JP2006145516A - Microchannel chip reaction control system, micro total reaction system having the same, and micro total analysis system - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a microchannel chip reaction control system for appropriately adjusting various kinds of conditions related to a target chemical reaction in the minute channel of a microchannel chip, such as the temperature conditions of the reaction region and the concentration and flow rate of a reagent solution. <P>SOLUTION: The microchannel chip reaction control system comprises the microchannel chip 1, having at least two microchannels 1a, 1b for introducing reagent solutions A, B and a microchannel 1c, where they are jointed; an analysis means 2 for sampling a product C obtained from the microchannel 1c for analysis; and a control means 3 for controlling the reaction conditions in the microchannel chip 1, based on the analysis result obtained from the analysis means 2. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention has at least two microchannels for introducing a reagent solution and a microchannel formed by joining the at least two channels, and a chemical reaction between the reagent solutions that merge therewith, Controls predetermined reaction conditions such as reagent flow rate, concentration, and / or reaction temperature in a microchannel chip for reacting a reagent with a reagent for the purpose of a synthetic reaction or test for the purpose of producing a substance The present invention relates to a microchannel chip reaction control system.

  The present invention also relates to a microchannel chip reaction control system that can preferably control temperature conditions.

  In recent years, attention has been drawn to microchannel chips that cause various microchemical reactions while flowing reagent solutions using channels (microchannels) having a minute channel cross-sectional area. In such a microchannel chip, for example, since the cross-sectional area of the flow path is very small, a small volume of the reagent solution and the sample is sufficient, and the specific surface area (surface area per unit volume) flowing through the flow path is sufficient. ), The heat exchange efficiency is extremely high, and it is easy to control the temperature quickly, so that high selectivity is obtained for the stereochemistry, geometric isomerism, and positional isomerism of the reaction product. There is a merit such that it can be performed efficiently. For this reason, the microchannel chip is used for a synthesis reaction (micro reaction system) for the purpose of producing a predetermined substance, or a reaction between a reagent solution and a test object for the purpose of inspection (micro total analysis system, μTAS). Often used.

  Here, in general chemical reactions, suitable temperature conditions exist for each reaction. This is because when the temperature is increased in the chemical reaction, the thermal kinetic energy of the particles in the solution increases. In order for a chemical reaction to occur, particles such as atoms, molecules, and ions must collide, and atomic recombination must occur between the particles. The atomic recombination that occurs between particles does not occur in all of the colliding particles. As shown in FIG. 1, an active complex in an unstable state with high energy is once created between particles having a certain energy or more called activation energy, and only particles that have formed an active complex It turns into a product. In addition, the vertical axis | shaft of FIG. 1 shows energy, and a horizontal axis shows the advancing direction of reaction. Here, the case where the energy of the product is lower than that of the reactant is an exothermic reaction, and the opposite case is the endothermic reaction, and FIG. 1 shows the case of the exothermic reaction. Therefore, in a chemical reaction, the reaction rate tends to increase with increasing temperature. This tendency is also clearly shown by the Arrhenius equation shown in Equation 1 below.

(Where A is the frequency factor, E _a is the activation energy, these are constants specific to the reaction, R is the gas constant, T is the absolute temperature, and k is the rate constant. The reaction speed becomes faster.

  However, an extremely high temperature reaction causes undesirable phenomena such as chemical decomposition of the reagent before the reaction. Therefore, suitable temperature conditions exist for each chemical reaction, and temperature control in the reaction region is very important. If the temperature control is insufficient, the chemical reaction is not performed as scheduled, and a system with poor productivity such as a decrease in the yield of the target main product is forced. However, in conventional chemical reactions using flasks, beakers, and large reaction tanks, it is very easy to adjust the temperature of the entire reaction area quickly and uniformly because chemical reactions are performed using a certain amount of reagent solution. It was difficult. On the other hand, in the chemical reaction in the microchannel chip, since the mass of the reagent solution in the reaction region is extremely small, the temperature can be set quickly and uniformly. Therefore, it is possible to obtain a temperature condition suitable for the chemical reaction.

  In chemical reactions, the concentration and mixing ratio of the reagent solution should be the same as the concentration and mixing ratio in the theoretical chemical formula even when mixing is performed for the purpose of producing a predetermined substance. It can not be said. In addition to the influence of the temperature in the reaction region, the progress of the chemical reaction is not limited to the wall surface wettability in the reaction region, the orientation factor such as the contact angle, the viscosity, density, surface tension and flow path of the reagent solution or product. It also changes slightly depending on various factors such as the interfacial tension with the liquid. The effects on the chemical reaction due to differences in the temperature of these reaction zones and the physical properties of reagent solutions and products are more prominent in reactions using microchannels with a large specific surface area in the microchannel chip. Differences are expected to occur, but the response guidelines have not yet been considered.

  Furthermore, in chemical reactions, by-products and intermediates are often generated. Here, the by-product is often a solid (crystal), so the crystals adhering to the channel locally narrow the channel and cause a decrease in the flow rate. There were problems such as becoming. In addition, various gases such as hydrogen and carbon dioxide may be generated during the chemical reaction. In a microchannel chip, even if a small amount of gas is generated due to a chemical reaction, serious problems such as a back flow of a reagent solution and a product occur.

  For this reason, in a chemical reaction using a microchannel chip, there is a demand for a technique for quickly and easily determining various parameters in an operating state such as the temperature of a reaction region, the concentration and flow rate of a reagent solution. In addition, the temperature of the reagent solution in the reaction region can be accurately controlled to control the temperature in the reaction region to ensure a good yield and selectivity of the product, and to cope with various disturbances during operation. There is a conventional demand to do this.

  As an example of disclosing the flow rate control method in the above microchannel chip, for example, Japanese Patent Application Laid-Open No. 2003-43052 (Patent Document 1) and the like can be cited. However, since this technique is a flow rate control method in a single flow path, This is not a technique for adjusting the concentration or mixing ratio of two or more reagent solutions, increasing or decreasing the total amount of products, or controlling the flow rate according to changes in temperature or pressure. In addition to the above-mentioned patent documents, there is no technology that can solve the above problem.

  In contrast, in a chemical reaction in a microchannel chip, since the mass of the solution in the reaction region is extremely small, in principle, the temperature can be set quickly and uniformly, and the temperature conditions suitable for the chemical reaction Can be obtained. However, a technique for managing and controlling the extremely small reaction region in the microchannel chip at a temperature suitable for the reaction has not been realized.

JP 2003-43052 A

  Conventionally, due to the problems described above, in a chemical reaction using a microchannel chip, many parameters such as the temperature and pressure of the reaction region and the concentration and mixing ratio of the reagent solution to be mixed are manipulated, and the reagent Considering the physical properties of the solution and product and the dimensions and shape of the channel cross section, it was necessary to determine the operating conditions during the reaction through a huge number of preliminary experiments. Furthermore, it has been necessary to quickly respond to crystal precipitation and gas generation during a chemical reaction. However, the prior art does not cope with these problems, and therefore there are many problems to be examined regarding the reaction control in the microchannel chip.

  The present invention has been made in view of the above-described problems, and various conditions relating to a target chemical reaction in a microchannel of a microchannel chip without performing a huge preliminary experiment, for example, a reaction region It is an object of the present invention to provide a microchannel chip reaction control system that can suitably adjust the temperature conditions and the concentration and flow rate of the reagent solution, and that can cope with problems caused by solids and gases generated during chemical reactions.

  The present invention also provides a microchannel chip reaction control system capable of efficiently producing and producing a desired reaction product by precisely controlling the temperature of a minute reaction region, among other conditions involved in the desired reaction. The issue is to provide.

  Furthermore, the present invention provides a micro reaction system that can efficiently produce a target product using the micro channel chip reaction control system described above, or a micro total analysis system that can obtain good test results. Let it be an issue.

In order to solve the above problems, the present invention provides a reaction control system for a microchannel chip having at least two microchannels for introducing a reagent solution and a microreaction channel formed by joining the at least two microchannels. Because
An analysis means for analyzing a product generated by a reaction between reagent solutions merged in the micro reaction channel; and a reaction in the micro reaction channel based on an analysis result obtained from the analysis means. Control means to control the conditions involved;
A microchannel chip reaction control system is provided.

  In one aspect of the microchannel chip reaction control system of the present invention, the control means is preferably a flow rate, concentration, temperature and / or pressure of each reagent solution in the microchannel and / or microreaction channel. Can control the temperature.

  In one aspect of the above system, the control means further includes a flow rate of each reagent solution in the microchannel and / or microreaction channel based on the ambient temperature and / or ambient pressure of the microchannel chip, Concentration, temperature and / or pressure can be controlled.

  In one aspect of the above system, the analysis means can measure the component ratio in the product generated in the microreaction channel. Further, the analyzing means may be capable of measuring the amount of at least one component in the product generated in the micro reaction channel.

  In a certain aspect of the system, the control means monitors the temperature of the microchannel chip and the component ratio or component amount in the product generated in the microreaction channel constantly or for a fixed time, and the monitoring result is obtained. By feedback as needed, the temperature of the microchannel chip, the flow rate and / or the concentration of each reagent solution can be controlled.

  Further, in a certain aspect of the above system, the control means further monitors the ambient temperature, ambient pressure, and pressure in the microchannel constantly or for a certain period of time, and feeds back the monitoring results as needed. The temperature of the microchannel chip, the flow rate and / or the concentration of each reagent solution can be controlled.

  In one aspect of the system of the present invention suitable for temperature control, a heat medium flow path is provided in parallel with a predetermined length portion of the minute reaction flow path, and a heat medium sent into the heat medium flow path is interposed. Thus, the temperature of the reaction zone is adjusted.

  In a certain aspect of the system, the heat medium flow path is formed in a double tube structure coaxial with the micro reaction flow path. In addition, a plurality of the heat medium flow paths may be provided along the minute reaction flow path.

In one aspect of the system, a temperature sensor is provided in the micro reaction channel. The temperature sensor may include a resistance temperature detector or a thermocouple.
In one aspect of the system, the analysis means may include a chromatography device.

  In a certain aspect of the system, the control means can control the operation of the heat medium feeding means for sending the heat medium to the heat medium flow path based on the outputs of the analysis means and the temperature sensor. The control means may be capable of independently adjusting the temperatures of the plurality of heat medium flow paths.

In another aspect of the system of the present invention suitable for temperature control, there is provided a temperature adjusting device that adjusts the temperature of the reaction region by irradiating the minute reaction channel with laser light.
In one aspect of the system, a temperature sensor is provided in the micro reaction channel. The temperature sensor may include a resistance temperature detector or a thermocouple.

  In one aspect of the above system, the control means adjusts the temperature of the reaction region by increasing or decreasing the output of the laser light and / or changing the focal length of the laser light.

In a certain aspect of the system, the temperature adjustment device can irradiate a plurality of regions in the microchannel chip with laser light.
The microchannel chip reaction control system of the present invention can be a system including any combination of the above-described configurations. That is, the configuration of the analysis means, the analysis target of the analysis means, the configuration of the control means, the conditions of the control target (types of control parameters and types of actuators), and the configuration of the temperature adjustment means (including the number and types of temperature sensors) Combinations are within the scope of the present invention.

  Furthermore, the present invention provides a micro total reaction system including the microchannel chip reaction control system according to any one of the above aspects, wherein the reaction conditions between the raw material compounds for substance production in the microchannel chip can be controlled. We also provide a total reaction system.

  Furthermore, the present invention is a micro total analysis system including the microchannel chip reaction control system according to any one of the above aspects, and is capable of controlling reaction conditions between a reagent compound and a test compound in the microchannel chip. Also provides a micro total analysis system.

  The microchannel chip reaction control system of the present invention includes a microchannel chip having at least two microchannels for introducing a reagent solution and a microchannel formed by joining the at least two microchannels, and the bonded Analytical means for sampling and analyzing products that have caused a reaction between reagent solutions in the microchannel, and controlling the conditions involved in the reaction in the microchannel based on the analysis results obtained from the analytical means Therefore, it is possible to satisfactorily control the chemical reaction in the minute flow path under favorable conditions without relying on enormous preliminary experiments and empirical rules. It becomes.

  For example, the reaction conditions for a synthesis reaction for the purpose of substance production or a reagent reaction for the purpose of inspection can be sequentially optimized based on the analysis result of the actually produced product. It is possible to set and maintain optimum reaction conditions that produce a product with a component ratio and component amount.

  In particular, since the microchannel chip is a reaction system with a very small amount using a microchannel, it is easily affected by slight fluctuations in various reaction conditions such as reagent flow rate and concentration, and temperature and pressure in the reaction region, Because of its microscale, it is relatively easy to add artificial variation to reaction conditions. The present invention provides a microchannel chip reaction control system that makes use of the characteristics of such a microreaction system and realizes efficient substance production and the like.

  According to the present invention having the configuration in which the heat medium flow path for temperature control is provided, the reaction is performed by supplying the heat medium adjusted in temperature to the heat medium flow path parallel to the predetermined length portion of the reaction flow path. A microchannel chip reaction control system capable of efficiently generating and producing a target reaction product by performing fine control such as making temperature adjustment accurately in each region uniform or adjusting to different temperatures, and The micro reaction system used is provided.

  According to the present invention configured to irradiate a micro reaction channel with laser light for temperature control, the reaction channel of the microchannel chip is irradiated with laser light from the outside to adjust the temperature of an arbitrary reaction region. A microchannel chip reaction that can produce and produce the desired reaction products efficiently by performing precise control such as making the temperature adjustment for each reaction region exactly uniform or adjusting to different temperatures by performing at the timing. A control system and a micro reaction system using the same are provided.

BEST MODE FOR CARRYING OUT THE INVENTION

DESCRIPTION OF EMBODIMENTS Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings.
FIG. 2 schematically shows a schematic configuration of the embodiment of the present invention. In the system of this embodiment, a synthesis reaction represented by a general formula “A + B → C” is performed, where A and B are reagent solutions, and C is a main product.

  In this system, two microchannels 1a and 1b for introducing reagent solutions A and B, respectively, and these microchannels 1a and 1b are joined to each other. A microchannel chip 1 having a reaction microchannel 1c in which a chemical reaction between compounds is performed, a component measuring device 2 (analyzing means) for sampling and analyzing the product C flowing out from the reaction microchannel 1c, Based on the component measurement result (analysis result) output from the measuring device 2, a control means 3 is provided for adjusting various conditions related to the chemical reaction in the reaction microchannel 1c.

  On the upstream side of the two microchannels 1a and 1b, an A storage tank and a B storage tank for storing the reagent solution A or B supplied to the microchannel chip 1, a solvent tank for supplying a solvent to each storage tank, and each solvent tank Concentration adjusting valve 4 for adjusting the reagent concentration in each storage tank by varying the inflow amount from the storage tank, a pump for sending each reagent solution from each storage tank to the microchannel chip 1, and each flow rate of reagent solutions A and B A flow rate adjusting valve 5 for adjusting the flow rate is connected. These pumps and valves are connected to the control means 3 in a controllable manner, thus controlling the respective reagent concentrations in the respective storage tanks, the respective driving pressures of the reagent solutions A and B and the respective inflow amounts to the microchannels 1a and 1b. An adjustment mechanism that can be independently controlled by an adjustment signal fed out from the means 3 is configured.

  In the microchannel chip 1, temperature sensors (for example, resistance temperature detectors and thermocouples) and pressure sensors are provided at a plurality of locations on the wall surface of the reaction microchannel 1 c (black circles in the figure indicate installation of these sensors). Examples are shown). The microchannel chip 1 is installed on an electric heater 6, and the electric heater 6 is controlled by a temperature adjustment signal fed from the control means 3 in accordance with an actual temperature value detected by the temperature sensor and a set temperature target value. Feedback control is possible. Thus, a temperature adjustment mechanism for adjusting the temperature in the reaction microchannel 1c to a temperature suitable for the target reaction is configured. Although not shown, in order to construct a system that is resistant to disturbances, a temperature sensor and an atmospheric pressure sensor for detecting the ambient temperature and atmospheric pressure of the microchannel chip 1 are further provided, and these are used as the temperature adjusting mechanism. You may connect to.

  The product stream C generated in the reaction microchannel 1c is sent to the product storage tank, and a part of the product stream C is taken into the component measuring device 2, preferably through the degassing device 7, and sampled. The component measuring device 2 is, for example, a chromatography device (typically HPLC), and analyzes the reaction state in the reaction system such as the component ratio and component amount in the sampled product. The degassing device 7 may be a device that degass the product to be analyzed by means of ultrasonic generation, helium, or the like. A component measurement result (for example, a waveform chart in the figure) obtained in the component measuring apparatus 2 is taken into the determination mechanism of the control means 3 and stored in a storage means (not shown) as necessary.

  The control means 3 includes a determination mechanism for determining an analysis result of the sampled product, a determination mechanism for determining an adjustment degree with respect to the adjustment mechanism of each part of the system according to an instruction from the determination mechanism, and an operation state of the pump according to an instruction from the determination mechanism And an adjustment mechanism for adjusting the valve opening. For example, these mechanisms may be shared by a single personal computer. The control means 3 can perform all controls and adjustments according to the stored computer program.

  If necessary, the control means 3 performs automatic adjustment for directing an arbitrary parameter to the target value. For example, in the determination mechanism, the analysis result actually obtained in the component measurement apparatus 2 is compared with a theoretical value (target value) for a desired analysis result (for example, an optimal generation amount or component ratio), and Specifically, the concentration of each reagent solution (the opening degree of the valve 4), the flow rate (the number of rotations of the pump and / or the valve 5) are set such that the difference is minimized and the analysis result of the product approaches the theoretical value. The calculation for obtaining the adjustment amount for the opening degree), the reaction temperature (current applied to the electric heater 6), etc. is performed. The adjustment mechanism sends out an electric signal to each adjustment mechanism according to the instructed adjustment parameter and adjustment amount.

  Alternatively, the detection values obtained from the temperature sensor and the pressure sensor may be monitored for a certain period of time or constantly, and feedback control may be performed via the electric heater 6 and the pump so that the temperature in the reaction region and the pressure in the flow path approach the target values. Good. In addition to this, the temperature sensor that detects the ambient temperature and ambient pressure and the disturbance data obtained from the pressure sensor are monitored for a certain period of time or at all times, and the control to enable the prediction of the influence of the disturbance on the system or the immediate response. May be performed. Further, when an abnormal value is detected from the temperature sensor or the pressure sensor, a warning means (not shown) may be activated.

  A “microchannel” is a channel having a microchannel cross-sectional area for flowing a reagent solution. The reaction control system according to the present invention is effective for reaction control between a small amount of liquids handled under a microscale. From this point of view, the term “microchannel” used in the present specification means a channel having a reaction space small enough to enable strict reaction control between a small amount of liquids. The microchannel is formed using a microfabrication technique such as a photolithography technique, and has a width and a height of, for example, about 10 to about 100 μm.

  The term “reagent solution” as used herein refers to a reactive component for causing a chemical reaction of interest within a microchannel, typically a raw material compound for a synthesis reaction or a test reaction. It means a solution containing a reagent compound or a test compound as a solute. The solvent may be appropriately selected in consideration of compatibility with the reactive component used or an appropriate viscosity. The kind of the reactive component and solvent used in the present invention is not particularly limited.

  As used herein, “conditions related to reaction in the microreaction channel” include the flow rate of reagent solution, reagent concentration, temperature, pressure, ambient temperature, ambient pressure, etc. in the microreaction channel. It is. One of the most important conditions for reaction control in this system is temperature. Strictly speaking, it is the temperature of the reagent solution, which can be regarded as the temperature of the wall of the fine reaction channel in contact with the reagent solution and the vicinity thereof. Since the microchannel chip handles a very small amount of reagent solution, the temperature control of the reagent solution via the temperature change in the vicinity of the fine reaction channel has high responsiveness, and the influence of the temperature change on the target reaction is large.

The reagent solution may be driven by a pump as in the present embodiment, but may be a method utilizing capillary action and electroosmotic flow.
The microchannel chip used in the present invention can be manufactured according to a conventional method in the technical field. A typical manufacturing method is as follows. Usually, the microchannel chip is composed of two substrates. On one side of one substrate, a micro flow channel is dug according to a predetermined design using photolithography technology, and a hole for a reservoir is drilled on the other substrate using mechanical processing such as ultrasonic processing. Provide solution supply and discharge ports. When these two substrates are bonded together using an adhesive technique such as fusion bonding by heat, a microchannel chip having a microchannel having a predetermined length and a channel cross section is obtained. The material of the substrate can be appropriately selected from glass, quartz, plastic, silicon resin, and the like.

Next, an adjustment method according to the present system will be described with reference to the virtual data in FIGS.
First, the result of FIG. 3 is assumed as an analysis result obtained from the component measurement device at a certain point in time during operation of the system. Here, the vertical axis of FIG. 3 is the component amount, and the horizontal axis is the holding time. Each peak is shown as a function of the elution amount and elution time of a particular component. When a chromatographic apparatus is used as the component measuring apparatus, standardization such as obtaining a calibration curve in advance is performed to enable conversion of the component amount of the product with respect to the analysis result.

  In addition, the measurement of the component ratio and component amount of the product by the component measuring device may be constantly monitored during the reaction, or the entire system may be started and stopped for a certain period of time in order to obtain the analysis results. .

  From the result of FIG. 3, it is assumed that the determination mechanism determines that “the production amount of the main product C is small under the current operating conditions, so that the production of the main product C is increased”. Based on the determination by the determination mechanism, the determination mechanism reviews the parameters of each part of the system, formulates parameters to be adjusted to increase the production amount of the main product C, and determines the adjustment amounts. Here, the specific parameters are the reaction region in the microchannel chip, particularly the temperature in the vicinity of the reaction microchannel 1c, the concentration and flow rate of the reagent solutions A and B. For the determination of parameters to be adjusted and the amount of adjustment in the decision mechanism, a database in which data is empirically stored in advance for the correlation of the fluctuation amount of each parameter may be used, or a determination mechanism for the measurement results obtained sequentially. And automatic optimization by a decision mechanism may be attempted. Of course, you may use a database and automatic optimization together. Here, the automatic optimization is adjusted so that the generation amount of the main product C is appropriate based on the tendency of increase / decrease of the design evaluation function such as the generation amount of the main product C caused by the variation of the control parameter group. This is a method for determining necessary parameters and determining the amount of adjustment. A calculation algorithm for automatic optimization is generally called an optimization algorithm. For example, as a specific adjustment method for increasing the production amount of the main product C, i) When the temperature of the reaction region in the microchannel chip is increased, the production amount of the main product C tends to increase. If obtained, attempt to increase the temperature of the reaction region in the microchannel chip, or ii) if the main product C does not tend to increase in production even if the temperature is increased, the flow rates and concentrations of the reagent solutions A and B Try to adjust.

  As described above, the temperature adjustment can be performed using an electric heater, a chiller, or the like, and the flow rate of the reagent solutions A and B can be increased or decreased by adjusting the rotation speed of the pump and adjusting the valve opening. The concentration of the reagent solutions A and B can be adjusted by dilution by injecting the solvent and concentration by superheating the storage tank.

  The series of measurements, judgments, determinations, and adjustments described above are automatically repeated in a timely manner using an optimization algorithm such as a personal computer, so that the temperature of the reaction region in the microchannel chip is set to the optimum condition for the chemical reaction. Thus, the reagent solutions A and B can be sent to the microchannel chip at an optimum flow rate and concentration. This system eliminates the need for enormous preliminary experiments to determine operating conditions.

  Next, description will be made using the virtual data of FIG. Intuitively, it is assumed that the flow rate and concentration of the reagent solution A are large. However, in the chemical reaction, even if the result is as shown in FIG. There are some cases where production increases. In some cases, the preliminary experiment in the conventional chemical reaction requires enormous time and labor to determine each parameter during operation. In this system, a microchannel chip whose reaction proceeds relatively quickly is used, and the operating conditions can be automatically determined there. Therefore, the production amount of the product C can be adjusted to the optimum condition quickly and reliably, the time and labor of the preliminary experiment can be reduced, and a stable product yield can be secured during operation. Become.

  In the chemical reaction, crystals may be precipitated as a by-product or gas may be generated. When crystals are deposited and adhere to the flow path, problems such as a decrease in flow rate and blockage of the flow path occur. However, in this system, as described above, since the product component ratio and / or the amount of the component are measured, the decrease in the product is determined and determined by determining the increase in the flow rates of the reagent solutions A and B. The adjustment mechanism can be adapted to increase. In addition, a flow rate blockage or the like appears in the measurement result as a drastic decrease in the flow rate, so that the system administrator can recognize it and take measures immediately. Even in the case of gas generation, in this system, the pressure in the microchannel chip is constantly monitored with a pressure sensor, etc., to increase the pump discharge pressure to prevent backflow or to mix a large amount of solvent. It is also possible to take measures such as dissolving the generated gas.

  In addition, regarding the influence on the reaction due to disturbances such as temperature change and pressure change around the system, the component ratio and / or component amount of the product is measured, and each mechanism for judgment, determination and adjustment as described above is set. Since it can be suitably controlled, it is possible to satisfactorily control and manage the temperature in the microchannel chip, the flow rates and concentrations of the reagent solutions A and B, including the response to the influence of disturbance. For this reason, the stable production of the main product C becomes possible.

  As described above, according to the present system, the temperature of the reaction region, the flow rate adjustment of the reagent solution, and the concentration adjustment can be automatically performed based on the analysis result of the sampled product. It can be generated well, or the reagent reaction for inspection can be performed stably and efficiently, and further, it is possible to cope with problems such as blockage and backflow of the flow path in the microchannel chip.

  As already mentioned, microchannel chip reaction control with high-precision temperature control is possible because the temperature control responsiveness of the microchannel chip is high and the temperature is a powerful constraint that affects the target reaction. Providing a system is important.

  In the following, an embodiment of a microchannel chip reaction control system suitable for controlling the temperature of the micro reaction channel will be described.

  FIG. 7 schematically shows a micro production system or a micro total analysis system according to an embodiment of the present invention suitable for temperature control. This system assigns A and B along a reaction equation of A + B → C. This is a system that produces a solution-like main product C using a reagent solution containing a fixed amount as a raw material. This system includes a microchannel chip 10 that provides a reaction space for mixing A and B to cause a reaction, a temperature adjusting mechanism 30 for adjusting a reaction region temperature in the microchannel chip 10, and a microchannel chip. 10 and a control device 50 that adjusts the operation of the temperature adjustment mechanism 30 based on the measurement results of various sensors provided downstream thereof.

  As shown in FIG. 8, in the microchannel chip 10, grooves are formed on the surfaces of a plurality of flat plate-like (two in the figure) substrates 11a and 11b and joined to each other to form a fine flow path or reaction inside. It constitutes a space. In this embodiment, raw material flow paths 12A and 12B (that is, micro flow paths for introducing a reagent solution) are formed at one corner of a rectangular chip, and these are formed at the junction 13 at Y. After joining in the shape of a letter, it becomes a meandering long mixing / reaction channel 14 (that is, a minute reaction channel), and communicates with the external channel 16 at the outlet 15 that opens at the opposite corner. As shown in FIG. 8B or FIG. 8C, the temperature adjustment parallel heat medium flow paths 18a, 18b, and 18c that receive supply of the heat medium from the temperature adjustment mechanism 30 are provided along the mixing / reaction flow path 14. Is provided. The parallel heat medium flow paths 18a, 18b, 18c are formed in parallel with the mixing / reaction flow path 14 to increase the heat exchange efficiency between the heat medium and the solution in the mixing / reaction flow path 14, Sufficient temperature control can be performed. In this example, the mixing / reaction flow path 14 of the microchannel chip 10 is provided in three dispersed locations, but the number and arrangement can be arbitrarily set.

  The microchannel chip 10 is provided with temperature sensors Ts1 to Ts9 such as resistance temperature detectors and thermocouples, which individually measure the temperature in the mixing / reaction channel 14 at one or more locations, at predetermined locations. Yes. In addition, a component measuring device 20 such as a chromatography device is provided in the external channel 16 on the downstream side of the mixing / reaction channel 14. The outputs of these sensors are input to the control device 50.

  The temperature adjustment mechanism 30 includes a heat medium pipe 32 that communicates with the parallel heat medium flow paths 18 a, 18 b, and 18 c of the microchannel chip 10 through the communication flow path 19, and a predetermined part provided in the middle of the heat medium pipe 32. A temperature heat medium source 34 and a pump 36 for pumping the heat medium are provided. The heat medium source 34 is, for example, a fluid tank provided with a temperature adjusting heat source. The temperature adjusting mechanism 30 can be cooled as well as heated by setting the temperature of the heat medium. In the embodiment shown in FIG. 8B, the heat medium flow path is formed so as to surround the mixing / reaction flow path 14, and in the embodiment shown in FIG. 8C, two parallel heat mediums are formed. Although the flow paths 18A and 18A are formed so as to sandwich both sides of the mixing / reaction flow path 14, they may be formed adjacent to one side.

  The control device 50 includes a determination unit 52 that determines the state of the system from the temperature measurement results by the temperature sensors Ts1 to Ts9 and the component measurement result of the reaction product by the component measurement device 20, and a temperature adjustment mechanism based on an instruction from the determination unit 52 A determination unit 54 that determines an instruction to 30 and 40 and an adjustment unit 56 that outputs a signal for adjusting the temperature adjustment mechanisms 30 and 40 according to the instruction of the determination unit 54 are provided. The determination unit 52, the determination unit 54, and the adjustment unit 56 may be individual computer chips, or may be shared by a single personal computer, for example.

  Hereinafter, in order to specifically show the advantages of the above-mentioned micro reaction system (or micro total analysis system), an example of a process when this system is operated will be described. FIG. 9 is a graph showing a typical pattern of data obtained as a result of the reaction of A + B → C in which the system of this embodiment is used. The vertical axis indicates the component amount, and the horizontal axis indicates the retention time. For example, when a chromatography apparatus is used as the component measuring device 20, it is necessary to perform standardization such as obtaining a calibration curve in advance and convert the component amount of the product with respect to the measurement result.

  It is assumed that the determination unit 52 determines from the result of FIG. 9 that “the production amount of the main product C is small under the current operating conditions, so that the production of the main product C is increased”. As described above, the reaction rate in the chemical reaction is dominantly determined by the temperature of the reaction region. Therefore, in order to increase the production of the main product C, it is predicted that it is possible to increase the temperature of the reaction region, and the determination unit 54 determines the temperature increase of the reaction region based on the result of the determination unit 52.

  Based on the determination by the determination unit 52, the determination unit 54 determines an adjustment amount for the temperature adjustment mechanism 30 in the reaction region. The control method may be open control in which the adjustment amount is determined using an empirical database prepared in advance, or by the determination unit 52 and the determination unit 54 so that the measurement result of the component measurement device 20 becomes a target value. It may be automatically adjusted. Of course, a control method using both of these may be used.

  Here, the automatic adjustment refers to a temperature adjustment in a certain reaction region, and a further adjustment amount is determined based on a result of an increase or decrease in the production amount of the main product C. Specifically, feedback control is performed based on a control arithmetic expression obtained theoretically or empirically describing the reaction process. For example, “(8) When the temperature of the reaction region in the microchannel chip 10 is increased and the tendency to increase the production amount of the main product C is obtained, It tries to increase the temperature of the inner reaction zone. "(B) If the risk of temperature runaway occurs due to an exothermic chemical reaction, try to cool the reaction zone." As described above, the control device 50 automatically repeats measurement → judgment → decision → adjustment based on the temperature sensors Ts1 to Ts9 provided in the microchannel chip 10 and the measurement results of the component measurement device 20. It is possible to set the temperature of the reaction region in the microchannel chip 10 to the optimum condition for the chemical reaction, and thus it is possible to construct a safe system that is high in productivity and can avoid temperature runaway. Become.

Here, a trial calculation is performed in order to show the superiority over the prior art when the microchannel chip of the present invention is used. As the conditions for the trial calculation, the specific heat of the reagent solution that performs chemical reaction in the microchannel chip is 4.2 [kJ / kg · K], the specific gravity of the reagent solution is 1000 [kg / m ³ ], 100 [μm] × 40 [μm], and the flow rate of the reagent solution in the reaction part is 0.001 [m / s]. Assume that it is necessary to increase the temperature in the reaction zone by 20 [K] to promote chemical reactions while operating the microreactor under these conditions. At that time, the amount of heat Q to be input to the reagent in the reaction region using the temperature adjustment mechanism 30 provided in the microchannel chip according to the present invention is:

It can be inferred that an extremely simple temperature adjustment mechanism 30, 40 can be used because it can be achieved with a very low heat quantity. Moreover, since the reaction part of the microreactor has a large specific surface area, it is easy to keep the temperature of the reaction region uniform when heat is applied from the outside.

For comparison, time to increase the temperature of the reagent solution by 20 [K] by adding 3.36 × 10 ^-7 [kW] to a conventional flask or beaker with 100 × 10 ^-6 [m ³ ] reagent Calculate t. However, here, the specific heat and specific gravity of the reagent solution are the same as the trial calculation in the microreactor. This time t is

Therefore, it turns out that it is not a very realistic system. Therefore, when temperature adjustment is performed by a chemical reaction in a conventional flask or beaker, an expensive temperature adjustment mechanism with high output is required.

  Furthermore, in the conventional flask and beaker system, since the specific surface area is smaller than that of the microreactor, it is extremely difficult to obtain a uniform temperature distribution in the reagent. In that case, when the temperature in the reagent is locally low, the reaction does not proceed sufficiently, and if the temperature in the reagent rises locally, the reactant in the reagent may be destroyed. There is a risk that no phenomenon will occur.

  Hereinafter, the temperature adjustment method by the temperature adjustment mechanism 30 of this embodiment will be described in detail. The temperature adjusting mechanism 30 attempts to adjust the temperature of the solution in the reaction region by circulating water or silicon oil having an appropriate temperature as a heat medium. In the following example, hot water is used to increase the reaction rate, but for temperature runaway or the like, cooling of the reaction region is attempted using cold water.

  Here, the lengths of the parallel heat medium channels 18a, 18b, and 18c necessary for temperature control using the parallel heat medium channels 18a, 18b, and 18c as shown in FIGS. To calculate. If the heat quantity q that can be transferred per unit length of the parallel heat medium flow paths 18a, 18b, and 18c is 0.1 [kW / m], the parallelism necessary to increase the above-described physical property fluid by 20 [K] under the same conditions. The length L of the heat medium flow paths 18a, 18b, 18c is:

Thus, it can be predicted that the temperature can be controlled using the parallel heat medium flow paths 18a, 18b, and 18c having very small lengths. This trial calculation was performed under various assumptions, and it would be necessary to design the lengths of the parallel heat medium flow paths 18a, 18b, 18c necessary for temperature control depending on the material of the chip and the experimental conditions.

  In the above description, the specific paths of the parallel heat medium flow paths 18a, 18b, and 18c in the microchannel chip 10 have not been described. For example, as shown in FIG. As shown in FIG. 11, the temperature can be adjusted independently by providing different pumps 36a, 36b, 36c and heat medium sources 34a, 34b, 34c in the parallel heat medium flow paths 18a, 18b, 18c as shown in FIG. Can be considered. In FIG. 11, the return flow path is omitted. In this example, since both the temperature and the flow rate of the heat medium are variable, fine temperature adjustment can be performed. If either one is provided, independent adjustment is possible. A common flow rate adjustment valve may be provided with the pump 36 in common.

  FIG. 12 shows another embodiment of the present invention, which is exactly the same as the previous embodiment except for the temperature adjustment mechanism. In this embodiment, the temperature adjustment mechanism 40 is a light heating device that emits light from a light source outside the microchannel chip 10. This includes two laser light irradiation devices 44 provided at positions facing the surface of the microchannel chip 10, a support / drive mechanism 46 that supports the laser light irradiation devices 44 and changes their positions and orientations, Irradiation control means (not shown) for adjusting the beam intensity, cross-sectional shape, focus, and the like. By using laser light in this way, a small region of the microchannel chip 10 can be irradiated with high intensity, and local temperature control can be performed, for example, at a specific location in the flow path.

  In the laser light irradiation device 44, the temperature adjustment may be performed by changing the laser light output or by changing the focal length of the laser light. As shown in FIG. 13, the beam can be focused to one point to perform pinpoint heating, but as shown in FIG. 14, the beam is irradiated to a band-like region along the mixing / reaction channel 14. Can also be heated. Of course, by selecting the cross-sectional shape and dimensions of the beam, an appropriate region can be heated as necessary. Further, the heating region can be easily changed by operating the support / drive mechanism 46 and directing the beam to a necessary place. Further, the support / drive mechanism 46 can be operated so that the beam reciprocates in a predetermined band. Thus, since the laser beam irradiation apparatus 44 irradiates coherent light from the outside, there exists an advantage that a heating location can be changed easily.

  Next, the operation of the temperature adjustment mechanism 40 using this laser beam will be described. The case where temperature control is performed using a laser as shown in FIG. 13 or FIG. 14 under the same conditions as the previous calculations will be calculated. Assuming that 80% of the laser power is absorbed to raise the reagent temperature, the required laser power P is

It becomes. The laser output of a laser transmitter that is relatively safe for the human body, such as that used in laser displacement meters, is about 3 [mW]. Therefore, if the temperature control method according to the present invention is used, a safe temperature control system can be constructed without using a high-power laser (the output of a carbon dioxide laser used for laser processing etc. is 35 [W] or more). It becomes possible to do. This trial calculation is based on various assumptions, and it is necessary to set the laser power necessary for temperature control according to the chip material and experimental conditions.

  Furthermore, as shown in FIG. 15, a temperature adjustment mechanism 30 using a heat medium and a temperature adjustment mechanism 40 using a laser beam may be used in combination. Thereby, for example, by using the former as a main body and performing a more local adjustment with the latter, a more precise adjustment can be performed. In addition, it is possible to provide a technique in which various temperature conditions are provided for the direction of solution flow in the microchannel chip 10 to advance a chemical reaction.

  Further, as shown in FIG. 16, the reagent is directly irradiated to the reagent for reasons such as the specific heat of the reagent and heat medium used for the target chemical reaction, the thermal conductivity, other physical properties, and the limitations of the apparatus. If it is not preferable to perform temperature control, the temperature may be adjusted by irradiating the heat medium with laser light.

  The present invention will be described more specifically with reference to the following examples. However, the description of the following examples is illustrative of the feasibility of the present invention, and the scope of the invention described in the claims. Should not be referred to for limited interpretation.

  As an example of automatic optimization of a chemical reaction to which the present invention is applied, an example in which a catalyst-free and heat-initiated polymerization of styrene is performed in a microreactor will be described. Styrene is polymerized to polystyrene by heating. When designing a reactor for carrying out this reaction, conventionally, a preliminary test by small sealed tube polymerization was performed, and a model equation for the reaction rate was determined therefrom, and the design parameters of the reactor were calculated. Table 1 shows an example of test results by sealed tube polymerization of 100% pure styrene.

  When the reaction rate equation is determined from this result by regression analysis, the following equation is obtained.

(Where n = 1, k ₀ = 1.53 × 10 ⁹ , E = 77200, r is the reaction rate [kgmol / h / m ³ ], C is the molar concentration of styrene [kgmol / m ³ ], n is the reaction order, k ₀ is the rate constant represented by the Arrhenius equation, k is the frequency factor [1 / hr], E is the activation energy [kJ / mol], R is the constant 8.314 [kJ / mol / K], T is the temperature [K] Is)
Here, the time change of the styrene concentration C is expressed by the following differential equation.

  The solution of this differential equation is:

(Where C ₀ is the initial molar concentration).
The yield x of polystyrene is equivalent to the conversion of styrene and is given by

  With the control mechanism according to the present invention, it is possible to automatically optimize the design evaluation function without the work of determining the above chemical reaction rate equation.

Here, consider the case where this reaction is carried out in a microreactor. The reactor volume is V [ml], and the raw material input volume flow rate is Q [ml / hr]. Here, assuming a plug flow reactor, for simplicity, the reaction time in the reactor is V / Q [hr] if the density change of the solution due to polymerization is ignored. It is proportional to the yield Qx per unit time of polystyrene. As an evaluation function when producing polystyrene, the value of yield × yield Qx ² is selected with the same importance placed on high yield of polystyrene and high yield due to ease of purification.

In the following example, the raw material volume flow rate Q and the reactor temperature are selected as design variables. The reactor volume is fixed at 1 [ml]. The volume flow rate control range is 0.05-2 [ml / hr], and the temperature control range is 120-160 ° C. At this time, the response surface of Qx ² is as shown in FIG.

Here, when the optimization method according to the present invention is applied, the control system calculates the current Qx ² from the flow rate and the output of the yield sensor in real time or with a slight delay time. Then, by changing the flow rate and temperature according to the designed optimization algorithm and monitoring the value of Qx ² each time, it becomes possible to search for the optimum point on the response phase with a few trials. The search trajectory on this response surface is shown in FIG.

  As an optimization algorithm, any known gradient method, annealing method, genetic algorithm, or the like may be used. The evaluation function is arbitrary as long as it is a function of a measured value and a set value, and can be freely changed according to the purpose without stopping the operation of the reactor. Also, when there are constraints on the control parameters (temperature, flow rate, etc.), it is possible to optimize the operation under those conditions.

  Hereinafter, an example of an optimization algorithm applicable to the microchannel chip reaction control of the present invention will be described in detail.

  The determination of reaction conditions in a wide variety of actual chemical reactions must be performed with caution because it results in increased yield, selectivity, and yield, as well as reduced amount of reagents to be discarded. However, in the prior art, the conditions for chemical reactions are often determined after empirical and extensive experimental trial and error.

  Therefore, the present application discloses a system that can determine reaction conditions without performing a carpet-bombing preliminary experiment by combining a mathematical technique and automatic control technology. Furthermore, since there is a possibility that a combination of reaction conditions that could not be predicted at first can be obtained by exploring the control system, it is possible to select conditions that can obtain a more ideal reaction result.

  First, based on constraints (reagent flow rate, pressure, temperature, and other conditions that should be specified during chemical reactions), target amounts (yield, selectivity, yield, and other chemical reactions) for changes in these constraints This is done by formulating the performance index as an evaluation function. When these conditions are formulated, in most cases, the constraint conditions and the evaluation function are nonlinear.

  For example, it can be sensuously understood that yields and yields cannot be said to be doubled simply by changing the conditions such as doubling the reagent flow rate or doubling the temperature in a chemical reaction. . For example, FIG. 18 shows an example of a peptide synthesis reaction result using a microreactor. The vertical axis in the graph in FIG. 18 indicates the yield, and the horizontal axis indicates the flow rate of the reagent solution. From this result, it is understood that there is an “optimal flow rate range” when peptide synthesis is performed in a microreactor. In addition, various reaction conditions (temperature, pressure, reagent concentration, flow rate, etc.) other than the reagent flow rate are adjusted to control the evaluation guidelines (yield, selectivity, etc.) of chemical reactions other than the yield to the optimum state. This is a very difficult task because they are complex and non-linear.

  Some of these problems can be solved by linear approximation, but there are many cases where they must be handled in a non-linear manner as in the aforementioned peptide synthesis results. When it becomes non-linear, the mathematical difficulty in solving the solution increases rapidly, and there is no guarantee that it can be solved like a linear problem. Therefore, there is no universal method for solving the problem, and various methods must be used depending on the case.

  In the following, explanations are given using the steepest-descent method, which is a kind of gradient method, as a mathematical optimization method, and the Adaptive Simulated Annealing (ASA) method, which is an exploratory optimization method. To do.

Mathematical Optimization Method As a mathematical optimization method, the steepest-descent method, which is the most basic method among gradient methods using gradient vectors of evaluation functions, will be described. The gradient vector g of the evaluation function f (x ₁ , x ₂ ,..., X _n ) is

(Where xn represents various constraint parameters)
Can be obtained.
Here, since the direction of g coincides with the maximum direction of the change rate of f, the search direction s ^(q) = −g ^(q) is a vector indicating the direction of the steepest descent as shown in FIG. In FIG. 19, the vertical axis and the horizontal axis are various constraint parameters, and the contour lines are values of the evaluation function. Here, the step width α is set to 1 or less,

As the calculation proceeds, the optimum value can be obtained.
However, the steepest descent method may not converge when the evaluation function has a distorted shape.

  The peptide synthesis (yield relative to reagent flow rate) in FIG. 18 clearly shows non-linear results. In this reaction, there is one extreme value, and the constraint condition (flow rate) is not so wide, so it is not difficult to experimentally find the optimum solution experimentally. However, also in the peptide synthesis reaction in FIG. 18, when the temperature, concentration, flow rate, pressure, etc. of the reagent solution are varied, each parameter affects the evaluation guidelines (yield, yield, selectivity, etc.) nonlinearly. Is likely to have multiple extreme values. In addition, as the number of parameters increases, the number of preliminary experiments increases, so the effect of incorporating the mathematical optimization method as described here is extremely large compared to the method of carpet bombing.

  Furthermore, as described above, there is no universal solution for nonlinear problems, and many other methods have been proposed as mathematical optimization methods. In the control method described in this specification, it is possible to select and cope with a suitable optimization method according to each chemical reaction. Table 2 shows a list of typical mathematical optimization methods for reference. In particular, when there are many constraints and each parameter has a wide range, it is preferable to use a combination of a plurality of mathematical methods for selecting the optimum conditions.

Exploratory optimization method One of the difficulties in optimization in a nonlinear problem is that the extreme value of the evaluation function is not limited to one as shown in FIG. 20, and there are many peaks (or valleys). It is. Each of these is a local optimum and does not necessarily correspond to a global optimum, that is, a true optimum. This happens as much as the properties of the evaluation function, the constraint condition, or both. As a method for obtaining the global optimum value without falling into the local optimum value, an exploratory optimization method may be used in this control.

Here, as a typical exploratory optimization method, an adaptive simulated annealing (ASA) method will be described as an example.
This method is an algorithm modeled on metal annealing (slow cooling means that each molecular energy that was in a high state uniformly settles in a low state). An image of convergence by ASA is shown in FIG. In FIG. 21, the vertical axis represents the value of the evaluation function, and the horizontal axis represents the constraint parameter. Here, in the example of FIG. 21, the smaller value of the evaluation function is set as the optimum value. First, optimization is started from the initial value. In the initial stage of the optimization search, energy that can escape from the local optimal value is given, and the search is partially allowed to allow the solution to be improved. This creates a variety of solutions and enables global search. As the search proceeds, the energy is reduced. By doing so, in the final stage of the search, the optimum value can be obtained without moving to another extreme value in the vicinity of the global optimum value.

  In the exploratory method, it is necessary to suitably adjust various conditions (initial value, energy reduction, etc.) used for the search for each chemical reaction. Can be prevented. GA (genetic algorithm) or the like may be used as an exploratory optimization method other than ASA.

  When only uniform optimization methods are used, “Yield is extremely high, but yield is extremely low”, “Yield and yield are high, but under high pressure conditions, running cost There are cases where conditions that are not suitable for actual microreactor operation, such as “High is dangerous” are obtained. In order to avoid these problems, optimization (multi-objective optimization) such as “Yield, yield, and selectivity are within this range, and what is the most suitable operating condition within that range?” ) Is required. For multi-objective optimization, you should not stick to a uniform optimization method, but you can get more favorable results by combining multiple mathematical and exploratory methods according to each chemical reaction .

It is a diagram for demonstrating the reaction principle in a typical reaction system. It is a schematic diagram which shows schematic structure of the system of this embodiment. It is a diagram which shows the virtual data for demonstrating the adjustment method by the system of this embodiment. It is a diagram which shows another virtual data for demonstrating the adjustment method by the system of this embodiment. It is a diagram illustrating a response curve of an evaluation function Qx ² polystyrene polymerization reaction according to the embodiment. Is a diagram showing the optimal point search path Qx ² according to the embodiment. It is a figure which shows the micro reaction system of the 1st Embodiment of this invention. 7A is a plan view of the microchannel chip, FIG. 7B is a view taken along the line AA in FIG. 7A, and FIG. 7C is a view taken along the line AA of the microchannel chip according to the modification. FIG. It is a graph which shows the example of the component measurement result at the time of use of the micro reaction system of FIG. It is an example which shows the flow of the heat medium of the micro reaction system of FIG. It is another example which shows the flow of the heat medium of the micro reaction system of FIG. It is a figure which shows the micro reaction system of the 2nd Embodiment of this invention. It is a figure which shows the example of the irradiation method of the laser beam in the micro reaction system of 2nd Embodiment. It is a figure which shows the other example of the irradiation method of the laser beam in the micro reaction system of 2nd Embodiment. It is a figure which shows the micro reaction system of the 3rd Embodiment of this invention. It is a figure which shows the modification of the micro reaction system of the 3rd Embodiment of this invention. It is a graph which shows the relationship between the energy distribution of the particle | grains in the case of a chemical reaction, and progress of reaction. It is a figure which shows an example of the peptide synthesis reaction result using a microreactor. It is a figure which shows the image by the steepest descent method as a mathematical optimization method. It is a figure which shows the example in which an evaluation function has a some extreme value. It is a figure which shows the image of the convergence by the solution adaptive annealing method as an exploratory optimization method.

Explanation of symbols

1 to 6
A, B Reagent solution C Product 1 Microchannel chip 1a, 1b Microchannel 1c for introducing reagent solution Jointed microchannel 2 Analyzing means 3 Control means
7 to 16
10 Microchannel chips 12A, 12B Raw material flow path 14 Mixing / reaction flow paths 18a, 18b, 18c Parallel heat medium flow path 18A Parallel heat medium flow path 20 Component measuring device 30, 40 Temperature adjusting mechanism 32 Heat medium pipe lines 34, 34a , 34b, 34c Heat medium source 36, 36a, 36b, 36c Pump 44 Laser light irradiation device 50 Control device Ts1-Ts9 Temperature sensor

Claims (23)

A reaction control system for a microchannel chip having at least two microchannels for introducing a reagent solution and a microreaction channel formed by joining the at least two microchannels,
An analysis means for analyzing a product generated by a reaction between reagent solutions merged in the micro reaction channel; and a reaction in the micro reaction channel based on an analysis result obtained from the analysis means. Control means to control the conditions involved;
Including microchannel chip reaction control system.   The microchannel chip reaction control system according to claim 1, wherein the control means is capable of controlling the flow rate, concentration, temperature and / or pressure of each reagent solution in the microchannel and / or microreaction channel.   The control means further controls the flow rate, concentration, temperature and / or pressure of each reagent solution in the microchannel and / or microreaction channel based on the ambient temperature and / or ambient pressure of the microchannel chip. The microchannel chip reaction control system of claim 2, which is controllable.   The microchannel chip reaction control system according to any one of claims 1 to 3, wherein the analyzing means is capable of measuring a component ratio in a product generated in the micro reaction channel.   The microchannel chip reaction control system according to any one of claims 1 to 4, wherein the analysis means is capable of measuring an amount of at least one component in a product generated in the micro reaction channel.   The control means monitors the component ratio or component amount in the product generated in the micro-channel chip and the temperature of the micro-channel chip constantly or for a certain period of time, and feeds back the monitoring result as needed. The microchannel chip reaction control system according to any one of claims 1 to 5, wherein the temperature of the channel chip, the flow rate and / or the concentration of each reagent solution can be controlled.   The control means further monitors the ambient temperature of the microchannel chip, the ambient pressure, and the pressure in the microchannel constantly or for a fixed time, and feeds back the monitoring result as needed, thereby the temperature of the microchannel chip, The microchannel chip reaction control system according to claim 6, wherein the flow rate and / or concentration of the reagent solution can be controlled.   The heat medium flow path parallel to the predetermined length portion of the minute reaction flow path is provided, and the temperature of the reaction region is adjusted via the heat medium sent into the heat medium flow path. 8. The microchannel chip reaction control system according to any one of 7 above.   9. The microchannel chip reaction control system according to claim 8, wherein the heat medium flow path is formed in a double tube structure coaxial with the micro reaction flow path.   The microchannel chip reaction control system according to claim 8 or 9, wherein a plurality of the heat medium flow paths are provided along the micro reaction flow path.   The microchannel chip reaction control system according to claim 8, wherein a temperature sensor is provided in the micro reaction channel.   The microchannel chip reaction control system according to claim 11, wherein the temperature sensor includes a resistance temperature detector or a thermocouple.   The microchannel chip reaction control system according to claim 8, wherein the analysis unit includes a chromatography device.   The micro of any one of claims 8 to 13, wherein the control means is capable of controlling an operation of a heat medium feeding means for sending a heat medium to the heat medium flow path based on outputs of the analysis means and a temperature sensor. Channel chip reaction control system.   The microchannel chip reaction control system according to claim 14, wherein the control means is capable of independently adjusting temperatures of the plurality of heat medium flow paths.   The microchannel chip reaction control system according to any one of claims 1 to 7, further comprising a temperature adjusting device that adjusts the temperature of the reaction region by irradiating the micro reaction channel with laser light.   The microchannel chip reaction control system according to claim 16, wherein a temperature sensor is provided in the minute reaction flow path.   The microchannel chip reaction control system according to claim 17, wherein the temperature sensor includes a resistance temperature detector or a thermocouple.   The microchannel chip reaction control according to any one of claims 16 to 18, wherein the control means adjusts the temperature of the reaction region by increasing or decreasing the output of the laser light and / or changing the focal length of the laser light. system.   The microchannel chip reaction control system according to any one of claims 16 to 19, wherein the temperature adjusting device can irradiate a plurality of regions in the microchannel chip with laser light.   The microchannel chip reaction control system according to any one of claims 16 to 20, further comprising the configuration according to any one of claims 8 to 15.   A micro total reaction system including the micro channel chip reaction control system according to any one of claims 1 to 21, wherein the micro total reaction system is capable of controlling reaction conditions between raw material compounds for substance production in the micro channel chip. .   A micro total analysis system including the micro channel chip reaction control system according to any one of claims 1 to 21, wherein the micro total analysis is capable of controlling a reaction condition between a reagent compound and a test compound in the micro channel chip. system.

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