WO2022004094A1 - Dispositif de formation de micro-gouttelettes et dispositif d'analyse - Google Patents

Dispositif de formation de micro-gouttelettes et dispositif d'analyse Download PDF

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Publication number
WO2022004094A1
WO2022004094A1 PCT/JP2021/015116 JP2021015116W WO2022004094A1 WO 2022004094 A1 WO2022004094 A1 WO 2022004094A1 JP 2021015116 W JP2021015116 W JP 2021015116W WO 2022004094 A1 WO2022004094 A1 WO 2022004094A1
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Prior art keywords
liquid
vibration
sample
unit
forming apparatus
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PCT/JP2021/015116
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English (en)
Japanese (ja)
Inventor
徹 宮坂
亨 柴田
隆之 神田
智美 疋田
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株式会社日立ハイテク
本多電子株式会社
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Publication of WO2022004094A1 publication Critical patent/WO2022004094A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/08—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor
    • B01J19/10—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor employing sonic or ultrasonic vibrations
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/02—Details
    • H01J49/04—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components

Definitions

  • the present invention relates to a microdroplet forming apparatus and an analyzer.
  • a liquid chromatography mass spectrometer is a typical analyzer that analyzes a liquid sample as droplets.
  • Liquid chromatography mass spectrometry is a chemical analysis method in which various components separated by liquid chromatography are ionized and separated and detected for each mass-to-charge ratio.
  • a liquid sample supplied from liquid chromatography is atomized into fine droplets, charged, and vaporized by heating to generate ions of analytical components.
  • the average particle size of the initial droplets formed by dividing the liquid sample is required to be tens to several ⁇ m. From the viewpoint of the efficiency of ionization (charging and vaporization), it is desirable that the diameter of the liquid to be formed is small, and it is also required that the particle size does not vary.
  • the atmospheric pressure spray method is currently widely used in mass spectrometers as a method for dividing a liquid sample into minute droplets.
  • the atmospheric pressure spray method is a method in which a liquid is introduced into a high-speed jet to divide the liquid into split droplets, but in order to form droplets with an average particle size of several tens to several ⁇ m, the speed of sound is used. It is necessary to use a high-speed jet close to. Therefore, the device becomes large-scale. Further, the droplets formed by the atmospheric pressure spray method have a problem that the particle size tends to be unstable and the particle size distribution is wide.
  • the particle size of the formed droplets and the distribution of the grain system also affect the charging required for ionization and the subsequent vaporization process, thus destabilizing the state of the analytical component ions to be formed.
  • the state of ions greatly affects the measurement accuracy of chemical analysis, which is detected separately for each mass-to-charge ratio. Therefore, there is a need for a method for making a small amount of liquid sample separated by liquid chromatography into fine droplets having an average particle size of 10 ⁇ m to several ⁇ m in a more stable manner.
  • Patent Document 1 a method using ultrasonic waves is known as another method for dividing a liquid sample into minute droplets, and is disclosed in, for example, Patent Document 1 and Patent Document 2.
  • the droplet diameter formed by ultrasonic waves is affected by the vibration frequency of ultrasonic waves. It is known that the relationship between the vibration frequency and the droplet diameter generally follows Lang's equation (J. Acous. Soc. Amer., 1962, 34, 6). According to Lang's formula, the vibration frequency for vibrating water or alcohol to form a droplet having a diameter of about 10 ⁇ m is about 200 to 300 kHz, and the vibration for forming a droplet having a diameter of 1 to 3 ⁇ m is formed. The frequency is known to be several MHz.
  • the vibration of an ultrasonic vibrator has a small amplitude, and it is difficult to directly separate it into liquid and droplets. Therefore, by utilizing the resonance phenomenon of a metal column or a diaphragm structure, vibration having an acceleration capable of expanding the amplitude and dividing the liquid is obtained.
  • the limit vibration frequency is about 200 MHz because the resonance vibration of metal is used.
  • Patent Document 1 discloses a method in which droplets sprayed by an air spray are attached to the surface of an ultrasonic vibrator to form fine droplets.
  • the vibration of the ultrasonic vibrator generally has a small amplitude, and it is difficult to form droplets.
  • the limit vibration frequency is about 200 kHz, and the diameter of the formed droplet is limited to 10 ⁇ m. It is difficult to form droplets of several ⁇ m or less by the disclosed method.
  • a small amount of liquid is supplied to a high-frequency vibrating surface of several hundred kHz or more, the droplets are likely to be scattered at the same time as the supply, and not only the fine droplets can hardly be formed, but also large liquid balls are scattered at the same time.
  • Patent Document 2 is a method of forming droplets by atomizing a liquid sample by vibrating the liquid sample stored in a container with an ultrasonic vibrator.
  • the vibrating liquid itself is used to amplify the applied vibrating force, and a part of the liquid is atomized into fine droplets, that is, atomized.
  • This method is different from the above method using metal resonance, and since it is possible to vibrate the liquid sample at a vibrating frequency of several MHz, it is possible to form droplets having an average particle size of about several ⁇ m. ..
  • an object of the present invention is to provide a microdroplet forming apparatus and an analyzer capable of dividing even a small amount of liquid sample separated by liquid chromatography into microdroplets having an average particle size of several ⁇ m. To do.
  • An ultrasonic vibration generating part that generates ultrasonic vibration
  • an ultrasonic vibration transmission expanding part that transmits the ultrasonic vibration generated in the ultrasonic vibration generating part while expanding it, and an ultrasonic wave expanded by the ultrasonic vibration transmitting expanding part.
  • the sample is provided with a sample vibration vibration unit that vibrates the liquid sample by vibration to form minute droplets of the liquid sample, and a sample supply unit that continuously supplies the liquid sample to the sample vibration vibration unit.
  • a liquid film forming member capable of holding the liquid sample supplied from the sample supply unit in the form of a liquid film is provided on the vibrating vibration surface of the vibration and vibration unit.
  • the analyzer of the present invention is an analyzer provided with the above-mentioned microdroplet forming apparatus of the present invention.
  • FIG. 1 Schematic diagram showing an embodiment of the microdroplet forming apparatus of the present invention
  • the figure which shows the detail of the part A (vibration vibration surface) of FIG. The figure which shows an example of the structure of a sample vibration vibration part.
  • FIG. 1 is a schematic diagram showing an embodiment of the microdroplet forming apparatus of the present invention.
  • the microdroplet forming apparatus 1 has an ultrasonic vibration generating unit 8 that generates ultrasonic vibration and an ultrasonic vibration that is transmitted while expanding the ultrasonic vibration generated by the ultrasonic vibration generating unit 8.
  • Transmission expansion unit 9 and ultrasonic vibration Sample vibration vibration unit 3 and sample vibration vibration unit 3 that vibrate the liquid sample with the ultrasonic vibration expanded by the transmission expansion unit 9 to form minute droplets of the liquid sample.
  • the microdroplet forming apparatus of the present invention forms microdroplets on the supplied liquid sample by utilizing ultrasonic vibration.
  • the "fine droplet” means a droplet having an average particle size of several tens of ⁇ m to several ⁇ m.
  • a piezoelectric element is used as the ultrasonic vibration generator 8.
  • the formed droplet diameter is affected by the vibration frequency, and the relationship between the vibration frequency and the droplet diameter is generally the Lang formula (J. Acous. It is known to follow Soc. Amer., 1962, 34, 6).
  • the relationship between the vibration frequency and the droplet diameter is also affected by the solvent type.
  • the vibration frequency for forming a droplet having a diameter of 10 ⁇ m is about 200 to 300 kHz, and the vibration frequency for forming a droplet having a diameter of 1 to 3 ⁇ m is several MHz.
  • the vibration frequency for forming the droplets for the analyzer needs to be about several hundred kHz to 10 MHz.
  • the configuration as a microdroplet forming apparatus for a liquid chromatography mass spectrometer will be described.
  • the liquid chromatography mass spectrometer samples continuously supplied from liquid chromatography are continuously analyzed by the mass spectrometer. The amount of the sample liquid, which is each sample, varies to some extent depending on the specifications of liquid chromatography.
  • the droplet diameter of the initial droplets formed in the atmosphere from the liquid sample is small, and it is desirable that the average particle size is about several ⁇ m.
  • the liquid volume of each sample liquid is several hundreds to several tens of ⁇ L or less, and the droplet diameter of the initial droplets formed in the atmosphere is several ⁇ m.
  • the vibration frequency of the ultrasonic vibration generator 8 in this embodiment was set to 2.4 MHz.
  • a liquid was used as the ultrasonic vibration expansion transmission unit 9 of this embodiment.
  • a vibration expanding means as a method generally widely used, there is a method of utilizing a resonance phenomenon in a metal columnar member, a diaphragm structure, or the like.
  • the resonance phenomenon of the metal columnar member it is necessary to shorten the length of the columnar structure to be used to resonate as the frequency increases.
  • the limit is about several hundred kHz in a realistic dimensional range.
  • the length of the metal columnar member for resonating at several 100 kHz is as short as 1 cm or less, and it is difficult to use it as a stable resonance member.
  • the diaphragm structure it is practically difficult to realize a resonance structure exceeding several hundred kHz.
  • a structure using a liquid is used to expand and transmit high-frequency vibration of 2.4 MHz.
  • the sample vibrating vibration unit 3 was arranged facing the ultrasonic vibration generating apparatus 8 and the space between them was filled with a liquid.
  • the sample vibration vibration unit 3 was arranged at a distance where the vibration generated by the ultrasonic vibration generator 8 is transmitted through the ultrasonic vibration transmission expansion unit 9 which is a liquid and is focused, that is, at a position where the vibration expands.
  • the ultrasonic vibration generated by the ultrasonic vibration generator 8 can be expanded and transmitted, and the sample vibration vibration unit 3 can be greatly ultrasonically vibrated.
  • a vibration transmission liquid supply pipe 6 and a vibration transmission liquid discharge pipe 7 are provided in a case portion that holds the ultrasonic vibration transmission expansion portion 9 of the liquid.
  • the liquid is sent from the liquid supply unit 41 to the ultrasonic vibration transmission expansion unit 9 through the vibration transmission liquid supply pipe 6, and is discharged from the vibration transmission liquid discharge pipe 7.
  • the piezoelectric element used in the ultrasonic vibration generator 8 used to generate ultrasonic vibration in the present invention generates heat when vibration is generated. If the temperature of the piezoelectric element rises due to the generated heat, there is a risk that the exciting force will decrease or the piezoelectric element will be destroyed. Therefore, in this embodiment, the vibration transmission liquid supply pipe 6 and the vibration transmission liquid discharge pipe 7 are provided in the case portion that holds the ultrasonic vibration expansion transmission unit 9. Then, the vibration expansion transmission liquid is circulated using the vibration transmission liquid supply pipe 6 and the vibration transmission liquid discharge pipe 7 using a liquid pump (not shown), and is cooled by using a heat exchanger (not shown). did. Since the vibration expansion transmission liquid comes into direct contact with the piezoelectric element which is an ultrasonic vibrator, it is possible to prevent the temperature rise of the piezoelectric element by cooling the vibration expansion transmission liquid.
  • the vibration transmission state in the liquid is affected by the viscosity, surface tension and density of the vibration expansion transmission liquid used. Therefore, it is necessary to appropriately design the distance between the ultrasonic vibration generator 8 and the sample vibration vibration unit 3 as described above according to the physical properties of the selected vibration expansion transmission liquid.
  • pure water is used as the vibration expansion transmission liquid from the viewpoint of being used for cooling the piezoelectric element and safety in case of leakage.
  • various liquids other than pure water can also be used as the vibration expansion transmission liquid of the present invention by performing the liquid in consideration of the above and the dimensional design according to the liquid.
  • FIG. 2 is a diagram showing details of the A portion (vibration vibration surface) of FIG.
  • the sample vibration vibration unit 3 of this embodiment has a diaphragm 11 constituting the sample vibration vibration unit 3 and a liquid film forming member 12a, and a flow path layer 13 to which a liquid sample is supplied is provided between the diaphragms 11 and the liquid film forming member 12a.
  • the diaphragm 11 is a diaphragm 11 that comes into contact with the vibration transmission liquid and vibrates by the ultrasonic vibration 10 transmitted in the vibration transmission liquid.
  • the ultrasonic vibration 10 transmitted through the liquid is configured to be focused by a part of the diaphragm 11.
  • the liquid sample 2 supplied through the flow path layer 13 formed between the thin plates is guided to the focal position of the diaphragm 11 and is vibrated and atomized by the vibration of the diaphragm 11.
  • a large number of holes are formed in the upper thin plate 12a at a position facing the focal position of the diaphragm, and droplets of the atomized liquid sample pass through these holes toward the upper part of the figure and are minute liquids. It becomes droplets and is atomized and ejected.
  • the structure of the sample vibration vibration unit 3 described above is a very important structure in the present invention.
  • a part of the liquid becomes minute droplets and atomizes, but most of the liquid scatters. This is a major factor that makes it difficult to use ultrasonic waves for making fine droplets of a liquid sample in an analyzer. Since the liquid sample in the analyzer is very valuable and often in a small amount, it is a big problem in forming fine droplets by ultrasonic waves.
  • the present invention proposes a method capable of forming a liquid film on a vibrating surface that vibrates ultrasonically even with a small amount of liquid. Then, by stably atomizing and atomizing a small amount of liquid sample using ultrasonic vibration, it is possible to provide a new microdroplet forming device that can be supplied to the analyzer and an analyzer having the new microdroplet forming device. I am aiming.
  • the cause of the scattering phenomenon when a small amount of liquid is supplied on the ultrasonic vibration surface is considered as follows.
  • the amount of liquid supplied on the vibrating surface is small, it tends to become a liquid ball due to the surface tension of the sample liquid itself.
  • the liquid that has become a liquid ball scatters due to vibration. It has been experimentally confirmed that alcohol, which has a lower surface tension than water, scatters less. However, even a small amount of alcohol cannot completely prevent scattering.
  • a method of forming a liquid film on the vibrating surface with a small amount of liquid a method of hydrophilically treating the vibrating surface can be considered. According to the experimental results, a certain effect was confirmed, but it was difficult to obtain a sufficient anti-scattering effect only by the hydrophilic treatment. Therefore, in the present invention, we have devised a configuration in which the liquid film forming member is arranged close to the vibrating surface.
  • the thin plate 12a arranged to face the diaphragm 11 of FIG. 2 corresponds to the liquid film forming member of the present invention.
  • the thin plate 12a is provided with a multi-hole portion at a position facing the focal position of the diaphragm shown in FIG. 3, which will be described later. With such a structure, it is possible to stably form a liquid film on the diaphragm even with a small amount of liquid sample supplied on the vibrating surface.
  • the spraying direction of the atomized fine droplets is also stable.
  • the spraying direction coincides with the vibration direction of the diaphragm. In FIGS. 1 and 2, it is ejected upward (in the direction of the arrow in FIG. 2).
  • FIG. 3 is a diagram showing an example of the structure of the vibrating vibration unit.
  • the sample vibration vibration unit 3 of this embodiment is composed of three thin plate materials shown in the figure.
  • the lowermost thin plate is the diaphragm 11
  • the central thin plate is the flow path plate 16
  • the uppermost thin plate is the multi-hole plate 12a.
  • the vibrating and vibrating portion of the present invention is configured by stacking and adhering these three thin plates.
  • a method of adhering three thin plates a method using an adhesive or the like can also be used, but in consideration of the influence of the adhesive and the adhesive strength, in this embodiment, each thin plate is overlapped and a high pressure is applied.
  • the lowermost diaphragm 11 is in contact with the vibration transmission liquid of the ultrasonic vibration expansion transmission unit 9 on the lower side, and is vibrated by the ultrasonic vibration 10 transmitted through the vibration transmission liquid. Since the diaphragm 11 is required to vibrate by the ultrasonic vibration 10 transmitted in the vibration transmission liquid, flexibility and elasticity are required. In this embodiment, the thickness of the SUS of the diaphragm 11 is reduced to 50 ⁇ m to facilitate vibration.
  • the portion of the diaphragm 11 that is vibrated is the portion where the ultrasonic vibration is focused.
  • the position of the vibrating focal point and its diameter are, of course, dependent on the design conditions. In this embodiment, it is designed so as to be within the range of the alternate long and short dash line (diameter several mm) in the figure even when the assembly accuracy is taken into consideration.
  • the diameter of the vibration focal point in this embodiment is about 1 mm. That is, the diaphragm 11 vibrates in a region having a diameter of about 1 mm at any place in the alternate long and short dash line due to the ultrasonic vibration transmitted through the vibration transmission liquid.
  • the central flow path plate 16 is provided with a hole having the shape shown in the figure.
  • the round portions 19 located at both ends are a supply hole and a discharge hole for the liquid sample, and are connected to the sample supply pipe 2 and the sample discharge pipe 5, respectively.
  • the large round portion 17 in the center coincides with the region where the diaphragm 11 may vibrate.
  • the slit portion 18 formed so as to connect the supply hole and the discharge hole of the liquid sample is sandwiched between the diaphragm 11 and the multi-hole plate 12a at the top and bottom, so that the flow path (flow path layer 13 in FIG. 1) is formed. To form.
  • the liquid sample 2 supplied from the supply hole is sent to the large round portion 17 in the center through this flow path, and is made into minute droplets by the vibration of the diaphragm.
  • the excess liquid sample which is not a minute droplet, is configured to be discharged from the discharge hole through the flow path on the opposite side. Since the cross-sectional area of the flow path is determined by the thickness as well as the opening width of the flow path plate, it is necessary to select an appropriate plate thickness. Considering the ease of handling and the cross-sectional area of the flow path, it is generally appropriate to use several tens to several hundreds of ⁇ m. In this example, a plate thickness of 100 ⁇ m was used.
  • the uppermost multi-hole plate 12a has a pair of round holes 15 at both ends and a region 14 having a large number of holes formed in the center.
  • the round holes 15 at both ends are holes for supplying and discharging the liquid sample to the flow path plate 16, and are adhered so as to coincide with the round portions 19 located at both ends of the flow path plate 16.
  • the region 14 having a large number of holes formed in the central portion coincides with the region that may vibrate, which is indicated by the alternate long and short dash line on the diaphragm 1.
  • the liquid sample supplied to the large round portion 17 in the center of the flow path plate 16 is vibrated by the vibration of the diaphragm 11, and the formed minute droplets are discharged through the central hole of the multi-hole plate 12a.
  • the inner surface be treated with hydrophilicity.
  • the outer surface of the multi-hole plate (liquid film forming means) 12a is treated with water repellent as a countermeasure against contamination.
  • the sample vibration vibrating unit 3 By configuring the sample vibration vibrating unit 3 as described above, it is possible to stably form a liquid film on the diaphragm even with a small amount of liquid sample, and it is possible to realize stable formation of fine droplets.
  • FIG. 4 is a diagram showing another example of the structure of the vibrating vibration part.
  • the opening does not necessarily have to be composed of a large number of circular holes 14 (a) as in FIGS. 3 and 4a), and is a slit-shaped opening hole as in FIGS. 4 (b) and 4 (c). Similar effects can be expected with the opening holes 14d having a deformed shape or a combination shape as shown in 14b and c and FIG. 4D.
  • the diameter of the opening hole is set to 150 ⁇ m. According to the experiment, the opening diameter and opening width for preventing the scattering of water and alcohol were 1 mm or less, but it was necessary to make them several hundred ⁇ m or less in consideration of stability.
  • the position of the vibration focus of the diaphragm can be accurately positioned, the area of the portion 17 that widens the flow path 21 near the focus position can be reduced. Needless to say, the smaller the partial area that widens the flow path 21 near the focal position, the smaller the sample solution can be sprayed. If the design is such that the vibration focus can be completely positioned on the flow path 21, even a single slit opening as shown in FIG. 4 (e) or a single spray hole as shown in FIG. 4 (f) can be used. It is also possible to obtain the same effect.
  • FIG. 5 is a diagram showing another embodiment of the structure of the microdroplet forming member, and is the other of the liquid film forming means 12 of the present invention that can be used when all the sample liquid supplied to the vibrating portion is atomized and sprayed. It is a figure explaining the Example of.
  • a small multi-hole plate (liquid film forming member) 12b is provided at the tip of the sample liquid supply pipe 22. This is configured to be placed close to the vibration focal position of the diaphragm 11.
  • the sample liquid supplied from the supply pipe 22 is configured to be supplied to the lower side of the multi-hole plate (liquid film forming member) 12b.
  • the sample liquid supplied to the lower side of the multi-hole plate (liquid film forming means) 12b spreads in the minute gap region between the multi-hole plate (liquid film forming member) 12b and the diaphragm 11 by a capillary phenomenon to form a liquid film. Form. Then, it can be ejected as minute droplets from the opening hole 14 provided in the multi-hole plate (liquid film forming member) 12b by the vibration of the diaphragm 11.
  • the shape of the opening hole 14 in the multi-hole plate (liquid film forming member) 12b in which the liquid film is provided on the diaphragm 11 is in addition to the circular hole (FIG. 4A) as described with reference to FIG. It is also possible to use a slit shape (FIGS. 4 (b) and (c)) and various shapes obtained by deforming or combining them (FIG. 4 (d)). Further, the higher the accuracy of the focal position of the diaphragm, the smaller the area of the liquid film forming member 12 such as the multi-hole plate arranged at the tip of the sample liquid supply pipe 22, and the smaller the amount of sample liquid. It becomes possible to correspond to.
  • the gap between the vibrating plate 11 and the liquid film forming member 12 such as the multi-hole plate is vibrated. It affects the formation state of minute droplets at the time. In particular, if the gap is wide and the liquid film becomes too thick, the efficiency of forming fine droplets drops sharply. Therefore, it is required that the minute gap formed between the liquid film forming member 12 such as the multi-hole plate and the diaphragm 11 is sufficiently narrow and stable, and the gap is constant.
  • the diaphragm 11 and the multi-hole plate 12a for forming a liquid film described with reference to FIGS. 1 to 4 it is easy to keep the gap between them constant because they are integrally molded.
  • a small multi-hole plate (liquid film forming member) 12b is provided at the tip of the sample liquid supply pipe 22, and the diaphragm 11 and the multi-hole plate (liquid film forming member) 12b are provided. It is difficult to make the gap between the two with high accuracy.
  • the multi-hole plate (liquid film forming means) 12b is the diaphragm 11.
  • the structure to be placed is a state in which the multi-hole plate (liquid film forming means) 12b and the diaphragm 11 are in contact with each other under a weak pressure.
  • Such a structure can be easily realized as compared with the case of designing a structure that guarantees the clearance accuracy.
  • the structure for maintaining the gap between the diaphragm 11 and the multi-hole plate (liquid film forming means) 12b with high accuracy Is no longer necessary. If the structure in which the multi-hole plate (liquid film forming means) 12b is placed on the diaphragm 11 with a weak force is used, the sample liquid can be supplied between the multi-hole plate (liquid film forming means) 12b and the diaphragm 11. This makes it possible to form a minute and uniform gap between the multi-hole plate (liquid film forming means) 12b and the diaphragm 11.
  • FIG. 6 is a diagram showing another embodiment of the liquid film forming means of the microdroplet forming member, and is a diagram illustrating another embodiment of the liquid film forming means 12 on the diaphragm 11.
  • a method of arranging a thin plate (liquid film forming member) 12 having holes and slits formed on the diaphragm 11 is disclosed.
  • a rod-shaped member 23 such as (a) fork-shaped, (b) antenna-shaped, or (c) simple rod-shaped as shown in FIG. 6 is used as a sample liquid. Even in a configuration in which the liquid film is attached to the tip of the supply pipe 22 and arranged on the diaphragm, the same effect as that of the liquid film forming means 12 using the thin plate described in the examples up to FIG. 5 can be obtained.
  • This method is a method of forming a liquid film by utilizing the wettability of the rod-shaped member, and the configuration can be made extremely simple. The wettability to the sample liquid is also important in the liquid film forming means on the thin plate shown in FIG.
  • FIG. 7 is a diagram showing an embodiment of an analyzer using the microdroplet forming apparatus of the present invention
  • FIG. 8 is a diagram showing another embodiment of the analyzer using the microdroplet forming apparatus of the present invention.
  • It is a figure explaining one Example of the analyzer using the microdroplet forming apparatus of this invention.
  • the figure is an example for a liquid chromatography mass apparatus in which the microdroplet forming apparatus of the present invention is arranged.
  • the configuration of the embodiment will be described below.
  • the microdroplet forming apparatus 1 of the present invention a droplet charging unit (droplet charging unit 28) that applies a charge to microdroplets to generate microcharged droplets, and drying for drying and ionizing the microcharged droplets. It is provided with an ion source (ion generation unit 33) having a unit and a detection unit (mass spectrometer 32) that introduces ions formed by the ion source and separates and detects each mass-to-charge ratio.
  • ion source ion generation unit 33
  • detection unit mass spectrometer 32
  • the vibration transmission liquid supply pipe 6 for circulating and cooling the liquid which is the ultrasonic vibration expansion transmission unit 9, the vibration transmission liquid discharge pipe 7, and the liquid
  • the sample liquid supplied from the liquid chromatography is squeezed by connecting the sample liquid supply tube 2 supplied from the chromatography and the sample discharge tube 5 to discharge the surplus sample liquid and vibrating the ultrasonic vibration generator 8.
  • a nitrogen supply unit 26 is arranged directly above the spray surface of the microdroplet forming apparatus 1. Nitrogen is supplied to the nitrogen supply unit 26 from the nitrogen supply pipe 24, and the microdroplets 4 sprayed from the microdroplet forming device 1 are sprayed into a pipe filled with nitrogen at a substantially atmospheric pressure. It is configured.
  • the microdroplets 4 generated by the microdroplet forming apparatus 1 of the present invention are conveyed to the upper 34 in the figure by the spray rate and the flow of nitrogen supplied from the nitrogen supply unit 26.
  • the initial spray rate of the minute droplets generated by the minute droplet forming apparatus 1 of the present invention is about several m / s or less to several tens of m / s, and the amount of nitrogen supplied is also the same as the flow velocity and in the pipe. Controls the amount of nitrogen supplied so that it can maintain almost atmospheric pressure.
  • a droplet initial heating unit 27 is connected above the nitrogen supply unit 26.
  • the droplet initial heating unit 27 heats the minute droplets with the heating heater 30 arranged on the wall surface, and vaporizes and removes the solvent of the minute droplets.
  • the inside of the induction tube of the minute droplets is filled with nitrogen in order to prevent combustion from occurring when the minute droplets are heated by a heater or the like. That is, a gas that can prevent combustion, such as an inert gas other than nitrogen, may be used.
  • a droplet charging unit 28 is connected above the droplet initial heating unit 27, and is configured to impart positive ions or electrons generated by the ion generation unit 33 to the sample droplets.
  • the ion generation unit 33 a general corona discharger or the like can be used.
  • a droplet acceleration unit 29 is configured above the droplet charging unit 28.
  • the droplet acceleration unit 29 accelerates the velocity of the sample liquid by gradually reducing the diameter of the pipe.
  • the tube diameter from the nitrogen supply unit 26 to the droplet charging unit 28 via the initial heating unit 27 is set to a diameter of about 25 mm.
  • the tube diameter of about 25 mm in diameter is gradually narrowed by 500 ⁇ m in diameter. That is, the pipe cross-sectional area ratio between the inlet and the outlet of the droplet acceleration unit 29 is 2500: 1.
  • the sample droplets sent at a speed of several m / s to several tens of m / s accelerate to the speed of sound or higher at once.
  • the analyzer connection unit 31 is an elongated thin tube having a diameter of 500 ⁇ m, and by connecting the droplet acceleration unit 29 and the mass spectrometer 32, the pressure gradient of the mass spectrometer 32 having an atmospheric pressure spray pipe and a vacuum pressure inside. Is configured to absorb and hold.
  • a heating heater 30 is also installed in the piping portion of the droplet acceleration unit 29 and the analyzer connection unit 31, and is configured to heat the sample droplets being transported and remove the solvent.
  • the solvent is removed by the droplet acceleration unit 29 and the analyzer connecting unit 31, and the sample components contained in the sample liquid are ionized to the mass analyzer 32. Will be supplied. In the mass spectrometer 32, the supplied sample ions are separated by mass, and the component features contained in the sample are identified.
  • the method of applying a charge to the sample droplets from which the solvent has been largely removed by heating with the droplet initial heating unit 27 is the atmospheric pressure ionization method (APCI) in the current liquid chromatography mass spectrometry method.
  • APCI atmospheric pressure ionization method
  • Atmospheric Pressure Chemical Ionization corresponds to the method.
  • an electrospray ionization (ESI) method is widely known, and it is selected according to the strength of the polarity of the sample to be analyzed. Is common.
  • the microdroplet forming apparatus of the present invention it is possible to charge the droplets by a method corresponding to the electrospray ionization method.
  • a method equivalent to the electrospray ionization method it is necessary to generate an electric field in the region where the sample liquid is separated into the droplets.
  • the conductive SUS316 is used as the material of the diaphragm 11 and the liquid film forming means 12
  • the droplets formed by applying a high voltage of about several kV to 10 kV to the conductive SUS316 are used. It is possible to add a charge to.
  • the amount of charge applied to the formed droplets is proportional to the applied voltage level, and the polarity matches the polarity of the applied voltage. Since the amount of electric charge generated in the droplet forming portion is affected by the strength of the electric field, the position of the electrode serving as the counter electrode is important as well as the voltage applied to the diaphragm 11 and the liquid film forming means 12.
  • the mesh plate of the nitrogen spray port of the nitrogen supply unit 26 is made of metal, and by setting the installation potential, the diaphragm 11 to which a voltage is applied and the counter electrode of the liquid film forming means 12 are used. Made it work.
  • the piezoelectric element is driven with a high voltage as a base voltage.
  • the diaphragm 11 and the liquid film forming means 12 also have a high voltage through the pure water which is the vibration transmitting liquid 9.
  • the portion to which a high voltage is applied is the diaphragm 11 and the liquid film forming means 12. Since it can be limited, it becomes easier to ensure safety.
  • the drive circuit of the piezoelectric element can be made very simple as compared with the method of superimposing the high voltage base power supply of the drive circuit of the piezoelectric element.
  • the microdroplet forming apparatus of the present invention is used for a liquid chromatography mass spectrometer, etc.
  • prevention of contamination is an important item to be considered.
  • measures for preventing contamination in the present invention and examples will be described.
  • the sample liquid to be analyzed by the mass spectrometer is sequentially sent from the liquid chromatography.
  • the liquid amount of each sample liquid is about several hundred ⁇ L to several tens of ⁇ L, and the speed of being sent is about several 100 ⁇ / min.
  • sample liquids are sent one after another within a few seconds to one minute, and the sample liquids are continuously made into fine droplets and sent to the analyzer. During that time, it is very important to prevent contamination between the sample liquids that are continuously sent one after another in order to carry out accurate analysis.
  • FIG. 1 Even one embodiment of the present invention shown in FIG. 1 has a structure in consideration of prevention of some contamination. These will be described below.
  • the surplus sample liquid that could not be made into fine droplets is sent out to the discharge tube side. It was configured. Further, as disclosed in FIGS. 2 and 3, thin plates are overlapped to form a flow path, so that the sample liquid is supplied through an extremely narrow flow path to prevent contamination. However, in the flow path structure shown in FIG. 3, a region 17 in which the flow path is widened is provided from the viewpoint of alignment with the focal position of ultrasonic vibration, but in order to prevent contamination, ultrasonic vibration is provided. It is important to improve the design system of the focal position and minimize the spread of the flow path. Further, it is also important to reduce the cross-sectional area of the flow path by reducing the thickness of the flow path plate 16 in FIG. 3b) in order to prevent contamination.
  • a method of sandwiching a known gas or liquid as a buffer between the sent samples may be used.
  • sandwiching a known gas or liquid as a buffer it becomes easy to prevent contamination between liquids as known in pipes and atomized parts, and dimensional restrictions on the flow path and the like are relaxed.
  • this method has problems that the efficiency of analysis is lowered by the amount of the gas or liquid used as the buffer region, and the gas or liquid used as the buffer liquid is consumed.
  • a method of providing a cleaning process for piping and spray areas This is a method of incorporating a sequence for cleaning the supply pipe, the vibrating part, etc. for each predetermined number of analyzes and analysis time. If the cleaning sequence is performed when the device is started or stopped, the analysis efficiency can be suppressed. If necessary, a method of operating the washing sequence is also conceivable.
  • a simple method is to add a known cleaning liquid instead of the sample liquid to be analyzed and apply ultrasonic vibration.
  • Ultrasonic vibration can be expected to be effective in cleaning pipes and the like.
  • the tip of the supply pipe 22 shown in FIGS. 5 and 6 is compared by laminating the thin plates shown in FIG. 3 and comparing the composition ratio in which the diaphragm 11, the flow path plate 16 and the multi-hole plate 12 are integrated.
  • the structure in which the multi-hole plate 12b for forming the liquid film and the rod-shaped member 23 are arranged is a simple structure and easy to disassemble and clean. Of course, it is also effective as a pollution control measure to periodically replace each supply pipe 22 having a liquid film formation at the tip.
  • the sample vibration vibration unit 3 of the integrated structure of the diaphragm 11, the flow path plate 16 and the multi-hole plate 12 also has a structure that is easy to replace. Further, a method of defining and operating the replacement cycle of parts that are prone to contamination or clogging is also effective as a contamination prevention measure in the microliquid machine forming means of the present invention.
  • the heater 30 is arranged in each part in the pipe path, and the pipe wall surface is covered. Due to the high temperature, the attached sample components are decomposed by heat.
  • the contamination in the transport / processing path of the sample droplet between the microdroplet forming apparatus and the analyzer is described. Careed so that it would hardly be a problem.
  • FIG. 8 is an example of an arrangement configuration up to the mass spectrometer when the microdroplet forming apparatus 1 of the present invention is arranged upside down and the microdroplets are sprayed downward.
  • the microdroplet formation method using high-speed air spray which is widely used in liquid chromatography mass analyzers, produces microdroplets by applying a very high-speed air flow to the supplied sample droplets.
  • the flying speed of the generated droplets is very fast, and some of them reach the speed of sound.
  • the flying speed of the fine droplets ejected by the fine droplet forming means of the present invention is very slow, ranging from several m / s or less to several tens of m / s. Therefore, it is possible to control the flight direction of the formed droplets by using a gentle air flow.
  • the microdroplets sprayed from the microdroplet forming apparatus of the present invention are configured to give a nitrogen flow from the side surface. Since the sprayed minute droplets are very light, it is possible to sufficiently control the flight direction by using an air flow of about several m / s to several tens of m / s. As in FIG. 7, the minute droplet whose flight direction is changed in the horizontal direction passes through the droplet initial heating unit 27, the droplet charging unit 28, the droplet acceleration unit 29, and the analyzer connection unit 31, and is a mass analyzer. Guided to 32.
  • the microdroplet forming means of the present invention when the microdroplet forming means of the present invention is arranged upside down, even if a large scattered droplet or the like is generated at the time of atomization, it falls on the mist surface of the microdroplet forming apparatus 1. There is no. Further, even if the cleaning liquid is ejected from the multi-hole plate of the microdroplet forming device for cleaning or the like, the nitrogen flow can be stopped so that the cleaning liquid can be discharged in the direction of gravity.
  • the water distribution pipe 35 is directed directly below the ejection direction of the microdroplet forming apparatus, and is configured to be able to collect large droplets and cleaning liquid falling from the microdroplet forming apparatus of the present invention. With such a configuration, the risk of contamination in the fine droplet forming portion of the present invention can be further reduced, and the cleaning process can be facilitated.
  • the microdroplets can be sprayed in any direction, and the sprayed droplets can be freely controlled by a relatively gentle air flow. Therefore, it is possible to correspond to various device configurations connected to the analyzer.
  • the microdroplet forming apparatus of the present invention it is possible to stably convert a small amount of sample liquid into microdroplets of several ⁇ m with a simple structure. rice field. Further, since it is possible to apply a charge to the formed minute droplets, it can also be used as an ion source for a chromatographic mass spectrometer. Further, the microdroplet forming apparatus of the present invention can spray the microdroplets in various directions and can easily control the transport direction by using the air flow, so that the liquid sample is made into microdroplets. It can also be applied to various analyzers that require.
  • the present invention is not limited to the above-described embodiment, and includes various modifications.
  • the above-described embodiment describes the present invention in an easy-to-understand manner, and is not necessarily limited to the one having all the configurations described. Further, it is possible to replace a part of the configuration of one embodiment with the configuration of another embodiment, and it is also possible to add the configuration of another embodiment to the configuration of one embodiment. It is also possible to add / delete / replace a part of the configuration of each embodiment with another configuration.
  • liquid film forming means 22 ... sample liquid supply pipe, 23 ... rod-shaped member (liquid film forming means), 24 ... (nitrogen) airflow inlet, 25 ... to analyzer Sample ion to be introduced, 26 ... Nitrogen supply unit, 27 ... Droplet initial heating unit, 28 ... Droplet charging unit, 29 ... Droplet acceleration unit, 30 ... Heating heater, 31 ... Analyzer connection unit, 32 ... Mass analysis Equipment, 33 ... ion generation unit, 34 ... transport direction of atomized droplets, 35 ... water distribution pipe.

Abstract

L'invention concerne un dispositif de formation de micro-gouttelettes capable de diviser même de petits échantillons liquides, qui ont été séparés par chromatographie liquide, en micro-gouttelettes ayant un diamètre moyen de particule de plusieurs µm, et un dispositif d'analyse.　Un dispositif à micro-gouttelettes selon la présente invention est caractérisé en ce qu'il comprend : une unité de génération de vibrations ultrasonores (8) qui génère des vibrations ultrasonores ; une unité de propagation et d'expansion de vibrations ultrasonores (9) qui se dilate et propage les vibrations ultrasonores générées par l'unité de génération de vibrations ultrasonores ; une unité de vibration d'excitation d'échantillon (3) qui imprime des vibrations sur un échantillon liquide en utilisant les vibrations ultrasonores qui ont été étendues par l'unité de propagation et d'expansion de vibrations ultrasonores, et forme des micro-gouttelettes de l'échantillon liquide ; et une unité d'alimentation d'échantillon (40) qui fournit en continu l'échantillon liquide à l'unité de vibration d'excitation d'échantillon, un élément de formation de film liquide étant disposé sur une surface de vibration d'excitation (A) de l'unité de vibration d'excitation d'échantillon de manière à pouvoir maintenir l'échantillon liquide, fourni par l'unité d'alimentation d'échantillon, sous forme de film liquide.
PCT/JP2021/015116 2020-06-30 2021-04-12 Dispositif de formation de micro-gouttelettes et dispositif d'analyse WO2022004094A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024038241A1 (fr) * 2022-08-19 2024-02-22 Vibrat-Ion Ltd Système d'aérosolisation et procédés d'utilisation associés
WO2024047723A1 (fr) * 2022-08-30 2024-03-07 株式会社日立ハイテク Source d'ions et dispositif d'analyse correspondant

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003071343A (ja) * 2001-08-31 2003-03-11 Olympus Optical Co Ltd 噴霧ヘッド
JP2004501482A (ja) * 2000-04-18 2004-01-15 ウォーターズ・インヴェストメンツ・リミテッド 改良されたエレクトロスプレー及び他のｌｃ／ｍｓインターフェース
JP2004179079A (ja) * 2002-11-28 2004-06-24 National Institute Of Advanced Industrial & Technology 試料霧化導入装置

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004501482A (ja) * 2000-04-18 2004-01-15 ウォーターズ・インヴェストメンツ・リミテッド 改良されたエレクトロスプレー及び他のｌｃ／ｍｓインターフェース
JP2003071343A (ja) * 2001-08-31 2003-03-11 Olympus Optical Co Ltd 噴霧ヘッド
JP2004179079A (ja) * 2002-11-28 2004-06-24 National Institute Of Advanced Industrial & Technology 試料霧化導入装置

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024038241A1 (fr) * 2022-08-19 2024-02-22 Vibrat-Ion Ltd Système d'aérosolisation et procédés d'utilisation associés
WO2024047723A1 (fr) * 2022-08-30 2024-03-07 株式会社日立ハイテク Source d'ions et dispositif d'analyse correspondant

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