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

Abstract

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 µg ml 21 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 µg g 21 .

Determination of polar alkylating agents

“…One of them [4] cites our article [1] with five negative though unsupported statements in a single sentence, but comes fairly close to plagiarism. Another [5] simply dismisses our method by stating rather curiously that it includes 'derivatisation followed by direct injection GC/MS', whereas the technique we used, reaction headspace GC, is given in our title.…”

“…As one of the authors of an article published in 2003 on the application of reaction headspace gas chromatography for the determination of some polar alkylating agents that are of current concern as genotoxic impurities [1], I consider it necessary to intervene following the recent publication in the Journal of Pharmaceutical and Biomedical Analysis of four articles from industry sources on the same subject [2][3][4][5].…”

“…The article in question [1] is one of several written by the team I worked with [6][7][8][9] which could, in retrospect, be considered inconvenient for the current position of industry representatives [10] with respect to a regulatory initiative on genotoxic impurities dating from 2004. Our contributions tend to contradict notions and attitudes frequently expressed or implied since 2004, for example that the regulatory authorities were not previously preoccupied by the subject of genotoxic impurities, that retrospective studies of existing products should not normally be required, and that the determination of analyte concentrations as high as 1 g g −1 presents a significant analytical challenge (a proposition that may surprise readers of the bioanalytical section of this journal).…”

Pharmaceutical analysis beyond compendial requirements

“…Recently, the safety of mesylates and tosylates has been called into question, because these anions may form the highly genotoxic esters in the presence of alcohols used as recrystallisation solvents or during formulation. We have published a GC/MS method for the determination of these products at sub-lg/g levels [1]. Even hydrochloride salts may present a theoretical risk, since under acidic recrystallisation or storage conditions alcohols are converted to genotoxic chloroalkanes, which are readily detected by the GC methods used for residual solvents and other volatile impurities.…”

Development and validation of an automated static headspace gas chromatography–mass spectrometry (SHS-GC–MS) method for monitoring the formation of ethyl methane sulfonate from ethanol and methane sulfonic acid

“…To overcome problems with solute stability prior to and during analysis, esters of methane sulfonic acid were also determined by GC after derivatisation with sodium thiocyanate by Lee et al [10]. The corresponding alkylthiocyanates and alkylisothiocyanates were analysed by static headspace (SHS) coupled to GC-MS. High sensitivity and acceptable repeatability were achieved.…”