| Summary: | Ion mobility-mass spectrometry experiments have been conducted to measure the drift-time and calculate collision cross-sections (CCSs) using travelling wave ion mobility spectrometry, and determine the CCS using drift-tube ion mobility spectrometry systems of analytes. The aim of the study was to identify if predictive approaches could facilitate rapid and definitive assignment of charge location sites and chemical structure. Molecular modelling was conducted to determine the energy minimised/geometry optimised structures and charge distribution of the protonated molecules studied. The geometry and charge distribution data were utilised in subsequent ion mobility calculations using two main methods 1) projection approximation and 2) trajectory method. Fluoroquinolone antibiotics were investigated as previous literature had postulated the ion mobility separation of charge location isomers differing only by their protonation site with little expected difference in their geometry (see Chapter 2). Projection approximation prediction of theoretical CCSs (tCCSs) for the singly protonated molecules of norfloxacin (with the proton assigned to all possible oxygen or nitrogen-containing protonation sites to generate candidates) revealed < 2 Å2 difference in tCCSs based on molecular modelling. In stark contrast the experimental CCS (eCCS) demonstrated > 10 Å2 difference between different components. The product ion spectra are consistent with the hypothesis of charge location isomer mobility separated components. Investigations with other fluoroquinolones, with both drift-tube ion mobility and travelling wave ion mobility, and using the trajectory method, remain consistent with the hypothesis of charge location isomers (see Chapter 3). A larger scale study sought to probe the accuracy of tCCSs over a large number of small molecule drug structures. If tCCSs accurately predict eCCSs, then tCCSs could be used to identify compounds and isomers based on their CCSs (see Chapter 4). Finally, software was developed to considerably accelerate the calculation of trajectory method tCCSs from 8-100 times faster than existing published approaches depending on available computing infrastructure (see Chapter 5). In summary this research project has explored whether eCCSs and tCCSs may be useful as a key structural tool alongside other traditional measurements including chromatographic retention time and m/z.
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