JP4585800B2 - Mixer and liquid analyzer - Google Patents

Description

  The present invention relates to a mixer for effectively mixing a small amount of fluid and an analysis apparatus including the mixer.

  Conventional mixing reaction apparatuses include a mixing reaction apparatus described in JP-A-6-226071 and a chemical analysis apparatus using the mixing reaction apparatus. In this mixing reaction apparatus, a very thin mixing chamber for performing a mixing reaction, a large number of micro nozzles provided at a high density on the bottom surface thereof, and a liquid A (reagent) supply means connected to the micro nozzles, mixing It consists of a sample suction pump for sucking B liquid (sample) into the chamber or supplying cleaning liquid. Since the reaction between the collected B liquid (sample) and A liquid (reagent) is achieved instantaneously, the process of chemical reaction that mixes uniformly and reacts at high speed is measured under uniform concentration conditions. It has become.

  As another mixer, there is a liquid mixer described in JP-A-2001-120971. This mixer is a liquid mixing system in which the liquid dividing fine grooves for dividing the liquid A and the liquid B to be mixed introduced from the liquid introduction port and the branch flow paths of the liquid dividing fine grooves are alternately connected. The narrow groove for use is formed separately on the overlapping surface of the two plates. In the fine groove for liquid mixing, both A and B liquids are stacked alternately in the depth direction of the groove and adjacent to each other in a thin layer, and diffusion proceeds rapidly between the liquids, so that a minute amount of liquid is mixed. And flows out from the liquid outlet.

  Furthermore, as another mixer, there is a micromixer described in JP-A-2002-346357. In this mixer, the cell substrate and the cover are overlapped and joined to each other, and the upper surface side of the cell substrate is subjected to etching processing to introduce the introduction channel corresponding to the liquids A and B, the mixing channel, and the mixed liquid C. An outflow channel is formed from.

Japanese Patent Laid-Open No. 6-226071 Japanese Patent Laid-Open No. 2001-120971 JP 2002-346357 A

  However, the present inventors have found that the form disclosed in the above-described prior art document is not sufficient to effectively mix a small amount of fluid. The mixing reaction apparatus is mainly applied to a gradient mixer provided in a micro LC (liquid chromatography) (a gradient mixer is a mixer that mixes while changing the mixing ratio of two kinds of solvent liquids). Then, the following can be cited as problems. When mixing two liquids at a minute flow rate, changing the flow ratio of liquid A and liquid B, for example, if the flow rate of liquid A is more than 5 times the flow rate of liquid B, mixing in the mixing reactor described above In the room, there is a possibility that problems such as the B liquid not mixing or the stagnation in the mixing chamber may occur due to the difference in flow rate between the two liquids.

  In addition, when the mixer described above is also applied to a gradient mixer, the mixed solvent solution is injected into the column which is a constituent part of the liquid chromatography without mixing the two solutions that cause the same problem sufficiently. In such a case, the chemical component in the liquid phase cannot be sufficiently separated, and the chemical component cannot be accurately detected in the subsequent process.

  Accordingly, an object of the present invention relates to a mixer capable of effectively mixing a small amount of fluid and a liquid analyzer including such a mixing mechanism.

The present invention solves at least one of the above problems.
(1) A mixer according to the present invention includes a first liquid supply section, a second liquid supply section, and a first substrate, and a plurality of the first liquid ejection sections. One nozzle, a second nozzle formed on the second substrate and provided with a plurality of ejection portions of the second liquid, the first liquid ejected from the first nozzle, and the second It has a mixing part with which the 2nd liquid spouted from the nozzle is mixed.

  For example, the first substrate is disposed to face the second substrate with the mixing unit interposed therebetween.

  By forming in this way, a first nozzle having a plurality of ejection portions for supplying the first liquid to the mixing portion, and a second nozzle having a plurality of ejection portions for supplying the second liquid to the mixing portion. Using this, it is possible to provide a mixing device that jets two liquids from a nozzle and effectively mixes them in a short time using the phenomenon of diffusion.

  As a specific form, in the mixing unit, it is preferable that a discharge path for the mixed liquid is formed between the first substrate and the second substrate.

  Alternatively, the first liquid supply unit, the second liquid supply unit, the first liquid supply unit connected to the first liquid supply unit, a plurality of the first liquid ejection unit, A second nozzle having a plurality of second liquid ejection portions formed in contact with the second liquid supply portion and formed toward the first liquid ejection portion; and the first nozzle A mixing unit in which the first liquid ejected from the second liquid and the second liquid ejected from the second nozzle are mixed is disposed in a region between the first nozzle and the second nozzle. It is characterized by that.

  (2) In these mixers, the positions where the ejection direction of the first liquid ejection part extends in the second substrate direction are the first liquid ejection part and the second liquid ejection part. It is formed between the second and the second liquid ejection portion.

  Thus, it is preferable from the viewpoint of efficient mixing that the first nozzle and the second nozzle are alternately arranged opposite to each other via the mixing portion.

  The first nozzle and the second nozzle may be alternately arranged in the same direction via the mixing portion depending on the convenience of the mixer.

  As another form, in the mixer of any one of the above forms, the supply of the first liquid communicates with a first supply path to which the first liquid is supplied and the first supply path. And a first supply header portion communicating with the plurality of first liquid ejection portions, wherein the volume of the first supply header portion is smaller than the volume of the mixing portion. By doing in this way, responsiveness can improve and mixing performance can be improved.

  Alternatively, in the mixer according to any one of the above forms, the supply of the first liquid communicates with the first supply path to which the first liquid is supplied and the first supply path, and A first supply header portion that communicates with the first liquid ejection portion, and the first supply header portion includes a first region that communicates with the first supply channel, and a first region that communicates with the first region. And a second region that communicates with the plurality of first liquid supply sections and communicates with the first liquid ejection section. Thereby, the difference of the ejection characteristic in each ejection part can be made small, and a mixing characteristic can be improved. Or it forms so that the area | region of the connection part from said 1st area | region to said 2nd area | region may be formed wider than the area | region of the connection part from said 1st supply path to said 1st area | region.

(3) It has a mixer provided with the form by which a some mixing part is operated effectively.
The first first liquid supply part, the second first liquid supply part, and the second formed between the first first liquid supply part and the second first liquid supply part Liquid supply section of
A first mixing section formed between the first first liquid supply section and the second liquid supply section; the second first liquid supply section; and the second liquid supply section. And a second mixing portion formed between the two.

  Furthermore, the first mixing section or the second mixing section includes a first substrate on which a plurality of jet outlets for jetting the first liquid are formed, and a jet outlet for jetting the second liquid. It is preferable to have the 2nd board | substrate with which two or more were formed, and the mixing part of the 1st liquid and 2nd liquid formed between said 1st board | substrate and said 2nd board | substrate.

  Thus, it is possible to effectively stack a plurality of mixers, increase the mixing volume, and widen the flow range of the mixed liquid. Moreover, a high pressure resistance is possible by laminating many mixers.

  (4) The liquid analyzer of the present invention includes an injector for injecting a sample into a solvent, a column in which the sample and the solvent are introduced from the injector, and components of the sample are separated, and the liquid discharged from the column A liquid analyzer having a detector for detecting a separated sample, wherein the first solvent liquid supply unit, the second solvent liquid supply unit, and a first substrate are formed, A first nozzle provided with a first solvent liquid ejection portion; a second nozzle formed on the second substrate and provided with a plurality of second solvent liquid ejection portions; and the first nozzle. And a mixing part in which the first solvent liquid ejected from the second nozzle and the second solvent liquid ejected from the second nozzle are mixed, and the solvent is mixed from the mixing part. It is a solvent.

  The liquid analyzer can be in the form of liquid chromatography, for example. However, the analyzer is not limited to this as long as the analyzer uses a liquid mixture such as the above-described mixer.

  Alternatively, an injector for injecting a sample into a solvent, a column from which the sample and the solvent are introduced from the injector and components of the sample are separated, and a detector for detecting the separated sample discharged from the column A first first solvent liquid supply unit, a second first solvent liquid supply unit, the first first solvent liquid supply unit, and a second first A first solvent liquid supply section formed between the first solvent liquid supply section and the second solvent liquid supply section. And a second mixing unit formed between the second first solvent solution supply unit and the second solvent solution supply unit.

  By such a form, this invention can provide the liquid analyzer provided with the mixer which can mix a trace amount fluid effectively, and such a mixing mechanism.

  In addition, even if the mixing ratio of the two liquids is changed and the flow range of the two liquids is widened, the two liquids are discharged in a minute amount from each other in a minute amount (or in the same direction). It is possible to provide a mixing apparatus in which liquids come into contact with each other in a minute amount and can perform diffusion mixing in a short time.

Further, in the embodiment of the present invention, the flow rate of the discharged mixed liquid can be widened, and good mixing is possible even if the mixing ratio is changed.
Further, the switching of the flow range can be selected by a valve so that the mixing volume can correspond to the target flow rate.

  As described above, according to the present invention, in particular, a mixer that can effectively mix a small amount of liquid such as a sample liquid or a solvent liquid in a short time, or a reaction apparatus that performs a chemical reaction, and different types of liquids are mixed and reacted. It is suitable for a chemical analysis apparatus for analyzing

  By such a form, this invention can provide the liquid analyzer provided with the mixer which can mix a trace amount fluid effectively, and such a mixing mechanism.

  Embodiments of the present invention will be described below. In addition, this invention is not limited to the form described in the Example, The change which show | plays the same objective effect based on a well-known technique is accept | permitted. Hereinafter, a liquid chromatography equipped with the mixer of the present invention will be described as an example.

  A first embodiment of the present invention will be described with reference to FIGS. FIG. 1 is a schematic diagram of a micro liquid chromatography as an example of a liquid analyzer, and FIG. 4 is a diagram showing a configuration of a micro mixer which is a mixer of the present embodiment.

As an example, as shown in FIG. 4, the mixer used here is a supply unit 6 for a solvent A as a first liquid, a supply unit 6 for a solvent B as a second liquid, and these liquids are supplied. A mixing chamber 5 that is a mixing unit, a first nozzle having a plurality of ejection units 3 that supply the first liquid to the mixing unit, and a plurality of ejection units 4 that supply the second liquid to the mixing unit And a second nozzle comprising The 1st nozzle and the 2nd nozzle are arrange | positioned facing through the mixing part. And the 1st nozzle and the 2nd nozzle are alternately arrange | positioned through the said mixing part. (As another form, the first nozzle and the second nozzle may be alternately arranged in the same direction via the mixing section.)
The discharged liquid mixture can have a wide flow range, can be mixed even if the mixing ratio is changed, and can be effectively mixed even at a minute flow rate.

LC (Liquid Chromatography) is an apparatus that separates chemical components in a liquid phase with a column so that they can be distinguished by color. In particular, chromatography using a column having a small diameter is called microchromatography. The purpose of microchromatography is to separate compounds that cannot be separated by a normal column and to apply a trace amount of compounds to the separation analysis.
FIG. 1 shows an outline of the configuration. Two types of liquids are supplied to the mixer 12 by pumps 11 corresponding to the solvent liquid A and the solvent liquid B, respectively. In the mixer, two kinds of liquids are mixed, and in this case, the pressure is increased to about 300 atm. Next, the two kinds of pressurized mixed liquid reach the column 14 through the injector 13 (sample injector). Column 14 has a packing member (as an example, packed with a very fine silica gel powder (particle size of about 10 μm)). Here, the compound is separated, and the liquid discharged from the column detects the target chemical component by the detector 15. This example is a micro liquid chromatography. This liquid chromatography is equipped with a gradient mixer. A gradient mixer is a mixer that mixes by changing the mixing ratio of two solvent solutions injected into a column that separates chemical components in a liquid phase. By changing the mixing ratio, various chemical components can be separated, and the detection accuracy of the chemical components can be increased.

  In recent years, there has been proteome analysis as research and development (for drug discovery and gene diagnosis) in the post-genome sequence era, and the needs for this analysis are increasing. However, when cells are collected and protein is extracted, the amount of protein extracted is extremely small, and unlike DNA, it cannot be amplified. Therefore, the development of proteome analysis micro LC for micro samples requires the micro fluid handling technology. In connection with this, the mixer corresponding to a trace amount fluid and the analyzer provided with it are required.

  The mixer uses the phenomenon of diffusion by injecting two liquids from the nozzle. The mixing volume was calculated from the target flow rate using the unit diffusion region per nozzle, and the number of nozzles was defined.

  Here, for the purpose of mixing water and methanol as two types of liquids, the specification of the mixer was obtained from the diffusion time as a design index of the mixer utilizing the diffusion phenomenon.

  For a mixer using two liquids ejected from a nozzle and utilizing the phenomenon of diffusion, the mixing volume was calculated from the target flow rate using a unit diffusion area per nozzle and the number of nozzles was defined.

  Briefly describing the design method, it is possible to determine the number of nozzles required for mixing, assuming that the time during which the liquid (methanol) is discharged from the nozzles to the mixing chamber is the same as the diffusion time. As shown in FIG. 2, the distance at which the liquid (methanol) diffuses from the nozzle to the mixing chamber (filled with water) was defined as the height of the mixing chamber. The number of nozzles was calculated by dividing the target flow rate (volume) by the unit diffusion region. As shown in Figs. 2 and 3, the unit diffusion region is the diffusion region per nozzle when the nozzles are adjacent to each other in the region obtained from the hemispherical model with the nozzle at the center and the diffusion distance as the radius. is there.

The procedure for calculating the mixer design specifications is shown below.
(1) Calculation of diffusion distance The diffusion distance from the nozzle is d (mm), the diffusion coefficient of methanol to water is D (mm2 / sec) = 8.4 x ^10-4 , and the diffusion arrival time is t (s) = 0.1,1,3,10,100, and the diffusion distance can generally be estimated by the following equation according to Fick's law. Diffusion distance d = √ (2Dt)
(2) Calculation of nozzle pitch The volume of the unit diffusion area (the diffusion area per nozzle when the nozzles are adjacent to each other: the shaded area) is maximum at θ = 45 °, and the adjacent nozzle pitch at each diffusion time at that time P (mm) is obtained by the following equation. Nozzle pitch P (mm) = 2dcos θ = √2d (when θ = 45 °)
(3) Calculation of volume of unit diffusion region The volume V (nl) of the unit diffusion region is obtained by the following equation.
Unit diffusion region: V = 4d3 sin2cosθ = √2d3 (when θ = 45 °)
(4) Calculation of the number of nozzles If the flow rate flowing into the mixing chamber is Q, the total number N of nozzles is the flow rate of the mixer: Q = 0.1 to 200 μl / min), the diffusion arrival time t (s) = 0.1,1, It is calculated by the following formula as 3,10,100.
Total number of nozzles N (pieces) = Q · t ÷ V
(5) Calculation of length of one side of mixer Assuming that the nozzles are arranged in a matrix, the length L of one side of the mixer is obtained by the following equation. One side of the mixer L (mm) = P (mm) x √N (pieces)
(6) Average flow velocity of the mixer The average flow velocity v (mm / s) at the flow rate Q (μl / s) of the mixer (when (200 μl / min)) is obtained from the following equation.
Cross section of diffused region S (mm2) = nozzle pitch P (mm) x side L (mm) of mixer Average flow velocity v = Q / (S / 2)
(7) Movement distance of diffusion region The movement distance of diffusion region: L ′ (mm) is obtained from the following equation.
Travel distance: L '(mm) = v · t
(8) Chip length (mm): L ″ (mm) is obtained from the following equation. The chip length is a distance required for mixing until the two liquids are discharged from the mixing chamber.
Chip length L ″ ((mm) = Square side L (mm) + Movement distance L ′ (mm)
Based on the above procedure, if the diffusion time (diffusion arrival time) is calculated as 0.1,1,3,10,100 (s) and the flow rate flowing into the mixing chamber is the maximum target flow rate 200μl / min, the diffusion time FIG. 9 shows the relationship between the mixer specifications.

A shorter diffusion time is preferable from the viewpoint of rapid mixing. However, when the diffusion time is 0.1, the pitch needs to be considerably reduced. For this reason, it is preferably larger than 0.1 from the viewpoint of ease of production. Further, when the diffusion time is 100, the volume is large and the mixing time is long.
For this reason, it is preferably less than 100 from the viewpoint of ease of production and rapid mixing. Of course, the present invention is not limited to this as long as other aspects such as manufacturability are emphasized.

An example mixer is shown in FIG. FIG. 4 (1) shows the outline of the whole form, and FIG. 4 (2) shows a specific cross-sectional structure. As shown in FIG. 4A, liquid is ejected from a plurality of nozzles formed in the upper substrate 1 and the lower substrate 2 into the mixing chamber 5 formed therebetween. As shown in FIG. 4 (2), a specific form of the form in which the nozzles are arranged to face the upper and lower surfaces of the inner wall of the mixing chamber will be described below. The first liquid is supplied from the plurality of nozzles 3 on the upper surface (first) formed on the upper surface substrate 1 of silicon, and the second liquid is supplied from the plurality of nozzles 4 on the lower surface (second) of the lower surface substrate 2 of silicon. Supply. The solvent A is supplied from the pump 11 to the upper surface nozzle of the upper substrate 1, and the solvent B is supplied from the pump 11 to the lower surface nozzle of the lower substrate 2. The solvent mixed in the mixing chamber 5 is led out from the outlet channel 8. Here, the flow path through which the mixing chamber 5 communicates with the injector 13 and the column 14 is formed so as to communicate between the upper substrate 1 and the lower substrate 2.

  The liquid supplied from the pump 11 is introduced from the supply unit 6 into the mixing chamber 5 through the nozzle 3 or 4. Here, the supply section 6 has a supply header section 62 connected to the nozzle 3 or 4 so as to connect the liquid to the supply path 61 and distribute and introduce the liquid to the plurality of nozzles 3 or 4.

One supply header 62 is formed in a space sandwiched between the upper substrate 1 and the mixer holder upper plate 7. Similarly, the other supply header 62 is formed in a space sandwiched between the lower substrate 2 and the mixer holder lower plate 9.
It is possible to manufacture a mixer that utilizes the phenomenon of diffusion by ejecting two liquids from the nozzles on the upper and lower surfaces. Here, opposing substrates constituting the inner wall are provided, a first liquid nozzle is formed on one substrate, and a second liquid nozzle is formed on the other substrate. A liquid mixing portion is formed between the two substrates.

  Further, the discharge path of the liquid mixed in the mixing unit is configured to communicate between the two substrates. Thereby, the liquid mixture of a favorable mixed state can be supplied.

  The mixing volume of this mixer is calculated using the unit diffusion area per nozzle from the maximum target flow rate, and the number of nozzles is obtained. By being discharged, the two liquids come into contact with each other in a minute amount, and diffusion mixing can be performed in a short time. Further, by alternately arranging the lower nozzle position and the upper nozzle position, the effect of convection in the mixing chamber is enhanced, which is effective in shortening the mixing time. Further, the lower nozzle position and the upper nozzle position may be arranged alternately or in the same direction.

  Further, this mixer can widen the flow rate range, and even if the mixing ratio is changed, the mixing volume of the mixer is obtained from the maximum target flow rate, so that mixing is possible if it is equal to or less than the target flow rate.

  As shown in FIG. 4, the mixer has a thin mixing chamber 5, and a large number of minute nozzles are provided on the wall surface. The minute nozzle is connected to the reagent supply path 6. The reagent is ejected from this nozzle into the mixing chamber 5. Since the mixing chamber 5 is thin, the jet spreads in the thickness direction, and further, molecular diffusion occurs rapidly in the lateral direction, and mixing is quickly achieved in the mixing chamber 5. For example, the nozzles 3 and 4 can be processed by a fine processing technique such as etching used in semiconductor manufacturing. Using this technology, when using the design value with a diffusion time of 3 seconds from Fig. 9, it is possible to arrange square nozzles with a side of about 30 µm at 100 µm intervals to make a mixing chamber size of about 50 µm x 15 mm x 15 mm. It is possible to place 20,000 nozzles on the bottom. Fig. 5 shows a cross-sectional view of the mixer that was prototyped using a design value with a diffusion time of 3 seconds and a target flow rate of 20 µl / min. In the case of flowing a fluid at a high pressure, the width on the nozzle outlet side is preferably smaller than the width on the side away from the outlet as shown in FIG. In this way, when the plate thickness is increased in order to ensure pressure resistance, a path with a very high aspect ratio can be formed with high accuracy. In addition, even if it is not a case where a fluid is flowed at a high pressure, it can be applied to a case where the plate thickness is increased from another viewpoint such as strength.

The mixer has a disc shape with a mixing chamber height of 50 μm and a circle with a diameter of about 15 mm as the bottom, and square nozzles of 30 × 30 × 50 μm are spaced approximately 100 μm on the upper and lower wall surfaces of the mixing chamber. Arranged in a matrix. Note that the upper nozzle and the lower nozzle are shifted by 50 μm.
Although this mixer was designed with a static flow, an experiment was conducted using a prototype mixer to confirm whether the two liquids were mixed. The experimental results are shown in FIG. 7 and represent the methanol concentration when about 10 seconds have passed. The experimental conditions are that methanol flows into the mixing chamber simultaneously from the upper nozzle and water from the lower nozzle. As shown in FIG. 5, a discharge port was provided on the right side of the mixing chamber. The flow rate is the same ratio. From the graph of FIG. 7, even if the flow rate is changed, the methanol concentration is about 50%, so that the mixing state can be seen. From the above, it was confirmed that the present invention is useful.
In addition, the manufacturing process of the mixer of one Example of this invention is shown in FIG. The upper side of the wafer cross section in FIG. 6 represents the inside of the mixing chamber, and the lower side represents the outside of the mixing chamber. (A) An oxide film 22 is formed on a silicon (Si) substrate 21 in order to form a SiO2 etching mask. The mixed portion inside the mixing chamber is developed and removed by patterning to create a SiO2 etching mask that exposes a predetermined area of the silicon substrate. An Al film 23 is formed on the side of the wafer mixing chamber. Here, Al sputtering was performed. Then, an Al etching mask having a large number of holes formed by patterning is created. The subsequent procedure is as shown in the figure. (B) Dry etching is performed to a depth of about half the thickness of the wafer in order to form a nozzle on the mixing chamber side. Next, as shown in (c), a SiO2 etching mask for developing the mixing chamber is prepared in the same manner. Specifically, the Al etching mask is removed, and the SiO 2 etching mask located around the region where the hole 24 is formed is exposed. Next, as shown in (d), the second Si etching is performed, and the silicon substrate 21 is etched to the middle of the depth of the hole formed as described above (for example, a depth of about 25 μm). Next, as shown in (e), the oxide film 22 of the etching mask is removed. Next, as shown in (f), the SiO2 film 25 is dropped and formed on both surfaces. The silicon substrate 21 is exposed by patterning the SiO2 film outside the mixing chamber at a position corresponding to the hole 24 to form a hole 26. Next, a hole 26 is formed by etching from the outer side surface of the mixing chamber of the silicon substrate 21 and communicated with the hole 24. Thereby, a nozzle part can be formed. The diameter of the hole 24 is formed to be narrower than the diameter of the hole 26.

  In addition, the switching of the flow range to each nozzle can be selected so that the mixing volume can correspond to the target flow rate by controlling the driving of the pump 11 shown in FIG. This can also be done by valves arranged in each path not shown.

  According to such a liquid analyzer equipped with a mixer and a mixer, the two liquids are brought into contact with each other in a minute amount so that the two liquids can be mixed at a wide range of flow rates while changing the mixing ratio. In addition, mixing is possible in a short time without providing an extra mixing mechanism from the outside. Therefore, since the measurement object can be favorably moved in the column, the analysis time and analysis performance can be improved.

  Next, the form of Example 2 is demonstrated below using FIG. The second embodiment can basically use the form described in the first embodiment, but the second embodiment uses a mixer having a plurality of mixing chambers.

  The mixer includes a first solvent A supply unit 31, a second solvent A supply unit 32, and a solvent B supply formed between the first solvent A supply unit 31 and the second solvent A supply unit 32. A first mixing unit 34 formed between the first solvent A supply unit 21 and the solvent B supply unit 33, the second solvent A supply unit 32, and the solvent B supply. And a second mixing part 35 formed between the part 33 and the second mixing part 35.

  The specific structure of each mixing portion can use the same form as that of the first embodiment.

  It is possible to stack a plurality of mixers, increase the mixing volume, and widen the flow range of the mixed liquid. Moreover, high pressure | voltage resistance can be obtained by laminating | stacking many mixers.

  In liquid chromatography, when a sample is injected into a column, it is pressurized under a high pressure of about 300 to 500 atm. Therefore, an internal pressure of about 300 to 500 atm is also applied to the wall surface of the silicon wafer which is the wall of the mixing chamber. In the vertical direction of FIG. 5, the internal pressure of the mixing chamber can be suppressed by applying a seal material to the supply portion that supplies the liquid to the mixing chamber. On the other hand, in the horizontal direction, an internal pressure of about 300 to 500 atm is also applied to the wall surface of the silicon wafer. Here, since the seal material cannot be applied structurally, the wall thickness can be increased to cope with the pressure resistance. . However, when used in the etching process, since the size of the silicon wafer is limited in processing, there is a problem that the size of the mixing chamber is also limited, and it is difficult to expand the flow rate range. Although the structure of the mixing chamber of FIG. 5 given in the embodiment was designed in consideration of pressure resistance, the target flow rate is 20 μl / min and the flow rate range is narrow. Therefore, the mixing chamber corresponding to 1 to 20 μl / min can be expanded, for example, by laminating the above-described mixing structure in 10 stages as shown in FIG. Can be enlarged to ~ 200 μl / min. The flow range can be switched using a valve or the like not shown. Depending on the flow rate, up to 10 steps can be selected. Moreover, by stacking, the differential pressure can be suppressed without changing the wall thickness of the mixing chamber corresponding to 1 to 20 μl / min. Note that, when stacking, it is effective to perform anodic bonding by sandwiching glass between silicon.

To assemble the mixer, two Si wafers with processed nozzles are bonded together, and anodic bonding is performed with SiO2 (glass) sandwiched between Si. Briefly explaining the anodic bonding of Si and SiO2, when Si is bonded to the anode, SiO2 is bonded to the cathode, Si and SiO2 are laminated, and a high voltage is applied to the bonding interface, Na + is deposited on the surface of SiO2, Move to the cathode. At this time, a negative hole is formed at the bonding interface of SiO 2, and the positive Si from the Si layer moves to fill the hole. Thereby, joining of Si and SiO2 becomes possible. Note that Si has electrical conductivity, and it is possible to join by sandwiching SiO2 between Si. In this case, two-step anodic bonding can be performed by switching the current.
In the above embodiment, silicon is used as the processing material. However, glass / stainless steel may be used in consideration of alkali resistance. Even stainless steel can be finely processed, such as a square nozzle of about 30 μm, and it can be expected to be more effective in chemical resistance than silicon.
Example 3 will be described below with reference to FIG.
By using this embodiment, the responsiveness and the mixing performance are improved.
Basically, the configuration described in the first embodiment can be provided. In the third embodiment, as shown in FIG. 10, the volume of the supply header 62 , which is a supply portion (flow path), is smaller than the volume of the mixing chamber 5. Specifically, it is possible to reduce the volume of the supply header 62 , which is a supply section (flow path), to 1/10 or less than the volume of the mixing chamber 5, so that a mixer corresponding to a small amount of liquid (several hundred μl / min or less) can be used. Is preferable in forming. Thereby, responsiveness can be improved and mixing performance can be improved. The form which adjusted the volume of the supply header 62 which is a supply part (flow path) using the O-ring 10 between each of the board | substrates 1 and 2 and the mixer holder upper board 7 and the lower board 9 was shown. In addition, the area close to the outlet channel 8 of the mixing chamber 5 is formed so as to reduce the number of nozzles 3 and 4 compared to the area farther away. Alternatively, an area where the nozzle is not installed is provided in an area close to the outlet channel 8. Thus, by providing a region in which the two liquids discharged from the nozzle move with time, diffusion mixing of the two liquids is promoted, and the mixing performance can be improved.

  When this form is used as a gradient mixer for liquid chromatography, two liquids can be mixed at a minute flow rate, and the responsiveness and mixing performance can be improved.

  According to this embodiment, the dead volume can be reduced and the responsiveness can be improved.

In terms of responsiveness, the volume of the supply section (flow path) that supplies the liquid to the mixing chamber is changed to several stages, and the volume of the mixing chamber and the volume of the supply section (flow path) that supplies the liquid to the mixing chamber I investigated the relationship.
The experimental method and conditions will be briefly explained. Using liquid chromatography, solvent liquid A (water) is mixed with A pump, solvent liquid B (acetone (0.1% (CH3) 2CO in H2O)) is mixed with B pump, mixer Supply 2 liquids to and mix. The liquid mixed in the mixer is discharged, and a gradient evaluation is performed by a UV detector 15 connected to the mixer. First, fill the mixing chamber with 100% solution A, and send solution B with the B pump to change the concentration of solution B to 0,5,10,50,100,0% every 5 minutes. The absorbance of solution B was detected. The total flow rate was set to 200 μl / min, and the mixer shown in FIG. 10 was mounted on the LC for evaluation.
In order to change the volume of the supply header 62 for supplying the liquid to the mixing chamber, the mixer holder upper plate 7 formed on the upper substrate 1 is used to form the supply header 62 connected to the supply path 61 of FIG. The groove depth H was changed. FIG. 11 shows the experimental result showing the gradient curve at that time.
The vertical axis shows the output value (mAu) of the absorbance of the liquid B detected by the UV detector, and the horizontal axis shows the measurement time (minutes). The gradient curves in the figure are the gradient curve 42 when the holder groove depth is 6 mm, the gradient curve 43 when the holder groove depth is 3.8 mm, and the holder groove depth 1 mm, respectively. A gradient curve 44 and a gradient curve 45 when a conventional mixer is used are shown. As shown in the figure, as the groove depth of the holder becomes deeper to 1 mm, 3.8 mm, and 6 mm, the gradient of the gradient curve becomes gentler and the rise time is delayed. In particular, when the concentration of the liquid B is suddenly increased to 50 to 100%, the output time of the absorbance of the liquid B at 100% is shorter as the groove depth is deeper. To obtain the slope (mAu / min) of the UV detection value of the supply groove volume (μl) at a concentration of 50 to 100%, for example, X1 is the time when the detection value of 50% concentration starts to rise, and the output at that time If the value is Y1, the time when the detected value of 100% concentration reaches X2, and the output value at that time is Y2, the slope of the UV detection value (mAu / min) is calculated as Y2-Y1 / X2-X1. it can. FIG. 12 shows the relationship between the supply groove volume (μl) at a concentration of 50 to 100% and the slope of the UV detection value (mAu / min). As a result, the responsiveness is improved by reducing the dead volume in the volume of the mixing chamber 5 and the volume of the supply header 62 which is a supply unit (flow path) for supplying the liquid to the mixing chamber. Recognize. The volume of the supply header 62 which is a supply unit (flow path) is set to 1/10 of the volume of the mixing chamber 5 (for example, 200 μl). Or set it to 1/10 of the set flow rate (per minute). Thereby, even if the liquid discharged from the nozzle into the mixing chamber leaks out from one nozzle, it can be suppressed to the minimum, and the rise time can be shortened to half or less compared with the conventional mixer. In order to set the target rise time as short as possible in correspondence with the result of the gradient curve, the volume of the supply header 62 as the supply unit is 1/20 to 1/30 of the volume of the mixing chamber 5 as long as it can be processed. It is desirable to reduce the size to twice or less.

Next, the form of Example 4 is demonstrated using FIG. Basically, the modes described in the first and third embodiments can be used. In the fourth embodiment, the supply header unit 62 is connected to the first region 62a that communicates with the liquid supply path 61 and the first region via a plurality of first liquid supply units, and the nozzle 3 or 4 And a second region 62b that communicates with.
Specifically, the supply header section 62 includes a porous body in the first region 62 a that communicates with the supply path 61. In this drawing, a filter is arranged.

  Specifically, the region of the connecting portion from the first region 62a to the second region 62b is formed wider than the region of the connecting portion from the supply path 61 to the first region 62a. The width of the boundary between the first region 62a and the second region 62b is larger than the width of the connecting portion from the first region 62a supply path 61.

  By comprising in this way, mixing performance can be improved.

  It is possible to reduce the dead volume by arranging the liquid so that the liquid spreads from the supply section to the entire nozzle disposed adjacent to the mixing chamber when the liquid is supplied to the mixing chamber. As a result, the effect of improving the responsiveness and mixing performance is expected.

  Here, it is effective to arrange a filter that plays a role of rectification in the mixing chamber.

The surface shape of the cutoff filter when the filter is disposed may be square or circular so as to cover the entire nozzle region disposed in the mixing chamber. In addition, when setting the thickness of the filter, it is desirable that the thickness of the filter = the set flow rate (per minute) / the entire nozzle area (mixing chamber nozzle arrangement surface) or less. When the mixing setting time is 3 s, the depth of the mixing chamber is 50 μm, the liquid enters the mixing chamber within about 1 minute, and the filter thickness is 1 to 2 mm or less in order to diffuse and mix in a short time. It is desirable to be. (In order to keep the time for the diffusion region in the filter to move within about 20 times the mixing set time, the thickness of the filter is preferably about 20 times the mixing chamber depth or less.)
Example 5 will be described with reference to FIG. This embodiment can basically use the form described in the first embodiment and the other embodiments. The supply path 61 is located in the center of the mixing chamber plan view of FIG. In the fifth embodiment, the size or interval of the hole of the upper surface nozzle 3 or the mask surface nozzle 4 is changed between the region close to the connecting portion to the supply header 62 of the supply path 61 and the region away from it. The point is a feature.

  For example, the diameter of the nozzle 3 or 4 in the first area close to the supply path 61 is larger than the diameter of the nozzle 3 or 4 in the second area away from the supply path 61 from the first area. It is formed small.

Alternatively, the distance between the nozzle 3 in the first region close to the supply path 61 or the adjacent ejection holes of the four ejection holes is the nozzle 3 in the second area farther from the supply path 61 than the first area. Or it is formed wider than the same interval of the ejection holes of the 4 ejection parts.
In FIG. 14, the outline | summary of the area | region in which the nozzle of the AB cross section of the previous Example was formed is shown. Individually, it is assumed that the supply path 61 is relatively disposed in the central portion.

  The size of the nozzle is changed between the central portion and the outside of the mixing portion. That is, even if the cross section area of the supply section (flow path) of the mixing chamber is smaller than the mixing chamber nozzle arrangement surface, the sizes of the first nozzle and the second nozzle are respectively set at the center and the outside of the mixing section. By changing the size, when the liquid enters the mixing chamber, the difference in time for the liquid to enter the central part and the outer part of the mixing part is reduced, and the flow rate ratio is changed. However, it is possible to follow the density change. As a result, the responsiveness can be improved and the mixing performance can be improved. For example, when a plurality of nozzles (ejection holes) are arranged in the formation region of the circular nozzle 3 or 4 in which the supply path 61 is relatively arranged in the center as shown in FIG. If the radius is R, XA + XB = R, XA: radius of the circle in the region where the nozzle diameter φA through which the A liquid flows is arranged, XB: radius of the circle in the region where the nozzle diameter φB through which the B liquid flows is arranged, XA Since φB> 2φA when> 2/3 R, the nozzle diameter on the outer side is larger than the central part of the mixing part, so that the liquid enters each part of the central part and the outer part of the mixing part. It is possible to reduce the time difference. The state of the nozzle shape in this case is shown in FIG.

  Similarly, in each of the first nozzle and the second nozzle, the nozzle pitch (nozzle interval) or nozzle density is changed at the central part and the outer part of the mixing part, so that the liquid is mixed in the mixing part. It is possible to reduce the difference in the time to enter the central portion and the outer portion, and an effect of following the density change is expected. For example, when a plurality of nozzles are arranged in a circular mixer as shown in FIG. 14, assuming that the radius of the circle is R, YA + YB = R, YA: a circle in a region where a nozzle pitch LA through which liquid A flows is arranged , YB: The radius of the circle in the area where the nozzle pitch LB where the B liquid flows is arranged, and when YA> 2/3 R, LB <1 / 2LA Since the nozzle pitch on the other side is larger, it is possible to reduce the difference in the time for the liquid to enter the mixing chamber at the center and outside of the mixing section.

  Example 6 will be described with reference to FIG.

  In the present embodiment, basically, the modes described in the first embodiment and other embodiments can be used. In this embodiment, in addition to the supply liquid from the upper surface nozzle 3 provided on the upper surface substrate 1 and the supply liquid from the lower surface nozzle 4 provided on the lower surface substrate 2, the third liquid is supplied by the third nozzle provided on the side. Supply to the mixing chamber 5. The third nozzle is formed by arranging a large number of grooves formed in the lower surface substrate 2 from the liquid supply part formed in the space between the upper surface substrate and the lower surface substrate 2 and the upper surface substrate 1 so as to be opposed thereto. The liquid is introduced into the mixing chamber 5 from a large number of nozzles.

  A conceptual diagram at this time is shown in FIG. By mixing three types of solvent liquids, the type, concentration, and components of the solvent liquid can be changed variously compared to the two types, and various compounds can be separated. The arrangement of the nozzles for supplying the third liquid should be the same as the nozzle pitch arranged on the upper and lower wall surfaces of the mixing chamber. However, when the height of the mixing chamber is low and it is difficult to arrange a plurality of third nozzles on the side surface of the mixing portion, it is desirable to reduce the pitch. The same applies to the nozzle diameter.

By using the mixer of this embodiment in the liquid chromatography of FIG. 1, in order to separate various compounds, by using various solvent liquids, the number of separation items is increased and a small amount of compounds are separated and analyzed. It is expected.

It is the schematic of micro liquid chromatography. It is a unit diffusion area sectional view at the time of designing a mixer. It is a unit diffusion area | region top view at the time of designing a mixer. It is the schematic which shows one Example of this invention. It is the schematic which shows one Example of this invention. It is a schematic diagram which shows the manufacturing process of one Example of this invention. It is an experimental result figure of the prototype mixer. It is a conceptual diagram of a laminated mixer. It is a specification example of a mixer. It is a schematic diagram which shows one Example of this invention. It is an experimental result figure of the prototype mixer. It is an experimental result figure of the prototype mixer. It is a schematic diagram which shows one Example of this invention. It is a schematic diagram which shows one Example of this invention. It is a schematic diagram which shows one Example of this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 ... Upper surface board, 2 ... Lower surface board, 3 ... Upper surface nozzle, 4 ... Lower surface nozzle, 5 ... Mixing chamber, 6 ... Supply part, 7 ... Mixer holder upper plate, 8 ... Outlet flow path, 9 ... Mixer holder lower plate, 10 ... O ring, 11 ... pump, 12 ... mixer, 13 ... injector, 14 ... column, 15 ... detector, 61 ... supply path, 62 ... supply header, 21 ... silicon (Si) substrate, 22 ... oxide film, 23 ... Al film, 24 ... hole, 25 ... SiO2 film, 26 ... hole, 31 ... first solvent A supply section, 32 ... second solvent A supply section, 33 ... solvent B supply section, 34 ... first mixing section 35 ... second mixing part, 42 ... gradient curve when the groove depth of the holder is 6 mm, 43 ... gradient curve when the groove depth of the holder is 3.8 mm, 44 ... depth of the groove of the holder Gradient curve when 1mm, 45 ... when using a conventional mixer The gradient curve

Claims (10)

A first liquid supply section; a second liquid supply section;
A first nozzle formed on the first substrate, connected to the first liquid supply unit, and provided with a plurality of the first liquid ejection units;
A second nozzle formed on the second substrate, connected to the second liquid supply unit, and provided with a plurality of second liquid ejection units;
A mixture formed between the first substrate and the second substrate, in which the first liquid ejected from the first nozzle and the second liquid ejected from the second nozzle are mixed. And
Mixer according to claim Rukoto disposed opposite staggered through the mixing section and the said the first nozzle second nozzle.   2. The mixer according to claim 1, wherein the mixing unit has a mixed liquid discharge path formed between the first substrate and the second substrate. 3. A mixer in which a plurality of the mixers according to claim 1 are stacked as a mixing chamber,
Between the first liquid supply section and the second liquid supply section in each mixing chamber, a first mixing section is formed,
Among the mixing chambers adjacent to each other, a second mixing section is formed between the first liquid supply section of one mixing chamber and the second liquid supply section of the other mixing chamber. A mixer characterized by.   4. The first mixing unit or the second mixing unit according to claim 3, wherein the first mixing unit or the second mixing unit includes a first substrate on which a plurality of ejection ports for ejecting the first liquid are formed, and a jet for ejecting the second liquid. A second substrate having a plurality of outlets, and a first liquid and a second liquid mixing portion formed between the first substrate and the second substrate. Mixer.   2. The first liquid supply unit according to claim 1, wherein the first liquid supply unit communicates with the first supply path to which the first liquid is supplied and the first supply path, and ejects the plurality of first liquids. And a first supply header section communicating with the section, wherein the volume of the first supply header section is smaller than the volume of the mixing section. 2. The first liquid supply section according to claim 1, wherein the first liquid supply section communicates with the first supply path to which the first liquid is supplied and the first supply path, and the plurality of first liquid ejection sections. A first supply header section to contact the
The first supply header portion includes a first region having a porous body that communicates with the first supply path, and a second region that communicates with the ejection portion of the first liquid. A mixer characterized by.   In Claim 6, The area | region of the connection part from said 1st area | region to said 2nd area | region was formed wider than the area | region of the connection part from said 1st supply path to said 1st area | region. And a mixer. 2. The supply of the first liquid according to claim 1, wherein the supply of the first liquid is in communication with a first supply path through which the first liquid is supplied and the first supply path, and the plurality of first liquid ejection portions are supplied to the first liquid supply path. A first supply header section to contact,
The ejection hole diameter of the ejection portion of the first liquid in the first area close to the first supply path is the first area of the second area away from the first supply path from the first area. A mixer characterized in that it is formed smaller than the diameter of the ejection hole of the liquid ejection part. 2. The supply of the first liquid according to claim 1, wherein the supply of the first liquid is in communication with a first supply path through which the first liquid is supplied and the first supply path, and the plurality of first liquid ejection portions are supplied to the first liquid supply path. A first supply header section to contact,
The interval between the ejection holes of the ejection portion of the first liquid in the first area close to the first supply path is the second area farther from the first supply path than the first area. A mixer characterized in that it is formed wider than the interval between the ejection holes of one liquid ejection section.   A liquid analyzer comprising the mixer according to claim 1.

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