PET probe synthesis and quality control integrated equipment

Abstract

The utility model discloses PET (Polyethylene Terephthalate) probe synthesis and quality control integrated equipment and belongs to the technical field of automatic equipment. The equipment comprises a synthesis module, a purification quality control module and a solvent replacement module, the synthesis module is used for automatically synthesizing PET probe injection and comprises a liquid medicine tray, a manipulator device, a detachable disposable liquid adding box, a reaction bottle and a temperature control device capable of accommodating the reaction bottle; the purification quality control module is used for carrying out quality inspection and purification on a synthetic part product; the solvent replacement module comprises a detachable disposable clamping sleeve; the pipelines on the disposable liquid adding box and the disposable clamping sleeve can be selectively connected according to needs. According to the utility model, a mode of combining a liquid medicine tray, a disposable liquid adding box, a disposable clamping sleeve and a movable assembly is adopted in a synthesis part, and a reagent bottle or gas is freely combined with a pipeline, so that synthesis processes of different medicines, different steps and different medicine dosages can be completed on one machine, and the multifunctional and automatic synthesis requirements are met.

Description

Technical Field

[0001] The utility model relates to the technical field of automation equipment, and in particular to an integrated device for PET probe synthesis and quality control. Background Art

[0002] Positron emission tomography (PET) is a relatively advanced clinical imaging technology in the field of nuclear medicine. It is non-invasive, highly sensitive, highly specific, and safe. It is a unique modern molecular imaging technology. Compared with conventional imaging examinations (B-ultrasound, CT, MRI, etc.), PET can complete the screening of lesions throughout the body at one time, and can detect lesions more sensitively, accurately, and at an early stage. It is considered to be one of the best means of diagnosing and guiding the treatment of tumors. It is now widely used in the diagnosis and differential diagnosis of various diseases, disease assessment, efficacy evaluation, organ function research, and new drug development.

[0003] The key to PET technology is the PET probe, also known as PET developer, which is radioactive. When used, it needs to be injected into the body. The PET probe can converge in the target tissue or organ, and the rays emitted by it are detected by the imaging instrument to obtain the distribution image of the drug in the body for the diagnosis of various diseases. With a variety of PET tracer types, it can also reflect the function and metabolic changes of organs and tissues at the cellular and molecular levels according to different application scenarios, and obtain three-dimensional images, and can also perform quantitative analysis to achieve early diagnosis, which is unmatched by other current imaging examinations.

[0004] The main problems of PET synthesis instruments on the market are as follows:

[0005] 1. Currently, there are two main forms of heating in commercial PET synthesis instruments: oil bath heating and dry heating. As one of the main components of the instrument, the heating component is located in a relatively central position inside the synthesizer. Different heating methods have a crucial impact on the overall instrument and the product synthesis rate and quality.

[0006] The advantages of oil bath heating are uniform heating and high stability, but the disadvantages are also very obvious. The main material of oil bath heating is bath oil. Bath oil vapor will be generated after heating, and the reaction bottle will rise from the oil bath pot after each heating, and the bath oil will be taken out of the oil bath pot. As the number of uses increases, the bath oil will gradually decrease and need to be added irregularly; and the condensation of bath oil vapor and the bath oil taken out of the oil bath pot increase the failure rate of equipment components and unnecessary pollution. In addition, in order to meet the synthesis conditions of most PET tracers, the oil bath pot will generally be heated to the required temperature and maintained for a long time after startup, which increases many risk factors.

[0007] The characteristics of dry heating are fast heating speed, precise temperature control, simple structure, small size, and easy installation and use. However, due to factors such as the design of the heating tube and the location of the sample, there is a temperature gradient in the heating process of the drug, which leads to uneven heating and affects the quality of the drug.

[0008] 2. Currently, most commercial PET synthesis instruments are cooled by compressed air. The environment in which the PET probe synthesizer is located requires a negative pressure environment. The use of compressed air cooling can easily destroy the negative pressure environment, causing the risk of leakage of air containing radioactive substances, and will also greatly increase the amount of waste gas recovery.

[0009] 3. The main synthesis method of current commercial PET synthesis instruments is cartridge-type reaction bottle synthesis. The advantages of this single synthesis method are that it is convenient and fast to replace consumables and the technology is mature, but the disadvantages are also very obvious. The disposable cartridge has limited drug addition and synthesis positions, which cannot break the restrictions on the types of synthetic drugs and cannot meet the various needs of drug research. This has resulted in a situation where drugs are constantly updated and the synthesizer cannot keep up.

[0010] 4. Currently, most commercial PET synthesis instruments use a disposable cartridge design, in which the solid phase extraction column C18 is mostly installed after activation. The advantage is that the C18 column can be fully activated. The disadvantage is that it is easily contaminated before installation and is labor-intensive. The C18 column plays a vital role in the entire drug synthesis process. If the C18 column is contaminated, it will cause irreversible consequences.

[0011] Therefore, developing a multifunctional automated synthesis instrument with high synthesis efficiency, safety and stability, and capable of synthesizing a variety of PET probes is a technical problem that needs to be solved by those skilled in the art. Utility Model Content

[0012] The purpose of the utility model is to provide a highly integrated multifunctional automated PET probe synthesis device, which can realize the synthesis process of different drugs, different steps and different dosages on one machine to meet various clinical and scientific research needs.

[0013] In order to achieve the above purpose, the utility model adopts the following technical solutions:

[0014] The utility model provides an integrated device for PET probe synthesis and quality control, comprising a synthesis module, a purification quality control module and a solvent replacement module.

[0015] The synthesis module is used to realize the synthesis reaction of the PET probe, and its components include: a medicine tray for placing reagent bottles, a manipulator device for grabbing reagent bottles, a detachable disposable liquid adding box, a reaction bottle and a temperature control device for accommodating the reaction bottle.

[0016] In order to realize the multifunctional synthesis of the probe and effectively reduce the use cost, the synthesis part of the synthesizer provided by the utility model is realized by combining a disposable liquid adding box with a mobile component, replacing most of the pipes and valves used in the traditional fixed pipe system, and has a high degree of dynamic reconfigurability.

[0017] In the utility model, the medicine tray and the manipulator device are controlled by an automated control system to realize automated mechanical movement. Specifically, the medicine tray is a circular disk that can rotate around its axis, and a number of loading positions for placing reaction reagent bottles are evenly arranged along its circumferential direction on the circular disk. The manipulator device includes a mechanical gripper for grasping and placing the reagent bottle and a mechanical arm fixedly connected to the mechanical gripper, and the mechanical arm can be lifted and lowered and moved horizontally. The two cooperate to transfer the reagent bottle on the medicine tray to the liquid adding position of the disposable liquid adding box and dock with it. After adding the sample, the reagent bottle is transferred back to the corresponding position of the medicine tray.

[0018] The disposable liquid adding box includes a hollow box body, and the top of the box body is provided with a plurality of liquid adding positions docking with reagent bottles, a plurality of gas interfaces connected with a gas source, and a plurality of negative pressure interfaces connected with a negative pressure device; the bottom of the box body is provided with at least four docking positions for docking with a reaction bottle, namely, an azeotropic evaporation position, a sample adding position, a reaction position, and a sample output position; a coaxial needle is installed on the liquid adding position, with the needle head facing the outside of the box body, wherein the needle head of the inner needle protrudes from the needle head of the outer needle, the needle tail of the inner needle is connected with the gas interface through a pipeline, and the gap between the inner and outer needles is connected with the sample adding position through a pipeline; the azeotropic evaporation position is connected with the gas interface and the negative pressure interface respectively through a pipeline; the reaction position is provided with a sealing plug; and the sample output position is connected with the sample inlet of the purification quality control module through a pipeline.

[0019] In the utility model, the automatic control system controls the gas output of the gas source or the negative pressure device to work and generate negative pressure.

[0020] The utility model sets a disposable liquid adding box between the medicine solution tray and the reaction bottle. The liquid adding box is detachable. When synthesizing different PET probes, the disposable liquid adding box can be replaced without resetting and cleaning procedures. The interface on the liquid adding box can be selectively connected through pipelines as needed, and the types and arrangement order of raw materials on the medicine solution tray can also be configured as needed. This setting method can meet the process requirements of synthesizing a variety of different PET probes.

[0021] The utility model realizes liquid addition by arranging a coaxial needle in the liquid adding position in combination with a gas-liquid pipeline. Specifically, the coaxial needle is composed of two needle tubes of different diameters sleeved together. When the reagent bottle is docked with the liquid adding position, the needle head of the coaxial needle will pierce the reagent bottle stopper, and gas is introduced into the reagent bottle through the inner needle to increase the pressure. The liquid in the reagent bottle flows out from the gap between the inner and outer needles and flows into the reaction bottle through the sample adding position through the pipeline.

[0022] The reaction bottle is a PET probe synthesis container, and the reaction bottle is placed in a temperature control device and can be lifted and moved. The bottom of the disposable liquid adding box is provided with a sample adding position, an azeotropic evaporation position, a reaction position, and a sample outlet position that are connected to the mouth of the reaction bottle, and are respectively used to add samples to the reaction bottle, provide an azeotropic evaporation environment, provide a closed environment required for the reaction, and export the synthesis product from the reaction bottle.

[0023] The purification quality control module is used to purify and inspect the synthesis product. The synthesis product after quality inspection enters the solvent replacement module for secondary purification.

[0024] The solvent replacement module is used for adsorbing and eluting radioactive raw materials and performing solvent replacement on synthetic products. Its components include a detachable disposable ferrule, on which a solid phase extraction column I for adsorbing radioactive elements and a solid phase extraction column II for performing solvent replacement on reaction products are provided. The sample outlet of the solid phase extraction column I is connected to the sample adding position through a pipeline; the sample inlet of the solid phase extraction column II is connected to the sample outlet of the purification quality control module through a pipeline.

[0025] In the utility model, the adsorption and elution of the radioactive raw material and the solvent replacement of the synthetic product are completed on the disposable cartridge. The solid phase extraction column, the raw material bottle, the eluent bottle, the solvent bottle, etc. are arranged on the pipeline of the disposable cartridge, and the pipeline is controlled by a three-way valve. According to the synthesis process requirements of different PET probes, the pipeline can be selectively connected to realize free assembly.

[0026] The disposable cartridge is detachable. When synthesizing different PET probes, the disposable cartridge can be replaced without the need for resetting and cleaning.

[0027] The utility model also includes a control module for controlling the rotation of the medicine tray, the gripping and placing of the manipulator device, the lifting and horizontal movement, the lifting and horizontal movement of the temperature control device, the heating and cooling, and the opening and closing of the gas pipeline and the liquid pipeline. Each unit of the control module is electrically connected to the computer, and the controllability of the instrument system is realized through the operation of the software program.

[0028] The utility model also comprises a power module, and the power module is divided into pneumatic and electric to provide power for the operation of the instrument.

[0029] The working process of the utility model is as follows: the radiation particles are firstly adsorbed and eluted by the solid phase extraction column I of the disposable cartridge part, and then enter the reaction bottle through the pipeline, at which time the reaction bottle is docked with the sample adding position of the disposable liquid adding box; the temperature control device is heated to the set temperature, and moves the reaction bottle to the azeotropic evaporation position to dock with it, turns on the negative pressure, introduces nitrogen bubbling and stirring, and evaporates and removes water; after cooling, the temperature control device moves the reaction bottle to the sample adding position to dock with it, the manipulator device moves the reagent bottle to the liquid adding position, and pressurizes the bottle into the bottle through the coaxial needle to transfer the reaction reagent to the reaction bottle; the temperature control device moves the reaction bottle to the reaction position to dock with it to form a sealed state, the temperature control device heats, and after reaching the specified temperature, the water cooling system works to cool down for temperature control; after the reaction is completed, the temperature control device moves the reaction bottle to the sample output position to dock with it, the automatic sampler transfers the synthesis product to the purification quality control module for detection and primary purification, and after coming out of the quality control module, the medicine is transferred to the solid phase extraction column II of the disposable cartridge to perform solvent replacement for secondary purification, and finally a high-concentration pure medicine solution is obtained.

[0030] Preferably, the disposable liquid adding box has at least two liquid adding positions, namely position A for adding acetonitrile and position B for adding precursor solution; the disposable liquid adding box has at least three gas interfaces for external nitrogen gas source; and at least one negative pressure interface.

[0031] Preferably, a limiting structure adapted to the mouth of the reagent bottle is provided at the liquid adding position of the disposable liquid adding box; a limiting structure adapted to the mouth of the reaction bottle is provided at the docking position. The limiting structure can improve the docking accuracy, and the limiting structure can be a limiting groove or a limiting convex ring. An annular sealing rubber pad is provided in the limiting structure, which is conducive to improving the fit with the mouth of the reaction bottle.

[0032] Preferably, the sample adding position and sample discharging position of the disposable liquid adding box are provided with ventilation tubes for balancing the air pressure.

[0033] Preferably, the pipeline connected to the gas interface at the azeotropic evaporation position extends into the bottom of the reaction bottle to provide bubbling gas for the reaction solution.

[0034] Preferably, the temperature control device comprises a pot body adapted to the reaction bottle, the pot body is made of heat-conducting material, and a dry heating component and a heat dissipation circulating water channel are arranged at the bottom of the pot body. The heat dissipation circulating water channel is connected to the radiator through a pipeline, the pipeline is filled with coolant, and the coolant circulation is driven by a circulating water pump.

[0035] For the specific process of PET probe synthesis, the utility model adopts a dry heater and a water circulation cooling system to achieve temperature control. When heating, the heater heats the entire pot body, and the pot body is a heat-conducting material that fits tightly to the reaction bottle, which can quickly heat up the reaction system in the reaction bottle. In the process of PET probe synthesis, radioactive particles have a half-life, and the time used in the synthesis process is required to be short. The dry heater and its unique design can achieve fast and stable heating, reducing the loss of half-life radioactive particles. When cooling, the heater stops heating, and the circulating water pump and the cold radiator start working, transporting the coolant to the heat dissipation circulating water channel and out of the water outlet into the cold radiator and back to the circulating water pump for reciprocating circulation. Compared with air cooling, the water circulation heat dissipation system is more stable and will not cause radioactive pollution.

[0036] Preferably, the pot body is made of aluminum alloy, which has relatively good thermal conductivity.

[0037] Preferably, a heat insulating layer is provided on the outside of the pot body, and the heat insulating layer may be made of, but not limited to, polytetrafluoroethylene.

[0038] Preferably, the purification quality control module includes a high performance liquid chromatography for purifying the synthetic product and a quality inspection unit for detecting the fractions.

[0039] The inlet and outlet of the HPLC are connected to the outlet of the disposable liquid adding box and the inlet of the solid phase extraction column II on the disposable ferrule through pipelines. The quality inspection unit includes a radioactive detector to monitor the distillate from the outlet of the HPLC in real time. When the product peak appears, the three-way valve of the HPLC outlet is switched to collect the fraction.

[0040] Preferably, the disposable cartridge is composed of a plurality of three-way five-way valves, and the three-way valve can be rotated to adjust the on-off of the pipeline. The solid phase extraction column I and the solid phase extraction column II are installed on the flow channel of the valve body, and the solid phase extraction column I is connected with the raw material bottle, the eluent bottle, etc. through the valve body pipeline; the solid phase extraction column II is connected with the activator bottle, the solvent bottle, etc. through the valve body pipeline. The rotation of the three-way valve is driven by the control module.

[0041] Preferably, the solvent replacement module also includes a plurality of syringe units, which are assembled with disposable ferrules. The syringe push rods are controlled by an automated control system to realize push-pull movements, which are used to extract eluent and elute solid phase extraction column I, extract activator and activate solid phase extraction column II, and extract replacement solvent and elute solid phase extraction column II.

[0042] The utility model completes the automatic activation of the solid phase extraction column II on the disposable cartridge, extracts the activator by the syringe and delivers it to the solid phase extraction column II for full moisturization. Compared with the traditional external manual activation and then installation method, the utility model can activate the solid phase extraction column II during the use of the instrument, can maintain the drug moist state for a long time, can effectively ensure the normal adsorption of radioactive ions, and avoid the solid phase extraction column from drying up and being contaminated.

[0043] Solid phase extraction column I can be but not limited to QMA solid phase extraction column; solid phase extraction column II can be but not limited to C18 solid phase extraction column.

[0044] The utility model has the beneficial effects:

[0045] The synthesis part of the utility model adopts a combination of a medicine solution tray, a disposable liquid adding box, a disposable ferrule and a movable component, replacing most of the pipes and valves used in the traditional fixed pipeline system, and can realize that the synthesis process of different medicines, different steps and different dosages can be completed on one machine, meeting the requirements of multi-functional automated synthesis. Specifically, the rotatable medicine solution tray provides more loading positions, and the types of drugs that can be added are increased; the pipelines on the disposable liquid adding box and the disposable ferrule can be selectively connected as needed, and the reagent bottles or gases can be freely combined with the pipelines, and the types of PET probes that can be made are increased, with strong development, a high upper limit on the types of synthetic drugs, and more in line with the requirements of laboratory drug research and development for the liberalization of different formulas, different drugs, and different steps. Moreover, the disposable liquid adding box and the disposable ferrule are both detachable and assembled, without the need for reset and cleaning procedures, which improves the synthesis efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 It is a schematic diagram of the structure of the utility model.

[0047] Figure 2 It is a structural schematic diagram of the disposable liquid adding box in the utility model.

[0048] Figure 3 It is a cross-sectional view of a disposable liquid filling box.

[0049] Figure 4 This is a schematic diagram of the bottom surface of the disposable liquid filling box.

[0050] Figure 5 It is a schematic diagram of the structure of the coaxial needle in the utility model.

[0051] Figure 6 It is a top view of the temperature control device in the utility model.

[0052] Figure 7 for Figure 6 Section view of the middle AA plane.

[0053] Figure 8 It is a side view of the temperature control device in the utility model.

[0054] Fig. 9 for Figure 8 Cross-sectional view of the middle bottom surface BB.

[0055] Fig.10 It is a structural schematic diagram of a disposable ferrule in the utility model.

[0056] Fig.11 A top view of a disposable card sleeve. DETAILED DESCRIPTION

[0057] The present invention is further described below in conjunction with specific embodiments. The following embodiments are only used to illustrate the present invention and are not intended to limit the scope of application of the present invention.

[0058] Example 1

[0059] like Figure 1-11 As shown, this embodiment provides an integrated device for PET probe synthesis and quality control, including: a synthesis module 1, a purification quality control module 2, a solvent replacement module 3, a control module and a power module (not marked in the figure).

[0060] The synthesis module 1 comprises: a medicine tray 11 for placing reagent bottles, a manipulator device 12 for grabbing reagent bottles, a detachable disposable liquid adding box 13, a reaction bottle 14 and a temperature control device 15 for accommodating the reaction bottle 14.

[0061] The medicine tray 11 is a disc that can rotate around the axis, and at least 15 loading positions for placing reaction reagent bottles are evenly arranged on the disc along its circumferential direction. The manipulator device 12 includes a mechanical gripper for grasping and placing the reagent bottle and a mechanical arm fixedly connected to the mechanical gripper, and the mechanical arm can adjust the position forward, backward, left, right, up and down. The medicine tray 11 and the manipulator device 12 are controlled by the control module to realize automatic mechanical movement. The two cooperate to transfer the reagent bottle on the medicine tray 11 to the liquid adding position of the disposable liquid adding box 13 and dock with it. After adding the sample, the reagent bottle is transferred back to the corresponding position of the medicine tray 11. Specifically, according to the synthesis needs of different drugs, the drugs are inserted into the loading position on the medicine tray in sequence. When the drug needs to be added, the manipulator device is started, and the mechanical gripper can grab the drug and reach the disposable liquid adding box 13 above the liquid adding position through the extension of the mechanical arm. After the liquid is added, the manipulator device will bring the empty medicine bottle back to the medicine tray 11 and release it.

[0062] The disposable liquid adding box 13 comprises a hollow box body, the top of which is provided with at least two liquid adding positions 131 for docking with reagent bottles, at least three gas interfaces 132 connected with nitrogen gas source, and at least one negative pressure interface 133 connected with negative pressure device; the bottom of the box body is provided with at least four docking positions for docking with reaction bottles, namely, azeotropic evaporation position 134, sample adding position 135, reaction position 136, and sample output position 137. The interfaces on the liquid adding box 13 can be selectively connected through pipelines as needed, and the gas output or the operation of the negative pressure device are controlled by the control module.

[0063] A limiting structure adapted to the mouth of the reagent bottle is provided at the liquid adding position 131, and a coaxial needle 138 is installed on the liquid adding position 131. The coaxial needle 138 is composed of two needle tubes of different diameters sleeved together, with the needle head facing the outside of the box body and the needle tail facing the inside of the box body, wherein the needle head of the inner needle protrudes from the needle head of the outer needle, and the needle tail of the inner needle is connected to the gas outlet of the gas interface 132 through a pipeline, and the gap between the inner and outer needles is connected to the sample adding position 135 through a pipeline. Specifically, when the reagent bottle is docked with the liquid adding position 131, the needle head of the coaxial needle 138 will pierce the reagent bottle stopper, and gas will be introduced into the reagent bottle through the inner needle for pressurization, and the liquid in the reagent bottle will flow out from the gap between the inner and outer needles, and flow into the reaction bottle 14 through the pipeline through the sample adding position 135.

[0064] The docking position at the bottom of the box body is provided with a limit structure adapted to the mouth of the reaction bottle. The reaction bottle 14 is in a state of being able to be raised and lowered and moved horizontally. In the synthesis process, it is docked with the azeotropic evaporation position 134, the sample adding position 135, the reaction position 136, and the sample outlet position 137 according to the process requirements, so as to provide an azeotropic evaporation environment, add samples to the reaction bottle, provide a closed environment required for the reaction, and export the synthesis product from the reaction bottle.

[0065] Specifically, the azeotropic evaporation position 134 is connected to the gas interface 132 and the negative pressure interface 133 through pipelines, wherein the pipeline connected to the gas interface extends into the bottom of the reaction bottle. In the evaporation and water removal process, nitrogen is introduced to play a role of bubbling and stirring. Due to the inertness of nitrogen and the low water vapor content in pure nitrogen, it is beneficial to increase the speed of evaporation and water removal; at the same time, negative pressure is turned on to provide vacuum conditions, reduce the boiling point, and help speed up evaporation and water removal.

[0066] The sample adding position 135 is connected to the liquid path of the liquid adding position coaxial needle 138 through a pipeline to realize adding reaction reagents into the reaction bottle 14. The sample adding position 135 is also provided with a short tube for balancing air pressure.

[0067] The reaction position 136 is a blind hole with a sealing gasket, and a sealed space is formed inside the reaction bottle after docking with the mouth of the reaction bottle 14. Specifically, in the synthesis reaction stage, the reaction bottle 14 is moved to the reaction position 136. Due to the heating in the previous evaporation and water removal stage, the internal temperature of the reaction bottle 14 is relatively high. After being moved to the reaction position 136, the temperature drops, and a negative pressure is formed inside the bottle, so that the mouth of the reaction bottle 14 and the sealing gasket are completely fitted to form a sealing system, and then the heating mode is turned on for a closed reaction.

[0068] Annular sealing rubber pads adapted to the mouth of the reaction bottle are provided on other docking positions to increase the fit of the docking.

[0069] The sample outlet 137 is connected to the sample inlet of the purification quality control module 2 through a pipeline, and the synthesis product is led out of the reaction bottle into the purification quality control module 2 by the automatic sample injector. A short tube for balancing the air pressure is also provided on the sample outlet 137.

[0070] The disposable liquid-adding box 13 is detachable. When synthesizing different PET probes, the disposable liquid-adding box can be replaced without the need for resetting and cleaning.

[0071] The reaction bottle 14 is a PET probe synthesis container. The reaction bottle 14 is contained in a temperature control device 15. The temperature control device 15 is controlled by a control module to lift and move horizontally, driving the reaction bottle 14 to be in a lifting and moving state. The temperature control device 15 includes a pot body 151 adapted to the reaction bottle. The pot body 151 is made of a heat-conducting material. A dry heating component 152 and a heat dissipation circulating water channel 153 are provided at the bottom of the pot body 151. The heat dissipation circulating water channel is connected to the radiator through a pipeline. The pipeline is filled with coolant, and the coolant circulation is driven by a circulating water pump. The operation of the heating component and the water cooling system in the temperature control device 15 is controlled and driven by the control module.

[0072] As a specific implementation of this embodiment, the heat conductive material is aluminum alloy. The pot body 151 is closely attached to the reaction bottle 14, which can quickly heat up and cool down the reaction system in the reaction bottle and ensure uniform heat conduction. A polytetrafluoroethylene heat insulation layer is arranged on the outside of the pot body 151.

[0073] The purification quality control module 2 is used to purify and inspect the synthetic product. Specifically, the purification quality control module 2 includes a high-performance liquid chromatography for purifying the synthetic product and a quality inspection unit for detecting the fraction. The quality inspection unit includes a radioactive detector, which monitors the distillate from the high-performance liquid chromatography outlet in real time. When the product peak appears, the three-way valve at the liquid chromatography outlet is switched to collect the fraction, and the fraction is introduced into the solvent replacement module 3 after dilution for secondary purification.

[0074] The solvent replacement module 3 is used for solvent replacement of radioactive raw materials and synthetic products. Specifically, the solvent replacement module 3 includes a detachable disposable ferrule 31, which is composed of several groups of three-way five-way valves, and the three-way valve is controlled by the control module and can be rotated to adjust the on-off of the pipeline. According to the process requirements, a QMA solid phase extraction column for adsorbing radioactive elements and a C18 solid phase extraction column for solvent replacement of reaction products are installed on the flow channel of the valve body respectively. The QMA solid phase extraction column is connected to the radioactive element raw material liquid bottle, the eluent bottle, etc. through the valve body pipeline; the C18 solid phase extraction column is connected to the activator bottle, the solvent bottle, etc. through the valve body pipeline.

[0075] The solvent replacement module 3 also includes a plurality of syringe units, which are assembled with a disposable ferrule. Each syringe push rod is controlled by a control module to realize push-pull movement, so as to realize the processes of extracting eluent and eluting the QMA solid phase extraction column, extracting activator and activating the C18 solid phase extraction column, extracting replacement solvent and eluting the C18 solid phase extraction column, etc.

[0076] The sample outlet of the QMA solid phase extraction column is connected to the sample adding position 135 of the disposable liquid adding box 13 through a pipeline. The sample inlet of the C18 solid phase extraction column is connected to the sample outlet of the purification quality control module 2 through a pipeline.

[0077] In this embodiment, the adsorption and elution of the radioactive raw material and the solvent replacement of the synthetic product are completed on the disposable cartridge. According to the synthesis process requirements of different PET probes, free assembly can be achieved through the selective connection of pipelines.

[0078] The activation of the C18 solid phase extraction column is completed on a disposable cartridge. Using a machine for automated activation can avoid the drying and contamination of the C18 column.

[0079] The disposable cartridge is detachable. When synthesizing different PET probes, the disposable cartridge can be replaced without the need for resetting and cleaning.

[0080] In this embodiment, each unit of the control module is electrically connected to the computer, and the controllability of the instrument system is achieved through the operation of the software program.

[0081] The power module is divided into pneumatic and electric, which provide power for the operation of the instrument.

[0082] In the synthesis process of different PET probes, there are great differences in reaction conditions, reaction process length, product purification method, injection solution configuration method, etc. The device provided in this embodiment is designed with only one reactor, which has good compatibility for the reaction of the single container. 18 Taking F-MK9470 as an example, one of the operation modes of the device in this embodiment is introduced as follows:

[0083] Preparation: First, place the raw material reagent bottles in order on the loading position of the medicine tray 11. Install the activated QMA solid phase extraction column, C18 solid phase extraction column, alcohol bottle, ascorbic acid bottle, eluent bottle, etc. on the disposable card sleeve 31.

[0084] Equipment installation self-test: first remove the old disposable liquid-filling box and disposable card sleeve, then select the new drug type in the running software program, and perform the zero self-test process, and then install the disposable liquid-filling box and the disposable card sleeve prepared above.

[0085] The specific operation process of the equipment is as follows:

[0086] Activation of C18 solid phase extraction column: one of the syringes extracts alcohol, turns the three-way five-way valve, and passes the alcohol through the C18 column to fully wet the C18 column. After that, the alcohol enters the waste liquid bottle, and the C18 column activation is completed. After activation, the normal saline is passed in for cleaning, and nitrogen is blown dry to avoid pipeline contamination.

[0087] 18 Capture of F: Turn the three-way five-way valve and start the vacuum pump to form negative pressure. 18 F ion H2 18 O is absorbed, adsorbed by the QMA solid phase extraction column and finally enters the recovery bottle. The equipment controls H2 by adjusting the negative pressure. 18 O flow rate, optimize H2 18 O 18 The effect of F being adsorbed by the QMA solid phase extraction column, and the radioactive probe records the initial activity before the reaction.

[0088] At the same time, the temperature control device 15 starts heating until the set temperature.

[0089] 18 F elution: one of the syringes draws the eluent, turns the three-way five-way valve, and pumps the eluent through the QMA solid phase extraction column. At the same time, the temperature control device 15 moves the reaction bottle 14 to the sample adding position 135 of the disposable liquid adding box 13 and rises. The eluent removes the adsorbed 18 F is eluted into the reaction bottle 14.

[0090] Evaporation and water removal: The temperature control device 15 brings the reaction bottle 14 down and moves to the azeotropic evaporation position 134. At the same time, the negative pressure and nitrogen are turned on, and the air valve is opened. After the set time is reached, the negative pressure and nitrogen are turned off, the temperature control device 15 brings the reaction bottle 14 down, and the monitoring system takes a picture of the state in the reaction bottle 14 for preservation, completing the first azeotropic evaporation. The temperature control device 15 brings the reaction bottle 14 to the sample addition position 135, the medicine tray 11 rotates the reagent bottle containing anhydrous acetonitrile to the bottom of the manipulator device, the mechanical gripper grabs the reagent bottle containing anhydrous acetonitrile, and moves the anhydrous acetonitrile bottle to the first liquid addition position through the movement of the mechanical arm, and the anhydrous acetonitrile is transferred to the reaction bottle 14 by pressurizing the bottle through the coaxial needle 138. The temperature control device 15 brings the reaction bottle 14 down and moves to the azeotropic evaporation position 134, and at the same time, the negative pressure and nitrogen are turned on, the air valve is opened, and azeotropic evaporation is performed. The azeotropic evaporation process is carried out 3 times in total, and the monitoring system records the results of each time.

[0091] Reaction: After the water removal is completed, the reaction bottle 14 cools down, and the temperature control device 15 moves the reaction bottle 14 to the sample adding position 135 and rises to dock with it. At the same time, the liquid medicine tray 11 rotates the reagent bottle containing the precursor to the bottom of the manipulator device, and the manipulator device moves the reagent bottle to the second liquid adding position, and the precursor solution is added to the reaction bottle 14 by coaxially increasing the pressure in the bottle. The temperature control device 15 descends with the reaction bottle 14, and then moves to the reaction position 136 to dock, maintaining the reaction temperature and starting the reaction.

[0092] Dilution: After the reaction is completed, the monitoring and recording of the reaction results are performed, and the temperature control device 15 takes the reaction bottle 14 to cool the reaction bottle 14. At the same time, the medicine tray 11 rotates the reagent bottle containing the diluent to the bottom of the manipulator device, and the manipulator device transfers the reagent bottle to the first liquid adding position. The temperature control device 15 takes the reaction bottle 14 to the sample adding position 135 to dock with it, and then turns on the nitrogen to transfer the diluent to the reaction bottle 14. The dilution process is carried out 3 times in total, and the monitoring system records the results of each time.

[0093] High-performance liquid phase purification: The temperature control device 15 moves the reaction bottle 14 down to the sample outlet position 137, and the liquid in the reaction bottle 14 is drawn into the quantitative loop of the liquid phase system. After switching the six-way valve position, the mobile phase is used to pass through the column. According to the feedback results of the radioactivity detector, when 18 When the product peak of F-MK9470 appears, switch the three-way valve at the liquid phase outlet to collect the product and transfer it to a centrifuge tube filled with diluent. The activity of the crude product is measured by a radioactive probe.

[0094] Solvent replacement: Turn the three-way five-way valve, start the program, and slowly pass the diluted solution in the centrifuge tube through the activated C18 short column at a constant force, and then wash the pipeline with distilled water. Use 1mL of ethanol solution (ethanol ratio is less than 10%) to rinse the product of the C18 short column into the transfer bottle, and after dilution, sterilize it with a sterile filter membrane and collect it in a sterile product bottle. Finally, turn on the nitrogen to blow the residual agent in the pipeline into the product bottle to obtain the final product.

[0095] The integrated device of this embodiment can realize the fully automatic synthesis of PET probes and can automatically detect drugs after the synthesis is completed, and can directly issue a quality control report. It has the advantages of simple operation, low cost, high degree of automation, strong developability, etc.

Claims

1. A PET probe synthesis and quality control integrated equipment, characterized in that: include: Synthesis module, purification quality control module and solvent replacement module; The synthesis module includes: a medicine tray for placing reagent bottles, a manipulator device for grabbing reagent bottles, a detachable disposable liquid adding box, a reaction bottle and a temperature control device for accommodating the reaction bottle; The disposable liquid adding box comprises a hollow box body, and the top of the box body is provided with a plurality of liquid adding positions docking with reagent bottles, a plurality of gas interfaces connected with gas sources, and a plurality of negative pressure interfaces connected with negative pressure devices; the bottom of the box body is provided with at least four docking positions for docking with reaction bottles, namely, an azeotropic evaporation position, a sample adding position, a reaction position, and a sample output position; a coaxial needle is installed on the liquid adding position, and the needle head faces the outside of the box body, wherein the needle head of the inner needle protrudes from the needle head of the outer needle, and the needle tail of the inner needle is connected to the gas interface through a pipeline, and the gap between the inner and outer needles is connected to the sample adding position through a pipeline; the azeotropic evaporation position is connected to the gas interface and the negative pressure interface respectively through pipelines; the reaction position is provided with a sealing gasket; the sample output position is connected to the sample inlet of the purification quality control module through a pipeline; The solvent replacement module includes a detachable disposable ferrule, on which a solid phase extraction column I for adsorbing radioactive elements and a solid phase extraction column II for solvent replacement of reaction products are provided. The sample outlet of the solid phase extraction column I is connected to the sample adding position through a pipeline; the sample inlet of the solid phase extraction column II is connected to the sample outlet of the purification quality control module through a pipeline.

2. The PET probe synthesis and quality control integrated equipment according to claim 1, characterized in that: The medicine solution tray is a circular disk that can rotate around its axis, and a number of loading positions for placing reaction reagent bottles are evenly arranged along its circumferential direction on the disk; the manipulator device includes a mechanical gripper for grasping and placing reagent bottles and a mechanical arm fixedly connected to the mechanical gripper, and the mechanical arm can be raised and lowered and moved horizontally.

3. The PET probe synthesis and quality control integrated equipment according to claim 1, characterized in that: The liquid adding position and docking position of the disposable liquid adding box are provided with limiting structures respectively adapted to the bottle mouths of the reagent bottle and the bottle mouths of the reaction bottle.

4. The PET probe synthesis and quality control integrated equipment according to claim 1, characterized in that: The sample adding position and sample discharging position of the disposable liquid adding box are provided with ventilation pipes for balancing the air pressure.

5. The PET probe synthesis and quality control integrated equipment according to claim 1, characterized in that: The temperature control device comprises a pot body adapted to the reaction bottle, the pot body is made of heat-conducting material, and a dry heating component and a heat dissipation circulating water channel are arranged at the bottom of the pot body.

6. The PET probe synthesis and quality control integrated equipment according to claim 5, characterized in that: The pot body is made of aluminum alloy metal.

7. The integrated PET probe synthesis and quality control device according to claim 1, characterized in that: The purification quality control module includes a high performance liquid chromatography for purifying the synthetic product and a quality inspection unit for detecting the fractions.

8. The PET probe synthesis and quality control integrated equipment according to claim 1, characterized in that: The disposable ferrule is composed of a number of three-way five-connected valves, and the three-way valve can be rotated to adjust the on-off of the pipeline; the solid phase extraction column I and the solid phase extraction column II are installed on the flow channel of the valve body, the solid phase extraction column I is connected with the raw material bottle and the eluent bottle through the valve body pipeline, and the solid phase extraction column II is connected with the activator bottle and the solvent bottle through the valve body pipeline.

9. The integrated PET probe synthesis and quality control device according to claim 1 or 8, characterized in that: The solvent replacement module also includes a plurality of syringe units, which are assembled with disposable ferrules and are used to extract eluent and elute solid phase extraction column I, extract activator and activate solid phase extraction column II, and extract replacement solvent and elute solid phase extraction column II.

10. The integrated PET probe synthesis and quality control device according to claim 1, characterized in that: It also includes a control module for controlling the rotation of the medicine tray, the grasping and placing, lifting and horizontal movement of the manipulator device, the lifting and horizontal movement of the temperature control device, the heating and cooling, and the opening and closing of the gas pipeline and the liquid pipeline.

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