CN101698146A - Microscale reactor for synthesizing radioactive drug and application thereof - Google Patents
Microscale reactor for synthesizing radioactive drug and application thereof Download PDFInfo
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- CN101698146A CN101698146A CN200910196345A CN200910196345A CN101698146A CN 101698146 A CN101698146 A CN 101698146A CN 200910196345 A CN200910196345 A CN 200910196345A CN 200910196345 A CN200910196345 A CN 200910196345A CN 101698146 A CN101698146 A CN 101698146A
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Abstract
The invention relates to the technology of microscale reactor, in particular to a microscale reactor for synthesizing radioactive drug. The microscale reactor is composed of a sealing-in body, a reaction flask, a separation column and an adsorption column, wherein the sealing-in body is sealed by a fluid channel layer, a middle layer and a control channel layer into a whole; the reaction flask, the separation column and the adsorption column are detachably spliced into the sealing-in body. The fluid passage layer comprises a fluid microchannel which causes fluid to communicate with each reaction flask, the separation column and the adsorption column; the control channel layer comprises a control air microchannel and an air chamber corresponding to the fluid microchannel; a microvalve is composed of an air chamber and a middle layer to control the fluid microchannel to open and close. The microfluidic chip of the invention can synthesize common positron nuclide of microscale volume. The invention has simple and easy preparation technology method, needs no expensive equipment, can reduce space and invested capital for protecting equipment for preparing radioactive drug and can reduce the workload of experimenters.
Description
Technical field
The present invention relates to the microscale reactor technology, particularly be suitable for the application of synthetic radiopharmaceutic micro-fluidic reactor of positron radionuclide and this micro-fluidic reactor.
Background technology
Micro-fluidic chip (Micro-fluidic Chip) or title chip lab (Lab on a chip) are based on the new technique that develops on the micro-electronic mechanical system technique basis, enjoy people to pay close attention in recent years, because the chemistry amount of required sample is few, its technology has been widely used in many analysis fields such as medical diagnosis on disease, drug screening and environment measuring.Prior art making miniflow diagnosing chip material mainly contains PDMS, and (dimethyl silicone polymer Polydimethylsiloxane) waits macromolecular material, and it has, and machine-shaping is convenient, low price, can cheap production in enormous quantities.
Synthesizing of radiopharmaceutical, particularly positron radionuclide medicine, because its required synthetic precursor or raw material chemistry amount are seldom, the above-mentioned technology of very suitable application is carried zhhj@fudan.edu.cn for the development of micro-fluidic chip The Application of Technology and has been supplied wide space.
The making general technology of common micro-fluidic chip is: the computer aided design cad figure, and------sheet glass/silicon chip is spared glue, and---photo-etching machine exposal---the hard mould in back develops, and------removing photoresist,------PDMS pours into a mould pre-part, and---micro-fluidic former is assembled wet etching by punching---surface treatment---chip to be made into mask; The equipment that this manufacture craft needs mostly is and costs an arm and a leg, as litho machine, and vacuum plasma generator, sol evenning machine etc.Its shortcoming is that technology is comparatively complicated, needs specialized apparatus.
The domestic market radioactivity is synthetic at present equips, such as: the multi-functional synthesis module of positive electron medicine of Beijing Pai Te biotech company, general volume is 1000 * 800 * 600mm (length * wide * height), needs to be equipped with the radiation proof lead screen case (hot cell) of corresponding size.The hot cell is that main material is made by thick 10-20mm lead usually, and equipment volume is big, heavy, and the price height has occupied huge fund and place resource.In addition, description of the process: the reative cell of existing micro-fluidic reaction chip mostly is the material that adopts the PDMS unanimity, makes by the mother matrix casting, because the qualification of the material of PDMS, the absorption radioactivity is more, and the preparation of radioactive element medicine is had certain inhibition influence.
On the other hand, the synthetic precursor (chemical reaction critical materials) of positron radionuclide medicine is very expensive usually, be generally 10,000 yuan/more than the gram, have in addition up to 1,700,000 yuan/gram (such as the synthetic precursor of 18 fluoro estradiol 18FES marks).These become the high partly cause of positron radionuclide drug price.Existing domestic radioactive label synthesis device reaction volume is big, and required synthetic agent is many, makes the synthetic cost of positron radionuclide medicine be difficult to descend.
In sum, be necessary to develop a kind of new positron radionuclide medicine synthesis technique really and improve technology, reduce cost, make the synthetic preparation in the laboratory of positron radionuclide medicine become possibility.
Summary of the invention
The objective of the invention is provides a kind of microscale reactor that is used for synthesis of radiopharmaceuticals in order to overcome the deficiency that prior art exists, and especially a kind of being applicable to synthesized the radiopharmaceutic improved microscale reactor equipment of positron radionuclide.This microscale reactor equipment is to make the sealing-in plate with the PDMS material to be formed by combining with the reaction bulb, adsorption column, the splitter that removably are plugged in the sealing-in plate, include little valve in the PDMS sealing-in plate wherein, functional parts such as microchannel, reaction bulb, adsorption column, splitter etc. are connected by these pipelines and valve, realize chemical synthesis and the function of separating jointly.
To achieve these goals, the radiopharmaceutic microscale reactor of synthetic positron radionuclide provided by the present invention comprises one 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, wherein this fluid channel layer comprises the fluid microchannel, but fluid is connected 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, is controlled the keying of corresponding fluid microchannel by this little valve.Wherein, the following flow process of passing through of described fluid channel layer and control channel layer is made: 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; With the glass female mold is the mastering formpiston; At formpiston is that the base version is made fluid channel layer and the control channel layer by the cast of PDMS silastic material; And with the sealing surface positioned in alignment of fluid channel layer, intermediate layer and control channel layer and adopt the air low temperature Surface Treatment with Plasma to carry out sealing-in.
The advantage of technique scheme of the present invention is: process is simple and easy to do, need not expensive equipment, can realize in common laboratory.And because the space size of this novel synthesis reactor has only 40 * 30 * 15mm, only need the less shielded box of volume just can radiation-resistant glass, among the present invention, only need to adopt the plumbous box of 250 * 250 * 200mm just can shield, reduce the space and the fund input of the safeguard of radiopharmaceutical preparation greatly.
Another aspect of the present invention provides a kind of microscale reactor, and wherein reaction bulb comprises the reaction tube of being made by glass material, the capillary of communication of fluid passage, and the metal capillary composition 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.When metal capillary is switched on, promptly reaction tube is heated; And after the outage, when feeding gases at high pressure by metal capillary, can cool off reaction tube.Owing to utilized glass reaction tube, advantageously reduced absorption to radioactive material.More advantageously, the outer wall of described reaction bulb also is provided with temperature sensor, can be used for measuring the temperature of reaction tube, carries out temperature control.
The present invention has provided a kind of micro-fluidic chip that adopts three-dimensional assembling form on the other hand, with reaction tube, adsorption column, splitter etc. removably are plugged in the fluid channel layer of sealing-in body, each parts are linked to each other with little valve with the fluid microchannel, realize chemical synthesis and the function of separating jointly.Can accomplish to be convenient to change the Chemical Decomposition post and reaction bulb cleans separately by this method.Promptly realize the plug and pull function of each detachable block, guaranteed multifunctionality, the stability of chemical synthesis, can reduce experimenter's workload simultaneously.
Among the present invention, use the synthetic positron radionuclide medicine of micro-fluidic chip and other radiopharmaceutic mark, can realize that the positron radionuclide medicine commonly used of micro-volume is synthetic, comprising:
18Fluorodeoxyglucose, (
18F-FDG),
18Fluoroacetate (
18F-FAC),
18The fluoro nitroimidazole (
18FMISO),
18The fluoro estradiol (
18FES),
18The fluoro deoxythymidine (
18And other radiopharmaceutical mark etc. F-FLT).
Another object of the present invention is to utilize microscale reactor to realize the synthetic radiopharmaceutic application of positron radionuclide, may further comprise the steps at least:
-adsorption step: utilize Compressed Gas to promote 18F-H2O, the 18F ion is stayed in adsorption column by specifying microchannel through adsorption column;
-elution step: utilize Compressed Gas to promote the microchannel process adsorption column of a kind of solution by appointment, the 18F on the wash-out adsorption column 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 arrival reaction bulb of other reaction solution respectively, behind heating evaporation, cool off by appointment;
-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.
The advantage of technique scheme is that because the reaction volume of the microscale reactor that is utilized is very little, needed reacting precursor dosage is very little, as long as 10-20ul, greatly having reduced the consumption of precursor agents, only is original 1%, has significantly saved the cost of medication preparation.
Description of drawings
Fig. 1 is the fluid channel layer plane distribution schematic diagram of microscale reactor according to an embodiment of the invention, and its orbicular spot is expressed as the reagent pipeline connection port, and straight line is represented the fluid passage;
Fig. 2 is the control channel layer plane distribution schematic diagram of microscale reactor according to an embodiment of the invention, and its orbicular spot is expressed as the control channel connector, and rectangular dots is represented air chamber, and straight line is represented gas control channel;
Fig. 3 is the plane distribution schematic diagram after the control pipe layers combination of the fluid line layer of Fig. 1 and Fig. 2;
Fig. 4 is the schematic diagram according to the PDMS layer Mold Making process of micro-fluidic chip of the present invention;
Fig. 5 is the generalized section according to little gate principle of micro-fluidic reaction chip of the present invention;
Fig. 6 is the structural principle schematic diagram according to glass reaction tube of the present invention;
Fig. 7 is the assembling schematic diagram according to micro-fluidic chip of the present invention;
Fig. 8 is the floor map according to micro-fluidic chip of the present invention, shows the adsorption column position;
Fig. 9 is a schematic diagram of using micro-fluidic chip when synthesizing 18FDG according to one embodiment of present invention;
Figure 10 is the analysis chart of the mixed liquor TLC after mannose triflate and the 18F ion fluorination reaction;
Figure 11 is the TLC analysis chart of 18FDG product, the phase acetonitrile/water (95/5=v/v) that wherein flows, Rf=0.45-0.65, radiochemicsl purity＞96%;
Figure 12 is a schematic diagram of using micro-fluidic chip when synthesizing 18FAC according to one embodiment of present invention;
Figure 13 is the TLC analysis chart of 18FAC product, Rf=0.16 wherein, and (95/5, V/V), radiochemicsl purity is greater than 95% for the phase acetonitrile/water that flows; And
Figure 14 is another TLC analysis chart of 8FAC product, Rf=0.8-0.9 wherein, and mobile phase methanol, radiochemicsl purity 98.4%, initial point is free 18F ion.
The specific embodiment
The microscale reactor that is used for synthetic positron radionuclide medicine provided by the present invention also claims micro-fluidic chip mainly to comprise a sealing-in body of being made up of fluid channel layer, control channel layer and intermediate layer, and elements compositions such as reaction bulb, separator and adsorption column.Wherein sealing-in forms this sealing-in body employing dimethyl silicone polymer (PDMS) for material is poured into a mould also, mainly comprise and be located at the fluid microchannel that connects each reaction bulb, separator and adsorption column in the fluid channel layer, be located at the gas control microchannel in the control channel layer, and the functional parts such as little valve of control microfluidic channel keying.
Figure 1 shows that its orbicular spot is expressed as the connector of reagent pipeline according to the plane distribution schematic diagram of the fluid channel layer in the sealing-in body in the micro-fluidic chip of invention, the straight line between the round dot is expressed as the fluid passage.Fig. 2 is the plane distribution schematic diagram of the control channel layer in the micro-fluidic chip sealing-in body, and its orbicular spot represents to control the connector of pipeline, and rectangular dots represents to control the air chamber of pipeline, and promptly little valve is the control gas pipeline between round dot and the rectangular dots.Fig. 3 is the plane distribution schematic diagram after the control pipe layers combination of the fluid line layer of Fig. 1 and Fig. 2.
The sealing-in body of this micro-fluidic chip is that the concrete making of microchannel mainly comprises four parts: the Mold Making of fluid channel layer and control channel layer, negative and positive mould turn over mould, the moulding by casting of silicon rubber, and the sealing-in of pour mass assembling.
1) making of mould:
The figure of fluid passage aspect and control channel aspect respectively as depicted in figs. 1 and 2, can be drawn with AutoCAD software respectively.Figure 3 shows that the plane distribution schematic diagram after the control channel layer combination of the fluid channel layer of Fig. 1 and Fig. 2.The graphics field is 26 * 30mm, live width 0.2-0.3mm, and gas and fluid passage inlet are 1mm.Technology by the ink screen printing is made into the silk screen version respectively with above-mentioned fluid channel layer and control channel layer, and the preferred 250 order oiliness polyester half tones of the present invention are referring to Fig. 4.To resist the strong acid etching ink then, be imprinted on the glass surface of cleaning oven dry in advance by the silk-screen method, the glass that will be printed on ink logo is put into glass etching liquid again, hydrofluoric acid containing 50ml for example, concentrated sulfuric acid 20ml, carry out etching in the etching solution of water 50ml, the degree of depth of glass etching is relevant with following factor: the concentration of etching solution, the temperature of solution, etched time.Be generally 5min/30 ℃.Concrete basis actual conditions is at that time decided, and generally at room temperature, etching period is 4-5 minute.Glass after the etching removes removal ink with 5% the NaOH aqueous solution.Thereby finish the making of former mould.The manufacturing process of described silk screen version is as follows: the CAD pattern---film output or template print pattern---blueprint machine blueprint (photoresists on the silk screen)---water dashes and develops---hot blast drying.
2) the negative and positive mould turn over mould:
With the former is mother matrix, pours into a mould with low-viscosity epoxy potting compound (A/B glue), and 25 ° of baking oven insulations wait for that epoxy glue solidifies.Then itself and glass are peeled off, be formpiston.Formpiston comprises fluid channel layer formpiston and two kinds of aspects of control channel layer formpiston.
3) cast of PDMS:
With the formpiston is mother matrix, PDMS glue (ratio of colloid and curing agent is 10: 1) is poured on the formpiston, and thickness 5mm, the vacuum suction de-bubble is put into 80 ℃ then, 2 hours heat preservation solidification.After PDMS curing, carefully PDMS is peeled off in ring formpiston version, be the PDMS pouring layer.
4) sealing-in assembling:
Fluid channel layer and control channel layer, it is stand-by to punch respectively.The PDMS intermediate layer 0.2mm that other prepares same material is thick, and the sealed knot face and the intermediate layer of fluid channel layer are handled through air plasma simultaneously, and two faces of handling are pressed close to mutually, and two rubber face can be gluing mutually.Wait for after two hours, again with identical method with other two need glue and face gluing.But notice that upper-lower position will aim at.This is three layers of sealing-in body.After finishing, prepare the carrier sheet glass of corresponding size, coat the PDMS glue of about 0.2-0.3mm in the above, after horizontal positioned is waited to solidify, also after air plasma is handled, three layers of sealing-in body are bonded on the glass carrier.So far the sealing-in system of micro-fluidic chip is finished.
Little valve is the key point of micro-fluidic chip, as shown in Figure 5, be provided with intermediate layer 30 between fluid channel layer 10 and the control channel 20, wherein the lower surface of fluid passage is provided with fluid passage 11, at the upper surface of control channel 20 position that should fluid passage 11 is provided with the air chamber 22 that is communicated with gas control channel 21, the air chamber 22 of this correspondence fluid passage 11 adds the intermediate isolating layer of being made by elastic deformable material 30 and has formed little valve that control fluid passage 11 opens and closes together.The last figure of Fig. 5 is expressed as little opening of valves state, and fluid passage 11 internal gas pressures of small semicircle are consistent with the air pressure of below air chamber 22, and the rubber of intermediate isolating layer 30 is in relaxed state, makes fluid passage 11 keep circulation.Figure below of Fig. 5 is expressed as little valve closure state, and when in the control channel 21 of control channel layer 20 and the air chamber 22 during pressurising, the caoutchouc elasticity body deformability of intermediate isolating layer 30 is heaved, and stops up the pipeline 11 of top, i.e. valve closing.
Describe the making of another critical piece reaction bulb (pipe) of the present invention referring to Fig. 6: reaction tube 40 is diameter 4mm, long 30mm, the thin-walled glass test tube of wall thickness 0.2mm, be the lampet blister, it is 0.4-0.7mm stainless steel capillary 41 that the reaction tube outer surface is wound with diameter, when the stainless steel capillary two ends pass to the direct current of 0.5A, be electrical heating wire.When the Stainless Steel Capillary tube inlet feeds the 0.5Bar Compressed Gas, be cooling tube.Reaction bulb all is immersed in the PDMS material of curing, and this PDMS material is promptly worked as insulation effect, works as backing material again.Other has two polytetrafluoroethylene (PTFE) capillaries 42 to be used for linking to each other with the corresponding pipe joint of PDMS fluid channel layer, also is furnished with the temperature of measurement in the sidewall of reaction bulb/pipe 40 and bottom and realizes temperature controlled sensor 43.
Fig. 7 is the solid assembling schematic diagram according to the example of micro-fluidic chip of the present invention, is pour mass above glass carrier 1, and its upper strata is a fluid channel layer 10, and lower floor is a control channel layer 20, and the centre is a separation layer 30.In fluid channel layer 10, be provided with fluid passage 11, in control channel layer 20, be provided with control channel 21.Reaction bulb 40, adsorption column 50 reaches separator 60 and is plugged on respectively in the connecting hole of fluid channel layer 10, is connected with fluid passage 11.And the little valve 22 of the gas in the control channel 20 is provided with corresponding to the position, control point of corresponding fluid passage 11, and together with gas control channel.
Fig. 8 is the floor map according to micro-fluidic chip of the present invention, shows the position at adsorption column 50 places.Shown in Figure 8 is 18F ionic adsorption post, for realizing the mark of 18F radionuclide, needs anion exchange resin that the 18F ion is separated.Adopt three-dimensional construction from part, help changing the ionic adsorption post.According to one embodiment of present invention, anion absorption (separations) post is separated in the PDMS chip body, making separately, by the PTFE tube of internal diameter 0.6mm, in fill out the anion exchange resin QMA filler of 15mm, sieve plate is the polypropylene fibre plate of 5um.Its two ends link to each other with the PDMS chip body.
Use micro-fluidic chip of the present invention and can realize positron radionuclide medicine commonly used synthetic of micro-volume, comprise: 18 fluorodeoxyglucose, (18F-FDG), 18 fluoroacetates (18F-FAC), 18 fluoro nitroimidazoles (18FMISO), 18 fluoro estradiol (18FES), 18 fluoro deoxythymidines (18F-FLT), and other radiopharmaceutical mark etc.Concrete synthesis technique mainly may further comprise the steps: 1) utilize Compressed Gas to promote 18F-H2O by specifying microchannel through adsorption column, the 18F ion is stayed in adsorption column; 2) utilize Compressed Gas to promote the microchannel process adsorption column of a kind of solution by appointment, the 18F on the wash-out adsorption column specifies microchannel to arrive reaction bulb by another then, and then cools off through heating evaporation in reaction bulb; 3) utilize Compressed Gas to promote the microchannel of other reaction solution by appointment respectively and arrive reaction bulb and behind heating evaporation, cool off, thereby realize synthetic reaction; 4) utilizing Compressed Gas to promote another solution is hydrolyzed to synthetic by specifying microchannel to arrive reaction bulb; And 5) utilize the liquid in the Compressed Gas driving a reaction bottle to arrive receiving flask through splitter by specifying microchannel; Repeat above necessary one or more steps, finally will synthesize and the medicine that separates obtaining.
Illustrate that further combined with embodiment utilizing microscale reactor of the present invention is the application that micro-fluidic chip synthesizes the positron radionuclide medicine below:
The mark of embodiment 1:18F-deoxyglucose synthesizes (Fig. 9):
Because in the micro-fluidic chip of the present invention, the power of liquid flow is from Pneumatic pressure, the amount that reagent adds is quantitative, the reagent that promptly will participate in reaction in advance adds in the corresponding pipeline, " all or none " formula that is incorporated as of reagent, promptly or all add, or add not at all, do not have intermediate form.The air pressure of liquid is 20-40Kpa, and gas control valve air pressure is 60-150Kpa.
During the equipment SBR, Q1, the Q2-Q13 pipe all adds air pressure 60-90Kpa, and this moment, all valves were in closed condition.Adsorption column 50 with 0.5M K2CO3 solution 100ul flushing, arrives neutral with the washing of 500ul in advance then.Fluid pipeline distributed load reagent corresponding, i.e. Y1:500ul, 18F-H2O; Y2: waste liquid bottle; Y3:20ul, leacheate (K222,300mg/K2CO3,55mg/0.5mlH2O/19.5ml MeCN); Y4:20ul, anhydrous acetonitrile; Y5:20ul, mannose triflate solution (100mg/8ml anhydrous acetonitrile); Y6:20ul, 1N NaOH; Y7:20ul, 1N HCl; Y8:50ul, water; Y10:30KpaN nitrogen; Y11: waste liquid bottle (emptying); The Y9 pipe outlet connects splitter (30mg AG50/50mg AG11A8/30mg Al2O3 (N)/15mgC18) terminal links to each other with receiving flask in addition.
Building-up process:
A. absorption: open Q1/Q2 valve (so-called Open valve is exactly with corresponding pipeline emptying), through adsorption column 50, the 18F ion stays on post 50 18F-H2O in the Y1 pipe under the promotion of Compressed Gas, and the water of outflow arrives the waste liquid bottle of Y2.Close the Q1/Q2 valve
B. wash-out and evaporation: open the Q3/Q4/Q6/Q13 valve, the solution in the Y3 pipe through adsorption column, arrives reaction bulb 40 by valve 4,6 backs under the promotion of Compressed Gas.The logical direct current heating of going up 0.5A of stainless steel capillary when practical stability is 95 ℃ at the bottom for the treatment of bottle, stops heating.The logical Compressed Gas cooling of stainless steel capillary is lower than 60 ℃ to stable.Close the Q3/Q4/Q6/Q13 valve.
C. evaporation again: open the Q5/Q6/Q13 valve, Y4 manages interior liquid under the promotion of Compressed Gas, Q5, and Q6 is through arriving reaction bulb 40.The logical direct current heating of going up 0.5A of stainless steel capillary when practical stability is 100 ℃ at the bottom for the treatment of bottle, stops heating.The logical Compressed Gas cooling of stainless steel capillary is lower than 60 ℃ to stable.Close the Q5/Q6/Q13 valve.
D. fluorination reaction: open the Q7/Q13 valve, the solution in the Y5 arrives reaction bulb 40 through the Q7 valve under the promotion of Compressed Gas.Close the Q7/Q13 valve, the logical direct current heating of going up 0.5A of stainless steel capillary when practical stability is 90 ℃ at the bottom for the treatment of bottle, keeps 2min.Open the Q7/Q13 valve again, continue the heating evaporate to dryness.When temperature is 100 ℃, stop heating.The logical Compressed Gas cooling of stainless steel capillary is lower than 60 ℃ to stable.
E. hydrolysis: open the Q8/Q13 valve, the solution in the Y6 arrives reaction bulb 40 through the Q8 valve under the promotion of Compressed Gas.Close the Q8/Q13 valve, room temperature keeps 2min.Open the Q9/Q13 valve, the solution in the Y7 arrives reaction bulb 40 through the Q9 valve under the promotion of Compressed Gas, and reactant liquor is neutralized.
F. Chemical Decomposition is purified: open the Q1/Q12/Q13 valve, the Compressed Gas in the Y10 extrudes the liquid in the reaction bulb 40, and by the Q11 valve, (30mgAG50/50mgAG11A8/30mgAl2O3 (N)/15mgC18) arrives receiving flask through splitter by pipeline Y9.Close the Q1/Q12/Q13 valve.Open the Q9/Q13 valve then, the liquid in the Y8 arrives reaction bulb 40 through the Q9 valve under the promotion of Compressed Gas.Open the Q1/Q12/Q13 valve again, the Compressed Gas in the Y10 extrudes the liquid in the reaction bulb 40, flows through splitter once more and arrives receiving flask.This is the 18FDG product.
Radio-TLC (radioactivity thin-layer chromatography) analysis result shows: the mark rate of mark intermediate is 92.5% (as Figure 10) product radiochemicsl purity＞95% (as Figure 11).
Synthetic (Figure 12) of embodiment 2:18F-fluoroacetate (18FAC)
The air pressure of liquid is 20-40Kpa, and gas control valve air pressure is 60-150Kpa.During the equipment SBR, Q1, the Q2-Q13 pipe all adds air pressure 60-90Kpa, and this moment, all valves were in closed condition.Adsorption column 50 with 0.5M K2CO3 solution 100ul flushing, arrives neutral with the washing of 500ul in advance then.Fluid pipeline distributed load reagent corresponding, i.e. Y1:500ul, 18F-H2O; Y2: waste liquid bottle; The Y3:20ul leacheate (K222,300mg/K2CO3,55mg/0.5mlH2O/19.5mlMeCN); The Y4:20ul anhydrous acetonitrile; Y5:20ul O-ethyl oxyacetate metilsulfate EOMG (5ulEOMG/500ul anhydrous acetonitrile); Y6:100ul water; Y7:40ul, 1N NaOH:Y8:80ul, 0.5N HCl; Y10:200ul water; Y11: waste liquid bottle (emptying); The Y9 pipe outlet connects adsorption of hydrolyzation post Oasis-HLB (diameter 2.5 * 15mm) in addition.
Building-up process:
G. absorption: open Q1/Q2 valve (so-called Open valve is exactly with corresponding pipeline emptying), through adsorption column 50, the 18F ion stays on post 50 18F-H2O in the Y1 pipe under the promotion of Compressed Gas, and the water of outflow arrives in the waste liquid bottle of Y2.Close the Q1/Q2 valve
H. wash-out and evaporation: open the Q3/Q4/Q6/Q13 valve, the solution in the Y3 pipe through adsorption column, arrives reaction bulb 40 by valve 4,6 backs under the promotion of Compressed Gas.The logical direct current heating of going up 0.5A of stainless steel capillary when practical stability is 95 ℃ at the bottom for the treatment of bottle, stops heating.The logical Compressed Gas cooling of stainless steel capillary is lower than 60 ℃ to stable.Close the Q3/Q4/Q6/Q13 valve.
I. evaporation again: open the Q5/Q6/Q13 valve, Y4 manages interior liquid under the promotion of Compressed Gas, Q5, and Q6 is through arriving reaction bulb 40.The logical direct current heating of going up 0.5A of stainless steel capillary when practical stability is 100 ℃ at the bottom for the treatment of bottle, stops heating.The logical Compressed Gas cooling of stainless steel capillary is lower than 60 ℃ to stable.Close the Q5/Q6/Q13 valve.
J. fluorination reaction: open the Q7/Q13 valve, the solution in the Y5 arrives reaction bulb 40 through the Q7 valve under the promotion of Compressed Gas.Close the Q7/Q13 valve, the logical direct current heating of going up 0.5A of stainless steel capillary when practical stability is 90 ℃ at the bottom for the treatment of bottle, keeps 3min.
K. thin up: open the Q8/Q13/Y13 valve, the solution in the Y6 arrives reaction bulb 40 through the Q8 valve under the promotion of Compressed Gas.
The absorption of L.HLB post: unlatching Q1/Q12/Q13 valve, the Compressed Gas of the front end in the Y10 extrudes the liquid in the reaction bulb, and the water of the 200ul at rear portion is managed through Oasis-HLB adsorption of hydrolyzation post by Y9 through reaction bulb 40 more simultaneously, directly ends emptying.Inferior outflow liquid is discarded.
M. hydrolysis: open the Q9/Q13/Q12 valve, the solution in the Y6 arrives Oasis-HLB through the Q9 valve under the promotion of Compressed Gas.Collect and flow out liquid.Keep 3min.Open the Q10/Q13/12 valve, (0.5N HCl) arrives the Oasis-HLB post through the Q10 valve to the solution in the Y8 under the promotion of Compressed Gas, arrive receiving flask.
N. the solution in the receiving flask is transferred pH5-8.5 with NaHCO3.Be product.
The TLC analysis result shows (Figure 13,14), radiochemicsl purity 95%.
The above-mentioned specific embodiment that only provides for the explanation principle of the invention about the introduction of technical characterictic of the present invention, advantage and beneficial effect is provided; it is not qualification to claim of the present invention; any modifications and variations of utilizing the principle of the invention to do under the prerequisite that does not break away from essence of the present invention may still drop in the claim protection domain of the present invention, therefore claimed scope of the present invention should by the defined technical characterictic of claims with and equivalent feature limit.
Claims (8)
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.
2. microscale reactor according to claim 1, it is characterized in that 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.
3. microscale reactor according to claim 2 is characterized in that the outer wall of described reaction bulb also is provided with temperature sensor.
4. 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.
5. microscale reactor according to claim 4 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.
6. microscale reactor according to claim 4 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.
7. the purposes of the microscale reactor of claim 1 in synthesis of radiopharmaceuticals.
8. method that adopts the described arbitrary microscale reactor synthesis of radiopharmaceuticals of claim 1 to 6 may further comprise the steps at least:
Adsorption step: utilize Compressed Gas to promote 18F-H2O, the 18F ion is stayed in adsorption column by specifying microchannel through adsorption column;
Elution step: utilize Compressed Gas to promote the microchannel process adsorption column of a kind of solution by appointment, the 18F on the wash-out adsorption column 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 arrival reaction bulb of other reaction solution respectively, behind heating evaporation, cool off by appointment;
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.
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