Chemical Development Department, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd., Ridgefield, CT 06877-0368, USA.
J Pharm Biomed Anal. 2013 Mar 5;75:1-6. doi: 10.1016/j.jpba.2012.11.016. Epub 2012 Nov 19.
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 μg/ml DMS was achievable, with a linearity range up to 10 μg/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.
硫酸二甲酯（DMS）常用于制药生产过程中作为烷基化剂。由于该化合物可能成为具有遗传毒性的杂质，因此应仔细监测药物中痕量的 DMS。DMS 与二苯并氮杂䓬衍生化后形成 N-甲基衍生物，该衍生物可保留在反相柱上，并随后与其他潜在杂质分离。这种衍生化相对较慢。然而，如果使用离子液体作为反应介质，则可以大大加快反应速度。在本文中，我们报告了使用 1-丁基-1-甲基吡咯烷双（三氟甲磺酰基）亚胺（IL1）和 1-丁基-4-甲基吡啶四氟硼酸盐（IL2）作为反应介质，用于 DMS 与二苯并氮杂䓬的衍生化。确定了在反应介质的性质的影响下，DMS 与二苯并氮杂䓬的底物之间的化学计量比可能为 1:1 或 2:1。使用 (+)ESI-MS/MS 方法对衍生化产物进行定量。或者，也可以在乙腈（ACN）中用吡啶进行 DMS 衍生化。N-甲基吡啶𬭩衍生物通过亲水相互作用液相色谱（HILIC）分离，并通过 (+)ESI-MS（SIM 模式）检测。在这两种情况下，均可以实现 DMS 的定量限（LOQ）为 0.05μg/ml，线性范围可达 10μg/ml。这两种分析方法均用于测定作为美托洛尔合成起始原料的 4-（2-甲氧基乙基）苯酚中的 DMS。
