JP5959835B2 - Reaction system - Google Patents

Description

  The present invention relates to a reaction vessel used for mixing a small volume of liquid, a reaction system using the vessel, and a reaction method using the system.

  In Diagnostic Nuclear Medicine, a radioactive drug (drug containing a radioactive substance) is administered into a living body, and an image reflecting the biological function is acquired through a PET (Positron Emission Tomography) gamma camera or the like.

For the production of a radiopharmaceutical, a very small amount of radioactive substance on the order of pg is used. For this reason, as a means for accelerating the reaction at the time of production, a production method using an extremely excessive amount of a labeling substance (about 10 ² to 10 ¹⁰ ) with respect to a radioactive substance is adopted (for example, Non-Patent Document 1 and 2).

  However, this production method is difficult to separate and purify, especially when the labeled product is a biomolecule, because the labeled biomolecule as a reaction product is similar to the unreacted labeled biomolecule. For this reason, the radiopharmaceutical produced by this production method includes not only labeled biomolecules but also unreacted labeled biomolecules. In this way, when a labeled biomolecule with the same target as the labeled biomolecule is contained in the radiopharmaceutical, the labeled biomolecule interacts with the target site, and the interaction between the labeled biomolecule and the target site Inhibit. As a result, the imaging accuracy is lowered. For this reason, in order to increase the imaging accuracy when using this type of radiopharmaceutical, it is necessary to increase the dose of the radiopharmaceutical to the living body.

  In a reaction field that handles a trace amount of substance, a microreactor whose mixing efficiency increases with a decrease in size in the width direction is known, and is applied to the production of a radiopharmaceutical (see, for example, Patent Documents 1 and 2). . Incidentally, the improvement in yield, reduction in reaction time, and other principles of effectiveness due to the use of a microreactor have already been confirmed (for example, see Non-Patent Document 3).

  However, when a microreactor is introduced in the production of a radiopharmaceutical, there are problems inherent to the microchannel. That is, in order to synthesize a clinically applicable amount of drug, the time to pass through the flow path must be long, and depending on the radioactive substance used (length of half-life), the radioactivity of the drug at the end of production may be It will be lower. In addition, there exist some which were disclosed by patent documents 3-7 in the literature regarding the microreactor and liquid feeding system which enable high-speed processing of a solution. Here, Patent Documents 3 and 5 to 7 disclose a microreactor that converts two types of raw materials into parallel multilayer flows, and Patent Document 4 discloses a liquid feeding system.

WO2006-071470 WO2010-101118A1 JP 2008-289449 A WO 2010-131297 A1 JP 2009-000592 A JP 2008-180606 A JP 2008-043912 A

Y. Murakami, H. Takamatsu, J. Taki, M. Tatsumi, A. Noda, R. Ichise, JF Tait, and S. Nishimura: 18F-labelled Annexin V: a PET Tracer for Apoptosis Imaging: Eur. J. Nucl Med. Mol. Imaging, 31, 469 (2004) P. Johnstrom, JC Clark, JD Pickard, AP Davenport: Automated synthesis of the generic peptide labeling agent N-Succinimidyl 4- [18F] fluorobenzoate and application to 18F-label the vasoactive transmitter urotensin-II as a Ligand for positron emission tomography: Nucl. Med. Biol., 35, 725 (2008) J. M. Gillies, C. Prenant, G. N. Chimon, G. J. Smethurst, W. Perrie, I. Hamblett, B. A. Dekker, J. Zweit: Microfluidic reactor for the radiosynthesis of PET radiotracers: Appl. Radiat. Isot., 64, 325 (2006)

  As described above, in the reaction apparatus using the microreactor described in Patent Document 1 or Patent Document 2, since the microchannel is used, the time for the radioactive substance to pass through the channel in order to synthesize a clinically applicable amount of the drug is used. It must be long. For this reason, depending on the radioactive substance to be used, the radioactivity of the medicine at the end of production is lowered due to attenuation. This is because the smaller the representative diameter of the microchannel, the better the mixing performance, while the pressure loss increases in inverse proportion to the fourth power of the representative diameter, making it difficult to increase the liquid flow rate.

  By the way, in the microreactors described in Patent Documents 3 and 5-7, a structure (multilayer flow structure) in which solutions are allowed to flow in multiple layers in parallel is adopted to increase the liquid feeding flow rate. However, it is necessary to provide a puddle on the back side of the portion where the raw material is introduced in order to form a problem of an increase in flow path capacity due to the multilayer flow structure and to form a stable multilayer flow structure.

  However, in order to increase the reaction efficiency of a very small amount of radioactive material on the order of pg, it is desirable to maintain the concentration of the radioactive material, and it is desirable to use a low volume solution of several tens to several hundreds μL at most. In light of this condition, the structure described in Patent Document 3 and the like has a problem that the dead volume in the multilayer flow structure channel is large.

  Moreover, the microreactor described in Patent Document 5 uses turbulent flow for mixing the solution. For this reason, a stable multilayer flow cannot be created, and reproducible mixing cannot be realized. In addition, the microreactor described in Patent Document 7 needs to flow a liquid that separates the solutions to be mixed, and there is a problem that the sample concentration in the reaction channel is lowered. That is, there is a problem that the reaction efficiency is poor and many samples are required.

  Therefore, the present invention is capable of feeding and recovering a small volume of liquid while the total capacity of the flow path constituting the multi-layer flow structure is much smaller than before, and also has a high mixing performance and liquid feeding capacity. An object is to provide a container, a reaction system using the container, and a reaction method using the system.

The present invention that solves the above-described problems includes a plurality of forms.
(1) The invention as one form is a reaction vessel for mixing the first and second liquids. As the reaction container, (1) a plurality of flow paths each having a constant width and spaced apart by a constant width in the width direction, the first liquid being placed in one end side of the flow path in the flow path A first flow path having a first nozzle to be introduced and guiding the first liquid introduced from the first nozzle to the other end side; (2) each having a certain width; and One or a plurality of channels having a certain width formed between the first channels, wherein the second liquid is introduced into the channel at the outflow end side of the first channel. A second flow path having a nozzle, and (3) a flow of a first liquid flowing out in a band shape from the first flow path and a flow of a second liquid flowing out in a band shape from the second flow path A funnel-like portion that shrinks the width of the multilayer flow along the flow along the flow; and (4) a processing portion that mixes the first and second liquids in the multilayer flow shrunk in the funnel-like portion. Suggest a thing.

  Here, the width of each laminar flow flowing into the processing unit is preferably 40 μm or less. The width of the laminar flow is determined by the relationship between the number of laminar flows forming the multi-layer flow and the flow path width of the processing section, and may be 35 μm or less, 30 μm or less, 25 μm or less, 20 μm or less, 15 μm or less, 10 μm or less, 5 μm or less. Good.

  Moreover, it is preferable that the flow path width | variety of a process part is 100 micrometers-1000 micrometers. The flow path width of the processing unit varies depending on the processing amount of the reaction vessel, and is 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, 500 μm, 550 μm, 600 μm, 650 μm, 700 μm, 750 μm, 800 μm, 850 μm, 900 μm. 950 μm may be used.

  In addition, the capacity of the first solution reservoir that temporarily holds the first liquid before being introduced into the first flow path, and the temporary capacity before the second liquid is introduced into the second flow path. The volume of the second solution reservoir to be held, the volume of the section in which the first liquid flows in the first flow path, the volume of the section in which the second liquid flows in the second flow path, and a funnel shape It is desirable that the sum of the capacity of the processing unit and the capacity of the processing unit is 135 μL or less. The total capacity is 130 μL or less, 125 μL or less, 120 μL or less, 115 μL or less, 110 μL or less, 110 μL or less, 105 μL or less, 100 μL or less, 95 μL or less, 90 μL or less, 85 μL or less, 80 μL or less, 75 μL or less, 70 μL or less, 65 μL. Hereinafter, it may be 60 μL or less, 55 μL or less, 50 μL or less, 45 μL or less, 40 μL or less, 35 μL or less, 30 μL or less, or 25 μL or less.

  Further, it is desirable that the volume of the first solution reservoir and the volume of the second solution reservoir are both 20 μL or less. Each capacity may be 15 μL or less, 10 μL or less, and 5 μL or less.

  Moreover, it is desirable that the first channel and the second channel are formed in parallel. More preferably, the first flow path and the second flow path are formed in parallel with a wall therebetween.

  The flow formed in the processing unit is preferably a laminar flow. Incidentally, when the flow velocity of the liquid passing through the processing section is v, the representative length of the flow path is d, and the kinematic viscosity coefficient of the liquid is ν, the flow velocity is such that the number of Ray nozzles Re (= vd / ν) is 2000 or less. It is desirable to select v and the representative length d.

(2) Another aspect of the invention is a reaction system that mixes the first and second liquids in a reaction vessel. As a reaction system, (1) a reaction unit including the reaction vessel having the above-described configuration, (2) a liquid feeding unit for supplying the first liquid and the second liquid to the reaction vessel, and (3) generated in the reaction vessel. A recovery unit for recovering the collected liquid, (4) a temperature control unit for controlling the temperature of the reaction vessel, and (5) a controller for controlling the liquid feeding unit, reaction unit, recovery unit, and temperature control unit Propose.

  Here, it is desirable that either one of the first and second liquids includes a radioactive substance, and further includes a radioactivity measurement unit that measures radioactivity for each of the liquid feeding unit and the recovery unit. That is, it is desirable to monitor the introduction of radioactive material and the recovery of the product solution containing the radioactive material.

  In addition, the liquid feeding unit includes a loop-like flow path prepared for introducing the first and second liquids, and a liquid feeding prepared for introducing a third liquid different from the first and second liquids. And a liquid feed switching valve for switching between introduction of the first liquid and the third liquid into the reaction container and introduction of the second liquid and the third liquid into the reaction container. It is desirable to control the switching of the liquid switching valve.

(3) The invention as another embodiment is a reaction method in a reaction system. As this reaction method, (1) the first liquid is formed from one end side of the first flow path composed of a plurality of flow paths each having a constant width and spaced apart by a constant width in the width direction. And a process of guiding the first liquid to the other end side, and (2) one or more of each having a certain width and having a certain width formed between the first flow paths. A process of introducing the second liquid from the outflow end side of the first flow path to the second flow path constituted by the flow paths, and (3) a first flow out of the first flow path in a band shape A process of shrinking along the flow the width of the multilayer flow in which the flow of liquid and the flow of the second liquid flowing out from the second channel are alternately arranged, and (4) in the contracted multilayer flow And a process of mixing the first and second liquids.

  According to the present invention, it is possible to achieve both a reduction in flow path capacity and the formation of a stable multilayer flow. For this reason, two types of liquids can be mixed in a short time. In addition, the amount of valuable liquid used can be reduced. Problems, configurations, and effects other than those described above will be clarified by the following description of embodiments.

The figure which shows the Example of the microreactor system for radiochemical reaction. FIG. 3 is a developed perspective view of the radiochemical reaction microreactor used in the radiochemical reaction microreactor system (Example 1). The front view and back view explaining the structure of a microreactor main body (Example 1). The elements on larger scale explaining the flow-path structure formed in the microreactor main body (Example 1). The figure explaining the relationship between the size and capacity | capacitance of each part of the flow-path structure formed in the microreactor main body (Example 1 and a comparative example). (Example 2) which is the schematic diagram of the liquid sending flow path used with the microreactor system for radiochemical reaction. The graph which shows the liquid feeding performance of a micro reactor main body (Example 3). The graph which shows the mixing performance of 1 Example of a micro reactor main body (Example 3). The graph which shows the collection | recovery result of the product solution at the time of sending 200 microliters each raw material solution to the microreactor system for radiochemical reaction (Example 4). The table | surface (Example 5) which shows the result of having implemented the radiochemical reaction in the microreactor system for radiochemical reaction.

  Hereinafter, embodiments of the present invention will be described with reference to the drawings. The embodiment of the present invention is not limited to the embodiments described later, and various modifications are possible within the scope of the technical idea. Note that components having the same function are denoted by the same or related reference symbols throughout the drawings for describing the embodiment, and the repetitive description thereof will be omitted. In the following embodiments, the description of the same or similar parts will not be repeated in principle unless particularly necessary.

  In the following, the present invention will be described by dividing it into a plurality of sections or a plurality of embodiments, but unless otherwise specified, each form is not irrelevant, and one is a modification of some or all of the other, There are relationships such as application examples, detailed explanations, and supplementary explanations. Further, in the following embodiments, when referring to the number of elements (including the number, numerical value, quantity, range, etc.), especially when clearly indicated and when clearly limited to a specific number in principle, etc. Except, it is not limited to the specific number, and may be more or less than the specific number.

  In the following embodiments, the constituent elements (including element steps and the like) are not necessarily required unless otherwise specified or apparently essential in principle. Similarly, in the following embodiments, when referring to the shapes, positional relationships, etc. of the components, etc., the shapes are substantially the same unless otherwise specified, or otherwise apparent in principle. And the like are included. The same applies to the above numbers and the like (including the number, numerical value, quantity, range, etc.).

[System configuration]
[overall structure]
The case where the reaction vessel according to the present invention is applied to a radiochemical reaction microreactor will be described. FIG. 1 shows an embodiment of a radiochemical reaction microreactor system using a radiochemical reaction microreactor, in which a radiopharmaceutical is produced. But the use of this invention is not restricted to manufacture of a radiopharmaceutical.

  A radiochemical reaction microreactor system 1 shown in FIG. 1 includes a liquid feeding unit 101, a reactor unit 201, a recovery unit 301, a temperature adjustment unit 401, a radioactivity measurement unit 501, and a control device 601.

  The liquid feeding unit 101 is a unit used for feeding the first raw material solution 123 and the second raw material solution 124 and the first solvent 121 and the second solvent 122 that transport the raw material solution. At least one of the first raw material solution 123 and the second raw material solution 124 contains a radioactive substance.

  The reactor unit 201 is a unit on which the radiochemical reaction microreactor 10 is mounted, and is used to generate a radiopharmaceutical by reacting the first raw material solution 123 and the second raw material solution 124. The radiochemical reaction microreactor 10 here corresponds to the reaction vessel in the present invention.

  The recovery unit 301 is a unit used for recovering the solution (product solution) generated in the radiochemical reaction microreactor 10. The temperature control unit 401 is a unit that manages the temperature of the radiochemical reaction microreactor 10. The radioactivity measurement unit 501 is a unit that measures the radioactivity of the liquid feeding unit 101 and the recovery unit 301. The control device 601 is a unit that controls the liquid feeding unit 101, the reactor unit 201, the recovery unit 301, the temperature adjustment unit 401, and the radioactivity measurement unit 501. The control device 601 is configured by a computer, for example.

[Detailed structure of each unit]
The liquid feeding unit 101 includes (1) a liquid feeding switching valve 102 for switching a solution suction / liquid feeding / waste liquid operation therein, (2) a solvent suction line 103, (3) a solvent waste liquid line 104, (4) Raw material introduction line 105, (5) Raw material sample loop 106, (6) Radioactivity sensor 107, (7) Syringe 108, (8) Syringe pump 109, (10) First solution introduction part 110, (11) Second It has a solution introduction part 111. In addition, the liquid supply unit 101 includes a device (not shown) such as (1) a pressure sensor for monitoring the pressure in the system, (2) a holder for fixing the syringe, (3) a power switch, (4) abnormal It includes an emergency stop switch when the operation occurs, (5) a communication connector, and (6) a fitting for connecting each line and sample loop to the switching valve 102.

  The microreactor unit 201 includes (1) a microreactor 10 for radiochemical reaction, and (2) a retention portion 202 for a reaction solution. Note that, between the radiochemical reaction microreactor 10 and the first solution introduction unit 110, between the radiochemical reaction microreactor 10 and the second solution introduction unit 111, and between the radiochemical reaction microreactor 10 and the retention unit 202 are not illustrated. Connected by fitting.

  The recovery unit 301 includes (1) a product and waste liquid recovery switching valve 302, (2) a product recovery line 303, (3) a waste liquid recovery line 304, and (4) a radioactivity sensor 305. The recovery switching valve 302 and the retention unit 202, the recovery switching valve 302 and the product solution recovery line 303, and the recovery switching valve 302 and the waste liquid recovery line 304 are connected by a fitting (not shown).

  The temperature adjustment unit 401 transmits and receives a temperature control signal 131A and a feedback signal 131B to and from the reactor unit 201. By sending and receiving these signals, the temperature of the radiochemical reaction microreactor 10 can be controlled. Methods for adjusting the temperature of the radiochemical reaction microreactor 10 include, for example, a method of circulating a heat medium using a circulating thermostat, a method of using a Peltier element, and the like. Examples of the temperature control target include a heat medium circulating around the radiochemical reaction microreactor 10, and the outside and inside of the radiochemical reaction microreactor 10. For example, by controlling the temperature of a solution flowing in the radiochemical reaction microreactor 10 or a place close to the flowing solution, more precise temperature control is possible.

  The radioactivity measurement unit 501 transmits and receives the radioactivity measurement signal 132A and the feedback signal 132B to and from the liquid feeding unit 101. When radioactivity is not detected when the raw material solution is introduced, the radioactivity measurement unit 501 sends feedback 132B to the liquid feeding unit 101 and interrupts liquid feeding by the liquid feeding unit 101. The installation position of the radioactivity sensor 107 in the liquid feeding unit 101 is close to the raw material sample loop 106 and as far as possible from the reactor unit 201 and the recovery unit 301. By setting to this position, more precise radioactivity measurement becomes possible.

  The radioactivity measurement unit 501 also transmits and receives the radioactivity measurement signal 133A and the feedback signal 133B to and from the recovery unit 301. The radioactivity measurement unit 501 determines whether or not the solution introduced from the retention unit 202 is a product solution based on the detection value of radioactivity given as the radioactivity measurement signal 133A from the radioactivity sensor 305, and the determination result is Based on this, a feedback signal 133B for switching the flow path of the recovery switching valve 302 is output. This switching makes it possible to separate the waste liquid 307 made of the liquid-sending solvent from the product solution 306. The installation position of the radioactivity sensor 305 is close to the recovery switching valve 302 and as far as possible from the liquid feeding unit 101 and the reactor unit 201. By setting to this position, more precise radioactivity measurement becomes possible.

  The control device 601 monitors and controls the operations of the five units described above. For example, the control device 601 transmits / receives a control signal 141B and a feedback signal 141A to / from the liquid feeding unit 101, and performs monitoring and control of operations in the liquid feeding unit 101. Note that the communication between the control device 601 and the other four units is relayed by the liquid feeding unit 101. For this reason, a data communication signal 142 is transmitted and received between the liquid feeding unit 101 and the reactor unit 201, and a data communication signal 143 is transmitted and received between the liquid feeding unit 101 and the recovery unit 301. A data communication signal 144 is transmitted / received between the adjustment unit 401 and a data communication signal 145 is transmitted / received between the liquid supply unit 101 and the radioactivity measurement unit 501. The control device 601 monitors and controls the reactor unit 201, the recovery unit 301, the temperature adjustment unit 401, and the radioactivity measurement unit 501 through these data communication signals.

  Specifically, the control device 601 controls the switching of the switching valve 102 in the liquid feeding unit 101, controls the suction and solution feeding of the solution into the syringe 108 by the drive control of the syringe pump 109, and fills the syringe 108. The disposal control of the solution to a waste liquid tank (not shown) is executed. In addition, the control device 601 also controls the suspension and resumption of liquid feeding control and suction control.

  If the control device 601 is used, the size of each syringe 108, the suction amount and suction speed of the solvent from the solvent suction line 103, the feeding amount and feeding speed of the solvent to the reactor unit 201, the solvent amount to the solvent waste liquid line 104, It is possible to set the amount of liquid to be fed, the speed of liquid feeding, the temperature of the radiochemical reaction microreactor 10, that is, the reaction temperature. In addition, a “time delay” of liquid feeding can be set, and the liquid feeding time can be changed for each syringe 108.

  Furthermore, if an input file that indicates two or more operations to be continued related to the operation of the syringe 108 and the valve in the suction / liquid feeding process is created in advance and read into the control device 601, a series of operations can be performed. It is also possible to execute automatic control of the operation. Equipped with an automatic control function, it is possible to avoid radiation exposure and perform remote automatic operation. Further, if the above-mentioned input file is stored in a storage area in the control device 601 and is read and operated as necessary, the input file can be appropriately rewritten.

  Further, the control device 601 includes pressure data in the system obtained from a pressure sensor (not shown) installed in the liquid feeding unit 101, temperature information obtained from the temperature adjustment unit 401, and radioactivity obtained from the radioactivity measurement unit 501. Detection values, time data, and the like can be recorded in an internal storage area. In addition, if the control device 601 previously determines a threshold value for the pressure in the system based on pressure resistance information such as a pressure sensor or a switching valve, the control system 601 makes the entire system emergency when the pressure in the system exceeds the threshold value. It can also be stopped.

  Here, the solvent suction line 103, the solvent waste liquid line 104, the raw material introduction line 105, the raw material sample loop 106, the first solution introduction unit 110, the second solution introduction unit 111, the retention unit 202, the product recovery line 303, The material such as the waste liquid recovery line 304 and the radiochemical reaction microreactor 10 may be any material that does not adversely affect the reaction to be performed, or a material that does not adsorb a substance in the liquid sending solution, and the temperature of the solution flowing inside the material. It is also possible to appropriately change it according to the concentration and physical properties. Examples of such materials include stainless steel, silicon, glass, hastelloy, silicon resin, and fluorine resin. In addition, such materials include glass lining, stainless steel, silicon coated surfaces such as nickel and gold, silicon surface oxidized, so-called corrosion resistance improved, and adsorptivity reduced. What was made can also be used.

[Solution feeding and recovery method]
Subsequently, a solution feeding / recovering method in the radiochemical reaction microreactor system 1 will be described.

  The radiochemical reaction microreactor system 1 reacts several tens of μL to several 100 μL of raw material solutions 123 and 124. For this reason, a method is adopted in which liquid feeding is performed in a state where the raw material solutions 123 and 124 are sandwiched between the solvents 121 and 122. This technique makes it possible to send a low volume reaction solution at a high flow rate. Specifically, the following method is executed.

  First, the setting of the liquid feed switching valve 102 is switched so that the first solvents 121 and 122 sucked from the solvent suction line 103 are sent to the syringe 108. Thereafter, the syringe pump 109 is pulled downward in the figure, and the first solvent 121 and the second solvent 122 are introduced into the syringe 108 through the corresponding solvent suction line 103 and the liquid feed switching valve 102.

  Next, the setting of the liquid feeding switching valve 102 is switched so that the first solvent 121 and the second solvent 122 are fed from the syringe 108 toward the first solution introducing unit 110 and the second solution introducing unit 111. After this switching, the syringe pump 109 is pushed upward in the figure, and the first solvent 121 in the syringe 108 is introduced into the radiochemical reaction microreactor 10 via the liquid feed switching valve 102 and the first solution introduction unit 110. Similarly, the second solvent 122 in the syringe 108 is introduced into the radiochemical reaction microreactor 10 via the liquid feed switching valve 102 and the second solution introduction unit 111.

  By the liquid feeding so far, the solution for liquid feeding is filled in the line. Thereafter, the setting of the liquid feed switching valve 102 is switched so that the first raw material solution 123 and the second raw material solution 124 introduced from the raw material introduction line 105 are fed to the raw material sample loop 106. When switching is completed, a syringe pump (not shown) is pushed in, and the first raw material solution 123 and the second raw material solution 124 in the syringe pass through the corresponding raw material introduction line 105 and liquid feed switching valve 102, respectively, and the raw material sample loop. 106. At this time, introduction of the first raw material solution 123 and the second raw material solution 124 containing the radioactive substance into the raw material sample loop 106 is monitored by the radioactivity sensor 107.

  Next, the liquid supply switching valve 102 is set so that the liquid supply solvent introduced from the syringe 108 is sent to the first solution introduction unit 110 and the second solution introduction unit 111 via the raw material sample loop 106. Switch to After this switching, the syringe pump 109 is pushed upward in the figure to introduce a solvent for liquid feeding into the liquid feeding switching valve 102. As a result, the first raw material solution 123 in the raw material sample loop 106 is pushed from behind by the first solvent 121 introduced using the syringe pump 109, and passes through the liquid feed switching valve 102 and the first solution introduction unit 110. Then, it is introduced into the microreactor 10 for radiochemical reaction. Similarly, the second raw material solution 124 in the raw material sample loop 106 is pushed from behind by the second solvent 122 introduced using the syringe pump 109, and passes through the liquid feed switching valve 102 and the second solution introduction unit 111. Then, it is introduced into the microreactor 10 for radiochemical reaction.

  As described above, liquid feeding is realized by sandwiching the first raw material solution 123 and the second raw material solution 124 between the first solvent 121 and the second solvent 122. Here, the first raw material solution 123 and the first solvent 121 before and after the first raw material solution 123 and between the second raw material solution 124 and the second solvent 122 before and after the first raw material solution 123 may be supplied with a gas interposed therebetween. The first raw material solution 123 and the second raw material solution 124 are mixed in the radiochemical reaction microreactor 10, and the product solution is introduced into the recovery switching valve 302 in the recovery unit 301 through the retention unit 202. Incidentally, the product solution is fed in a state where the product solution is sandwiched between the mixed solution of the first solvent 121 and the second solvent 122. Note that the mixed solution of the first solvent 121 and the second solvent 122 is recovered as the waste liquid 307 through the recovery switching valve 302 and the waste liquid recovery line 304.

  On the other hand, the product solution 306 generated by mixing the first raw material solution 123 and the second raw material solution 124 is recovered through the recovery switching valve 302 and the product recovery line 303. The switching of the recovery switching valve 302 here can be switched according to the amount of the solution sent, or can be switched by detecting the radioactivity by the radioactivity sensor 305 installed in the recovery unit 301.

  In the case of FIG. 1, two syringes 108 are mounted inside the liquid feeding unit 101, but the number of syringes can be increased by an additional liquid feeding unit including two syringes 108 as one set. As shown in FIG. 1, in the case of the radiochemical reaction microreactor system 1 in which only two syringes 108 are mounted, once the solvent in the syringes 108 has been sent out (used up), the solvent suction line is thereafter used. An operation of refilling the syringe 108 with the solvent through 103 is required, and a certain amount of time is required for the operation. However, if an additional unit can be installed, the first solvent 121 and the second solvent 122 can be continuously fed without waiting for refilling (suction) of the first solvent 121 and the second solvent 122, and radiation can be performed. A plurality of reactions can be performed continuously in the chemical reaction microreactor 10.

[Example 1]
[Structure of Microreactor 10 for Radiochemical Reaction]
Next, the structure of the radiochemical reaction microreactor 10 will be described in detail. FIG. 2 is a developed perspective view of the radiochemical reaction microreactor 10.

  As shown in FIG. 2, the radiochemical reaction microreactor 10 includes a microreactor body 20 formed from a PEEK plate material having a thickness of several millimeters, a lid member 30 formed from a PEEK plate material disposed on the upper surface side of the microreactor body 20, and A lid member 40 formed from a SUS316 stainless steel plate material disposed on the upper surface side of the lid member 30, an adapter member 50 formed from a PEEK plate material disposed on the lower surface side of the microreactor body 20, and a SUS316 disposed on the lower surface side of the adapter member 50. And an adapter member 60 formed of a stainless steel plate material.

  The radiochemical reaction microreactor 10 is configured by laminating the adapter member 60, the adapter member 50, the microreactor main body 20, the lid member 30, and the lid member 40, and fastening their peripheral portions with screws (not shown). Here, the lid member 30 constitutes a ceiling portion of the channel opened upward on the surface side (upper surface in the drawing) of the microreactor body 20. An inlet port portion 51 for introducing a solution containing a radioactive substance into the microreactor main body 20 or a solution containing a substance labeled with the radioactive substance into the surface (upper surface in the drawing) of the adapter member 50 facing the microreactor main body 20. And an outlet port portion 52 are formed and communicate with the lower surface of the adapter member 50, respectively.

  An inlet portion 63 for introducing a solution containing a radioactive substance into the microreactor body 20 and a solution containing a substance labeled with the radioactive substance on the surface of the adapter member 60 facing the adapter member 50 (upper surface in the drawing) An outlet portion 64 is formed. The inlet 63 communicates with solution inlets 61a and 61b formed on the back surface (lower surface in the drawing) of the adapter member 60. The outlet portion 64 communicates with the solution outlet 62 formed on the back surface (lower surface in the drawing) of the adapter member 60.

  An outer peripheral portion such as a flow path formed in the microreactor body 20 and an outer peripheral portion of the inlet port portion 51 and the outlet port portion 52 formed in the adapter member 50 are not shown in the figure made of an O-ring made of fluororubber or the like. The sealing member is installed.

  In the case of the present embodiment, the lid member 30 and the lid member 40, and the adapter member 50 and the adapter member 60 are provided with two different materials, respectively, but this stably stabilizes the flow path formed in the microreactor body 20. This is because the difference in hardness between the SUS316 stainless steel plate material and the PEEK plate material forming the microreactor body 20 is taken into consideration.

  For this reason, the same PEEK material lid member 30 as the microreactor body 20 is installed between the SUS316 stainless steel plate lid member 40 and the microreactor body 20, and the same PEEK as the microreactor body 20 between the adapter member 60 and the microreactor body 20. A material adapter member 50 is provided.

  When the microreactor body 20 is formed of a material having a hardness close to that of the SUS316 stainless steel plate material, the lid members 30 and 40 and the adapter members 50 and 60 are configured by one member formed of the SUS316 stainless steel plate material. Also good.

  In this embodiment, the microreactor body 20 is formed of a PEEK plate material. However, any material that does not adversely affect the reaction performed in the microreactor body 20 or that does not adsorb substances in the solution introduced into the microreactor body 20 may be used. Depending on the type of reaction, it can be changed as appropriate. As such a material, for example, stainless steel, silicon, gold, glass, hastelloy, silicon resin, fluorine resin, or the like can be used. Also, a glass lining, a metal surface coated with nickel or gold, a silicon surface oxidized, so-called improved corrosion resistance, or improved adsorbability may be used. .

  The material of the above-described seal member (not shown) may be any material that does not adversely affect the reaction, and can be appropriately changed according to the type of reaction to be performed. For example, silicon resin, fluorine resin, or the like can be used.

  In this embodiment, the seal member is an assembly-type chip that can be disassembled using fluororubber. A decomposable microreactor has high maintainability because it can be disassembled and cleaned when clogging or the like occurs in the interior. In FIG. 2, ten holes or screw holes are formed in the outer peripheral portion of the adapter member 60, the adapter member 50, the microreactor body 20, the lid member 30, and the lid member 40 to facilitate screw fastening. In addition, it is good also as a microreactor which cannot be decomposed | disassembled by directly fixing the cover member 30 and the adapter member 50 to the front and back of the microreactor main body 20 using other methods, such as laser joining and an adhesive agent. In a microreactor that cannot be disassembled, leakage of radioactive materials or the like due to a sealing failure caused by a broken O-ring or the like can be avoided. Moreover, when using for the reaction which manufactures the radiopharmaceutical applied to clinical, the quality of a chemical | medical agent is securable by making it disposable.

  FIG. 3 shows a front view and a back view of the microreactor main body 20 constituting the radiochemical reaction microreactor 10. FIG. 4 shows a partially enlarged view of the liquid feeding structure formed in the microreactor body 20.

  As shown in FIG. 3, four fastening holes 29 are formed in the peripheral portion of the microreactor body 20 in the vertical direction and three in the horizontal direction. A rectangular groove 28 with rounded corners is provided on the center side of the hole 29. A seal member (not shown) is attached to the groove 28.

  On the surface side of the microreactor body 20 shown in FIG. 3A, a flow path for mixing the first liquid and the second liquid is formed closer to the center than the groove 28. FIG. 4 shows a partially enlarged view of the flow path.

  The flow paths in the present embodiment are, in order from the upstream side, the first solution supply section 21, the first solution guide flow path section 22, the second solution supply section 23, the funnel-shaped section 24, and the processing section 25. And the solution discharge unit 26.

  The first solution guide channel section 22 is configured as an aggregate of thirteen channels (first channels) each having a certain width and formed apart by a certain width in the width direction. . Each flow path constituting the first solution induction flow path section 22 is configured as a space sandwiched between two walls formed in parallel with each other. Both ends of the 13 flow paths are formed as open ends. A first solution supply unit 21 for introducing the first raw material solution 123 from the back side of the microreactor body 20 is formed at the most upstream part of the 13 flow paths. The 1st raw material solution 123 introduced from the 1st solution supply part 21 is induced | guided | derived as a strip | belt-shaped flow to the outflow port located in the lower end side in a figure. The outlet of the first solution guide channel 22 is connected to the inlet opening of the funnel 24.

  Here, the first solution supply unit 21 is formed by 13 openings (first solution supply nozzle 21 </ b> A) that connect the front surface and the back surface of the microreactor body 20. As shown in FIG. 4, the first solution supply nozzles 21 </ b> A are formed in one row in the width direction of the microreactor body 20 at substantially the same length interval as the surface diameter of the nozzles. The first raw material solution 123 is introduced into the first solution guide channel portion 22 through the first solution supply nozzle 21A.

  As shown in FIG. 3 (b), a first solution reservoir 27a for temporarily storing the first raw material solution 123 as a supply liquid is formed on the back surface of the microreactor body 20, and the first solution An opening on the back side of the first solution supply nozzle 21A is located in the region of the reservoir 27a. Incidentally, the 1st solution storage part 27a is formed as a recessed part depressed in the thickness direction with respect to the back surface of the microreactor body 20. The first solution reservoir 27 a is connected to the inlet port portion 51 of the adapter member 50.

  The second solution supply unit 23 is disposed in a space sandwiched between 13 flow paths that constitute the first solution induction flow path unit 22 and is used for introducing the second raw material solution 124 into the funnel-shaped part 24. . As shown in FIG. 4, when the first solution induction channel portion 22 is formed as 13 parallel channels, each channel has the same width as the first solution induction channel portion 22. In addition, twelve flow paths (second flow paths) separated by a certain width in the width direction are formed. In this specification, the 2nd solution supply part 23 is arrange | positioned in the most downstream position of these 12 flow paths.

  The outlet of the second flow path in which the second solution supply unit 23 is disposed is connected to the inlet side opening of the funnel-shaped unit 24. Here, the second solution supply unit 23 is formed by twelve openings (second solution supply nozzles 23 </ b> A) that connect the front surface and the back surface of the microreactor body 20. As shown in FIG. 4, the second solution supply nozzles 23 </ b> A are formed in one row in the width direction of the microreactor body 20 at substantially the same length interval as the surface diameter of the nozzles. The second raw material solution 124 is introduced into the second solution guide channel portion 22 through the second solution supply nozzle 23A.

  As shown in FIG. 3B, a second solution reservoir 27b for temporarily storing a second raw material solution 124 as a supply liquid is formed on the back surface of the microreactor body 20, and the second solution An opening on the back surface side of the second solution supply nozzle 23A is located in the area of the reservoir 27b. Incidentally, the second solution reservoir 27b is formed as a recess recessed in the thickness direction with respect to the back surface of the microreactor body 20. The second solution reservoir 27 b is connected to the inlet port portion 51 of the adapter member 50.

  As described above, the first solution supply unit 21 (that is, the first solution supply nozzle 21A) is located upstream of the second solution supply unit 23 (that is, the second solution supply nozzle 23A). That is, the flow path length from the first solution supply part 21 to the inlet of the funnel-shaped part 24 is formed sufficiently longer than the flow path length from the second solution supply part 23 to the inlet of the funnel-shaped part 24. Thus, as a result of the first raw material solution 123 flowing in a strip shape over a relatively long distance from the uppermost stream portion of the first solution guiding flow path portion 22 (first flow path) to the outlet, the fine first raw material solution is obtained. 123 stable flows can be established (formed). As a result, the second raw material solution 124 can be introduced into the funnel-shaped portion 24 so as to be sandwiched between the strip-shaped flow formed by the first raw material solution 123.

  Incidentally, the funnel-shaped part 24 is manufactured in a funnel shape so that the flow path width on the inflow side is the widest and the flow path width becomes narrower on the outflow side. The outlet of the funnel-shaped part 24 is connected to a predetermined length processing part 25 having the same channel width as the channel width. For this reason, in the case of FIG. 4, it is formed by 25 belt-like flows (13 first raw material solution 123 flows and 12 second raw material solution 124 flows) introduced into the funnel-like portion 24. Can be introduced into the processing unit 25 in a contracted state in the width direction. That is, even if the flow path width of the processing unit 25 is large to some extent, the width of the laminar flow formed therein can be reduced. As described above, by introducing the first raw material solution 123 and the second raw material solution 124 into the processing unit 25 as a large number of laminar flows, stable mixing can be achieved while securing the liquid feeding amount.

  The product solution generated by the reaction in the processing unit 25 is guided to the solution discharge unit 26. As shown in FIGS. 3A and 3B, the solution discharge part 26 is formed as a hole connecting from the front surface to the back surface of the microreactor body 20. Accordingly, the product solution is led out from the front surface of the microreactor body 20 to the back surface. As shown in FIG. 2, the solution discharge part 26 on the back side of the microreactor body 20 is connected to the outlet port part 52 of the adapter member 50. Further, the outlet port part 52 is connected to the outlet part 64 of the adapter member 60. Thereby, the product solution generated in the flow path of the microreactor body 20 is discharged from the solution discharge port 62 formed on the back surface (lower surface in the drawing) side of the adapter member 60.

[Flow of Solution in Microreactor 10 for Radiochemical Reaction]
Next, the flow of liquid realized on the flow path of the microreactor body 20 according to the present embodiment will be described with reference to FIGS.

  The first raw material solution 123 fed from the first solution introduction unit 110 shown in FIG. 1 is introduced into the radiochemical reaction microreactor 10 from the first solution introduction port 61a formed on the lower surface of the adapter member 60. . The solution introduction port 61a is formed to have a large diameter for attaching a socket (not shown), and the adapter member 60, the small hole of the adapter member 50, and the inlet port portion 51 installed on the upper side surface of the adapter member 50, The one raw material solution 123 is guided to the first solution reservoir 27a.

  The first solution reservoir 27a has a minimum capacity for storing an amount of the first raw material solution 123 that can be supplied to all the first solution supply nozzles 21A at an equal pressure.

  The first raw material solution 123 filling the first solution reservoir 27a is supplied at a pressure equal to all the first solution supply nozzles 21A. As a result, the first raw material solution 123 is discharged almost uniformly from all the first solution supply nozzles 21 </ b> A, and is guided from the first solution supply nozzles 21 </ b> A to the first solution guide channel portion 22.

  The first solution guide channel section 22 has a channel width that is approximately the same as the surface diameter of the first solution supply nozzle 21A, and the channel depth is also approximately the same size. After passing through the channel length of about ten times the channel width, the first raw material solution 123 flows out to the funnel-shaped portion 24 in which the channel width is formed in a funnel shape.

  The funnel-shaped portion 24 is a groove that is slightly dug down the surface of the microreactor body 20. A second solution supply section 23 having a large number of second solution supply nozzles 23 </ b> A is formed at the terminal end (lowermost portion) of the space formed between the first solution guide flow path sections 22. The position of the second solution supply nozzle 23 </ b> A is shifted from the first solution supply nozzle 21 </ b> A by one nozzle in the width direction of the microreactor body 20.

  The second solution supply nozzle 23A has the same configuration as the first solution supply unit 21, and has a second solution reservoir 27b shown in FIG. 3B on the back side of the microreactor body 20. Similar to the first raw material solution 123, the second raw material solution 124 also includes the adapter member 60, a small hole in the adapter member 50, the inlet port portion 51 installed on the upper surface of the adapter member 50, the microreactor body 20 from the second solution introduction port 61 b. The liquid is supplied to the front side of the microreactor body 20 through the second solution reservoir 27b formed on the back surface of the microreactor. The second raw material solution 124 is discharged from the second solution supply nozzle 23 </ b> A and guided to the funnel portion 24.

  In the first solution induction channel section 22 through which the first raw material solution 123 introduced from the first solution supply section 21 is guided, the longitudinal direction of the microreactor body 20 (the direction of solution flow) from the position of the first solution supply nozzle 21A. ) Between the first flow paths constituting the first solution guiding flow path section 22 so as to be independent from each other as a large number of strip-shaped flows of the first raw material solution 123. A space is formed. This space is referred to as a second flow path in this specification. Thus, since the first solution supply nozzle 21A and the second solution supply nozzle 23A are alternately shifted in the width direction, the first raw material solution 123 discharged from the multiple first solution supply nozzles 21A and a large number The second raw material solution 124 discharged from the second solution supply nozzle 23 </ b> A forms a multilayer flow that alternately flows in the width direction in the funnel-shaped portion 24.

  As described above, the first solution supply unit 21, the first solution guide channel unit 22, the second solution supply unit 23, and the funnel-shaped unit 24 divide the two types of solutions into a plurality of strip-shaped flows, respectively, Are formed in a multi-layered flow. As the multilayer flow formed by the funnel-shaped portion 24 flows in the longitudinal direction of the microreactor body 20 (solution flow direction), the cross-sectional area in the width direction of each subdivided flow is contracted to become an accelerated flow. It flows into the processing unit 25. That is, when moving from the funnel-shaped part 24 to the processing part 25, the width of the solution flow is gradually contracted in a direction perpendicular to the contact interface of the multilayer flow, and the width direction of the individual solution layers constituting the multilayer flow The length becomes narrower.

  The processing unit 25 is a flow path extending in the longitudinal direction of the microreactor main body 20, and the end thereof reaches the solution discharge unit 26. The length of the processing unit 25 only needs to ensure the time required for mixing the first raw material solution 123 and the second raw material solution 124. Therefore, the flow path width and length of the processing unit 25 may be determined according to the diffusion time during which the two types of solutions can be completely mixed, and the shape does not need to be linear as shown in FIG. For example, it may be meandering or spiral. A plurality of holes are formed in the outlet port portion 52 of the adapter member 50 and the outlet portion 64 of the adapter member 60 so that the flow path length can be changed according to the purpose.

  The first raw material solution 123 and the second raw material solution 124 that have been mixed from the liquid discharge portion 26 formed at the lower center of the microreactor body 20, the outlet port portion 52 of the adapter member 50 and the solution discharge port 62 of the adapter member 60. Then, it is recovered by the recovery unit 301 connected to the outside of the radiochemical reaction microreactor 10.

[Mixing performance]
Next, it will be described that by using the radiochemical reaction microreactor 10 having the flow channel structure according to the embodiment, both the high mixing performance by the multilayer flow and the high flow rate can be achieved.

  The mixing of different solutions is to make the molecules constituting each solution diffuse to each other. When mixing the solution by molecular diffusion, the time required to complete the mixing is derived from the width of the solution in the direction perpendicular to the contact interface, that is, the diffusion distance of the molecule. Specifically, the mixing time is proportional to the square of the width of the solution in the direction perpendicular to the contact interface.

  Therefore, in the present embodiment, the first solution supply nozzle 21A, the second solution supply nozzle 23A, the first solution guide channel section 22 and the processing section 25 correspond to the width of the solution in the direction perpendicular to the contact interface related to the diffusion distance. The width is shortened.

  On the other hand, when the width of the solution in the direction perpendicular to the contact interface is shortened, the pressure loss increases in inverse proportion to the fourth power of the width of the solution in the direction perpendicular to the contact interface, and the amount of solution delivered decreases. End up. Therefore, in the present embodiment, by forming a large number of solution flows in parallel, both speeding up the mixing speed and increasing the amount of liquid fed are achieved.

  As described above, in the case of the present embodiment, since a multi-layer flow is formed in the funnel-shaped portion 24, the ratio of the contact area to the flow rate of the two types of liquids increases, and the molecular diffusion generated on the contact surface is actively performed. Become. Thereby, the amount of molecular diffusion within a predetermined time increases, and the mixing process in the microreactor can be made efficient from both the mixing speed and the solution processing amount.

  Further, since the funnel-shaped portion 24 has a shape in which the flow path width contracts toward the downstream, the width of each band-shaped flow constituting the formed multilayer flow is narrowed toward the downstream, and the molecular diffusion distance is shortened. As a result, one-stage high-speed mixing is possible. In addition, since there is no irregularity in mixing using molecular diffusion, the two liquids can be reliably mixed if the interface contact state is maintained for a time required for mixing.

[Reduction of channel capacity]
Next, the reduction of the channel capacity necessary for carrying out a very small amount of radiochemical reaction will be described. Here, a description will be given using the chart shown in FIG. The chart shown in FIG. 5 shows the size and capacity of each part of the flow path of this example. In FIG. 5, the size and capacity of each part of the flow path are also shown for a standard capacity microreactor for comparison with the example.

  In this embodiment, a very small amount of radioactive material on the order of pg is handled. For this reason, in order to maintain the solution concentration, a low volume solution of several tens of μL to several hundreds of μL is introduced into the microreactor body 20.

  Therefore, the volume of the flow path part is 135 μL or less in total including the first solution reservoir part 27a and the second solution reservoir part 27b, the first solution guide flow path part 22, the funnel part 24, and the treatment part 25. Is preferred. For example, 130 μL or less, 125 μL or less, 120 μL or less, 115 μL or less, 110 μL or less, 110 μL or less, 105 μL or less, 100 μL or less, 95 μL or less, 90 μL or less, 85 μL or less, 80 μL or less, 75 μL or less, 70 μL or less, 65 μL or less, 60 μL or less, 55 μL Hereinafter, it is preferably 50 μL or less, 45 μL or less, 40 μL or less, 35 μL or less, 30 μL or less, or 25 μL or less.

  In particular, when the capacity of the first solution reservoir 27a and the second solution reservoir 27b is larger than the amount of the raw material solution, the raw material solution and the raw material solution are mixed in the first solution reservoir 27a and the second solution reservoir 27b. There is a possibility that the solvent to be delivered will diffuse. Accordingly, the volumes of the first solution reservoir 27a and the second solution reservoir 27b are preferably lower than the volume of the raw material solution to be fed, and preferably 20 μL or less. More preferably, each volume may be 15 μL or less, 10 μL or less, and 5 μL or less.

  By the way, as a method of reducing the capacity of the flow path portion, there is a method of reducing the flow path width. The reduction of the flow path width was set to 200 μm, which does not significantly reduce the liquid feeding flow rate. As another method of reducing the capacity of the flow path portion, there is a method of reducing the number of multi-layer flows flowing through the funnel-shaped portion 24. The number of reductions in the multi-layer flow was 25 lines where the molecular diffusion rate did not decrease significantly.

  In the chart of FIG. 5, unlike FIG. 4 described above, the first solution supply nozzle 21A has a diameter of 200 μm and is provided with 13 pieces. In addition, the diameter of the second solution supply nozzle 23A is 200 μm, and twelve are provided. In this case, on the inlet side of the funnel-shaped portion 24, the first raw material solution 123 and the second raw material solution 124 are alternately arranged in 25 rows at intervals of 200 μm.

  When this multi-layer flow is contracted in the width direction and introduced into the processing section 25 having a flow path width of 200 μm, the laminar flow width per row is equal to the diffusion distance, so the size is 8 μm. This means that when the diffusion coefficient of the first raw material solution 123 and the second raw material solution 124 is considered as water, the mixing is completed in only 0.01 seconds or less.

  In addition, the flow path length of the process part 25 in a present Example is 13 mm, and a flow path capacity | capacitance is 0.5 microliter. As calculated from the mixing time of 0.008 s, if the liquid is sent at a total flow rate of at least 4 mL / min, the first raw material solution 123 and the second raw material solution 124 are completely mixed while passing through the processing unit 25. Can be terminated.

  In addition, in order to hold | maintain a multilayer flow without disturbing, it is desirable for the flow in a flow path to be a laminar flow. In this embodiment, the upper limit of the Reynolds number Re indicating the flow state is set to 2000 or less so that the flow is laminar in the processing unit 25. Here, the Reynolds number Re is represented by Re = vd / ν, where v is the flow velocity of the liquid, d is the representative length of the flow path, and ν is the kinematic viscosity coefficient of the liquid. Here, when d is 200 μm which is the flow path width of the processing unit 25, ν is considered to be water, and the total flow rate of the first raw material solution 123 and the second raw material solution 124 is assumed to be 20 mL / min, the Reynolds number Re Becomes 2000 or less.

  That is, in the processing unit 25 of the present embodiment, the laminar flow can be maintained at a total flow rate of about 20 mL / min or less including both the first raw material solution 123 and the second raw material solution 124.

  As described above, in the present embodiment, the first raw material solution 123 and the second raw material solution 124 are set to be laminar in the processing unit 25. Therefore, the mixing performance of the radiochemical reaction microreactor 10 is determined by the number of layers in the multilayer flow and the flow path width in the processing unit 25.

  In order to reduce the capacity of the radiochemical reaction microreactor 10 according to the embodiment while maintaining the same mixing performance as the standard capacity microreactor shown in FIG. 5 as a comparative example, a laminar flow formed in the processing unit 25 is used. The width is preferably 10 μm or less.

  However, when the number of multi-layer flows is increased, the capacity of the liquid reservoir 27 increases, and therefore the flow path width of the processing unit 25 is preferably 100 μm to 1000 μm. The flow path width of the processing unit varies depending on the processing amount of the reaction vessel, and is 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, 500 μm, 550 μm, 600 μm, 650 μm, 700 μm, 750 μm, 800 μm, 850 μm, 900 μm. 950 μm may be used.

  In order to achieve a molecular diffusion rate equivalent to that of the present embodiment in a general microreactor Y-shaped channel, a fine channel corresponding to a laminar flow width of 8 μm of the multilayer flow formed in the processing section 25 in this embodiment. Must be formed. However, if an attempt is made to flow the solution with a channel width corresponding to 8 μm, pressure loss is applied and it is difficult to increase the flow rate.

However, in this embodiment, the laminar flow width is 8 μm, but the flow path width is 200 μm, so the mixing performance is the same as the flow path width of 8 μm, the pressure loss is 1/1 × 10 ⁵ , and the flow rate is kept high. You can also. As described above, in this embodiment, although the flow path includes 25 200 μm multi-layer flows, the capacity of the flow path portion is as small as 31 μL and the molecular diffusion speed equivalent to a flow width of several tens of μm can be realized. In addition, the liquid can be fed at a high speed of 20 mL / min.

  Further, in this embodiment, a run-up section (that is, the first solution guide channel portion 22) for stabilizing the flow of the first raw material solution 123 is provided, and the position where the flow of the first raw material solution 123 is stable (that is, the first raw solution 123). By providing the second solution supply part 23 in the vicinity of the outlet and introducing the second raw material solution 124, a stable multilayer flow can be formed in the funnel-like part 24 as compared with Patent Documents 5-7. it can.

  In the case of the present embodiment, since the mixing of the first raw material solution 123 and the second raw material solution 124 in the processing unit 25 is performed using a laminar flow, the reproducibility is higher than when turbulent flow is used. A mixing process can be realized.

  In the case of the present embodiment, not only the flow path capacity is reduced, but also the liquid isolating the flow path as in Patent Document 7 is not required, so that the sample concentration in the processing unit 25 can be increased. The reaction efficiency can be increased.

[Example 2]
Here, an embodiment of a flow path used for feeding a sample to the radiochemical reaction microreactor 10 in the radiochemical reaction microreactor system 1 (FIG. 1) will be described. FIG. 6 shows an outline of the liquid supply flow path according to this example.

  The capacity of the syringe 108 for feeding the first solvent 121 and the second solvent 122 may be selected according to the amount of solvent to be fed. In this embodiment, the volume is 5 mL.

  Similarly, the capacity of the syringe 901 for injecting the raw material solution for injecting the first raw material solution 123 and the second raw material solution 124 into the raw material sample loop 106 may be selected according to the amount of the raw material solution. In this embodiment, it is 1 mL.

  The flow path width of the solvent suction line 103 may be selected according to the volumes of the first solvent 121 and the second solvent 122 to be fed. However, when the flow path width becomes narrow, the suction time to the syringe 108 becomes long. In this embodiment, it is 1 mm.

  The flow path widths of the solvent waste liquid line 104 and the raw material introduction line 105 may be selected according to the volumes of the first raw material solution 123 and the second raw material solution 124 to be fed. In order to reduce the dead volume, it is desirable that the flow path width is narrow. In this embodiment, the thickness is 0.5 mm.

  The channel widths of the first solution introduction unit 110 and the second solution introduction unit 111 may be selected according to the volumes of the raw material solutions 123 and 124 to be sent. In order to increase the liquid feeding capacity, it is desirable that the channel width is wide. In this embodiment, the thickness is 0.5 mm.

  The flow path widths of the staying part 202 and the product recovery line 303 may be selected according to the volumes of the first raw material solution 123 and the second raw material solution 124 to be sent. In order to improve reaction efficiency, it is desirable that it is 1 mm or less. In this embodiment, the thickness is 0.5 mm.

  In order to increase the sample recovery rate, the raw material introduction line 105, the raw material sample loop 106, the first solution introduction unit 110, the second solution introduction unit 111, the retention unit 202, and the product collection line 303 have the same flow path width. It is desirable that In this embodiment, the thickness is unified at 0.5 mm.

  The flow path lengths of the waste liquid line 104, the raw material introduction line 105, the first solution introduction part 110, the second solution introduction part 111, the retention part 202, the product recovery line 303, and the waste liquid recovery line 304 are long enough to prevent operation. If it is good. In the present embodiment, the following settings were made. The channel length of the sample loop drain 902 is 60 mm, the channel length of the raw material introduction line 105 is 240 mm, the channel length of the first solution introduction part 110 is 600 mm, the channel length of the second solution introduction part 111 is 600 mm, and the retention part The total flow path length of 202 and the product recovery line 303 is 285 mm.

  The capacity of the raw material sample loop 106 may be larger than the planned liquid transport capacity of the first raw material solution 123 and the second raw material solution 124 to be fed. In order to reduce the dead volume, it is the same as the liquid feeding capacity of the first raw material solution 123 and the second raw material solution 124 or larger than the planned liquid feeding capacity of the first raw material solution 123 and the second raw material solution 124. It is desirable that the volume is as close as possible to the planned liquid delivery volume. In the present example, the planned feed volumes of the first raw material solution 123 and the second raw material solution 124 were each 200 μL, and the capacity of the raw material sample loop 106 was also 200 μL.

  The injection amounts of the first raw material solution 123 and the second raw material solution 124 introduced from the raw material introduction line 105 are set to 300 μL each in consideration of the capacity of the sample loop drain 902 and the raw material introduction line 105, and the loop from the raw material sample loop 106 is performed. Overflowing volume was set to 200 μL.

  It is desirable that the liquid feed switching valve 102 has a small dead volume. Therefore, in this embodiment, the dead volume of the liquid feeding switching valve 102 is set to 3.4 μL.

[Example 3]
In the present embodiment, the evaluation result of the liquid feeding performance by the aforementioned radiochemical reaction microreactor body 20 will be described. Here, the liquid feeding performance of the radiochemical reaction microreactor body 20 was evaluated from the pressure loss during liquid feeding. It is assumed that the liquid supply flow path having the dimensions shown in Example 2 (FIG. 6) is used for supplying the solvent to the microreactor body 20.

  FIG. 7 shows the liquid feeding performance 701 by the radiochemical reaction microreactor body 20 and the liquid feeding performance 702 of the standard capacity microreactor shown in FIG. 5 as a comparative example. The vertical axis represents pressure loss, and the horizontal axis represents the total flow rate.

  As shown in FIG. 7, in the radiochemical reaction microreactor body 20 according to the present embodiment, the volume of the flow path portion is 31 μL, which is smaller than 184 μL of the standard capacity microreactor, but the pressure loss is smaller than the standard capacity microreactor. Is equivalent to Therefore, the radiochemical reaction microreactor system 1 (FIG. 1) according to the present embodiment can safely supply liquid up to a pressure loss of 500 kPa. Thus, it became clear that the microreactor body 20 according to the present example has a liquid feeding performance capable of feeding at a flow rate equivalent to that of a standard capacity microreactor having a capacity of 6 times.

  In the microreactor main body 20 according to the present embodiment, the liquid can be fed at a high flow rate of 20 mL / min because the actual flow path width of the processing unit 25 is as relatively large as 200 μm as shown in FIG. It is. However, since a multi-layer flow is introduced into the processing unit 25, it is calculated that an 8 μm laminar flow is formed in the processing unit 25. That is, it is calculated that the microreactor body 20 according to the present embodiment has a mixing performance equivalent to a flow path width of 8 μm while having a throughput of a flow path width of 200 μm. The actual mixing performance is shown in Example 4.

[Example 4]
In this embodiment, the result of evaluating the mixing performance of the microreactor body 20 will be described. In this example, the mixing performance of the microreactor was evaluated using the Villermaux-Dushman reaction, which is known as a mixing performance evaluation method. The liquid delivery channel described in Example 2 (FIG. 6) was used for sending the solvent to the microreactor body 20.

  FIG. 8 shows the evaluation results of the mixing performance 801 by the microreactor body 20, the mixing performance 802 of the standard capacity microreactor shown as a comparative example in FIG. 5, and the mixing performance 803 by the batch method. The vertical axis is the mixing performance, and the horizontal axis is the total flow rate.

  As shown in FIG. 8, the radiochemical reaction microreactor 10 according to the present example showed a higher mixing performance than the batch method up to a total flow rate of 0.5 mL / min to 20 mL / min. In addition, the radiochemical reaction microreactor 10 according to the present example showed higher mixing performance than the standard capacity microreactor at a total flow rate of 0.2 mL / min to 20 mL / min.

  From Examples 1 to 4, the microreactor body 20 has a low flow volume of 31 μL, and the flow width of the processing unit 25 is calculated to be 8 μm, so the liquid feeding performance is high and the mixing performance is also high. Became clear.

[Example 5]
In this example, the liquid feed flow channel having the dimensions shown in Example 2 (FIG. 6) is applied to the radiochemical reaction microreactor system 1 according to this example, and 200 μL of the first raw material solution 123 and the second raw material are used. The collection result of the product solution 306 when the solution 124 is fed is shown.

In this embodiment, 200 μL of 10 MBq [ ¹¹ C] CH ₃ I, DMSO solution 200 μL is used as the first raw material solution 123, and DMSO solution 200 μL is used as the second raw material solution, the first solvent 121, and the second solvent 122. In addition, the first raw material solution 123 and the second raw material solution 124 were sent to the microreactor 10 of the radiochemical reaction microreactor system 1 at room temperature at 1 mL / min.

Further, the radioactivity of the product solution that passed through the radiochemical reaction microreactor 10 and the retention unit 202 in the reactor unit 201 was detected by the radioactivity sensor 305 in the recovery unit 301 and measured by the radioactivity measurement unit 501. Further, it was detected by the radioactivity sensor 107 in the liquid feeding unit 101 and measured by the radioactivity measurement unit 501. Here, assuming that the radioactivity of [ ¹¹ C] CH ₃ I introduced into the raw material sample loop 106 was 100%, the ratio of radioactivity of the product solution was calculated and used as the recovery rate.

  FIG. 9 is a graph showing the recovery result of the product solution. The vertical axis represents the addition recovery rate, and the horizontal axis represents the solution feeding amount. As shown in FIG. 9, 75% of the product solution was recovered at the product solution (sample) recovery position 1001.

  Therefore, in the radiochemical reaction microreactor system 1 according to the present embodiment, when the first raw material solution 123 and the second raw material solution 124 are fed by 200 μL, respectively, for a total of 400 μL, the mixed solution that has passed through the microreactor body 20 is 75%. It became clear that it could be recovered.

[Example 6]
In the present embodiment, a result of performing a radiochemical reaction in the microreactor system 1 for radiochemical reaction using the microreactor body 20 by applying the liquid feeding flow path having the dimensions shown in Embodiment 2 (FIG. 6) is shown. In addition, the total flow path length of the retention part 202 and the product collection | recovery line 303 was 2038 mm in the liquid feeding flow path.

Also, 200 μL of 10 MBq [ ¹¹ C] CH ₃ I, DMSO solution is used as the first raw material solution 123, 2 mg / mL MASB, 200 μL of DMSO solution is used as the second raw material solution 124, and the DMSO solution is used as the first solvent 121 and the second Solvent 122 is used. In addition, the first raw material solution 123 and the second raw material solution 124 were sent to the microreactor 10 of the radiochemical reaction microreactor system 1 at room temperature at 1 mL / min.

  In addition, the product solution was allowed to stand for 2 minutes in the retention unit 202 in the reactor unit 201 and recovered from the product recovery line 303 in the recovery unit 301. The recovered sample was 400 μL at the product solution recovery position 1001.

The recovered product solution was analyzed by HPLC, and the yield of [ ¹¹ C] DASB, which was the target product, was calculated from the peak area ratio in RI detection.

FIG. 10 shows the production rate of the target product [ ¹¹ C] DASB in the reaction mixture obtained as a result of the radiochemical reaction of [ ¹¹ C] CH ₃ I and MASB using the microreactor 10 for radiochemical reaction, and the batch method. The production rate of the target product [ ¹¹ C] DASB in the reaction mixture obtained as a result of the radiochemical reaction of [ ¹¹ C] CH ₃ I with MASB is shown.

In the batch method, 10 MBq of [ ¹¹ C] CH ₃ I, DMSO solution 200 μL, 2 mg / mL MASB, DMSO solution 200 μL are placed in a 5 mL glass V vial and stirred at room temperature with a magnetic stirrer for 2 minutes. did.

As shown in FIG. 10, [ ¹¹ C] DASB, which is the target product, was produced in the microreactor system 1 for radiochemical reaction (FIG. 1) at a production rate equivalent to that of the batch method.

  According to the present embodiment, when the radiochemical reaction microreactor system using the radiochemical reaction microreactor 10 is used, a radiochemical reaction is performed by sending a 400 μL low volume raw material solution in a short time of 2 minutes. It was revealed that the desired product solution was produced and recovered.

DESCRIPTION OF SYMBOLS 1 ... Radiochemical reaction microreactor system 10 ... Radiochemical reaction microreactor 20 ... Microreactor main body 21 ... 1st solution supply part 21A ... 1st solution supply nozzle 22 ... 1st solution induction flow path part 23 ... 2nd solution supply part 23A ... second solution supply nozzle 24 ... funnel-shaped part 25 ... processing part 26 ... solution discharge part 27a ... first solution reservoir 27b ... second solution reservoir 28 ... groove 29 ... hole 30 ... lid member 40 ... lid member 50 ... Adapter member 51 ... Inlet port portion 52 ... Outlet port portion 60 ... Adapter member 61a ... First solution introduction port 61b ... Second solution introduction port 62 ... Solution discharge port 63 ... Inlet portion 64 ... Outlet portion 101 ... Liquid feeding unit 102 ... Liquid feed switching valve 103 ... Solvent suction line 104 ... Solvent waste liquid line 105 ... Raw material introduction line 106 ... Raw material sample loop 107 Radioactivity sensor 108 ... Syringe 109 ... Syringe pump 110 ... First solution introduction part 111 ... Second solution introduction part 121 ... First solvent 122 ... Second solvent 123 ... First raw material solution 124 ... Second raw material solution 131A ... Temperature control Signal 131B ... Feedback signal 132A ... Radioactivity measurement signal 132B ... Feedback signal 133A ... Radioactivity measurement signal 133B ... Feedback signal 141A ... Feedback signal 141B ... Control signal 142 ... Data communication signal 143 ... Data communication signal 144 ... Data communication signal 145 ... Data communication signal 201 ... Reactor unit 202 ... Residual part 301 ... Recovery unit 302 ... Recovery switching valve 303 ... Product recovery line 304 ... Waste liquid recovery line 305 ... Radioactivity sensor 401 ... Temperature control unit 501 ... Radioactivity measurement Knit 601 ... Control device 701 ... Liquid feeding performance of microreactor body 20 702 ... Liquid feeding performance of standard capacity microreactor 801 ... Mixing performance of microreactor body 20 802 ... Mixing performance of standard capacity microreactor 803 ... Mixing performance of batch method 901 ... Raw material solution injection syringe 902 ... Sample loop drain 1001 ... Product solution (sample) collection position

Claims (7)

In a reaction system for mixing first and second liquids,
A first flow path composed of a plurality of flow paths each having a constant width and spaced apart by a fixed width in the width direction;
A first nozzle for introducing the first liquid into each flow path of the first flow path;
Each of the first flow paths is composed of one or a plurality of flow paths having a constant width and having a constant width formed between the plurality of flow paths forming the first flow path. A second channel having a channel length shorter than the channel;
A second nozzle disposed at a position downstream of the first nozzle and introducing the second liquid into the second flow path;
Connected to the downstream ends of the first flow path and the second flow path, the flow of the first liquid flowing out from the first flow path in a band shape and the flow out from the second flow path in a band shape A funnel-like portion that contracts along the flow the width of the multilayer flow in which the flow of the second liquid is alternately arranged;
A reaction vessel having a processing section for mixing the first liquid and the second liquid in a multilayer flow contracted in the funnel-shaped portion, connected to the reaction vessel, and sent from the reaction vessel. A reaction unit having a retention part for holding a liquid,
A liquid-feeding unit for supplying the first liquid and the second liquid to the reaction container,
A recovery unit for recovering the liquid produced in the reaction unit;
A temperature control unit for controlling the temperature of the reaction unit;
A radioactivity measuring unit that measures the radioactivity of the liquid held in the liquid feeding unit and the recovery unit by sensors provided in the liquid feeding unit and the recovery unit;
The liquid-feeding unit, the reaction unit, the recovery unit, have a control device for controlling the temperature control unit,
The said control apparatus controls the said recovery unit so that only the liquid containing a radioactive substance may be collect | recovered based on the radioactivity measurement result of the said recovery unit by the said radioactivity measurement unit . In a reaction system for mixing first and second liquids,
A first flow path composed of a plurality of flow paths each having a constant width and spaced apart by a fixed width in the width direction;
A first nozzle for introducing the first liquid into each flow path of the first flow path;
Each of the first flow paths is composed of one or a plurality of flow paths having a constant width and having a constant width formed between the plurality of flow paths forming the first flow path. A second channel having a channel length shorter than the channel;
A second nozzle disposed at a position downstream of the first nozzle and introducing the second liquid into the second flow path;
Connected to the downstream ends of the first flow path and the second flow path, the flow of the first liquid flowing out from the first flow path in a band shape and the flow out from the second flow path in a band shape A funnel-like portion that contracts along the flow the width of the multilayer flow in which the flow of the second liquid is alternately arranged;
A reaction vessel having a processing section for mixing the first liquid and the second liquid in a multilayer flow contracted in the funnel-shaped portion, connected to the reaction vessel, and sent from the reaction vessel. A reaction unit having a retention part for holding a liquid,
A liquid-feeding unit for supplying the first liquid and the second liquid to the reaction container,
A recovery unit for recovering the liquid produced in the reaction unit;
A temperature control unit for controlling the temperature of the reaction unit;
A controller for controlling the liquid feeding unit, the reaction unit, the recovery unit, and the temperature control unit;
Have
The liquid feeding unit is
A first loop-shaped channel prepared for introduction of the first liquid;
A second loop-shaped channel prepared for introduction of the second liquid;
Prepared for introduction of a third liquid different from the first liquid, and through the first liquid-feeding switching valve to the first nozzle of the reaction vessel via the first loop-shaped channel. A first liquid-feeding flow path that is connected or directly connected to the first nozzle of the reaction vessel;
The second nozzle of the reaction vessel is prepared for introduction of the third liquid different from the second liquid and passes through the second loop-shaped channel through the second liquid feeding switching valve. Or a second liquid-feeding passage connected directly to the second nozzle of the reaction vessel;
The first liquid feed switching valve for switching introduction of the first liquid and the third liquid into the first nozzle of the reaction vessel;
The second liquid feed switching valve for switching the introduction of the second liquid and the third liquid into the second nozzle of the reaction vessel;
The control device controls the first and second liquid supply switching valves so that the first and second liquids are supplied in a state where the first and second liquids are sandwiched between the third liquid and the third liquid, respectively. And a reaction system. The reaction system according to claim 1 or 2 ,
The width of each laminar flow which flows into the processing part of the reaction vessel is 40 μm or less. The reaction system according to claim 1 or 2 ,
The reaction system characterized in that a flow path width of the processing section of the reaction vessel is 100 μm to 1000 μm. The reaction system according to claim 1 or 2 ,
The reaction vessel is
A first solution reservoir that temporarily holds the first liquid before introducing it into the first flow path; and a temporary solution before introducing the second liquid into the second flow path. A second solution reservoir for holding,
The volume of the first solution reservoir, the volume of the second solution reservoir, the volume of the section through which the first liquid flows in the first flow path, and the capacity of the first flow path in the second flow path 2. The reaction system, wherein the sum of the volume of the section in which the two liquids flow, the volume of the funnel-shaped portion, and the volume of the processing portion is 135 μL or less. The reaction system according to claim 5 , wherein
The reaction system characterized in that the volume of the first solution reservoir and the volume of the second solution reservoir are both 20 μL or less. The reaction system according to claim 1, wherein
The reaction system characterized in that the flow formed in the processing section is a laminar flow.

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