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Rapid Analysis of Ingredients in Cream Using Ultrasonic Mist–Direct Analysis in Real-Time Time-of-Flight Mass Spectrometry

  • Haruo Shimada
  • Katsuyuki Maeno
  • Kazumasa Kinoshita
  • Yasuo Shida
Research Article

Abstract

A novel method for the simultaneous detection of ingredients in pharmaceutical applications such as creams and lotions was developed. An ultrasonic atomizer has been used to produce a mist containing ingredients. The analyte molecules in the mist can be ionized by using direct analysis in real time (DART) at lower temperature than traditionally used, and we thus solved the problem of normal DART-MS measurement using a high-temperature gas. Thereby, molecular-related ions of heat-unstable components and nonvolatile components became detectable. The deprotonated molecular ion of glycyrrhizic acid (m/z 821), which is unstable at high temperatures, was detected without pyrolysis by ultrasonic mist–DART-MS using unheated helium gas, although it was not detected by normal DART-MS using heated helium gas. The cationized molecular ions of derivatives of polyethylene glycol fatty acid monoesters, which are nonvolatile compounds, were also detected as m/z peaks observed from 800 to 2300. Although the protonated molecular ion of tocopherol acetate was not detected in ionization by ultrasonic mist, it was detected by ultrasonic mist–DART-MS even in the emulsion. It was not necessary to dissolve a sample completely to detect its ions. This method enabled us to obtain the composition of pharmaceutical applications simply and rapidly.

Graphical Abstract

Keywords

DART-MS Ultrasonic mist Cosmetics Emulsion Multicomponent identification 

Introduction

The high-throughput compound analysis of mixtures is important in the chemical industry. Rapid and simple analysis techniques are required not only to increase the efficiency of product development and cost performance but also for quality control management. During the development of topical pharmaceutical and cosmetic products such as creams and lotions, unexpected phenomena that affect the product quality sometimes occur in long-term storage, such as precipitation by the aggregation and segregation of polar components and nonpolar components, and the syneresis of creams. To identify the causes of such phenomena and to check whether the designed materials are blended correctly, it is important to develop a method that clarifies the composition of materials in products rapidly and efficiently. In the last decade, novel methods for the rapid analysis of pharmaceutical and cosmetic formulations have been reported [1, 2, 3, 4]. Among the many analysis methods used, only mass spectrometry (MS) has the benefit of obtaining information on mass number, which is inherent to individual molecules, even in a mixture. Liquid chromatography/mass spectrometry (LC/MS) and gas chromatography/mass spectrometry (GC/MS) are widely used for the analysis of complex mixtures. Although these methods are beneficial not only for identification but also for quantitative analysis, they require several tedious and time-consuming processes, including sample pretreatment and optimization of the analysis conditions for each compound, such as the selection of the mixed solvent as the mobile phase for separation and the detection conditions. Creams and lotions are used as pharmaceutical and cosmetic formulations. They consist of oil parts, water parts, and active surfactants, and they form semisolids and liquids, respectively. When an analyte contained in a cream is subjected to LC/MS or GC/MS, the matrix components in the cream must be dispersed in the solvent. The analyte must also be completely dissolved in the solvent. The insoluble matrix components must also be removed by filtration or centrifugation [5]. Research to establish suitable conditions for separating target compounds and other elements requires several experiments based on trial and error. Although ESI and MALDI techniques have been widely used for soft ionization, they do not enable the rapid simultaneous analysis of mixtures consisting of a wide variety of components because of their weakness in detecting low-polarity compounds [6] and low-molecular-weight compounds [7], respectively.

The direct analysis in real time (DART) ionization technique was developed for mass spectrometry and reported in 2005 by Cody et al. [8]. DART ionization is a simple and rapid detection method for the analysis of compounds because the analyte can be ionized directly under ambient conditions without any separation process. The mechanism of DART ionization has been reported [8, 9, 10]. The ionization is considered to occur under processes including the Penning ionization of water caused by the reaction of metastable helium atoms with atmospheric moisture [8]. Because the ionization occurs in front of the ion introduction orifice of the mass detector under an open-air condition, DART-MS has been applied to a variety of materials, e.g., biological fluids and homogenized tissues [11], the surface of the skin [12, 13], whole organisms such as bacterial cells [14] and a whole fly [15], psychotropic plants [16], explosive substances [8], and various forms of food materials such as red wine [17], margarine [18], and chewing gum [19]. Since molecular-related ions can be detected, it is also suitable for mixture analysis to obtain molecular information from a complex mixture sample. DART-MS has also been used for rapid confirmation of the molecular weight of final products in drug discovery [20]. However, when DART ionization is performed, the sample is exposed to a high temperature environment by the heated helium gas because the analyte must be desorbed from the sample surface before it is delivered into the mass detector. Therefore, it is difficult to detect nonvolatile compounds and heat-unstable compounds. Some ingredients in creams and lotions are heat-unstable and nonvolatile. Because some of the active surfactants used as key components for emulsification are difficult to vaporize owing to their amphiphilic property [21], those with a molecular weight exceeding 800 are particularly difficult to detect by DART-MS [6]. Furthermore, some active surfactants consist of many analogues that are widely distributed in the material products [21], which also makes identification by DART-MS difficult. In such a case, it is difficult to speculate on the composition even if the decomposition components are detected by using heated helium gas because the ions consist of many complicated pyrolysis products.

An ultrasonication-assisted spray ionization (UASI) technique was reported in 2010 by Chen et al. [22] and Wu et al. [23]. Ultrasonication was performed at frequencies of 40 kHz and 1.7 MHz using a tapered capillary. This method is suitable for the analysis of a wide mass range of biomolecules. An ultrasonic atomization technique can generate a mist of submicrometer-size droplets [24]. Since the mist droplets generated by an ultrasonic mist generator can include solvent-soluble substances such as active surfactants [25], nonvolatile and heat-unstable compounds can be delivered into the mass detector without heating. If the mist is mixed with ionized water clusters from the metastable helium gas followed by the vaporization of the solvent in mist of droplets, the components in the solvent should be ionized, and DART-MS analysis under an unheated condition should be possible. Consequently, it should be feasible to easily and rapidly detect many components in topical pharmaceutical products by DART-MS.

Our aim is to develop a rapid and simple analysis method in which many components in creams and lotions can be determined in fewer experimental steps. In this study, we combined the use of an ultrasonic mist generator with DART ionization and we attempted to detect the nonvolatile and heat-unstable components in a cream and a lotion.

Experimental

Materials

HPLC-grade acetonitrile and reagent grade polyethylene glycol (PEG) 200, 400, 600, and 1000 were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Glycyrrhizic acid was purchased from Iwaki Seiyaku Co. Ltd. (Tokyo, Japan). Polyethylene glycol (40) monostearate [PEG(40)MS] (the number in the parentheses indicates the chain length of PEG) was purchased from Nikko Chemicals Co. Ltd. (Tokyo, Japan). All other chemicals were of analytical grade. The cream sample used in this study consisted of tocopherol acetate (2%), glycyrrhizic acid (0.3%), methyl-p-hydroxybenzoate (0.1%), ethyl-p-hydroxybenzoate (0.1%), palmitic acid (1%), stearic acid (2%), glycerol (10%), PEG(40)MS (3%), stearyl alcohol (5%), liquid paraffin (10%), and water (66.5%). The lotion sample used in this study consisted of tocopherol acetate (2%), glycyrrhizic acid (0.3%), methyl-p-hydroxybenzoate (0.1%), ethyl-p-hydroxybenzoate (0.1%), glycerol (10%), PEG(40)MS (3%), stearyl alcohol (0.2%), and water (84.3%), whose numbers in parenthesis indicate weight percentages.

Apparatus

All experiments were performed using a MicrOTOFQII mass spectrometer (Bruker Daltonics, Billerica, MA, USA). The glass capillary tube in the inlet of the mass spectrometer was used with voltages of +1500 V and –2500 V for the negative and positive ion modes, respectively. The dry gas flow rate and temperature were set to 8 L/min and 180 °C, respectively. A DART SVP (IonSense, Inc., Saugus, MA, USA) was used as the DART ionization source. The DART ionization conditions were modified from those described previously by Cody et al. [8]. In the normal DART-MS measurement, a melting-point tube was dipped in a sample solution followed by its exposure to excited helium gas. The excited helium gas was exhausted at a rate of 3 L/min and the gas temperature was set to 450 °C. The discharged needle potential was +4 kV. Calibration of the positive ion mode was performed using a mixture solution of 1 mg/ml PEG 200, 400, 600, and 1000. Calibration of the negative ion mode was performed using a mixture solution of 1 mg/mL saturated fatty acids with even numbers of carbons from 8 to 24 and glycyrrhetinic acid.

The ultrasonic mist–DART-MS system is shown in Figure 1. An HM-2412 (Honda Electronics Co. Ltd., Aichi, Japan) ultrasonic mist generator operating at 2.4 MHz and 12 W was used. The mist generator (Figure 1a) was placed on the bottom of the water vessel (Figure 1b), which was 30 mm below the water surface. A sample bottle made of polypropylene containing 3 mL of a sample solution (Figure 1d) was installed on the sample holder (Figure 1c). The atomized liquid droplets (Figure 1e) were transported to the part for mixing (Figure 1g) through the hole in the plastic tube (Figure 1f) by air supplied by compressor 2 at a rate of 500 mL/min (NON-NOISE s-100; JPD Co. Ltd., Tokyo, Japan). The liquid droplets were mixed with metastable helium gas, which was released from the DART orifice. The mixed gas was transported to the MicrOTOFQIImass spectrometer (Figure 1j) through the ceramic tube (Figure 1i). Excess mist was discarded by compressor 1 (VAC-U1; AMR Inc., Tokyo, Japan) at an exhaust pressure of –10 kPa through the rubber tube (8 mm o.d., 6 mm i.d. × 1.6 m length). A current of about 4 A was passed through a heater made from a 0.3-mm-diameter kanthal wire placed around the ceramic tube (Figure 1h) to heat its inner wall to 150 °C. The sampling time was 10 s.
Figure 1

Ultrasonic mist–DART-MS system. (a) Ultrasonic mist generator. (b) Water. (c) Sample bottle holder. (d) Sample bottle. (e) Liquid droplets. (f) Hole in gas tube. (g) Mixing part. (h) Kanthal wire (0.3 mm diameter). (i) Ceramic tube (6 mm o.d., 5 mm i.d. × 93 mm length). (j) Glass capillary of mass detector. Excess mist was discarded by compressor 1 at an exhaust pressure of –10 kPa through the rubber tube (8 mm o.d., 6 mm i.d. × 1.6 m length). The air speed transported from compressor 2 was 500 mL/min. Ultrasonic mist generation was carried out at 2.4 MHz and 12 W. The gas flow (air and helium) is indicated by arrows

Sample Preparation

A 500 μg/mL solution of glycyrrhizic acid was prepared in acetonitrile/water (2/1). One hundred μg/mL solutions of tocopherol acetate and PEG(40)MS were also prepared in acetonitrile/water (2/1). The cream sample and lotion sample (7.5 mg each) were dispersed in 3 mL of distilled water, respectively, for ultrasonic mist–DART-MS analysis.

Results and Discussion

Optimization for the Detection of Glycyrrhizic Acid Using the Ultrasonic Mist–DART-MS System

Glycyrrhizic acid is an anti-inflammatory agent widely used in pharmaceutical creams. Since it decomposes at 200 °C [26], it is difficult to vaporize and its molecular ions are not detected by normal DART-MS. Glycyrrhizic acid was therefore used for the optimization of this system as a typical compound that is unstable at high temperatures and difficult to detect by normal DART-MS. The mist density was adjusted by controlling the air flow speed using compressor 2 (Figure 1), so that a large amount of the sample was introduced gradually into the mass detector to prevent sample contamination to the next analysis run. The helium gas temperature was optimized for the detection of molecular-related ions without the decomposition of glycyrrhizic acid. Three mL of glycyrrhizic acid (500 μg/mL) was set in the sample cup (Figure 1d). The sample mist droplets generated by the ultrasonicator were transported to the front of the DART orifice by the air flow from compressor 2 (Figure 1g), where they were mixed with metastable helium gas. The consumption speed of the sample by atomization was 0.15 mL/min. The minimum amount of sample required for atomization was 0.7 mL. The mixed gas was then transported to the mass detector (Figure 1j) through the ceramic tube (Figure 1i). To prevent the adhesion of the analyte to the inside of the ceramic tube, the tube was heated to 150 °C by the kanthal heater (Figure 1h). When the helium gas temperature was set to 450 °C, a deprotonated molecular ion of m/z 821 was observed along with ions of m/z 469 and 645, which were considered to be the pyrolysis products of the analyte (Figure 2a and c). Since the ions of m/z 449 and 529 shown in Figure 2a were detected in a blank solvent, they are considered to be substances eluted from the sample bottle made of polypropylene. When the helium gas temperature was set to 50 °C, pyrolysis did not occur and only the deprotonated molecular ion of glycyrrhizic acid ([M – H] 821) was observed (Figure 2b).
Figure 2

Ultrasonic mist–DART-MS spectra of glycyrrhizic acid. A solution of glycyrrhizic acid (0.5 mg/mL) was measured in the negative ion mode. (a) The helium gas temperature was set to 450 °C. The m/z peaks of 469 and 645 were assigned to the pyrolysis products of glycyrrhizic acid shown in Figure 2c. (b) The helium gas temperature was set to 50 °C. The m/z peak of 821 was assigned to a deprotonated molecular ion of glycyrrhizic acid. (c) Structure of glycyrrhizic acid

Effect of Ultrasonic Mist Combined with DART Ionization

In addition to glycyrrhizic acid, tocopherol acetate and PEG(40)MS were used to investigate the effect of ultrasonic mist–DART ionization, as typical heat-unstable, low-polarity, and nonvolatile components, respectively. Figure 3a, d, and g show the normal DART-MS spectra of glycyrrhizic acid, tocopherol acetate, and PEG(40)MS, respectively. The ions of m/z 469 and 645 in Figure 3a were considered to be the heat degradation products of glycyrrhizic acid (Figure 2c). It has been difficult to detect the molecular ion of unstable compounds such as glycyrrhizic acid under the high-temperature condition (He, 450 °C) in normal DART-MS analysis. The ion of m/z 469 was also assigned to glycyrrhetinic acid, which is known as the aglycon of glycyrrhizic acid as well as its pyrolysis product. To distinguish between the two components (glycyrrhizic acid and glycyrrhetinic acid), it is necessary to detect the molecular-related ions. The effect of using only the ultrasonic mist for ionization without DART ionization was then investigated with the electrode voltage for DART ionization set to zero (Figure 3b, e, and h). The deprotonated molecular ion (m/z 821) was detected in the ultrasonic mist-MS spectrum (Figure 3b). Although the ultrasonic mist was used in order to perform the DART-MS analysis under unheated conditions, several ions were also detected in the ultrasonic atomization without DART ionization. Ultrasonication-assisted spray ionization (UASI) was reported by Chen et al. in 2010 [22], for which only a low-frequency ultrasonicator (ca. 40 kHz) and a tapered capillary are required, and the sample solution is emitted at the outlet of the tapered capillary. Ultrasound ionization was also reported by Wu et al. in 2010 [23]. They used a piezoelectric device to produce ultrasound of 1.7 MHz. Many biomolecule samples (e.g., amino acids, peptides, and proteins) have been detected by the above methods as singly charged and multiply charged gas-phase ions. In this study, a high-frequency ultrasonicator (2.4 MHz) was used for ultrasonic atomization to produce smaller particles (the particle size was approximately 2.8 μm as a mean number of diameter).
Figure 3

Effect of ultrasonic mist–DART ionization. Normal DART-MS spectra of (a) glycyrrhizic acid (500 μg/mL) in the negative ion mode, (d) tocopherol acetate (100 μg/mL) in the positive ion mode, and (g) PEG(40)MS (100 μg/mL) in the positive ion mode measured with the helium gas temperature set to 450 °C. Ultrasonic mist–MS spectra of (b) glycyrrhizic acid (500 μg/mL) in the negative ion mode, (e) tocopherol acetate (100 μg/mL) in the positive ion mode, and (h) PEG(40)MS (100 μg/mL) in the positive ion mode measured with the helium gas temperature set to 50 °C. [M + Na]+ and [M + 2Na]2+ show single- and double-charged sodium adduct ions, respectively. Ultrasonic mist–DART-MS spectra of (c) glycyrrhizic acid (500 μg/mL) in the negative ion mode, (f) tocopherol acetate (100 μg/mL) in the positive ion mode, and (i) PEG(40)MS (100 μg/mL) in the positive ion mode measured with the helium gas temperature set to 50 °C. An enlargement of (i) in the range of m/z 2020–2120 is shown in (j)

The deprotonated molecular ion (m/z 821) was also detected in the ultrasonic mist–DART-MS (Figure 3c), which combines the DART ionization with the ultrasonic mist–DART-MS.

The molecular-related ions ([M + H]+ 473 and [M + NH4]+ 490) of tocopherol acetate were detected by normal DART-MS (Figure 3d) instead of ultrasonic mist-MS (Figure 3e). Although the deprotonated molecular ion of glycyrrhizic acid was detected in the ultrasonic mist-MS spectrum (Figure 3b), no molecular-related ions of tocopherol acetate were detected (Figure 3e). They were also detected in the ultrasonic mist–DART-MS spectrum (Figure 3f). These results show that the disadvantage of ultrasonic mist-MS was thought to be the difficulty to detect low polarity components such as tocopherol acetate, and the sensitivity of it was enhanced by DART ionization.

The protonated molecular ion of PEG(40)MS (theoretical [M + H]+ 2045) was also not detected in the normal DART-MS measurement (Figure 3g), although the singly and doubly charged sodium adduct ions of PEG(40)MS derivatives were also detected in the ultrasonic mist-MS spectrum (Figure 3h) and ultrasonic mist–DART-MS spectrum (Figure 3i). The m/z peaks observed below a mass number of 1000 in Figure 3g were the pyrolysis products of the analyte, which included polyethylene glycols. The disadvantage of DART-MS measurement, which is the difficulty of detecting nonvolatile or unstable components by exposing a sample to high-temperature environments, was improved by using ultrasonic atomization. An enlargement of Figure 3i near the molecular-related ion of PEG(40)MS is shown in Figure 3j. The ion of m/z 2068 was the cationized molecular ion ([M + Na]+) of PEG(40)MS, which is a monoester consisting of PEG(40) and stearic acid, as shown in Figure 3j. However, the material of PEG(40)MS used in this study was a mixture consisting of many analogues and impurities. The analogues imply that the PEG moiety in the PEG(40)MS material consists of several polyethylene glycol chains with carbon numbers from 25 to 45. The ions of m/z 2024 and 2112 in Figure 3j were assigned to PEG(39)MS and PEG 41)MS, respectively. The impurities imply that the fatty acid moiety in the material consists of palmitic acid. The ions of m/z 2040 and 2084 were assigned to PEG(40) palmitic acid monoester [PEG(40)MP] and PEG(41)MP, respectively.

It is considered that ultrasonic mist atomization is advantageous for the analysis of large-molecular-weight compounds such as PEG(40)MS as well as heat-unstable compounds such as glycyrrhizic acid. While the molecular ion of glycyrrhizic acid was detected in ultrasonic mist-MS, that of tocopherol acetate was not detected (Figure 3e), although it was detected in normal DART-MS analysis (Figure 3d). It is considered that normal DART-MS is suitable for the analysis of low-polarity compounds such as tocopherol acetate. Although ultrasonic mist-MS is not suitable for the detection of low-polarity components, it is suitable for the detection of polar and nonvolatile components. Undesirable properties of these ionization techniques were improved by using the combination of the DART ionization with the ultrasonic mist atomization. This technique was found to be advantageous for the detection of a wide variety of compounds because all the ions in this chapter were conclusively detected (Figure 3c, f, and i).

Ultrasonic Mist–DART-MS of Cream and Lotion

The cream sample was dispersed in water (2.5 mg/mL). The sample solution was cloudy (the particle size of the emulsion was approximately 0.50 μm as a mean number of diameter). The mass spectra in the negative and positive ion modes measured by ultrasonic mist–DART-MS are shown in Figure 4a and c, respectively. Deprotonated molecular ions of glycerol, methyl-p-hydroxybenzoate, ethyl-p-hydroxybenzoate, palmitic acid, stearic acid, and glycyrrhizic acid were detected in the negative ion mode (Figure 4a). Protonated molecular ions of tocopherol acetate and m/z peaks derived from PEG(40)MS derivatives were detected in the positive ion mode (Figure 4c). Among these components, tocopherol acetate, stearyl alcohol, paraffin, PEG(40)MS, palmitic acid, and stearic acid were considered to be contained in the emulsified particles since tocopherol acetate, stearyl alcohol, and paraffin are not soluble in water but are soluble in oil and PEG(40)MS, palmitic acid, and stearic acid are active surfactants for inducing emulsification. The lotion sample was also dispersed in water (2.5 mg/mL) and analyzed by ultrasonic mist–DART-MS as in the above experiments. The sample was also slightly cloudy (the average particle size of the emulsion was approximately 0.06 μm as a mean number of diameter). Deprotonated molecular ions of glycerol, methyl-p-hydroxybenzoate, ethyl-p-hydroxybenzoate, and glycyrrhizic acid were detected in the negative ion mode (Figure 4b). Protonated molecular ions of tocopherol acetate and m/z peaks derived from PEG(40)MS derivatives were also detected in the positive ion mode (Figure 4d).
Figure 4

Ultrasonic mist–DART-MS spectra of cream and lotion. The cream sample (2.5 mg/mL) was measured in the (a) negative ion mode and (c) positive ion mode with the helium gas temperature set to 50 °C. The lotion sample (2.5 mg/mL) was measured in the (b) negative ion mode and (d) positive ion mode with the helium gas temperature set to 50 °C. The m/z peaks of 91, 151, 165, 255, 283, and 821 of the cream in the negative ion mode were assigned to glycerol, methyl-p-hydroxybenzoate, ethyl-p-hydroxybenzoate, palmitic acid, stearic acid, and glycyrrhizic acid, respectively. The m/z peaks observed in the lotion except for those of 255 and 283 were the same as those observed in the cream. The m/z peak of 473 of the cream and lotion in the positive ion mode was assigned to tocopherol acetate. The m/z peaks of the cream and lotion observed from 800 to 2300 in the positive ion mode were assigned to derivatives of polyethylene glycol fatty acid monoesters

Since tocopherol acetate did not dissolve in water because of its low polarity, it is thought to have dissolved in the emulsification particles in the sample solution. Surprisingly, the protonated molecular ion of tocopherol acetate was observed in the emulsion (Figure 4c). This ion was detected as a result of DART ionization because no signal was observed in the tocopherol acetate solution in ultrasonic mist-MS (Figure 3e).

Contamination of the mass detector with the analyte did not occur, since the excess analyte was discarded through compressor 1 shown in Figure 1. Many ingredients were detected in the negative/positive ion mode through the additive effect of ultrasonic mist and DART ionization. However, paraffin and stearyl alcohol, which were particularly low polarity components, were not detected. The detection of such nonpolar components has not yet been realized.

Direct analysis by mass spectrometry such as by DART-MS is a powerful method for the rapid and simple identification of compounds because it does not require sample preparation before analysis. However, two factors have delayed its practical application: (1) the difficulty of detecting heat-unstable compounds because of exposure to a high-temperature environment owing to the heated helium gas, and (2) the difficulty of detecting nonvolatile compounds such as high-molecular-weight materials because of the lack of desorption. Therefore, we have developed a simple and unique system to avoid the disadvantages of DART-MS and to maximize its advantages. The system consists of an ultrasonic mist generator and a DART-MS system. The samples in this study did not need to be completely dissolved; the cream sample could be analyzed as a dispersion in water.

Conclusion

A novel method has been developed by combining ultrasonic atomization and DART ionization. The molecular-related ions of a wide variety of components such as heat-unstable components, nonvolatile components, and low-polarity components in a cream and lotion became detectable simultaneously. It was not necessary to dissolve the sample completely. This method enabled us to obtain their composition information simply and rapidly.

Notes

Acknowledgements

The authors thank Mr. S. Kamikubo and Mr. T. Nishiguchi for the fabrication of the ultrasonic mist device. They also thank Ms. Y. Noritake for MS measurements.

References

  1. 1.
    Marzorati, M., Bigler, P., Plattner, M., Vermathen, M.: Feasibility of 1H-high resolution-magic angle spinning NMR spectroscopy in the analysis of viscous cosmetic and pharmaceutical formulations. Anal. Chem. 85(8), 3822–3827 (2013)CrossRefGoogle Scholar
  2. 2.
    Weston, D.J., Bateman, R., Wilson, I.D., Wood, T.R., Creaser, C.S.: Direct analysis of pharmaceutical drug formulations using ion mobility spectrometry/quadrupole-time-of-flight mass spectrometry combined with desorption electrospray ionization. Anal. Chem. 77(23), 7572–7580 (2005)CrossRefGoogle Scholar
  3. 3.
    Huang, M.-Z., Zhou, C.-C., Liu, D.-L., Jhang, S.-S., Cheng, S.-C., Shiea, J.: Rapid characterization of chemical compounds in liquid and solid states using thermal desorption electrospray ionization mass spectrometry. Anal. Chem. 85(19), 8956–8963 (2013)CrossRefGoogle Scholar
  4. 4.
    Goto, N., Morita, Y., Terada, K.: Deposits from creams containing 20% (w/w) urea and suppression of crystallization (Part 3): novel analytical methods based on Raman spectroscopy for the characterization of deposits and deposition phenomena of creams containing 20% (w/w) urea. Chem. Pharm. Bull. (Tokyo). 64(8), 1099–1107 (2016)CrossRefGoogle Scholar
  5. 5.
    Mubarak, M.A.S.E., Lamari, F.N., Kontoyannis, C.: Simultaneous determination of allantoin and glycolic acid in snail mucus and cosmetic creams with high performance liquid chromatography and ultraviolet detection. J. Chromatogr. A 1322, 49–53 (2013)CrossRefGoogle Scholar
  6. 6.
    Sugimura, N., Furuya, A., Yatsu, T., Shibue, T.: Comparison of the applicability of mass spectrometer ion sources using a polarity-molecular weight scattergram with a 600 sample in-house chemical library. Eur. J. Mass Spectrom. (Chichester) 21(2), 91–96 (2015)CrossRefGoogle Scholar
  7. 7.
    Dattelbaum, A.M., Iyer, S.: Surface-assisted laser desorption/ionization mass spectrometry. Expert Rev. Proteom. 3(1), 153–161 (2006)CrossRefGoogle Scholar
  8. 8.
    Cody, R.B., Laramée, J.A., Durst, H.D.: Versatile new ion source for the analysis of materials in open air under ambient conditions. Anal. Chem. 77(8), 2297–2302 (2005)CrossRefGoogle Scholar
  9. 9.
    Song, L., Gibson, S.C., Bhandari, D., Cook, K.D., Bartmess, J.E.: Ionization mechanism of positive-ion direct analysis in real time: a transient microenvironment concept. Anal. Chem. 81(24), 10080–10088 (2009)CrossRefGoogle Scholar
  10. 10.
    Song, L., Dykstra, A.B., Yao, H., Bartmess, J.E.: Ionization mechanism of negative-ion direct analysis in real time: a comparative study with negative ion-atmospheric pressure photoionization. J. Am. Soc. Mass Spectrom. 20(1), 42–50 (2009)CrossRefGoogle Scholar
  11. 11.
    Yu, S., Crawford, E., Tice, J., Musselman, B., Wu, J.-T.: Bioanalysis without sample cleanup or chromatography: the evaluation and initial implementation of direct analysis in real time ionization mass spectrometry for the quantification of drugs in biological matrixes. Anal. Chem. 81(1), 193–202 (2009)CrossRefGoogle Scholar
  12. 12.
    Mess, A., Enthaler, B., Fischer, M., Rapp, C., Pruns, J.K., Vietzke, J.-P.: A novel sampling method for identification of endogenous skin surface compounds by use of DART-MS and MALDI-MS. Talanta 103, 398–402 (2013)CrossRefGoogle Scholar
  13. 13.
    Park, H.M., Kim, H.J., Jang, Y.P., Kim, S.Y.: Direct analysis in real time mass spectrometry (DART-MS) analysis of skin metabolome changes in the ultraviolet B-induced mice. Biomol. Ther. (Seoul) 21(6), 470–475 (2013)CrossRefGoogle Scholar
  14. 14.
    Pierce, C., Barr, J., Cody, R.B., Massung, R.F., Woolfitt, A.R., Moura, H., Thompson, H.A., Fernandez, F.M.: Ambient generation of fatty acid methyl ester ions from bacterial whole cells by direct analysis in real time (DART) mass spectrometry. Chem. Commun. 8, 807–809 (2007)CrossRefGoogle Scholar
  15. 15.
    Yew, J.Y., Cody, R.B., Kravitz, E.A.: Cuticular hydrocarbon analysis of an awake behaving fly using direct analysis in real-time time-of-flight mass spectrometry. Proc. Natl. Acad. Sci. U.S.A. 105(20), 7135–7140 (2008)CrossRefGoogle Scholar
  16. 16.
    Kawamura, M., Hanajiri, R., Goda, Y.: Simple and rapid screening for psychotropic natural products using direct analysis in real time (DART)–TOFMS. Yakugaku Zasshi 129(6), 719–725 (2009)CrossRefGoogle Scholar
  17. 17.
    Guo, T., Fang, P., Jiang, J., Zhang, F., Yong, W., Liu, J., Dong, Y.: Rapid screening and quantification of residual pesticides and illegal adulterants in red wine by direct analysis in real time mass spectrometry. J. Chromatogr. A 1471, 27–33 (2016)CrossRefGoogle Scholar
  18. 18.
    Alberici, R.M., Fernandes, G.D., Porcari, A.M., Eberlin, M.N., Barrera-Arellano, D., Fernández, F.M.: Rapid fingerprinting of sterols and related compounds in vegetable and animal oils and phytosterol enriched margarines by transmission mode direct analysis in real time mass spectrometry. Food Chem. 211, 661–668 (2016)CrossRefGoogle Scholar
  19. 19.
    Haefliger, O.P., Jeckelmann, N.: Direct mass spectrometric analysis of flavors and fragrance in real applications using DART. Rapid Commun. Mass Spectrom. 21(8), 1361–1366 (2007)CrossRefGoogle Scholar
  20. 20.
    Petucci, C., Diffendal, J., Kaufman, D., Mekonnen, B., Terefenko, G., Musselman, B.: Direct analysis in real time for reaction monitoring in drug discovery. Anal. Chem. 79(13), 5064–5070 (2007)CrossRefGoogle Scholar
  21. 21.
    Raith, K., Schmelzer, C.E., Neubert, R.H.: Towards a molecular characterization of pharmaceutical excipients: mass spectrometric studies of ethoxylated surfactants. Int. J. Pharm. 319(1/2), 1–12 (2006)CrossRefGoogle Scholar
  22. 22.
    Chen, T.-Y., Lin, J.-Y., Chen, J.-Y., Chen, Y.-C.: Ultrasonication-assisted spray ionization mass spectrometry for the analysis of biomolecules in solution. J. Am. Soc. Mass Spectrom. 21(9), 1547–1553 (2010)CrossRefGoogle Scholar
  23. 23.
    Wu, C.-I., Wang, Y.-S., Chen, N.G., Wu, C.-Y., Chen, C.-H.: Ultrasound ionization of biomolecules. Rapid Commun. Mass Spectrom. 24(17), 2569–2574 (2010)CrossRefGoogle Scholar
  24. 24.
    Lang, R.J.: Ultrasonic atomization of liquids. J. Acoust. Soc. Am. 34(1), 6–8 (1962)CrossRefGoogle Scholar
  25. 25.
    Takaya, H., Nii, S., Kawaizumi, F., Takahashi, K.: Enrichment of surfactant from its aqueous solution using ultrasonic atomization. Ultrason. Sonochem. 12(6), 483–487 (2005)CrossRefGoogle Scholar
  26. 26.
    Sung, M.W., Li, P.C.: Chemical analysis of raw, dry-roasted, and honey-roasted licorice by capillary electrophoresis. Electrophoresis 25(20), 3434–3440 (2004)CrossRefGoogle Scholar

Copyright information

© American Society for Mass Spectrometry 2017

Authors and Affiliations

  1. 1.Shiseido Global Innovation CenterYokohamaJapan
  2. 2.Bio Chromato, Inc.FujisawaJapan
  3. 3.Clean Energy Research CenterUniversity of YamanashiKofuJapan

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