CN101698146B - Microscale reactor for synthesizing radioactive drug and application thereof - Google Patents

Abstract

The invention relates to microreactor technology, in particular to a microreactor for synthesizing radiopharmaceuticals, a sealing body which is sealed together by a fluid channel layer, an intermediate layer and a control channel layer, and detachably inserted into the It consists of a reaction bottle, a separation column and an adsorption column of the sealed body. Its fluid channel layer includes fluid microchannels that can be fluidly connected to each reaction bottle, separation column and adsorption column. The control channel layer includes gas chambers that control gas microchannels and corresponding fluid microchannels. The microvalve control is composed of air chambers and intermediate layers. Fluidic microchannels open and close. The application of the microfluidic chip of the present invention can realize the synthesis of commonly used positron nuclide drugs in a small volume. The preparation method of the present invention is simple and easy, does not need expensive equipment, can reduce the space and capital investment of protective equipment for radiopharmaceutical preparation, and can reduce the workload of experimenters at the same time.

Description

Microreactor for the synthesis of radiopharmaceuticals and its application

technical field

The invention relates to micro-reactor technology, in particular to a micro-fluidic reactor suitable for synthesizing positron nuclide radiopharmaceuticals and the application of the micro-fluidic reactor.

Background technique

Micro-fluidic Chip (Micro-fluidic Chip) or lab on a chip (Lab on a chip) is a new technology developed on the basis of micro-electro-mechanical system technology. It has attracted people's attention in recent years. Its technology has been widely used in many analytical fields such as disease diagnosis, drug screening and environmental detection. In the prior art, materials for making microfluidic diagnostic chips mainly include polymer materials such as PDMS (Polydimethylsiloxane, Polydimethylsiloxane), which have the advantages of convenient processing and molding, low price, and can be mass-produced cheaply.

The synthesis of radiopharmaceuticals, especially positron nuclide drugs, is very suitable for the application of the above-mentioned technologies due to the small amount of synthetic precursors or raw materials required, which provides a basis for the application and development of microfluidic chip technology zhhj@fudan.edu.cn Provides a wide space.

The general process of making an ordinary microfluidic chip is: computer-aided design CAD graphics—making a mask—glass sheet/silicon sheet uniform glue—photolithography machine exposure—mold hardening after development—wet etching—— Deglue - microfluidic negative mold - PDMS casting preform - punching - surface treatment - chip assembly; most of the equipment required for this production process is expensive, such as photolithography machines, vacuum plasma generators, Glue machine, etc. The disadvantage is that the process is more complicated and requires special equipment.

At present, the radiosynthesis equipment in the domestic market, such as: the multifunctional synthesis module of positron drugs of Beijing Paite Biotechnology Co., Ltd., generally has a volume of 1000×800×600mm (length×width×height), and it needs to be equipped with a radiation-proof lead shielding box of the corresponding size. (hot chamber). The hot cell is usually made of 10-20mm thick lead as the main material. The equipment is bulky, heavy, and expensive, occupying huge capital and site resources. In addition, process description: the reaction chamber of the current microfluidic reaction chip is mostly made of the same material as PDMS, which is made by master casting. Due to the limitation of the material of PDMS, it absorbs more radioactivity, which has certain influence on the preparation of radioactive element drugs. inhibitory effect.

On the other hand, the precursors (key raw materials for chemical reactions) synthesized by positron nuclide drugs are usually very expensive, generally more than 10,000 yuan/gram, and some even as high as 1.7 million yuan/gram (such as 18 fluoroestradiol 18FES labeled synthetic precursors). These contribute in part to the high price of positronuclides. The current domestic radioactive labeling synthesis equipment has a large reaction volume and requires many synthesis reagents, which makes it difficult to reduce the cost of positron nuclide drug synthesis.

In summary, it is indeed necessary to develop a new positronium drug synthesis technology to improve the process, reduce costs, and make it possible to synthesize positronium drugs in the laboratory.

Contents of the invention

The object of the present invention is to overcome the deficiencies in the prior art and provide a microreactor for synthesizing radiopharmaceuticals, especially an improved microreactor device suitable for synthesizing positron nuclide radiopharmaceuticals. The microreactor equipment is composed of a sealing plate made of PDMS material and a reaction bottle, an adsorption column, a separation column, etc. that are detachably plugged into the sealing plate. Channels and other functional components connect reaction bottles, adsorption columns, separation columns, etc. through these pipes and valves to jointly realize the functions of chemical synthesis and separation.

In order to achieve the above object, the microreactor for synthesizing positron nuclide radiopharmaceuticals provided by the present invention includes a sealing body which is combined and sealed by a fluid channel layer, an intermediate layer and a control channel layer, and a detachable insert A combination of reaction flasks, separation columns, and adsorption columns connected to the fluid channel layer of the sealing body, wherein the fluid channel layer includes fluid microchannels, which can be fluidly connected to each reaction bottle, separation column, and adsorption column. The control channel layer includes control gas microchannels and air chambers corresponding to fluid microchannels. The air chambers and intermediate layers of the corresponding fluid microchannels form a microvalve, which controls the opening and closing of the corresponding fluid microchannels. Wherein, the fluid channel layer and the control channel layer are manufactured through the following processes: printing the ink pattern on the channel layer on the flat glass by a screen printing process; using an etching solution to etch the surface of the glass plate printed with the ink pattern, Then wash off the ink to complete the making of the female mold; use the glass female mold as the master to make the male mold; make the fluid channel layer and the control channel layer poured by PDMS silicone rubber material on the male mold as the base plate; and the fluid channel layer, the middle The sealing surfaces of the control channel layer and the control channel layer are aligned and sealed by air low-temperature plasma surface treatment.

The advantages of the above-mentioned technical solution of the present invention are: the process method is simple and easy to implement, does not require expensive equipment, and can be realized in general laboratories. And because the space size of this novel synthesis reactor is only 40 * 30 * 15mm, only need the shielding box with smaller volume just can anti-radiation shielding, in the present invention, only need to adopt the lead box of 250 * 250 * 200mm to shield, Greatly reduce the space and capital investment of protective equipment for radiopharmaceutical preparation.

Yet another aspect of the present invention provides a microreactor, wherein the reaction bottle includes a reaction tube made of glass, a capillary communicating with a fluid channel, and a metal capillary surrounding the outer wall of the reaction tube; two of the metal capillary The terminal is connected to a DC power supply, and the inlet and outlet of the metal capillary are connected to a high-pressure gas supply source. When the metal capillary is energized, the reaction tube is heated; when the power is cut off, the reaction tube is cooled when the high-pressure gas is passed through the metal capillary. Adsorption of radioactive materials is advantageously reduced due to the use of glass reaction tubes. More advantageously, the outer wall of the reaction bottle is also provided with a temperature sensor, which can be used to measure the temperature of the reaction tube and implement temperature control.

Another aspect of the present invention is to provide a microfluidic chip in the form of three-dimensional assembly, in which reaction tubes, adsorption columns, separation columns, etc. Pipelines are connected with microvalves to jointly realize the functions of chemical synthesis and separation. Through this method, it is convenient to replace the chemical separation column and the reaction bottle for separate cleaning. That is, the plug-and-pull function of each detachable part is realized, which ensures the versatility and stability of chemical synthesis and reduces the workload of experimenters.

In the present invention, microfluidic chips are used to synthesize positron nuclide drugs and other radiopharmaceutical labels, which can realize the synthesis of commonly used positron nuclide drugs in a small volume, including: ¹⁸ fluorodeoxyglucose, ( ¹⁸ F-FDG) , ¹⁸ fluoroacetate ( ¹⁸ F-FAC), ¹⁸ fluoronitroimidazole ( ¹⁸ FMISO), ¹⁸ fluoroestradiol ( ¹⁸ FES), ¹⁸ fluorodeoxythymidine ( ¹⁸ F-FLT) , and other radiopharmaceutical labels.

Another object of the present invention is to utilize microreactor to realize the application of synthesizing positron nuclide radiopharmaceutical, at least comprise the following steps:

- Adsorption step: Use compressed gas to push 18F-H2O through the designated micro-pipe through the adsorption column, so that 18F ions remain in the adsorption column;

-Eluting step: use compressed gas to push a solution through the designated micro-pipe through the adsorption column, elute the 18F on the adsorption column, then pass through another designated micro-pipe to reach the reaction bottle, and then cool down after being heated and evaporated in the reaction bottle;

-Synthesis step: Use compressed gas to push other reaction solutions through designated micro-pipes to reach the reaction bottle, and cool after heating and evaporation;

- Hydrolysis step: using compressed gas to push another solution through the designated micro-channel to the reaction bottle for hydrolysis; and

- Separation step: Use compressed gas to push the liquid in the reaction bottle through the designated micro-channel through the separation column to the collection bottle.

The advantage of the above technical solution is that, due to the small reaction volume of the microreactor used, the required reaction precursor dose is very small, as long as 10-20ul, which greatly reduces the consumption of precursor reagents, only 1 %, significantly saving the cost of drug preparation.

Description of drawings

Fig. 1 is a schematic diagram of the plane distribution of the fluid channel layer of the microreactor according to an embodiment of the present invention, wherein the dots represent the reagent pipeline connection ports, and the straight lines represent the fluid channels;

Fig. 2 is a schematic diagram of the plane distribution of the control channel layer of the microreactor according to an embodiment of the present invention, wherein the dots represent the control channel connection ports, the rectangular points represent the gas chambers, and the straight lines represent the gas control channels;

Fig. 3 is a schematic diagram of plane distribution after the combination of the fluid pipeline layer of Fig. 1 and the control pipeline layer of Fig. 2;

4 is a schematic diagram of the PDMS layer mold manufacturing process of the microfluidic chip according to the present invention;

5 is a schematic cross-sectional view of the microvalve principle of the microfluidic reaction chip according to the present invention;

6 is a schematic diagram of the structural principle of the glass reaction tube according to the present invention;

7 is a schematic diagram of the assembly of the microfluidic chip according to the present invention;

8 is a schematic plan view of the microfluidic chip according to the present invention, showing the position of the adsorption column;

Fig. 9 is a schematic diagram of applying a microfluidic chip when synthesizing 18FDG according to an embodiment of the present invention;

Fig. 10 is the analysis diagram of the mixed solution TLC after the fluorination reaction between mannose trifluoride and 18F ion;

Figure 11 is a TLC analysis chart of 18FDG product, wherein mobile phase acetonitrile/water (95/5=v/v), Rf=0.45-0.65, radiochemical purity>96%;

Fig. 12 is a schematic diagram of applying a microfluidic chip when synthesizing 18FAC according to an embodiment of the present invention;

Fig. 13 is the TLC analysis figure of 18FAC product, wherein Rf=0.16, mobile phase acetonitrile/water (95/5, V/V), radiochemical purity is greater than 95%; And

Figure 14 is another TLC analysis chart of 8FAC product, wherein Rf=0.8-0.9, mobile phase methanol, radiochemical purity 98.4%, and the origin is free 18F ion.

Detailed ways

The microreactor for synthesizing positron nuclide drugs provided by the present invention, also known as microfluidic chip, mainly includes a sealing body composed of a fluid channel layer, a control channel layer and an intermediate layer, as well as a reaction bottle and a separator , and adsorption columns and other components. Among them, the sealing body is made of polydimethylsiloxane (PDMS) by casting and sealing, and mainly includes fluid microchannels connected to each reaction bottle, separator and adsorption column in the fluid channel layer, and is located in the fluid channel layer. Control the gas in the channel layer to control the microchannel, and control the opening and closing of the microfluidic channel and other functional parts such as the microvalve.

Fig. 1 is a schematic diagram showing the plane distribution of the fluid channel layer in the sealing body of the microfluidic chip according to the invention, wherein the dots represent the connection ports of the reagent pipelines, and the straight lines between the dots represent the fluid channels. Figure 2 is a schematic diagram of the planar distribution of the control channel layer in the sealing body of the microfluidic chip, where the dots indicate the connection port of the control pipeline, and the rectangular dots indicate the air chamber of the control pipeline, that is, the microvalve, between the dots and the rectangular dots For the control gas pipeline. Fig. 3 is a schematic plan view of the combination of the fluid pipeline layer in Fig. 1 and the control pipeline layer in Fig. 2 .

The specific production of the sealing body of the microfluidic chip, that is, the microchannel, mainly includes four parts: the mold making of the fluid channel layer and the control channel layer, the turning of the male and female molds, the casting of silicone rubber, and the sealing and assembly of the casting body .

1) Mold making:

The graphics of the fluid channel level and the control channel level are shown in Figure 1 and Figure 2 respectively, which can be drawn with AutoCAD software. FIG. 3 is a schematic plan view showing the combination of the fluid channel layer in FIG. 1 and the control channel layer in FIG. 2 . The graphic area is 26×30mm, the line width is 0.2-0.3mm, and the gas and liquid channel inlet is 1mm. The above-mentioned fluid channel layer and control channel layer are respectively made into screen plates by the process of ink screen printing, and a 250-mesh oily polyester screen plate is preferred in the present invention, see FIG. 4 . Then print the anti-acid etching ink on the pre-cleaned and dried glass surface by silk screen printing, and then put the glass printed with the ink pattern into the glass etching solution, such as etching containing 50ml of hydrofluoric acid, 20ml of concentrated sulfuric acid, and 50ml of water Etching is carried out in the liquid, and the depth of glass etching is related to the following factors: the concentration of the etching liquid, the temperature of the solution, and the etching time. Generally 5min/30℃. It depends on the actual situation at that time, generally at room temperature, the etching time is 4-5 minutes. The etched glass was deinked with 5% NaOH aqueous solution. Thereby completing the making of female mold. The production process of the screen plate is as follows: CAD pattern—film output or sulfuric acid paper printing pattern—printing machine printing [photosensitive glue on the screen]—water flushing development—hot air drying.

2) Overturning of Yin and Yang molds:

Use the female mold as the master plate, pour with low-viscosity epoxy pouring glue (A/B glue), keep warm in a 25° oven, and wait for the epoxy glue to cure. Then it is peeled off from the glass, which is the positive mold. The male mold includes two levels of the fluid channel layer male mold and the control channel layer male mold.

3) Pouring of PDMS:

Using the male mold as the master, pour PDMS glue (the ratio of colloid to curing agent is 10:1) onto the male mold with a thickness of 5mm, vacuum pump to remove air bubbles, and then put it in 80°C for 2 hours for curing. After the PDMS is cured, carefully peel off the PDMS from the ring positive template, which is the PDMS casting layer.

4) Sealing assembly:

The fluid channel layer and the control channel layer are respectively punched for use. In addition, prepare a PDMS middle layer of the same material with a thickness of 0.2mm. The sealing surface of the fluid channel layer and the middle layer are treated with air plasma at the same time, and the two treated surfaces are brought close to each other, and the two rubber surfaces will be glued to each other. After waiting for two hours, glue the other two surfaces that need to be glued together in the same way. But pay attention to the alignment of the upper and lower positions. This is a three-layer seal. After completion, prepare a carrier glass sheet of the corresponding size, coat it with PDMS glue of about 0.2-0.3 mm, place it horizontally to be cured, and bond the three-layer sealing body on the glass carrier after air plasma treatment. So far, the sealing body of the microfluidic chip is completed.

The microvalve is a key point of the microfluidic chip. As shown in FIG. The position of the upper surface corresponding to the fluid channel 11 is provided with an air chamber 22 communicating with the gas control channel 21, and the air chamber 22 corresponding to the fluid channel 11 and the intermediate isolation layer 30 made of an elastically deformable material together form the control fluid channel 11 open and close microvalve. The upper figure of Fig. 5 shows that the microvalve is open, the air pressure in the small semicircular fluid channel 11 is consistent with the air pressure in the lower air chamber 22, and the rubber of the middle isolation layer 30 is in a relaxed state, so that the fluid channel 11 keeps flowing. The lower figure of Figure 5 shows the closed state of the microvalve. When the control channel 21 and the air chamber 22 of the control channel layer 20 are pressurized, the rubber elastic body of the middle isolation layer 30 deforms and bulges, blocking the upper pipeline 11, that is, the valve is closed. .

Referring to Fig. 6 below, describe the making of another main component reaction bottle (tube) of the present invention: reaction tube 40 is diameter 4mm, long 30mm, the thin-walled glass test tube of wall thickness 0.2mm, in the shape of small light bulb, reaction tube outer surface wraps around There is a stainless steel capillary 41 with a diameter of 0.4-0.7mm. When the two ends of the stainless steel capillary are connected with a direct current of 0.5A, it becomes an electric heating wire. When the inlet of the stainless steel capillary is fed with 0.5Bar compressed gas, it is a cooling tube. The reaction bottle is completely submerged in the cured PDMS material, and the PDMS material is used not only for heat preservation, but also as a support material. Another two polytetrafluoroethylene (PTFE) capillary tubes 42 are used to connect with the corresponding pipeline interface of the PDMS fluid channel layer, and the side wall and bottom of the reaction bottle/tube 40 are also equipped with sensors 43 for temperature measurement and temperature control.

7 is a three-dimensional assembly diagram of an example of a microfluidic chip according to the present invention. Above the glass carrier 1 is a cast body, the upper layer is a fluid channel layer 10, the lower layer is a control channel layer 20, and the middle is an isolation layer 30. A fluid channel 11 is provided in the fluid channel layer 10 , and a control channel 21 is provided in the control channel layer 20 . The reaction bottle 40 , the adsorption column 50 , and the separator 60 are respectively plugged into the connection holes of the fluid channel layer 10 and communicate with the fluid channel 11 . And the gas microvalve 22 in the control channel 20 is set corresponding to the control point position of the corresponding fluid channel 11, together with the gas control channel.

FIG. 8 is a schematic plan view of the microfluidic chip according to the present invention, showing the position of the adsorption column 50 . Figure 8 shows the 18F ion adsorption column. In order to realize the labeling of the 18F radionuclide, an anion exchange resin is required to separate the 18F ions. The three-dimensional assembly method is used to facilitate the replacement of the ion adsorption column. According to one embodiment of the present invention, the anion adsorption (separation) column is separated from the main body of the PDMS chip, and is made separately. The PTFE tube with an inner diameter of 0.6mm is filled with an anion exchange resin QMA filler of 15mm, and the sieve plate is a 5um polypropylene fiberboard. . Its two ends are connected with the main body of the PDMS chip.

The application of the microfluidic chip of the present invention can realize the synthesis of commonly used positron nuclide drugs in a small volume, including: 18 fluorodeoxyglucose, (18F-FDG), 18 fluoroacetate (18F-FAC), 18 fluorine Nitroimidazole (18FMISO), 18-fluoroestradiol (18FES), 18-fluoro-deoxythymidine (18F-FLT), and other radiopharmaceutical labels. The specific synthesis process mainly includes the following steps: 1) Use compressed gas to push 18F-H2O through the designated micropipe through the adsorption column, so that 18F ions remain in the adsorption column; 2) Use compressed gas to push a solution through the designated micropipe through the adsorption column column, elutes the 18F on the adsorption column, then reaches the reaction flask through another designated micropipe, and is heated and evaporated in the reaction flask and then cooled; After being heated and evaporated, it is cooled to realize the synthesis reaction; 4) using compressed gas to push another solution through the designated micro-pipe to reach the reaction bottle to hydrolyze the compound; and 5) using compressed gas to push the liquid in the reaction bottle through the designated micro-pipe to pass through The separation column reaches the collection bottle; repeat one or more steps necessary above to obtain the final drug to be synthesized and separated.

The application of the microreactor of the present invention, that is, the microfluidic chip, to synthesize positron nuclide drugs is further described below in conjunction with the examples:

Example 1: Labeled synthesis of 18F-deoxyglucose (Figure 9):

Since in the microfluidic chip of the present invention, the power of liquid flow comes from pneumatic pressure, the amount of reagents added is quantitative, that is, the reagents to participate in the reaction are added to the corresponding pipelines in advance, and the addition of reagents is an "all or nothing" formula, That is, either all of them are added, or they are not added at all, and there is no intermediate form. The air pressure of the liquid is 20-40Kpa, and the air pressure of the gas control valve is 60-150Kpa.

When the equipment is in the ready state, the Q1, Q2-Q13 pipes are all pressurized at 60-90Kpa, and all valves are closed at this time. The adsorption column 50 is pre-washed with 100ul of 0.5M K2CO3 solution, and then washed with 500ul of water until neutral. The liquid pipeline distributes and loads the corresponding reagents, that is, Y1: 500ul, 18F-H2O; Y2: waste liquid bottle; Y3: 20ul, eluent (K222, 300mg/K2CO3, 55mg/0.5mlH2O/19.5ml MeCN); Y4: 20ul , anhydrous acetonitrile; Y5: 20ul, trifluoromannose solution (100mg/8ml anhydrous acetonitrile); Y6: 20ul, 1N NaOH; Y7: 20ul, 1N HCl; Y8: 50ul, water; Y10: 30KpaN nitrogen; Y11: Waste liquid bottle (empty); In addition, the outlet of the Y9 pipeline is connected to the separation column (30mg AG50/50mg AG11A8/30mg Al2O3(N)/15mgC18), and the end is connected to the collection bottle.

Synthesis:

A. Adsorption: Open the Q1/Q2 valve (the so-called opening the valve is to empty the corresponding pipeline), the 18F-H2O in the Y1 tube passes through the adsorption column 50 under the push of the compressed gas, the 18F ions stay on the column 50, and the water flowing out reaches Y2 waste bottle. Close Q1/Q2 valve

B. Elution and evaporation: Open the Q3/Q4/Q6/Q13 valve, the solution in the Y3 tube will pass through the adsorption column under the push of the compressed gas, and then reach the reaction bottle 40 after passing through the valves 4 and 6. The stainless steel capillary is heated by a 0.5A direct current, and the heating is stopped when the bottom of the bottle is actually stable at 95°C. The stainless steel capillary is cooled by compressed gas to a steady temperature below 60°C. Close the Q3/Q4/Q6/Q13 valves.

C. Evaporation again: open the Q5/Q6/Q13 valve, the liquid in the Y4 tube is driven by the compressed gas, and Q5 and Q6 pass through to reach the reaction bottle 40 . The stainless steel capillary is heated by a 0.5A direct current, and the heating is stopped when the bottom of the bottle is actually stable at 100°C. The stainless steel capillary is cooled by compressed gas to a steady temperature below 60°C. Close Q5/Q6/Q13 valves.

D. Fluorination reaction: open the Q7/Q13 valve, and the solution in Y5 reaches the reaction bottle 40 through the Q7 valve under the push of the compressed gas. Close the Q7/Q13 valve, connect the stainless steel capillary to a 0.5A direct current heating, and when the bottom of the bottle is actually stable at 90°C, keep it for 2 minutes. Open the Q7/Q13 valve again, continue heating and evaporate to dryness. When the temperature was 100°C, the heating was stopped. The stainless steel capillary is cooled by compressed gas to a steady temperature below 60°C.

E. Hydrolysis: Open the Q8/Q13 valve, and the solution in Y6 reaches the reaction bottle 40 through the Q8 valve under the push of the compressed gas. Close the Q8/Q13 valve and keep at room temperature for 2 minutes. Open the Q9/Q13 valve, the solution in Y7 is driven by the compressed gas to reach the reaction bottle 40 through the Q9 valve, and the reaction solution is neutralized.

F. Chemical separation and purification: open the Q1/Q12/Q13 valve, the compressed gas in the Y10 will press the liquid in the reaction bottle 40 out, pass through the Q11 valve, and pass through the separation column (30mgAG50/50mgAG11A8/30mgAl2O3(N)/15mgC18 by the pipeline Y9 ) to the collection bottle. Close the Q1/Q12/Q13 valves. Then open the Q9/Q13 valve, and the liquid in Y8 reaches the reaction bottle 40 through the Q9 valve under the impetus of the compressed gas. Then open the Q1/Q12/Q13 valve, the compressed gas in Y10 will press out the liquid in the reaction bottle 40, and flow through the separation column again to reach the collection bottle. This is 18FDG product.

Radio-TLC (radioactive thin-layer chromatography) analysis results showed that the labeling rate of the labeled intermediate was 92.5% (as shown in Figure 10) and the radiochemical purity of the product was >95% (as shown in Figure 11).

Example 2: Synthesis of 18F-fluoroacetate (18FAC) (Figure 12)

The air pressure of the liquid is 20-40Kpa, and the air pressure of the gas control valve is 60-150Kpa. When the equipment is in the ready state, the Q1, Q2-Q13 pipes are all pressurized at 60-90Kpa, and all valves are closed at this time. The adsorption column 50 is pre-washed with 100ul of 0.5M K2CO3 solution, and then washed with 500ul of water until neutral. The liquid pipeline distributes and loads the corresponding reagents, that is, Y1: 500ul, 18F-H2O; Y2: waste liquid bottle; Y3: 20ul eluent (K222, 300mg/K2CO3, 55mg/0.5mlH2O/19.5mlMeCN); Y4: 20ul anhydrous Acetonitrile; Y5: 20ul O-ethylglycolate methanesulfonate EOMG (5ulEOMG/500ul anhydrous acetonitrile); Y6: 100ul water; Y7: 40ul, 1N NaOH: Y8: 80ul, 0.5N HCl; Y10: 200ul of water; Y11: waste liquid bottle (empty); In addition, the outlet of the Y9 pipeline is connected to the adsorption hydrolysis column Oasis-HLB (diameter 2.5×15mm).

Synthesis:

G. Adsorption: Open the Q1/Q2 valve (the so-called open valve is to empty the corresponding pipeline), the 18F-H2O in the Y1 tube passes through the adsorption column 50 under the push of the compressed gas, the 18F ions remain on the column 50, and the outflowing water reaches Y2 in the waste bottle. Close Q1/Q2 valve

H. Elution and evaporation: open the Q3/Q4/Q6/Q13 valve, the solution in the Y3 tube passes through the adsorption column under the push of the compressed gas, and reaches the reaction bottle 40 after passing through the valves 4 and 6. The stainless steel capillary is heated by a 0.5A direct current, and the heating is stopped when the bottom of the bottle is actually stable at 95°C. The stainless steel capillary is cooled by compressed gas to a steady temperature below 60°C. Close the Q3/Q4/Q6/Q13 valves.

I. Evaporation again: open the Q5/Q6/Q13 valve, the liquid in the Y4 tube is driven by the compressed gas, and Q5 and Q6 reach the reaction bottle 40 through it. The stainless steel capillary is heated by a 0.5A direct current, and the heating is stopped when the bottom of the bottle is actually stable at 100°C. The stainless steel capillary is cooled by compressed gas to a steady temperature below 60°C. Close Q5/Q6/Q13 valves.

J. Fluorination reaction: open the Q7/Q13 valve, and the solution in Y5 reaches the reaction bottle 40 through the Q7 valve under the push of the compressed gas. Close the Q7/Q13 valve, connect the stainless steel capillary to a 0.5A direct current heating, and when the bottom of the bottle is actually stable at 90°C, keep it for 3 minutes.

K. Dilute with water: open the Q8/Q13/Y13 valve, and the solution in Y6 will reach the reaction bottle 40 through the Q8 valve under the impetus of the compressed gas.

L. HLB column adsorption: Open the Q1/Q12/Q13 valve, the compressed gas in the front end of Y10 will press out the liquid in the reaction bottle, and at the same time, the 200ul water in the rear will pass through the reaction bottle 40, and the Y9 tube will pass through the Oasis-HLB adsorption Hydrolysis column, until emptying. The secondary effluent was discarded.

M. Hydrolysis: Open the Q9/Q13/Q12 valve, and the solution in Y6 will reach Oasis-HLB through the Q9 valve under the push of compressed gas. Collect the effluent. Keep it for 3min. Open the Q10/Q13/12 valve, and the solution (0.5N, HCl) in Y8 will pass through the Q10 valve to the Oasis-HLB column under the push of compressed gas, and then to the collection bottle.

N. Adjust the pH of the solution in the collection bottle to 5-8.5 with NaHCO3. That is the product.

The results of TLC analysis (Fig. 13, 14) showed that the radiochemical purity was 95%.

It can be understood that the above-mentioned introduction about the technical features, advantages and beneficial effects of the present invention is only a specific embodiment provided to illustrate the principle of the present invention, and is not a limitation of the claims of the present invention, and can be used without departing from the essence of the present invention. Any modifications and changes made by the principles of the present invention may still fall within the protection scope of the claims of the present invention, so the protection scope of the present invention should be defined by the technical features defined in the appended claims and their equivalent features.

Claims (7)

1. microscale reactor that is used for synthesis of radiopharmaceuticals, by fluid channel layer, the intermediate layer, control channel layer combination sealing-in and the sealing-in body that is integral, and the reaction bulb that removably is plugged in the fluid channel layer of described sealing-in body, splitter, adsorption column combines, it is characterized in that, this fluid channel layer comprises the fluid microchannel, but fluid is communicated in each reaction bulb, splitter and adsorption column, this control channel layer comprises the air chamber of control gas microchannel and corresponding fluid microchannel, air chamber by described corresponding fluid microchannel, little valve is formed in the intermediate layer, controls the keying of described fluid microchannel;

Described reaction bulb comprises the reaction tube of being made by glass material, the capillary of communication of fluid passage, and the metal capillary that is centered around the reaction tube outer wall, two termination dc sources of described metal capillary, and the entrance and exit of described metal capillary is communicated with the gases at high pressure source of supply.

2. microscale reactor according to claim 1 is characterized in that the outer wall of described reaction bulb also is provided with temperature sensor.

3. microscale reactor according to claim 1 is characterized in that described fluid channel layer and control channel layer make by following steps:

-with the printing ink figure of silk-screen printing technique printed channels aspect on plate glass;

-utilize etching solution that etching is carried out on the glass plate surface that is printed on ink logo, flush away printing ink is finished the making of former then;

-be the mastering formpiston with the glass female mold;

-be basic edition at formpiston to make fluid channel layer and the control channel layer of pouring into a mould by the PDMS silastic material; And

-with the sealing surface positioned in alignment of fluid channel layer, intermediate layer and control channel layer and carry out sealing-in.

4. microscale reactor according to claim 3 is characterized in that described serigraphy adopts anti-strong acid etching ink technology to shift at the printing ink figure of the enterprising row of channels aspect of plate glass.

5. microscale reactor according to claim 3 is characterized in that adopting the sealing surface of air low temperature plasma surface treatment convection cell channel layer, intermediate layer and control channel layer to carry out sealing-in.

6. the purposes of the microscale reactor of claim 1 in synthesis of radiopharmaceuticals.

7. method that adopts the described arbitrary microscale reactor synthesis of radiopharmaceuticals of claim 1 to 5 may further comprise the steps at least:

Adsorption step: utilize Compressed Gas to promote ¹⁸F-H ₂O makes by specifying microchannel through adsorption column ¹⁸The F ion stays in adsorption column;

Elution step: utilize Compressed Gas to promote the microchannel process adsorption column of a kind of solution by appointment, on the wash-out adsorption column ¹⁸F specifies microchannel to arrive reaction bulb by another then, and then cools off through heating evaporation in reaction bulb;

Synthesis step: utilize Compressed Gas to promote the microchannel of other reaction solution by appointment respectively and arrive reaction bulb and behind heating evaporation, cool off;

Hydrolysing step: utilize Compressed Gas to promote another solution and be hydrolyzed by specifying microchannel to arrive reaction bulb; And

Separating step: utilize the liquid in the Compressed Gas driving a reaction bottle to arrive receiving flask through splitter by specifying microchannel.

Images