Drifting into the Future with IMS

The fundamentals behind drift-tube ion mobility spectrometry (IMS) are found in rather old technology – and combining this technique with mass spectrometry (MS) was first demonstrated many years ago. However, recent instrument developments show that sometimes bringing back “old” ideas and applying them to new technology may be part of our analytical future. My conjecture is that this combination is potentially a significant step up for the analysis of complex bioanalytical samples for three main reasons: i) the increased separation power available, particularly for isobaric compounds; ii) the incorporation of precise collisional cross section (^DTCCS) values into compound databases; and iii) the filtering out of MS noise via the drift-tube separation of ions. Full assessment of these benefits for particular applications will take a lot more work; however, today’s technology already offers some opportunities for analysts to gain new and valuable information from measurements.

Separation of ions according to their shape-to-charge ratio displays some complementarity to that of mass-to-charge. Over the last few years, this has enabled IMS-MS to mature and finally be implemented in commercially available instruments compatible with separation techniques. However, the advantage of adding IMS into hyphenated workflows is not confined to the addition of a separation dimension or gain in peak capacity afforded between the ionization source and the mass spectrometer. For example, normally impossible separation of isobaric compounds can be realized in some instances, while the low field conditions of drift-tube IMS allow precise collisional cross sectional area (^DTCCS) values to be directly derived from drift-time and mass-to-charge measurements providing an additional molecular descriptor when trying to confirm compound identity.

The third, sometimes overlooked, benefit is that IMS separation results in a filtering effect that can improve signal-to-noise of mass spectra in complex samples, as well as providing some clustering of different molecular classes and charge states in the drift space.

On paper and in practice, I find this approach to be a powerful addition to aid identity confirmation, particularly for LC-MS workflows where false positive results can be readily eliminated. Furthermore, less stress is placed upon the chromatographic separation when a high-precision ^DTCCS value (±0.5 percent) is required in addition to retention time and putative sum formula for confirming compound identity.

Despite these promises, we still, of course, need to assess measurement repeatability, reproducibility and contend with the analytical trade-offs that are inevitably encountered. For example, transmission losses during ion trapping and mobility separation processes will affect limits of detection in comparison with “IMS-less” analysis, while addition of ^DTCCS values to databases will require careful assessment of the uncertainty associated with the measurement.

With these considerations in mind, I believe that the most substantial benefits will be apparent for complex bioanalytical applications where the identity confirmation from reliable ^DTCCS values, elucidation of the biological roles of isomeric structures, and the filtering characteristics of drift-time confined mass spectra will come to the fore. My estimation is that much work is yet to be done, but that the approach has the potential to provide a very significant advancement for existing non-targeted approaches and a more robust and accessible platform than is currently available from other multidimensional methodologies.