WO2016174769A1

WO2016174769A1 - Solvent replacement device and solvent replacement method

Info

Publication number: WO2016174769A1
Application number: PCT/JP2015/062986
Authority: WO
Inventors: 直己万里; 範人久野; 由花子浅野
Original assignee: 株式会社日立製作所
Priority date: 2015-04-30
Filing date: 2015-04-30
Publication date: 2016-11-03

Abstract

This solvent replacement device is provided with: a container 9 for holding microparticles 10; a first introduction path 1 for introducing into the container 9 a solution 13 that is evaporated to dryness within the container 9; a heating unit 11 for evaporating to dryness by removing a solvent from the solution 13 that is held in the container 9; and a second introduction path 2 for introducing into the container 9 a dissolving solution 15 for dissolving solids 14 obtained by evaporating the solution 13 to dryness.

Description

Solvent replacement apparatus and solvent replacement method

The present invention relates to a solvent replacement apparatus and a solvent replacement method mainly used for radiopharmaceutical synthesis.

In recent years, image diagnosis and evaluation of drug pharmacokinetics using PostronｒｏEmission Tomography (PET) have been actively conducted. PET is a technique for diagnosing by administering a drug containing a radioisotope that releases positron (a radiopharmaceutical) into the body by intravenous injection or inhalation, and imaging the distribution in the body.

PET can obtain physiological and biochemical function information of organs, and unlike conventional CT and MRI, which can form images of morphology, it can image the activity state of cells. . For this reason, it is used for identifying the cause of various diseases such as cancer, heart disease and brain disease and for diagnosing disease states.

Examples of positron nuclides used for PET diagnosis include ¹¹ C, ¹³ N, ¹⁵ O, and ¹⁸ F. These positron nuclides have very short half-lives of 20.4 minutes, 9.97 minutes, 2.04 minutes, and 109.8 minutes, respectively. Therefore, radiopharmaceuticals containing them must be synthesized with high efficiency in a short time. Is required.

For example, in [ ¹⁸ F] FDG widely used as a radiopharmaceutical, target water containing ¹⁸ F ⁻ is adsorbed and concentrated with an anion exchange column, and the eluate obtained by elution with a predetermined aqueous solution is heated. After evaporating to dryness, the mixture is reacted with a precursor dissolved in an organic solvent ( ¹⁸ F labeling reaction).

The evaporating and evaporating treatment of the eluate performed before the ¹⁸ F labeling reaction is for removing water that inhibits the reaction between ¹⁸ F ⁻ and the precursor from these reaction solutions to prevent a reduction in reaction efficiency. It is processing.

Conventionally, the evaporation to dryness treatment is performed by heating the glass vial reaction container to which the eluate from the anion exchange column has been transferred from the bottom. For example, in [ ¹⁸ F] FDG synthesis, the evaporation to dryness treatment is performed. Account for about 35% of the total synthesis time. For this reason, reduction of the processing time required for evaporation to dryness is required.

Therefore, in recent years, application of the microreactor method has been studied. Since the microreactor method ensures a wide surface area per unit volume, highly efficient evaporation to dryness is possible.

Regarding the microreactor method, Patent Document 1 discloses a PET labeling compound that evaporates and dries by supplying a solution into a groove formed by microfabrication and passing an evaporation operation gas above the solution. A manufacturing method is disclosed.

JP 2010-260799 A

In the batch method using the glass vial described above, the heating surface area per unit volume is narrow, so that the time required for evaporation to dryness becomes long. In this method, a method of re-dissolving the solidified product by heat reflux is the mainstream. In this case, ¹⁸ F ⁻ in the solidified product may remain in the container without being sufficiently re-dissolved.

On the other hand, in the method described in Patent Document 1, a wide heating surface area per unit volume is secured by the fine flow path, and thus efficient evaporation to dryness is possible. However, when evaporation to dryness is performed in a fine channel, the solidified product is widely dispersed and localized in the channel, and it is difficult to efficiently re-dissolve the solidified product in the channel.

The present invention has been made in view of the above-described problems, and an object thereof is to provide a solvent replacement apparatus and a solvent replacement method that can efficiently dry and re-dissolve a solution.

As a preferred embodiment of the solvent replacement device according to the present invention, a fine particle holding unit for holding fine particles, a solvent removing unit for removing the solvent from the solution held in the fine particle holding unit, and evaporation drying in the fine particle holding unit. A solvent replacement apparatus comprising: a solidified solution and a flow path for introducing a solution for dissolving a solidified product obtained by evaporation to dryness of the solution into the fine particle holding unit.

Further, as a preferred embodiment of the solvent replacement method according to the present invention, a step of introducing a solution to be evaporated and dried in a fine particle holding part for holding fine particles into the fine particle holding part, and the solution introduced into the fine particle holding part Removing the solvent contained in the solvent by a solvent removing unit and evaporating and drying the solution; introducing a solution for dissolving the solidified product obtained by evaporating and drying the solution into the fine particle holding unit; and It is a solvent substitution method characterized by having.

According to the present invention, it is possible to realize a solvent replacement apparatus and a solvent replacement method that can efficiently dry and re-dissolve a solution.

It is a figure which shows the structure of the solvent replacement apparatus which concerns on 1st Embodiment. It is a figure explaining the flow of the solvent substitution method using the solvent substitution apparatus shown in FIG. It is a figure which shows the structural example of the solvent replacement apparatus which concerns on 1st Embodiment provided with the flow-path heating part. It is a figure which shows the structure of the solvent replacement apparatus which concerns on 1st Embodiment provided with the flow path which consists of a some flow path. It is a figure which shows the structural example of the heating part provided in the solvent substitution apparatus which concerns on 1st Embodiment, The heating part (A) by water vapor | steam, the heating part (B) by light, and the heating part (C) by microwave Show. It is a figure which shows the stirring form of a solution in the solvent displacement apparatus which concerns on 1st Embodiment, and shows stirring (A) by ultrasonic wave, and stirring (B) by suction and discharge of a solution. It is a figure which shows the structural example of the solvent substitution apparatus which concerns on 1st Embodiment in the form at the time of collection | recovery of a solution. It is a figure which shows the structure of the solvent replacement apparatus which concerns on 2nd Embodiment. It is a figure explaining the flow of the solvent substitution method using the solvent substitution apparatus shown in FIG. It is a figure which shows the structural example of the solvent replacement apparatus which concerns on 2nd Embodiment provided with the flow-path heating part. It is a figure which shows the stirring form of the solution in the solvent displacement apparatus which concerns on 2nd Embodiment, and shows the stirring (A) by the reciprocating motion of a solution, and the stirring (B) by an ultrasonic wave.

Hereinafter, an embodiment of the present invention will be described with reference to the drawings.

(First embodiment)
FIG. 1 is a diagram illustrating a configuration of a solvent replacement device according to the first embodiment.
As shown in FIG. 1, the solvent replacement apparatus according to the first embodiment includes a container 9 as a fine particle holding unit for holding fine particles 10, and a solution 13 (hereinafter simply referred to as solution 13) to be evaporated and dried in the container 9. And a flow passage 23 for introducing a solution 15 for dissolving the solidified product in the container 9 obtained by evaporating and drying the solution 13 into the container 9.

The flow passage 23 has a first introduction path 1 connected via a valve 4 and a second introduction path 2 connected via a valve 5, and the first introduction path 1 is connected to the solution 13. Is introduced, and the solution 15 is introduced from the second introduction path 2.

Further, the solution discharge path 3 is connected to the flow path 23 via the valve 6, and the liquid in the container 9 is configured to be discharged from the solution discharge path 3.

The container 9 has a reduced hollow shape, and is configured such that the fine particles 10 are held at the center of the bottom. In the solution discharge path 3, a particle removal filter 7 for removing particles 10 and other foreign matters contained in the solution is provided at a position closer to the flow passage 23 than the valve 6.

The heating unit 11 is provided on the lower end side of the container 9 so as to surround the side surface of the reduced diameter portion of the container 9. Below the container 9 and the heating unit 11, a stirring unit 12 for stirring the fine particles 10 in the container 9 is provided.

The heating unit 11 is a heater that heats the container 9. The solvent is removed from the solution 13 in the container 9 by the heating of the heater, and the solution 13 is evaporated to dryness. The gas evaporated by the heating of the heating unit 11 is collected by the exhaust path 8 provided in the container 9.

Next, a method of evaporation to dryness and re-dissolution using the apparatus shown in FIG. 1 will be described with reference to FIG. In the following description, an example where magnetic fine particles 10A are used as the fine particles 10 will be described.

(A) With the valve 4, the valve 5 and the valve 6 closed, the container 9 containing the magnetic fine particles 10A is heated by the heating unit 11. The magnetic fine particles 10A are heated through the heated container 9 (FIG. 2A).

(B) The valve 4 is opened, and the solution 13 to be evaporated and dried in the container 9 is introduced from the first introduction path 1 through the flow path 23 into the container 9. The solution 13 is dropped onto the surface of the heated magnetic fine particle 10A from above the container 9 via the valve 4 (FIG. 2B). The solution 13 comes into contact with the magnetic fine particles 10 </ b> A and is heated to the boiling point or more, and the solvent is vaporized and discharged from the exhaust port 8.

Although not shown in FIG. 2, when a radioactive substance-containing solution is introduced as the solution 13 into the container 9, contamination to the external environment is prevented, and contamination from the external environment to the radiopharmaceutical is suppressed. Therefore, it is desirable to provide a filter or the like at the exhaust port 8.

(C) The solution 13 is evaporated to dryness by vaporization of the solvent, and the solute contained in the solution 13 is solidified on the surface of the magnetic fine particle 10A. As a result, a solidified product 14 is generated around the magnetic fine particles 10A (FIG. 2C).

(D) Next, after the valve 4 is closed and the valve 5 is opened, the solution 15 is introduced into the container 9 through the flow passage 23 from the second introduction path 2 (FIG. 2D).

(E) Next, after the valve 5 is closed, the stirrer 12 (stirrer in FIG. 2) is operated to stir the magnetic fine particles 10A in the solution 15 and dissolve the solidified material 14 in the solution 15. (FIG. 2E). At this time, the magnetic fine particle 10 </ b> A may be stirred while the container 9 is heated by operating the heating unit 11 together.

In addition, although this embodiment showed the example which introduce | transduces the solution 15 into the container 9 independently from the 2nd introduction path 2, the solution containing a precursor is replaced with the 2nd introduction path 2 instead of the solution 15. May be introduced into the container 9, and the solidified product 14 may be reacted with the precursor while being dissolved in the solution containing the precursor.

(F) Next, the valve 6 is opened, and the solution 15 in which the solidified product 14 is dissolved is introduced into the solution discharge path 3 and collected (FIG. 2F). The magnetic fine particles 10A mixed in the dissolving liquid 15 are removed by the fine particle removing filter 7, and the magnetic fine particles 10A are prevented from being mixed into the recovered dissolving liquid 15.

2, the solution 15 is collected from above the container 9. In the case of this form, since the entire inner peripheral surface of the container 9 becomes a heating region for the magnetic fine particles 10A, the solution 13 can be efficiently evaporated and dried.

In the present embodiment, the solution 15 is introduced into the container 9 once and collected from the solution discharge path 3. However, the solution 15 is introduced into the container 9 a plurality of times, The solution 15 may be collected a plurality of times. This may improve the solute recovery rate.

In the above-described steps of the present embodiment, liquid such as the solution 13 and the solution 15 can be sent using a pump. In addition, as long as liquid feeding is possible, it can also be performed by other methods. For example, liquid feeding using nitrogen gas, liquid feeding by vacuuming, or the like is also possible. The flow rate during liquid feeding needs to be adjusted appropriately in each step. For example, in the step (B), the flow rate when the solution 13 is sent to the container 9 is such that the evaporation and drying of the solution 13 is completed in parallel with the supply of the solution 13 in the region where the magnetic fine particles 10A in the container 9 exist. It is desirable to set the flow rate value to be obtained.

In the embodiment shown in FIG. 2, the magnetic fine particles 10A are used as the fine particles 10 (see FIG. 1). Therefore, when a stirrer is used as the stirring unit 12, the magnetic fine particles 10A are brought into close contact with the surface of the container 9. Can do. Thereby, when the magnetic fine particle 10A is heated, the heat from the heating unit 11 is efficiently transmitted to the magnetic fine particle 10A. Further, when the solution 15 is collected from the solution discharge path 3, the magnetic fine particles 10A are held on the surface of the container 9 by the magnetic force of the stirrer. For this reason, mixing of the magnetic fine particles 10A into the recovered solution 15 can be suppressed.

In the present embodiment, as the fine particles 10, in addition to magnetic fine particles made of iron, cobalt, nickel, or an alloy thereof as raw materials, metal fine particles made of gold, silver, copper, or an alloy containing these as main components are suitable. Can be used.

In the case where adsorption due to electrical coupling between the positively charged fine metal particles (including magnetic fine particles) and ¹⁸ F ⁻ is concerned, the fine particle surface may be coated with polytetrafluoroethylene (PTFE) or the like. Since all of these metals have high thermal conductivity, heat from the container 9 is easily transmitted and is efficiently heated, so that they are suitable for evaporating and drying the solution.

Further, as the fine particles 10, non-magnetic fine particles 10 can be used as long as they have resistance to heat treatment in the container 9 and liquid such as the solution 13 and the solution 15 supplied into the container 9. It is. That is, as the nonmagnetic fine particles 10, it is desirable to use a material having high thermal conductivity, high resistance to chemicals used (for example, acetonitrile) (chemical resistance), and excellent heat resistance (around 100 ° C.). As such nonmagnetic fine particles 10, for example, glass, ceramic hydroxyapatite, or the like can be used.

On microparticles 10 of nonmagnetic described above, for example ^{18 F} ^- When adsorbing the heat resistance, excellent chemical resistance, and ^{18 F} ^- coating the particle surface with such a low adsorption polytetrafluoroethylene (PTFE) May be.

As the fine particles 10, the smaller the particle diameter, the larger the particle surface area, and the larger the heating surface area in the step (B) is preferable. Specifically, for example, particles having a particle diameter of 5 mm or less are preferable, and particles having a particle diameter of 100 μm or more and 2 mm or less are more preferable.

In the example shown in FIG. 2, the solution 13 is dropped onto the magnetic fine particles 10A at room temperature and brought into contact with the magnetic fine particles 10A. However, the solution 13 may be heated before being dropped onto the magnetic fine particles 10A. Good (see FIG. 3).

In the example shown in FIG. 3, the solution 13 passing through the inside of the flow path 23 is heated by the flow path heating unit 21 installed on the side surface of the flow path 23. Thereby, the time required for the solution 13 to evaporate and dry in the container 9 can be shortened. However, in this case, in order to avoid the solidification of the solution 13 in the flow passage 23, the heating temperature by the flow path heating unit 21 is set to be equal to or lower than the boiling point of the solution 13.

Moreover, in the example shown in FIG. 2, although the form which introduce | transduces the solution 13 into the container 9 by the flow path 23 which consists of a single flow path was shown, for example, as shown in FIG. 4, the flow path in the container 9 is shown. 23 may be configured by a plurality of small-diameter flow paths. With the configuration shown in FIG. 4, the solution 13 can be dispersed and supplied onto the fine particles 10, and an improvement in evaporation efficiency is expected.

As the heating unit 11 that is a heater, for example, a hot plate, a Peltier element, an oil bath can be used, and water vapor (FIG. 5A), light generation source (FIG. 5B), microwave generation source (FIG. 5C), super A sound wave source can be used. Although not shown in FIG. 2, it is preferable to install a temperature sensor on the surface of the heating unit 11 or the container 9 so that the inside of the container 9 can be controlled to a desired temperature according to the use state of the user.

The heating unit 11 may not only simply heat but also install a mechanism for spraying nitrogen gas or the like, and spray the gas in parallel with the heating to promote the evaporation of the solution.

In the form shown in FIG. 2, a configuration using a stirrer as the stirring unit 12 is shown. However, as a method of stirring the fine particles 10, for example, ultrasonic irradiation is performed using an ultrasonic wave generation source (FIG. 6A) as the stirring unit 12. It is also possible to perform these, and it is also possible to use these together. As another stirring method, dissolution may be promoted by sucking and discharging the solution 15 containing the fine particles 10 through the flow passage 23 (FIG. 6B).

For example, when non-magnetic fine particles are used as the fine particles 10, stirring can be performed using ultrasonic waves (FIG. 6A) or suction / discharge of the solution 15 (FIG. 6B).

As shown in FIG. 6A, when an ultrasonic generation source is installed in the vicinity of the container 9, this ultrasonic generation source can be used as the stirring unit 12 and also used as the heating unit 11. Is possible.

The example shown in FIG. 2 shows a method of recovering the solution 15 in the container 9 from the solution discharge path 3 provided above the container 9, but in this embodiment, for example, as shown in FIG. The solution 15 may be collected from below the container 9. In this case, since the solution 15 is collected at the bottom of the container 9 by gravity, an improvement in the recovery rate of the solution 15 can be expected. At this time, the recovery amount can also be improved by extruding the solution 15 with nitrogen gas or the like.

In the example shown in FIG. 2, the solution 13 and the solution 15 are introduced from separate introduction paths (first introduction path 1 and second introduction path 2). In addition, the solution 15 may be introduced from the same introduction path by shifting the introduction timing.

According to the present embodiment, the solution 13 is evaporated and dried on the surface of the fine particles 10 by heating the solution 13 to be evaporated and dried in the container 9 holding the fine particles 10. For this reason, compared with the case where it heats simply in the container 9, a heating surface area increases and the efficiency of the evaporation 13 of the solution 13 improves to that extent. For this reason, the evaporation and drying time of the solution 13 is shortened.

In the conventional method of evaporating and drying a solution in a fine channel, the solidified product after evaporation to dryness is widely dispersed and localized in the fine channel. Liquid was needed. In this case, the solidified product tends to remain in the fine flow path, and it is difficult to efficiently re-dissolve the obtained solidified product.

On the other hand, in this embodiment, the solution 13 is supplied onto the fine particles 10 and evaporated to dryness, so that the solidified product 14 is concentrated on the surface of the fine particles 10 and the surrounding area. For this reason, compared with the conventional method of evaporating and drying the solution in the fine channel, the amount of the solution 15 required to redissolve the solidified product 14 can be greatly reduced. In particular, in the case where the solidified product 14 is dissolved using a solution containing a precursor instead of the solution 15, the solidified product 14 can be dissolved with a smaller amount of solution than the conventional solution. The amount of precursor consumed can be reduced. In addition, since the amount of the solidified substance 14 that remains in the apparatus without being dissolved in the dissolving liquid 15 is reduced, the recovery efficiency of the target solute of the solution 13 is improved.

Furthermore, by stirring the fine particles 10 to which the solidified material 14 is adhered in the solution 15, the dissolution efficiency of the solidified material 14 in the solution 15 is improved, and the solute (solidified material 14) from the solution 13 is improved. Recovery efficiency is improved.

(Second Embodiment)
FIG. 8 is a diagram illustrating a configuration of a solvent replacement device according to the second embodiment. As shown in FIG. 8, in the solvent replacement device according to the second embodiment, a pair of filters 32 that form the fine particle holding portion 33 is installed in the flow passage 30, and between the pair of filters 32, Fine particles 10 are held. As the filter 32, a filter having a pore size that allows liquid to pass through and does not pass through the fine particles 10 is used.

The flow path 30 dissolves the solution 13 (hereinafter simply referred to as the solution 13) to be evaporated and dried in the particle holding unit 33, and the solidified product in the particle holding unit 33 obtained by evaporation and drying of the solution 13. This is a flow path through which the solution 15 is introduced and introduced into the fine particle holding unit 33.

A first introduction path 1 for introducing the solution 13 into the fine particle holding unit 33 is connected via the valve 4 below the flow path 30 in FIG. In addition, the solution discharge path 3 for discharging the liquid in the fine particle holding unit 33 is connected to the flow path 30 via the valve 6 so as to be parallel to the first introduction path 1.

In addition, a valve 31 is installed in the flow passage 30 on the side facing the first introduction path 1 and the solution discharge path 3 with the fine particle holding portion 33 interposed therebetween. 8 is connected.

A second introduction path 2 for introducing the solution 15 is connected to the branch path 35 provided in a region of the flow path 30 between the valve 31 and the fine particle holding portion 33 via the valve 5. .

The heating unit 11 is provided on both side surfaces of the fine particle holding unit 33. The heating unit 11 is a heater that heats the fine particle holding unit 33. By the heating of the heater, the solvent is removed from the solution 13 in the fine particle holding unit 33, and the solution 13 is evaporated to dryness. The gas evaporated by the heating of the heating unit 11 is exhausted through the exhaust path 8 provided in the fine particle holding unit 33.

Next, a method of evaporation to dryness and re-dissolution using the apparatus shown in FIG. 8 will be described with reference to FIG.

(A) With the valve 4, the valve 5 and the valve 6 closed and the valve 31 opened, the heating unit 11 heats the microparticles 10 held in the microparticle holding unit 33 (FIG. 9A).

(B) The valve 4 is opened, and the solution 13 to be evaporated and dried in the fine particle holding unit 33 is introduced from below the fine particle holding unit 33 through the first introduction path 1 (FIG. 9B). The solution 13 comes into contact with the surface of the fine particles 10 and is heated to the boiling point or more, and the solvent is vaporized and discharged from the exhaust port 8. Although not shown in FIG. 9, also in the second embodiment, when a radioactive substance-containing solution is introduced into the fine particle holding unit 33 as the solution 13, contamination to the external environment is prevented, and the radiopharmaceutical is used. In order to suppress contamination from the external environment, it is desirable to provide a filter or the like at the exhaust port 8.

(C) The solution 13 is evaporated to dryness by evaporation of the solvent, and the solute contained in the solution 13 is solidified on the surface of the fine particles 10. Thereby, the solidified substance 14 produces | generates around the microparticles | fine-particles 10 (FIG. 9C). In the form shown in FIG. 9, since the solution 13 is introduced from the lower side of the fine particle holding unit 33, the solidified product 14 is generated locally on the lower side of the region where the fine particles 10 are present.

(D) Next, with the

valves

4 and 31 closed and the

valves

5 and 6 opened, the solution 15 is introduced from the second introduction path 2 into the fine particle holding unit 33. The solution 15 introduced into the fine particle holding part 33 passes through the region where the fine particles 10 exist (FIG. 9D).

The dissolving liquid 15 passing through the fine particles 10 causes the fine particles 10 to stir and move in the fine particle holding portion 33, and the solidified material 14 attached to the surface of the fine particles 10 is dissolved in the dissolving liquid 15. At this time, the dissolution of the solidified product 14 may be promoted by heating the fine particle holding unit 33. The solution 15 in which the solidified material 14 is dissolved is discharged from the solution discharge path 3.

In the form shown in FIG. 9, since the solution 15 is introduced from above the fine particle holding part 33, the solidified material 14 localized below the fine particle existence region is efficiently discharged to the solution discharge path 3. Is done.

In the present embodiment, the solution 15 is introduced into the particle existence region of the particle holding unit 33 once and collected from the solution discharge path 3, but the solution 15 is contained in the particle holding unit 33. It may be introduced a plurality of times, and the solution 15 in the fine particle holding unit 33 may be collected a plurality of times. This may improve the solute recovery rate. At this time, the solution recovery rate can also be improved by extruding the solution in the fine particle holding unit 33 with nitrogen gas or the like.

In the above-described steps of the present embodiment, the liquid such as the solution 13 and the solution 15 can be fed using a pump. In addition, as long as liquid feeding is possible, it can also be performed by other methods, for example, liquid feeding using nitrogen gas, liquid feeding by vacuuming, or the like is also possible.

It is necessary to adjust the flow rate at the time of liquid feeding appropriately in each step. For example, in the step (B), the flow rate when the solution 13 is fed to the fine particle holding unit 33 is such that the solidification of the solution is completed in parallel with the supply of the solution 13 in the fine particle existence region, and the upper part ( It is necessary to set the flow rate so that the liquid does not leak to the discharge port 8 side.

Since the fine particles 10 are heated through the inner wall of the flow passage 30 of the fine particle holding unit 33, it is preferable to use a material having high thermal conductivity. As in the first embodiment, iron, cobalt, nickel, or Magnetic fine particles made from these alloys as raw materials, and metal fine particles made from gold, silver, copper, or alloys containing these as main components can be preferably used. Also in the present embodiment, fine particles such as glass and ceramic hydroxyapatite can be used in addition to these metal fine particles.

In the case where adsorption due to electrical coupling between the positively charged fine metal particles (including magnetic fine particles) and ¹⁸ F ⁻ is concerned, the fine particle surface may be coated with polytetrafluoroethylene (PTFE) or the like.

Among these, when magnetic fine particles such as iron, cobalt, nickel, etc. are used as the fine particles 10, the fine particles 10 are adhered to the inner wall of the fine particle holding portion 33 by installing a magnetic substance in the vicinity of the fine particle holding portion 33. The heat from the heating unit 11 can be efficiently transmitted to the fine particles 10. In this case, when the adhesion between the fine particles 10 and the inner wall of the fine particle holding portion 33 is strong, the installation of the filter 32 may be omitted.

Also in the second embodiment, the fine particles 10 are preferably those having a particle diameter of 5 mm or less, and more preferably 100 μm or more and 2 mm or less.

In the example shown in FIG. 9, the solution 13 is supplied onto the fine particles 10 at room temperature, but the solution 13 may be heated before contacting the fine particles 10 (see FIG. 10). In the example shown in FIG. 10, the solution 13 passing through the inside of the flow path 30 is heated by the flow path heating unit 21 installed on the side surface of the flow path 30 on the valve 6 side of the particulate holding unit 33. Thereby, the time required for the solution 13 to evaporate and dry in the fine particle holding part 33 can be shortened. However, in this case, the heating temperature by the flow path heating unit 21 is set to be equal to or lower than the boiling point of the solution 13 in order to avoid solidification of the solution 13 in the flow passage 30 to the fine particle holding unit 33.

As the heating unit 11 that is a heater, a hot plate, a Peltier element, an oil bath, water vapor, a light generation source, a microwave generation source, an ultrasonic generation source, and the like can be used as in the first embodiment. .

Also in the second embodiment, although not shown, the temperature sensor is installed on the surface of the flow path where the heating unit 11 or the heating unit 11 is in contact, so that the inside of the fine particle holding unit 33 is used by the user. It is preferable because it can be controlled to a desired temperature according to the temperature.

In the form shown in FIG. 9, when the solution 15 passes around the fine particles 10, the fine particles 10 are moved so as to promote the dissolution of the solidified material 14 attached to the surface of the fine particles 10 in the solution 15. However, for example, the solution 15 may be reciprocated in the flow passage 30 to pass through the fine particle holding portion 33 (region where the fine particles 10 are present) a plurality of times (FIG. 11A). Further, an ultrasonic wave generation source (FIG. 11B) may be used as the stirring unit 12 and ultrasonic irradiation may be performed together. By performing the stirring shown in FIG. 11A and FIG. 11B, improvement in dissolution efficiency of the solidified product 14 in the solution 15 can be expected.

As shown in FIG. 11B, when an ultrasonic generation source is installed in the vicinity of the fine particle holding unit 33, the ultrasonic generation source is used as the stirring unit 12 and used as the heating unit 11. It is also possible.

According to the present embodiment, heating the solution 13 with the fine particles 10 held in the fine particle holding unit 33 increases the heating surface area as compared with the case where the solution 13 is simply heated in the flow path. The efficiency of evaporation to dryness is improved. For this reason, the evaporation and drying time of the solution 13 is shortened.

On the other hand, in the present embodiment, since the solution 13 is evaporated and dried using the fine particles 10, the solidified product 14 is concentrated on the surface of the fine particles 10 and a narrow region around the fine particles 10. For this reason, the amount of the solution 15 required to redissolve the solidified product 14 can be greatly reduced. Moreover, since the quantity of the solidified substance 14 which does not melt | dissolve in the solution 15 but remains in an apparatus by this reduces, the collection efficiency of the solute of the solution 13 which is a target object improves.

Furthermore, as the fine particles 10 to which the solidified material 14 is attached are agitated as the dissolved solution 15 passes, the dissolution efficiency of the solidified material 14 in the dissolved solution 15 is improved, and the solute (solidified material) from the solution 13 is increased. Recovery efficiency is improved.

In both the first embodiment and the second embodiment, the configuration in which the heating unit 11 is provided as the solvent removal member is shown. However, as the solvent removal member, the solution in the container 9 or the fine particle holding unit 33 may be used. As long as the solvent can be removed, the heating unit 11 is not necessarily limited, and for example, a ventilation member that removes the solvent by allowing gas to pass through the container 9 or the fine particle holding unit 33 may be provided as the solvent removal member. .

In the solvent replacement apparatus and the solvent replacement method according to the embodiments described above, the method of evaporating and drying the ¹⁸ F ⁻ -containing solution and re-dissolving are mainly shown, but other than this, for example, ¹¹ C, ¹³ N, etc. It can be applied to solutions containing various positrons.

For example, in [ ¹⁸ F] FDG synthesis, target water containing ¹⁸ F ⁻ is adsorbed and concentrated on an anion exchange column, and then eluted with a predetermined aqueous solution (for example, potassium carbonate / cryptofix-containing acetonitrile aqueous solution) (anion exchange). column purification), the resulting solution was evaporated to dryness by heating (first dryness), then mixed with the precursor dissolved in an organic solvent (mannose triflate) which is reacted ^{(18 F-labeled} reaction). This reaction solution is again evaporated to dryness (second evaporation to dryness), hydrolyzed with an aqueous HCl solution or aqueous NaOH solution (hydrolysis), and then synthesized through the purification process (final purification) as a final preparation.

When the evaporation to dryness step is performed by a method using a conventional glass vial reaction vessel, the standard time required for each step described above is about 2 minutes for anion exchange column purification and about 1 time for evaporation to dryness for the first time. 7 minutes, ¹⁸ F labeling reaction is about 5.5 minutes, second evaporation to dryness is about 2.5 minutes, hydrolysis is about 5.5 minutes, and final purification is about 5 minutes. It took a minute.

According to the solvent replacement apparatus and the solvent replacement method according to each of the above-described embodiments, for example, it can be applied to the first evaporation to dryness and the second evaporation to dryness in [ ¹⁸ F] FDG synthesis. In this case, the time required for the evaporating and drying process is shortened, and the processing time required for the entire [ ¹⁸ F] FDG synthesis is shortened.

Further, in the ¹⁸ F labeling reaction, ¹⁸ F ⁻ is usually present in a very small amount (f to p mol level). Therefore, when the concentration of the precursor solution (eg, mannose triflate solution) is low, ¹⁸ F ⁻ and the precursor Reaction may not proceed sufficiently. For this reason, for example, as a mannose triflate solution, a high concentration solution of about 20 mg / mL is used. On the other hand, when the solidified product 14 containing ¹⁸ F ⁻ is dissolved in a large amount of the solution 15, when mixed with a precursor solution (for example, mannose triflate solution), the precursor concentration in the mixture becomes low. The reaction between the precursor and ¹⁸ F ⁻ may not proceed sufficiently.

According to the solvent replacement apparatus and the solvent replacement method of each of the above-described embodiments, the solidified product obtained by evaporation to dryness is concentrated in a narrow region around the fine particles, and the amount of the solution 15 is smaller than that of the conventional solution. Thus, the solidified product 14 can be redissolved. For this reason, in the mixed solution of the solution 15 and the precursor in which the solidified product 14 is dissolved, the precursor concentration is maintained at a high concentration, so that the reaction between the two can proceed well.

DESCRIPTION OF SYMBOLS 1 ... 1st introduction path, 2 ... 2nd introduction path, 3 ... Solution discharge path, 4-6 ... Valve | bulb,
DESCRIPTION OF SYMBOLS 7 ... Fine particle removal filter, 8 ... Exhaust passage, 9 ... Container, 10 ... Fine particle, 10A ... Magnetic fine particle, 11 ... Heating part, 12 ... Stirring part, 13 ... Solution, 14 ... Solidified substance, 15 ... Dissolved solution, 21 ... Flow path heating section, 23, 30 ... flow path, 31 ... valve, 32 ... filter, 33 ... particulate holding section, 35 ... branch path

Claims

A fine particle holding part for holding fine particles;
A solvent removal unit for removing the solvent from the solution held in the fine particle holding unit;
A solvent passage comprising: a solution that evaporates and dries in the fine particle holding portion; and a flow passage that introduces a solution that dissolves the solidified product obtained by evaporating and drying the solution into the fine particle holding portion. apparatus.
The solvent replacement device according to claim 1, wherein the fine particle holding unit is constituted by a hollow container.
2. The solvent replacement device according to claim 1, wherein the fine particle holding part is formed in a part of the flow passage for allowing the solution and the solution to pass therethrough.
The fine particle holding unit holds fine particles mainly composed of at least one selected from the group consisting of iron, cobalt, nickel, gold, silver, copper, glass, and ceramic hydroxyapatite. The solvent displacement apparatus as described.
The solvent replacement device according to claim 1, wherein the solvent removing unit is a heating unit that heats the fine particle holding unit.
The solvent according to claim 5, wherein the heating unit is at least one selected from a Peltier element, an ultrasonic wave generation source, a microwave generation source, a light generation source, a hot plate, an oil bath, and water vapor. Replacement device.
2. The solvent replacement device according to claim 1, wherein the fine particle holding unit has a stirring unit for stirring the fine particles held in the fine particle holding unit.
The solvent replacement apparatus according to claim 7, wherein the stirring unit includes at least one selected from a stirrer or an ultrasonic wave generation source.
The flow path includes a first introduction path for introducing a solution to be evaporated and dried in the fine particle holding unit into the fine particle holding unit, and a solution for dissolving the solidified product obtained by evaporation and drying of the solution. The solvent replacement device according to claim 1, wherein the solvent replacement device is configured to have a second introduction path to be introduced into the section.
The solvent replacement device according to claim 1, wherein the flow path is provided with a flow path heating unit that heats a region between the fine particle holding unit and the first introduction path.
The solvent replacement device according to claim 1, wherein a solution discharge path for discharging the liquid in the fine particle holding unit is connected to the flow path.
Introducing a solution to be evaporated and dried in the fine particle holding unit for holding the fine particles into the fine particle holding unit;
Removing the solvent contained in the solution introduced into the fine particle holding unit by a solvent removing unit and evaporating the solution to dryness;
And a step of introducing a solution for dissolving the solidified product obtained by evaporation and drying of the solution into the fine particle holding unit.
Preheat the fine particles held in the fine particle holding portion,
After introducing the solution into the fine particle holding unit for holding the heated fine particles, evaporating to dryness while bringing the solution into contact with the fine particles, and generating a solidified product on the surface of the fine particles,
The solution is introduced into the fine particle holding unit that holds the fine particles to which the solidified material is adhered, and the dissolved solution in which the solidified material is dissolved is discharged from the fine particle holding unit through a solution discharge path. The solvent replacement method according to claim 12.
Introducing the solution into the fine particle holding part for holding the fine particles to which the solidified material has adhered,
The solvent replacement method according to claim 13, wherein the fine particles mixed with the solution are stirred in the fine particle holding unit to dissolve the solidified product in the solution.