Towards a generic method for ion chromatography/mass spectrometry of low‐molecular‐weight amines in pharmaceutical drug discovery and development

Rationale Low‐molecular‐weight amines are encountered in pharmaceutical analysis, e.g. as reactants in chemical syntheses, but are challenging to analyse using ultrahigh‐performance liquid chromatography/mass spectrometry (UHPLC/MS) due to their high polarity causing poor retention. Ion chromatography/mass spectrometry (IC/MS) is an emerging technique for polar molecule analysis that offers better separation. A generic IC/MS method would overcome problems associated with using UHPLC/MS in drug discovery and development environments. Methods Amine standards were analysed using IC/MS with gradient elution (variety of column temperatures evaluated). An electrospray ionisation (ESI) quadrupole mass spectrometer was operated in positive ion polarity in scanning mode. The make‐up flow composition was evaluated by assessing the performance of a range of organic modifiers (acetonitrile, ethanol, methanol) and additives (acetic acid, formic acid, methanesulfonic acid). The ESI conditions were optimised to minimise adduct formation and promote generation of protonated molecules. Results The performance attributes were investigated and optimised for low‐molecular‐weight amine analysis. Organic solvents and acidic additives were evaluated as make‐up flow components to promote ESI, with 0.05% acetic acid in ethanol optimal for producing protonated molecules. The hydrogen bonding capability of amines led to abundant protonated molecule–solvent complexes; optimisation of source conditions reduced these, with collision‐induced dissociation voltage having a strong effect. The detection limit was ≤1.78 ng for the amines analysed, which is fit‐for‐purpose for an open‐access chemistry environment. Conclusions This study demonstrates the value of IC/MS for analysing low‐molecular‐weight amines. Good chromatographic separation of mixtures was possible without derivatisation. Ionisation efficiency was greatest using a make‐up flow of 0.05% acetic acid in ethanol, and optimisation of ESI source conditions promoted protonated molecule generation for easy determination of molecular weight.