Development of miniature mass spectrometry system for therapeutic drug monitoring

A bench-top miniature mass spectrometry system, Mini 12, with a rectilinear ion trap mass analyzer has been developed and characterized in this thesis work. The ion processing system, vacuum system, and control system were designed. An integrated sample loading system facilitates the automated operation. A user interface has been developed to acquire and to display analytical results for personnel who have limited mass spectrometry knowledge. Peak widths of 0.6 Thomson (full width at half maximum) and mass range of up to m/z 900 were both demonstrated. Multi-stage MS experiments up to MS5 were accomplished. Consumable cartridges have been designed for use with ambient paper spray ionization and the recently developed extraction spray ionization method has been employed to improve the quantitation performance. Detecting trace-level therapeutic drugs, monitoring food safety, and environmental protection, were demonstrated. MS/MS scan capabilities were implemented for obtaining the intensities of the fragment ions from the analyte and its internal standard, of which the ratio was used in quantitative analysis of complex samples. Limits of quantitation (LOQ) of 7.5 ng/mL with relative standard deviations below 10% have been achieved for selected therapeutic drugs in whole blood throughout their therapeutic ranges. By way of developing 3D arrays of large numbers of ion traps but with simple configurations, the concept of ion sponge has also been explored in this thesis work. An ion sponge device with 484 trapping units in a volume of 10 × 10 × 3.2 cm has been constructed by simply stacking 9 meshes together. A single rf was used for trapping ions and mass-selective ion processing. The ion sponge provides a large trapping capacity and is highly transparent for transfer of ions, neutrals, and photons for gas phase ion processing. Multiple layers of quadrupole ion traps, with 121 trapping units in each layer, can operate as a single device for MS or MS/MS analysis, or as a series of mass-selective trapping devices with interlayer ion transfers facilitated by AC and DC voltages. Automatic sorting of ions to different trapping layers based on their mass-to-charge (m/z) ratios was achieved with traps of different sizes. Tandem in-space MS/MS has also been demonstrated with precursor ions and fragment ions trapped in separate locations. Tandem mass spectrometry (MS/MS) is an essential tool in complex mixture analysis, due to its capability of elucidating chemical structures, suppressing chemical noises, and achieving quantitation at high precisions. The typical MS/MS analysis has been done by isolating the target precursor ions, while wasting other ions, followed by a fragmentation that produces the product ions. In this thesis, configurations of dual linear ion traps were explored to develop high efficiency MS/MS analysis. The ions trapped in the first linear ion trap were axially, mass-selectively transferred to the second linear ion trap for MS/MS analysis. Ions from multiple compounds simultaneously introduced into the mass spectrometer could be sequentially analyzed. This development enables a highly efficient use of sample and also significantly improves the analysis speed and the quantitation precision for the ion trap mass spectrometers with discontinuous atmospheric pressure interfaces, especially for the miniature systems with ambient ionization sources. (Abstract shortened by UMI.