System and method for producing lead

Abstract

A method is provided for separating lead radioactive isotopes from a mixture containing lead radioactive isotopes and radium or thorium radioactive isotopes, along with a system comprising multiple chromatography columns. The system may comprise a first cartridge having a lead complex-forming medium that preferentially binds to lead radioactive isotopes rather than radium or thorium radioactive isotopes, and a second cartridge having a weak cation exchange medium, wherein the pH of the loading solution used to load the second cartridge is pH 2L Furthermore, the pH of the eluent used to elute the lead radioactive isotope from the second cartridge is pH 2E And, 2L pH 2E Higher. The system may further include third and fourth cartridges having chromatographic media for extracting and purifying the lead radioactive isotopes so as to provide a purified lead radioactive isotope solution that can be used for medical and other applications, such as labeling radiopharmaceutical compounds.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 519,817, filed on 15 August 2023, the entire contents of which are incorporated herein by reference.

[0002] The research disclosed herein was partially supported by government funding under grant numbers R44CA250872 and R44CA254613, granted by the NIH SBIR program. The government has certain rights in this invention.

[0003] All publications and patent applications referenced herein are incorporated herein in whole by reference to the same extent as when individual publications or patent applications are specifically and individually indicated to be incorporated by reference.

[0004] This disclosure generally relates to the field of nuclear medicine, and more specifically to systems and methods for obtaining and separating radionuclides (radioactive atoms) and radioactive materials used in nuclear medicine, molecular imaging, therapeutics, and radiopharmaceuticals. [Background technology]

[0005] In nuclear medicine, radioactive atoms, also known as radionuclides, isotopes, or radioisotopes, are used for diagnosis and treatment. The radionuclides used for these purposes can attach to ligands (e.g., peptides, antibodies, small molecules), and these ligands can precisely direct the radionuclides to target tissues or cells. Isotopes of lead (Pb), including lead-212 (Pb-212) and lead-203 (Pb-203), have emerged as effective pairs of radionuclides for targeted radioligand therapy and imaging, respectively.

[0006] The commercialization of pharmaceuticals based on Pb-212 and Pb-203 requires the mass production of these radionuclides, which presents many challenges, including but not limited to chemical separation, damage from radiolysis of materials, radiation safety issues, and transportation. Pb-212 is a product of the decay of natural thorium-232 (Th-232). Th-232 has a very long half-life (t 1 / 2 = 1.4 × 10 10 Because it has a half-life of t, the amount of Th-232 required to produce the amount of Pb-212 relevant to medical applications (i.e., mCi~Ci amount) is on the order of tons of Th-232. Therefore, other methods of producing lead-212 via a shorter-lived parent nuclide are more desirable. A radium (Ra) isotope with a suitable half-life (Ra-224, t) 1 / 2 Pb-212 (3.63 days) can be used as a useful intermediate for obtaining Pb-212, but it is highly radioactive, making storage and processing difficult. Therefore, in order to develop a large-scale supply of Pb-212, novel methods and systems are needed that can overcome the effects of radioactivity and facilitate production on a commercial scale. [Overview of the Initiative]

[0007] Various embodiments of this disclosure relate to systems and methods for isolating, purifying, and producing radioactive isotopes of lead from radioactive isotopes of radium.

[0008] In one embodiment, an embodiment of the present disclosure relates to a method for separating lead radioactive isotopes from a mixture comprising lead radioactive isotopes and radioactive isotopes of radium or thorium, the method comprising: (a) loading a first load solution comprising the mixture into a first cartridge, the first cartridge comprising a first chromatography medium comprising a lead complex-forming medium which preferentially binds to the lead radioactive isotopes rather than to the radioactive isotopes of radium and thorium in the presence of the first load solution, thereby binding the lead radioactive isotopes to the lead complex-forming medium and separating them from the first load solution; and (b) forming a first eluate comprising a first eluate comprising the lead radioactive isotopes dissolved in liquid. (c) a step of eluting the bound lead radioactive isotope from the first cartridge using (c) a step of loading a second load solution containing the first eluate into the second cartridge, wherein the second cartridge has a second chromatography medium containing a weak cation exchange medium that preferentially binds to the lead radioactive isotope rather than to the radium and thorium radioactive isotopes in the presence of the second load solution, thereby binding the lead radioactive isotope to the weak cation exchange medium and separating it from the second load solution, and (d) a step of eluting the lead radioactive isotope from the second cartridge using the second eluent to form a second eluate containing the lead radioactive isotope dissolved in the liquid, wherein the second load solution has a pH 2L The second eluent has a pH of 2E It has a pH of, 2L pH 2E It is a higher method.

[0009] In another aspect, embodiments of the present disclosure relate to a system for separating lead radioisotopes from a mixture containing lead radioisotopes and radium or thorium radioisotopes. The system includes first and second cartridges in series with each other. Each of the first and second cartridges has an inlet, an outlet, and a chamber between the inlet and the outlet containing a chromatography medium. (a) The chamber of the first cartridge includes a first chromatography medium containing a lead complexing medium that (i) preferentially binds to the lead radioisotope over the radium and thorium radioisotopes in the presence of a first loading solution containing the mixture, thereby separating the lead radioisotope from the first loading solution, and (ii) elutes the lead radioisotope in the presence of a first eluent to form a first eluate containing the lead radioisotope dissolved in a second solution. And (b) the chamber of the second cartridge includes a second chromatography medium containing a weak cation exchange medium that (i) preferentially binds to the lead radioisotope over the radium and thorium radioisotopes from a second loading solution containing the first eluate, thereby separating the lead radioisotope from the second loading solution, and (ii) elutes the lead radioisotope in the presence of a second eluent to form a second eluate containing the lead radioisotope dissolved in a solution. The second loading solution has a pH 2L and the second eluent has a pH 2E and pH 2L is higher than pH 2E . It is a system.

Brief Description of the Drawings

[0010] A better understanding of the features and advantages of the methods and apparatuses described herein can be obtained by reference to the following detailed description, which illustrates exemplary embodiments, and the accompanying drawings.

[0011] [Figure 1]FIG. 1 is a flowchart showing a process for separating a lead radioisotope (e.g., Pb-212) from a mixture containing a radium radioisotope (e.g., Ra-224) or a thorium radioisotope (e.g., Th-228). According to one embodiment, up to two consecutive cartridges are used for separation.

[0012] [Figure 2] FIG. 2 is a flowchart showing a process for separating a lead radioisotope (e.g., Pb-212) from a mixture containing a radium radioisotope (e.g., Ra-224) or a thorium radioisotope (e.g., Th-228). According to one embodiment, up to four consecutive cartridges are used for separation.

[0013] [Figure 3] FIG. 3 is a flowchart showing the process for separating Pb-212 from a liquid source of Ra-224, carried out according to Example 1 herein.

[0014] [Figure 4] FIGS. 4a and 4b are plots showing % Pb breakthrough and radiochemical purity of the Pb-212 product as a function of % Pb, according to Example 1.

[0015] [Figure 5] FIG. 5 is a flowchart showing the process for separating Pb-212 from a liquid source of Ra-224, carried out according to Example 2 herein.

[0016] [Figure 6] FIGS. 6a and 6b are plots showing % Pb breakthrough and radiochemical purity of the Pb-212 product as a function of % Pb, according to Example 2.

[0017] [Figure 7]Figure 7 is a flowchart showing the steps for separating Pb-212 from a liquid source of Ra-224, as performed according to Example 3 of this specification.

[0018] [Figure 8] Figures 8a and 8b are plots showing the %Pb breakthrough as a function of %Pb and the radiochemical purity of the Pb-212 product according to Example 3. [Modes for carrying out the invention]

[0019] The terms “comprising,” “having,” “including,” and “containing,” as used herein, and their grammatical variations, are inclusive or open, and do not exclude additional undescribed elements and / or process steps, even if a feature or component defined as part thereof consists of or is essentially composed of a particular feature or component. Where used herein in relation to compounds, compositions, uses, or methods, the term “consisting essentially of” means that additional elements and / or process steps may exist, but these additions do not essentially affect the way the described compound, composition, method, or use functions. Where used herein in relation to features of compounds, compositions, uses, or methods, the term “consisting of” excludes the presence of additional elements and / or process steps in that feature. Compounds, compositions, uses, or methods described herein as containing particular elements and / or steps may also, in some embodiments, essentially consist of those elements and / or steps, and in other embodiments, whether or not those embodiments are specifically mentioned. Uses or methods described herein as including specific elements and / or processes may also consist in some embodiments of those elements and / or processes, and in other embodiments of those elements and / or processes, regardless of whether these embodiments are specifically mentioned.

[0020] Referring to an element with the indefinite article "a" does not preclude the possibility of multiple elements unless the context explicitly requires that there be only one of them. The singular forms "a," "an," and "the" refer to multiple objects unless the context clearly indicates otherwise. In this specification, when used with the term "comprising," the use of the words "a" or "an" may mean "one," which also coincides with the meanings of "one or more," "at least one," and "one or more."

[0021] In this disclosure, a numerical range described by endpoints includes all numbers, all integer values, and, where appropriate, all intermediate values ​​of fractions, encompassing all numbers within that range (for example, 1 to 5 may include 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5, etc.).

[0022] Unless otherwise specified, “certain embodiments,” “various embodiments,” “an embodiment,” and similar terms include, either alone or in combination with any other embodiment described herein, whether such other embodiments are directly or indirectly referenced, or whether such features or embodiments are described in the context of methods, products, uses, compositions, compounds, etc.

[0023] As used herein, the terms “treat,” “treatment,” “therapeutic,” and their synonyms include “improvement of symptoms,” “reduction of disease progression,” “improvement of prognosis,” and “reduction of recurrence.”

[0024] As used herein, the term "diagnostic agent" includes "imaging agent." Therefore, "diagnostic radionuclide" includes radionuclides suitable for use in imaging agents.

[0025] The term "subject" refers to an animal (e.g., a mammal or a non-mammal). The subject may be a human or a non-human primate. The subject may be an experimental mammal (e.g., a mouse, rat, rabbit, hamster, etc.). The subject may be an agricultural animal (e.g., a horse, sheep, cattle, pig, camelid, etc.) or a domestic animal (e.g., a dog, cat, etc.). In some embodiments, the subject is a human.

[0026] As used herein, the terms “salt” and “solvate” have their usual meanings in chemistry. Therefore, when a compound is a salt or solvate, it is associated with a suitable counterion. Methods for preparing salts or exchanging counterions are well known to those skilled in the art. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (e.g., without limitation, hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K) or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water, an organic solvent, or a mixture thereof. Counterions may be altered by ion exchange techniques, such as ion exchange chromatography. Unless a specific form is specifically indicated, all zwitterions, salts, solvates, and counterions are shown.

[0027] In certain embodiments, the salt or counterion may be pharmaceutically acceptable for administration to a subject. As used herein, “pharmaceutically acceptable” means suitable for in vivo use in a subject and is not necessarily limited to therapeutic uses, but also includes diagnostic uses. More generally, with respect to any pharmaceutical composition disclosed herein, non-limiting examples of suitable excipients include any suitable buffers, stabilizers, salts, antioxidants, complexing agents, isotonic agents, cryoprotectants, lyophilization protectants, suspending agents, emulsifiers, antimicrobial agents, preservatives, chelating agents, binders, surfactants, wetting agents, non-aqueous vehicles such as fixed oils, or polymers for sustained or controlled release. For example, Berge et al. (1977) (J. Pharm Sci. 66:1-19), or "Remington—The Science and Practice of Pharmacy," 21st edition (edited by Gennaro et al., Lippincott Williams & Wilkins, Philadelphia) are referenced, and each of these references is incorporated in its entirety by reference.

[0028] As used herein, the term “alkyl group” encompasses saturated linear or branched carbon radicals having, for example, 1 to about 20 carbon atoms, or in certain embodiments, 1 to about 12 carbon atoms. In other embodiments, alkyl groups are “lower alkyl” groups having 1 to about 6 carbon atoms. Examples of such groups, but not limited to, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, ethylhexyl, and octyl.

[0029] As used herein, the term “eluent” encompasses a solution used to remove a substance (e.g., lead or lead radioactive isotopes) adsorbed and / or bound to a chromatographic medium. In certain embodiments, the eluent replaces (e.g., by ion exchange) or otherwise breaks the bond between the substance (e.g., lead or lead radioactive isotopes) and the chromatographic medium (e.g., stationary phase) so that the substance leaches out of the cartridge or column containing the chromatographic medium along with the eluent (e.g., mobile phase). According to certain embodiments, the eluent may include a solution containing, for example, a weak acid and / or a mineral acid.

[0030] As used herein, the term "eluate" encompasses the mobile phase that flows out of a column or cartridge containing a chromatographic medium, for example, as a result of elution by an eluent introduced into the column or cartridge. In certain embodiments, the eluate may contain a substance (e.g., lead or lead radioactive isotopes) that was adsorbed and / or bound to the chromatographic medium, and the substance is dissolved in the solution used to elute the substance from the column or cartridge.

[0031] As used herein, the term "system" refers to the entirety of the physical components of the present invention necessary for the isolation, purification, and production of lead. The system includes, for example, containers, reagents, resin materials, cartridges, tubes, pumps, and automated systems.

[0032] As used herein, lead (Pb) refers to the element lead and includes both radioactive and observationally stable isotopes. Isotopes of Pb include, but are not limited to, Pb-196, Pb-197, Pb-198, Pb-199, Pb-200, Pb-201, Pb-202, Pb-203, Pb-204, Pb-205, Pb-206, Pb-207, Pb-208, Pb-209, Pb-210, Pb-211, Pb-212, Pb-213, Pb-214, Pb-215, and Pb-216.

[0033] As used herein, radium (Ra) refers to the element radium and includes Ra isotopes. These isotopes include, but are not limited to, Ra-223, Ra-224, Ra-225, Ra-226, Ra-227, Ra-228, Ra-229, and Ra-230.

[0034] As used herein, thorium (Th) refers to the element thorium and includes Th isotopes. These isotopes include, but are not limited to, Th-228, Th-232, Th-230, Th-227, Th-229, Th-231, Th-233, and Th-234.

[0035] As used herein, the term "cartridge" refers to a pre-assembled container containing resin used in separation and extraction processes, which functions as a reaction vessel in which the solution and eluent interact with the resin and the analyte. The terms "cartridge" and "column" are used interchangeably.

[0036] As used herein, the terms “adsorbed onto,” “adsorbed onto,” and “adsorbed to” are interchangeable and all refer to the adsorption of an atom (or element) onto the resin of the cartridge.

[0037] As used herein, the term "chromatographic media" refers to a solid material, such as a resin or matrix, filled in a cartridge containing chemical reagents and extractants designed to extract or separate specific elements by diverse chemical mechanisms under different liquid conditions. In this specification, chromatographic media include, but are not limited to, extraction chromatography resins, ion exchange resins, and other chemical separation media.

[0038] As used herein, the term “lead-complexing media” encompasses a medium, such as a resin or matrix, that has an affinity for lead and preferentially binds to lead over certain other chemical species, such as radium and / or thorium. According to certain embodiments, the lead-complexing media may include binding sites that can bind to lead by forming chemical complexes with lead, rather than by ion-exchange interactions based on the ionic charge of lead. For example, the lead-complexing media may include binding sites that are uncharged / ionically neutral in aqueous solution. According to one embodiment, the lead-complexing media may include crown ether complexing sites comprising 4,4'(5')-di-t-butylcyclohexano 18-crown-6 (also referred to herein as “Pb Resin”) diluted in isodecanol, and 4,4'(5')-di-t-butylcyclohexano 18-crown-6 (also referred to herein as “Sr Resin”) diluted in 1-octanol.

[0039] As used herein, the term “weak cationic exchange media” encompasses a medium such as a resin or matrix that preferentially binds to a target species via a weakly acidic group based on its affinity for the cationic form of that species. According to certain embodiments, the weak cationic exchange media includes a weakly acidic binding site that interacts with a cationic species via ionic interactions to bind to the cationic species. For example, the weak cationic exchange media has a weakly acidic binding site such as a carboxylic acid and / or carboxylate group that is negatively charged at high pH (which may be an acidic pH) and neutral at low pH, and other weakly acidic groups may also be suitable. According to certain embodiments, the weak cationic exchange media may include a carboxyalkyl group such as a carboxymethyl group or a carboxyethyl group bound to a silica support, such as CM-silica, BioSuite CM, and Sep-Pak Accell.

[0040] As used herein, the term “strong cationic exchange media” encompasses a medium such as a resin or matrix that preferentially binds to a target species via strongly acidic groups based on its affinity for the cationic form of that species. According to certain embodiments, the strong cationic exchange media includes strongly acidic binding sites that interact with cationic species via ionic interactions to bind to the cationic species. For example, the strong cationic exchange media includes strongly acidic binding sites such as sulfonic acid and / or sulfonate groups that are ionized (and therefore bind to cations over a wide pH range). According to certain embodiments, the strong cationic exchange media may include sulfonic acid functional groups attached to a support such as a divinylbenzene copolymer lattice, for example, MP-50 and AG-50Wx8.

[0041] As used herein, the term "generator" refers to a system that produces radionuclides. Generators are typically based on parent-daughter nuclide pairs, in which a relatively long-lived parent isotope (e.g., Ra-224) decays into a relatively short-lived daughter isotope (e.g., Pb-212) suitable for use in a given application (e.g., nuclear medicine).

[0042] As used herein, "vessel" refers to a physical container that holds a material in the form of a liquid, semi-solid, or solid. The terms "vessel" and "container" are used interchangeably. [Chromatography media and cartridges]

[0043] In this disclosure, various chromatographic media can be used in the cartridge. According to certain embodiments, the media may comprise a stationary phase material such as a solid resin or other matrix material, which is functionalized, or otherwise provided, by chemical sites that can interact with and preferentially bind to certain substances such as lead. For example, the chromatographic media may be a medium that has an affinity for a particular chemical species (e.g., lead) such that when a solution containing the particular chemical species is introduced into a cartridge containing the medium, the medium binds to (adsorbs) and retains the chemical species, thereby separating the species from other chemical species in the solution that do not have an affinity for the medium, and thus other chemical species pass through the medium without binding. The chemical species bound to the medium may then be eluted or released from the medium on the cartridge by introducing an eluent containing a chemical composition that separates the chemical species from the medium into the medium. According to a particular embodiment, the chromatography medium comprises an inert inorganic material (such as silica or alumina particles or silica gel), an organic material (such as a polymer), or an inorganic-organic solid support, the support being used to target a specific chemical species (e.g., lead ions (Pb)) by any mechanism such as ion exchange, extraction, molecular recognition, or other means. 2+ Organic molecules that hold )) are functionalized (for example, by grafting or impregnation).

[0044] According to one embodiment, the medium comprises a lead complex-forming medium that has an affinity for lead and preferentially binds to lead over other specific chemical species such as radium and / or thorium. According to a particular embodiment, the lead complex-forming medium may include binding sites that can bind to lead by forming chemical complexes with lead, rather than by ion-exchange interactions based on the ionic charge of lead. For example, the lead complex-forming medium may include binding sites that are uncharged / ionically neutral in aqueous solution. According to one embodiment, the lead complex-forming medium may include binding sites corresponding to one or more diglycolamide complex-forming sites and crown ether complex-forming sites. For example, according to a particular embodiment, the lead complex-forming medium comprises a solid carrier impregnated with a solution containing crown ether complex-forming sites as an extractant, and one or more linear or branched C1-C groups, particularly cyclohexyl or benzyl groups. 12 Dicyclohexano-8-crown-6 or dibenzo-18-crown-6, substituted with an alkyl group, may be contained in an organic diluent immiscible with water, typically in a long-chain hydrocarbon alcohol of C8 or higher. Non-limiting examples of lead complexing media having crown ether complexing sites include 4,4'(5')-di-t-butylcyclohexano-18-crown-6 (also referred to herein as "Pb Resin") diluted in isodecanol, and 4,4'(5')-di-t-butylcyclohexano-18-crown-6 (also referred to herein as "Sr Resin") diluted in 1-octanol. According to certain embodiments, the lead complexing media used herein may be 40% (w:w) or less than 40% (w:w) crown ether, such as Sr Resin or Pb Resin (Eichrom; Lisle, IL, USA). In some embodiments, the crown ether is 18-crown-6 ether, and the resin may be 40%(w:w) of 18-crown-6 or less than 40%(w:w) of 18-crown-6. The general formula for this crown ether compound is shown in Formula 1 below, and the compound may exist as a mixture of isomers.

[0045] [Formula 1]

[0046] [ka]

[0047] As another example, the lead complex-forming medium may include N,N,N',N'-tetra-alkyldiglycolamide (DGAs) having the chemical formula shown in Formula 2 below, where each R group may be independently the same or different, and is a branched or linear alkyl group having 2-12 carbon atoms, for example, 5-10 carbon atoms.

[0048] [Formula 2]

[0049] [ka]

[0050] For example, according to a particular embodiment, the lead complex-forming medium may comprise one or more of N,N,N',N'-tetra-n-octyldiglycolamide and N,N,N',N'-tetra-2-ethylhexyldiglycolamide.

[0051] According to one embodiment, the medium comprises a weak cation exchange medium that preferentially binds to a species based on its affinity for the cation form of the target species. According to a particular embodiment, the weak cation exchange medium includes a binding site that interacts with a cationic species via ionic interactions in order to bind to the cationic species. For example, the weak cation exchange medium has a binding site corresponding to a weak acid, such as a carboxylic acid and / or carboxylate group, which is negatively charged at high pH (which may be an acidic pH) and neutral at low pH, and other weak acidic groups may also be suitable. According to a particular embodiment, the weak cation exchange medium may include a carboxyalkyl group, such as a carboxymethyl group or a carboxyethyl group, bound to a silica support. Non-limiting examples of such weak cation exchange mediums include, for example, CM-silica, BioSuite CM, and Sep-Pak Accell.

[0052] According to one embodiment, the medium includes a strong cation exchange medium that, like a weak cation exchange medium, preferentially binds to a species based on its affinity for the cation form of the target species. According to a particular embodiment, the strong cation exchange medium includes binding sites that interact with cationic species via ionic interactions to bind to cationic species. Unlike the weak cation exchange medium, the strong cation exchange medium includes binding sites corresponding to strong acids, such as sulfonic acids and / or sulfonate groups, which are ionized over a wide pH range (and therefore bind to cations over a wide pH range). According to a particular embodiment, the strong cation exchange medium may include sulfonic acid functional groups attached to a support such as a divinylbenzene copolymer lattice. Non-limiting examples of such strong cation exchange mediums include, for example, MP-50 and AG-50Wx8. Table 1 shows non-limiting examples of resins that can be used in this disclosure. (Table 1) Chromatographic media JPEG2026529085000004.jpg250170

[0053] The media used herein may have any particle size effective for separation, such as 20 μm–50 μm, 50 μm–100 μm, or 100 μm–150 μm. In one embodiment, the particle size of the media used in the cartridge disclosed herein is 50 μm–100 μm. In one embodiment, the media used in the cartridge disclosed herein may adsorb (capture) at least 80%, at least 85%, at least 90%, at least 95%, at least 99.00%, at least 99.50%, at least 99.99%, at least 99.999%, or at least 99.9999% of the target radionuclide (e.g., radium-224 or lead-212). According to certain embodiments, using multiple cartridges (e.g., 2, 3, 4, or 5) in series with selected media having specific binding / extraction properties offers significant advantages in removing unwanted elements compared to using only one type of separation medium in a single cartridge. According to certain embodiments, the use of the cartridges disclosed herein may lead to a breakthrough in the removal of unwanted nuclides (e.g., radium-224) at concentrations of less than 0.01%, less than 0.001%, less than 0.0001%, or less than 0.00001%.

[0054] According to certain embodiments, multiple different cartridges, such as cartridges containing different chromatographic media, may be configured to be reversibly separable and connectable. For example, the cartridges may be connected together by conduits and inter-carrier connections such as male-female Luer locks, Luer slips, etc. The Luer lock or Luer slip openings (inner diameter) between cartridges may be approximately 1 mm–10 mm in diameter (less than 2 mm, less than 3 mm, less than 4 mm, less than 5 mm, less than 6 mm, less than 7 mm, less than 8 mm, less than 9 mm, or less than 10 mm), and may also have a diameter of 1 / 2, 1 / 3, 1 / 4, or 1 / 5 the size of the cartridge diameter. According to certain embodiments, specific cartridges connected in series may be connected together so that the eluate from a first cartridge in the row flows to the next cartridge in the row. The cartridges may also be separated before elution from the eluate of the first cartridge, intended to be loaded into a second cartridge, in order to allow for the disposal or recycling of the initial solution from the first cartridge. For example, in a first cartridge having a medium that preferentially binds to lead, the first cartridge may be positioned in conjunction with a second cartridge such that the solution used to load the lead-containing mixture into the first cartridge passes through the first cartridge and is collected for disposal or recycling without being sent to the second cartridge. Similarly, any subsequent washings of the first cartridge may be recycled or discarded without being sent to the second cartridge. In other words, the first and second cartridges may not be fluidly connected (or should not be fluidly connected) during the loading and / or rinsing stages. According to a further embodiment, the first cartridge may be fluidly connected to the second cartridge to send a lead-containing eluent to the second cartridge, for example, when an eluent is supplied to the first cartridge to elute the lead bound to the medium of the first cartridge.For example, the second cartridge may be positioned directly below the first cartridge and connected (e.g., via a conduit) so that the eluate flowing out of the first cartridge flows directly into the second cartridge. The second, third, and fourth cartridges may also be connected in series so that unwanted load and / or rinse solutions can be recycled or discarded without being sent to subsequent cartridges in the row, while the cartridges may be fluidically connected to each other if it is intended that the eluate from one cartridge be sent to another cartridge in the row. For example, the third cartridge may be positioned directly below the second cartridge and connected (e.g., via a conduit) so that the eluate flowing out of the second cartridge flows directly into the third cartridge. As another example, the fourth cartridge may be positioned directly below the third cartridge and connected (e.g., via a conduit) so that the solution flowing out of the third cartridge flows directly into the fourth cartridge. Further descriptions of embodiments of the present disclosure are provided below. [System and method for chromatographic separation and collection of lead from radium]

[0055] This specification describes separation processes and systems developed to facilitate the extraction of lead from liquid sources of radium and / or thorium, and more particularly, the extraction of lead radioisotopes from radium and / or thorium radioisotope sources. According to certain embodiments, the processes and systems can be used to produce large quantities of high-purity lead. According to further embodiments, the processes and systems can be used for the separation and collection of lead radioisotopes without the need to store highly radiodegradable radium radioisotopes in storage columns or cartridges. According to yet another embodiment, the separation processes and systems streamline the production of lead-based products for nuclear medicine, such as radiopharmaceuticals, and enable a stable supply of nuclear medicine doses that can meet commercial demand for patients.

[0056] Referring to Figure 1, one embodiment provides a system 100 for separating lead radioactive isotopes from a mixture 110 (Ra-224 source in Figure 1) containing lead radioactive isotopes and radium or thorium isotopes. The system 100 includes a first cartridge (first Pb / Ra separation column in Figure 1) 102 and a second cartridge (second Pb / Ra separation column in Figure 1) 104 in series with respect to each other, each of the first and second cartridges having its own independent inlet 106a and outlet 106b, and each cartridge also includes its own independent chamber 108 containing a chromatography medium between the cartridge inlet and outlet. According to the embodiments herein, a load solution, rinse solution, eluent, etc., are introduced into the inlet of each cartridge, pass through the chamber to the cartridge outlet, where the eluent and used solution are discharged from the cartridge. Figure 1 shows the specific radioisotopes Pb-212 and Ra-224, but it should be noted that the system and method are not limited to these, and other lead radioisotopes may also be separated from radium and / or thorium radioisotopes. Furthermore, the aqueous solution shown in Figure 1 is illustrative, and other aqueous solution compositions, such as any described herein, can be provided.

[0057] According to a particular embodiment, the chamber 108 of the first cartridge 102 includes a first chromatography medium that includes a lead complexing medium, which (i) preferentially binds to the lead radioactive isotope rather than the radium and thorium radioactive isotopes in the presence of a first load solution 102a containing a mixture, thereby separating the lead radioactive isotope from the first load solution, and (ii) elutes the lead radioactive isotope in the presence of a first eluent 102b to form a first eluent 102c containing the lead radioactive isotope dissolved in a second solution. For example, a method for separating lead radioactive isotopes from a mixture containing lead radioactive isotopes and radium or thorium radioactive isotopes may include the step of loading a first load solution 102a containing the mixture into a first cartridge 102 (through the cartridge inlet), the first cartridge containing a first chromatography medium containing a lead complex-forming medium that preferentially binds to the lead radioactive isotopes rather than to the radium and thorium radioactive isotopes in the presence of the first load solution, thereby binding the lead radioactive isotopes to the lead complex-forming medium and separating them from the first load solution. In a particular embodiment, by loading the first solution into a first cartridge having a lead complex-forming medium that preferentially binds to the lead radioactive isotopes, the lead radioactive isotopes are retained bound (adsorbed) to the medium, while the remaining first load solution, which does not bind to the medium, including the radium and thorium radioactive isotopes, flows out of the cartridge as used solution 102(e). The used solution may be discarded or, optionally, processed for further extraction of lead radioactive isotopes therefrom and recycled by being returned to the original mixture 110 and / or first cartridge. According to a particular embodiment, the method further includes the step of eluting the bound lead radioactive isotopes from the first cartridge using a first eluent 102b (introduced through the cartridge inlet) to form a first eluent 102c (flowing out from the cartridge outlet) containing the lead radioactive isotopes dissolved in the liquid. That is, the first eluent elutes the bound lead from the lead complexing medium so that the lead flows out of the first cartridge.

[0058] According to certain embodiments, a rinse solution 102d may also be provided to the first cartridge to further rinse radium and thorium radioisotopes and any other impurities from the cartridge after loading the first solution and before eluting the bound lead with the first eluent. The rinse solution 102d passing through the cartridge may also form a used solution 102(e) which can be discarded or optionally treated for further extraction of lead radioisotopes therefrom and returned to the original mixture 110 and / or first cartridge for recycling, and the rinse solution may have an aqueous composition similar to that of the loading solution, but without radioisotopes.

[0059] According to a particular embodiment, the chamber 108 of the second cartridge 104 includes a second chromatography medium comprising a weak cation exchange medium that (i) preferentially binds to the lead radioactive isotope rather than the radium and thorium radioactive isotopes from the second load solution comprising the first eluate, thereby separating the lead radioactive isotope from the second load solution, and (ii) elutes the lead radioactive isotope in the presence of a second eluent to form a second eluate comprising the lead radioactive isotope dissolved in the solution. For example, according to one embodiment, a method for separating lead radioisotopes from radium and / or thorium radioisotopes may include the step of loading a second load solution 104a containing the first eluate 102c into a second cartridge 104 (via the cartridge inlet), the second cartridge having a second chromatography medium containing a weak cation exchange medium that preferentially binds to the lead radioisotopes rather than the radium and thorium radioisotopes in the presence of the second load solution, thereby binding the lead radioisotopes to the weak cation exchange medium and separating them from the second load solution. According to a particular embodiment, by loading the second solution into a second cartridge having a weak cation exchange medium that preferentially binds to the lead radioisotopes, the lead radioisotopes are retained bound to the medium, while the remaining second load solution, which does not bind to the medium, including the radium and thorium radioisotopes, flows out of the cartridge as used solution 104(e). The used solution 104(e) may be discarded, recycled by being returned to the original mixture 110 and / or the first cartridge, and / or optionally treated therefrom for further extraction of lead radioactive isotopes, and recycled by being returned to the second cartridge.

[0060] According to a particular embodiment, the method further includes the step of eluting the bound lead radioactive isotope from the second cartridge using a second eluent 104b (introduced through the cartridge inlet) to form a second eluent 104c (flowing out from the cartridge outlet) containing the lead radioactive isotope dissolved in liquid. That is, the second eluent elutes the bound lead from the weak cation exchange medium so that the lead flows out of the second cartridge.

[0061] According to certain embodiments, a rinse solution 104d may also be provided to the second cartridge to further rinse radium and thorium radioisotopes and any other impurities from the cartridge after loading the second solution and before eluting the bound lead with the second eluent. The rinse solution 104d passing through the cartridge may similarly be discarded, optionally processed and recycled back into the original mixture 110 and / or the first cartridge, and / or optionally processed and recycled back into the second cartridge for further extraction of lead radioisotopes therefrom, and the rinse solution may have an aqueous composition similar to that of the loading solution, except that it does not contain radioisotopes.

[0062] According to one embodiment, the second load solution has a pH 2L The second eluent has a pH of 2E It has a pH of, 2L pH 2E higher. That is, the pH of the second eluent used for elution from the second cartridge may be lower than the pH of the second loading solution used for loading into the second cartridge. According to another embodiment, the pH of the first loading solution is 1L It has a pH, and the first eluent is pH 1E It has a pH of, 1E pH 1L Higher. That is, the pH of the first eluent used for elution from the first cartridge may be higher than the pH of the first loading solution used for loading into the first cartridge.

[0063] According to one embodiment, the first cartridge includes a lead complex-forming medium which is an ionically neutral medium. For example, according to one embodiment, the lead complex-forming medium may include one or more diglycolamide complex-forming sites and crown ether complex-forming sites. According to one embodiment, the first cartridge includes a lead complex-forming medium which is one or more of 4,4'(5')-di-t-butylcyclohexano 18-crown-6 (Pb Resin, with isodecanol as a diluent), 4,4'(5')-di-t-butylcyclohexano 18-crown-6 (Sr Resin, with 1-octanol as a diluent), N,N,N'N'-tetraoctyldiglycolamide (TODGA), and N,N,N'N'-tetraamyldiglycolamide (TPDGA). In yet another embodiment, the lead chelate medium in the first cartridge may be any of the lead complex-forming media described herein, such as those shown in Table 1.

[0064] According to one embodiment, the medium in the second cartridge includes a weak cation exchange medium comprising a carboxyalkyl ionizing group bonded to a silica-based support. For example, according to a particular embodiment, the weak cation exchange medium may include one or more of CM-silica, BioSuite CM, and Sep-Pak Accell Plus CM. In yet another embodiment, the weak cation exchange medium in the second cartridge may include any of the weak cation exchange mediums described herein, such as those shown in Table 1.

[0065] According to one embodiment, the first loading solution supplied to load lead into the first cartridge contains a mineral acid. For example, the mineral acid present in the first loading solution is one or more of HNO3, HCl, HBr, HI, and H2SO4. According to a particular embodiment, the concentration of the first loading solution containing the mineral acid is in the range of 0.1–10M, 0.1–8M, 0.2–8M, 0.5–5M, 1–4M, 1–3M, and / or about 2M.

[0066] In one embodiment, the first load solution provided in the first cartridge contains lead and radium radioisotopes in an aqueous (liquid) form in nitric acid (HNO3). The first load solution may be contained and stored in a container (i.e., the original container). The concentration of nitric acid in the aqueous form of the first load solution may range from 0.1–10 M, preferably 0.1–8 M, more preferably 0.2–8 M, more preferably 0.5–5 M, more preferably 1–4 M, more preferably 1–3 M, and even more preferably about 2 M. When the first load solution is loaded into the first cartridge, the lead radioisotopes in the first load solution are adsorbed onto the medium of the first cartridge. The radium and / or thorium radioisotopes in the first solution pass through the first cartridge and can be recovered and collected in a container with a recovery rate of at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. The collection container for recovering radium and / or thorium may be the original container that contained the radium and / or thorium and lead in the first load solution, or it may be a separate container.

[0067] In one embodiment, the first cartridge is also rinsed with nitric acid (HNO3). The rinsing product can be collected in the original container or a separate container. The concentration of nitric acid used in the first rinsing solution may be 0.1–3 M, more preferably 0.5–2.5 M, more preferably 1.5–2.5 M, and even more preferably about 2 M. One or more rinsing steps may be performed.

[0068] In certain embodiments, radium radioisotopes passing through the first cartridge (e.g., in the spent solution 102(e)) may be recycled for further use in lead production by further extraction processes, such as extracting lead from a solution containing radium radioisotopes, or by making the recovered radium further decayable to produce further lead radioisotopes, which can then be separated and extracted via the systems and processes described herein. The systems and methods enable lead production from radium present in solution, which may be a more radiolytically stable form than radium stored on a storage medium. The recovered radium may be further concentrated to reduce its volume and increase the concentration of radium in an aqueous form, such as in nitric acid.

[0069] According to one embodiment, the first eluent provided for eluting lead radioactive isotopes from a first cartridge contains a weak acid. For example, according to one embodiment, the first eluent containing the weak acid has a pH in the range of 1-5.5, 2-5, 3-5, 4-5 and / or about 4.5. According to one embodiment, the weak acid contains one or more carboxylate groups, sulfate groups, or phosphate groups, in equilibrium with the acidic forms of these groups. For example, the weak acid may be a buffer solution optionally adjusted to a suitable pH. According to one embodiment, the weak acid is prepared from one or more salts of acetate, citrate, and oxalic acid. The salt that forms the counterion may include any pharmaceutically acceptable salt, such as sodium and / or ammonium acetate. In one embodiment, the weak acid is prepared from ammonium acetate. According to one embodiment, the weak acid may contain concentrations of 0.1-2.0 M, 0.5-1.5 M, 0.75-1.25 M and / or about 1 M in the first eluent.

[0070] In one embodiment, lead adsorbed on the first cartridge is eluted by a first eluent containing a weak acid formed from a salt containing a carboxylate (i.e., acetate, oxalate, or citrate) accompanied by a sodium or ammonium counterion. Several types of carboxylate-containing salts may be used to elute lead from the first cartridge. In one embodiment, the salt is ammonium acetate. The concentration of ammonium acetate in the first eluent may be 0.1 to 2.0 M, preferably 0.5 to 1.5 M, more preferably 0.75 to 1.25 M, and even more preferably 1 M. The pH of the weak acid in the first eluent may be buffered to 1 to 5.5, preferably 2 to 5, more preferably 3 to 5, more preferably 4 to 5, and even more preferably 4.5. In addition to carboxylate, the salt may also contain sulfate or phosphate.

[0071] In one embodiment, a first eluent provided to elute lead radioactive isotopes from a first cartridge comprises a dilution mineral acid. For example, in one embodiment, the first eluent comprises a dilution mineral acid comprising any of HNO3, HCl, HBr, HI, and H2SO4. According to one embodiment, the first eluent comprises a dilution mineral acid having a concentration of 0.1 M or less, such as 0.001-0.1 M and / or 0.01-0.1 M.

[0072] In one embodiment, lead adsorbed on the first cartridge is eluted with a higher concentration of mineral acid. For example, the first eluent may contain a higher concentration of mineral acid, including any of HNO3, HCl, HBr, HI, and H2SO4. For example, the concentration of mineral acid in the first eluent may be higher than 4M, such as 4-10M, and even higher than 5M, such as 5-10M.

[0073] According to one embodiment, the second loading solution provided for loading lead radioactive isotopes into the second cartridge is the first eluate formed when the first eluent is supplied to the first cartridge to elute lead radioactive isotopes from the first cartridge. For example, the first eluate may be flowed directly from the first cartridge to the second cartridge to function as the second loading solution. According to one embodiment, the first eluate is flowed from the first cartridge to the second cartridge without modification. According to another embodiment, the first eluate may be modified, for example, by adjusting the pH of the solution, before being loaded into the second cartridge to form the second loading solution.

[0074] According to one embodiment, the second load solution contains a weak acid, for example, a weak acid used as a first eluent that passes through the first cartridge to form a first eluent. According to one embodiment, the second load solution containing the weak acid has a pH in the range of 1-5.5, 2-5, 3-5, 4-5 and / or 4.5. According to one embodiment, the weak acid contains one or more carboxylate groups, sulfate groups, or phosphate groups, and is in equilibrium with the acidic form of these groups. For example, the weak acid may be a buffer solution optionally adjusted to a suitable pH. According to one embodiment, the weak acid is prepared from one or more salts of acetate, citrate, and oxalic acid. The salt that forms the counterion may include any pharmaceutically acceptable salt, such as sodium and / or ammonium acetate. In one embodiment, the weak acid is prepared from ammonium acetate. According to one embodiment, the weak acid may contain concentrations of 0.1-2.0 M, 0.5-1.5 M, 0.75-1.25 M and / or about 1 M in the first eluent.

[0075] In one embodiment, a second loading solution provided for loading lead radioactive isotopes into a second cartridge comprises a dilution mineral acid. For example, in one embodiment, the second loading solution comprises a dilution mineral acid comprising any of HNO3, HCl, HBr, HI, and H2SO4. According to one embodiment, the second loading solution comprises a dilution mineral acid having a concentration of 0.1 M or less, such as 0.001-0.1 M and / or 0.01-0.1 M.

[0076] In one embodiment, the second load solution may contain a higher concentration of mineral acid, including any of HNO3, HCl, HBr, HI, and H2SO4. For example, the concentration of mineral acid in the second load solution may be higher than 4M, such as 4-10M, and even higher than 5M, such as 5-10M.

[0077] According to one embodiment, the second cartridge may be further rinsed after being loaded with the second loading solution and before being eluted with the second eluent. For example, the second cartridge may be rinsed with a rinsing solution that does not contain radioactive isotopes but has the same acid as the one used in the second loading solution. The second solution may further rinse the second cartridge for radioactive isotopes of radium and / or thorium, and the rinsing solution may be discarded or optionally processed and recycled back into the original solution mixture, the first cartridge and / or the second cartridge. According to one embodiment, the solution used to rinse the second cartridge is diluted HCl. According to a particular embodiment, the concentration of HCl used for rinsing may typically be 0.001 to 0.1 M and / or 0.01 to 0.1 M, but in a particular embodiment, the concentration may be 0.001 to 1 M, for example 0.005 to 0.5 M, or even 0.01 to 0.25 M.

[0078] According to one embodiment, the second eluent used to elute lead radioactive isotopes from the second cartridge contains a mineral acid. For example, according to one embodiment, the second eluent contains one or more of HNO3, HCl, HBr, HI, and H2SO4. According to one embodiment, the second eluent contains a mineral acid at concentrations of 0.01-5M, 0.02-4M, 0.02-3M, and / or 0.02-2M. For example, according to one embodiment, if the second load solution is a diluted mineral acid, the second eluent may contain a higher concentration of mineral acid. According to one embodiment, the second eluent contains a mineral acid at a concentration sufficient to form the anionic form of lead in the second eluent. For example, according to a particular embodiment, the anionic form of lead is PbCl4 2- Includes.

[0079] In one embodiment, lead adsorbed on the second cartridge is eluted with a second eluent, which is hydrochloric acid (HCl). The concentration of HCl may be 0.01 to 5 M, preferably 0.02 to 4 M, more preferably 0.02 to 3 M, and even more preferably 0.02 to 2 M (e.g., 0.05 M, 0.5 M, 1 M, or 2 M). [Additional cartridges]

[0080] In another embodiment, the system 100 disclosed herein for separating and purifying lead radioisotopes from aqueous radium and / or thorium radioisotopes may further include additional cartridges in addition to the first and second cartridges described above. In one embodiment, the system further includes a third cartridge 112, as shown in Figure 2. In another embodiment, the system further includes a third cartridge 112 and a fourth cartridge 114, as shown in Figure 2. According to a particular embodiment, any residual radium radioisotopes that may be present in the eluate of the second cartridge may be adsorbed onto the resin of the third cartridge, while lead radioisotopes may pass through for collection or adsorption onto the fourth cartridge.

[0081] For example, referring to Figure 2, according to a particular embodiment, the system 100 further includes a third cartridge (Pb polishing column in Figure 2) 114 in series with one or more of the first and second cartridges. The third cartridge includes its own independent inlet 106a, outlet 106b, and its own independent chamber 108 between the inlet and outlet of the cartridge, containing the chromatographic medium. According to embodiments herein, the load solution, rinse solution, eluent, etc., are introduced into the inlet of the third cartridge, pass through the chamber to the outlet of the cartridge, where the eluate and used solution are discharged from the cartridge. Figure 2 shows the specific radioisotopes Pb-212 and Ra-224, but it should be noted that the system and method are not limited to these, and other lead radioisotopes may also be separated from radium and / or thorium radioisotopes. Furthermore, the contents of the aqueous solution shown in Figure 1 are illustrative, and other aqueous solution compositions, such as any described herein, can be provided.

[0082] According to a particular embodiment, the chamber 108 of the third cartridge 102 includes a chromatography medium containing a strong cation exchange medium through which the lead radioactive isotopes in the third load solution 112a pass, so as to (i) preferentially bind to radium or thorium radioactive isotopes rather than the lead radioactive isotopes in the presence of the third load solution 112a containing the second eluate 104c, thereby separating the radium or thorium radioactive isotopes from the third load solution 112a, and (ii) form a third lead-containing solution 112c having the lead radioactive isotopes dissolved in the solution and having a reduced content of the radium or thorium radioactive isotopes compared to the content of the radium or thorium radioactive isotopes in the second eluate 104c. That is, the strong cation exchange medium of the third cartridge may be made permeable to lead radioactive isotopes while preferentially binding to radium or thorium radioactive isotopes, thereby further purifying the lead radioactive isotopes in the solution passing through the cartridge. For example, according to one embodiment, the method may include the step of loading a third load solution 112a containing a second eluate 104c into a third cartridge (through a cartridge inlet), wherein the third cartridge has a third chromatography medium comprising a strong cation exchange medium that preferentially binds to radium or thorium radioisotopes rather than the lead radioisotopes in the presence of the third load solution 112a, thereby forming a third lead-containing solution 112c having the lead radioisotopes dissolved in the solution and having a reduced content of the radium or thorium radioisotopes compared to the content of the radium or thorium radioisotopes in the second eluate 104c. The third lead-containing solution 112c may be collected and used for radionuclides, for example, in radioactive labeling of radiopharmaceutical compounds for diagnostic and / or therapeutic purposes.

[0083] According to certain embodiments, after the third load solution 112a is introduced and solution 112c is formed, a rinse solution 112d may also be provided to the third cartridge. The rinse solution 112d passing through the cartridge may be collected and used in the same way as the third lead-containing solution 112c by combining it with, for example, the third lead-containing solution or a subsequent rinse of the third cartridge. According to one embodiment, the rinse solution 112d used for rinsing the third cartridge is HCl. For example, the rinse solution 112d may contain HCl at a concentration of 0.01 to 5 M, preferably 0.02 to 4 M, more preferably 0.02 to 3 M, and even more preferably 0.02 to 2 M (e.g., 0.05 M, 0.5 M, 1 M, or 2 M). As yet another option, the third lead-containing solution 112c may be returned to the third cartridge and recycled for further removal of radium and / or thorium radioactive isotopes.

[0084] According to one embodiment, the strong cation exchange medium contained in the third cartridge contains sulfonic acid groups. According to one embodiment, the strong cation exchange medium contains sulfonic acid groups bonded to divinylbenzene.

[0085] According to one embodiment, the third load solution used to load into the third cartridge corresponds to the second eluent. For example, according to one embodiment, the second eluent is flowed from the second cartridge to the third cartridge without modification. According to another embodiment, the second eluent is modified, for example, by adjusting the pH of the second eluent, before being loaded from the third load solution into the third cartridge.

[0086] According to one embodiment, the third loading solution used to load into the third cartridge contains a mineral acid. For example, according to one embodiment, the third loading solution contains one or more of HNO3, HCl, HBr, HI, and H2SO4. According to one embodiment, the third loading solution contains a mineral acid at concentrations of 0.01-5M, 0.02-4M, 0.02-3M, and / or 0.02-2M. According to one embodiment, the third loading solution contains a mineral acid at a concentration sufficient to form the anionic form of lead in the third loading solution. According to one embodiment, the third loading solution contains HCl.

[0087] In one embodiment, the third lead-containing solution corresponds to the third load solution that has passed through the third cartridge, and has a reduced content of radium or thorium isotopes compared to the third load solution.

[0088] Referring again to Figure 2, according to a particular embodiment, the system 100 further includes a fourth cartridge (pharmaceutical matrix conversion column in Figure 2) 114 in series with one or more of the first, second, and third cartridges. The fourth cartridge includes its own independent inlet 106a, outlet 106b, and its own independent chamber 108 located between the inlet and outlet of the cartridge and containing the chromatographic medium. According to embodiments herein, the load solution, rinse solution, eluent, etc., are introduced into the inlet of the fourth cartridge, pass through the chamber to the outlet of the cartridge, where the eluate and used solution are discharged from the cartridge. Figure 2 shows the specific radioisotopes Pb-212 and Ra-224, but it should be noted that the system and method are not limited to these, and other lead radioisotopes may also be separated from radium and / or thorium radioisotopes. Furthermore, the contents of the aqueous solution shown in Figure 1 are illustrative, and other aqueous solution compositions, such as any described herein, can be provided.

[0089] According to a particular embodiment, the chamber 108 of the fourth cartridge 114 includes a fourth chromatography medium which includes a lead complexing medium that (i) preferentially binds to the lead radioactive isotopes rather than to the radium and thorium radioactive isotopes in the presence of a fourth load solution 114a which includes the third lead-containing solution 112c, thereby separating the lead radioactive isotopes from the fourth load solution, and (ii) elutes the lead radioactive isotopes in the presence of a fourth eluent introduced into the lead complexing medium to form a fourth eluent which includes the lead radioactive isotopes dissolved in the liquid. For example, a method for separating lead radioactive isotopes from a fourth load solution containing a third lead-containing solution may include the steps of loading the fourth load solution 114a containing the third elate 112c into a fourth cartridge 114 (through the cartridge inlet), wherein the fourth cartridge includes a fourth chromatography medium containing a lead complex-forming medium that preferentially binds to the lead radioactive isotopes rather than to the radium and thorium radioactive isotopes in the presence of the fourth load solution, thereby binding the lead radioactive isotopes to the lead complex-forming medium and separating them from the fourth load solution. In a particular embodiment, by loading the fourth solution into a fourth cartridge having a lead complex-forming medium that preferentially binds to the lead radioactive isotopes, the lead radioactive isotopes are retained bound to the medium, while the remaining fourth load solution, including the radium and thorium radioactive isotopes, flows out of the cartridge as spent solution 114(c). The used solution may be discarded or, optionally, processed for further extraction of lead radioactive isotopes therefrom and recycled by being returned to either the original mixture 110 and / or the first cartridge or the third cartridge. According to a particular embodiment, the method further includes the step of eluting the bound lead radioactive isotopes from the fourth cartridge using a fourth eluent 114b (introduced through the cartridge inlet) to form a fourth eluent 1114c (flowing out from the cartridge outlet) containing the lead radioactive isotopes dissolved in the liquid. That is, the fourth eluent elutes the bound lead from the lead complexing medium so that the lead flows out of the fourth cartridge.

[0090] According to one embodiment, the fourth load solution used for loading the fourth cartridge is pH 4L It has a pH, and the fourth eluent has a pH 4E It has a pH of, 4E pH 4L Higher.

[0091] According to certain embodiments, a rinse solution 114d may also be provided to the fourth cartridge to further rinse radium and thorium radioisotopes and any other impurities from the cartridge after loading the fourth load solution and before eluting the bound lead with the fourth eluent. The rinse solution 114d passing through the cartridge forms a used solution 114(e) which can also be discarded or optionally treated for further extraction of lead radioisotopes therefrom and recycled by being returned to any of the original mixture 110 and / or the first to third cartridges, and the rinse solution may have a similar aqueous composition to the load solution, except that it does not contain radioisotopes. According to one embodiment, the fourth cartridge is rinsed with HCl, such as HCl at a concentration of 0.01 to 5 M, preferably 0.02 to 4 M, more preferably 0.02 to 3 M, and even more preferably 0.02 to 2 M (e.g., 0.05 M, 0.5 M, 1 M, or 2 M).

[0092] According to one embodiment, the first cartridge contains a lead complex-forming medium of the same type as the lead complex-forming medium in the fourth cartridge. According to one embodiment, the fourth cartridge contains a lead complex-forming medium that is ionically neutral. For example, according to one embodiment, the lead complex-forming medium may contain one or more diglycolamide complex-forming sites and crown ether complex-forming sites. According to one embodiment, the fourth cartridge contains a lead complex-forming medium that is one or more of 4,4'(5')-di-t-butylcyclohexano 18-crown-6 (Pb resin, isodecanol as a diluent), 4,4'(5')-di-t-butylcyclohexano 18-crown-6 (Sr resin, 1-octanol as a diluent), N,N,N'N'-tetraoctyldiglycolamide (TODGA), and N,N,N'N'-tetraamyldiglycolamide (TPDGA). In yet another embodiment, the lead chelating medium in the fourth cartridge may be different from any of the lead complexing mediums described herein and / or the lead complexing medium provided in the first cartridge, such as those shown in Table 1.

[0093] According to one embodiment, the fourth load solution is the third lead-containing solution. For example, according to one embodiment, the third lead-containing solution may be flowed from the third cartridge to the fourth cartridge without modification. According to another embodiment, the third lead-containing solution may be modified before being loaded into the fourth cartridge to form the fourth load solution.

[0094] According to one embodiment, the fourth loading solution used to load into the fourth cartridge contains a mineral acid. For example, according to one embodiment, the fourth loading solution contains one or more of HNO3, HCl, HBr, HI, and H2SO4. According to one embodiment, the fourth loading solution contains a mineral acid at concentrations of 0.01-5M, 0.02-4M, 0.02-3M, and / or 0.02-2M. According to one embodiment, the fourth loading solution contains HCl.

[0095] According to one embodiment, the fourth eluent provided for eluting lead radioactive isotopes from the fourth cartridge contains a weak acid. For example, according to one embodiment, the fourth eluent containing the weak acid has a pH in the range of 1-5.5, 2-5, 3-5, 4-5 and / or 4.5. According to one embodiment, the weak acid contains one or more carboxylate groups, sulfate groups, or phosphate groups, and is in equilibrium with the acidic form of these groups. For example, the weak acid may be a buffer solution optionally adjusted to a suitable pH. According to one embodiment, the weak acid is prepared from one or more salts of acetate, citrate, and oxalic acid. The salt that forms the counterion may include any pharmaceutically acceptable salt, such as sodium and / or ammonium acetate. In one embodiment, the weak acid is prepared from ammonium acetate. According to one embodiment, the weak acid may contain concentrations of 0.1-2.0 M, 0.5-1.5 M, 0.75-1.25 M, and / or about 1 M in the fourth eluent.

[0096] In one embodiment, lead adsorbed on the fourth cartridge is eluted by a fourth eluent containing a weak acid formed from a carboxylate-containing salt (i.e., acetate, oxalate, or citrate) accompanied by a sodium or ammonium counterion. Several types of carboxylate-containing salts may be used to elute lead from the first cartridge. In one embodiment, the salt is ammonium acetate. The concentration of ammonium acetate in the fourth eluent may be 0.1 to 2.0 M, preferably 0.5 to 1.5 M, more preferably 0.75 to 1.25 M, and even more preferably 1 M. The pH of the weak acid in the fourth eluent may be buffered to 1 to 5.5, preferably 2 to 5, more preferably 3 to 5, more preferably 4 to 5, and even more preferably 4.5. In addition to carboxylate, the salt may also contain sulfate or phosphate.

[0097] In one embodiment, a fourth eluent provided to elute lead radioactive isotopes from a fourth cartridge comprises a dilution mineral acid. For example, in one embodiment, the fourth eluent comprises a dilution mineral acid comprising any of HNO3, HCl, HBr, HI, and H2SO4. According to one embodiment, the fourth eluent comprises a dilution mineral acid having a concentration of 0.1 M or less, such as 0.001-0.1 M and / or 0.01-0.1 M.

[0098] In one embodiment, lead adsorbed on the fourth cartridge is eluted with hydrochloric acid (HCl). The concentration of HCl may be 0.01 to 5 M, preferably 0.02 to 4 M, more preferably 0.02 to 3 M, and even more preferably 0.1 to 2 M (e.g., 0.1 M, 1 M, or 2 M).

[0099] In one embodiment, the lead adsorbed on the fourth cartridge is eluted with a higher concentration of mineral acid. For example, the fourth eluent may contain a higher concentration of mineral acid, including any of HNO3, HCl, HBr, HI, and H2SO4. For example, the concentration of mineral acid in the fourth eluent may be higher than 4M, such as 4-10M, and even higher than 5M, such as 5-10M.

[0100] According to certain embodiments, the fourth eluent may be collected and used for radioactive nuclear medicine applications, such as radiolabeling of radiopharmaceuticals using lead radioisotopes. According to yet another embodiment, the fourth eluent may be modified, for example, by increasing or decreasing the pH, or by adding other stabilizers.

[0101] According to a particular embodiment, the method for producing a radiopharmaceutical includes the step of introducing an unchelated radiopharmaceutical into an aqueous solution containing one of the second to fourth eluents so as to form a radiopharmaceutical chelated with a lead radioactive isotope. According to another embodiment, the radiopharmaceutical includes a radiolabeled chelating agent prepared according to the above production method.

[0102] In a further embodiment, the positions of the third and second cartridges in the system can be swapped such that the third cartridge receives a first eluate from the first cartridge, and the second cartridge receives a third lead-containing solution from the third cartridge (at which point the fourth cartridge would receive a second eluate from the second cartridge). In one embodiment of the process in this configuration, the process would include loading a third load solution containing a first eluate into the third cartridge, wherein the third cartridge has a third chromatography medium comprising a strong cation exchange medium that preferentially binds to radium or thorium radioisotopes rather than lead radioisotopes in the presence of the load solution, thereby separating the radium or thorium radioisotopes from the third load solution to form a third lead-containing solution having the lead radioisotopes dissolved in the solution and having a reduced content of the radium or thorium radioisotopes compared to the content of the radium or thorium radioisotopes in the first eluate. The third lead-containing solution would then be supplied to the second cartridge as a second load solution. According to this embodiment, if a fourth cartridge is used as part of the system along with second and third cartridges whose arrangement in series has been reversed, the process further includes loading a fourth load solution containing a second eluent into the fourth cartridge, wherein the fourth cartridge has a fourth chromatography medium containing a lead complex-forming medium that preferentially binds to the lead radioactive isotope rather than the radium and thorium radioactive isotopes in the presence of the fourth load solution, thereby separating the lead radioactive isotope from the fourth load solution; and eluting the bound lead radioactive isotope from the fourth cartridge using a fourth eluent to form a fourth eluent containing the lead radioactive isotope dissolved in liquid. [Measurement of purity and yield]

[0103] In this disclosure, the purity of radium may be measured using rapid alpha spectrometry measurement and the decay of radium-224 via liquid scintillation counting. The yield of radium may be measured using liquid scintillation counting and HPGe gamma analysis. The yield of lead may be measured using HPGe gamma analysis.

[0104] According to certain embodiments of this specification, the yield of lead isotopes by the process in system 100 (e.g., the first and second cartridges, or all four cartridges) is at least 80%, at least 90%, and / or at least 95%. The radiochemical purity of lead isotopes (relative to all parent isotopes) processed according to the system described herein may be at least 95%, such as at least 99.9%, at least 99.99%, at least 99.999%, at least 99.9999%, and / or at least 99.99999%. That is, according to certain embodiments, the radiochemical purity of lead-212 relative to parent isotopes may be at least 95%, such as at least 99.9%, at least 99.99%, at least 99.999%, at least 99.9999%, and / or at least 99.99999%.

[0105] In certain embodiments, the principle of these measurements is that isotopes of the same element have the same chemical behavior, and therefore radiochemical tracers can be introduced into the system to calculate recovery and detection efficiency [1]-[3]. Generally, some chemical losses are expected during the chromatography process and sample analysis (e.g., detection efficiency, losses in source sample preparation), and therefore the use of another exogenous isotope can be used to confirm the chemical yield of the analyte throughout the process. 2In Pb-212, the common tracer isotope is Pb-203. Pb-203 offers several advantages because it is easily detectable, has a half-life more suitable for research and development, and has a simpler decay series than Pb-212. This allows Pb-203 to function as a tracer or substitute for Pb-212 in studies investigating chemical separation (e.g., those shown in the examples below). Pb-203 and Pb-212 are expected to exhibit identical chemical behavior throughout the separation process. [Examples]

[0106] The following embodiments are provided to illustrate aspects of the present disclosure, and the present invention is not limited thereto. [Example 1]

[0107] Figure 3 shows one embodiment of the flow schema used in this embodiment 1 for separating Pb-212 from a liquid source of Ra-224.

[0108] In this embodiment, the elution scheme used the following column: • Column 1 (PC): QML Pb Resin, 50-100 μm, pre-treated with 5 mL of 2.0 M HNO3. • Second column (SC): QML CM-Silica, 20-45 μm, pre-treated with 5 mL of 1.0 M ammonium acetate (pH 4.5). • Third column / guard column (GC): QML MP50, 75-150 μm

[0109] The steps in the aforementioned elution scheme are as follows: 1) Load the Ra-224 source in 2.0M HNO3 (initial 20mL, adding 0.5mL each cycle) into the PC. Collect the Ra-224 from the PC into the same supply container. 2) Rinse the PC with 0.5 mL of 2.0 M HNO3 into the Ra-224 supply container. 3) Remove the Ra-224 supply container. Place the PC waste liquid vial under the PC. 4) Rinse the PC with 9.5 mL of 2.0 M HNO3. Collect the PC waste liquid in a vial. 5) Remove the PC waste liquid vial. 6) Add SC under PC. 7) Add the SC waste liquid vial below the column. 8) Transfer Pb-212 from the PC to the SC using 10 mL of 1.0 M ammonium acetate (pH 4.5). Collect the eluate in the SC waste liquid vial. 9) Remove the PC. 10) Rinse the SC with 10 mL of 0.01 M HCl. Collect the SC waste liquid in a vial. 11) Remove the SC waste liquid vial. 12) Add the Pb-212 vial. 13) Add GC below SC. 14) Using 4.0 mL of 2.0 M HCl, Pb-212 is recovered from the SC through the GC into a Pb-212 vial.

[0110] Figures 4a-4b show the %Pb breakthrough and radiochemical purity of the Pb-212 product as a function of %Pb recovery in Example 1. %Pb breakthrough is the amount of Pb-212 eluted with Ra-224 in the first column. This Pb-212 is then included with Ra-224 and stored for future milking of the Ra-224 source. The radiochemical purity of Pb is with respect to Ra-224 and / or Th-228. The radiochemical purity of Pb-212 does not consider the ingrowth of Pb-212 decay products. %Pb recovery is the amount of Pb-212 recovered in the entire separation scheme. [Example 2]

[0111] Figure 5 shows one embodiment of the flow scheme used in this Example 2 for separating Pb-212 from a liquid source of Ra-224. The flow and parameters in this Example are the same as in Example 1, except that (1) the PC is changed from Pb-resin to TPDGA, and (2) the PC rinse solution is reduced to 0.25 M HNO3.

[0112] In this embodiment, the elution scheme used the following column: • Column 1 (PC): 1 mL of TPDGA Resin, 50-100 μm, pre-treated with 5 mL of 2.0 M HNO3. • Second column (SC): QML CM-Silica, 20-45 μm, pre-treated with 5 mL of 1.0 M ammonium acetate (pH 4.5). • Third column / guard column (GC): QML MP50, 75-150 μm

[0113] The steps in the aforementioned elution scheme are as follows: 1) Load the Ra-224 source in 2.0M HNO3 (initial 20mL, adding 1.0mL each cycle) into the PC. Collect the Ra-224 in the same supply container. 2) Rinse the PC with 1.0 mL of 0.25 M HNO3 and transfer it to the Ra-224 supply source. 3) Remove the Ra-224 supply container. Place the PC waste liquid vial under the PC. 4) Rinse the PC with 4.0 mL of 0.25 M HNO3. Collect the PC waste liquid in a vial. 5) Remove the PC waste liquid vial. 6) Add SC under PC. 7) Add the SC waste liquid vial below the column. 8) Transfer Pb-212 from the PC to the SC using 10 mL of 1.0 M ammonium acetate (pH 4.5). Collect the eluate in the SC waste liquid vial. 9) Remove the PC. 10) Rinse the SC with 10 mL of 0.01 M HCl. Collect the SC waste liquid in a vial. 11) Remove the SC waste liquid vial. 12) Add the Pb-212 vial. 13) Add GC below SC. 14) Using 4.0 mL of 2.0 M HCl, Pb-212 is recovered from the SC through the GC into a Pb-212 vial.

[0114] Figures 6a-6b show the %Pb breakthrough as a function of %Pb recovery and the radiochemical purity of the Pb-212 product in Example 2. [Example 3]

[0115] Figure 7 shows one embodiment of the flow scheme used in this Example 3 for separating Pb-212 from a liquid source of Ra-224. The flow and parameters in this Example are the same as in Example 1, except that the volumes of the load solution and rinse solution are optimized to maximize the Pb recovery rate, Ra recovery rate, and Pb purity.

[0116] In this embodiment, the elution scheme used the following column: • Column 1 (PC): 1 ml Pb Resin, 50-100 μm, pre-treated with 10 ml of 2.0 M HNO3. • Second column (SC): HML CM-Silica, 20-45 μm, pre-treated with 10 mL of 1.0 M ammonium acetate (pH 4.5). • Third column / guard column (GC): QML MP50, 75-150 μm

[0117] The steps in the aforementioned elution scheme are as follows: 1) Load the Ra-224 source in 2.0M HNO3 into the PC. Collect the Ra-224 in the same supply container. (Initial source volumes: Source A = 24 mL; Source B = 58 mL; Source C = 87 mL; volume increases by 1.0 mL after each cycle) 2) Rinse the PC with 1.0 mL of 0.1 M HNO3 and transfer it to the Ra-224 supply source. 3) Remove the Ra-224 supply container. Place the PC waste liquid vial under the PC. 4) Rinse the PC with 9.0 mL of 0.1 M HNO3. Collect the PC waste liquid in a vial. 5) Remove the PC waste liquid vial. 6) Add SC under PC. 7) Add the SC waste liquid vial below the column. 8) Transfer Pb-212 from the PC to the SC using 15 mL of 1.0 M ammonium acetate (pH 4.5). Collect the eluate in the SC waste liquid vial. 9) Remove the PC. 10) Rinse the SC with 10 mL of 0.01 M HCl. Collect the SC waste liquid in a vial. 11) Remove the SC waste liquid vial. 12) Add the Pb-212 vial. 13) Add GC below SC. 14) Using 4.0 mL of 2.0 M HCl, Pb-212 is recovered from the SC through the GC into a Pb-212 vial.

[0118] Figures 8a-8b show the %Pb breakthrough as a function of %Pb recovery and the radiochemical purity of the Pb-212 product in Example 3. [Listed embodiments]

[0119] The embodiments of this disclosure include, but are not limited to, those listed below.

[0120] Embodiment 1. A method for separating lead radioactive isotopes from a mixture containing lead radioactive isotopes and radium or thorium radioactive isotopes, the method comprising:

[0121] (a) A step of loading a first load solution containing the mixture into a first cartridge, wherein the first cartridge contains a first chromatography medium containing a lead complex-forming medium that preferentially binds to the lead radioactive isotope rather than the radium and thorium radioactive isotopes in the presence of the first load solution, thereby binding the lead radioactive isotope to the lead complex-forming medium and separating it from the first load solution,

[0122] (b) A step of eluting the bound lead radioactive isotope from the first cartridge using the first eluent to form a first eluent containing the lead radioactive isotope dissolved in the liquid,

[0123] (c) A step of loading a second load solution containing the first eluate into a second cartridge, wherein the second cartridge has a second chromatography medium containing a weak cation exchange medium that preferentially binds to the lead radioactive isotope rather than the radium and thorium radioactive isotopes in the presence of the second load solution, thereby binding the lead radioactive isotope to the weak cation exchange medium and separating it from the second load solution,

[0124] (d) A step of eluting the lead radioactive isotope from the second cartridge using a second eluent to form a second eluent containing the lead radioactive isotope dissolved in the liquid,

[0125] Here, the second load solution is pH 2L The second eluent has a pH of 2E It has a pH of, 2L pH 2E Higher.

[0126] Embodiment 2. The method according to Embodiment 1, wherein the first load solution passing through the first cartridge is treated to further bind lead isotopes to the lead complex-forming medium, and is returned to the first cartridge for recycling or discarded.

[0127] Embodiment 3. The method according to any one of Embodiments 1-2, wherein the second load solution passing through the second cartridge is returned to the first cartridge and recycled to further bind lead isotopes to the lead complex-forming medium, or is treated to further bind lead isotopes to the weak cation exchange medium, and then returned to the second cartridge and recycled, or discarded.

[0128] Embodiment 4. The first load solution has a pH 1L The first eluent has a pH of 1E It has a pH of, 1E pH 1L A higher method according to any of embodiments 1-3.

[0129] Embodiment 5. A method according to any of Embodiments 1-4, further comprising:

[0130] (e) A step of loading a third load solution containing the second eluate into a third cartridge, wherein the third cartridge has a third chromatography medium comprising a strong cation exchange medium that preferentially binds to radioactive isotopes of radium or thorium rather than to the radioactive isotopes of lead in the presence of the third load solution, thereby separating the radioactive isotopes of radium or thorium from the third load solution to form a third lead-containing solution having the radioactive isotopes of lead dissolved in the solution and having a reduced content of the radioactive isotopes of radium or thorium compared to the content of the radioactive isotopes of radium or thorium in the second eluate.

[0131] Embodiment 6. The method according to Embodiment 5, wherein the third lead-containing solution flowing out of the third cartridge is optionally returned to the third cartridge and recycled to further reduce the content of radioactive isotopes of radium or thorium in the third lead-containing solution.

[0132] Embodiment 7. A method according to any of Embodiments 5-6, further comprising:

[0133] (f) A step of loading a fourth load solution containing the third lead-containing solution into a fourth cartridge, wherein the fourth cartridge has a fourth chromatography medium containing a lead complex-forming medium that preferentially binds to the lead radioactive isotope rather than to the radium and thorium radioactive isotopes in the presence of the fourth load solution, thereby separating the lead radioactive isotope from the fourth load solution.

[0134] (g) A step of eluting the bound lead radioactive isotope from the fourth cartridge using a fourth eluent to form a fourth eluent containing the lead radioactive isotope dissolved in the liquid.

[0135] Embodiment 8. The method according to Embodiment 7, wherein the fourth load solution passing through the fourth cartridge is treated to further separate lead isotopes therefrom and recycled back into the first or fourth cartridge, or recycled back into the second cartridge to further separate lead isotopes therefrom, or discarded.

[0136] Embodiment 9. The fourth load solution has a pH 4L The pH is as follows: The fourth eluent has pH 4E It has a pH of, 4E pH 4L A higher method according to any of embodiments 7-8.

[0137] Embodiment 10. The method according to any of the above embodiments, wherein the first cartridge contains a lead complexing medium of the same type as the lead complexing medium in the fourth cartridge.

[0138] Embodiment 11. The method according to any of the above embodiments, wherein the lead comprises lead-212 or lead-203.

[0139] Embodiment 12. The method according to any of the preceding embodiments, wherein radium exists in the form of radium-224 or radium-223.

[0140] Embodiment 13. The method according to any of the preceding embodiments, wherein thorium exists in the form of thorium-228 or thorium-232.

[0141] Embodiment 14. The method according to any of the above embodiments, wherein either or both of the first cartridge and the fourth cartridge include a lead complex-forming medium which is an ionically neutral medium.

[0142] Embodiment 15. The method according to any of the above embodiments, wherein either or both of the first cartridge and the fourth cartridge include a lead complexing medium containing one or more diglycolamide complexing sites and crown ether complexing sites.

[0143] Embodiment 16. The method according to any of the above embodiments, wherein either or both of the first and fourth cartridges comprise a lead complex-forming medium comprising one or more of 4,4'(5')-di-t-butylcyclohexano 18-crown-6, 4,4'(5')-di-t-butylcyclohexano 18-crown-6 (diluent: 1-octanol), and N,N,N'N'tetra-alkyldiglycoamides in isodecanol, where alkyl = identical or different linear or branched alkyl groups having 2-12 carbon atoms.

[0144] Embodiment 17. The method according to any of the above embodiments, wherein the second cartridge comprises a weak cation exchange medium containing carboxyalkyl ionized groups bonded to a silica-based support.

[0145] Embodiment 18. The method according to any of the above embodiments, wherein the second cartridge comprises a carboxymethyl functional group bonded to a silica-based support.

[0146] Embodiment 19. The method according to any of the above embodiments, wherein the third cartridge comprises a strong cation exchange medium containing a sulfonic acid group.

[0147] Embodiment 20. The method according to any of the above embodiments, wherein the third cartridge comprises a strong cation exchange medium containing a sulfonic acid group bonded to divinylbenzene.

[0148] Embodiment 21. The method according to any of the above embodiments, wherein the first load solution contains a mineral acid.

[0149] Embodiment 22. The method according to Embodiment 21, wherein the mineral acid present in the first load solution is one of HNO3, HCl, HBr, HI, and H2SO4.

[0150] Embodiment 23. The method according to any one of Embodiments 21-22, wherein the concentration of the mineral acid in the first load solution is in the range of 0.1-10 M, 0.1-8 M, 0.2-8 M, 0.5-5 M, 1-4 M, 1-3 M and / or about 2 M.

[0151] Embodiment 24. The method according to any of the above embodiments, wherein the first eluent contains a weak acid.

[0152] Embodiment 25. The method according to Embodiment 24, wherein the first eluent containing the weak acid has a pH in the range of 1-5.5, 2-5, 3-5, 4-5 and / or about 4.5.

[0153] Embodiment 26. The method according to any one of Embodiments 24-25, wherein the weak acid comprises a carboxylate group, a sulfate group, or a phosphate group.

[0154] Embodiment 27. The method according to any one of Embodiments 24-26, wherein the weak acid comprises one or more salts of acetate, citric acid, and oxalic acid.

[0155] Embodiment 28. The method according to any one of Embodiments 24-27, wherein the weak acid comprises ammonium acetate.

[0156] Embodiment 29. The method according to any one of Embodiments 20-28, wherein the weak acid comprises concentrations of 0.1-2.0 M, 0.5-1.5 M, 0.75-1.25 M and / or about 1 M.

[0157] Embodiment 30. The method according to any of the above embodiments, wherein the first eluent contains a diluted mineral acid having a concentration of 0.1 M or less.

[0158] Embodiment 31. The method according to Embodiment 30, wherein the first eluent contains a diluted mineral acid comprising any of HNO3, HCl, HBr, HI, and H2SO4.

[0159] Embodiment 32. The method according to any one of Embodiments 30-31, wherein the first eluent contains a diluted mineral acid having a concentration of 0.1 M or less, 0.001-0.1 M and / or 0.01-0.1 M.

[0160] Embodiment 33. The method according to any of the above embodiments, wherein the second load solution is the first eluent.

[0161] Embodiment 34. The method according to any of the above embodiments, wherein the first eluate is flowed without being changed from the first cartridge to the second cartridge.

[0162] Embodiment 35. The method according to any one of Embodiments 1-33, wherein the first eluate is modified before being loaded into the second cartridge to form a second load solution.

[0163] Embodiment 36. The method according to any of the above embodiments, wherein the second load solution contains a weak acid.

[0164] Embodiment 37. The method according to Embodiment 36, wherein the second load solution containing the weak acid has a pH in the range of 1-5.5, 2-5, 3-5, 4-5 and / or 4.5.

[0165] Embodiment 38. The method according to any one of Embodiments 36-37, wherein the weak acid comprises a carboxylate group, a sulfate group, or a phosphate group.

[0166] Embodiment 39. The method according to any one of Embodiments 36-38, wherein the weak acid comprises one or more salts of acetate, citric acid, and oxalic acid.

[0167] Embodiment 40. The method according to any one of Embodiments 36-39, wherein the weak acid comprises ammonium acetate.

[0168] Embodiment 41. The method according to any one of Embodiments 36-40, wherein the weak acid comprises concentrations of 0.1-2.0 M, 0.5-1.5 M, 0.75-1.25 M and / or about 1 M.

[0169] Embodiment 42. The method according to any of the above embodiments, wherein the second load solution contains a diluted mineral acid having a concentration of 0.1 M or less.

[0170] Embodiment 43. The method according to Embodiment 42, wherein the second load solution comprises a diluted mineral acid containing any of HNO3, HCl, HBr, HI, and H2SO4.

[0171] Embodiment 44. The method according to any one of Embodiments 42-43, wherein the second load solution comprises a diluted mineral acid having a concentration ranging from 0.1 M or less, 0.001-0.1 M and / or 0.01-0.1 M.

[0172] Embodiment 45. The method according to any of the above embodiments, wherein the second eluent contains a mineral acid.

[0173] Embodiment 46. The method according to Embodiment 45, wherein the second eluent comprises any of HNO3, HCl, HBr, HI, and H2SO4.

[0174] Embodiment 47. The method according to any one of Embodiments 45-46, wherein the second eluent contains a mineral acid at a concentration of 0.01-5 M, 0.02-4 M, 0.02-3 M and / or 0.02-2 M.

[0175] Embodiment 48. The method according to any one of Embodiments 45-47, wherein the second eluent contains a mineral acid at a concentration sufficient to form an anionic form of lead in the second eluent.

[0176] Embodiment 49. The anionic form of lead is PbCl4 2- The method according to any one of embodiments 45-48, including the method described above.

[0177] Embodiment 50. The method according to any one of Embodiments 45-49, wherein the second eluent contains a mineral acid equivalent to HCl.

[0178] Embodiment 51. The method according to any of the above embodiments, wherein the third load solution is the second eluent.

[0179] Embodiment 52. The method according to any of the above embodiments, wherein the second eluate is flowed from the second cartridge to the third cartridge without modification.

[0180] Embodiment 53. The method according to any of Embodiments 1-50, wherein the second eluent is modified before being loaded into the third cartridge to form a third load solution.

[0181] Embodiment 54. The method according to any of the above embodiments, wherein the third load solution contains a mineral acid.

[0182] Embodiment 55. The method according to Embodiment 54, wherein the third load solution comprises any of HNO3, HCl, HBr, HI, and H2SO4.

[0183] Embodiment 56. The method according to any one of Embodiments 54-55, wherein the third load solution contains a mineral acid at concentrations of 0.01-5 M, 0.02-4 M, 0.02-3 M and / or 0.02-2 M.

[0184] Embodiment 57. The method according to any one of Embodiments 54-56, wherein the third load solution contains a mineral acid at a concentration sufficient to form an anionic form of lead in the third load solution.

[0185] Embodiment 58. The anionic form of lead is PbCl4 2- The method according to any one of embodiments 54-57, including the method described above.

[0186] Embodiment 59. The method according to any one of Embodiments 54-58, wherein the third load solution contains a mineral acid equivalent to HCl.

[0187] Embodiment 60. The method according to any of the above embodiments, wherein the third lead-containing solution corresponds to the third load solution that has passed through the third cartridge, and has a reduced radium or thorium isotope content compared to the third load solution.

[0188] Embodiment 61. The method according to any of the above embodiments, wherein the fourth load solution is a third lead-containing solution.

[0189] Embodiment 62. The method according to any of the preceding embodiments, wherein the third lead-containing solution is flowed from the third cartridge to the fourth cartridge without modification.

[0190] Embodiment 63. The method according to any of Embodiments 1-61, wherein the third lead-containing solution is modified before being loaded into the fourth cartridge to form the fourth load solution.

[0191] Embodiment 64. The method according to any of the above embodiments, wherein the fourth load solution contains a mineral acid.

[0192] Embodiment 65. The method according to Embodiment 64, wherein the fourth load solution comprises any of HNO3, HCl, HBr, HI, and H2SO4.

[0193] Embodiment 66. The method according to any one of Embodiments 64-65, wherein the fourth load solution contains a mineral acid at concentrations of 0.01-5 M, 0.02-4 M, 0.02-3 M and / or 0.02-2 M.

[0194] Embodiment 67. The method according to any one of embodiments 64-66, wherein the fourth load solution contains a mineral acid equivalent to HCl.

[0195] Embodiment 68. The method according to any of the above embodiments, wherein the fourth eluent contains a weak acid.

[0196] Embodiment 69. The method according to Embodiment 68, wherein the fourth eluent containing the weak acid has a pH in the range of 1 to 5.5, 2-5, 3-5, 4-5 and / or 4.5.

[0197] Embodiment 70. The method according to any one of Embodiments 68-69, wherein the weak acid comprises a carboxylate group, a sulfate group, or a phosphoric acid group.

[0198] Embodiment 71. The method according to any one of Embodiments 68-70, wherein the weak acid comprises one or more salts of acetate, citric acid, and oxalic acid.

[0199] Embodiment 72. The method according to any one of Embodiments 68-71, wherein the weak acid comprises ammonium acetate.

[0200] Embodiment 73. The method according to any one of Embodiments 68-72, wherein the weak acid comprises concentrations of 0.1-2.0 M, 0.5-1.5 M, 0.75-1.25 M and / or about 1 M.

[0201] Embodiment 74. The method according to any of the above embodiments, wherein the fourth eluent contains a diluted mineral acid having a concentration of 0.1 M or less.

[0202] Embodiment 75. The method according to Embodiment 74, wherein the fourth eluent contains a diluted mineral acid comprising any of HNO3, HCl, HBr, HI, and H2SO4.

[0203] Embodiment 76. The method according to any one of Embodiments 74-75, wherein the fourth eluent contains a diluted mineral acid having a concentration in the range of 0.1 M or less, 0.001-0.1 M and / or 0.01-0.1 M.

[0204] Embodiment 77. The method according to any of the preceding embodiments, further comprising the step of rinsing one or more of the lead complex-forming medium of the first cartridge, the lead complex-forming medium of the fourth cartridge, and the weak cation exchange medium of the second cartridge with a rinsing solution to further elute one or more radium or thorium.

[0205] Embodiment 78. The method according to any of the preceding embodiments, further comprising the step of rinsing the strong cation exchange medium of the third cartridge with a rinse solution to further elute lead.

[0206] Embodiment 79. A method according to any of the preceding claims, further comprising:

[0207] (g) A step of loading a third load solution containing the first eluate into a third cartridge, wherein the third cartridge has a third chromatography medium comprising a strong cation exchange medium that preferentially binds to radioactive isotopes of radium or thorium rather than to the radioactive isotopes of lead in the presence of the load solution, thereby separating the radioactive isotopes of radium or thorium from the third load solution to form a third lead-containing solution having the radioactive isotopes of lead dissolved in the solution and having a reduced content of the radioactive isotopes of radium or thorium compared to the content of the radioactive isotopes of radium or thorium in the first eluate;

[0208] (h) A step of providing the third lead-containing solution as the second load solution to the second cartridge.

[0209] Embodiment 80. The method according to Embodiment 79, further comprising:

[0210] (i) A step of loading a fourth load solution containing a second eluent into a fourth cartridge, wherein the fourth cartridge has a fourth chromatography medium containing a lead complex-forming medium that preferentially binds to the lead radioactive isotope rather than to the radium and thorium radioactive isotopes in the presence of the fourth load solution, thereby separating the lead radioactive isotope from the fourth load solution.

[0211] (j) A step of eluting the bound lead radioactive isotope from the fourth cartridge using a fourth eluent to form a fourth eluent containing the lead radioactive isotope dissolved in the liquid.

[0212] Embodiment 81. An aqueous solution of a lead radioactive isotope obtained by any of the methods described in the previous embodiments.

[0213] Embodiment 82. A method for producing a radiopharmaceutical, comprising the step of introducing an unchelated radiopharmaceutical into an aqueous solution containing a fourth eluent to form a lead-chelated radiopharmaceutical.

[0214] Embodiment 83. A radiopharmaceutical prepared according to the method of Embodiment 82.

[0215] Embodiment 84. A system for separating lead radioactive isotopes from a mixture containing lead radioactive isotopes and radium isotopes or thorium isotopes, the system comprising a first cartridge and a second cartridge in series with respect to each other, the first cartridge and the second cartridge each having an inlet, an outlet, and a chamber between the inlet and the outlet containing a chromatography medium, where,

[0216] (a) The chamber of the first cartridge includes a first chromatography medium which includes a lead complex-forming medium which (i) preferentially binds to the lead radioactive isotope rather than the radium and thorium radioactive isotopes in the presence of a first load solution which includes the mixture, thereby separating the lead radioactive isotope from the first load solution, and (ii) elutes the lead radioactive isotope in the presence of a first eluent which includes the lead radioactive isotope dissolved in a second solution.

[0217] (b) The chamber of the second cartridge includes a second chromatography medium comprising a weak cation exchange medium, which (i) preferentially binds to the lead radioactive isotope rather than the radium and thorium radioactive isotopes from the second load solution containing the first eluate, thereby separating the lead radioactive isotope from the second load solution, and (ii) elutes the lead radioactive isotope in the presence of a second eluent to form a second eluate containing the lead radioactive isotope dissolved in the solution.

[0218] Here, the second load solution is pH2L The second eluent has a pH of 2E It has a pH of, 2L pH 2E Higher.

[0219] Embodiment 85. The first load solution has a pH 1L The first eluent has a pH of 1E It has a pH of, 1E pH 1L A higher-than-average system as described in embodiment 84.

[0220] Embodiment 86. A system according to any of Embodiments 84-85, further comprising:

[0221] (c) A third cartridge in series with the first and second cartridges, the third cartridge having an inlet, an outlet, and a chamber between the inlet and the outlet containing a chromatography medium, wherein the chamber of the third cartridge has a chromatography medium containing a strong cation exchange medium that passes through the lead radioactive isotopes in the third load solution, (i) preferentially binding to radium or thorium radioactive isotopes rather than the lead radioactive isotopes in the presence of a third load solution containing the second eluate, thereby separating the radium or thorium radioactive isotopes from the third load solution, and (ii) forming a third lead-containing solution having the lead radioactive isotopes dissolved in the solution and having a reduced content of the radium or thorium radioactive isotopes compared to the content of the radium or thorium radioactive isotopes in the second eluate.

[0222] Embodiment 87. The system described in Embodiment 86, further comprising:

[0223] (d) A fourth cartridge in series with the first, second, and third cartridges, the fourth cartridge having an inlet, an outlet, and a chamber between the inlet and the outlet containing a chromatography medium, wherein the chamber of the fourth cartridge has a chromatography medium containing a lead complexing medium, the fourth cartridge having a lead complexing medium that (i) preferentially binds to the lead radioactive isotopes rather than to the radium and thorium radioactive isotopes in the presence of a fourth load solution containing the third lead-containing solution, thereby separating the lead radioactive isotopes from the fourth load solution, and (ii) elutes the lead radioactive isotopes in the presence of a fourth eluent introduced into the lead complexing medium to form a fourth eluent containing the lead radioactive isotopes dissolved in the liquid.

[0224] Embodiment 88. The fourth load solution has a pH 4L The pH is as follows: The fourth eluent has pH 4E It has a pH of, 4E pH 4L A higher-than-average system as described in embodiment 87.

[0225] Embodiment 89. The system according to any one of embodiments 87-88, wherein the first cartridge contains a lead complexing medium of the same type as the lead complexing medium in the fourth cartridge.

[0226] Embodiment 90. The system according to any of the preceding embodiments, wherein the lead comprises lead-212 or lead-203.

[0227] Embodiment 91. The system according to any of the preceding embodiments, wherein radium exists in the form of radium-224 or radium-223.

[0228] Embodiment 92. The system according to any of the preceding embodiments, wherein thorium exists in the form of thorium-228 or thorium-232.

[0229] Embodiment 93. The system according to any of the above embodiments, wherein either or both of the first cartridge and the fourth cartridge include a lead complex-forming medium which is an ionically neutral medium.

[0230] Embodiment 94. The system according to any of the above embodiments, wherein either or both of the first cartridge and the fourth cartridge include a lead complexing medium containing one or more diglycolamide complexing sites and crown ether complexing sites.

[0231] Embodiment 95. The system according to any of the above embodiments, wherein either or both of the first and fourth cartridges comprise a lead complex-forming medium comprising one or more of 4,4'(5')-di-t-butylcyclohexano 18-crown-6, 4,4'(5')-di-t-butylcyclohexano 18-crown-6 (diluent: 1-octanol), and N,N,N'N'tetra-alkyldiglycoamides in isodecanol, where alkyl = identical or different linear or branched alkyl groups having 2-12 carbon atoms.

[0232] Embodiment 96. The system according to any of the above embodiments, wherein the second cartridge comprises a weak cation exchange medium containing carboxyalkyl ionized groups bonded to a silica-based support.

[0233] Embodiment 97. The system according to any of the above embodiments, wherein the second cartridge comprises a weak cation exchange medium containing a carboxymethyl functional group bonded to a silica-based support.

[0234] Embodiment 98. The system according to any of the above embodiments, wherein the third cartridge comprises a strong cation exchange medium containing a sulfonic acid group.

[0235] Embodiment 99. The system according to any of the above embodiments, wherein the third cartridge comprises a strong cation exchange medium sulfonic acid group bonded to divinylbenzene.

[0236] Embodiment 100. The lead complex-forming medium is a system according to any of the above embodiments, wherein the lead complex-forming medium preferentially binds to the lead radioactive isotope in the presence of a first load solution containing a mineral acid.

[0237] Embodiment 101. The system according to Embodiment 100, wherein the lead complex-forming medium preferentially binds to the lead radioactive isotope in the presence of a mineral acid containing any of HNO3, HCl, HBr, HI, and H2SO4.

[0238] Embodiment 102. The system according to any one of Embodiments 100-101, wherein the lead complex-forming medium preferentially binds to the lead radioactive isotope in the presence of a mineral acid having a concentration of 0.1-10 M, 0.1-8 M, 0.2-8 M, 0.5-5 M, 1-4 M, 1-3 M and / or about 2 M.

[0239] Embodiment 103. The lead complexing medium is a system according to any of the above embodiments, wherein the lead complexing medium elutes lead radioactive isotopes in the presence of a first eluent containing a weak acid.

[0240] Embodiment 104. The system according to Embodiment 103, wherein the lead complexing medium elutes lead radioactive isotopes in the presence of a weak acid having a pH in the range of 1-5.5, 2-5, 3-5, 4-5 and / or about 4.5.

[0241] Embodiment 105. The lead complexing medium is a system according to any one of Embodiments 103-104, wherein the lead complexing medium elutes lead radioactive isotopes in the presence of a weak acid containing a carboxylate group, a sulfate group, or a phosphate group.

[0242] Embodiment 106. The lead complexing medium is a system according to any one of Embodiments 103-105, wherein the lead complexing medium elutes lead radioactive isotopes in the presence of a weak acid containing one or more salts of acetate, citrate, and oxalic acid.

[0243] Embodiment 107. The lead complexing medium is a system according to any one of Embodiments 103-106, wherein the lead complexing medium elutes lead radioactive isotopes in the presence of a weak acid containing ammonium acetate.

[0244] Embodiment 108. The lead complex-forming medium is the system according to any one of Embodiments 103-107, which elutes lead radioisotopes in the presence of a weak acid having a concentration of 0.1 to 2.0 M, 0.5 - 1.5 M, 0.75 - 1.25 M, and / or about 1 M.

[0245] Embodiment 109. The lead complex-forming center (medial) is the system according to any of the preceding embodiments, which elutes lead radioisotopes in the presence of the first eluent containing a dilute mineral acid having a concentration of 0.1 M or less.

[0246] Embodiment 110. The lead complex-forming center (medial) is the system according to Embodiment 109, which elutes lead radioisotopes in the presence of a dilute mineral acid containing any one of HNO3, HCl, HBr, HI, and H2SO4.

[0247] Embodiment 111. The lead complex-forming medium is the system according to any one of Embodiments 109-110, which elutes lead radioisotopes in the presence of a first eluent containing a dilute mineral acid having a concentration in the range from 0.1 M or less, 0.001 - 0.1 M, and / or 0.01 - 0.1 M.

[0248] Embodiment 112. The weak cation exchange medium is the system according to any of the preceding embodiments, which preferentially binds to lead radioisotopes in the presence of a second loading solution corresponding to the first eluent.

[0249] Embodiment 113. The weak cation exchange medium is the system according to any of the preceding embodiments, which preferentially binds to lead radioisotopes in the presence of a second loading solution corresponding to the first eluent that is flowed without being changed from the first cartridge to the second cartridge.

[0250] Embodiment 114. The weak cation exchange medium is the system according to any one of Embodiments 84-112, which preferentially binds to lead radioisotopes in the presence of a second loading solution corresponding to the first eluent that has been changed before being loaded into the second cartridge to form the second loading solution.

[0251] Embodiment 115. The weak cation exchange medium is the system according to any of the previous embodiments that preferentially binds to lead radioisotopes in the presence of a second loading solution containing a weak acid.

[0252] Embodiment 116. The weak cation exchange medium is the system according to Embodiment 115 that preferentially binds to lead radioisotopes in the presence of a second loading solution containing a weak acid, the second loading solution containing a pH in the range of 1 to 5.5, 2 - 5, 3 - 5, 4 - 5, and / or 4.5.

[0253] Embodiment 117. The weak cation exchange medium is the system according to any of Embodiments 115 - 116 that preferentially binds to lead radioisotopes in the presence of a weak acid containing any one or more of carboxylate groups, sulfate groups, or phosphate groups.

[0254] Embodiment 118. The weak cation exchange medium is the system according to any of Embodiments 115 - 117 that preferentially binds to lead radioisotopes in the presence of a weak acid containing any one salt or a plurality of salts of acetate, citrate, and oxalate.

[0255] Embodiment 119. The weak cation exchange medium is the system according to any of Embodiments 115 - 118 that preferentially binds to lead radioisotopes in the presence of a weak acid containing ammonium acetate.

[0256] Embodiment 120. The weak cation exchange medium is the system according to any of Embodiments 115 - 119 that preferentially binds to lead radioisotopes in the presence of a weak acid containing a concentration of 0.1 to 2.0 M, 0.5 - 1.5 M, 0.75 - 1.25 M, and / or approximately 1 M.

[0257] Embodiment 121. The weak cation exchange medium is the system according to any of the previous embodiments that preferentially binds to lead radioisotopes in the presence of a second loading solution containing a diluted mineral acid having a concentration of 0.1 M or less.

[0258] Embodiment 122. The system according to Embodiment 121, wherein the weak cation exchange medium preferentially binds to lead radioactive isotopes in the presence of a second load solution containing a diluted mineral acid, which includes one of HNO3, HCl, HBr, HI, and H2SO4.

[0259] Embodiment 123. The system according to any one of Embodiments 121-122, wherein the weak cation exchange medium preferentially binds to lead radioactive isotopes in the presence of a second load solution containing a diluted mineral acid having a concentration in the range of 0.1 M or less, 0.001-0.1 M and / or 0.01-0.1 M.

[0260] Embodiment 124. The weak cation exchange medium is a system according to any of the above embodiments, wherein the weak cation exchange medium elutes lead radioactive isotopes in the presence of a second eluent containing a mineral acid.

[0261] Embodiment 125. The system according to Embodiment 124, wherein the weak cation exchange medium elutes lead radioactive isotopes in the presence of a second eluent containing any of HNO3, HCl, HBr, HI, and H2SO4.

[0262] Embodiment 126. The system according to any one of Embodiments 124-125, wherein the weak cation exchange medium elutes lead radioactive isotopes in the presence of a second eluent containing a mineral acid at concentrations of 0.01-5 M, 0.02-4 M, 0.02-3 M, and / or 0.02-2 M.

[0263] Embodiment 127. The system according to any one of Embodiments 124-126, wherein the weak cation exchange medium elutes lead radioactive isotopes in the presence of a second eluent containing a mineral acid at a concentration sufficient to form the anionic form of lead in liquid.

[0264] Embodiment 128. The anionic form of lead is PbCl4 2- A system according to any of embodiments 124-127, including the system described above.

[0265] Embodiment 129. The system according to any one of Embodiments 124-128, wherein the weak cation exchange medium elutes lead radioactive isotopes in the presence of a second eluent containing a mineral acid equivalent to HCl.

[0266] Embodiment 130. The system according to any of the above embodiments, wherein the strong cation exchange resin preferentially binds to the radioactive isotopes of radium and thorium in a third load solution corresponding to the second eluent.

[0267] Embodiment 131. The system according to any of the above embodiments, wherein the strong cation exchange resin preferentially binds to the radioactive isotopes of radium and thorium in a second eluent that flows from the second cartridge to the third cartridge without modification.

[0268] Embodiment 132. The system according to any of Embodiments 84-129, wherein the strong cation exchange resin preferentially binds to the radioactive isotopes of radium and thorium in a second eluent that is modified before being loaded into the third cartridge to form a third load solution.

[0269] Embodiment 133. The system according to any of the preceding embodiments, wherein the strong cation exchange resin preferentially binds to radioactive isotopes of radium and thorium in the presence of a third load solution containing a mineral acid.

[0270] Embodiment 134. The system according to Embodiment 133, wherein the strong cation exchange resin preferentially binds to radioactive isotopes of radium and thorium in the presence of a third load solution containing any of HNO3, HCl, HBr, HI, and H2SO4.

[0271] Embodiment 135. The system according to any one of Embodiments 133-134, wherein the strong cation exchange resin preferentially binds to radioactive isotopes of radium and thorium in the presence of a third load solution containing a mineral acid at concentrations of 0.01-5 M, 0.02-4 M, 0.02-3 M and / or 0.02-2 M.

[0272] Embodiment 136. The system according to any one of Embodiments 133-135, wherein the strong cation exchange resin preferentially binds to the radioisotopes of radium and thorium in the presence of a third loading solution containing a mineral acid at a concentration sufficient to form anionic forms of lead in the liquid.

[0273] Embodiment 137. The anionic form of lead is PbCl4 2- The system according to any one of Embodiments 133-136, which contains

[0274] Embodiment 138. The system according to any one of Embodiments 133-137, wherein the strong cation exchange resin preferentially binds to the radioisotopes of radium and thorium in the presence of a third loading solution containing a mineral acid corresponding to HCl.

[0275] Embodiment 139. The system according to any of the preceding embodiments, wherein the lead complexing resin of the fourth cartridge preferentially binds to the lead radioisotope in the presence of a third lead-containing solution directly flowing from the third cartridge to the fourth cartridge.

[0276] Embodiment 140. The system according to any of the preceding embodiments, wherein the system includes a conduit configured to directly flow the third lead-containing solution to the fourth cartridge.

[0277] Embodiment 141. The system according to any of the preceding embodiments, wherein the lead complexing resin of the fourth cartridge preferentially binds to the lead radioisotope in the presence of a third lead-containing solution flowing from the third cartridge to the fourth cartridge without being changed.

[0278] Embodiment 142. The system according to any of Embodiments 84-140, wherein the lead complexing resin of the fourth cartridge preferentially binds to the lead radioisotope in the presence of a third lead-containing solution that is changed before being loaded into the fourth cartridge to form a fourth loading solution.

[0279] Embodiment 143. The system according to any of the preceding embodiments, wherein the lead complex-forming medium of the fourth cartridge preferentially binds to lead radioactive isotopes in the presence of a fourth load solution containing a mineral acid.

[0280] Embodiment 144. The system according to Embodiment 143, wherein the lead complexing medium of the fourth cartridge preferentially binds to lead radioactive isotopes in the presence of a fourth load solution containing any of HNO3, HCl, HBr, HI, and H2SO4.

[0281] Embodiment 145. The system according to any one of Embodiments 143-144, wherein the lead complexing medium of the fourth cartridge preferentially binds to lead radioactive isotopes in the presence of a fourth load solution containing a mineral acid at concentrations of 0.01-5 M, 0.02-4 M, 0.02-3 M, and / or 0.02-2 M.

[0282] Embodiment 146. The system according to any one of Embodiments 143-145, wherein the lead complex-forming medium of the fourth cartridge preferentially binds to lead radioactive isotopes in the presence of a fourth load solution containing a mineral acid equivalent to HCl.

[0283] Embodiment 147. The lead complex-forming medium of the fourth cartridge is a system according to any of the preceding embodiments, wherein the lead complex-forming medium preferentially binds to lead radioactive isotopes in the presence of a fourth eluent containing a weak acid.

[0284] Embodiment 148. The system according to Embodiment 147, wherein the lead complexing medium of the fourth cartridge preferentially binds to lead radioactive isotopes in the presence of a fourth eluent containing a weak acid having a pH in the range of 0.1–2.0 M, 0.5–1.5 M, 0.75–1.25 M and / or about 1 M.

[0285] Embodiment 149. The system according to any one of Embodiments 147-148, wherein the lead complex-forming medium of the fourth cartridge preferentially binds to lead radioactive isotopes in the presence of a weak acid containing a carboxylate group, a sulfate group, or a phosphate group.

[0286] Embodiment 150. The system according to any of Embodiments 147-149, wherein the lead complex-forming medium of the fourth cartridge preferentially binds to lead radioactive isotopes in the presence of a weak acid containing one or more salts of acetate, citrate, and oxalic acid.

[0287] Embodiment 151. The system according to any one of Embodiments 147-150, wherein the lead complex-forming medium of the fourth cartridge preferentially binds to lead radioactive isotopes in the presence of a weak acid containing ammonium acetate.

[0288] Embodiment 152. The system according to any of Embodiments 147-151, wherein the lead complexing medium of the fourth cartridge preferentially binds to lead radioactive isotopes in the presence of a weak acid containing concentrations of 0.1-2.0 M, 0.5-1.5 M, 0.75-1.25 M and / or about 1 M.

[0289] Embodiment 153. The lead complexing medium of the fourth cartridge is a system according to any of the above embodiments, wherein the lead radioactive isotopes are eluted in the presence of a fourth eluent containing a diluted mineral acid having a concentration of 0.1 M or less.

[0290] Embodiment 154. The system according to Embodiment 153, wherein the lead complexing medium of the fourth cartridge elutes lead radioactive isotopes in the presence of a fourth eluent containing a dilution mineral acid which includes one of HNO3, HCl, HBr, HI, and H2SO4.

[0291] Embodiment 155. The system according to any one of Embodiments 153-154, wherein the lead complexing medium of the fourth cartridge elutes lead radioactive isotopes in the presence of a fourth eluent containing a diluted mineral acid having a concentration of 0.1 M or less, 0.001-0.1 M and / or 0.01-0.1 M.

[0292] Embodiment 156. A system according to any of the embodiments described above, wherein the system is configured to contain, and includes rinsing one or more of the lead complexing medium of the first cartridge, the lead complexing medium of the fourth cartridge, and the weak cation exchange medium of the second cartridge with a rinsing solution to further elute one or more of radium or thorium.

[0293] Embodiment 157. The system according to any of the above embodiments, wherein the system is configured to perform a step of rinsing the strong cation exchange medium of the third cartridge with a rinse solution in order to further elute lead.

[0294] Embodiment 158. A system according to any of the embodiments described above, comprising:

[0295] A third cartridge in series with the first and second cartridges, comprising an inlet, an outlet, and a chamber between the inlet and the outlet containing a chromatography medium, wherein the chamber of the third cartridge comprises a chromatography medium containing a strong cation exchange medium that passes through the lead radioactive isotopes in the third load solution, (i) preferentially binding to radium or thorium radioactive isotopes rather than the lead radioactive isotopes in the presence of the third load solution containing the first eluate, thereby separating the radium or thorium radioactive isotopes from the third load solution, and (ii) forming a third lead-containing solution having the lead radioactive isotopes dissolved in the solution and having a reduced radium or thorium radioactive isotope content compared to the radium or thorium radioactive isotope content in the first eluate,

[0296] Here, the second cartridge is configured to receive the third lead-containing solution in the second load solution, and the weak cation exchange resin of the second cartridge preferentially binds to lead isotopes in the presence of the third lead-containing solution.

[0297] Embodiment 159. The system described in Embodiment 158, further comprising:

[0298] A fourth cartridge in series with the first, second, and third cartridges, the fourth cartridge having an inlet, an outlet, and a chamber between the inlet and the outlet containing a chromatography medium, wherein the chamber of the fourth cartridge has a chromatography medium containing a lead complexing medium that (i) preferentially binds to the lead radioactive isotopes rather than to the radioactive isotopes of radium and thorium in the presence of a fourth load solution containing a second eluent, thereby separating the lead radioactive isotopes from the fourth load solution, and (ii) elutes the lead radioactive isotopes in the presence of a fourth eluent introduced into the lead complexing medium to form a fourth eluent containing the lead radioactive isotopes dissolved in the liquid. [Reference List:] [1]WO2024 / 05018 [2] Horwitz et al., “A Lead-Selective Extraction Chromatographic Resin and its Application to Isolation of Lead from Geological Samples,” Analytica Chimica Acta, 292, (1994), 263-273. [3] Horwitz et al., “A Novel Strontium-Selective Extraction Chromatographic Resin”, Solvent Extraction and Ion Exchange, Vol. 10, (No. 2), (1992). [4] McNeil et al., “Optimized Production, Purification, and Radiolabeling of the 203Pb / 2212Pb Theranostic Pair for Nuclear Medicine,” Nature Scientific Reports, 13, (2023), 10623. [5]McAlisterら、“Chromatographic Generator Systems for Actinides and Natural Decay Series Elements”、Radiochim. Acta、99、(2011)、151-159. [6]Sainiら、“Optimized Methods for the Production of High Purity 203Pb Using Electroplated Thallium Targets”、J. Nucl. Med.、64、(2023)、1791-1797.

Claims

1. A method for separating lead radioactive isotopes from a mixture containing lead radioactive isotopes and radium or thorium radioactive isotopes, (a) A step of loading a first load solution containing the mixture into a first cartridge, wherein the first cartridge contains a first chromatography medium containing a lead complex-forming medium that preferentially binds to the lead radioactive isotope rather than the radium and thorium radioactive isotopes in the presence of the first load solution, thereby binding the lead radioactive isotope to the lead complex-forming medium and separating it from the first load solution, (b) A step of eluting the bound lead radioactive isotope from the first cartridge using a first eluent to form a first eluent containing the lead radioactive isotope dissolved in the liquid, (c) A step of loading a second load solution containing the first eluate into a second cartridge, wherein the second cartridge has a second chromatography medium containing a weak cation exchange medium that preferentially binds to the lead radioactive isotope rather than the radium and thorium radioactive isotopes in the presence of the second load solution, thereby binding the lead radioactive isotope to the weak cation exchange medium and separating it from the second load solution, (d) A step of eluting the lead radioactive isotope from the second cartridge using a second eluent so as to form a second eluent containing the lead radioactive isotope dissolved in the liquid, Includes, The second load solution has a pH ２Ｌ The second eluent has a pH of ２Ｅ It has a pH of ２Ｌ pH ２Ｅ A higher method.

2. The method according to claim 1, wherein the first load solution passing through the first cartridge is treated to further bind lead isotopes to the lead complex-forming medium, and is returned to the first cartridge for recycling or discarded.

3. The method according to claim 1, wherein the second load solution passing through the second cartridge is returned to the first cartridge and recycled to further bind lead isotopes to the lead complex-forming medium, or is treated to further bind lead isotopes to the weak cation exchange medium, and then returned to the second cartridge and recycled, or discarded.

4. The first load solution has a pH １Ｌ The first eluent has a pH of １Ｅ It has a pH of １Ｅ pH １Ｌ A higher method according to claim 1.

5. (e) A step of loading a third load solution containing the second eluate into a third cartridge, wherein the third cartridge has a third chromatography medium comprising a strong cation exchange medium that preferentially binds to radioactive isotopes of radium or thorium rather than to the radioactive isotopes of lead in the presence of the third load solution, thereby separating the radioactive isotopes of radium or thorium from the third load solution to form a third lead-containing solution having the radioactive isotopes of lead dissolved in the solution and having a reduced content of the radioactive isotopes of radium or thorium compared to the content of the radioactive isotopes of radium or thorium in the second eluate. The method according to any one of claims 1-4, further comprising:

6. The method according to claim 5, wherein the third lead-containing solution flowing out of the third cartridge is optionally returned to the third cartridge and recycled in order to further reduce the content of radioactive isotopes of radium or thorium in the third lead-containing solution.

7. (f) A step of loading a fourth load solution containing the third lead-containing solution into a fourth cartridge, wherein the fourth cartridge has a fourth chromatography medium containing a lead complex-forming medium that preferentially binds to the lead radioactive isotope rather than to the radium and thorium radioactive isotopes in the presence of the fourth load solution, thereby separating the lead radioactive isotope from the fourth load solution. (b) A step of eluting the bound lead radioactive isotope from the fourth cartridge using the fourth eluent to form a fourth eluent containing the lead radioactive isotope dissolved in the liquid, The method according to any one of claims 5-6, further comprising:

8. The method according to claim 7, wherein the fourth load solution passing through the fourth cartridge is treated to further separate lead isotopes therefrom and recycled by being returned to the first or fourth cartridge, or recycled by being returned to the second cartridge to further separate lead isotopes therefrom, or discarded.

9. The fourth loading solution has a pH ４Ｌ and the fourth eluent has a pH ４Ｅ , and the pH ４Ｅ is higher than the pH ４Ｌ The method according to any one of claims 7-8.

10. The method according to any one of claims 1 to 9, wherein the first cartridge contains a lead complex-forming medium of the same type as the lead complex-forming medium in the fourth cartridge.

11. A system for separating lead radioactive isotopes from a mixture containing lead radioactive isotopes and radium or thorium isotopes, The system includes a first cartridge and a second cartridge arranged in series with respect to each other, and each of the first and second cartridges has an inlet, an outlet, and a chamber between the inlet and the outlet containing a chromatography medium. (a) The chamber of the first cartridge includes a first chromatography medium which includes a lead complexing medium which (i) preferentially binds to the lead radioactive isotope rather than the radium and thorium radioactive isotopes in the presence of a first load solution which includes the mixture, thereby separating the lead radioactive isotope from the first load solution, and (ii) elutes the lead radioactive isotope in the presence of a first eluent which includes the lead radioactive isotope dissolved in a second solution. (b) The chamber of the second cartridge includes a second chromatography medium which includes a weak cation exchange medium which (i) preferentially binds to the lead radioactive isotope rather than the radium and thorium radioactive isotopes from the second load solution which includes the first eluate, thereby separating the lead radioactive isotope from the second load solution, and (ii) elutes the lead radioactive isotope in the presence of a second eluent to form a second eluate which contains the lead radioactive isotope dissolved in the solution. The second load solution has a pH ２Ｌ The second eluent has a pH of ２Ｅ It has a pH of ２Ｌ pH ２Ｅ A higher-level system.

12. The first load solution has a pH １Ｌ The first eluent has a pH of １Ｅ It has a pH of １Ｅ pH １Ｌ A higher, more advanced system according to claim 11.

13. (c) A third cartridge in series with the first and second cartridges, having an inlet, an outlet, and a chamber between the inlet and the outlet containing a chromatography medium, wherein the chamber of the third cartridge has a chromatography medium containing a strong cation exchange medium that passes through the lead radioactive isotopes in the third load solution, (i) preferentially binding to radium or thorium radioactive isotopes rather than the lead radioactive isotopes in the presence of a third load solution containing the second eluate, thereby separating the radium or thorium radioactive isotopes from the third load solution, and (ii) forming a third lead-containing solution having the lead radioactive isotopes dissolved in the solution and having a reduced radium or thorium radioactive isotope content compared to the radium or thorium radioactive isotope content in the second eluate. The system according to at least one of claims 11-12, further comprising:

14. (d) A fourth cartridge in series with the first, second, and third cartridges, having an inlet, an outlet, and a chamber between the inlet and the outlet containing a chromatography medium, wherein the chamber of the fourth cartridge has a chromatography medium containing a lead complexing medium that (i) preferentially binds to the lead radioactive isotopes rather than to the radioactive isotopes of radium and thorium in the presence of a fourth load solution containing the third lead-containing solution, thereby separating the lead radioactive isotopes from the fourth load solution, and (ii) elutes the lead radioactive isotopes in the presence of a fourth eluent introduced into the lead complexing medium to form a fourth eluent containing the lead radioactive isotopes dissolved in the liquid. The system according to claim 13, further comprising:

15. The pH of the fourth load solution is ４Ｌ The pH is as follows: The fourth eluent has pH ４Ｅ It has a pH of ４Ｅ pH ４Ｌ A higher, more advanced system according to claim 14.

16. The system according to any one of claims 14-15, wherein the first cartridge includes a lead complex-forming medium of the same type as the lead complex-forming medium in the fourth cartridge.

17. The system according to any one of claims 11-16, wherein the lead comprises lead-212 or lead-203.

18. The system according to any one of claims 11-17, wherein radium exists in the form of radium-224 or radium-223.

19. The system according to any one of claims 11-18, wherein thorium exists in the form of thorium-228 or thorium-232.

20. The system according to any one of claims 14-19, wherein either or both of the first cartridge and the fourth cartridge include a lead complex-forming medium which is an ionically neutral medium.

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