Control of chemical effects in the separation process of a differential mobility mass spectrometer system

Abstract

Differential mobility spectrometry (DMS) separates ions on the basis of the difference in their migration rates under high versus low electric fields. Several models describing the physical nature of this field mobility dependence have been proposed but emerging as a dominant effect is the clusterization model sometimes referred to as the dynamic cluster-decluster model. DMS resolution and peak capacity is strongly influenced by the addition of modifiers which results in the formation and dissociation of clusters. This process increases selectivity due to the unique chemical interactions that occur between an ion and neutral gas-phase molecules. It is thus imperative to bring the parameters influencing the chemical interactions under control and find ways to exploit them in order to improve the analytical utility of the device. In this paper, we describe three important areas that need consideration in order to stabilize and capitalize on the chemical processes that dominate a DMS separation. The first involves means of controlling the dynamic equilibrium of the clustering reactions with high concentrations of specific reagents. The second area involves a means to deal with the unwanted heterogeneous cluster ion populations emitted from the electrospray ionization process that degrade resolution and sensitivity. The third involves fine control of parameters that affect the fundamental collision processes, temperature and pressure.

Figure 1

Plot of CV versus MRM normalized signal intensity during infusion of six compounds at 10 μL/min. The compounds were 1) oxfendazole, 2) clonazepam, 3) flusilazole, 4) bromazepam, 5) chlorprothixene, 6) pamaquin. The modifier was 2-propanol in all cases metered at different flows into the nitrogen transport gas to give final modifier concentrations of A) 0%, B) 1.6%, C) 3.1%, and D) 6.2%. The (M+H)⁺ ions of the 4 compounds had the same nominal mass but different product ions were monitored for each. The separation voltage was 4200 V p-p and the carrier gas was maintained at approximately 42°C. The 2-propanol modifier was delivered with an LC pump to accurately control the gas phase modifier concentration.

Figure 2

Plot of CV versus MRM normalized signal intensity during infusion of four compounds at 10 μL/min. The four compounds were 1) desmethylclomipramine, 2) dianabol, 3) clobazam, 4) temazepam. The data were generated (A) with no modifier, (B) water added as the modifier, and (C) 2-propanol added as the modifier to transport gas. The (M+H)⁺ ions of the 4 compounds had the same nominal mass but different product ions were monitored for each. The separation voltage was 4500 V p-p and the carrier gas was maintained at approximately 42°C. The modifiers were introduced at saturating concentrations by bubbling the transport gas (curtain gas) through a reservoir of each liquid. This technique is simple but does not accurately control the concentration of the modifier.

Figure 3

Plot of CV versus MRM normalized signal intensity during infusion of 5 compounds. The compounds were 1) morphine, 2) haloperidol, 3) succinyl choline, 4) clenbuterol, and 5) verapamil. The data were generated with no modifier added to the nitrogen transport gas (A), no modifier added to a transport gas mixture comprised of 54% nitrogen and 46% helium (B), and 2-propanol added to the nitrogen transport gas at a concentration of 2.5% (C). The (M+H)⁺ ions of the 5 compounds had different nominal masses. The separation voltage was 3500 V p-p. As in Figure 1 an HPLC pump was used to dispense the modifier.

Figure 4

Plot of CV scans versus MRM signal for pamaquin ions at various solvent flow rates, 1) 1 μL/min, 2) 5 μL/min, 3) 10 μL/min, 4) 25 μL/min, and 5) 125 μL/min. The apparent loss of resolution at high flows is due to the generation of a heterogeneous cluster ion population when ions are desorbed from the charged droplets. The desolvation gas temperature was maintained constant throughout. The carrier gas flow was heated to ≈ 42°C, and the SV set to 3000 V p-p in all cases.

Figure 5

Fragmentation of SF₆ anions due to RF heating in the DMS analytical gap. A) For a bulk gas temperature of 150°C fragmentation occurs at approximately SV = 1100 V in the dispersion plot; B) mass spectrum before fragmentation shows only m/z=146 (SF₆⁻); C) mass spectrum after fragmentation (SF₆⁻ → SF₅⁻ + F) shows SF₅⁻.(m/z 127).

Figure 6

Diagram of a DMS/MS interface showing the heated desolvation region. For more details regarding this interface design see reference (1).

Figure 7

Plot of CV versus MRM signal intensity during infusion of 5-fluorouracil (mw 129) in 50/50 methanol/water solvent at 10 μL/min. A) Performance in the absence of the heat exchanger, where the transport gas temperature was ≈ 42° C. B) Improved peak shape and intensity when the transport gas was heated to ≈ 165° C. The baseline for 5-FU without the DMS installed under these inlet flow conditions was 1.2 × 10⁵ cps.

Figure 8

Heterogeneous versus homogeneous clustering processes for samples of minoxidil. A) CV scan data acquired for minoxidil under fixed source and interface temperature conditions, where the total solvent load from the source was adjusted. A tee was installed in the source so that a constant flow of 10 μL/min minoxidil could be mixed with a variable pump flow comprising 50/50 methanol/water. The total solvent flow presented to the source was 1) 10 μL/min, 2) 50 μL/min, 3) 100 μL/min, 4) 250 μL/min, 5) 500 μL/min, and 6) 750 μL/min. B) CV scan data for samples of minxodil introduced at 10 μL/min under two different transport gas conditions. (I). No modifier added to the nitrogen transport gas. (II). Modifier of the same composition as the electrospray solvent was vaporized in the transport gas using a liquid flow of 700 μL/min. The total transport gas flow was 3.7 L/min in both cases.

Figure 9

Effect of transport gas temperature on the separation of 6 different isobaric compounds of nominal m/z 309. The transport gas temperatures were A) 47°C; B) 98°C; C) 122°C; D) 146°C; E) 179°C. The separation voltage was 3500 V p-p and 2-propanol modifier was provided to the curtain gas at a concentration of ≈ 5%. The compounds were isobaric with nominal m/z 309 Daltons. The numbers in the figure refer to the following compounds: 1) nifenazone; 2) bestatin; 3) warfarin, 4) quinoxifen, and 5) benoxinate.

Figure 10

Compensation for Pressure Variation. DMS peak drift with barometric pressure was tracked over a 27 hour window where the barometric pressure decreased from 102.6 kPa to 101.6 kPa. The data show the CV drift that occurs when the separation voltage is not corrected to maintain a constant E/N ratio (trace marked with +), and the elimination of systematic drifting when the separation voltage is corrected to maintain a constant E/N ratio (trace marked with o).