Developing a Vacuum Electrospray Source To Implement Efficient

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Developing a vacuum electrospray source to implement efficient atmospheric sampling for miniature ion trap mass spectrometer Quan Yu, Qian Zhang, Xinqiong Lu, Xiang Qian, Kai Ni, and Xiaohao Wang Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.7b03797 • Publication Date (Web): 01 Nov 2017 Downloaded from http://pubs.acs.org on November 8, 2017

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Analytical Chemistry

Developing a vacuum electrospray source to implement efficient atmospheric sampling for miniature ion trap mass spectrometer Quan Yu1,*, Qian Zhang 1, Xinqiong Lu1, Xiang Qian1,**, Kai Ni1, Xiaohao Wang1,2 1

(Division of Advanced Manufacturing, Graduate School at Shenzhen, Tsinghua University, Shenzhen

518055) 2

(State Key Laboratory of Precision Measurement Technology and Instruments, Department of

Precision Instruments and Mechanology, Tsinghua University, Beijing 100084)

* Correspondence to: [email protected] ** Correspondence to: [email protected]

Abstract: The performance of a miniature mass spectrometer in atmospheric analysis is closely related to the design of its sampling system. In this study, a simplified vacuum electrospray ionization (VESI) source was developed based on a combination of several techniques, including the discontinuous atmospheric pressure interface, direct capillary sampling, and pneumatic-assisted electrospray. Pulsed air was used as a vital factor to facilitate the operation of electrospray ionization in vacuum chamber. This VESI device can be used as an efficient atmospheric sampling interface when coupling with a miniature rectilinear ion trap (RIT) mass spectrometer. The developed VESI-RIT instrument enables regular ESI analysis of liquid, and its qualitative and quantitative capabilities have been characterized by using various solution samples. A limit of detection of 8 ppb could be attained for arginine in a methanol solution. In addition, extractive electrospray ionization of organic compounds can be implemented by using the same VESI device, as long as the gas analytes are injected with the pulsed auxiliary air. This methodology can extend the use of the proposed VESI technique to rapid and online analysis of gaseous and volatile samples.

Introduction Mass spectrometry (MS) is recognized as a versatile technique for chemical and

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biological analyses. The development of an integrate miniature mass spectrometer has elicited sustained interest in the past two decades,1-4 because this research can provide a practical solution for real-time measurements in various areas such as environmental monitoring,5 household chemical analysis,6 clinical examination,7 and food safety testing.8 Considerable efforts are continuously expended to improve the instrument performance and reduce the device size, as well as to further explore the application potential of portable MS systems. A miniature mass spectrometer usually has a simplified and compact system structure, and the combination property of the instrument depends largely on key subsystems, including the ion source, mass analyzer, and vacuum system. In general, the ion source may to some extent define the detection object of the instrument, whereas the mass analyzer has a critical effect on the basic MS performance (e.g., sensitivity, resolution, and mass range). As for the vacuum system, its quality will determine the robustness of the instrument.2 Among mass analyzers, the ion trap is most favored by current small MS instruments because of its simple structure, modest vacuum requirements, and intrinsic MS/MS capabilities. Typical operating pressure of an ion trap can generally be provided by using a miniaturized vacuum system with one diaphragm and one turbo pump, even if the instrument uses a constantly open atmospheric pressure interface.9-11 Given that direct introduction of atmospheric samples can easily overwhelm the limited pumping capacity, membrane inlet with internal ionization has been used more often in miniature MS systems to implement continuous measurements.12-15 In addition, recent studies have shown that capillary introduction of liquid is also a practicable sampling strategy for a miniature mass spectrometer, and it presents several unique merits such as self-aspirating ability and ultra-low sample consumption that are useful for portable applications.16,17 As a trapping analyzer, ion trap is essentially operated in a periodic trapping-scanning mode, thereby making it more flexible to design its sampling and vacuum system than other beam-type analyzers (sector, time-of-flight, quadrupole). For instance, the discontinuous atmospheric pressure interface (DAPI)18 is recognized as a well-customized sampling technology for miniature ion trap instruments. This


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approach can improve the efficiency of atmospheric ion introduction without increasing the pumping requirements.19 Moreover, it provides a pressure variation that effectively matches the ion trap analysis that the initial high pressure facilitates ion capturing and cooling, whereas the subsequent reduced pressure is appropriate for ion scans. In fact, the application of pulsed introduction strategy is not limited to sampling ions from external sources. The system can also be used in a miniature ion trap system with internal ionization to carry analytes into the vacuum chamber and provide pulsed buffer gas for ion cooling.16,20 The introduction of neutral samples into vacuum is obviously much easier and more effective than that of ions. Briefly, charged particles are prone to degradation by hitting the tube wall or reacting with background gas,21-23 whereas the neutrals generally suffer from minimal adsorption or diffusion losses during transmission. Under the assumption that the same ionization technique is used, the use of samples will be enhanced when neutrals are directly sampled and then ionized for MS analysis. In fact, internal ionization (e.g., electron impact ionization24,25 and ultraviolet photoionization26) coupling with direct sampling interface, such as the membrane and capillary inlet, has consistently been an efficient introduction strategy for small MS instruments.3,16,27,28 Typical utility of these devices lies on the detection of volatile organic compounds with low molecular mass (usually less than several hundred amu), but this has yet become an application limitation. Electrospray ionization (ESI) is one of the most widely-used techniques that can ionize a wide variety of polar compounds in solutions.29,30 Many variants on ESI have been reported,31,32 and these devices are traditionally marked as atmospheric pressure ion sources. By coupling with a DAPI, nano-ESI and ESI sources have been successfully used in miniature mass spectrometers.1,2,18 However, a conventional ESI system generally needs a bulky injection pump to drive liquid transport, and this may limit its application in in-situ measurements. Efforts have been made to develop pump-free ESI sources by using other injection forces.33,34 An extraordinary promotion of ESI is paper spray (PS) technique, which has ambient ionization35 ability and significant simplification in device assembly.36,37 PS sources together with its many variants have been commonly



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used in miniature systems to extensively expand the application of MS analysis in outdoor enviroments.7,38,39 Although DAPI has been successfully used in miniature mass spectrometers to effectively connect various atmospheric pressure ion sources to the vacuum region, significant ion loss (ion transfer efficiency is roughly 0.2%18) remains inevitable and may become a main obstacle in the improvement of detection sensitivity. One potential solution is to implement those conventional atmospheric pressure ionization techniques inside the vacuum chamber. The solvent was easy to freeze at the spray tip because of rapid evaporative cooling.40-42 Drops freezing can likely occur during the entire electrospray process in vacuum because the solvent will continuously evaporate and cause evaporative cooling. In that case, Coulomb explosion may be terminated that can significantly reduce ionization efficiency. Some related studies have been carried out to produce a stable electrospray under vacuum as a primary cluster ion source for secondary ion mass spectrometry analysis.40-44 To prevent ice formation, additional devices such as a wire heater42 or a continuous infrared laser40,41,45 were commonly used to heat the liquid. However, the ion sources described in these studies were too complex for miniaturization. To develop a proper ion source for miniature ion trap mass spectrometers, some of the above-mentioned approaches were skillfully combined to produce a concept of vacuum electrospray ionization (VESI). Specifically, sample solution was introduced into the vacuum chamber by direct capillary sampling, and simultaneously, a high voltage (HV) was applied onto the sample. In addition, pulsed auxiliary gas was carefully injected into the vacuum chamber to create a temporary quasi-atmospheric environment for ESI operation. Air is the preferred choice of auxiliary gas for a miniature instrument, because no additional gas cylinder is needed. The airflow was a critical component of VESI, because it incorporated several functions, including heating the liquid or spray droplets, nebulizing the solvent, and facilitating the capture and cooling of the ions. Based on this concept, a VESI device has been constructed and tested on a miniature ion trap mass spectrometer. Initial research on the characterization and application of the proposed VESI was demonstrated.


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Experimental The developed VESI source was mounted on a miniature ion trap mass spectrometer, and the schematic of the instrument structure is shown in Figure 1a. The entire system evolved from a previous instrument that mainly consisted of a sample inlet system, rectilinear ion trap (RIT) mass analyzer, ion detector, vacuum system, and electronics system. In the current version, the sample inlet system was transformed into the VESI source after several modifications were conducted. The vacuum was maintained by a miniature diaphragm pump (MVP 006, Pfeiffer Vacuum Inc.) and turbo molecular pump (HiPace 10, Pfeiffer Vacuum Inc.). The other components of the instrument and operating parameters were mostly the same as previously reported.16 The total power consumption of the MS instrument was less than 40 W. Moreover, the VESI source can be replaced by an ESI-DAPI device20 (see Supporting Information Figure S2) to carry out some comparative studies. The VESI features a compact design that fits the miniature nature of the entire MS system. The design can be considered as a simple change to a conventional DAPI module that the only additional components are a power source for HV supply and a capillary for both sampling and ESI operation. Specifically, the VESI module comprises a liquid sample inlet channel and gas-flow channel, which were connected by a PEEK tee assembly. A fused-silica capillary (15 µm i.d., 375 µm o.d.) was used as the sampling tube and led into the vacuum chamber via a sheath tube (tube 3, 1 mm i.d.). Liquid samples can be directly drawn into the chamber because of the pressure difference between the surrounding air and the vacuum. Based on previous research, the sampling rates for methanol and water using the 15 µm capillary were approximately 568 and 90 nL/min, respectively.16 The outlet of the silica capillary was carefully positioned 1 mm out of the sheath tube to form a spray tip. Given that this spray module was directly mounted in front of the mass analyzer, the generated ions could then enter the RIT without using any additional transfer components to minimize transmission loss. Similar to the operation of a conventional DAPI device, pulsed air was regularly injected via the gas-flow channel, which comprises a pinch



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valve (390NC24330, ASCO Valve), silicone tubing (1.5 mm i.d.), and two stainless steel tubes (tube 1, 1 mm i.d., and tube 2, 250 µm i.d.). topen is used to represent the pulse width of signal for controlling the pinch valve opening. Figure 1b shows the typical timing sequence.

Results and Discussion Efforts have been made toward validating the feasibility of the proposed VESI technique. At the beginning of the study, a mixed solution of arginine, ciprofloxacin, and aspartame (all with a concentration of 100 ppm) was prepared using methanol that contained 0.2% formic acid to test and characterize the VESI. The solution was continuously sampled through the capillary, and a high voltage was directly applied to the samples. During this sampling process, the pressure of the chamber increased from 5×10-4 Pa to 6×10-3 Pa. However, when the pinch valve remains closed, no mass spectra can be acquired by adjusting other experimental parameters (e.g., spray voltage, sampling rate, chamber pressure, RF, and DC trapping potential of RIT46). The ion signals began when air was gradually introduced into the chamber through the gas-flow channel. A typical spectrum, as shown in Figure 2a, can be obtained by operating common mass analysis after the pulsed air injection with an adequately long delay time. Protonated molecular ion peaks (m/z 175, 295, and 332) of the three compounds were observed from the spectrum, thereby indicating that electrospray ionization could actually occur in the chamber. Furthermore, based on the acquired ion chromatogram profiles (Figure 2b), the ionization process exhibited a certain stability for consecutive measurements that the relative standard deviations (RSD) of different ions were all less than 6%. The above-mentioned experiment indicated that air injection can facilitate the production of ESI ions in a vacuum. Additional experiments were subsequently performed to better reveal the ionization process. The typical timing sequence for VESI-RIT mass spectrometer was similar to that for a conventional DAPI-RIT system, which mainly involved three stages, namely, ion injection, ion cooling, and ion scan. In a VESI-RIT system, ions were likely generated after the injection of auxiliary gas


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with a width generally between 10 and 30 ms. These ions were then directly introduced into the RIT analyzer, in which a low RF voltage was constantly applied for ion trapping after the air injection ended. The cooling time was set at roughly 1200 ms to reach a chamber pressure below 0.01 Pa. Then, mass analysis was performed. Unlike most atmospheric sources, ion production in VESI is supposed to be unsustainable and will significantly relate to air injection. To determine such a relationship, the time sequence was slightly modulated, as shown in Figure 3a. The cooling voltage was applied with a certain delay (marked as RF-delay) after the beginning of air injection. In general, no ions can be trapped in this RF-delay step. Hence, the production profile of VESI ions will be demonstrated by scanning the delay length. Figure 3b shows the ion signals acquired with different RF-delay, and a typical variation of the chamber pressure was also illustrated as a reference. Evidently, removing the cooling voltage at the short beginning and long ending of the operation cycle causes little effects on ion intensity, thereby indicating that VESI ions are mainly captured during a certain time interval from 100 ms to 400 ms after air injection. This period is in rough accordance with the pressure profile. Notably, the change in ion intensity is related to two stages, namely, the ion production and ion cooling. Although pulsed air injection can probably facilitate both stages, separately evaluating the effects using current experimental platform is difficult. Auxiliary air is a crucial component for both the VESI and RIT operation, and it performs more functions in a VESI-RIT instrument than in a conventional ESI-DAPI mass spectrometer. For these two types of MS systems, the entire MS analysis procedure was influenced by the status of the injected air. The opening width of the pinch valve was then changed to investigate the effect of air injection on the performance of the developed VESI-RIT and ESI-DAPI-RIT instrument. The other experimental parameters, such as the spray voltage and control signal sequence of RIT, were kept constant. The acquired results are shown in Figure 4a. As previously reported, the pinch valve remained closed when topen was less than 6 ms.16 For the VESI experiments, no ion signals were obtained because of the absence of air under such conditions. When topen was increased to greater than 6 ms, the pinch valve began



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to work and air was introduced into the vacuum chamber. It is reasonable to speculate that VESI process was promoted with the aid of air pulse, and simultaneously, the efficiency of ion cooling was enhanced18; both processes lead to an increasing ion intensity. However, excessive injection of air can cause detection instability that the trend line became fluctuant when topen > 11 ms, possibly because of the multifunctional feature of air. Namely, the effects of air injection volume on different processes with air participation were inconsistent. Hence, the combined influence may become complicated. Although the VESI and ESI-DAPI devices have a similar structure in pulsed gas-flow channel, their transmission objects are different. Air injection was apparently much easier than ion transfer because the latter suffered from more losses during transmission. Therefore, a wider topen (> 10 ms) was needed for ion detection in the ESI-DAPI experiments, and the detection sensitivity was lowered as compared to the VESI experiments. For VESI operation, spray voltage is another indispensable condition in addition to auxiliary gas. When ion signals were first observed in the experiments, the possibility of sonic-spray ionization (SSI)47 mechanism was also considered because the designed VESI structure is similar to the SSI source. However, the signal disappeared after the high voltage was removed. Furthermore, the influence of the spray voltage on VESI was studied. The results are shown in Figure 4b. Ion intensity increased with the applied voltage, and a voltage greater than 1.5 kV was required to operate the VESI. This observation was consistent with the characteristics of a traditional ESI source.48 Hence, the detected ions were mainly produced from ESI mechanism. To further demonstrate the performance of VESI-RIT system, quantitative analysis was carried out to characterize the sensitivity and limit of detection (LOD) of the instrument. A series of methanol solutions of arginine at concentrations from 20 ppb to 2 ppm were prepared and directly introduced into the instrument for mass analysis. The spray voltage was set at 4.5 kV, and the operating voltage of ion detector was adjusted from the default -1200 V to -1400 V to improve the detection sensitivity. The calibration curve is shown in Figure 5. The results indicated a satisfactory linear


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response between ion intensity and solution concentration for this experiment. A LOD of 8 ppb for arginine can be obtained by using the developed VESI-RIT instrument. In addition, the dead volume for capillary sampling is extremely low, and the total sample consumption is estimated to be lower than 100 nL for each analysis.16 Ion production from an electrospray source is greatly related to the solution flow rate.48 In general, liquid transfer rate in a capillary is determined by many factors, including the pressure difference between the two capillary outlets, capillary dimension, and sample viscosity.34 One feature of the self-aspirating capillary introduction is that the sampling rate is difficult to change during the experiment. This approach helps ensure the stability of detection for a single measurement. However, given that viscosity varied greatly among different substances, the performance of VESI became dependent on the solution composition. In some cases, the experimental configurations needed to be readjusted for optimization when the sample was changed. For example, early attempts to analyze various sample solutions prepared using a common methanol/water (1:1) solvent were all unsuccessful. Methanol-water solution had a much lower flow rate in 15 µm capillary than methanol because of its higher viscosity, thereby significantly reducing the sensitivity of the VESI-RIT instrument in the detection of methanol-water solutions. A capillary with a larger i.d. (20 µm) was then used to increase the sampling rate. With the other experimental parameters unchanged, the instrument was able to detect analytes in methanol/water (1:1) solutions, and the mass spectrum shown in Figure 6a was obtained. Direct solution analysis is the fundamental function of the developed VESI-RIT mass spectrometer. Efforts have also been made to extend the application of the instrument to detect gas samples based on the extractive electrospray ionization (EESI) 49,50

technique, without making any modifications to the apparatus. Given that the

EESI process also takes place in vacuum as VESI, this technique is called vacuum extractive electrospray ionization (VEESI). A common VEESI analysis was easy to perform using the VESI-RIT system. A proper electrospray solution was introduced to produce charged solvent sprays via VESI process, and then auxiliary air carrying gaseous organic analytes was pulsed into the VESI source. The mixing of the charged



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droplets and organic molecules can generally lead to charge transfer, thereby benefiting the generation of analyte ions in the vacuum chamber. Various types of samples have been readily analyzed using VEESI mass spectrometry, and one of these experiments was implemented as detailed below. Methanol that contained 3 ppm arginine (used as an internal standard) and 0.2% formic acid was used as the electrospray solution. A mixed sample solution that contained aniline, 2-4 dimethyl aniline, and 2-isopropylaniline was placed near the gas inlet. When the pinch valve was opened, the volatized analytes were drawn into the chamber with the pulsed airflow. The following operating steps were in accordance with the typical VESI-RIT experiments. The acquired mass spectrum is shown in Figure 6b, on which all the protonated molecular ion peaks of the anilines analytes (m/z 94, 122, and 136) and arginine standard (m/z 175) are clearly observed. In addition to this result, other mass spectra acquired from VEESI experiments by analyzing some actual complex samples can be found in Supporting Information (Figure S2). Moreover, as the sampling of gas analytes is commonly carried out in an open environment, the detection stability of VEESI analysis can be affected by environmental conditions, i.e., airflow disturbance, temperature, and humidity. Hence, a sealed device or proper technique used to ensure steady analyte introduction for VEESI is needed when accurate quantitation is demanded.

Conclusions The concept of operating electrospray ionization under vacuum can reduce ion loss during the transmission from the atmospheric ion source to the analyzer chamber. Pulsed air has previously been used to facilitate ion detection in ion traps. It was used as a vital element to promote the vacuum ionization process probably by heating the liquid and desolvating the charged droplets. An extremely simplified VESI source was designed and perfectly coupled to a miniature RIT mass spectrometer. The advantage of VESI includes self-aspiration ability and minimal sample consumption. In addition, the VESI-RIT configuration can present better detection sensitivity than the ESI-DAPI-RIT in our experiments. Superior analytical performance of the VESI-RIT


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was demonstrated that an excellent quantitation ability and a LOD of 8 ppb were achieved in direct analysis of arginine solutions. Moreover, an application extension of the VESI device was also proposed for direct analysis of volatized organic compounds via the so-called VEESI technique. The developed ion source, which enables both VESI and VEESI operation, would provide an alternative way of implementing efficient atmospheric sampling for miniature ion trap mass spectrometers.

ACKNOWLEDGEMENTS This work is financially supported by the National Natural Science Foundation of China (Grant No. 21775085) and the Shenzhen Fundamental Research Program (Nos. JCYJ20160428182352200, JCYJ20160531195459678).

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Figure 1. (a) Schematic of the miniature VESI ion trap mass spectrometer and (b) typical timing sequence 46x14mm (600 x 600 DPI)


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Figure 2. (a) A typical VESI mass spectrum of the mix solution and (b) acquired ion chromatogram profile of different compounds 207x298mm (300 x 300 DPI)



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Figure 3. (a) Schematic timing sequence for VESI-RIT mass spectrometer, (b) ion signals acquired by regulating the RF-delay time and the related pressure profile after opening the pinch valve for 10 ms. 101x135mm (600 x 600 DPI)


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Figure 4. (a) Effect of the air injection time on ion signals acquired using ESI-DAPI and VESI. (b) Effect of spray voltage on signal intensities of arginine and ciprofloxacin ions. 102x144mm (300 x 300 DPI)



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Figure 5. Calibration curve of arginine solutions with concentrations ranging from 20 ppb to 2 ppm. Inset shows an acquired VESI-RIT spectrum of 20 ppb solution. 50x35mm (600 x 600 DPI)


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Figure 6. (a) VESI-RIT mass spectrum of a mix solution containing 30 ppm arginine, 40 ppm ciprofloxacin, 40 ppm reserpine and methanol/water (1:1) with 0.2% formic acid as the solvent. (b) VEESI-RIT mass spectrum of a volatilized anilines mixture. 100x138mm (300 x 300 DPI)


Developing a Vacuum Electrospray Source To Implement Efficient

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