Detection of sulfur-containing impurities in pharmaceuticalsamplesbyhighperformanceliquid chromatography/chemical reaction interface mass spectrometry Christine Eckers 1 *, Fred P. Abramson 2 and Paolo Lecchi 2 1 GlaxoSmithKline, NFSP(N), Harlow CM19 5AW, UK 2 Department of Pharmacology RE6640, George Washington University, 2300 I St. N.W, Washington DC 20037, USA Received 17 January 2001; Revised 11 February 2001; Accepted 11 February 2001 This paper describes the use of chemical reaction interface mass spectrometry CRIMS) combined with liquid chromatography for the detection of trace level sulfur-containing impurities in pharmaceuticalmaterials.Amixtureofsulfur-andnon-sulfur-containingcompoundswereanalyzed initially to test the system. Then the determination of trace level impurities in a cimetidine drug substancewascarriedout.Detectionofsulfur-containingimpuritiesatlessthan0.1%ofthemajor componentwasobtainedwithgoodlinearity.Theresultsobtainedareconsistentwiththeexpected resultsforthissampleandillustratetheapplicabilityofthetechnique.Copyright # 2001JohnWiley &Sons,Ltd. Monitoring impurities in pharmaceutical materials is im- portant to ensure safety and efficacy, and guidelines have been issued to this effect by the International Conference on Harmonization ICH). 1 Trace level impurities in pharma- ceutical materials can be structurally related to the drug substance, as in the case of intermediates, degradation products or synthetic by-products. Additionally, impurities may originate from sources unrelated to the major drug substance, e.g., from production vessels and sample contain- ers. In formulated products impurities may also arise as contaminants of the excipients of the formulation or during the formulation process. Knowing the composition is a crucial requirement for any pharmaceutical preparation; thus, monitoring the presence of contaminants is an essential step in quality control procedures. Liquid chromatography combined with mass spectro- metry LC/MS) has become the first choice for the identification of unknown impurities in pharmaceutical compounds. The most widely used LC/MS techniques employ atmospheric pressure ionization which can provide molecular weight information on unknowns and structural information if tandem mass spectrometry is used. However, monitoring analytes present at trace levels and often with an unknown structure can be cumbersome, even for more sophisticated mass-spectrometric techniques. Therefore, additional methods are continually being sought. In this report we investigate the use of high performance liquid chromatography HPLC) combined with chemical reaction interface mass spectrometry CRIMS) for the determination of trace levels of sulfur-containing materials in pharmaceutical products. The CRIMS analytical strategy is to combine organic molecules the sample) with a reactant gas in a microwave-powered cavity. The result of this high efficiency chemical process is a predictable set of low molecular weight MW) compounds that are characteristic of the elements contained in the original molecules. 2 For example, when nitrogen trifluoride NF 3 ) is the reactant gas, any carbon contained in the analyte becomes CF 4 and sulfur produces SF 6 . 3 Conventional electron impact ionisation EI) mass spectrometry is used to detect these reaction products as CF 3  at m/z 69 or SF 5  at m/z 127). CRIMS is a versatile multielemental detector that allows certain organic elements contained in the analyte to be monitored. A particular feature of CRIMS analysis is the fact that elements with a low interference from the background can be considered a potential label suitable for the accurate quantitative deter- mination of the structures that carry them. We have already reported this concept using Cl as an `intrinsic label' for the determination of benzodiazepine metabolites 4 or to follow the reactions of clozapine with glutathione. 5 More recently we showed that sulfur can be used as a label for the characterization of heparins from different sources. 6 In this study we show that HPLC/CRIMS is a suitable technique for the quantitative determination of sulfur-containing contami- nants in pharmaceutical preparations. EXPERIMENTAL Materials GlaxoSmithKline Harlow, United Kingdom) provided all the samples used in this study unless otherwise noted. HPLC grade solvents were obtained from EM Science Gibbstown, *Correspondence to : C. Eckers, GlaxoSmithKline, NFSPN), Harlow CM19 5AW, UK. Contract/grant sponsor: National Institute of Health; Contract/ grant number: RO1-GM36143. DOI:10.1002/rcm.257 Copyright # 2001 John Wiley & Sons, Ltd. RAPID COMMUNICATIONS IN MASS SPECTROMETRY Rapid Commun. Mass Spectrom. 2001; 15: 602±607