Development of a Portable Mass Spectrometer Characterized by

Apr 11, 2013 - Hitachi, Ltd., Central Research Laboratory, Kokubunji, Japan. ‡. Hitachi High-Technologies Corp., Hitachinaka, Japan. §. National Re...
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Development of a Portable Mass Spectrometer Characterized by Discontinuous Sample Gas Introduction, a Low-Pressure Dielectric Barrier Discharge Ionization Source, and a Vacuumed Headspace Technique Shun Kumano,*,† Masuyuki Sugiyama,† Masuyoshi Yamada,† Kazushige Nishimura,† Hideki Hasegawa,† Hidetoshi Morokuma,‡ Hiroyuki Inoue,§ and Yuichiro Hashimoto† †

Hitachi, Ltd., Central Research Laboratory, Kokubunji, Japan Hitachi High-Technologies Corp., Hitachinaka, Japan § National Research Institute of Police Science, Kashiwa, Japan ‡

ABSTRACT: The present study has attempted to downscale a mass spectrometer in order to make it portable and enable onsite analysis with it. The development of a small mass spectrometer required the use of a compact pump whose displacement was small, decreasing the sensitivity of that spectrometer. To get high sensitivity with a small mass spectrometer, we have integrated novel techniques: a highly sensitive ionization source and efficient extraction of sample vapor. The low-pressure dielectric barrier discharge ionization (LP-DBDI) source made it possible to increase the conductance between the source and the mass analyzer, compared with ambient ionization sources, enhancing the efficiency of the ion transfer from the ionization source to the mass analyzer. We have also developed a vacuumed headspace method efficiently transporting the sample vapor to the ionization source. The sensitivity was further enhanced by also using a discontinuous sample gas introduction technique. A prototype portable mass spectrometer using those novel techniques was found to be sensitive enough to detect 0.1 ppm methamphetamine, 1 ppm amphetamine, 1 ppm 3,4-methylenedioxymethamphetamine, and 10 ppm cocaine in liquid.

M

sensitivity. Ouyang et al. have developed a portable mass spectrometer with a rectilinear ion trap and an electrospray ionization source.7 They got high sensitivity with a small pump by developing a discontinuous atmospheric interface (DAPI) to increase the efficiency of the ion transfer from an ambient ionization source to the mass analyzer. We have made a highly sensitive portable mass spectrometer using novel techniques different from those described above. We previously developed a highly sensitive ionization source, a low-pressure dielectric barrier discharge ionization (LP-DBDI) source,18 differing from the glow discharge ionization source.19 The LP-DBDI requires one or more dielectric barriers and is operated using AC voltage.20 The dielectric limits the average current density, resulting in a low-temperature plasma expected to lead to soft ionization. We confirmed that the LP-DBDI source was more than 50 times as sensitive as an atmosphericpressure chemical ionization source. This source compensates the sensitivity decrease due to the use of a small-displacement pump. For efficient ion transfer and sample vapor transport, we

ass spectrometry (MS) is a powerful analytical method that has been used in a wide range of fields, such as MS imaging and the analysis of biological fluids.1−6 Year by year, the sensitivity and resolution of mass spectrometers have been improved, further increasing the kinds of measurable sample and application fields. Mass spectrometers, however, are generally so bulky that they can be used only in laboratories. The development of portable mass spectrometers has therefore been of particular interest.7−17 Portable mass spectrometers are expected to find applications not possible with conventional mass spectrometers, namely, onsite analyses for environment investigations, illicit drug screenings, blood tests, and so on. The common difficulty in the development of a portable mass spectrometer is that a compact pump whose displacement is small, such as 10 L/s, must be used because pumps dominate the weight of mass spectrometers. The use of a smalldisplacement pump limits the volume of sample gas entering the mass analyzer, leading to a decrease in the sensitivity. Thus, the key challenge in developing a portable mass spectrometer was to improve the sensitivity. Contreras et al. reported a portable mass spectrometer with a toroidal ion trap, a gas chromatograph, and an electron impact ionization source.16 They use a solid-phase microextraction technique that concentrates sample in absorbent, thereby enhancing the © 2013 American Chemical Society

Received: January 28, 2013 Accepted: April 11, 2013 Published: April 11, 2013 5033

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Figure 1. Portable mass spectrometer developed in the present study. (A) Configuration of the system. (B) Control sequence of the portable mass spectrometer. (C) Schematic of low-pressure dielectric barrier discharge ionization source.

DC voltage and an incap-end-cap voltage. Resonance phenomena were used to eject the ions by sweeping the frequency of the supplemental AC applied to the rod electrodes from 50 to 500 kHz. Those ions were detected by an electron multiplier (5903 MAGNUM Electron Multiplier, PHOTONIS, Brive, France). The whole system was controlled by a homemade electronic circuit and LabView software (National Instrument, TX, USA). Figure 1B shows the control sequence of the instrument. Electric power for the LP-DBDI was turned on simultaneously with the opening of the pinch valve. After a certain number of milliseconds, RF voltage was applied in order to trap ions. The accumulation time is defined as the time when both RF voltage and the electric power for the LP-DBDI were applied. After the valve was closed, the cooling time, which was typically 750 ms, was needed in order to reduce the pressure inside the chamber to a proper value for the mass scanning. The supplemental AC was applied in order to eject the trapped ions according to their m/z. The incap and end-cap voltage was normally −10 V, but if the amount of ions entering the LIT needed to be controlled, the incap voltage was adjusted during the ion accumulation time. The rod DC voltage was set to −20 V. In the postscan time, all the ions in the LIT were ejected by setting all voltages to 0. Reagents. Methamphetamine hydrochloride was purchased from Dainippon Sumitomo Pharma (Osaka, Japan); cocaine hydrochloride was purchased from Takeda Pharmaceutical Company Limited (Osaka, Japan), and methoxyphenamine hydrochloride was purchased from Sigma Aldrich (St. Louis, MO, USA). Amphetamine and 3,4-methylenedioxymethamphetamine (MDMA) were synthesized in our laboratory. Those reagents were dissolved in water at a concentration of 10 mg/ mL and stored in a refrigerator or a freezer. In the measurements, those reagents were mixed with 60% K2CO3 solution in a glass vial that was then capped. The vial was connected to the instrument within 1 min after the mixing. K2CO3 was mixed to decrease the solubility of compounds in liquid. This salting out effect facilitates the vaporization of sample and has often been used to increase the sensitivity of an analytical method.21 With a commercial mass spectrometer (DS1000, Hitachi, Ltd., Tokyo, Japan), we confirmed that a

also developed a discontinuous sample gas introduction technique and a vacuumed headspace method. The LP-DBDI source and the vacuumed headspace method were combined with a homemade linear ion trap (LIT). A prototype of the portable mass spectrometer we developed was then evaluated.

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EXPERIMENTAL SECTION Configuration of the Instrument. The prototype of the portable mass spectrometer developed in the present study is shown schematically in Figure 1A. A headspace technique was used for the sample introduction. The glass vial holding the sample solution was connected with a 5-L/min diaphragm pump (MVP006-4, Pfeiffer Vacuum, Assler, Germany) for controlling the pressure in the vial. The sample vial was also connected via a pinch valve (Takasago electric, Japan) to a 30 mm-long glass tube with an outer diameter of 4 mm and an inner diameter (ID) of 2.4 mm, which was the LP-DBDI source. When the headspace was at atmospheric pressure, a 45 mm-long Teflon tube with an ID of 0.25 mm was used between the sample vial and the pinch valve. When the headspace pressure was decreased to 10 000 Pa, on the other hand, a 35 mm-long stainless steel tube with an ID of 0.75 mm was used. The headspace gas entered the LP-DBDI source only when the valve was opened. Two discharge electrodes to which 3 kV and 10 kHz AC voltage was applied to generate barrier discharge were placed inside and outside of the glass tube. The inside electrode was 10 mm long, and the outside electrode was 5 mm long. The distance between them was 3 mm. The ions generated by the LP-DBDI source were transported to the chamber through a 1.5 mm orifice. A compact LIT used as the mass analyzer in the chamber was evacuated by a 10 L/s turbomolecular pump (HiPace10, Pfeiffer Vacuum, Assler, Germany) and a 5 L/min diaphragm pump (MVP006-4, Pfeiffer Vacuum, Assler, Germany). The rod electrodes were 4.9 mm in diameter and 20 mm long, and the inscribed diameter of those electrodes was 5.1 mm. For the ejection of the ions trapped, two of those electrodes had a slit 0.5 mm wide and 18 mm long. When 1.5 MHz RF voltage was applied to the rod electrodes, the ions were trapped in the axial direction by a pseudopotential due to the RF voltage and in the longitudinal direction by the potential due to the difference between rod 5034

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Figure 2. Estimation of the ion source pressure. (A) Theoretical model of flow from sample to chamber via the ion source. (B) Estimated pressure change in the ion source based on the experimentally measured pressure change in the chamber when the headspace was at atmospheric pressure. (C) Ionization efficiency at various times after the valve opening. (D) Mass spectrum of 1 ppm methamphetamine 70 ms after the valve opening.

DBDI source and is ionized there, the ions generated being transported to the LIT. Although the chamber pressure increases and exceeds 0.1 Pa when the valve opens, it is reduced to the proper value for the mass scanning by closing the valve. Different from a continuous sample gas introduction, this discontinuous introduction eliminates the need to maintain the chamber pressure around 0.1 Pa during the accumulation time in our setup. This enables the use of a large conductance between the LP-DBDI source and the chamber, resulting in high-efficiency ion transfer. The pressure of the LP-DBDI source depended on the conductance between the sample vial and the LP-DBDI source as well as that between the source and the chamber. The pressure change in the LP-DBDI source after the valve opening was estimated theoretically by using a simple model (Figure 2A) and the measurement data of the pressure in the chamber (Figure 2B). The pressure relationship can be expressed as follows:

K2CO3 solution containing 0.1 ppm methamphetamine produced vapor containing 7 ppb methamphetamine.

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RESULTS AND DISCUSSION Discontinous Sample Gas Introduction and LowPressure Dielectric Barrier Discharge. We previously developed a highly sensitive ionization source, the LP-DBDI source, whose optimum pressure is around several thousand Pa.18 It is shown schematically in Figure 1C. Even when an ion trap was used for the mass analyzer, the pressure of the chamber in which the ion trap was located had to be around 0.1 Pa to obtain unit mass resolution.22 To keep the pressure difference between the ionization source (several thousand pascals) and the mass analyzer (0.1 Pa) using the smalldisplacement pump, there had to be an orifice with small conductance. A small-conductance orifice in the path of ions, however, reduces transfer efficiency. We developed a discontinuous sample gas introduction and intermittent ionization based on the DAPI,22−24 which is a recently developed sophisticated way to overcome a similar conductance problem. The concept of our technique is described as follows. The pinch valve is located between the sample vial and the LPDBDI source and controls the sample gas introduction to that source. When the valve opens, the headspace gas enters the LP-

C1 =

Q1 P2 − P1

ΔP2 = 5035

,

C2 =

Q2 P3 − P2

(1)

(Q 2 − Q 1) ·Δt V

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where C1 is conductance between the sample vial and the LPDBDI source and C2 is the conductance between such source and the chamber; Q1 and Q2 are, respectively, the flow amount into the LP-DBDI source and that into the chamber; P1, P2, and P3 are, respectively, the pressures in the sample vial, the LPDBDI source, and the chamber; ΔP2 is the change in the pressure of the LP-DBDI source; V is the volume of the LPDBDI source; and Δt is the unit time. A pressure gauge connected to the chamber was used to measure the chamber pressure P3 when the valve was opened for 80 ms. The P2 based on eqs 1 and 2 was calculated using the fitted line for the change in P3 and is shown in Figure 2B. P3 increased continuously until the valve was closed, but P2 saturated at about 1400 Pa 5 ms after the valve was opened. The saturation of P2 indicates that Q1 and Q2 became almost the same. The flow condition in the ion source was considered to be stable in this saturation period. As described above, this saturation value of P2 was the optimum pressure for the ionization. The relation between the efficiency of the ionization and the time after valve opening was investigated using methamphetamine K2CO3 solution as a sample, and the results are shown in Figure 2C. The obtained ion intensity increased in a timedependent manner. This result implied that the condition of the plasma generated in the LP-DBDI source changed in time, although the estimated pressure there was stable from 25 to 75 ms after the valve opening (Figure 2B). Electric power for the LP-DBDI source was turned on simultaneously with the opening of the pinch valve. Because the ion was detected 25 ms after valve opening, the plasma was generated at this point but probably did not become stable, which might lead to the change in the ionization efficiency. Another possibility is the change in the trapping efficiency. As shown in Figure 2B, the pressure in the chamber where the LIT was located increased continuously. This increase in the pressure possibly enhanced the trapping efficiency. Further study is necessary to clarify this phenomenon observed in Figure 2C. Figure 2D shows the mass spectrum obtained 70 ms after the valve opening. Our previous study indicated that which ions were obtained, M+ or [M + H]+, depended on the ionization source pressure. In the present study, where this pressure was about 1400 Pa, [M + H]+ ions were obtained. Noise seen at low m/z area would be chemical noises from nontargets, which likely degraded the sensitivity, thus possibly requiring further improvements of the LP-DBDI source for the detection of compounds present at low concentrations. Vacuumed Headspace Technique. A headspace technique is usually used to extract compounds vaporized from sample solutions and put them to analyzing devices.25−27 In the setup of our mass spectrometer, the vial encapsulating sample liquid was connected directly to the LP-DBDI source as shown in Figure 1. Sample vapor entered the LP-DBDI source, was ionized there, and was transported to the LIT. To increase the efficiency of the transport of the sample vapor to the LP-DBDI source, we have developed a vacuumed headspace technique. Generally, the headspace is at atmospheric pressure or is pressurized (e.g., when a gas chromatograph is connected26). On the other hand, because the LP-DBDI source was used in our mass spectrometer, even if the headspace was depressurized, the headspace gas including sample molecules flowed into the LP-DBDI source according to the pressure difference between the LP-DBDI source and the headspace. Depressurizing the headspace has a condensation effect. The concentration of sample molecules in the headspace gas depends on its vapor

pressure, which is not affected by the surrounding pressure. A decrease in the pressure of the headspace of the sample vial results in an increase in the concentration of the sample molecules in the headspace of the vial. For example, when the vapor pressure of a sample is 1 Pa and the headspace pressure is 105 Pa, the sample molecules are 0.001% of the headspace gas. When the headspace pressure decreases to 103 Pa, the fraction of sample molecules in the headspace gas increases to 0.1%. This suggested that, when headspace pressure decreased, if the flow volume from the sample vial to the DBDI source was unchanged, more sample molecules entered the source than when headspace pressure did not decrease. Under the condition that the flow volume Q2 into the mass analyzer and the pressure P2 in the LP-DBDI source were constant, the relation between the pressure in the sample vial and the ion intensity was analyzed using methoxyphenamine. When we decreased the pressure in the sample vial P1, we increased the conductance C1 by changing ID and length of the tube between the sample vial and the LP-DBDI source. The conductance C1 was chosen not to change the maximum pressure in the chamber P3 during the valve opening, meaning that the mass flow into the mass analyzer Q2 was unchanged. Because the conductance C2 unchanged, according to eq 1, the pressure in the LP-DBDI source P2 was constant during the experiments. The obtained result is shown in Figure 3A. As expected, the decrease in the headspace pressure resulted in an increase in the ion intensity. However, the headspace pressure was not decreased to below the vapor pressure of water because of a bumping of the sample solution. Not only methoxyphenamine but also some chemical noise ions were enhanced in the mass spectra in Figure 3B,C. This is because the vacuumed headspace technique has the same effect on the sample of interest that it has on other molecules in the vial. In analyses using the headspace method, heating the sample generally increases the efficiency of the sample introduction. That, however, requires a large amount of electric power, and a portable mass spectrometer should operate on battery power. For portable mass spectrometers, decreasing the headspace pressure would be a suitable alternative to heating the sample. Performance of Portable Mass Spectrometer. As described above, the discontinuous sample gas introduction using a pinch valve, the intermittent ionization by the lowpressure LP-DBDI source, and the vacuumed headspace technique were developed and combined with the compact LIT to enhance the sensitivity of our portable mass spectrometer. One of the possible applications of the portable mass spectrometer would be onsite screening for illicit drugs. Immunoassay kits are widely used for such screening28,29 but are sometimes problematic because a cross reaction of antibodies can cause false-positive results.30,31 In addition, newly synthesized drugs cannot be detected until new antibodies are generated, which requires a long time. The portable mass spectrometer is a likely alternative to the immunoassay kit, so we evaluated its sensitivity for illicit drugs. Amphetamine and methamphetamine, which are the most abused illicit drugs in Japan, were dissolved in K2CO3 solution at the concentrations of 1 and 0.1 ppm, respectively. In this measurement, tandem mass spectrometry was also performed. After the ion accumulation time and cooling time, sample molecules were isolated by applying a filtered noise field wave to the LIT.32 AC voltage was then applied to cause collisioninduced dissociation (CID) leading to fragmentation of the isolated ions. Additional gas introduction was not required in 5036

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the isolation-and-CID process. The obtained MS/MS spectra were compared with the previously presented data,22,33 and the recorded signals in MS spectra were confirmed to be derived from target samples. In the experiment, the headspace pressure was maintained at 10 000 Pa. The obtained mass spectra are shown in Figure 4. Figure 4A shows that a protonated molecule of amphetamine was clearly detected at m/z 136. As shown in the inset of Figure 4A, the m/ z 136 ion was fragmented by CID to an m/z 91 ion and m/z 119 ion, which are well-known fragments of amphetamine. Similarly, a protonated molecule of methamphetamine at m/z 150 and its well-known fragmented ion at m/z 91 was detected as shown in Figure 4B. Not only amphetamine and methamphetamine but also MDMA and cocaine were used for the measurement. Figure 4C shows the mass spectrum for 1 ppm MDMA in K2CO3 solution. A protonated molecule of MDMA was recognized at m/z 194 and was fragmented to m/z 163 and m/z 135 ions by CID. Figure 4D shows the mass spectrum for 10 ppm cocaine in K2CO3 solution. A protonated molecule of cocaine at m/z 304 and its fragment ion at m/z 182 were detected. The concentration curve for methamphetamine in the range from 0 to 3 ppm is shown in Figure 5, where the intensity of the extracted ion chromatogram (EIC) of the fragmented ion at m/z 91 was used. The measurements were conducted three times at each concentration. The signal-tonoise ratio calculated from the EIC intensity for a blank sample and that for a 0.1 ppm methamphetamine sample was 15.5. As described above, a K2CO3 solution with 0.1 ppm methamphetamine produced 7 ppb methamphetamine vapor. The headspace pressure during the measurement was decreased to 10 000 Pa, which is one tenth of the atmospheric pressure. The vacuumed headspace technique theoretically increases the concentration of methamphetamine in air 10-fold, meaning that vapor containing 70 ppb methamphetamine was introduced into the instrument. The results shown in Figures 4 and 5 suggested that our portable mass spectrometer was sensitive enough to detect 1 ppm amphetamine, 0.1 ppm

Figure 3. Vacuumed headspace method. (A) Effect of the sample vial pressure on the sensitivity of the instrument. (B) Mass spectrum of 0.1 ppm methoxyphenamine when the sample vial pressure was 45 000 Pa. (C) Mass spectrum of 0.1 ppm methoxyphenamine when the sample vial pressure was set to be 7000 Pa.

Figure 4. MS spectra and MS/MS spectra of illicit drugs. (A) 1 ppm amphetamine in K2CO3 solution. (B) 0.1 ppm methamphetamine in K2CO3 solution. (C) 1 ppm MDMA in in K2CO3 solution. (D) 10 ppm cocaine in K2CO3 solution. As precursor ions, m/z 136 ion in amphetamine, m/z 150 ion in methamphetamine, m/z 194 ion in MDMA, and m/z 304 ion in cocaine were selected. The obtained MS/MS spectrum was inserted into the MS spectrum as an inset. 5037

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AUTHOR INFORMATION

Corresponding Author

*Phone: +81-42-323-1111. E-mail: shun.kumano.xe@hitachi. com. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was partially supported by “R&D Program for Implementation of Anti-Crime and Anti-Terrorism Technologies for a Safe and Secure Society,” Strategic Funds for the Promotion of Science and Technology of the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government.

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Figure 5. Concentration curve for methamphetamine in K2CO3 solution.

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methamphetamine, 1 ppm MDMA, and 10 ppm cocaine in liquid. The difference in the sensitivity of our instrument for sample molecules could be related to their proton affinity and vapor pressure. In the LP-DBDI source, sample molecules were ionized by the addition of protons. Thus, molecules having high proton affinity were preferentially ionized. Matsumura et al. demonstrated the order of the proton affinity of three illicit drugs: amphetamine < methamphetamine (965 kJ/mol) < MDMA.34 The proton affinity of a tertiary amine is generally higher than that of a primary amine, implying that that of cocaine is higher than that of MDMA. The vapor pressure of sample molecules is also an important factor in analyses using the headspace method. The Chemspider Web site shows that vapor pressure increases in the following order: cocaine (1.87 × 10−6 mmHg) < MDMA (3.17 × 10−3 mmHg) < methamphetamine (1.47 × 10−1 mmHg) < amphetamine (3.07 × 10−1 mmHg). Methamphetamine has lower proton affinity than that of MDMA and cocaine but has a vapor pressure about 100 or more times higher than they do, thus leading to our mass spectrometer’s high sensitivity for methamphetamine. On the other hand, although cocaine is considered to have the highest proton affinity among samples used in the present study, its vapor pressure being the lowest should be the reason for its comparatively low-sensitivity detection.

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CONCLUSION In the present study, we attempted to develop a portable mass spectrometer. To downsize a mass spectrometer, a smalldisplacement pump has to be used, leading to a decrease in the amount of the sample gas introduced, which in turn results in low sensitivity. To overcome such problem, we have developed the LP-DBDI source with a discontinuous sample gas introduction technique for efficient ionization and ion transfer and also developed the vacuumed headspace method for efficient sample introduction. A prototype portable mass spectrometer using those new technologies detected 0.1 ppm methamphetamine, 1 ppm amphetamine, 1 ppm MDMA, and 10 ppm cocaine in K2CO3 solution. Since the present study evaluated the performance of the prototype, our next endeavor will be to pack all components (pump, electric circuits, the chamber where the LIT is located, etc.) into a space small enough to be portable. 5038

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