the United States, residual impurities are defined as any component that is not the chemical entity defined as API or an excipient in the pharmaceutical product. 3,4 The safety of commercial pharmaceutical products is not only dependent on the toxicological properties of the API itself, but it also depends on the impurities that it can contain. The nature and quantity of these impurities is governed by a number of different factors, including the synthetic route of pharmaceutical substance, synthesis conditions, the quality of the starting material of pharmaceutical substances, reagents, solvents, puri- fication steps, excipients, packaging, and storage of the final product. 5 Based on standards of ICH, 3,6 pharmaceutical substance impurities can be classified into the following cate- gories: organic impurities (process- and drug-related), inorganic impurities, and impurities from residual solvents. In this sense, bromine or iodine can be found in API, especially, originated from organic impurities and residual solvents. 7 Therefore, increased analytical attention and effort have been devoted to ensure that residual levels of some halogens (as Br and I) are either eliminated or minimized. 7–12 Official guidelines 13 propose total Br and I determination in API only as a test for identification or assay where these analytes are present in high concentration. However, information related to the levels of contamination by Br and I in APIs is relatively scarce in the literature, and values of maximum concentration for Br and I in API were not found in official guidelines. This fact can be partially explained by considering the difficulties involved in a Departamento de Qu ımica, Universidade Federal de Santa Maria, Campus, 97105-900, Santa Maria, Rio Grande do Sul, Brazil. E-mail: ericommf@gmail.com; Tel: +55 55 3220 9445 b Instituto Nacional de Ci^ encia e Tecnologia de Bioanal  ıtica, Campinas, SP, Brazil c Instituto de Qu ımica e Geoci^ encias, Universidade Federal de Pelotas, 96010-610, Pelotas, RS, Brazil d Escola de Qu ımica e Alimentos, Universidade Federal do Rio Grande, 96201-900, Rio Grande, Rio Grande do Sul, Brazil † Electronic supplementary information (ESI) available. See DOI: 10.1039/c2ja30212h This journal is ª The Royal Society of Chemistry 2012 J. Anal. At. Spectrom., 2012, 27, 1889–1894 | 1889 Dynamic Article Links C < JAAS Cite this: J. Anal. At. Spectrom., 2012, 27, 1889 www.rsc.org/jaas PAPER Published on 19 September 2012. Downloaded by Central Salt & Marine Chemicals Research Institute (CSMCRI) on 16/08/2013 07:21:13. View Article Online / Journal Homepage / Table of Contents for this issue