Prof. Peter O’Connor, Department of Chemistry, University of Warwick, Coventry, CV4 7AL
Dr Andrew Ray and Dr Stephen Holman, AstraZeneca, Macclesfield
Identification and structural elucidation of impurities and degradants is an important part of drug development, and mass spectrometry (MS) is a key technique applied in this area. Degradants such as oxidative products or impurities formed by nitrosation can be difficult to fully elucidate the structure by collision-induced dissociation (CID), the fragmentation approach most commonly used. However, multiple fragmentation methods have been developed over recent years, but they have not been extensively applied to small drug molecules. However, these techniques require a high abundance ion to fragment, making them challenging for analysing low abundance components. Fortunately, recent research has revealed that the dynamic range can be extended by addressing the space-charge limit in collision cells and utilising selected ion accumulation in trapped ion devices, as demonstrated in a range of recent publications.
. For the first part of the project, newer fragmentation methods that have not been studied extensively for the analysis of small molecule pharmaceuticals will be investigated. Complementarity will be assessed, and understanding of how best to characterise pharmaceuticals using these methods will be obtained. It is anticipated, based on previous data, that combinations of fragmentation methods will enable almost every bond in a molecule to be broken, allowing more accurate and detailed elucidation of structure.
The Ion Cyclotron Resonance laboratory at the University of Warwick has a unique capability in the UK in being able to run a wide range of fragmentation techniques; more than any other laboratory. Furthermore, most of these methods (except for CID) can be combined with a new pulse sequence called 2-dimensional mass spectrometry (2DMS) which allows generation of tandem mass spectrometry information (for the chosen fragmentation method) for all molecules in a mixture simultaneously.
For the second part of the project, we aim to employ an older method, known as Dynamic Range Extension for Mass Spectrometry (DREaMS). It is anticipated that this approach will allow us to enrich low abundance molecules in a sample (such as impurities), and reject more abundant but less “experimentally interesting” ions. This will then enable detailed study using the fragmentation and 2DMS methods discussed above.
Thus, by the end of this project, we should be able to show that 1) we can generate substantial extra fragment information using multiple fragmentation modes yielding more structural information about pharmaceutically-relevant small molecules, and 2) we can increase low abundance ions in the mixture to effectively enrich the signal for minor contaminants and perform the same MS/MS methods as in (1) on the low-level impurities.
Training that the project would provide to the student:
This project will allow the student to develop skills in fundamental MS and data analysis, developing skills in mass spectrometry fragmentation techniques and applying these to small molecule structural elucidation. The development of the DREaMS technique will develop skills in instrumentation development, coding, and bringing 2D MS to the sensitivity levels required by the pharmaceutical industry.
The student will be able to develop skills in presenting both oral and posters at scientific conferences, with an expectation of a number of journal publications.
The student will engage with a world-leading biopharmaceutical company through regular meetings to discuss scientific progress.