Assay at low ppm level of dimethyl sulfate in starting materials for API synthesis using derivatization in ionic liquid media and LC-MS

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• 作者：Nelu Grinberg^a ; Florin Albu^b ; Keith Fandrick^a ; Elena Iorgulescu^c ; Andrei Medvedovici^b ; ^c ; ^{avmedved@yahoo.com}
• 关键词：Dimethyl sulfate ; Derivatization with dibenzazepine or pyridine ; RPLC/(+)ESI-MS/MS ; HILIC/(+)ESI-MS (SIM) ; Ionic liquid as derivatization media
• 刊名：Journal of Pharmaceutical and Biomedical Analysis
• 出版年：2013
• 出版时间：5 March, 2013
• 年：2013
• 卷：75
• 期：Complete
• 页码：1-6
• 全文大小：533 K

文摘

Dimethyl sulfate (DMS) is frequently used in pharmaceutical manufacturing processes as an alkylating agent. Trace levels of DMS in drug substances should be carefully monitored since the compound can become an impurity which is genotoxic in nature. Derivatization of DMS with dibenzazepine leads to formation of the N-methyl derivative, which can be retained on a reversed phase column and subsequently separated from other potential impurities. Such derivatization occurs relatively slowly. However, it can be substantially speed up if ionic liquids are used as reaction media. In this paper we report the use of 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide (IL1) and 1-butyl-4-methylpyridinium tetrafluoroborate (IL2) as reaction media for the derivatization of DMS with dibenzazepine. It was determined that the stoichiometry between the substrate and DMS may be 1:1 or 2:1, in relation with the nature of the reaction media. An (+)ESI-MS/MS approach was used for quantitation of the derivatized product. Alternatively, DMS derivatization may be carried out with pyridine in acetonitrile (ACN). The N-methylpyridinium derivative was separated by hydrophilic interaction liquid chromatography (HILIC) and detected through (+)ESI-MS (in the SIM mode). In both cases, a limit of quantitation (LOQ) of 0.05 ¦Ìg/ml DMS was achievable, with a linearity range up to 10 ¦Ìg/ml. Both analytical alternatives were applied to assay DMS in 4-(2-methoxyethyl)phenol, which is used as a starting material in the synthesis of metoprolol.