Astatine-211 separation and purification system and method based on a microfluidic chip

Abstract

This invention discloses a microfluidic chip-based system and method for the separation and purification of astatine-211, belonging to the field of radionuclide separation technology. The system integrates a pretreatment and sample introduction module, a core microfluidic extraction chip module, and a fluid drive and monitoring module. The chip features a solvent-resistant nano-barrier coating, an asymmetric deep-step flow channel, and a wave-shaped secondary flow-guiding separation structure. The method involves a fully enclosed, automated, continuous operation of feed presaturation, microfluidic forward extraction, microfluidic washing, and differential back-extraction concentration. This invention solves the problems of high radiation risk, high reagent consumption, severe radionuclide decay loss, and conventional microfluidic interface instability and chip swelling failure associated with traditional wet manual methods, achieving rapid, safe, high-purity, and low-loss large-scale automated preparation of astatine-211.

Description

Technical Field

[0001] This invention relates to the field of radioisotope separation and purification technology, and more specifically, to a microfluidic chip-based astatine-211 separation and purification system and method. Background Technology

[0002] Astatine-211 ( 211 Alpha-1 (A) is one of the most clinically valuable radionuclides for targeted alpha therapy. It possesses a suitable half-life, high linear energy transfer efficiency, and a strong killing effect on tumor cells, making it central to the development of precision radiotherapy drugs. Currently, industrial and laboratory preparation... 211 At is mainly obtained by bombarding bismuth targets with cyclotrons, and is separated and purified from the irradiated bismuth target material. 211 At is a crucial step before drug labeling.

[0003] existing 211 Atmospheric ion (AT) separation and purification technologies are mainly divided into two categories: dry distillation and wet chemical extraction. Wet extraction is widely used due to its mature technology and stable recovery rate, but it has significant drawbacks in practical applications: traditional wet extraction relies heavily on manual, intermittent processing, resulting in a cumbersome and time-consuming process. 211 At has a short half-life, and prolonged operation will cause a large amount of radionuclide decay and loss, significantly reducing the final effective yield. At the same time, traditional processes consume huge amounts of reagents, and the extraction process is prone to generating strong radioactive aerosols and toxic acid mists, which not only cause environmental pollution, but also expose operators to extremely high radiation exposure risks, making it difficult to meet the production needs of clinical-grade radionuclides that are automated, safe, and standardized.

[0004] Microfluidic chip technology, with microscale fluid manipulation at its core, possesses advantages such as minimal reagent consumption, short mass transfer distances, rapid reaction speeds, ease of integration, and automated closed-loop operation, making it a promising solution for... 211 At the ideal technical path for rapid separation and purification. However, directly applying microfluidic technology... 211 Liquid-liquid extraction and separation of AT still faces insurmountable technical barriers in both materials and fluid dynamics. On the one hand, 211 Strong organic solvents such as diisopropyl ether (DIPE), essential for AT extraction, can cause severe swelling, penetration, and erosion of conventional polymeric microfluidic chip substrates such as polydimethylsiloxane (PDMS), leading to channel deformation, blockage, and even chip failure, failing to meet the requirements for long-term stable operation. On the other hand, diisopropyl ether has a certain degree of miscibility with high-concentration hydrochloric acid systems, which significantly reduces the liquid-liquid interfacial tension and induces dynamic changes in the volume of the two-phase fluid within the microchannel. This makes it difficult for conventional microfluidic devices to stably maintain a laminar interface, easily leading to interface collapse, entrainment and cross-contamination between the aqueous and organic phases, and hindering efficient and thorough phase separation.

[0005] Currently, there is still a lack of automated microfluidic systems internationally that can simultaneously withstand strong organic solvents, stably maintain the liquid-liquid interface in low interfacial tension systems, and integrate pretreatment, extraction, washing, back-extraction, and online concentration functions, making it difficult to achieve... 211 At the point of view, a closed-loop, rapid, and high-purity separation process is needed. Therefore, developing a microfluidic separation and purification system and method with solvent-resistant barrier protection, stable interface pinning structure, and fully automated integration is of great significance for overcoming existing technical bottlenecks and realizing the clinical-grade, standardized, and safe preparation of astatine-211. Summary of the Invention

[0006] To overcome the shortcomings of the prior art, this invention provides a microfluidic chip-based astatine-211 separation and purification system, comprising a pretreatment and sample introduction module, a core microfluidic extraction chip module, and a fluid drive and monitoring module; wherein, The pretreatment and injection module includes a target dissolution cell, an evaporation temperature control component, and a reagent presaturation component. The evaporation temperature control component is used to remove nitric acid medium from the target dissolution cell to form an aqueous phase solution containing astatine-211. The reagent presaturation component is used to ensure that the organic extractant and the high-concentration hydrochloric acid medium reach mutual saturation before entering the core microfluidic extraction chip module. The core microfluidic extraction chip module includes at least one microfluidic extraction chip, and the microfluidic extraction chip includes a microchannel and a nano-barrier coating formed on the inner wall of the microchannel. The microchannel includes a microchannel body and a Y-shaped wavy flow-guiding and separation structure disposed at the end of the microchannel body. The microchannel is provided with an asymmetric depth stepped flow channel. The asymmetric depth stepped flow channel includes two branches extending from the microchannel body to the wavy flow-guiding and separation structure, respectively. The two branches are an aqueous phase flow channel and an organic phase flow channel, and the depth of the aqueous phase flow channel is greater than the depth of the organic phase flow channel. The fluid drive and monitoring module includes a multi-channel injection pump and an online radiation detector. The outlet of the target dissolution pool and the outlet of the reagent presaturation component are connected to the inlet of the aqueous phase flow channel and the inlet of the organic phase flow channel, respectively, through the multi-channel injection pump. The online radiation detector is located at the outlet of the microfluidic extraction chip and is used to monitor the radioactivity of the effluent in real time.

[0007] Compared with existing technologies, this invention integrates a pretreatment and sample introduction module, a core microfluidic extraction chip module, and a fluid drive and monitoring module to form a complete fully enclosed automated separation and purification system for astatine-211. The target dissolution pool and evaporation temperature control components complete target dissolution and media conversion; the reagent presaturation component pre-saturates the organic and aqueous phases, preventing volume fluctuations within the microchannels; the nano-barrier coating on the chip's inner wall effectively resists the swelling and penetration of strong organic solvents into the substrate; the asymmetric deep-step flow channel stabilizes the liquid-liquid interface at the step edges using its geometric structure and Laplace pressure difference; and the wave-shaped flow-guiding separation structure provides secondary stabilization when interface fluctuations occur, ensuring complete physical separation of the two phases. Combined with a multi-channel syringe pump for precise fluid drive and real-time monitoring by an online radiation detector, the entire system can operate automatically in a closed environment, significantly reducing the risk of radiation exposure for operators, reducing reagent consumption, shortening separation time, and minimizing decay losses of astatine-211 due to its half-life, ultimately achieving stable, efficient, and high-purity separation and purification.

[0008] In one possible implementation, the nano-barrier coating is obtained by atomic layer deposition (ALD), and the material is an alternating layer of SiO2, Al2O3, or SiO2 and Al2O3, with a thickness of 10-100 nm. By employing ALD to obtain nano-barrier coatings of specific inorganic materials, the density and conformal coverage of the coating can be further improved, enhancing the chip's resistance to strong organic solvents, preventing channel deformation, blockage, or failure, and improving the long-term stability of the system.

[0009] In one possible implementation, the wave-shaped flow-guiding separation structure includes continuous semi-circular microstructures on the opposing end faces of the two Y-shaped branches at the end of the microchannel body, used to provide secondary interface pinning points. The wave-shaped flow-guiding separation structure, composed of continuous semi-circular microstructures, can provide additional interface pinning points when fluctuations occur at the two-phase interface, further suppressing interface collapse, avoiding mutual entrainment or cross-contamination between the aqueous and organic phases, and improving the reliability and stability of the separation.

[0010] In one possible implementation, the depth of the aqueous phase channel in the asymmetric depth stepped flow channel is 100 μm, and the depth of the organic phase channel is 50 μm. By defining the specific depths of the aqueous and organic phase channels, a suitable geometrical stepped structure can be stably formed, reliably generating a Laplace pressure differential for pinning the interface, ensuring stable operation of the two phases in a parallel laminar flow state, and ensuring smooth mass transfer and separation processes.

[0011] In one possible implementation, the substrate of the microfluidic extraction chip is polydimethylsiloxane, a cyclic olefin copolymer, or a cyclic olefin polymer. Cyclic olefin copolymers (COC) or cyclic olefin polymers (COP) have inherent resistance, eliminating the need for ALD coating to prevent swelling. To maintain the stability of the hydrodynamic interface, the "aqueous phase channel side" of the COC chip is locally hydrophilized using masked ultraviolet ozone or plasma technology, making the organic phase channel hydrophobic and the aqueous phase channel hydrophilic.

[0012] In one possible implementation, the core microfluidic extraction chip module includes a first microfluidic extraction chip, a second microfluidic extraction chip, and a third microfluidic extraction chip connected in series. The first microfluidic extraction chip is an extraction chip used to receive the aqueous feed liquid and the pre-saturated organic extractant to extract astatine-211 from the aqueous phase to the organic phase. The second microfluidic extraction chip is a washing chip, used to receive the organic phase and washing hydrochloric acid from the extraction chip to remove impurities entrained in the organic phase; The third microfluidic extraction chip is a back-extraction chip, used to receive the organic phase and alkaline back-extraction solution from the washing chip to back-extract astatine-211 from the organic phase to the aqueous phase, obtaining a concentrated astatine-211 product solution. Compared with the prior art, this invention, by employing an extraction chip, a washing chip, and a back-extraction chip connected in series, enables the system to continuously complete the entire process of extraction, washing, and back-extraction, achieving stepwise purification and impurity removal of astatine-211, and improving the radiochemical purity of the final product.

[0013] The second objective of this invention is to provide a method for the separation and purification of astatine-211 based on a microfluidic chip, comprising the following steps: Step S1, Preparation and Presaturation of Feed Solution: The irradiated bismuth target is dissolved in nitric acid, and after the nitric acid is removed by evaporation, it is dissolved in high-concentration hydrochloric acid to obtain an aqueous feed solution containing astatine-211; at the same time, the organic extractant is mixed with hydrochloric acid of the same concentration for presaturation treatment to obtain a presaturated organic extractant. Step S2, Microfluidic positive extraction: The aqueous phase solution prepared in step S1 and the pre-saturated organic extractant are simultaneously injected into the microfluidic extraction chip. Parallel laminar flow is formed in the asymmetric depth stepped flow channel for mass transfer, so that astatine-211 is extracted from the aqueous phase to the organic phase. The two phases are physically separated by the wave-shaped flow-guiding separation structure to obtain an organic phase enriched with astatine-211. Step S3, Microfluidic washing: The organic phase enriched with astatine-211 obtained in step S2 is simultaneously injected into the microfluidic extraction chip with hydrochloric acid for washing to remove impurities entrained in the organic phase. Step S4, Microfluidic Back-extraction and Concentration: The organic phase washed in step S3 and the alkaline back-extraction solution are simultaneously injected into the microfluidic extraction chip for back-extraction, so that astatine-211 is back-extracted from the organic phase to the aqueous phase. By controlling the flow rate of the organic phase to be greater than that of the aqueous phase, the online concentration of astatine-211 in the aqueous phase is achieved during back-extraction, and a high-purity astatine-211 product solution is obtained.

[0014] Compared with existing technologies, this invention constructs a complete automated separation and purification process for astatine-211 by sequentially performing four steps: feed preparation and presaturation, microfluidic forward extraction, microfluidic washing, and microfluidic back extraction and concentration. Presaturation treatment avoids volume changes and interfacial instability between the two phases within the microchannel; microfluidic laminar flow enables rapid mass transfer and efficient extraction of astatine-211; washing further removes entrained impurities; and back extraction and flow rate control achieve the transfer of astatine-211 to the aqueous phase and online concentration. The entire method is automated within a closed system, eliminating the need for intermittent manual operation. This significantly shortens processing time, reduces radionuclide decay losses, lowers reagent consumption and the risk of radioactive acid mist leakage, and ultimately yields a high-purity, high-concentration astatine-211 product solution, meeting the requirements for subsequent drug labeling.

[0015] In one possible implementation, in step S2, the contact time between the aqueous feed solution and the organic extractant within the asymmetric depth stepped flow channel is 0.1-5 s. By controlling the contact time between the two phases within the flow channel, the processing time can be further shortened while ensuring sufficient extraction of astatine-211, thereby minimizing the decay loss of short-half-life nuclides and improving the effective yield.

[0016] In one possible implementation, in step S3, the concentration of hydrochloric acid is 6-8 mol / L; In step S4, the alkaline back-extraction solution is a 1-4 mol / L NaOH solution. By using a suitable concentration of hydrochloric acid and sodium hydroxide back-extraction solution, a stable and matched reaction environment can be provided for extraction, washing, and back-extraction, improving the mass transfer efficiency and impurity removal effect of astatine-211, and ensuring that the separation and purification process is carried out efficiently and stably.

[0017] In one possible implementation, in step S4, the flow rate ratio of the organic phase to the aqueous phase is (2-5):1. By controlling the ratio of the organic phase flow rate to the aqueous phase flow rate, astatine-211 can be concentrated online in the aqueous phase during back-extraction, resulting in a small-volume, high-concentration product solution, which is more convenient for subsequent labeling and use of radiopharmaceuticals. Attached Figure Description

[0018] Figure 1 This is a block diagram of the present invention; Figure 2This is a perspective view of the microchannel of the present invention.

[0019] Explanation of reference numerals in the attached figures: 1. Organic phase flow channel; 2. Aqueous phase flow channel; 3. Continuous semi-circular microstructure. Detailed Implementation

[0020] To make the above-mentioned objects, features, and advantages of the present invention more apparent and understandable, specific embodiments of the present invention are described in detail below. It should be noted that the following embodiments are only used to illustrate the implementation methods and typical parameters of the present invention, and are not intended to limit the parameter range described in the present invention. Reasonable variations derived therefrom are still within the protection scope of the claims of the present invention.

[0021] It should be noted that the endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0022] Unless otherwise defined, all terms, symbols, and other scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In some instances, terms having a conventionally understood meaning are defined herein for clarification or ease of reference, and such definitions should not be construed as indicating a significant difference from conventional understanding in the art. The technical methods described or referenced herein are generally well understood by those skilled in the art and employed through conventional methods. Unless otherwise stated, the use of commercially available kits, reagents, and instruments shall be performed according to the manufacturer's instructions and parameters.

[0023] The present invention provides a detailed description of the construction method of a microfluidic extraction chip for the separation and purification of astatine-211. Specifically: Microchannels were cast using soft photolithography with polydimethylsiloxane (PDMS) as the substrate. Figure 2 As shown, the microchannel is configured as an asymmetric depth stepped flow channel. In a preferred embodiment, the flow channel for carrying the aqueous phase, i.e., aqueous phase flow channel 2, has a depth of 100 μm, and the flow channel for carrying the organic phase, i.e., organic phase flow channel 1, has a depth of 50 μm. The two flow channels converge in the main section, forming a geometric step with a height of 50 μm at the bottom. Figure 2 The dashed line in the diagram represents the boundary between the organic phase channel 1 and the aqueous phase channel 2. A Y-shaped diversion outlet is provided at the end of the microchannel body. The sidewall of the channel at the Y-shaped separation outlet is processed into a continuous semi-circular microstructure 3 with a radius of about 5μm, forming a wave-shaped flow guiding and separation structure.

[0024] The prepared PDMS-based microfluidic extraction chip was placed in an atmospheric pressure atomic layer deposition (ALD) reaction chamber, and a metal precursor and an oxidant were alternately introduced at 60°C, with nitrogen purging in between. The metal precursor was silicon tetrachloride, and the oxidant was ozone or water vapor. By controlling the number of ALD cycles to 25-50, a dense silicon dioxide nano-barrier layer with a thickness of 10-100 nm was conformally grown on the inner wall of the microchannel of the microfluidic extraction chip. It is worth mentioning that the nano-barrier coating can also be prepared by using aluminum oxide or alternating layers of silicon dioxide and aluminum oxide.

[0025] By forming a silica nano-barrier layer on the inner wall of the microchannel, the substrate is transformed from oleophobic to chemically inert to strong organic solvents, effectively preventing substrate swelling, channel deformation, or blockage caused by extractants such as diisopropyl ether, and ensuring channel dimensional stability. During fluid-driven operation, the asymmetric depth-stepped flow channel generates a Laplace pressure difference at the two-phase interface, stably pinning the liquid-liquid interface to the step edge. Combined with the wave-shaped flow-guiding separation structure at the Y-shaped separation outlet at the end, a secondary interface pinning effect is provided, stably maintaining the parallel laminar flow state of the two phases without the use of a separating membrane, avoiding interface collapse, entrainment, or cross-contamination, and ensuring that Astatine-211 achieves second-level rapid mass transfer and efficient separation at the microscale.

[0026] It is worth mentioning that the substrate of the aforementioned microfluidic extraction chip can also be replaced with cyclic olefin copolymer (COC) or cyclic olefin polymer (COP). COC / COP materials have natural resistance to acids, alkalis, and DIPE, eliminating the need for ALD coating to prevent swelling. To maintain the stability of the hydrodynamic interface, the aqueous phase channel 2 of the COC chip is locally hydrophilized using masked ultraviolet ozone or plasma technology, making the organic phase channel 1 hydrophobic and the aqueous phase channel 2 hydrophilic.

[0027] The following examples further illustrate this point.

[0028] Example 1

[0029] like Figure 1 As shown, this embodiment provides an astatine-211 separation and purification system, including a pretreatment and sample injection module, a core microfluidic extraction chip module, and a fluid drive and monitoring module.

[0030] The pretreatment and injection module includes a target dissolution cell, an evaporation temperature control component, and a reagent presaturation component. The evaporation temperature control component is used to remove nitric acid medium from the target dissolution cell to form an aqueous phase solution containing astatine-211. The reagent presaturation component is used to ensure that the organic extractant and the high-concentration hydrochloric acid medium reach mutual saturation before entering the core microfluidic extraction chip module. In this embodiment, the core microfluidic extraction chip module adopts a three-stage chip series structure, consisting of an extraction chip, a washing chip, and a back-extraction chip. In this embodiment, each chip uses polydimethylsiloxane as the substrate, and a 100nm thick silica nano-barrier coating is formed on the inner wall of the microchannel using atomic layer deposition. The microchannel contains asymmetric depth stepped flow channels, with the depth of the aqueous phase flow channel 2 greater than that of the organic phase flow channel 1, forming geometric steps at their intersection to pin the liquid-liquid interface. At the end of the microchannel body, the two opposing Y-shaped branches have continuous semi-circular microstructures 3 on their opposing cross-sections, forming a wave-shaped flow-guiding separation structure to stabilize the interface and achieve complete physical separation of the two phases.

[0031] The fluid drive and monitoring module includes a multi-channel syringe pump and an online radiation detector. The outlet of the target dissolution pool and the outlet of the reagent presaturation component are connected to the inlets of the aqueous phase channel 2 and the organic phase channel 1, respectively, via the multi-channel syringe pump. The online radiation detector is located at the outlet of the microfluidic extraction chip for real-time monitoring of the radioactivity of the effluent. The multi-channel syringe pump independently drives each phase fluid into the chip and can control the organic phase flow rate to be greater than the aqueous phase flow rate during the back-extraction stage to achieve online concentration. The online radiation detector is located at the chip outlet to monitor the radioactivity of the effluent in real time.

[0032] The system in this embodiment can achieve fully enclosed and automated operation, is resistant to organic solvent corrosion, can stably maintain the two-phase interface, and complete the integrated operation of extraction, washing, back-extraction and online concentration.

[0033] This embodiment also provides an automated method for separating and purifying astatine-211 using the above-described three-stage tandem chip system, specifically including the following steps: Step S1, Preparation and Pre-saturation of the Feed Solution: The irradiated bismuth target was placed in a target dissolution pool to complete the nitric acid dissolution. The nitric acid medium in the system was removed using an evaporation temperature control component. The residual solid was then redissolved with high-concentration hydrochloric acid to prepare an aqueous solution containing astatine-211. At the same time, in a reagent presaturation component, the organic extractant diisopropyl ether was fully mixed with the same concentration of high-concentration hydrochloric acid to presaturate the solution, thus obtaining a presaturated organic extractant. This avoids changes in the microchannel fluid volume caused by the miscible system and ensures the stability of the subsequent microfluidic interface.

[0034] Step S2, Microfluidic positive extraction: A multi-channel injection pump synchronously delivers the prepared aqueous feed solution and pre-saturated organic extractant into the extraction chip, where the two phases form a stable parallel laminar flow system within the asymmetric depth stepped flow channel. The differentiated depth structure of the aqueous phase flow channel 2 and the organic phase flow channel 1 achieves liquid-liquid interface pinning, ensuring stable contact between the two phases within the flow channel. The contact time between the aqueous feed solution and the organic extractant within the asymmetric depth stepped flow channel is controlled within the range of 0.1-5s, ensuring sufficient mass transfer during the extraction of astatine-211. The two phases are then completely physically separated by a wave-shaped flow-guiding separation structure at the end. The aqueous waste liquid loaded with matrix impurities is discharged separately, while the organic phase enriched with astatine-211 is continuously transported to the next processing unit.

[0035] Step S3, Microfluidic Washing: The enriched astatine-211 organic phase flowing out from the previous stage is introduced into the washing chip, and fresh hydrochloric acid is simultaneously introduced as the washing liquid phase. The concentration of hydrochloric acid used in this washing step is controlled at 6 mol / L. The two phases are in continuous laminar contact in the chip channel, effectively washing away trace metal impurities and residual salt components entrained in the organic phase, achieving deep removal of impurities and further improving the radiochemical purity of astatine-211.

[0036] Step S4, Microfluidic Back-Extraction and Concentration: The washed and purified organic phase is transported to the back-extraction chip, while an alkaline back-extraction solution (1 mol / L sodium hydroxide solution) is simultaneously introduced into the chip's aqueous phase inlet. A multi-channel syringe pump precisely controls the fluid flow rate parameters, setting the ratio of organic phase flow rate to aqueous phase flow rate to 2:1, ensuring the organic phase flow rate is always greater than the alkaline back-extraction solution flow rate. Under alkaline conditions, astatine-211 rapidly transfers from the organic phase to the aqueous phase. Utilizing the differentiated flow rate ratio, online concentration of astatine-211 is achieved simultaneously with the back-extraction reaction. An online radiation detector at the chip outlet monitors the radioactivity of the effluent in real time, ensuring consistent product quality throughout the process. The final product is a high-purity, high-concentration astatine-211 solution, directly meeting the requirements for subsequent radiopharmaceutical labeling.

[0037] Example 2

[0038] This embodiment provides a single-chip integrated astatine-211 separation and purification system, which includes a pretreatment and sample injection module, a core microfluidic extraction chip module, and a fluid drive and monitoring module.

[0039] The pretreatment and injection module includes a target dissolution cell, an evaporation temperature control component, and a reagent presaturation component. The evaporation temperature control component is used to remove nitric acid medium from the target dissolution cell to form an aqueous phase solution containing astatine-211. The reagent presaturation component is used to ensure that the organic extractant and the high-concentration hydrochloric acid medium reach mutual saturation before entering the core microfluidic extraction chip module. The core microfluidic extraction chip module employs a single microfluidic extraction chip with polydimethylsiloxane as the chip substrate. A 10nm thick alumina nano-barrier coating is prepared on the inner wall of the chip's microchannels using atomic layer deposition to prevent organic solvents from swelling and eroding the substrate. The chip integrates sequentially connected extraction, washing, and back-extraction zones. All three functional zones utilize asymmetric depth stepped flow channels: the aqueous phase channel 2 has a depth of 100μm, and the organic phase channel 1 has a depth of 50μm. The intersection forms geometric steps for pinning the liquid-liquid interface. At the end of the microchannel body, continuous semi-circular microstructures 3 are located on the opposing cross-sections of the two Y-shaped branches, forming a wave-shaped flow-guiding separation structure to stabilize the interface and achieve complete physical separation of the two phases.

[0040] The fluid drive and monitoring module includes a multi-channel syringe pump and an online radiation detector. The outlet of the target dissolution pool and the outlet of the reagent presaturation component are connected to the inlets of the aqueous phase channel 2 and the organic phase channel 1, respectively, via the multi-channel syringe pump. The online radiation detector is located at the outlet of the microfluidic extraction chip for real-time monitoring of the radioactivity of the effluent. The multi-channel syringe pump independently drives each phase fluid into the chip and can control the organic phase flow rate to be greater than the aqueous phase flow rate during the back-extraction stage to achieve online concentration. The online radiation detector is located at the chip outlet to monitor the radioactivity of the effluent in real time.

[0041] This embodiment adopts a single-chip integrated structure, which continuously completes the entire process of extraction, washing, back-extraction and online concentration on the same chip. The system has high integration, short flow path and fast mass transfer. It can automatically complete the separation and purification of astatine-211 under fully enclosed conditions, effectively reducing the risk of radiation exposure and reducing the loss of radionuclide decay.

[0042] This embodiment also provides an automated method for separating and purifying astatine-211 using the above-described single-chip system, specifically including the following steps: Step S1, Preparation and Presaturation of Feed Solution: The irradiated bismuth target is dissolved in nitric acid. After the nitric acid is removed by evaporation, the residue is dissolved in high-concentration hydrochloric acid to prepare an aqueous feed solution containing astatine-211. At the same time, diisopropyl ether organic extractant is pre-mixed and pre-saturated with hydrochloric acid of the same concentration to prepare a pre-saturated organic extractant for use as feed.

[0043] Step S2, Microfluidic Positive Extraction: Aqueous phase feed solution and pre-saturated organic extractant are simultaneously pumped into the single-chip integrated extraction section using a multi-channel high-precision injection pump; the two phases form a stable parallel laminar flow in the asymmetric depth stepped flow channel, and the contact time between the two phases is controlled between 0.1 seconds and 5 seconds; Astatine-211 is transferred from the aqueous phase to the organic phase, and then the two phases are automatically separated by a wave-shaped flow-guiding separation structure. The aqueous phase waste liquid containing bismuth impurities is discharged, and the organic phase enriched with Astatine-211 directly enters the downstream washing section.

[0044] Step S3, Microfluidic Washing: The organic phase enriched with astatine-211 is introduced into the single-chip washing section, and 7 mol / L fresh hydrochloric acid washing solution is pumped in simultaneously; the two phases are in stable laminar contact in the microchannel to wash away trace amounts of bismuth impurities entrained in the organic phase, and the purified organic phase is then transported to the back-extraction section.

[0045] Step S4, Microfluidic Back-Extraction and Online Concentration: The washed organic phase is fed into the single-chip back-extraction section, and a 4 mol / L sodium hydroxide alkaline back-extraction solution is simultaneously introduced; the ratio of the organic phase flow rate to the aqueous phase flow rate is controlled at 5:1, and the organic phase flow rate is kept greater than the aqueous phase flow rate; under alkaline conditions, astatine-211 is reverse-transferred to the aqueous phase, and online concentration is achieved simultaneously; the radioactivity is monitored in real time at the chip outlet by an online radiation detector, and finally, a high-purity astatine-211 product liquid is collected.

[0046] Example 3

[0047] This embodiment provides an astatine-211 separation and purification system, including a pretreatment and sample injection module, a core microfluidic extraction chip module, and a fluid drive and monitoring module.

[0048] The pretreatment and injection module includes a target dissolution cell, an evaporation temperature control component, and a reagent presaturation component. The evaporation temperature control component is used to remove nitric acid medium from the target dissolution cell to form an aqueous phase solution containing astatine-211. The reagent presaturation component is used to ensure that the organic extractant and the high-concentration hydrochloric acid medium reach mutual saturation before entering the core microfluidic extraction chip module. In this embodiment, the core microfluidic extraction chip module adopts a three-stage chip series structure, consisting of an extraction chip, a washing chip, and a back-extraction chip. In this embodiment, each chip uses polydimethylsiloxane as the substrate, and the inner wall of the microchannel is coated with a 50nm thick nano-barrier layer of silica and alumina through atomic layer deposition. The main extraction channel of the chip is an asymmetric depth stepped flow channel, with the depth of the aqueous phase flow channel 2 greater than that of the organic phase flow channel 1, forming a geometric step at the junction to pin the liquid-liquid interface. At the end of the main microchannel, the two opposing Y-shaped branches have continuous semi-circular microstructures 3 on their opposing cross-sections, forming a wave-shaped flow-guiding separation structure to stabilize the interface and achieve complete physical separation of the two phases.

[0049] The fluid drive and monitoring module includes a multi-channel syringe pump and an online radiation detector. The outlet of the target dissolution pool and the outlet of the reagent presaturation component are connected to the inlets of the aqueous phase channel 2 and the organic phase channel 1, respectively, via the multi-channel syringe pump. The online radiation detector is located at the outlet of the microfluidic extraction chip for real-time monitoring of the radioactivity of the effluent. The multi-channel syringe pump independently drives each phase fluid into the chip and can control the organic phase flow rate to be greater than the aqueous phase flow rate during the back-extraction stage to achieve online concentration. The online radiation detector is located at the chip outlet to monitor the radioactivity of the effluent in real time.

[0050] While the disclosure is as stated above, its scope of protection is not limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of this disclosure, and all such changes and modifications will fall within the protection scope of this invention.

Claims

1. A microfluidic chip-based astatine-211 separation and purification system, characterized in that, It includes a pretreatment and sample introduction module, a core microfluidic extraction chip module, and a fluid drive and monitoring module; among which, The pretreatment and injection module includes a target dissolution cell, an evaporation temperature control component, and a reagent presaturation component. The evaporation temperature control component is used to remove nitric acid medium from the target dissolution cell to form an aqueous phase solution containing astatine-211. The reagent presaturation component is used to ensure that the organic extractant and the high-concentration hydrochloric acid medium reach mutual saturation before entering the core microfluidic extraction chip module. The core microfluidic extraction chip module includes at least one microfluidic extraction chip, and the microfluidic extraction chip includes a microchannel and a nano-barrier coating formed on the inner wall of the microchannel. The microchannel includes a microchannel body and a Y-shaped wavy flow-guiding and separation structure disposed at the end of the microchannel body. The microchannel is provided with an asymmetric depth stepped flow channel. The asymmetric depth stepped flow channel includes two branches extending from the microchannel body to the wavy flow-guiding and separation structure, respectively. The two branches are an aqueous phase flow channel and an organic phase flow channel, and the depth of the aqueous phase flow channel is greater than the depth of the organic phase flow channel. The fluid drive and monitoring module includes a multi-channel injection pump and an online radiation detector. The outlet of the target dissolution pool and the outlet of the reagent presaturation component are connected to the inlet of the aqueous phase flow channel and the inlet of the organic phase flow channel, respectively, through the multi-channel injection pump. The online radiation detector is located at the outlet of the microfluidic extraction chip and is used to monitor the radioactivity of the effluent in real time.

2. The astatine-211 separation and purification system of claim 1, wherein, The nano-barrier coating is obtained by atomic layer deposition and the material is SiO2, Al2O3 or an alternating stack of SiO2 and Al2O3. The thickness of the nano-barrier coating is 10-100 nm.

3. The astatine-211 separation and purification system of claim 1, wherein, The wave-shaped flow-guiding and separation structure includes continuous semi-circular microstructures on the opposing end faces of two Y-shaped branches at the end of the microchannel body, which are used to provide secondary interface pinning points.

4. The astatine-211 separation and purification system of claim 1, wherein, In the asymmetric depth stepped flow channel, the depth of the aqueous phase flow channel is 100 μm, and the depth of the organic phase flow channel is 50 μm.

5. The astatine-211 separation and purification system of claim 1, wherein, The substrate of the microfluidic extraction chip is polydimethylsiloxane, cyclic olefin copolymer or cyclic olefin polymer.

6. The astatine-211 separation and purification system as described in claim 1, characterized in that, The core microfluidic extraction chip module includes a first microfluidic extraction chip, a second microfluidic extraction chip, and a third microfluidic extraction chip connected in series. The first microfluidic extraction chip is an extraction chip used to receive the aqueous feed liquid and the pre-saturated organic extractant to extract astatine-211 from the aqueous phase to the organic phase. The second microfluidic extraction chip is a washing chip, used to receive the organic phase and washing hydrochloric acid from the extraction chip to remove impurities entrained in the organic phase; The third microfluidic extraction chip is a back-extraction chip, used to receive the organic phase and alkaline back-extraction solution from the washing chip to back-extract Astatine-211 from the organic phase to the aqueous phase and obtain a concentrated Astatine-211 product solution.

7. A method for separating and purifying astatine-211 based on a microfluidic chip, utilizing the astatine-211 separation and purification system as described in any one of claims 1-6, characterized in that, Includes the following steps: Step S1, Preparation and Presaturation of Feed Solution: The irradiated bismuth target is dissolved in nitric acid, and after the nitric acid is removed by evaporation, it is dissolved in high-concentration hydrochloric acid to obtain an aqueous feed solution containing astatine-211; at the same time, the organic extractant is mixed with hydrochloric acid of the same concentration for presaturation treatment to obtain a presaturated organic extractant. Step S2, Microfluidic positive extraction: The aqueous phase solution prepared in step S1 and the pre-saturated organic extractant are simultaneously injected into the microfluidic extraction chip. Parallel laminar flow is formed in the asymmetric depth stepped flow channel for mass transfer, so that astatine-211 is extracted from the aqueous phase to the organic phase. The two phases are physically separated by the wave-shaped flow-guiding separation structure to obtain an organic phase enriched with astatine-211. Step S3, Microfluidic washing: The organic phase enriched with astatine-211 obtained in step S2 is simultaneously injected into the microfluidic extraction chip with hydrochloric acid for washing to remove impurities entrained in the organic phase. Step S4, Microfluidic Back-extraction and Concentration: The organic phase washed in step S3 and the alkaline back-extraction solution are simultaneously injected into the microfluidic extraction chip for back-extraction, so that astatine-211 is back-extracted from the organic phase to the aqueous phase. By controlling the flow rate of the organic phase to be greater than that of the aqueous phase, the online concentration of astatine-211 in the aqueous phase is achieved during back-extraction, and a high-purity astatine-211 product solution is obtained.

8. The method for separating and purifying astatine-211 as described in claim 7, characterized in that, In step S2, the contact time between the aqueous feed solution and the organic extractant in the asymmetric depth stepped flow channel is 0.1-5s.

9. The method for separating and purifying astatine-211 as described in claim 7, characterized in that, In step S3, the concentration of hydrochloric acid is 6-8 mol / L; In step S4, the alkaline back-extraction solution is a 1-4 mol / L NaOH solution.

10. The method for separating and purifying astatine-211 as described in claim 7, characterized in that, In step S4, the flow rate ratio of the organic phase to the aqueous phase is (2-5):1.

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