Miniature full-automatic nuclide drug chromatography purification device

Abstract

The utility model relates to the field of chromatographic analysis, in particular to a miniature full-automatic nuclide drug chromatographic purification device, which comprises a high-pressure selector valve, a high-pressure selector valve, a high-pressure selector valve, a low-pressure selector valve and a high-pressure selector valve, the high-pressure selector valve is provided with a public port, six ports are arranged on the periphery of the high-pressure selector valve, and a third port, a fourth port, a fifth port and the sixth port are respectively connected with a raw material suction position, a cleaning solvent, a weak solvent and a strong solvent; the high-pressure injection pump is connected to the public port of the high-pressure selection valve through a buffer ring; an inlet of the chromatographic column is connected to a second port of the high-pressure selector valve; an inlet of a flow cell of the LED ultraviolet detector is connected with an outlet of the chromatographic column, and an outlet of the flow cell of the LED ultraviolet detector is connected with a collection selector valve; and the outlet of the flow cell of the LED ultraviolet detector is connected with the common end of the collection selection valve through a pipeline, the pipeline is partially coiled into a loop, and the loop is close to a probe of the gamma detector. According to the utility model, the flow design, the interface compatibility and the pressure resistance can meet various chromatographic modes. The total weight of the whole device is smaller than 10 kg, and the device can be easily integrated into a hot chamber.

Description

Technical Field

[0001] The utility model relates to the field of chromatographic analysis, in particular to a micro-automatic radionuclide drug chromatographic purification device. Background Art

[0002] Radionuclide pharmaceuticals are specialized drugs containing radionuclides for medical diagnosis and treatment. They are radioactive pharmaceuticals composed of radioactive isotopes combined with molecular reagents specifically targeted to specific organs and tissues. Based on their intended use, they can be categorized as diagnostic or therapeutic radionuclide pharmaceuticals. Radionuclides commonly used in clinical diagnosis and treatment include 99mTc, 125I, 131I, 14C, 68Ga, 177Lu, 18F, 90Y, and 89Sr. These radionuclides typically have half-lives ranging from a few days to a few hours. Therefore, when used for medical purposes, radionuclide pharmaceuticals cannot be stored for long periods of time or transported. They generally require on-site preparation and use in hospitals or regional production centers. Currently, many commercial and research facilities have developed equipment related to the automated synthesis of radionuclide pharmaceuticals.

[0003] However, different radionuclide drugs require different purification methods. The conventional approach is to inject the test sample into the liquid chromatography system and elute the sample with an appropriate proportion of organic solvent. The liquid chromatography system consists of functional modules such as an infusion pump, an injector, a detector, and a collector. After the sample is injected into the chromatographic column, the eluent delivered by the infusion pump flushes the different substances from the column inlet to the column outlet. Different compounds are separated according to their migration speeds and generate absorbance signals or radioactivity signals on the detector. The outflow of the compound can be judged based on the intensity of the signal. When the compound that needs to be purified flows out, it is collected in the product container, and the rest is discharged as waste liquid.

[0004] Chinese patent publication number CN218854253U discloses an automated synthesis device for 68Ga-labeled radiopharmaceuticals. The fully automated preparation process can effectively reduce workers' exposure time to radioactive substances, eliminate mechanical repetitive manual operations, greatly improve the reproducibility and reliability of radiopharmaceutical production, and facilitate the standardized production of 68Ga-labeled positron-emitting drugs.

[0005] However, the above-mentioned publicly available schemes have the following shortcomings: they are limited to the purification of corresponding varieties, and do not meet the requirements of general chromatographic methods in terms of process design, interface compatibility and pressure resistance. Utility Model Content

[0006] The utility model aims to propose a micro-automatic radionuclide drug chromatography purification device to solve the problem that conventional liquid chromatographs in the background technology are large in size and do not meet the requirements of general chromatography methods.

[0007] The technical solution of the utility model is a micro-automatic radionuclide drug chromatography purification device, comprising:

[0008] The high-pressure selector valve has a common port in the center and six ports around the common port. The six ports are marked as ports 1 to 6 in clockwise order. Ports 3, 4, 5 and 6 are connected to the raw material suction position, cleaning solvent, weak solvent and strong solvent respectively.

[0009] A high-pressure injection pump is connected to the common port of the high-pressure selector valve through a buffer ring;

[0010] a chromatographic column, the inlet of which is connected to port No. 2 of the high-pressure selector valve;

[0011] An LED ultraviolet detector, wherein the flow cell inlet is connected to the chromatographic column outlet, the flow cell outlet is connected to a collection selection valve, the normally open end of the collection selection valve is connected to a waste liquid container, the normally closed end is connected to a product collection position, and the waste liquid container is connected to port 1 of the high-pressure selection valve;

[0012] As well as the gamma detector, the outlet of the flow cell of the LED ultraviolet detector is connected to the common end of the collection selection valve using a pipeline, and the pipeline is partially coiled into a loop, and the loop is placed close to the probe of the gamma detector so that the probe detects the radioactive material flowing through the loop.

[0013] Preferably, it also includes a hot chamber; a high-pressure injection pump, a buffer ring, a high-pressure selection valve, a waste liquid container, a collection selection valve, a product collection position, a γ detector, an LED ultraviolet detector, a chromatographic column and a raw material absorption position are all located in the hot chamber.

[0014] Preferably, port No. 3 of the high-pressure selection valve is connected to the sample suction line, the sample suction line port is connected to the bottom of the sample base, the sample base and the vibration motor are connected using soft rubber material to provide an oscillation function, and a socket for plugging in the sample tube is opened on the top of the sample base, and there is a through hole between the top socket and the bottom connection port.

[0015] Preferably, the cleaning solvent is used to clean strongly retained impurities in the chromatographic column after separation, the weak solvent is used to elute weakly retained impurities in the chromatographic column during separation, and the strong solvent is used to elute the target radiopharmaceutical product in the chromatographic column during separation.

[0016] Preferably, the outlet of the flow cell of the LED ultraviolet detector is connected to the common end of the collection selection valve using a pipeline, and the pipeline is partially coiled into a loop with a diameter of 30-50 mm and 1-2 turns.

[0017] Preferably, the high-pressure injection pump is a 10 ml injection pump, the infusion volume step is 0.01 ml, and the volume of the buffer ring is 10 ml.

[0018] Preferably, the high-pressure selection valve is made of polyetheretherketone, and its pressure resistance meets the requirements of diameter and column pressure during chromatographic separation. The high-pressure selection valve has a diameter of 1 mm and a pressure resistance of 30 MPa.

[0019] Compared with the prior art, the utility model has the following beneficial technical effects: it also adopts a similar structure of liquid chromatography, but simplifies the device into a portable system of high-pressure injection pump, high-pressure selection valve, LED ultraviolet detector, gamma detector and collection selection valve, and combines the multi-step functions of automatic injection, automatic chromatographic elution, quantitative detection and automatic collection on the same device. Its process design, interface compatibility and pressure resistance meet various commonly used chromatographic modes such as reversed-phase chromatography, ion exchange chromatography, and immunoaffinity chromatography. The whole process is fully automatic, and after the sample to be separated is in the sample tube, the system automatically performs the purification and self-cleaning steps. It can be used as a separation module and integrated with various different automated preparation devices. The total weight of the whole device is less than 10 kg, and the volume is less than that of a conventional chromatography module, and it is easy to integrate into the hot room. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is a structural diagram of an embodiment of the utility model;

[0021] Figure 2 is a radiolabeled amino acid compound;

[0022] Figure 3 is a chromatogram with the γ probe response and time as the coordinate axes.

[0023] Figure numerals: 1. High-pressure injection pump; 2. Buffer ring; 3. High-pressure selection valve; 4. Waste liquid container; 5. Collection selection valve; 6. Product collection position; 7. γ detector; 8. LED ultraviolet detector; 9. Chromatographic column; 10. Raw material absorption position; 11. Cleaning solvent; 12. Weak solvent; 13. Strong solvent; 14. Hot chamber. DETAILED DESCRIPTION

[0024] Example 1

[0025] like Figure 1 As shown, the present invention proposes a micro-automatic radionuclide drug chromatography purification device, comprising:

[0026] The high-pressure selection valve 3 has a common port at the center and six ports around the common port. The six ports are marked as ports 1 to 6 in clockwise order. Ports 3, 4, 5 and 6 are connected to the raw material absorption position 10, the cleaning solvent 11, the weak solvent 12 and the strong solvent 13 respectively; the port 3 of the high-pressure selection valve 3 is connected to the sample absorption pipeline, which is generally connected to the automated synthesis or automated elution system of radioactive drugs. The sample absorption pipeline port is connected to the bottom of the sample base. The sample base and the vibration motor are connected with a soft rubber material to provide an oscillation function. A socket for plugging in the sample tube is opened on the top of the sample base, and there is a through hole between the top socket and the bottom connection port; the cleaning solvent 11 is used to clean the strongly retained impurities in the chromatographic column 9 after separation, the weak solvent 12 is used to elute the weakly retained impurities in the chromatographic column during separation, and the strong solvent 13 is used to elute the target radioactive drug product in the chromatographic column during separation;

[0027] The high-pressure injection pump 1 is connected to the common port of the high-pressure selection valve 3 through the buffer ring 2;

[0028] Chromatographic column 9, the inlet of which is connected to port No. 2 of high-pressure selection valve 3;

[0029] An LED ultraviolet detector 8 has a flow cell inlet connected to a chromatographic column 9 outlet, and a collection selection valve 5 connected to the flow cell outlet. The normally open end of the collection selection valve 5 is connected to a waste liquid container 4, and the normally closed end is connected to a product collection position 6. The waste liquid container 4 is connected to the No. 1 port of the high-pressure selection valve 3 for discharging waste liquid when cleaning the buffer ring.

[0030] The outlets of the flow cells of the γ detector 7 and the LED ultraviolet detector 8 are connected to the common end of the collection selection valve 5 using pipelines, and the pipelines are partially coiled into a loop with a diameter of 30-50 mm and 1-2 turns. The loop is placed close to the probe of the γ detector 7 so that the probe can detect the radioactive substances flowing through the loop.

[0031] Example 2

[0032] like Figure 1 As shown, the present invention proposes a miniature fully automatic radionuclide drug chromatography purification device. Compared with the first embodiment, this embodiment introduces each component in detail.

[0033] The high-pressure syringe pump 1 and its accompanying buffer ring 2 are configured according to the required injection volume. A typical configuration is a 10mL syringe pump with 0.01mL infusion volume increments and a 10mL buffer tube capacity. Syringes and buffer rings 2 can be replaced with smaller or larger sizes as needed. The buffer ring 2 is an inert tubing with an internal volume that matches the syringe's volume range. This ensures that when the syringe draws a fixed amount of liquid, the drawn liquid enters the buffer ring 2 and does not enter the syringe and contaminate it. In this example, the buffer ring 2 is made of polyetheretherketone.

[0034] The high-pressure selection valve 3 is used to select different liquid pathways. This device uses a 6-position selection valve with a common interface, numbered C, and six selectable interfaces, numbered 1-6, corresponding to port number 1, port number 2, port number 3, port number 4, port number 5, and port number 6, respectively. The rotor of the high-pressure selection valve 3 has a slot. As the rotor rotates, when the slot connects the common end and a port with a certain code, the pathway is connected to the common end. The valve body, rotor, and stator are made of inert materials that do not react with the analyte and the reagents used. Because the chemical compatibility of the material must meet the requirements of ion exchange chromatography and reverse phase chromatography, the material selected in this embodiment is polyetheretherketone. The valve's pressure resistance must meet the diameter and column pressure requirements for chromatographic separation. In this embodiment, the diameter of the high-pressure selection valve 3 is 1 mm and the pressure resistance is 30 MPa.

[0035] The chromatographic column 9 is the core component for achieving separation. The powdered filler in the column provides separation capability. Depending on whether inorganic ion-type radiopharmaceuticals or organic compound-type radiopharmaceuticals are to be purified, common choices are ion exchange and reversed-phase C18 fillers, respectively.

[0036] The detector measures the effluent content of the chromatographic column. Based on general separation requirements, the device is equipped with an LED UV detector 8 with a detection wavelength of 254 nm and a gamma detector 7. The LED UV detector 8 measures general organic compounds for normalized quantification, while the gamma detector specifically detects compounds containing radionuclides. In addition to the time-varying effluent of different compounds resulting from chromatographic separation, the device also provides these two distinct detection methods and data collection mechanisms.

[0037] When the eluate flows through the detector and the target compound is detected, the collection selector valve 5 collects the effluent into a dedicated container as the purified radiopharmaceutical product. If the eluate does not contain the target compound, it is automatically directed by the collection selector valve 5 to the waste container 4. All connecting pipelines must meet the chemical inertness and pressure resistance requirements of chromatographic separation. In this example, 1 / 16-inch outer diameter, 0.25 mm inner diameter polyetheretherketone tubing is used.

[0038] All the above functions are realized by an integrated workstation.

[0039] In summary, the working mode of this new type of device is as follows:

[0040] The device can realize the following functions:

[0041] 1. Automatic injection;

[0042] 2. Automatic elution of the chromatographic column and collection of target products;

[0043] 3. Flush and regenerate the chromatographic column.

[0044] For a system with a syringe volume of V and a buffer ring volume.

[0045] In chromatographic separation methods, the required injection volume is V0. Generally, in hardware design, the volume of buffer loop 2, V> V0, the elution volume of weak solvent 12, V1, and the elution volume of strong solvent 13, V2. After separation, the column is rinsed and regenerated with a volume of cleaning solvent 11, V3, and a volume of weak solvent 12, V4. The elution flow rate per minute of column 9 is v.

[0046] A complete working cycle runs as follows:

[0047] A.Automatic injection

[0048] After the chromatographic column 9 is cleaned and regenerated, the high-pressure selector valve 3 switches to port 5, pre-drawing a weak solvent 12 with a volume of V-V0. The high-pressure selector valve then switches to port 3, drawing a sample with a volume of V0. At this point, the buffer ring 2 is filled. The high-pressure selector valve 3 then switches to port 2, injecting the liquid in the buffer ring 2 into the chromatographic column 9 at a flow rate of v per minute. The sample region enters the chromatographic column 9 first, completing the injection. The remaining weak solvent 12 with a volume of V-V0 in the ring is then pushed out to further clean the buffer ring 2 and remove sample residue.

[0049] B. Column elution and automatic collection of target products

[0050] After the injection is completed, continue with the weak solvent 12 flushing step. The high-pressure selection valve 3 is switched to port No. 5 to draw V volume of weak solvent 12. After that, the high-pressure selection valve 3 is switched to port No. 2 to inject the weak solvent 12 in the buffer ring 2 into the chromatographic column 9 at a flow rate of v per minute. Repeat several times until the cumulative infusion volume of weak solvent 12 reaches V1-(V-V0). At this time, together with the weak solvent 12 with a volume of V-V0 used in the previous injection process, a total of V1 volume of weak solvent 12 flushing is input. After that, the high-pressure selection valve 3 is switched to port No. 6 to draw V volume of strong solvent 13. After that, the high-pressure selection valve 3 is switched to port No. 2 to inject the strong solvent 13 in the buffer ring 2 into the chromatographic column 9 at a flow rate of v per minute. Repeat several times until the cumulative infusion volume of strong solvent 13 reaches V2. In the strong solvent 13 elution step, the selected detector gives a corresponding signal, indicating that the target sample is eluted and flows out, and the collection selection valve 5 will switch to the normally closed end to collect the eluate containing the radioactive drug product into the product collection position 6.

[0051] C. Column flushing and regeneration

[0052] After elution from the chromatographic column 9 is complete, the high-pressure selector valve 3 switches to port 4, drawing a volume V of cleaning solvent 11. The high-pressure selector valve 3 then switches to port 2, injecting the cleaning solvent 11 from the buffer ring 2 into the chromatographic column 9 at a flow rate v per minute. This process is repeated multiple times until the cumulative volume of cleaning solvent 11 reaches V3. This completely removes any residual impurities from the chromatographic column 9. After elution from the chromatographic column 9 is complete, the high-pressure selector valve 3 switches to port 5, drawing a volume V of weak solvent 12. The high-pressure selector valve 3 then switches to port 2, injecting the weak solvent 12 from the buffer ring 2 into the chromatographic column 9 at a flow rate v per minute. This process is repeated multiple times until the cumulative volume of weak solvent 12 reaches V4, allowing the chromatographic column 9 to be ready for the next injection.

[0053] The following purification method is established using a radiolabeled amino acid, 3-iodo-131-L-tyrosine, as an example. Figure 2 The middle molecule is the compound, in which I is radioactive 131 I.

[0054] Hardware Specifications: The device is equipped with a 10mL syringe, a 10mL buffer loop, and a 254nm LED UV detector. Chromatographic column: C18 column, 5x150mm.

[0055] Weak solvent: 97% normal saline-3% ethanol, dissolved with 3mmol / L citric acid and 7mmol / L sodium citrate, pH 5.5.

[0056] Strong solvent: 88% normal saline-12% ethanol, dissolved with 3mmol / L citric acid and 7mmol / L sodium citrate, pH 5.5.

[0057] Cleaning solvent: 1:9 water-ethanol.

[0058] Flow rate v: 4mL / min

[0059] Injection volume V0: 2mL

[0060] Weak solvent elution volume V1: 20mL

[0061] Strong solvent elution volume V2: 14 mL

[0062] Cleaning solvent flushing volume V3: 12mL

[0063] Weak solvent regeneration volume V4: 15mL

[0064] Figure 3The following is a chromatogram of the sample, plotted against time and gamma probe response. The peak eluting between 5 and 6 minutes represents the target compound. During the strong solvent elution period, the system automatically detects any effluent that exhibits radioactivity. The peak during the wash solvent rinse period represents a mixture of impurities flushed by the wash solvent. Including injection and aspiration times, this process takes approximately 15 minutes per sample.

[0065] The present invention also adopts a similar structure of liquid chromatography, but simplifies the device into a portable system of high-pressure injection pump 1, high-pressure selection valve 3, LED ultraviolet detector 8, gamma detector 7 and collection selection valve 5, combining the multi-step functions of automatic injection, automatic chromatographic elution, quantitative detection and automatic collection on the same device. Its process design, interface compatibility and pressure resistance meet the requirements of various commonly used chromatographic modes such as reversed-phase chromatography, ion exchange chromatography, and immunoaffinity chromatography. The entire process is fully automatic, and after the sample to be separated is in the sample tube, the system automatically performs the purification and self-cleaning steps. It can be used as a separation module and integrated with various different automated preparation devices. The total weight of the entire device is less than 10 kg, and the volume is less than that of a conventional chromatography module, making it easy to integrate into a hot room.

[0066] The embodiments of the present invention are described in detail above with reference to the accompanying drawings, but the present invention is not limited thereto. Various changes can be made within the knowledge scope of those skilled in the art without departing from the purpose of the present invention.

Claims

1. A miniature fully automatic radionuclide drug chromatography purification device, characterized in that: include: The high-pressure selector valve (3) has a common port at the center and six ports around the common port. The six ports are marked as ports 1 to 6 in clockwise order. Ports 3, 4, 5 and 6 are connected to the raw material suction position (10), the cleaning solvent (11), the weak solvent (12) and the strong solvent (13) respectively. A high-pressure injection pump (1) is connected to a common port of a high-pressure selection valve (3) via a buffer ring (2); a chromatographic column (9), the inlet of which is connected to the second port of the high-pressure selection valve (3); An LED ultraviolet detector (8) has a flow cell inlet connected to a chromatographic column (9) outlet, a flow cell outlet connected to a collection selection valve (5), a normally open end of the collection selection valve (5) connected to a waste liquid container (4), a normally closed end connected to a product collection position (6), and a waste liquid container (4) connected to port 1 of a high-pressure selection valve (3); The outlets of the flow cells of the gamma detector (7) and the LED ultraviolet detector (8) are connected to the common end of the collection selection valve (5) using pipelines, and the pipelines are partially coiled into a loop, and the loop is placed close to the probe of the gamma detector (7) so that the probe can detect the radioactive substances flowing through the loop.

2. The micro fully automatic radionuclide drug chromatography purification device according to claim 1, characterized in that: The invention also includes a hot chamber (14); a high-pressure injection pump (1), a buffer ring (2), a high-pressure selection valve (3), a waste liquid container (4), a collection selection valve (5), a product collection position (6), a gamma detector (7), an LED ultraviolet detector (8), a chromatographic column (9) and a raw material absorption position (10) are all located in the hot chamber (14).

3. The micro fully automatic radionuclide drug chromatography purification device according to claim 1, characterized in that: The third port of the high-pressure selection valve (3) is connected to the sample suction pipeline, and the sample suction pipeline port is connected to the bottom of the sample base. The sample base and the vibration motor are connected using soft rubber material to provide an oscillation function. A socket for plugging in the sample tube is opened on the top of the sample base, and a through hole is formed between the top socket and the bottom connection port.

4. The micro fully automatic radionuclide drug chromatography purification device according to claim 1, characterized in that: The cleaning solvent (11) is used to clean strongly retained impurities in the chromatographic column (9) after separation, the weak solvent (12) is used to elute weakly retained impurities in the chromatographic column during separation, and the strong solvent (13) is used to elute the target radiopharmaceutical product in the chromatographic column during separation.

5. The micro fully automatic radionuclide drug chromatography purification device according to claim 1, characterized in that: The outlet of the flow cell of the LED ultraviolet detector (8) is connected to the common end of the collection selection valve (5) using a pipeline, and the pipeline is partially coiled into a loop with a diameter of 30-50 mm and 1-2 turns.

6. The micro fully automatic radionuclide drug chromatography purification device according to claim 1, characterized in that: The high-pressure injection pump (1) is a 10ml injection pump, the infusion volume step is 0.01ml, and the volume of the buffer ring (2) is 10ml.

7. The micro fully automatic radionuclide drug chromatography purification device according to claim 1, characterized in that: The material of the high-pressure selection valve (3) is polyetheretherketone, and its pressure resistance meets the requirements of diameter and column pressure during chromatographic separation. The high-pressure selection valve (3) has a diameter of 1mm and a pressure resistance of 30MPa.

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