Ambient Pressure Inverse Ion Mobility ... - ACS Publications

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Ambient pressure inverse ion mobility spectrometry coupled to mass spectrometry Wenjie Liu, Austen Lambert Davis, William F. Siems, Du-Lin Yin, Brian H Clowers, and Herbert H. Hill, Jr. Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.6b03727 • Publication Date (Web): 06 Feb 2017 Downloaded from http://pubs.acs.org on February 15, 2017

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Analytical Chemistry

Ambient pressure inverse ion mobility spectrometry coupled to mass spectrometry Wenjie Liu1,2, Austen L. Davis1, William F. Siems1, Dulin Ying3, Brian H. Clowers1*, Herbert H. Hill, Jr.1 1

Department of Chemistry, Washington State University, Pullman, WA, 99163, United States College of Life Science, Tarim University, Alar, Xinjiang, 843300, China 3 College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha, 410081, China 2

* To whom Correspondence should be addressed. Brian H. Clowers, Department of Chemistry, Washington State University, Pullman, WA 99164, email: [email protected]: Tel 509-335-4300

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Abstract: Although higher resolving powers are often achieved using ambient pressure drift tube ion mobility mass spectrometry (DT-IMMS) systems, lower duty cycles are often required which directly impacts sensitivity. Moreover, the mechanism of ion gating using BradburyNielsen or Tyndall-Gate configurations routinely results in ion gate depletion effects which discriminate against low mobility ions. This paper reports a new method of ambient pressure ion mobility operation in which inverse ion mobility spectrometry is coupled to a time of flight mass spectrometer to improve sensitivity and minimize the effects of ion gate depletion. In this mode of operation, the duty cycle is improved to approximate 99% from a typical value of less than 1%, improving the signal intensity by over 2 orders of magnitude. Another advantage of inverse ion mobility mass spectrometry is a reduction of the impact of ion gate depletion on low mobility molecules which translates into higher sensitivity for this class of analytes. To demonstrate these benefits afforded by this instrumental mode of operation differences in sensitivity, resolving power, and ion discrimination are compared between the inverse and normal modes of operation using tetraalkylammonium standards. These results show that the ion throughput is significantly increased for analytes with a broad range of mobilities with little impact on resolving power. While the mobility-based discrimination is minimized using the inverse mode of operation, the noise level in the inverse mode is highly dependent upon the stability of ionization source.

Keywords: Ambient pressure inverse mode ion mobility spectrometry, mass spectrometry, duty cycle, resolving power, sensitivity


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Introduction With the added separation dimension afforded by the mobility domain the combination of ion mobility and mass spectrometry provides a marked improvement in peak capacity which enables the separation of isomers and, and for select systems, the measurement of ion-neutral collisional cross section (ion neutral CCS or Ω)1-4. Hyphenated with chromatography and mass spectrometry, ion mobility spectrometry provides yet another dimension of separation which further enhances separation power and minimizes analysis time. The power and potential of IMS when hyphenated with other analytical methods, such as chromatography and mass spectrometry, has been obvious from the beginning; chromatography separates compounds based on their equilibration between two phases in a time frame of minutes to seconds; ion mobility spectrometry separates ions according to their size/charge ratio in milliseconds; and mass spectrometry separates ions based on their mass/charge ratio in microseconds5-7. Compared to other mobility methods such as low pressure ion mobility mass spectrometry (LPIMMS), travelling wave ion mobility mass spectrometry (TWIMS), and differential mobility mass spectrometry (DMS-MS)8, ambient pressure drift tube ion mobility mass spectrometry (APDTIMS) routinely provides high mobility resolving power (~100), enabling the separation of analytes with mobilities that differ by less 0.05 cm2/Vs. Nevertheless, the sensitivity of APDTIMS is susceptible to ion losses when injecting a packet of ions into the drift region for separation with a duty cycle (DC) less than 1%9-12. Using this traditional mode of operation, more than 99% of ions are lost during the closed phase of ion gating cycle. It is for this reason, that ambient pressure DTIMS is inherently lower in sensitivity than other types of IMS. To increase sensitivity, multiplexing methods such as Hadamard transform13-16, Fourier transform, and correlation ion mobility mass spectrometry has provided an effective approach for improving the duty cycle from 1% up to 50%.17-18 Another approach to improve the duty cycle is the use of an ion trap injection device. With this approach, ions are accumulated during the separation 3 ACS Paragon Plus Environment


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cycle of the ion mobility spectrum and then injected into the spectrometer as a pulse of ions. In theory, the duty cycle can be improved with this method to almost 100%19-21. In practice, however, trapping capacity limited by charge repulsion places an upper bound on the number of ions that may be stored in such devices. While ion-trapping experiments can improve the duty cycle of an IMS coupled to an MS, the IMS must be operated at a low pressure, reducing the resolving power of the IMS and the accuracy of collision cross section measurements, while increasing the level of instrumental complexity and expense. Another problem associated with IMS at atmospheric pressure is the ion gate depletion effect during the ion injection period22-23. Because the region immediately preceding the ion gate is continuously depleted of ions by the lower potential wire set, assuming a Bradbury-Nielsen ion gate and a positive ion, during the closed state of the gating cycle, when the ion gate is opened ions with different mobilities traverse the plane of the ion gate at different time intervals. When the closure potential is applied to the gating wires at the end of gating pulse, the electric field induced will “pull back” the ions that have not traveled a sufficient distance. Overall, slower ions will be lost because of this action, i.e. heavier ions suffer serious ion loss because of the discriminative ion gate depletion effect. This paper reports for the first time the ability to measure mobility spectra using an ion mobilitymass spectrometer operating at an ion gate duty cycle of over 99%. By periodically disturbing the incoming ion stream, the perturbed ion current can be monitored to associate reductions in ion current on a m/z basis with mobility of the target analyte. While other schemes are possible, the most convenient method to disturb the ion current is that associated with inversion ion mobility spectrometry (IIMS). In IIMS the disturbance is produced by periodically closing the ion gate to produce a gap in the ion beam. Unlike standard IMS in which the ions are introduced as a pulse into the drift region of the ion mobility spectrometer and separated by their mobilities, in inverse ion mobility mass spectrometry (IIMMS) the location of the minimum ion current signal 4 ACS Paragon Plus Environment

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denotes an ion packets mobility24-27. Compared to a stand alone inverse ion mobility approach, the additional dimension of m/z allows for the mobility to be reconstructed and the signal further enhanced by applying m/z-specific signal processing approaches. To highlight the benefits and potential challenges of this approach, the resolving power, resolution, sensitivity and ion discriminative effect of inverse IMMS are compared with results from the normal mode of IMMS operation.

EXPERIMENTAL Chemicals and Reagents. All solvents were HPLC grade from Sigma-Aldrich (St. Louis, MO) and used without further purification. Glacial acetic acid was purchased from J. T. Baker (Phillipsburgh, NJ). Eight tetraalkylammonium bromides including tetrapropylammonium bromide (T3A), tetrabutylammonium bromide (T4A), tetrapentylammonium bromide (T5A), tetrahexylammonium bromide (T6A), tetraheptylammonium bromide (T7A), tetraoctylammonium (T8A), tetradecylammonium bromide(T10A) and tetradodecylammonium bromide (T12A) were purchased from Sigma- Aldrich (St. Louis, MO) . A 100 µM stock solution was prepared in 50% acetonitrile and 0.1% formic acid and further dilutions were made to realize final concentrations used during data acquisition. Ion Mobility Spectrometry. The specific details of the ambient pressure stacked ring drift tube ion mobility spectrometer (IMS) has been reported previously11, 28. The stacked ring IMS cell consisted of two regions: a 6 cm desolvation region and a 23 cm drift region separated by a Bradbury-Nielsen (B-N) ion gate made with alloy 46 wires spaced 0.5 mm apart. The inner diameter of both desolvation region and drift region was 50 mm. The ion-gate was operated with a closure voltage of ±46 volts and the gate pulse width varied from 144 to 1200 microseconds in normal pulsed mode. In the inverse mode, the gating time was prolonged and only 144 to 1200 microseconds close time was applied to the adjacent gating wires. The electric field across the 5 ACS Paragon Plus Environment


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IMS drift region was 313 V/cm. The temperature of the IMS was operated at either 75°C or 120 °C depending on the class of experiment conducted. Atmospheric pressure was 93.3 kPa during the experiment process at Pullman. A 6 cm long 75 µm ID and 150 um OD silica capillary tube with polyimide coating was used as electrospray emitter and installed 8 mm behind the shielding screen. A 2.4 kV bias potential was applied to the ESI needle relative to the drift voltage of the drift tube. The electrical potential used to produce ESI was applied through a stainless steel zero dead volume union (Valco Instruments, Houston, Texas, USA) that connected the emitter with the fused-silica capillary transfer line (360 µm o.d. × 75 µm i.d., ∼30 cm long). (Figure 1). In addition to the mobility modes of operation, the B/N gate could be opened to introduce all ions to the mass spectrometer without ion mobility separation. For both normal mode and inverse mode, the data were collected using signal averaged and real-time acquisition using data acquisition software provided by TOFWERK AG (Thun, Switzerland) [Figure 1] Time of Flight Mass Spectrometry The time of flight mass spectrometer was manufactured by TOFWERK AG and has been described elsewhere11. Briefly, the interface between the IMS and the TOF region of the MS consisted of a pinhole nozzle with a 300 µm diameter. The pressure inside the interface was stepped down in two stages, from atmospheric pressure (approximately 950 mbar) to 2-4 mbar within the interface. Two segmented quadrupole ion guides conducted the ions traversing the pressure interface region towards the ion focusing lenses to TOF pusher. The mass spectrometer operated with a V mode to achieve higher sensitivity and higher sampling rate to keep up with the speed of ion mobility separation. Data Analysis


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The data were acquired using a time-to-digital convert (HPTDC-PCI, Cronologic, Frankfurt, Germany) controlled by TOFWERK software which produced output HDF5 files directly compatible with Igor Pro 6.31 (Wavemetrics, Lake Oswego, OR). Once imported into Igor Pro the m/z-specific drift times could be extracted. The inverse mode IMMS spectra were obtained by inverting the baseline of ion intensity spectra followed by a denoising procedure leveraging a Fourier transform and removal of high frequency noise (See below). The resolving powers of each ion peak were calculated with the drift time (td) of the ion divided by the full peak width at half height (w0.5) of the ion mobility peak. This relationship was given by Eq.1:

Rm =

td w0.5

(1)

Where Rm was the measured resolving power.

RESULTS AND DISCUSSION

Duty Cycle of the Inverse Ion Mobility Mass Spectrometry. Generally, the normal, signal averaged pulsed mode for ion mobility spectrometry relies upon a duty cycle of less than 1% (200 µs pulse width divided by 60 ms scan time). Stated differently, more than 99% of ions are lost to the gating wires during the closed gating stage. There are two notable consequences when coupling such an ion mobility system to mass spectrometry. First, when using volatile analytes neutral molecules are routinely swept out of the system using a countercurrent flow of gas, however, when lower volatility compounds are used the ion gate wires may become contaminated as neutralized analytes deposit. Additionally, the deposition of analytes onto the ion gate wires can alter the electric field in the gating region and directly influence transfer efficiency of the system. Figure S1 shows an example of a contaminated gate



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with the discolored wires corresponding to the negative potential wire set relative to the drift tube voltage. Second, sensitivity is significantly decreased due to the low duty cycle, which hinders efforts to couple chromatography to ambient ion mobility mass spectrometry systems. However, by interfacing inverse ion mobility to mass spectrometry, the duty cycle can be increased to more than 99%, thus most of the ions could pass the ion gate and be detected by the mass spectrometer. Figure 2 shows typical the m/z-specific mobility traces extracted from the two-dimensional ion mobility mass spectrometry spectrum for eight tetraalkylammonium (TXA) ions. While TXA ions are not representative of all ions, they do provide a convenient ion set covering a wide range of mobilities. For normal mode (Figure 2C), T3A, T4A and T5A were the three dominant peaks with the other TXA ions exhibiting much lower intensities. For T10A and T12A, only trace level signals were obtained using the same acquisition time. Figure 2 shows the impact the duty cycle differences between the normal mode (Figure 2C) and the inverse mode (Figure 2A) have on the observed peak profiles . In the inverse mode ions were steadily detected in the mass spectrometer throughout the whole drift period except for the ion gaps created by briefly perturbing the ion flow by placing the ion gate briefly in the closed mode. Though all analyte ions showed ion gaps at their characteristic mobilities, raw two dimensional spectrum of the inverse mode was very different from that of the normal mode (data not shown). However, a close examination of the m/z extracted mobility data could be reconstructed in a fashion to produce spectra that were more akin to the normal mode operation. These data, shown in Figure 2B, were reconstructed by subtracting the intensity of the averaged response of each ion from their raw data. A detailed accounting of the reconstruction approach will be addressed below. It is worth noting that in normal mode, the intensity profiles of 3 TXA ions, T8A, T10A and T12A were scaled by 10, 10 and 20 times respectively for visual clarity. A 8 ACS Paragon Plus Environment

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cursory comparison between Figures 2B and 2C suggest that the signal to noise ratios (SNR) between the normal and inverse modes of operation differ, however, the tradeoff between SNR in the mobility domain must be balance with the signal fidelity found in the resulting m/z spectra. [Figure 2] In the normal mode of operation, the mobility peaks emerge from the baseline as a positive signal, whereas, in the inverse mode negative perturbations in the signal produced from the ion source correspond to mobility. Nevertheless, a significant advantage of inverse ion mobility mass spectrometry experiment is the production of mass spectra that more closely resembled theoretical profiles of target ion species. Isotopic profiles and relative abundances of common target ions is an important analytical metric to many applications, such as quantitative isotopic labeling experiments, radiological dating, and molecular identification. Figure 3 compares the isotope ratios of various TXA ions with various gate pulse widths under normal and inverse modes of operation. Because there were more ions available for statistical calculations in the inverse mode, the isotope ratios between [M+1]+, [M+2] + and [M+3] + were closer to those determined by theoretic methods. However, the results of normal mode heavily depended on the gate pulse width. For short pulses, such as 120 µs, all eight ions investigated showed 20% to 92% bias from the theoretic results. Though prolonged gate pulse width improved this performance, the resolving powers are subsequently decreased. Signal to noise ratio and resolving power of inverse ion mobility mass spectrometry. To investigate the signal to noise ratio, individual mass selected ion mobility spectra were compared between the normal mode and the inverse mode. Because of fluctuation of the electrospray ionization source, the baselines for the inverse mode spectra were noisier than those of the normal mode with most of the baseline noise being dominated by high frequency signal. Thus, a low-pass filtering approach leveraging the fast Fourier transform (FFT) was adopted to reconstruct the spectra for the inverse mode. Figure 4 demonstrates the steps 9 ACS Paragon Plus Environment


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comprising this procedure. Briefly, a Fourier transform frequency spectrum analysis was performed to obtain the signal and noise frequency distribution, next the high frequency components were discarded by driving the higher frequency components to zero. In our experimental conditions, any frequency higher than 150 Hz could be discarded without distorting peak shapes or peak positions following an inverse Fourier transform. Following the inverse transform the data were reverted to produce a data representation that is more commonly used for viewing ion mobility data. Application of this routine improved the signal to noise ratio of T7A was improved from 15.2 to 51.7. [Figure 4] One of the most important advantages of ambient pressure ion mobility spectrometry is high resolving power. In standalone ion mobility spectrometry, Tabrizchi observed an improved resolving power up to 30-60% higher was obtained for the inverted mode when compared with the normal mode. The work reported here, however, did not show such a large difference in the resolving power between the two modes. The improvement in resolving power that Tabrizchi observed was explained as a result of charge repulsion and ion diffusion in inverse mode27. In addition, Spangler expanded the traditional ion transportation theory to account for the additional space charge repulsion resulting from the increased number of ions that are introduced into the drift tube by the inverse technique26. However, the fact that we did not see an improvement in the resolving power between the two modes may be the result of different charge densities in the two systems. While it is difficult to estimate an accurate charge density for the investigated peaks in our system, it appears to be lower than that of Tabrizchi’s work. In our system, the ion current was about 0.5 nA which was about 10 times lower than that in Tabrizchi’s work, resulting in a lower charge density.


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To illustrate the similarities in our work in the resolving powers for the normal and inverse mode of operation Figure 5 shows four tetra alkyl ammonium spectra including T5A, T7A, T10A, T12A. The resolving power of T10A under normal mode was 94, while the inverse mode showed a resolving power of 92. Under the same conditions, the inverse IMMS mode and normal mode showed almost the same resolving power. This similar resolving power under normal mode and inverse IMMS mode was also observed with T12A, with a resolving power of 98 and 96 for normal mode and IIMMS mode, respectively. For T5A and T7A, the resolving powers under normal mode were 87 and 91, while 85 and 93 for inverse mode. Thus, all four compounds showed no significant differences in resolving power between the two modes. The lack of improvement in resolving power in these experiments may be because the charge density differences of all peaks in this study were not strong enough to change the resolving power. Nevertheless, the separation efficiency of IIMMS remained within 5% of the theoretically predicted maximum. To illustrate this, an example of the resolution of Ractopamine diastereoisomers using IIMMS is shown in Fig S2. [Figure 5]

Ion Discrimination Effect. The transmission efficiencies for different ions were impacted by ionization, ion gating, drift field, ion mobility mass spectrometry interface, and the ion optics. The traditionally Bradbury-Nielsen ion gate modulates an ion beam from the ion source by applying a perpendicular electric field to the drift field that can neutralize ions. As stated previously, when the ion gate was closed, ions are neutralized and destroyed on the gating wires thus a depletion ion zone is formed orthogonal to the plane of the grid wires in both direction. Theoretically, different drift voltages require different optimum gating voltages, and different ions require their own optimum gating voltages as well. However, for complex samples, ions with varying mobilities are routinely separated in the drift tube and only a single gating voltage is applied for 11 ACS Paragon Plus Environment


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practical reasons. In order to prevent ion gate leakage the applied gate voltages must be strong enough to stop all ions simultaneously. Unfortunately, this single gating voltage applied to different ions will result in different transmission efficiency under the same conditions. To explore the impact of ion gating using the inverse ion mode on transmission, ion intensities of different ions using different gate pulse width under normal mode and inverse mode were compared to the open or mass only mode. Under the mass only mode, the ion gate was continually in the open configuration during the entire sampling period thus eliminating the influence of the ion gate on ion transmission efficiency. [Figure 6] Figure 6 shows significant transmission efficiency differences in the gating period. Low mass ions had higher transmission efficiencies while heavier ions demonstrated lower ion transmission efficiencies under normal mode. This discrimination effect resulted in serious ion loss for larger molecules which translates into lower limits of detection for these species. If we define the intensities of TXA ions under mass only mode as the references of transmission efficiency for various ions, then various TXA ion transmission efficiencies under inverse mode and normal mode could be compared. For the 8 TXA, the following equation was used for the calculation of ion discrimination effect based on the final ion intensities:

% =

( )

× 100

Where TEi% is the relative ion transmission efficiency for selected ion, ITiA(N) is the intensity of selected ion under normal mode or inverse mode, and ITiA(M) is the intensity of selected ion under mass only mode. To compare with the inverse mode, the TE% of normal mode was multiplied by the time difference of the duty cycle. [Figure 7]


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The relative ion transmission efficiency is showed in Figure 7. In the normal mode, the ion transmission efficiency decreased rapidly as the drift time increases from T3A to T12A. For example, T4A produced a relative transmission efficiency of 97.2% while T5A demonstrated a relative transmission efficiency of 54.64% compared to mass only mode. For T6A the TE% dropped to 31.71%. The heaviest ion investigated, T12A, showed a TE% of less than 1%. The change of relative transmission efficiency was mainly due to the gating efficiency of different ions, in which heavier ions traversed the gating wires slower than did the smaller ions. Because the axial drift velocity of the heavier ions is comparatively slow these ions are subject to gate closing effects via “pull back,” whereas, the small, more mobile ions could pass the ion gate most efficiently. This mass discrimination effect led to lower sensitivities for heavier ions, especially when narrow gate pulse widths were used. For inverse ion mobility mass spectrometry, however, this discriminative effect was effectively eliminated by a significantly prolonged gate opening period, thus various ions show similar relative transmission efficiency from T5A through T12A, varying from 95.2% to 98.9%. With this additional TE% gain, the ions intensity differences between normal mode and inverse mode showed great differences for heavier ions. For example, the ion counts for T10A increased ~700 times while the duty cycle increased ~180 times. One extreme example was the intensity differences between T12A under inverse mode and normal mode, which increased ~14000 times. Longer gate pulse width for the normal mode largely alleviates this discriminative effect (e.g. 1080 µs), however, this operational mode significantly degrades resolving power. It is interesting to note that the smallest TXA ion selected, T3A shows a higher TE% for normal mode over inverse mode. One reason for this phenomenon might be that the higher mobility of the light ions may have resulted in a high ion loss at the interface due to diffusion and Columbic repulsion 29-30. Thus, although few ions are allowed to pass the ion gate for the normal mode, the ion loss in the drift tube is less than inverse mode for lower charge density. 13 ACS Paragon Plus Environment


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Conclusions In summary, this paper, for the first time, evaluated the performance of inverting the traditional ion mobility gating scheme when coupling the drift cell with mass spectrometry. Compared to conventional pulsed ion mobility mass spectrometry, IIMMS mode leverages a duty cycle that routinely exceeds 99% while the traditional mode of operation often relies upon a

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