High Accuracy Ion Mobility Spectrometry for Instrument Calibration

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High Accuracy Ion Mobility Spectrometry for Instrument Calibration Brian C. Hauck, William F. Siems, Charles Steve Harden, Vincent M. McHugh, and Herbert H. Hill, Jr. Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.7b04987 • Publication Date (Web): 13 Mar 2018 Downloaded from http://pubs.acs.org on March 14, 2018

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Analytical Chemistry

High Accuracy Ion Mobility Spectrometry for Instrument Calibration

Brian C. Hauck,1, a),* William F. Siems,1 Charles S. Harden,2, a) Vincent M. McHugh,3 Herbert H. Hill, Jr.1

1. Washington State University, Department of Chemistry, 305 Fulmer Hall, Pullman, WA 99164 2. LEIDOS – U.S. Army Edgewood Chemical Biological Center Operations, P.O. Box 68, Gunpowder, MD 21010 3. U.S. Army Edgewood Chemical Biological Center, Aberdeen Proving Ground, MD 21010

Submitted to Analytical Chemistry November 2017

a)

Current Affiliation: Science and Technology Corporation (STC) – U.S. Army Edgewood Chemical Biological Center Operations, Gunpowder, MD 21010

*Correspondence: Brian C. Hauck (email: [email protected], tel: 410-436-1905)

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ABSTRACT Ion mobility spectrometry (IMS) is widely used to characterize compounds of interest (COIs) based on their reduced mobility (K0) values. In an attempt to increase the accuracy and agreement of studies, the most recommended method has been to use a reference compound with a known K0 value to calibrate the instrument and calculate COI K0 values from normalized spectra. Researchers are limited by the accuracy of previous K0 value reference measurements on which to base their calibrations. Any inaccuracy in these reference K0 values, typically ± 2%, will propagate through to the calculated K0 value of the COI. For this reason there is a need to standardize reference K0 values with improved accuracy. By improving the accuracy of reference measurements, a lower degree of error will propagate through new K0 value calculations. The K0 values of the ammonium reactant ion, the potential reference standard dimethyl methylphosphonate (DMMP), and three explosive COIs were characterized at multiple drift gas temperatures, drift gas water contents, and electric field strengths on an accurate ion mobility spectrometry instrument. K0 values reported here are known to ± 0.1% as a result of reducing the error of all instrumental parameters.


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Ion mobility spectrometry (IMS) is a widely used technique for many analytical applications including biological1-3 and structural4-6 analyses, and the detection and identification of other compounds of interest (COIs) such as explosives,7 drugs,8-10 and chemical warfare agent (CWA) related compounds.11 These applications rely on the knowledge of the reduced mobility (K0) values of ions, which are calculated from the measured drift time (td) of the ion across the length (L) of the instrument under a voltage (V) gradient applied across L, and is normalized to standard temperature (T) and pressure (P), as shown in Equation (1).12

L2  273 .15  P  K0 =    Vt d  T  760 

(1)

While K0 values have historically been calculated by researchers using Equation (1), errors arose when necessary measurements were not made accurately, such as failing to mitigate or report drift gas temperature gradients. Because of the labor associated with accurately measuring each variable, the use of an internal reference standard was instead proposed as a way to calculate the K0 value of a COI using Equation (2).

(K 0 std ) td std t d COI

=

Ci t d COI

= K 0 COI

(2)

A reference standard of known mobility (K0

std)

is used to calculate an instrument factor (Ci),

sometimes referred to as an instrument constant. Ci is defined relative to the reference standard, takes into account all instrument parameters, and is unique for each separate instrument.19-25 Under the same operational conditions, the product of any COI K0 value (K0

COI)

and its

measured drift time (td COI) will produce the same Ci on the instrument. As a result, K0 COI can be calculated from the quotient of Ci to td COI.



Because calibration using Equation (2) is based on a well-known and defined value for K0 std,

K0 COI is only as accurate as the value of K0 std used. However K0 values are also dependent, to

varying degrees, on the electric field strength and temperature dependent clustering reactions occurring within the drift gas.13-16 If the reference standard is susceptible to changes in instrumental parameters, and if these changes are not well characterized, it may be appropriate for use in one measurement and not for another. Therefore, accurately known K0 values for the reference standard at multiple instrumental conditions are also needed. To date few IMS reference standards are known to uniformly apply to all IMS operating conditions and those that are relatively well characterized have historically been known to only ± 2%.17-19 For example, the average K0 value from across the available literature, and under similar conditions, for the proton bound dimer of dimethyl methylphosphonate (DMMP2H+) is 1.42 ± 0.04 cm2V-1s-1 (± 2.8%).15, 19, 23-30 When this K0 value is used for K0 std, the propagated uncertainty prevents the predicted K0 COI from being known to less than ± 0.04 cm2V-1s-1. Low accuracy values for K0 std also cause sequential error propagation. This can be seen in a group of published K0 values based on calibration by 2,6-di-tert-butyl pyridine (DtBP), proposed as a reference standard by Eiceman et al.22 No numerical K0 value was reported for DtBP in that study, but Viitanen et al. estimated a K0 value of 1.42 cm2V-1s-1 based on a figure.31 That value was used as K0 std in Equation (2) and new K0 values have since been calculated by Viitanen et al. and other researchers using this inaccurate calibration.26, 31-39 Similar studies that also report K0 values based on an inaccurate calibration further perpetuates the phenomenon. Consequently, a wide range of K0 values will be produced for the same COI by different researchers when calibrating against dissimilar experimental conditions with unaccounted error.


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For some time there has been interest in increasing the accuracy of measurements in order to standardize K0 values and solve this issue.19, 21, 22, 25, 39, 41, 42 Improved measurement and control of the variables in Equation (1) to within 0.1% error on a high accuracy instrument has shown an improved accuracy in K0 values to within ± 0.1%.40 Using this instrument, a database of accurate reference K0 values can be built for reference during calibration to lower the propagation of error in Equation (2). The objective of this work was to start this database and measure a series of accurate K0 values for a potential positive mode reference standard and three negative mode explosive COIs. K0 values were measured as a function of drift gas temperature, drift gas water content, and electric field strength to characterize the effect of each parameter on the K0 values.

EXPERIMENTAL Ion Mobility time-of-flight Mass Spectrometer (IM-tofMS) The accurate ion mobility instrument (AIMI) was interfaced to a time-of-flight mass spectrometer (tofMS) (Ionwerks, Inc.; Houston, TX). DS 102 and DS 602 rotary vane and TurboV 70 and Turbo-V 250 turbomolecular pumps (Agilent Technologies Vacuum Products Division; Lexington, MA) evacuated the vacuum interface to 1.6 Torr past a 300 µm pinhole. The focusing and flight regions were evacuated to 3.5×10-2 and 3.3×10-6 Torr, respectively. A chevron stacked multi-channel plate detector (Photonis; Sturbridge, MA) was used to detect ions, and software developed at Ionwerks Inc. and run on the IDL Virtual Machine Platform (Harris Geospatial Solutions; Broomfield, CO) was used to generate spectra. The AIMI drift tube, commercial components, and procedures used have previously been described in detail16, 40 and are summarized here. The AIMI drift tube was a stacked-ring design



of Alloy 46 electrodes and alumina ceramic insulating rings. The length of the drift tube was 16.249 ± 0.007 cm at room temperature, defined as the distance between two Bradbury-Nielson (BN) ion gates, and was corrected for thermal expansion. Drift times were calculated as the difference between drift time measurements taken from each BN ion gate. The drift gas was preheated using a resistive wire heater, and two RTD-850 sensors connected to CN7823 temperature controllers (Omega; Stamford, CT) maintained the temperature of the aluminum thermal case that housed the AIMI drift tube. K0 values were analyzed at four drift gas temperatures: 26.18 ± 0.03, 30.05 ± 0.01, 40.15 ± 0.01, and 50.21± 0.04 ºC, hereon referred to as 26, 30, 40, and 50 ºC respectively. Voltage was supplied to the drift tube and Ni-63 ion source by an LS020 20 kV reversible power supply (Excelis; Rochester, NY) and measured by an HVP-250 10,000:1 high voltage divider probe (CPS High Voltage; Tigard, OR) connected to an 8846A digital multimeter (Fluke; Everett, WA). The divider ratio of the probe was measured directly, and all direct voltage measurements were corrected for the drawdown of current during measurement. 20 and 10 MΩ fixed resistors (±1%; Caddock Electronics, Inc.; Riverside, CA) and 5 MΩ variable resistors (Newark Electronics; Chicago, IL) were used and all directly measured. The voltage difference between the first and second BN ion gate references was used in K0 value calculations. A 2307420 mercury barometer (NovaLynx; Grass Valley, CA) measured ambient pressure and was corrected for temperature and latitude.

Chemicals and Solvents Dimethyl methylphosphonate (DMMP) was obtained as a 97% pure standard (Sigma Aldrich Chemical Co.; St. Louis, MO). 2,4,6-trinitrotoluene (TNT), 1,3,5-Trinitroperhydro1,3,5-triazine (RDX), and pentaerythritol tetranitrate (PETN) were obtained as 5 mg/mL in


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methanol, 10 mg/mL in 1:1 methanol:acetonitrile, and 10 mg/mL in acetone, respectively, stock solutions (AccuStandard; New Haven, CT) and were diluted with HPLC grade methanol (Fisher Scientific; Waltham, MA) to create 0.1, 1, and 1 mg/mL solutions, respectively. Dynacal permeation tubes (VICI Metronics; Poulsbo, WA) created an ammonia drift gas dopant, HPLC grade dichloromethane (Fisher Scientific) was a negative mode reagent gas dopant, and HPLC grade water (Fisher Scientific) was a drift gas modifier. Commercial compressed air (

High Accuracy Ion Mobility Spectrometry for Instrument Calibration

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