An analysis method and system based on field flow fractionation and morphological mass spectrometry

Abstract

The application provides an analysis method and system based on field flow fractionation and morphological mass spectrometry, comprising the following steps: S1, obtaining an eluate sample and a precursor solution, and obtaining a treated eluate sample through environmental simulation treatment; S2, taking part of the precursor solution and the eluate sample to perform offline laser desorption ionization time-of-flight mass spectrometry to obtain molecular weight information; S3, injecting the treated eluate sample into an asymmetric flow field flow fractionation system to non-destructively separate free ion state components and colloidal state components to obtain effluent; S4, passing the effluent into a UV-Vis detector, a MALS detector and an ICP-MS detector to obtain multi-dimensional detection information; and S5, combining the molecular weight information and the multi-dimensional detection information to analyze the source and formation mechanism of colloids or chemical morphologies in the eluate sample. The application has the beneficial effects that the application can non-destructively separate the eluate sample, accurately quantify, and simultaneously analyze particle size, element composition, oxidation state and multi-core chemical morphology.

Description

Technical Field

[0001] This invention relates to the technical field of radiochemical analysis and nuclear medicine quality control, and more specifically, to an analytical method and system based on field-current separation and spectrophotometry. Background Technology

[0002] Radionuclide generators are core equipment in nuclear medicine molecular imaging and therapy. The chemical purity and physical state of their eluents directly determine the safety of clinical drug use and the success rate of radiopharmaceutical labeling. Currently, pharmacopoeias in various countries primarily rely on clarity checks, parent nuclide leakage rate measurements (radioactive detectors), and direct-injection inductively coupled plasma-mass spectrometry (ICP-MS) to detect total heavy metal content for generator eluents. However, these traditional methods have revealed serious limitations in practical applications, leading to frequent performance fluctuations in research and development and clinical use.

[0003] First, current technologies cannot distinguish between ionic and colloidal leakage. Isotope generator packing materials may mechanically pulverize under long-term acidic and fluid scouring environments, forming nano- to submicron-sized metallic colloids. These colloids can penetrate 0.22 μm sterile filter membranes and carry the parent nuclide into the eluent. Traditional radiometric detection or ICP-MS can only report excessive total concentration of the parent nuclide, but cannot determine whether the leakage is due to the failure of chemisorption bonds (ionic leakage) or physical breakage of the packing material (colloidal leakage), thus misleading the direction of process improvement.

[0004] Secondly, current technologies cannot resolve the formation of secondary colloids in clinical labeling environments. Trace amounts of free metal impurities in the eluent hydrolyze and aggregate to form secondary colloids with a large specific surface area when the pH is adjusted for drug labeling. These colloids adsorb and retain target daughter nuclides, resulting in substandard radiochemical purity. However, conventional detection methods cannot simulate or identify this dynamic phase transition process, let alone quantitatively assess its impact on labeling efficiency.

[0005] Furthermore, existing technologies cannot provide chemical speciation information. For transition metals or platinum group metals, their aqueous solutions exhibit various oxidation states, charges, and mononuclear or polynuclear complex forms. ICP-MS completely destroys all chemical bonds in high-temperature plasma, providing only the total elemental concentration and completely losing information on the valence state, degree of polymerization, and hydrodynamic particle size of metal complexes. While laser desorption / ionization time-of-flight mass spectrometry (LDI-TOF) can provide molecular weight information, it is typically used as a standalone technique and lacks integration with separation and elemental detection methods, making it difficult to form a complete speciation analysis chain.

[0006] Finally, current technologies cannot achieve raw material traceability. Precursor raw materials from different sources or batches may differ in molecular assembly (such as multinucleate species, coordination number, and oxidation state distribution), and these differences will directly affect the rinsing performance and stability of the generator. However, traditional methods lack the ability to establish a correlation between the chemical form of raw materials and the performance of the final product, resulting in the inability to move the quality control process forward and the lack of scientific basis for raw material selection.

[0007] In summary, there is an urgent need in this field for a detection method and system that can achieve non-destructive separation and accurate quantification of elution samples, and simultaneously analyze particle size, elemental composition, oxidation state and polynuclear chemical morphology, in order to overcome the shortcomings of existing technologies. Summary of the Invention

[0008] The technical problem to be solved by this invention is how to achieve non-destructive separation and accurate quantification of eluent samples, and simultaneously analyze particle size, elemental composition, oxidation state and multinucleated chemical morphology. In order to overcome the defects of the above-mentioned prior art (or related technology), this invention provides an analytical method and system based on field flow separation and spectrometry.

[0009] This invention provides an analytical method based on field-current separation coupled with spectrophotometry, comprising: Step S1: Obtain the eluent sample of the isotope generator and prepare the precursor solution of the isotope generator. Take a portion of the eluent sample and perform environmental simulation treatment to obtain the treated eluent sample. Step S2: Take a portion of the precursor solution and the untreated eluent sample and perform offline laser desorption / ionization time-of-flight mass spectrometry analysis to obtain molecular weight information about the metal polynuclear complex and / or multi-charge complex; Step S3: The treated eluent sample is injected into the asymmetric field flow separation system, and the free ionic components and colloidal components in the treated eluent sample are separated non-destructively according to the hydrodynamic radius to obtain the effluent. Step S4: The effluent is sequentially passed through a UV-Vis detector, a MALS detector, and an ICP-MS detector for online coupled detection to obtain corresponding multidimensional detection information; Step S5: Combining the molecular weight information and the multidimensional detection information, the source and formation mechanism of the colloidal or chemical forms in the eluent sample are analyzed as the analysis result.

[0010] The analytical method based on field-current separation and spectrophotometry of this invention has the following advantages compared with the prior art: This invention organically combines offline laser desorption / ionization time-of-flight mass spectrometry with an online multidimensional detection system that includes an asymmetric field flow separation system, a UV-Vis detector, a MALS detector, and an ICP-MS detector. This system can simultaneously acquire multidimensional detection information on the free ionic and colloidal components in the eluent sample, including particle size, elemental composition, oxidation state, and polynuclear chemical forms. Combined with molecular weight information, the source and formation mechanism of colloidal or chemical forms in the eluent sample can be obtained. This overcomes the limitation of traditional methods, where ICP-MS can only report the total elemental concentration and cannot distinguish chemical forms. This invention achieves non-destructive and accurate analysis of trace colloids and complex chemical forms in isotope generator eluent samples.

[0011] In one possible implementation, the environmental simulation process in step S1 includes: A buffer reagent was added to a portion of the eluent sample to adjust the pH value to a preset gradient range of 2.5-4.5 to simulate the process of trace metal ion hydrolysis to generate secondary nanocolloids. After incubation for a preset time, the treated eluent sample was obtained.

[0012] Compared with existing technologies, the above-mentioned technical solution can effectively simulate the in-situ hydrolysis behavior of trace metal ions caused by changes in the acid-base environment during clinical drug labeling by precisely adjusting the pH value of the eluent sample to a preset gradient range of 2.5-4.5 and incubating it. This allows the method to not only detect the initial state of the eluent sample, but also to provide early warning of the risk of secondary colloid formation and daughter nuclide retention that may occur under clinical use conditions, thereby significantly improving the safety of clinical drug use and the labeling success rate.

[0013] In one possible implementation, the separation channel of the asymmetric field flow separation system used in step S3 has no stationary phase packing material, and uses Milli-Q water or dilute acid containing 0.01%-0.1% (w / v) SDS as the carrier liquid.

[0014] Compared with existing technologies, the above-mentioned technical solution can effectively suppress particle aggregation and adsorption without destroying the original structure of nanocolloids, ensuring efficient and repeatable non-destructive separation of free ionic components and colloidal components based on hydrodynamic radii. Compared with traditional chromatographic separation methods containing stationary phase packing, this method avoids sample contamination and irreversible adsorption in the eluent, significantly improving the accuracy and authenticity of chemical speciation analysis.

[0015] In one possible implementation, the UV-Vis detector in step S4 is used to identify the characteristic oxidation state absorption peaks of metal elements in the effluent at different retention times and include them in the multidimensional detection information.

[0016] Compared with existing technologies, the above-mentioned technical solution can obtain the valence state information of the separated components in real time without damaging the eluent sample, making up for the deficiency of ICP-MS in providing oxidation state information due to the destruction of chemical bonds by high-temperature plasma. This is of great significance for resolving the complex valence state distribution of transition metals and platinum group metals in the eluent sample and judging their chemical reactivity and labeling suitability.

[0017] In one possible implementation, the MALS detector in step S4 is used to calculate the absolute radius of gyration and molecular weight of the separated nanocolloids in the effluent in real time and include them in the multidimensional detection information.

[0018] Compared with existing technologies, the above technical solution can obtain the absolute physical parameters of colloidal particles online without the need for standards or particle size assumptions, and accurately distinguish between true solutions, nanocolloids and large-sized aggregates. This provides direct evidence for determining the source of colloids, such as physical breakage or secondary hydrolysis of fillers, and provides quantitative basis for optimizing the granulation process and elution conditions of isotope generator fillers.

[0019] In one possible implementation, the ICP-MS detector in step S4 is used to simultaneously monitor the signal intensity of at least one target isotope in the effluent and include it in the multidimensional detection information.

[0020] Compared with existing technologies, the above-mentioned technical solution can achieve high-sensitivity simultaneous tracking of multiple elements, accurately distinguish the distribution of parent and daughter nuclides and matrix elements in different elution time windows, and accurately identify false and true leakage by combining the separation of asymmetric field flow separation system, avoiding misjudgments caused by traditional radioactive detection or total element analysis, and significantly improving the reliability of quality control.

[0021] In one possible implementation, step S5, the criteria for determining the source and formation mechanism of colloidal or chemical forms in the eluent sample include at least one of the following: If a strong co-elution peak between the matrix element and the parent nuclide is detected by the ICP-MS detector within the colloidal retention time range, it is determined to be colloidal leakage caused by physical shedding of the isotope generator filler. If the free ion peak area of ​​the treated eluent sample is detected by the ICP-MS detector to be smaller than that of the untreated eluent sample, and a new matrix element and daughter nuclide co-elution peak appears within the colloidal retention time interval, then it is determined that hydrolysis retention has occurred. If offline laser desorption / ionization time-of-flight mass spectrometry analysis shows that the precursor solution contains abnormal polynuclear species or oxidized states, and the abundance is positively correlated with the colloidal peak area in the spectrum of the asymmetric field flow separation system, then the heterogeneity of the precursor solution is determined to be the source of the performance change of the eluent sample.

[0022] Compared with existing technologies, the above-mentioned technical solution can transform multi-dimensional detection information into analytical conclusions that can directly guide production. It can clearly distinguish between colloidal leakage caused by physical shedding of packing material, hydrolysis retention caused by pH changes, and performance fluctuations caused by chemical heterogeneity of precursor solutions. This enables R&D personnel to quickly locate the root cause of the problem and take targeted measures such as optimizing the mechanical strength of packing material, improving purification processes, or screening qualified raw materials, thus realizing a technical closed loop from detection to decision-making.

[0023] In one possible implementation, the isotope generator used in step S1 is selected from... 68 Ge / 68 Ga generator 99 Mo / 99m Tc generator 90 Sr / 90 Y generator 188 W / 188 Re generator, 225 Ac / 213 Bi generator 224 Ra / 212 Pb generator, 103 Ru / 103m One type of Rh generator.

[0024] This invention also provides an analysis system based on field-current separation and spectrophotometry, which, when applied to the above-mentioned analysis method based on field-current separation and spectrophotometry, includes: The ultraviolet-visible spectroscopy detection module is used to receive the effluent and identify the characteristic oxidation state absorption peaks of metal elements in the effluent at different retention times as the first detection information. The multi-angle light scattering detection module has its inlet connected to the outlet of the ultraviolet-visible spectroscopy detection module via a pipeline, and is used to calculate in real time the absolute radius of gyration and molecular weight of the separated nanocolloids in the effluent as the second detection information; An inductively coupled plasma mass spectrometry module has its inlet connected to the outlet of the multi-angle light scattering detection module via a pipeline, and is used to simultaneously monitor the signal intensity of at least one target isotope in the effluent as a third detection information. A laser desorption / ionization time-of-flight mass spectrometry module is used to receive the untreated eluent sample and a portion of the precursor solution for offline laser desorption / ionization time-of-flight mass spectrometry analysis to obtain molecular weight information about metal polynuclear complexes and / or multi-charge complexes; The comprehensive analysis module is electrically connected to the ultraviolet-visible spectroscopy detection module, the multi-angle light scattering detection module, the inductively coupled plasma mass spectrometry module, and the laser desorption / ionization time-of-flight mass spectrometry module, respectively. It is used to combine the molecular weight information, the first detection information, the second detection information, and the third detection information to analyze the source and formation mechanism of colloidal or chemical forms in the eluent sample as the analysis result.

[0025] Compared with existing technologies, the analytical system based on field-current separation and spectrophotometry of this invention has the following advantages: This invention organically combines an offline laser desorption / ionization time-of-flight mass spectrometry module with an online multidimensional detection system that includes an asymmetric field flow separation system, a UV-Vis spectroscopy detection module, a multi-angle light scattering detection module, and an inductively coupled plasma mass spectrometry module. This system can simultaneously acquire the particle size, elemental composition, oxidation state, and polynuclear chemical morphology of both free ionic and colloidal components in the eluent sample. Combined with molecular weight information analysis, the source and formation mechanism of colloidal or chemical morphologies in the eluent sample can be obtained. This overcomes the shortcomings of traditional methods, such as ICP-MS, which can only report the total elemental concentration and cannot distinguish chemical morphologies. This invention achieves non-destructive and accurate analysis of trace colloids and complex chemical morphologies in isotope generator eluent samples. Attached Figure Description

[0026] Figure 1 This is a flowchart of the method steps of the present invention; Figure 2 This is a schematic diagram of the system structure of the present invention. Detailed Implementation

[0027] First, those skilled in the art should understand that these embodiments are merely illustrative of the technical principles of the present invention and are not intended to limit the scope of protection of the present invention. Those skilled in the art can make adjustments as needed to adapt to specific application scenarios.

[0028] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.

[0029] See Figure 1 This invention discloses an analytical method based on field-current separation and spectrophotometry, comprising the following steps: Step S1: Obtain the eluent sample of the isotope generator and prepare the precursor solution of the isotope generator. Take a portion of the eluent sample and perform environmental simulation treatment to obtain the treated eluent sample. Step S2: Take a portion of the precursor solution and untreated eluent samples and perform offline laser desorption / ionization time-of-flight mass spectrometry analysis to obtain molecular weight information about metal polynuclear complexes and / or multi-charge complexes; Step S3: The treated eluent sample is injected into the asymmetric field flow separation system, and the free ionic and colloidal components in the treated eluent sample are separated non-destructively according to the hydrodynamic radius to obtain the effluent. Step S4: The effluent is sequentially passed through a UV-Vis detector, a MALS detector, and an ICP-MS detector for online coupled detection to obtain the corresponding multidimensional detection information; Step S5: Combining molecular weight information and multidimensional detection information, the source and formation mechanism of colloidal or chemical forms in the eluent sample are analyzed as the analytical results.

[0030] In this embodiment of the invention, in step S1, the eluent sample is usually a solution obtained by eluting from the generator column using 0.05M~0.1M hydrochloric acid or acetate buffer, and its volume is generally 1mL~10mL. A portion of the eluent sample is taken for environmental simulation treatment to obtain the treated eluent sample.

[0031] In this embodiment of the invention, the environmental simulation treatment in step S1 specifically includes: adding a buffer reagent (such as 0.1M~1.0M sodium acetate solution or sodium citrate solution) to a portion of the eluent sample to adjust the pH value to a preset gradient range of 2.5-4.5 (e.g., adjusted to pH 2.5, pH 3.0, pH 3.5, pH 4.0, and pH 4.5 respectively) to simulate the weakly acidic environment commonly encountered in clinical radiopharmaceutical labeling processes, thereby inducing trace metal ions (such as Ti) in the eluent sample. 4+ Zr 4+ Fe 3+ (etc.) undergo in-situ hydrolysis to generate secondary nanocolloids. The eluent sample after pH adjustment is incubated at room temperature or 37°C for 10 min to 60 min to obtain the treated eluent sample. This environmental simulation treatment can effectively simulate the colloidal phase transition process that may occur in the actual labeling reaction.

[0032] In this embodiment of the invention, in step S2, a portion of the precursor solution (i.e., the original metal salt solution used to prepare the isotope generator, such as RuCl3·xH2O, GeCl4, etc.) and an untreated eluent sample are taken and analyzed by offline laser desorption / ionization time-of-flight mass spectrometry (LDI-TOF). During the analysis, the eluent sample is spotted onto a stainless steel target plate, dried, and then mass spectra are acquired in both positive and negative ion modes, with the mass scan range set to m / z 100~5000. Through this analysis, the metal polynuclear complexes (such as [Ru2OCl6]) present in the eluent sample can be obtained. 4- [Ru3O2Cl8] 2- This step involves resolving the microscopic chemical morphology differences in the precursor solution and providing baseline data for subsequent source tracing analysis.

[0033] In this embodiment of the invention, in step S3, the treated eluent sample after environmental simulation treatment in step S1 is injected into an asymmetric flow field flow separation system (AF4). The separation channel of the asymmetric flow field flow separation system has no stationary phase packing material; separation is achieved by the balance between the cross-flow field perpendicular to the flow direction and the Brownian motion of the particles. The preferred separation conditions are: using a regenerated cellulose membrane with a molecular weight cutoff of 10 kDa, a channel thickness of 350 μm to 500 μm, and a carrier liquid containing 0.01%-0.1% (w / v) sodium dodecyl sulfate (SDS) in Milli-Q water or a dilute acid (e.g., 0.01 M). HNO3 was used to inhibit the aggregation and non-specific adsorption of colloidal particles. The injection volume was 50 μL to 200 μL, the focusing time was 3 min to 8 min, and the cross-flow rate was initially set to 1.0 mL / min to 3.0 mL / min and then gradually decreased to 0.1 mL / min to 0.5 mL / min within 10 min to 30 min. This enabled the non-destructive separation of free ionic components (hydrodynamic radius usually <2 nm) and colloidal components (hydrodynamic radius usually 2 nm to 500 nm) in the sample based on the hydrodynamic radius, resulting in the effluent.

[0034] In this embodiment of the invention, in step S4, the effluent obtained in step S3 is sequentially passed through a UV-Vis (Ultraviolet-visible spectroscopy) detector, a MALS (Multi-Angle Light Scattering) detector, and an ICP-MS (Inductively Coupled Plasma Analyzer) detector. Mass Spectrometry (Inductively Coupled Plasma Mass Spectrometry) detectors are used in-line coupled detection to obtain corresponding multidimensional detection information. A UV-Vis detector (e.g., a diode array detector equipped with a flow cell) continuously scans within the wavelength range of 200 nm to 800 nm to identify the characteristic oxidation state absorption peaks of metal elements in the effluent at different retention times. For example, Ru(III) has characteristic absorption at approximately 350 nm to 400 nm, while Ru(IV) has characteristic absorption at approximately 450 nm to 500 nm. This absorption peak information is included in the multidimensional detection information. A MALS detector (e.g., a multi-angle light scattering instrument equipped with a 633 nm laser source, typically containing more than 18 scattering angles) is connected in series after the UV-Vis detector to calculate in real time the absolute radius of gyration (Rg, typically 5 nm to 200 nm) and molecular weight (Mw, typically 10) of the separated nanocolloids in the effluent. 4 Da~10 9 The calculation (Da) requires no standard calibration and is performed based on the Zimm or Berry diagram method of static light scattering. The resulting data is incorporated into the multidimensional detection information. The inlet of the ICP-MS detector (such as a quadrupole or sector magnetic field ICP-MS) is directly connected to the outlet of the MALS detector via an acid-resistant pipeline. The ICP-MS detector uses high-temperature argon plasma (approximately 7000K~10000K) ionization to simultaneously monitor the signal intensity of at least one target isotope, for example, monitoring... 47 Ti、 90 Zr、 68 Ge 68 Ga、 103 Ru、 103m Rh et al. used time-resolved analysis (TRA) mode for data acquisition, and set the residence time of each mass number to 10ms~100ms to ensure good alignment with the elution time axis of the asymmetric field flow separation system. The resulting isotope signal intensity-time curves were included in the multidimensional detection information.

[0035] In this embodiment of the invention, the determination condition in step S5 includes at least one of the following: Colloidal leakage determination: If matrix elements (such as...) are detected by an ICP-MS detector within the colloidal retention time range (usually 10 min to 25 min, corresponding to a particle size of 10 nm to 200 nm)... 47 Ti、 90 Zr) and parent nuclides (such as 68 The presence of strong co-elution peaks with highly consistent peak shapes, along with MALS detector data confirming the presence of nanoscale particles (Rg>10nm) in the colloidal retention time range, indicates that the colloidal state leakage is caused by the physical shedding of the isotope generator filler. In this case, the parent nuclide signal does not increase significantly within the free ion retention time range (usually 2min~6min). Hydrolysis Retention Determination: Compare the untreated eluent sample with the treated eluent sample after environmental simulation treatment in step S1. If the free ion peak area of ​​the treated eluent sample is detected by the ICP-MS detector (corresponding to the target progeny nuclide, such as...) 68 Ga) was reduced by more than 30% compared to untreated eluent samples, and new matrix elements (such as Ga) appeared during the colloidal retention time range. 47 Ti) and daughter nuclides (such as Ti) and daughter nuclides (such as Ti) 68 If a co-elution peak of Ga is detected and a newly formed nanoparticle (with a particle size of 20 nm to 100 nm) is detected by the MALS detector, it is determined that hydrolysis and retention have occurred. That is, trace impurity metal ions hydrolyze to form colloids after the pH increases and adsorb and capture daughter nuclides. Determination of precursor heterogeneity: If offline laser desorption / ionization time-of-flight mass spectrometry analysis shows that the precursor solution contains abnormal polynuclear species (e.g., abnormal peaks in the m / z 800~1200 range) or atypical oxidation state characteristics (e.g., the Ru(IV) / Ru(III) peak intensity ratio deviates from the normal range compared to the standard), and the abundance of the abnormal polynuclear species is positively correlated with the colloidal peak area in the spectrum of the asymmetric field flow separation system (e.g., colloidal peaks appearing after incubation at pH 4.0) (correlation coefficient R0). 2 If the value is greater than 0.85, then the heterogeneity of the precursor solution is determined to be the source of the changes in the performance of the eluent sample.

[0036] In this embodiment of the invention, the isotope generator used in step S1 is selected from... 68 Ge / 68 Ga generator 99 Mo / 99m Tc generator 90 Sr / 90 Y generator 188 W / 188 Re generator, 225 Ac / 213 Bi generator 224 Ra / 212 Pb generator, 103 Ru / 103m One type of Rh generator requires only adaptive adjustment of the pH value of the carrier liquid in the asymmetric field flow separation system, the target isotope monitored by the ICP-MS detector, and the characteristic wavelength detected by the UV-Vis detector for different types of generators.

[0037] See Figure 2 This invention also discloses an analysis system based on field-current separation and spectrophotometry, which, when applied to the above-mentioned analysis method based on field-current separation and spectrophotometry, includes: The ultraviolet-visible spectroscopy detection module is used to receive the effluent from the asymmetric field flow separation system and identify the characteristic oxidation state absorption peaks of metal elements in the effluent at different retention times as the first detection information. The ultraviolet-visible spectroscopy detection module is preferably equipped with an optical fiber flow cell (optical path 10 mm) and a diode array detector with a wavelength range of 190 nm to 800 nm. The multi-angle light scattering detection module has its inlet connected to the outlet of the ultraviolet-visible spectroscopy detection module via a pressure-resistant PEEK pipe (inner diameter 0.25mm, length ≤30cm). It is used to calculate the absolute radius of gyration and molecular weight of the separated nanocolloids in the effluent in real time as the second detection information. The multi-angle light scattering detection module is preferably equipped with 18 scattering angles (angle range 15°~165°) and a 633nm laser light source. The inductively coupled plasma mass spectrometry module has its inlet connected to the outlet of the multi-angle light scattering detection module via an acid-resistant PEEK pipeline. This module is used to simultaneously monitor the signal intensity of at least one target isotope in the effluent as a third detection information. The inductively coupled plasma mass spectrometry module is preferably equipped with a collision / reaction cell (such as using a helium collision mode to eliminate multi-atom interference) and a high-salt resistant interface cone. A laser desorption / ionization time-of-flight mass spectrometry module is used to receive untreated eluent samples and a portion of the precursor solution for offline laser desorption / ionization time-of-flight mass spectrometry analysis to obtain molecular weight information about metal polynuclear complexes and / or multi-charge complexes. This laser desorption / ionization time-of-flight mass spectrometry module is preferably equipped with a 337nm or 355nm pulsed laser, and the mass analyzer reflection mode resolution is ≥10000 FWHM. The comprehensive analysis module is electrically connected to the UV-Vis spectroscopy detection module, the multi-angle light scattering detection module, the inductively coupled plasma mass spectrometry module, and the laser desorption / ionization time-of-flight mass spectrometry module (e.g., via a high-speed data acquisition card and network cable or USB connection). It is used to combine molecular weight information and multidimensional detection information to analyze the source and formation mechanism of colloidal or chemical forms in the eluent sample as the analysis result. This comprehensive analysis module can be an industrial control computer or workstation with dedicated control software installed.

[0038] In this embodiment of the invention, the cascaded sequence of the modules in the above-mentioned analytical system based on field-flow separation and spectrometry ensures that the same effluent is sequentially passed through optical detection (UV-Vis detector, MALS detector) and elemental detection (ICP-MS detector), achieving a precise correspondence between physicochemical properties and elemental composition. The entire analytical system needs to be calibrated for time delay before analysis. Typically, gold nanoparticle standards with known particle sizes (such as 20 nm and 60 nm) are used to determine the dead volume time difference between each detector to ensure accurate alignment of the signals from multiple detectors on the time axis. Example 1

[0039] This embodiment demonstrates how to use the method of the present invention to determine... 68 Ge / 68 Whether the leakage of germanium in the Ga generator is due to the failure of chemical adsorption or physical shedding, the process is as follows: Take a sample suspected of having a germanium leak. 68 Ge / 68 The Ga generator eluent sample was directly injected into the AF4-ICP-MS system according to step S3. The separation conditions were set as follows: carrier liquid 0.05% SDS + 0.01M HNO3, crossflow linearly decreased from 2.0 mL / min to 0.2 mL / min over 20 min, with simultaneous monitoring. 47 Ti、 90 Zr and 68 Ge signal; Results: No free ion observations were observed during the free ion window (2-5 min). 68 Ge signal was observed, but it was also observed in the colloidal window (12-18 min). 47 Ti、 90 Zr and 68 The strong co-elution peak of Ge was detected by a MALS detector, and the corresponding particle Rg was 45±8nm. Based on this, it was determined that the colloidal leakage was caused by the physical breakage of the TiO2-ZrO2 composite filler. The recommended improvement direction is to optimize the filler sintering process to enhance mechanical strength. Example 2

[0040] This embodiment demonstrates how to use the method of the present invention to simulate and diagnose the reasons why rinsing fluid may lead to a decrease in labeling rate in a clinical labeling environment. The process is as follows: Take a certain batch 68 Ge / 68 The eluent from the Ga generator was divided into two portions: one portion was kept at its original pH (approximately 1.5) as a control; the other portion was adjusted to pH 4.0 with 1M sodium acetate and incubated for 30 min. Both portions were analyzed according to steps S3-S4. Control group: 68Ga only exhibits a sharp ion peak in the dead volume (2-4 min); Simulation group: Dead volume 68 The Ga peak area decreased by 62%, and a new peak appeared in the colloidal window (14-20 min). 47 Ti and 68 The Ga co-elution peak, with a particle size of approximately 30 nm as measured by a MALS detector, was identified as Ti. 4+ Impurities hydrolyze at pH 4.0 to form TiO2 nanocolloids, which are then adsorbed and captured. 68 Ga 3+ This leads to a decrease in the labeling rate. It is recommended to pretreat the eluent to remove Ti impurities. Example 3

[0041] This embodiment uses 103 Ru / 103m Taking the development of an Rh generator system as an example, this paper demonstrates the application of the method of the present invention in the tracing of the source and the definition of the process window in complex chemical systems. The process is as follows: LDI-TOF analysis was performed on RuCl3·xH2O feedstocks from two sources (lots A and B) (see step S2). Lot A showed a strong peak at m / z 950 (corresponding to [Ru3O2Cl8]). 2- (Batch B) The peak is 10 times weaker. Prepare solutions of the same concentration from the two raw materials, adjust the pH to 4.0, and then analyze according to steps S3~S4. Batch A exhibits a strong colloidal peak within the colloidal window (10-16 min), with a particle size of approximately 80 nm measured by a MALS detector and a high particle size indicated by an ICP-MS detector. 103 Ru signal; Batch B has an extremely weak colloidal peak; it is determined that Batch A contains a polynuclear precursor, which easily polymerizes into large-size colloids under weakly acidic conditions, thus trapping daughter molecules. 103m Based on this, batch number B is selected as the preferred raw material, and it is recommended that the process avoid the pH window of 3.5 to 4.5.

[0042] In the description of this invention, the references to "one embodiment," "some embodiments," "in this embodiment," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0043] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. An analytical method based on field-current separation and spectrophotometry, characterized in that, Includes the following steps: Step S1: Obtain the eluent sample of the isotope generator and prepare the precursor solution of the isotope generator. Take a portion of the eluent sample and perform environmental simulation treatment to obtain the treated eluent sample. Step S2: Take a portion of the precursor solution and the untreated eluent sample and perform offline laser desorption / ionization time-of-flight mass spectrometry analysis to obtain molecular weight information about the metal polynuclear complex and / or multi-charge complex; Step S3: The treated eluent sample is injected into the asymmetric field flow separation system, and the free ionic components and colloidal components in the treated eluent sample are separated non-destructively according to the hydrodynamic radius to obtain the effluent. Step S4: The effluent is sequentially passed through a UV-Vis detector, a MALS detector, and an ICP-MS detector for online coupled detection to obtain corresponding multidimensional detection information; Step S5: Combining the molecular weight information and the multidimensional detection information, the source and formation mechanism of the colloidal or chemical forms in the eluent sample are analyzed as the analysis result.

2. The analytical method based on field-current separation and spectrophotometry according to claim 1, characterized in that, The environmental simulation process in step S1 includes: A buffer reagent was added to a portion of the eluent sample to adjust the pH value to a preset gradient range of 2.5-4.5 to simulate the process of trace metal ion hydrolysis to generate secondary nanocolloids. After incubation for a preset time, the treated eluent sample was obtained.

3. The analytical method based on field-current separation and spectrophotometry according to claim 1, characterized in that, In step S3, the separation channel of the asymmetric field flow separation system has no stationary phase packing and uses Milli-Q water or dilute acid containing 0.01%-0.1% (w / v) SDS as the carrier liquid.

4. The analytical method based on field-flow separation and spectrophotometry according to claim 1, characterized in that, The UV-Vis detector in step S4 is used to identify the characteristic oxidation state absorption peaks of metal elements in the effluent at different retention times and include them in the multidimensional detection information.

5. The analytical method based on field-current separation and spectroscopic mass spectrometry according to claim 1, characterized in that, The MALS detector in step S4 is used to calculate the absolute radius of gyration and molecular weight of the separated nanocolloids in the effluent in real time and include them in the multidimensional detection information.

6. The analytical method based on field-current separation and spectroscopic mass spectrometry according to claim 1, characterized in that, The ICP-MS detector in step S4 is used to simultaneously monitor the signal intensity of at least one target isotope in the effluent and include it in the multidimensional detection information.

7. The analytical method based on field-current separation and spectrophotometry according to claim 1, characterized in that, In step S5, the criteria for determining the source and formation mechanism of colloidal or chemical forms in the eluent sample include at least one of the following: If a strong co-elution peak between the matrix element and the parent nuclide is detected by the ICP-MS detector within the colloidal retention time range, it is determined to be colloidal leakage caused by physical shedding of the isotope generator filler. If the free ion peak area of ​​the treated eluent sample is detected by the ICP-MS detector to be smaller than that of the untreated eluent sample, and a new matrix element and daughter nuclide co-elution peak appears within the colloidal retention time interval, then it is determined that hydrolysis retention has occurred. If offline laser desorption / ionization time-of-flight mass spectrometry analysis shows that the precursor solution contains abnormal polynuclear species or oxidized states, and the abundance is positively correlated with the colloidal peak area in the spectrum of the asymmetric field flow separation system, then the heterogeneity of the precursor solution is determined to be the source of the performance change of the eluent sample.

8. The analytical method based on field-flow separation and spectrophotometry according to claim 1, characterized in that, The isotope generator used in step S1 is selected from... 68 Ge / 68 Ga generator 99 Mo / 99m Tc generator 90 Sr / 90 Y generator 188 W / 188 Re generator, 225 Ac / 213 Bi generator 224 Ra / 212 Pb generator, 103 Ru / 103m One type of Rh generator.

9. An analytical system based on field-flow separation and spectrophotometry, characterized in that, The analytical method based on field-current separation and spectrophotometry as described in any one of claims 1-8 includes: The ultraviolet-visible spectroscopy detection module is used to receive the effluent and identify the characteristic oxidation state absorption peaks of metal elements in the effluent at different retention times as the first detection information. The multi-angle light scattering detection module has its inlet connected to the outlet of the ultraviolet-visible spectroscopy detection module via a pipeline, and is used to calculate the absolute radius of gyration and molecular weight of the separated nanocolloids in the effluent as second detection information; An inductively coupled plasma mass spectrometry module has its inlet connected to the outlet of the multi-angle light scattering detection module via a pipeline, and is used to simultaneously monitor the signal intensity of at least one target isotope in the effluent as a third detection information. A laser desorption / ionization time-of-flight mass spectrometry module is used to receive the untreated eluent sample and a portion of the precursor solution for offline laser desorption / ionization time-of-flight mass spectrometry analysis to obtain molecular weight information about metal polynuclear complexes and / or multi-charge complexes; The comprehensive analysis module is electrically connected to the ultraviolet-visible spectroscopy detection module, the multi-angle light scattering detection module, the inductively coupled plasma mass spectrometry module, and the laser desorption / ionization time-of-flight mass spectrometry module, respectively. It is used to combine the molecular weight information, the first detection information, the second detection information, and the third detection information to analyze the source and formation mechanism of colloidal or chemical forms in the eluent sample as the analysis result.

Images