Rapid characterisation of quinazoline drug impurities using electrospray mass spectrometry-mass spectrometry and computational chemistry approaches

Abstract

Structural characterisation of impurities from synthetic pathways of drugs is an important process in pharmaceutical development. Dissociation pathways of the impurities can vary between different classes of compounds, often resulting in a challenging and a time-consuming process of data interpretation. A detailed understanding of the specific structural features of the fragmentation behaviour of impurity gas-phase ions affords faster characterisation of the unknown sub-structures. Establishing electrospray ionisation-tandem mass spectrometry (ESI-MS/MS) fragmentation rules, based on structure specific and common fragmentation patterns, can improve the process as a screening method in the R&D of new drugs.

This project is focused on understanding dissociation pathways of protonated quinazolines using tandem mass spectrometry. Different ionisation techniques and mass analysers were used to allow comparison studies, which may help to define characteristic fragmentation processes of protonated quinazolines. It was found that the choice of mass spectrometer influences the dissociation pathways of protonated quinazolines to some extent, but it is the structure of the molecule that predominantly controls the fragmentation behaviour.

Additionally, Density Functional Theory (DFT) calculations have been performed to investigate stabilities of protonated molecules and their product ions to improve the prediction of MS/MS data. It was found that specific forms of product ions and their probability of formation correlate to experimental data acquired using quadrupole-ion trap mass spectrometry (QIT MS) within 10 % difference in intensity. The approach of DFT-MS/MS may help interpretation of MS/MS data by indicating the favoured protonation sites and proposing most probable forms of product ions. It is suggested that the product ion mass spectrum is most probably a combination of individual product ion mass spectra formed from the heterogeneous population of singly protonated molecules; i.e. protonation does not have to occur on the most basic atom in the molecule, but it can be distributed on a number of most probable sites of protonation. In addition, the position of the charge does not have to be fixed and may transfer to a different heteroatom in the molecule prior the fragmentation.

These observations offer the possibility to partially assign structures to isomeric molecules using MS/MS and improve structural identification of quinazoline ions.

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Identifiers

ORCID for John Langley: orcid.org/0000-0002-8323-7235

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