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WO2020184474A1 - Dispositif d'analyse - Google Patents

Dispositif d'analyse Download PDF

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Publication number
WO2020184474A1
WO2020184474A1 PCT/JP2020/009829 JP2020009829W WO2020184474A1 WO 2020184474 A1 WO2020184474 A1 WO 2020184474A1 JP 2020009829 W JP2020009829 W JP 2020009829W WO 2020184474 A1 WO2020184474 A1 WO 2020184474A1
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WIPO (PCT)
Prior art keywords
light
optical resonator
light source
frequency
gas
Prior art date
Application number
PCT/JP2020/009829
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English (en)
Japanese (ja)
Inventor
吉田　賢二
真一 二宮
英生 富田
哲夫 井口
西澤　典彦
フォルカ ゾンネンシャイン
稜平 寺林
直浩 神谷
Original Assignee
積水メディカル株式会社
国立大学法人東海国立大学機構
株式会社島津製作所
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Application filed by 積水メディカル株式会社, 国立大学法人東海国立大学機構, 株式会社島津製作所 filed Critical 積水メディカル株式会社
Priority to JP2021505046A priority Critical patent/JPWO2020184474A1/ja
Publication of WO2020184474A1 publication Critical patent/WO2020184474A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
    • G01N21/3504—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light for analysing gases, e.g. multi-gas analysis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/39—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using tunable lasers
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01S—DEVICES USING THE PROCESS OF LIGHT AMPLIFICATION BY STIMULATED EMISSION OF RADIATION [LASER] TO AMPLIFY OR GENERATE LIGHT; DEVICES USING STIMULATED EMISSION OF ELECTROMAGNETIC RADIATION IN WAVE RANGES OTHER THAN OPTICAL
    • H01S3/00—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01S—DEVICES USING THE PROCESS OF LIGHT AMPLIFICATION BY STIMULATED EMISSION OF RADIATION [LASER] TO AMPLIFY OR GENERATE LIGHT; DEVICES USING STIMULATED EMISSION OF ELECTROMAGNETIC RADIATION IN WAVE RANGES OTHER THAN OPTICAL
    • H01S3/00—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range
    • H01S3/10—Controlling the intensity, frequency, phase, polarisation or direction of the emitted radiation, e.g. switching, gating, modulating or demodulating
    • H01S3/13—Stabilisation of laser output parameters, e.g. frequency or amplitude

Definitions

  • the present invention relates to an analyzer.
  • radiocarbon isotope 14C as a labeling compound to a living body and analyze it in order to evaluate the pharmacokinetics of pharmaceuticals.
  • Phase I and Phase IIa It has been analyzed.
  • a very small amount of radiocarbon isotope 14 C (hereinafter, “ 14 C")
  • 14 C Administering and analyzing the drug (also called) to the human body is expected to significantly shorten the development lead time in the drug discovery process because it provides insight into the efficacy and toxicity of drugs caused by pharmacological problems. ing.
  • FIG. 1 is a conceptual diagram of a carbon isotope analyzer according to an embodiment.
  • FIG. 2 is a conceptual diagram of the carbon isotope analyzer according to the embodiment.
  • 3A and 3B are a histogram of the beat RF spectrum and the beat line width measured when passive feedback is used.
  • FIG. 4 is a diagram showing the intensity of the return light from the optical resonator and the error signal obtained by stabilization by passive feedback.
  • FIG. 5 is a diagram showing the intensity of the return light from the resonator and the error signal when stabilization by passive feedback is not used.
  • FIG. 6 is a diagram showing the time change of the light intensity transmitted through the optical resonator.
  • FIG. 7 is a diagram showing the frequency drift of the quantum cascade laser.
  • FIG. 8 is a diagram showing a 4.5 ⁇ m band absorption spectrum of 14 CO 2 and a competing gas.
  • 9A and 9B are diagrams showing the principle of high-speed scanning cavity ring-down absorption spectroscopy using laser light.
  • FIG. 10 is a diagram showing the temperature dependence of the absorption amounts ⁇ of 13 CO 2 and 14 CO 2 in CRDS.
  • FIG. 11 is a conceptual diagram of a modified example of the optical resonator.
  • FIG. 12 is a diagram showing the relationship between the absorption wavelength and the absorption intensity of the analysis sample.
  • 13 (a) and 13 (b) are diagrams showing the time change of the ringdown rate and the pressure inside the cell due to the difference in the automatic valve opening / closing operation method when the sample gas is introduced into the gas cell.
  • the light source is preferably a quantum cascade laser.
  • the gas to be analyzed is preferably a carbon dioxide isotope containing the radioactive carbon isotope 14 C. That is, the gas to be analyzed is preferably a gas containing the radioactive carbon dioxide isotope 14 CO 2 .
  • the light having the absorption wavelength of the carbon dioxide isotope is preferably light in the 4.5 ⁇ m band.
  • FIG. 1 is a conceptual diagram of a carbon isotope analyzer according to an embodiment.
  • the carbon isotope analyzer 1 includes a light generator 20, a carbon dioxide isotope generator 40, a spectroscopic device 10, and an arithmetic unit 30.
  • the radioactive isotope 14 C which is a carbon isotope
  • the light having an absorption wavelength of the carbon dioxide isotope 14 CO 2 produced from the radioisotope 14 C is light in the 4.5 ⁇ m band.
  • biological sample refers to blood, plasma, serum, urine, feces, bile, saliva, other body fluids and secretions, exhaled gas, oral gas, skin gas, other biological gas, and even the liver. It means any sample that can be collected from a living body, such as various organs such as heart, liver, kidney, brain, and skin, and their crushed substances.
  • origin of the biological sample includes all organisms including animals, plants and microorganisms, preferably mammals, and more preferably humans. Mammals include, but are not limited to, humans, monkeys, mice, rats, guinea pigs, rabbits, sheep, goats, horses, cows, pigs, dogs, cats and the like.
  • the light generator 20 uses a light source 23, a waveguide 21 that guides light emitted from the light source 23, a branching means (beam splitter) 27 provided on the waveguide 21, and a luminous flux branched by the branching means 27.
  • a passive feedback unit 25 for receiving is provided.
  • the passive feedback unit 25 reflects the light from the condenser lens 25 and transmits the light to the light source 23 via the condenser lens 25 and the branch means 27, and the condenser lens 25b that collects the light corresponding to the branch means 27. It has a mirror 25a to be sent back. Since the passive feedback unit 25 reduces the dependence of the rear reflection on the angle adjustment, it is possible to easily re-enter the QCL described later.
  • a quantum cascade laser (Quantum Cascade Laser: QCL) capable of emitting light having a wavelength in the mid-infrared region can be used.
  • QCL Quantum Cascade Laser
  • the waveguide 21 it is preferable to use an optical fiber capable of transmitting the generated high-intensity ultrashort pulsed light without deteriorating the characteristics.
  • the material a fiber made of molten quartz can be used.
  • the light generator 20 further includes an optical separator 29, a polarizer 22, a ⁇ / 4 wave plate, a detector 24, a mixer 26a, a low bus filter 26b, and a PID (Proportional-Integral-Differential).
  • a PDH lock unit including a control servo 28 is provided.
  • EOM electro-optical phase modulator
  • a photodiode can be used as the detector 24.
  • the PID control servo 28 is an example of a feedback control unit.
  • an isolator between the optical separator 29 and the light source 23 to prevent the return light from the resonator.
  • a laser current controller that corrects the frequency by modulating the current.
  • the light that has passed through the low bus filter 26b is output by the PID control servo 28 as two PID control voltages, a higher frequency component and a lower frequency component.
  • a higher frequency component laser current (PID fast )
  • PID slow mirror distance
  • the light is phase-modulated and the reflected light intensity is demodulated at that modulation frequency to obtain signals with different codes before and after the resonance frequency, which is fed back as an error signal to resonate the light frequency. It can be locked to the resonance frequency of the vessel.
  • the frequency of light can be stabilized and the line width of light can be narrowed.
  • the electro-optical phase modulator EOM modulates the phase frequency of the laser with a line width of several tens to several hundreds of kHz of the resonator.
  • the modulated laser passes through the polarizing plate and the ⁇ / 4 wave plate, and is incident on the optical resonator to be stabilized. Since the return light from the optical resonator passes through the ⁇ / 4 wave plate twice and rotates 90 degrees with the incident light, it can be taken out by a polarizing plate and detected by a photodetector.
  • the output of the photodetector and the EOM modulation frequency signal are mixed by a mixer and passed through a low-pass filter to obtain an error signal.
  • the output for PID control of the laser current based on the high frequency component of this error signal (PID fast ) and the output for PID control of the mirror distance of passive feedback based on the low frequency component (PID slow ) are servoed. generate. It can be stabilized by feeding back the PID fast and PID slow to the piezo element that changes the mirror distance between the laser current and the passive feedback, and matching the laser frequency to the resonance frequency of the optical resonator. The obtained results are shown in FIGS. 3 to 7.
  • the carbon dioxide isotope generator 40 As the carbon dioxide isotope generating device 40, various devices can be used without particular limitation as long as the carbon isotope can be converted into the carbon dioxide isotope.
  • the carbon dioxide isotope generator 40 preferably has a function of oxidizing the sample and converting carbon contained in the sample into carbon dioxide.
  • carbon dioxide such as a total organic carbon (hereinafter referred to as "TOC") generator, a sample gas generator for gas chromatography, a sample gas generator for combustion ion chromatography, and an elemental analyzer (EA).
  • a carbon generator (G) 41 can be used.
  • these CO and N 2 O each have an absorption spectrum in the 4.5 ⁇ m band, and therefore compete with the absorption spectrum in the 4.5 ⁇ m band of 14 CO 2 . Therefore, it is preferable to remove CO and N 2 O in order to improve the analysis sensitivity.
  • Examples of the method for removing CO and N 2 O include a method for collecting and separating 14 CO 2 as follows. Further, the oxidation catalyst or platinum catalyst, CO, a method of removing and reducing the N 2 O, and the combined use of the collection and separation methods used.
  • FIG. 9A and 9B are diagrams showing the principle of cavity ring-down spectroscopy (hereinafter, also referred to as “CRDS”) using a laser beam.
  • CRDS cavity ring-down spectroscopy
  • FIG. 9A when the piezo element 13 is operated and the mirror spacing satisfies the resonance condition, a high-intensity signal is transmitted from the optical resonator.
  • the incident light when the incident light is blocked, the light accumulated in the optical resonator decreases exponentially with time.
  • an exponential attenuation signal [Ringdown signal] as shown in FIG. 9A can be observed.
  • Another method of observing the ringdown signal is to quickly block the input laser beam with an optical switch.
  • the transmitted time-dependent ringdown signal has a curve as shown by the dotted line in FIG. 9A.
  • the optical resonator is filled with an absorbent substance, as shown by the solid line in FIG. 9A, the laser beam is absorbed each time it reciprocates in the optical resonator, so that the light attenuation time is shortened. Since the decay time of this light depends on the concentration of the light-absorbing substance in the optical cavity and the wavelength of the incident laser light, the absolute concentration of the absorbing substance can be calculated by applying Beer-Lambert's law. Further, the concentration of the absorbent substance in the optical cavity can be measured by measuring the amount of change in the attenuation rate (ring down rate) which is proportional to the concentration of the absorbent substance in the optical cavity.
  • the transmitted light leaked from the optical resonator is detected by a photodetector, the 14 CO 2 concentration is calculated using an arithmetic unit, and then the 14 C concentration can be calculated from the 14 CO 2 concentration.
  • the intervals between the mirrors 12a and 12b of the optical resonator 11, the radius of curvature of the mirrors 12a and 12b, the length and width in the longitudinal direction of the main body, and the like are preferably changed according to the absorption wavelength of the carbon dioxide isotope to be analyzed.
  • the assumed optical resonator length is 1 mm to 10 m. In the case of carbon dioxide isotope 14 C, a long optical cavity length is effective in securing the optical path length, but as the optical resonator length increases, the volume of the gas cell increases and the required sample amount increases.
  • the optical resonator length is preferably between 10 cm and 60 cm. Further, the radius of curvature of the mirrors 12a and 12b is preferably the same as or longer than the optical resonator length.
  • the mirror spacing can be adjusted on the order of several micrometers to several tens of micrometers as an example. Fine adjustment by the piezo element 13 can also be performed in order to create the optimum resonance condition.
  • a pair of mirrors 12a and 12b a pair of concave mirrors has been illustrated and described, but if a sufficient optical path can be obtained, a combination of a concave mirror and a plane mirror or a combination of plane mirrors can be used. It doesn't matter if there is.
  • the cell 16 filled with the gas to be analyzed preferably has a smaller volume. This is because the resonance effect of light can be effectively obtained even with a small number of analytical samples.
  • the capacity of the cell 16 can be exemplified by 8 mL to 1000 mL.
  • the cell volume can be appropriately selected depending on the amount of 14 C source that can be used for measurement, for example, and 80 mL to 120 mL of cells are suitable for 14 C sources that can be obtained in large quantities such as urine, such as blood and For 14 C sources with limited availability, such as tears, 8 mL-12 mL cells are suitable.
  • FIG. 10 is a diagram showing the temperature dependence of ⁇ due to the absorption of 13 CO 2 and 14 CO 2 obtained by calculation. From FIG. 10, 14 C / Total C 10 -10, 10 -11, in 10 -12, for a equal to or absorption by 13 CO 2 at room temperature 300K exceeds the absorption of 14 CO 2, the cooling I found that I needed to do it. On the other hand, it can be seen that if the variation ⁇ 0 to 10 1 s -1 of the ringdown rate, which is a noise component derived from the optical resonator, can be realized, the measurement of 14 C / Total C ratio to 10-11 can be realized. From this, it became clear that cooling of about -40 degrees Celsius is required as the temperature at the time of analysis. For example, when the 14 C / Total C and 10-11 as the lower limit of quantification, increase of CO 2 gas partial pressure by concentration of CO 2 gas (e.g. 20%), suggesting that it is necessary and the temperature ..
  • FIG. 13 shows a conceptual diagram (partially cutaway diagram) of a specific embodiment of the optical resonator.
  • the optical resonator 51 is arranged at both ends of a cylindrical heat insulating chamber 58 as a vacuum device, a measuring gas cell 56 arranged in the heat insulating chamber 58, and a measuring gas cell 56. Cools the pair of high-reflectivity mirrors 52, the mirror drive mechanism 55 arranged at one end of the measurement gas cell 56, the ring piezo actuator 53 arranged at the other end of the measurement gas cell 56, and the measurement gas cell 56.
  • a Peltier element 59 is provided, and a water-cooled heat sink 54 having a cooling pipe 54a connected to a circulation cooler (not shown). The water-cooled heat sink 54 can dissipate heat generated from the Peltier element 59.
  • Figure 12 (quoted from Applied Physics Vol.24, pp.381-386, 1981) shows the absorption wavelengths of analytical samples 12 C 16 O 2 , 13 C 18 O 2 , 13 C 16 O 2 , and 14 C 16 O 2. The relationship of absorption strength is shown.
  • carbon dioxide containing each carbon isotope has a unique absorption line. In actual absorption, each absorption line has a finite width due to the spread due to the pressure and temperature of the sample. Therefore, it is preferable that the pressure of the sample is atmospheric pressure or less and the temperature is 273K (0 ° C.) or less.
  • the specific set temperature in the optical resonator 11 is preferably 273 K (0 ° C.) or less.
  • the lower limit is not particularly limited, but from the viewpoint of cooling effect and economy, it is preferable to cool to 173K to 253K (-100 ° C to -20 ° C), particularly to about 233K (-40 ° C).
  • a cooling device for cooling the optical resonator 11 may be provided in the spectroscopic device 10. Since the light absorption of 14 CO 2 is temperature-dependent, by lowering the set temperature in the optical resonator 11 with a cooling device, the absorption line of 14 CO 2 and the absorption line of 13 CO 2 and 12 CO 2 can be separated. This is because it becomes easier to distinguish and the absorption intensity of 14 CO 2 becomes stronger.
  • the cooling device for cooling the optical resonator 11 include a Peltier element. In addition to the Peltier element, for example, a liquid nitrogen tank, a dry ice tank, or the like can be used. From the viewpoint of miniaturizing the spectroscopic device 11, it is preferable to use a Peltier element, and from the viewpoint of reducing the manufacturing cost of the device, it is preferable to use a liquid nitrogen water tank or a dry ice tank.
  • the dehumidifying condition is preferably a gas condition (moisture content) that does not cause dew condensation or freezing under the temperature condition when the CRDS analysis cell is cooled to ⁇ 40 ° C. or lower (233 K or lower).
  • Dehumidification may be performed by a cooling means such as a Peltier element, but dehumidification may also be performed by a membrane separation method using a polymer film for removing water vapor such as a fluorine-based ion exchange resin film.
  • a hygroscopic agent or a gas dryer may be arranged in the carbon dioxide generation unit (sample introduction unit).
  • the hygroscopic agent for example, CaH 2 , CaSO 4, Mg (ClO 4 ) 2 , molecular sieve, H 2 SO 4 , Sicacide, phosphorus pentoxide, Sicapent (registered trademark) or silica gel should be used. Can be done. Of these, phosphorus pentoxide, sikapent (registered trademark), CaH 2 , Mg (ClO 4 ) 2 or molecular sieves are preferable, and sikapent (registered trademark) is more preferable.
  • a Nafion (registered trademark) dryer manufactured by Perma Pure Inc. is preferable.
  • the hygroscopic agent and the gas dryer may be used alone or in combination.
  • the above-mentioned "gas condition (moisture content) that does not condense or freeze under the temperature condition" was confirmed by measuring the dew point.
  • the dehumidification can be performed so that the dew point is ⁇ 40 ° C. or lower (233K or lower).
  • the dew point display may be an instantaneous dew point or an average dew point per unit time. The dew point can be measured using a commercially available dew point sensor.
  • the Zentor dew point sensor HTF Al2O3 (registered trademark) (manufactured by Mitsubishi Chemical Analytech), Vaisala DRYCAP (registered trademark) DM70 handy type dew point meter ( (Made by Vaisala) can be used.
  • ⁇ Carbon dioxide isotope introduction emission control device As a method of introducing the carbon dioxide isotope generated by the carbon dioxide isotope generation device 40 of FIG. 1 into the spectroscopic device 10, there are a flow through method (Flow through) and a stopped flow method (Stopped flow).
  • the flow-through method does not require a complicated introduction mechanism, so sample analysis can be performed relatively easily, but it is not suitable for high-sensitivity measurement.
  • the stopped flow method enables high-sensitivity measurement, but has a drawback that introduction control is required and sample loss is likely to occur. Therefore, the present inventors have studied the problem of introduction control in the stopped flow method capable of high-sensitivity measurement. As a result, the above-mentioned problems have been solved by optimizing the design of the automatic valve opening / closing system and the gas filling method.
  • the carbon dioxide isotope introduction / discharge device 60 as shown in FIG. 1 can be used.
  • the carbon dioxide isotope introduction / emission control device 60 of FIG. 1 is provided on the introduction pipe 61a connecting the carbon dioxide isotope generation device 40 and the optical resonator 11 and on the upstream side (carbon dioxide isotope generation device 40 side) of the introduction pipe 61a.
  • the introduction valve 63b arranged on the downstream side (optical resonator 11 side) of the introduction pipe 61a, the discharge pipe 61b connecting the optical resonator 11 and the pump 65, and the discharge pipe 61b. It is provided with a discharge valve 63c provided.
  • the three-port valve 63a is closed to make the pressure in the carbon dioxide generator higher than the atmospheric pressure. Further, the introduction valve 63b and the discharge valve 63c are opened to make the pressure in the cell lower than the atmospheric pressure. Specifically, it is set to 30 Torr or less, more preferably 10 Torr or less.
  • the carbon dioxide generator used as a sample introduction system needs to keep flowing the carrier gas at a constant flow rate. In this case, by closing the three-port valve 63a and opening it to the atmosphere, it is possible to prevent the carrier gas from the carbon dioxide generator before the CO 2 gas is released from being introduced into the gas cell. Further, by opening the introduction valve 63b and the discharge valve 63c, the gas from the three port valve 63a to the inside of the gas cell is discharged, so that the pressure in the gas cell can be reduced.
  • the column temperature is heated to the threshold temperature or higher.
  • the threshold temperature is 80 ° C. to 200 ° C., preferably 90 ° C. to 120 ° C., and more preferably 90 ° C. to 110 ° C. Since the column temperature CO 2 gas exceeds a certain temperature is emitted in pulses, by any timing CO 2 gas to grasp whether released, CO 2 gas discharged in pulses within the gas cell You can see the time to reach it.
  • the present inventors have found that the CO 2 gas reaches the gas cell several seconds after the column temperature exceeds a predetermined temperature (threshold temperature). Specifically, it was found that when the threshold temperature is 100 ° C., the CO 2 gas reaches the gas cell after 20 to 30 seconds, preferably 25 to 27 seconds.
  • the three-port valve 63a is opened, the introduction valve 63b is closed, and the gas (carbon dioxide isotope) is introduced into the gas cell.
  • the introduction time varies depending on the size of the gas cell and the like, but is preferably less than 1 second.
  • the valve 63c is closed.
  • the third step With the introduction valve 63b closed, the three-port valve 63a is closed, the pressure in the carbon dioxide generator is made higher than the atmospheric pressure, and the pressure in the gas cell is lowered.
  • the gas pressure rises from 0 Torr to 60 Torr in 1 second until the three-port valve 63a is opened to introduce the gas from the carbon dioxide generator into the gas cell and then the introduction valve is closed. If nothing is done, the gas cell pressure is too high and it is not suitable for measuring the absorption line. Therefore, the pressure in the gas cell is reduced in the fourth step.
  • the discharge valve 63c is opened (for about 1 second) until the pressure in the gas cell reaches about 10 to 40 Torr, and then the discharge valve 63c is closed.
  • the pressure in the gas cell is preferably 18-22 Torr.
  • the discharge valve 63c is opened with the introduction valve 63b closed, the pressure in the gas cell gradually decreases because the gas in the gas cell is discharged. After the pressure in the gas cell drops to about 20 Torr, the discharge valve 63c is closed.
  • FIG. 13A and FIG. 13B show the relationship between the ringdown rate and the gas cell pressure change in the optical resonator when the carbon dioxide isotope introduction / emission control device of the present invention is used.
  • the three port valve 63a, the introduction valve 63b, and the discharge valve 63c are opened, and the carrier gas from the carbon dioxide generator before the CO 2 gas is released is introduced into the gas cell.
  • the pressure inside the cell after the introduction of CO 2 gas is as high as about 60 Torr, which is not suitable for measuring absorption lines.
  • carrier gas exists in the cell when the CO 2 gas reaches the gas cell, when the CO 2 gas is confined in the gas cell, it is diluted with the carrier gas, the CO 2 gas concentration in the cell decreases, and the CO 2 gas
  • the ring-down signal which is proportional to the amount of carbon dioxide absorbed, becomes smaller.
  • the valve is appropriately opened and closed by using the carbon dioxide isotope introduction / emission control device of the present invention, the cell after the introduction of CO 2 gas is used.
  • the pressure inside is about 20 Torr, which is suitable for measuring the absorption line, and since dilution with the carrier gas hardly occurs, the CO 2 gas concentration in the cell does not decrease, and the ring-down signal does not decrease.
  • the wavelength of the laser was constantly swept, and the absorption line spectrum of CO 2 was acquired approximately once every 5 seconds.
  • the arithmetic unit 30 of FIG. 1 is particularly limited as long as it can measure the concentration of the absorbent substance in the optical resonator from the above-mentioned decay time and ring down rate and can measure the carbon isotope concentration from the concentration of the absorbent substance.
  • the arithmetic control unit 31 may be configured by arithmetic means or the like used in a normal computer system such as a CPU.
  • Examples of the input device 32 include a pointing device such as a keyboard and a mouse.
  • Examples of the display device 33 include an image display device such as a liquid crystal display and a monitor.
  • Examples of the output device 34 include a printer and the like.
  • As the storage device 35 a storage device such as a ROM, RAM, or magnetic disk can be used.
  • the detection sensitivity for the radiocarbon isotope 14 C in the sample is assumed to be about "0.1 dpm / ml".
  • the carbon isotope analyzer 1 has an advantageous effect that it can measure a sample containing a low concentration of radioactive carbon isotopes.
  • the detection sensitivity of the radiocarbon isotope 14C in the sample of the carbon isotope analyzer 1 is about "0.1 dpm / ml", more preferably "0.1 dpm / ml" or less.
  • the carbon isotope analyzer has been described above with reference to embodiments, the carbon isotope analyzer is not limited to the apparatus according to the above-described embodiment, and various modifications can be made. A modified example of the carbon isotope analyzer will be described below, focusing on the changes.
  • the spectroscopic device may further include vibration absorbing means. This is because it is possible to prevent the mirror spacing from shifting due to vibration from the outside of the spectroscope and improve the measurement accuracy.
  • vibration absorbing means for example, a shock absorber (polymer gel) or a seismic isolation device can be used.
  • a seismic isolation device a device capable of applying vibration of the opposite phase of the external vibration to the spectroscopic device can be used.
  • the mirror spacing is adjusted by the piezo element 13 in the spectroscopic device 10 as the ring-down signal acquisition means.
  • the optical resonator in the light generator 20 is used.
  • a light blocking device for blocking light to 11 may be provided to control on / off of the irradiation light applied to the optical resonator.
  • various devices can be used without particular limitation as long as they can quickly block light having an absorption wavelength of carbon dioxide isotope, and for example, an optical switch can be used. It is necessary to block the light sufficiently faster than the decay time of the light in the optical resonator.
  • Radioisotope 14C will be described as an example for analysis.
  • the biological carbon source is removed by performing deproteinization as a pretreatment of the biological sample.
  • the protein removal method include a protein removal method in which a protein is insolubilized with an acid or an organic solvent, a protein removal method by ultrafiltration or dialysis utilizing a difference in molecular size, and a protein removal method by solid phase extraction.
  • the deproteinization method using an organic solvent is preferable because the 14 C-labeled compound can be extracted and the organic solvent itself can be easily removed.
  • the organic solvent is first added to the biological sample to insolubilize the protein. At this time, the 14 C-labeled compound adsorbed on the protein is extracted into the organic solvent-containing solution.
  • the organic solvent-containing solution may be collected in another container, and then an organic solvent may be further added to the residual to extract the solution.
  • the extraction operation may be repeated a plurality of times. If the biological sample is feces, an organ such as a lung, or other form that is difficult to mix uniformly with an organic solvent, the biological sample and the organic solvent are uniformly mixed by homogenizing the biological sample. It is preferable to carry out a treatment for the above. If necessary, the insolubilized protein may be removed by centrifugation, filtration through a filter, or the like. The extract containing the 14 C labeled compound is then dried by evaporating the organic solvent to remove the carbon source from the organic solvent. As the organic solvent, methanol (Methanol), ethanol (EtOH), or acetonitrile (ACN) is preferable, and acetonitrile is more preferable.
  • Methanol ethanol
  • EtOH ethanol
  • ACN acetonitrile
  • Step S3 The pretreated biological sample is heated and burned to generate a gas containing carbon dioxide isotope 14 CO 2 from a radioactive isotope 14 C source. Then, N 2 O and CO are removed from the obtained gas.
  • Step S4 Moisture is removed from the obtained 14 CO 2 .
  • the 14 CO 2 or passed over drying agent such as calcium carbonate it is preferred to remove water by condensation of moisture by cooling the 14 CO 2.
  • the reduction in the mirror reflectance due to icing and frosting of the optical resonator 11 due to the water content contained in CO 2 lowers the detection sensitivity, and therefore the analysis accuracy is improved by removing the water content.
  • Step S5 14 CO 2 is filled in the optical resonator 11 having a pair of mirrors 12a and 12b as shown in FIG. Then, it is preferable to cool 14 CO 2 to 273 K (0 ° C.) or less. This is because the absorption intensity of the irradiation light is increased. Further, it is preferable to keep the optical resonator 11 in a vacuum atmosphere. This is because the measurement accuracy is improved by reducing the influence of the external temperature.
  • Step S7 The irradiation light is sent into the optical resonator via the ⁇ / 4 wave plate, and the carbon dioxide isotope 14 CO 2 is irradiated with the irradiation light to resonate.
  • the optical separator (switch) 29 blocks the light incident on the optical resonator 11.
  • Step S8 The light returned from the optical resonator is sent to the PID controller via the ⁇ / 4 wavelength plate and the polarizer to output the PID control voltage, the high frequency component is sent directly to the light source, and the low frequency component is sent. It is sent to the light source via the passive feedback unit (PDH lock process).
  • PDH lock process passive feedback unit
  • Step S9 The ringdown signal obtained by irradiating the carbon dioxide isotope with the irradiation light is measured.
  • the mirror spacing is 10 to 60 cm and the radius of curvature of the mirror is the same as or greater than the mirror spacing.
  • a medical diagnostic device and an environmental measurement device including a part of the configuration described in the embodiment can be manufactured in the same manner.
  • the light generator described in the embodiment can be used as the measuring device.
  • a piezo element is attached to the mirror, and the applied voltage of the piezo is modulated so that the QCL frequency becomes stable using the error signal from the PDH.
  • the QCL driver current was modulated so that the QCL frequency became stable using the error signal from the PDH.
  • a polarizing plate Thiorlabs, model number: WP12LM-IRA
  • a ⁇ / 4 plate Thiorlabs, model number: WPLQ05M-4500
  • EO-12.5T3-MIR (resonance frequency: 11.0 to 13.8 MHz, AR coating: 3.0 to 4.5 ⁇ m) manufactured by QUBIG was used for the EOM.
  • ADU Analog to Digital Unit manufactured by QUBIG, which is a dedicated RF driver, was also used.
  • the output of the photodetector for measuring reflected light is mixed with the modulated signal of EOM by a mixer, and an error signal for PDH is generated by passing through a low-pass filter.
  • PID fast The output for PID control of the laser current based on the high frequency component of this error signal (PID fast) and the output for PID control of the mirror distance of passive feedback based on the low frequency component (PID slow) are supplied to the Digilock module. Generated. PID fast and PID slow were fed back to the piezo element that changed the mirror distance of the laser current and passive feedback, and the laser frequency was matched to the resonance frequency of the optical cavity and stabilized.
  • the characteristics of frequency stabilization by passive feedback were evaluated using the beat signals of a mid-infrared optical frequency comb and a quantum cascade laser with stable frequencies.
  • the RF spectrum of the beat measured when passive feedback is used is shown in FIG. 3A. It was observed that the passive feedback narrowed the beat line width and improved the strength.
  • the RF spectrum of the beat was repeatedly measured (RBW: 100 kHz, Sweep time: 1 ms, measurement time: 600 s).
  • a histogram of the beat line width when passive feedback is used is shown in FIG. 3B. It can be seen that the beat line width is narrowed by using passive feedback. From now on, the QCL can be narrowed by passive feedback.
  • FIG. 6 shows the time change of the light intensity transmitted through the optical resonator.
  • the laser current is modulated, a resonance peak can be seen according to the transmitted light characteristics of the FPI (Fabry-Perot interferometer).
  • FPI Fabry-Perot interferometer
  • FIG. 7 shows the time change of the center wavelength of the RF spectrum of the measured beat. Without PDH frequency stabilization, the beat signal fluctuates significantly beyond ⁇ about 20 MHz. On the other hand, it can be seen that the frequency fluctuation of the QCL can be suppressed to about ⁇ 10 MHz by stabilizing the frequency by PDH.
  • the frequency fluctuation ( ⁇ about 10 MHz) of the quantum cascade laser stabilized by PDH fluctuates with the temperature change of the resonator length of the optical resonator. It was suggested that it was derived from.
  • the laser frequency When acquiring a ring-down signal with CRDS, the laser frequency only needs to match the resonance frequency determined by the resonator length of the optical resonator for CRDS, so fluctuations due to temperature changes in the resonator length of the optical resonator Does not have to be considered.
  • carbon was exemplified as an analysis target.
  • the present invention is not limited to this, and any gas such as hydrogen (which may be deuterium) may be analyzed.
  • the cavity is formed by two mirrors provided in the optical resonator
  • the present invention is not limited to this, and three or more mirrors are used.
  • the cavity may be constructed of mirrors of.
  • Carbon isotope analyzer 10 Spectrometer 11 Optical resonator 12 Mirror 13 Piezo element 15 Photodetector 16 cell 20 Light generator 21 Optical fiber 22 Polarizer 23 Light source 24 Detector 25 Passive feedback 25a Mirror 25b Condensing lens 26a Mixer 26b Low bus filter 28 PID control servo 29 Optical separator 30 Arithmetic device 40 Carbon dioxide isotope generator 60 Carbon dioxide isotope introduction / discharge control device 61a Introduction pipe 61b Discharge pipe 63a Three port valve 63b Introduction valve 63c Discharge valve 65 Pump

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Abstract

L'invention concerne un dispositif d'analyse qui comporte : une source lumineuse ; un résonateur optique qui est rempli de gaz à analyser et qui reçoit la lumière émise par la source lumineuse ; un photodétecteur qui détecte l'intensité de la lumière émise par le résonateur optique ; une unité de rétroaction passive configurée pour stabiliser la longueur d'onde de la lumière émise à partir de la source lumineuse par alimentation optique de la lumière émise par la source lumineuse en retour vers la source lumineuse ; une unité de verrouillage PDH configurée pour verrouiller la fréquence de la lumière émise par la source lumineuse à la fréquence de résonance du résonateur optique ; et une unité de commande de rétroaction qui délivre en sortie un signal de commande présentant une première fréquence pour un verrouillage PDH à la source lumineuse et qui délivre en sortie un signal de commande présentant une seconde fréquence pour une rétroaction passive à l'unité de rétroaction passive, la première fréquence étant supérieure à la seconde fréquence.
PCT/JP2020/009829 2019-03-08 2020-03-06 Dispositif d'analyse WO2020184474A1 (fr)

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