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.

An automated sample preparation and analysis procedure was developed to monitor the formation of ethyl methane sulfonate from reaction mixtures containing ethanol and methane sulfonic acid. The system is based on a liquid handling robot combined with a static headspace module. The formed ethyl methane sulfonate is analysed after derivatisation with pentafluorothiophenol using static headspace-gas chromatography-mass spectrometry (SHS-GC-MS). Using the automated reaction-derivatisation-headspace GC-MS system, the formation of ethyl methane sulfonate can be monitored in different reaction mixtures under different reaction conditions, including temperature, water content and pH. Excellent linearity, repeatability and robustness were obtained, allowing the system to be used in kinetic studies.

A generic approach for the determination of residues of alkylating agents in active pharmaceutical ingredients by in situ derivatization-headspace-gas chromatography-mass spectrometry.

A simple, reliable and fast procedure for the simultaneous determination of residues of some common alkylating agents (AAs), such as mesylates, besylates, tosylates and sulfates, employed in drug synthesis, has been developed by in situ derivatization-headspace-gas chromatography-mass spectrometry. Pentafluorothiophenol is used as a derivatizing agent in different water/dimethyl sulfoxide ratios. Compared to former analytical procedures, this approach returns improvements in analysis time, selectivity, analyte stability and method sensitivity (LOD=0.11 microgg(-1) for methyl tosylate). The method exhibits low matrix dependence, excellent accuracy, precision (R.S.D.=2.8-10% range at 1 microgg(-1)) and robustness through the use of deuterated internal standards. Knowledge of the synthetic route allows a targeted approach to the determination of specific AAs since the procedure does not distinguish between acid species. The procedure was successfully applied to different pharmaceutical matrixes, and is particularly suitable for routine analysis with high sample throughput.