Determination of polar alkylating agents as thiocyanate/isothiocyanate derivatives by reaction headspace gas chromatography

We report a new method for the determination of the methyl, ethyl and isopropyl esters of methanesulfonic acid, and of dimethyl sulfate. Derivatisation with aqueous sodium thiocyanate gives a mixture of the corresponding alkylthiocyanates and alkylisothiocyanates which, unlike the underivatised analytes, are readily analysed by GC. On-column isomerisation is negligible. These lower alkyl derivatives are sufficiently volatile for static reaction headspace analysis, and detection limits obtained by electron impact MS are below 0.05 mug ml(-1) with respect to the injection solution. The method was used to demonstrate that levels of methanesulfonic acid esters in a drug substance ( a mesylate salt that had been processed using methanol and ethanol) are below 1 mug g(-1).