System and method for producing lead

Abstract

The present invention provides a method for separating lead radioisotopes from a mixture comprising lead radioisotopes and radium or thorium radioisotopes, and a system comprising a plurality of chromatography columns. The system can comprise a first cartridge column having a lead complexing medium that preferentially binds lead radioisotopes over radium or thorium radioisotopes; and a second cartridge column having a weak cation exchange medium, wherein the pH of a loading solution used to load the second cartridge column is pH 2L , the pH of an eluent used to elute lead radioisotopes from the second cartridge column is pH 2E , and the pH 2L is greater than pH 2E . The system can further comprise a third cartridge column and a fourth cartridge column having chromatographic media to extract and purify lead radioisotopes, thereby providing a purified solution of lead radioisotopes that can be used for medical and other purposes, such as for labeling radiopharmaceutical compounds.

Description

[0001] This application is a divisional application of Chinese patent application 202480023651.4, which was filed on August 15, 2024, and is entitled "System and method for producing lead".

[0002] Cross-references to related applications

[0003] This application claims priority to U.S. Provisional Application No. 63 / 519,817, filed August 15, 2023, the entire contents of which are incorporated herein by reference.

[0004] Statement on Federally Funded Research

[0005] The work disclosed in this application was partially accomplished with funding from the National Institutes of Health (NIH) Small Business Innovation Research (SBIR) program, grant numbers R44CA250872 and R44CA254613. The government holds certain rights to this invention.

[0006] References

[0007] All publications and patent applications mentioned in this specification are incorporated herein by reference in their entirety, to the same extent that each individual publication or patent application is specifically and individually indicated to be incorporated herein by reference. Technical Field

[0008] This application 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 for use in nuclear medicine, molecular imaging, therapy, and radiopharmacy. Background Technology

[0009] Nuclear medicine uses radioactive atoms for diagnosis and treatment, referred to as radionuclides or isotopes. Radionuclides used for these purposes can be linked to ligands (such as peptides, antibodies, and small molecules), which can specifically target the radionuclides to specific tissues or cells. Isotopes of lead (Pb) include lead-212 (Pb-212) and lead-203 (Pb-203), which have become effective radionuclide pairs for targeted radioligand therapy and imaging, respectively.

[0010] The industrialization of drugs based on Pb-212 and Pb-203 requires the production of large quantities of these radionuclides, which presents numerous challenges, including but not limited to chemical separation, radiation degradation damage to materials, radiation safety issues, and transportation. Pb-212 is a product of the decay of natural thorium-232 (Th-232). Because Th-232 has a very long half-life (t... 1 / 2 = 1.4x10 10The amount of Th-232 required to prepare medically relevant amounts of Pb-212 (i.e., mCi to Ci amounts) is many times greater than that of Th-232. Therefore, other methods for preparing Pb-212 via a shorter-lived parent are more desirable. Radium (Ra) isotopes (Ra-224, t...) with convenient half-lives... 1 / 2 (3.63 days) can serve as a useful intermediate for obtaining Pb-212, but it can exhibit strong radiodegradability, making it difficult to store and handle. Therefore, to develop a large-scale supply of Pb-212, new methods and systems are needed that can overcome the effects of radiodegradation and facilitate industrial-scale production. Summary of the Invention

[0011] Various embodiments of the present invention relate to systems and methods for separating, purifying, and generating lead radioisotopes from radioactive isotopes of radium.

[0012] On one hand, embodiments of the present invention relate to a method for separating lead radioisotopes from a mixture comprising lead radioisotopes and radioisotopes of radium or thorium, the method comprising: (a) loading a first cartridge column with a first loading solution comprising the mixture, the first cartridge column containing a first chromatographic medium comprising a lead complexing medium that, in the presence of the first loading solution, preferentially binds lead radioisotopes to the lead complexing medium rather than to the radioisotopes of radium and thorium, such that the lead radioisotopes bind to the lead complexing medium and are separated from the first loading solution; and (b) eluting the bound lead radioisotopes from the first cartridge column with a first eluent, thereby forming a first eluent. (c) A first eluent contains a lead radioisotope dissolved in the first eluent; (d) a second cassette column is loaded with a second loading solution containing the first eluent, the second cassette column having a second chromatographic medium containing a weak cation exchange medium that preferentially binds the lead radioisotope to the weak cation exchange medium in the presence of the second loading solution, so that the lead radioisotope binds to the weak cation exchange medium and separates from the second loading solution; and (e) the lead radioisotope is eluted from the second cassette column with a second eluent, thereby forming a second eluent containing a lead radioisotope dissolved in the second eluent, wherein the second loading solution has a pH, i.e., pH 2L The second eluent has a pH value, i.e., pH 2E ; and pH 2L greater than pH 2E .

[0013] On the other hand, embodiments of the present invention relate to a system for separating lead radioisotopes from a mixture comprising lead radioisotopes and radium or thorium radioisotopes, the system comprising a first cassette column and a second cassette column connected in series, each having an inlet, an outlet, and a chamber containing a chromatographic medium located between them, wherein: (a) the chamber in the first cassette column contains a first chromatographic medium comprising a lead complexing medium, the lead complexing medium (i) preferentially binds lead radioisotopes to the radioisotopes of radium and thorium in the presence of a first loading solution containing the mixture, thereby separating lead radioisotopes from the first loading solution, and (ii) in a first wash... (a) Lead radioisotopes are eluted in the presence of a desiccant, thereby forming a first eluent containing lead radioisotopes dissolved in a second solution; and (b) the chamber in the second cassette column contains a second chromatographic medium comprising a weak cation exchange medium, which (i) preferentially binds lead radioisotopes from the second loading solution containing the first eluent compared to radioisotopes of radium and thorium, thereby separating lead radioisotopes from the second loading solution, and (ii) lead radioisotopes are eluted in the presence of a second eluent, thereby forming a second eluent containing lead radioisotopes dissolved in the second eluent, wherein the second loading solution has a pH, i.e., pH 2L The second eluent has a pH value, i.e., pH 2E ; and pH 2L greater than pH 2E . Attached Figure Description

[0014] The features and advantages of the methods and apparatus described in this invention will be better understood below through a detailed description of exemplary embodiments and accompanying drawings, in which: Figure 1 The flowchart, according to one embodiment, shows the steps of separating a lead radioisotope (e.g., Pb-212) from a mixture containing a lead radioisotope and a radium radioisotope (e.g., Ra-224) or a thorium radioisotope (e.g., Th-228) using two tandem ferrule columns for separation.

[0015] Figure 2 The flowchart, according to one embodiment, shows the steps of separating a lead radioisotope (e.g., Pb-212) from a mixture containing a lead radioisotope and a radium radioisotope (e.g., Ra-224) or a thorium radioisotope (e.g., Th-228) using up to four tandem cassette columns for separation.

[0016] Figure 3 This is a flowchart showing the steps for separating Pb-212 from a liquid source of Ra-224 according to Example 1.

[0017] Figure 4a and 4b This is a graph showing the Pb% penetration and radiochemical purity of the Pb-212 product as a function of Pb% according to Example 1.

[0018] Figure 5 This is a flowchart showing the steps for separating Pb-212 from a liquid source of Ra-224 according to Example 2.

[0019] Figure 6a and 6b This is a graph showing the Pb% penetration and radiochemical purity of the Pb-212 product as a function of Pb% according to Example 2.

[0020] Figure 7 This is a flowchart showing the steps for separating Pb-212 from a liquid source of Ra-224 according to Example 3.

[0021] Figure 8a and 8b This is a graph showing the Pb% transmittance and radiochemical purity of the Pb-212 product as a function of Pb% according to Example 3. Detailed Implementation

[0022] The terms “comprising,” “having,” “including,” and “containing,” and their grammatical variations, as used herein, are inclusive or open-ended and do not exclude additional, unspecified elements and / or method steps, even if the feature / component is defined as being part of or substantially composed of the defined feature(s) and / or component(s). The term “substantially composed of” as used herein with respect to a compound, composition, use, or method indicates that additional elements and / or method steps may be present, but these additional conditions do not materially affect the function of the compound, composition, method, or use. If used herein with respect to a feature of a compound, composition, use, or method, the term “composed of” indicates that no additional elements and / or method steps are present in that feature. A compound, composition, use, or method described herein as comprising certain elements and / or steps may also be substantially composed of those elements and / or steps in some embodiments, and in other embodiments, whether or not those embodiments are specifically specified. The uses or methods described herein that include certain elements and / or steps may also consist substantially of these elements and / or steps in some embodiments and in other embodiments, whether or not such embodiments are specifically indicated.

[0023] When the indefinite article “a” is used to describe an element, the possibility of more than one element is not excluded, unless it is explicitly required that there is one and only one element. Unless otherwise expressly stated, the singular forms “a,” “an,” and “the” include the plural forms. When the words “a” or “an” are used with the term “comprising,” they can mean “single,” but also encompass the meanings of “one or more,” “at least one,” and “one or more.”

[0024] In this invention, the numerical range defined by the endpoints includes all numerical values ​​within that range, including all real numbers, all integers, and, where appropriate, all fractional intermediate values ​​(e.g., the range of 1 to 5 may include 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5, etc.).

[0025] Unless otherwise stated, the terms “certain embodiments,” “various embodiments,” “one embodiment,” and similar terms include specific features described alone or in combination with any one or more other embodiments described herein, whether or not directly or indirectly referencing other embodiments, and regardless of whether that feature or embodiment has been described in the content of a method, product, use, composition, compound, etc.

[0026] The terms “treatment” (in both verb and noun forms) and “therapeutic” as used in this article include relieving symptoms, reducing disease progression, improving prognosis, and reducing recurrence.

[0027] The term "diagnostic agent" as used in this document includes "imaging agent". Therefore, "diagnostic radionuclide" includes radionuclides applicable to imaging agents.

[0028] The term "subject" refers to an animal (e.g., a mammal or a non-mammal). A subject can be a human or a non-human primate. A subject can be a laboratory mammal (e.g., a mouse, rat, rabbit, hamster, etc.). A subject can be an agricultural animal (e.g., a horse, sheep, cattle, pig, camel, etc.) or livestock (e.g., a dog, cat, etc.). In some implementations, the subject is a human.

[0029] The terms “salt” and “solvent” as used herein have their common meanings in chemistry. Thus, when a compound is a salt or solvate, it associates with a suitable counterion. How to prepare salts or exchange counterions is known in the art. Generally, said salts can be prepared by reacting these compounds in free acid form with a stoichiometric amount of a suitable base (e.g., but not limited to: hydroxides of Na, Ca, Mg, or K, carbonates, bicarbonates, etc.), or by reacting these compounds in free base form with a stoichiometric amount of a suitable acid. These reactions are typically carried out in water or organic solvents, or mixtures of both. Counterions can be exchanged, for example by ion exchange techniques, such as ion exchange chromatography. Unless a specific form is specifically specified, all zwitterions, salts, solvates, and counterions can be considered.

[0030] In some embodiments, the salt or counterion may be pharmaceutically acceptable for administration to a subject. As used herein, “pharmaceutically acceptable” means suitable for use in a subject, but is not necessarily limited to therapeutic use and may also include diagnostic use. More generally, non-limiting examples of suitable excipients for any pharmaceutical composition disclosed herein include any suitable buffers, stabilizers, salts, antioxidants, complexing agents, tonics, cryoprotectants, solubilizers, suspending agents, emulsifiers, antimicrobial agents, preservatives, chelating agents, binders, surfactants, wetting agents, non-aqueous media such as fixed oils, or polymers for sustained or controlled release. See, for example, Berge et al., 1977. (J. PharmSci. 66: 1–19), or Remington—The Science and Practice of Pharmacy, 21st edition (edited by Gennaro et al., Lippincott Williams & Wilkins Philadelphia), each incorporated herein by reference.

[0031] As used herein, the term "alkyl" encompasses a saturated straight-chain or branched carbon group having, for example, 1 to 20 carbon atoms, or, in a particular embodiment, 1 to 12 carbon atoms. In other embodiments, alkyl is a "lower alkyl" having 1 to 6 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, ethylhexyl, octyl, etc.

[0032] As used herein, the term "eluent" encompasses solutions used to remove substances (e.g., lead or lead radioisotopes) adsorbed and / or bound to the chromatographic medium. In some embodiments, the eluent replaces (e.g., via ion exchange) or interferes with the bond between the substance (e.g., lead or lead radioisotopes) and the chromatographic medium (e.g., stationary phase), such that the substance elutes together with the eluent (e.g., mobile phase) from a ferrule column or column containing the chromatographic medium. According to some embodiments, the eluent may comprise, for example, a solution containing a weak acid and / or an inorganic acid.

[0033] As used herein, the term "eluent" encompasses the mobile phase that elutes from a cassette column or ferrule containing chromatographic media, for example, during elution with an eluent added to the column or ferrule. In some embodiments, the eluent will contain a substance (e.g., lead or a lead radioisotope) adsorbed and / or bound to the chromatographic media, dissolved in a solution used to elute these substances from the column or ferrule.

[0034] As used herein, the term "system" refers to the entirety of the physical components of the present invention for the separation, purification, and generation of lead. This system includes, for example, containers, reagents, resin materials, ferrule columns, tubing, pumps, and automation systems.

[0035] As used in this article, lead (Pb) refers to the element lead and its radioactive and observed stable isotopes. Pb isotopes 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.

[0036] As used in this article, radium (Ra) refers to the element radium and its isotopes, including but not limited to Ra-223, Ra-224, Ra-225, Ra-226, Ra-227, Ra-228, Ra-229, and Ra-230.

[0037] The term thorium (Th) as used in this article refers to the element thorium and its isotopes, including but not limited to Th-228, Th-232, Th-230, Th-227, Th-229, Th-231, Th-233, and Th-234.

[0038] As used herein, the term "cassette column" refers to a pre-assembled container filled with resin for separation and extraction, which serves as a reaction vessel in which the solution and eluent interact with the resin and analyte. The terms "cassette column" and "column" are used interchangeably.

[0039] The terms “adsorbed onto,” “adsorbed onto…,” and “adsorbed on” used in this article are used interchangeably and all refer to the adsorption of an element onto the resin in the ferrule column.

[0040] As used herein, the term "chromatographic medium" refers to a solid material, such as a resin or matrix, packed in a ferrule column containing chemical reagents and extractants, used to extract or separate specific elements under various liquid conditions through a wide range of chemical mechanisms. Here, chromatographic media includes, but is not limited to, extraction chromatographic resins, ion exchange resins, and other media used for chemical separation.

[0041] As used herein, the term “lead complexing medium” encompasses a medium, such as a resin or matrix, that has an affinity for lead and preferentially binds to lead compared to certain other chemicals such as radium and / or thorium. According to some embodiments, the lead complexing medium may comprise a connected structural portion that binds to lead by forming a chemical complex with it, in contrast to ion exchange interactions based on the charge of lead ions. For example, the lead complexing medium may comprise a connected structural portion that is an uncharged / ionically neutral medium in aqueous solution. According to one embodiment, the lead complexing medium may comprise a crown ether-complexing structural portion comprising 4,4'(5')-di-tert-butylcyclohexano-18-crown ether-6 (also referred to herein as “Pb resin”) diluted in isodecanol and 4,4'(5')-di-tert-butylcyclohexano-18-crown ether-6 (also referred to herein as “Sr resin”) diluted in 1-octanol.

[0042] As used herein, the term "weak cation exchange medium" encompasses a medium, such as a resin or matrix, that preferentially binds to the species of interest via a weak acid group based on its affinity for the cationic form of the species. According to certain embodiments, the weak cation exchange medium includes a weak acid-linked structural portion that interacts with the cationic species via ionic interactions, thereby binding to the cationic species. For example, the weak cation exchange medium has a weak acid-linked structural portion, such as a carboxylic acid and / or carboxylate group, which carries a negative charge at higher pH (which may be acidic) and is neutral at lower pH; other weak acid groups are also suitable. According to certain embodiments, the weak cation exchange medium may contain a carboxyl alkyl group, such as carboxymethyl or carboxyethyl, linked to a silica support, including, for example, CM-silica, BioSuite CM, and Sep-PakAccell.

[0043] As used herein, the term "strong cation exchange medium" encompasses a medium, such as a resin or matrix, that preferentially binds the species of interest via strong acid groups based on its affinity for the cationic form of the substance of interest. According to some embodiments, a strong cation exchange medium includes a strongly acid-linked structural portion that interacts with the cationic species via ionic interactions, thereby binding the cationic species. For example, a strong cation exchange medium includes a strongly acid-linked structural portion, such as sulfonic acid and / or sulfonate groups, which ionize over a wide pH range (and thus bind cations over a wide pH range). According to some embodiments, a strong cation exchange medium may include sulfonic acid functional groups linked to a support, such as a divinylbenzene copolymer lattice, including, for example, MP-50 and AG-50Wx8.

[0044] As used in this article, the term "generator" refers to a system used to produce radionuclides. Generators are typically based on parent-daughter nuclide pairs, in which a longer-lived parent isotope (e.g., Ra-224) decays into a shorter-lived daughter isotope (e.g., Pb-212), which is suitable for a given application (e.g., nuclear medicine).

[0045] As used in this article, a container refers to a physical vessel that holds materials in liquid, semi-solid, or solid form. The terms "container" and "vessel" are used interchangeably.

[0046] Chromatographic media and ferrule column

[0047] In this invention, various chromatographic media are used in cassette columns. According to some embodiments, the media may comprise a stationary phase material, such as a solid resin or other matrix material, which is functionalized or has interacting chemical structural moieties and preferentially binds certain materials, such as lead. For example, the chromatographic media may be a medium with an affinity for certain chemical species (e.g., lead), such that when a solution containing that chemical species is introduced into a cassette column containing the medium, the medium binds (absorbs) and retains those species, thereby separating the species in the solution from other species to which the medium has no affinity, and allowing those other species to pass through the medium unbound. Species bound to the medium can subsequently be eluted or released from the medium on the cassette column by introducing an eluent into the medium containing a chemical composition that can separate the chemical species from the medium. According to certain embodiments, the chromatographic medium comprises any inert, inorganic (e.g., silica or alumina particles, or silica gel), organic (e.g., polymer), or inorganic-organic solid support that is functionalized with organic molecules, for example by grafting or impregnation, which retains the chemical species of interest (e.g., lead ions (Pb)) through ion exchange, extraction, molecular recognition, or any other mechanism. 2+ )).

[0048] According to one embodiment, the medium comprises a lead-complexing medium that has an affinity for lead and preferentially binds to lead compared to certain other chemical species such as radium and / or thorium. According to some embodiments, the lead-complexing medium may comprise a linked structural portion capable of binding to lead by forming a complex with lead, contrary to ion exchange interactions based on the charge of lead ions. For example, the lead-complexing medium may comprise a linked structural portion that is an uncharged / ionically neutral medium in aqueous solution. According to one embodiment, the lead-complexing medium may comprise a linked structural portion corresponding to any one or more of a diethylene glycol amide-complexing structural portion and a crown ether-complexing structural portion. For example, according to some embodiments, the lead-complexing medium may comprise a solid support impregnated with a solution containing a crown ether-complexing structural portion as an extractant, particularly dicyclohexano-8-crown ether-6 or dibenzo-18-crown ether-6, wherein the cyclohexyl or benzyl group is associated with one or more straight-chain or branched C1 to C2 groups. 12 Alkyl substitution, in water-immiscible organic diluents, typically long-chain hydrocarbon alcohols, such as C8 or longer chains. Non-limiting examples of lead complex media having crown ether-complex moiety include 4,4'(5')-di-tert-butylcyclohexano-18-crown ether-6 (also referred to herein as "Pb resin") diluted in isodecanol, and 4,4'(5')-di-tert-butylcyclohexano-18-crown ether-6 (also referred to herein as "Sr resin") diluted in 1-octanol.

[0049] According to some embodiments, the lead complexing medium used herein may be 40% (w:w) crown ether or <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 ether-6, and the resin may be 40% (w:w) 18-crown ether-6 or <40% (w:w) 18-crown ether-6. The general formula of the crown ether compound is shown in formula (1) below, wherein the compound may exist as a mixture of isomers.

[0050] Equation (1): .

[0051] As another example, the lead complexing medium may contain N,N,N',N'-tetraalkyldiglycolamide (DGA) having the chemical formula shown in formula (2) below, wherein the R group may be independently the same or different, branched or straight-chain alkyl groups having 2-12 carbon atoms, for example having 5-10 carbon atoms.

[0052] Equation (2): .

[0053] For example, according to certain embodiments, the lead complexing medium may comprise one or more of N,N,N',N'-tetra-n-octyl diethylene glycol amide and N,N,N',N'-tetra-2-ethylhexyl diethylene glycol amide.

[0054] According to one embodiment, the medium comprises a weak cation exchange medium that preferentially binds to the species of interest based on its affinity for the cationic form of the species. According to some aspects, the weak cation exchange medium includes a connecting structural portion that interacts with the cationic species via ion interactions, thereby binding the cationic species. For example, the weak cation exchange medium has a connecting structural portion corresponding to a weak acid, such as a carboxylic acid and / or a carboxylate group, which carries a negative charge at higher pH (which may be acidic) and is neutral at lower pH; other weak acid groups are also suitable. According to some embodiments, the weak cation exchange medium may contain a carboxyl alkyl group, such as carboxymethyl or carboxyethyl, bonded to a silica support. A non-limiting list of such weak cation exchange media includes, for example, CM-silica, BioSuite CM, and Sep-Pak Accell.

[0055] According to one embodiment, the medium comprises a strong cation exchange medium, which, similar to a weak cation exchange medium, preferentially binds the species of interest based on its affinity for the cationic form of the species. According to some aspects, the strong cation exchange medium includes a connecting structural portion that interacts with the cationic species via ion interactions, thereby binding the cationic species. Unlike the weak cation exchange medium, the strong cation exchange medium includes a connecting structural portion corresponding to a strong acid, such as sulfonic acid and / or sulfonate groups, which ionize over a wide pH range (and thus bind cations over a wide pH range). According to some embodiments, the strong cation exchange medium may include sulfonic acid functional groups linked to a support, such as a divinylbenzene copolymer lattice. A non-limiting list of such strong cation exchange media includes, for example, MP-50 and AG-50Wx8. Table 1 shows a non-limiting list of resins that can be used in this invention.

[0056] Table 1. Chromatographic Media

[0057] The media used herein can have any particle size that is effective for separation, such as 20 μm to 50 μm, 50 μpm to 100 μpm, or 100 μm to 150 μm. In one embodiment, the particle size of the media used in the cassette column described herein is 50 μm to 100 μm. In one embodiment, the media used in the cassette column described herein can 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 a specified radionuclide (e.g., radium-224 or lead-212). According to some aspects, multiple (e.g., 2, 3, 4, or 5) cassette columns connected in series are used, wherein media with specific binding / extraction characteristics are selected, which provides the advantage of removing more unwanted elements than in the case of using only a single separation medium in a single cassette column. According to certain implementations, the ferrule column described herein can achieve a penetration rate of less than 0.01%, less than 0.001%, less than 0.0001%, or less than 0.00001% for unwanted nuclides (e.g., radium-224).

[0058] According to certain embodiments, multiple different cassette columns, such as cassette columns with different chromatographic media, can be configured for reversible separation and combination. For example, these cassette columns can be connected together via tubing; the connection between the cassette columns is, for example, a male-female Luer lock, a Luer sliding cap, etc. The opening (inner diameter) of the Luer lock or Luer sliding cap between the cassette columns can be a diameter of approximately 1 mm to 10 mm (e.g., 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 equal to or less than 10 mm), and its diameter can be one-half, one-third, one-quarter, or one-fifth of the cassette column diameter. According to certain embodiments, cassette columns connected in series can be connected together so that the eluent from the first cassette column in the series flows to the subsequent cassette columns in the series. These cassette columns can also be separated, thereby allowing the initial solution from the first cassette column to be discarded or recycled before eluting the eluent to be loaded onto the second cassette column from the first cassette column. For example, for a first cassette column having a medium that preferentially binds lead, the first cassette column can be arranged relative to the second cassette column such that a solution loaded onto the first cassette column for loading a lead-containing mixture passes through the first cassette column and is collected for disposal or recycling, without flowing into the second cassette column. Any subsequent washes from the first cassette column can similarly be recycled or discarded without flowing into the second cassette column. In other words, the first and second cassette columns may not be in fluid communication during the loading and / or washing phases. According to other embodiments, to allow the lead-containing eluent to flow into the second cassette column, the first cassette column can be in fluid communication with the second cassette column, allowing the eluent to flow into the second cassette column, for example, when eluent is supplied to the first cassette column to elute lead that has bound to the medium in the first cassette column. For example, the second cassette column can be located directly below and connected to the first cassette column (e.g., via a conduit) so that the eluent flowing from the first cassette column flows directly into the second cassette column. The second, third, and fourth cassette columns can be similarly connected in series, allowing unwanted loading and / or washing solutions to be recycled or discarded and not passed into subsequent cassette columns in the series; however, if it is desired to pass eluent from one cassette column into another cassette column in the series, these cassette columns can be in fluid communication with each other. For example, the third cassette column can be located directly below and connected to the second cassette column (e.g., via a conduit) so that eluent flowing from the second cassette column flows directly into the third cassette column. As another example, the fourth cassette column can be located directly below and connected to the third cassette column (e.g., via a conduit) so that solution flowing from the third cassette column flows directly into the fourth cassette column. Embodiments of the invention are further explained below.

[0059] Systems and methods for separating and collecting lead from radium chromatography

[0060] This document describes a separation method and system for facilitating the extraction of lead from liquid sources of radium and / or thorium, and more specifically, the extraction of lead radioisotopes from radioisotope sources of radium and / or thorium. According to some embodiments, the method and system can be used to generate large quantities of highly purified lead. According to further embodiments, the method and system can be used to separate and collect lead radioisotopes without requiring the storage of highly radiodecomposed radium radioisotopes on storage columns or cassette columns. According to other embodiments, the separation method and system can be used for the automated production of lead-based products for nuclear medicine, such as radiopharmaceuticals, providing a stable supply of nuclear medicine doses to meet commercial patient needs.

[0061] See Figure 1 According to one embodiment, a system 100 is provided for extracting radioactive isotopes from a mixture 110 containing lead radioactive isotopes and radium or thorium isotopes. Figure 1 The Ra-224 source shown separates lead radioactive isotopes. System 100 includes a first ferrule column 102 connected in series with each other. Figure 1 The primary Pb / Ra separation column shown) and the second ferrule column 104 ( Figure 1 The second Pb / Ra separation column shown (the first and second cassette columns each have their own inlet 106a and outlet 106b, and each cassette column contains its own separate chamber 108 located between the inlet and outlet, which contains the chromatographic medium. According to this embodiment, the loading solution, washing solution, eluent, etc., are added to each cassette column at the inlet and pass through the chamber to the outlet, where the eluent and waste liquid exit the cassette column. Although... Figure 1 Specific radioactive isotopes Pb-212 and Ra-224 have been described, but it should be noted that the system and method are not limited to this; other radioactive isotopes of lead can also be separated from radioactive isotopes of radium and / or thorium. Furthermore, Figure 1 The aqueous solution composition shown is exemplary, and other aqueous solution compositions, such as any of those described herein, may also be provided.

[0062] According to certain embodiments, the chamber 108 of the first cassette column 102 contains a first chromatographic medium comprising a lead complexing medium that (i) preferentially binds to lead radioisotopes in the presence of a first loading solution 102a containing the mixture, thereby separating the lead radioisotopes from the first loading solution, and (ii) elutes the lead radioisotopes in the presence of a first eluent 102b, thereby forming a first eluent 102c containing lead radioisotopes dissolved in a second solution. For example, a method for separating lead radioisotopes from a mixture containing lead radioisotopes and radium or thorium radioisotopes may include loading a first cassette column 102 (via a cassette column inlet) with a first loading solution 102a containing the mixture, the first cassette column containing a first chromatographic medium comprising a lead complexing medium that, in the presence of the first loading solution, preferentially binds lead radioisotopes to the lead complexing medium rather than to radium and thorium radioisotopes, thereby binding the lead radioisotopes to the lead complexing medium and separating them from the first loading solution. According to some aspects, by loading the first solution onto the first cassette column having a lead complexing medium that preferentially binds lead radioisotopes, the lead radioisotopes remain bound (adsorbed) to the medium, while the remaining portion of the first loading solution (including radium and thorium radioisotopes) unbound from the medium passes through the cassette column and is discharged as waste liquid 102(e). The waste liquid may be discarded, or optionally treated and recycled back to the original mixture 110 and / or back to the first cassette column for further extraction of lead radioisotopes therefrom. According to some embodiments, the method further includes eluting the bound lead radioisotope from the first cassette column with a first eluent 102b (introduced via the cassette column inlet), thereby forming a first eluent 102c (flowing out from the cassette column outlet), the first eluent containing the lead radioisotope dissolved in the first eluent. That is, the first eluent elutes the bound lead from the lead complexing medium, causing the lead to flow out of the first cassette column.

[0063] According to certain embodiments, after loading the first solution and before eluting the bound lead with the first eluent, a cleaning solution 102d may also be provided to the first cassette column to further clean the radioactive isotopes of radium and thorium, as well as any other impurities, from the cassette column. The cleaning solution 102d passing through the cassette column similarly forms waste liquid 102(e), which may be discarded, or optionally treated and recycled back to the original mixture 110 and / or returned to the first cassette column for further extraction of lead radioactive isotopes. This cleaning solution may have an aqueous composition similar to the loading solution, but without the radioactive isotopes.

[0064] According to certain embodiments, the chamber 108 of the second cassette column 104 contains a second chromatographic medium comprising a weak cation exchange medium that (i) preferentially binds to lead radioisotopes more than radium and thorium radioisotopes in the presence of a second loading solution containing a first eluent, thereby separating the lead radioisotopes from the second loading solution, and (ii) elutes the lead radioisotopes in the presence of a second eluent, thereby forming a second eluent containing lead radioisotopes dissolved in the second eluent. For example, according to one embodiment, a method for separating lead radioisotopes from radium and / or thorium radioisotopes includes loading a second cassette column 104 with a second loading solution 104a (via the cassette column inlet) containing a first eluent 102c, the second cassette column having a second chromatographic medium comprising a weak cation exchange medium that preferentially binds to lead radioisotopes more than radium and thorium radioisotopes in the presence of the second loading solution, so that the lead radioisotopes bind to the weak cation exchange medium and are separated from the second loading solution. According to some aspects, by loading the second loading solution onto a second cassette column having a weak cation exchange medium that preferentially binds lead radioisotopes, the lead radioisotopes remain bound to the medium, and the remaining portion of the second loading solution (containing radioisotopes of radium and thorium) that is not bound to the medium passes through the cassette column and is discharged as waste liquid 104(e). Waste liquid 104(e) may be discarded, or may optionally be treated and recycled back to the original mixture 110 and / or back to the first cassette column, and / or may optionally be treated and recycled back to the second cassette column for further extraction of lead radioisotopes therefrom.

[0065] According to some embodiments, the method further includes eluting the bound lead radioisotope from the second cassette column using a second eluent 104b (introduced via the cassette column inlet), thereby forming a second eluent 104c (flowing out from the cassette column outlet), the second eluent containing the lead radioisotope dissolved in the second eluent. That is, the second eluent is used to elute the bound lead from the weak cation exchange medium, causing the lead to flow out from the second cassette column.

[0066] According to certain embodiments, after loading the second loading solution and before eluting the bound lead with the second eluent, a cleaning solution 104d may also be provided to the second cassette column to further clean the radioactive isotopes of radium and thorium, as well as any other impurities, from the cassette column. The cleaning solution 104d passes through the cassette column, similarly forming waste liquid 104(e), which may be discarded, or optionally processed and recycled back to the original mixture 110 and / or back to the first cassette column, and / or optionally processed and recycled back to the second cassette column for further extraction of lead radioactive isotopes; and the cleaning solution may have an aqueous composition similar to the loading solution, but without radioactive isotopes.

[0067] According to one implementation, the second loading solution has a pH, i.e., pH 2L The second eluent has a pH value, i.e., pH 2E ; and pH 2L greater than pH 2E That is, the pH of the second eluent used to elute from the second ferrule column can be lower than the pH of the second loading solution used to load onto the second ferrule column. According to another embodiment, the first loading solution has a pH, i.e., pH... 1L The first eluent has a pH value, i.e., pH 5. 1E ; and pH 1E greater than pH 1L In other words, the pH of the first eluent used to elute from the first cassette column can be higher than the pH of the first loading solution used to load onto the first cassette column.

[0068] According to one embodiment, the first ferrule column comprises a lead-chelating medium, which is an ionicly neutral medium. For example, according to one embodiment, the lead-chelating medium may comprise one or more of a diethylene glycol amide-complexing moiety and a crown ether-complexing moiety. According to one embodiment, the first ferrule column comprises a lead-chelating medium that is one or more of the following substances: 4,4'(5')-di-tert-butylcyclohexano-18-crown ether-6 (Pb resin, using isodecanol as a diluent), 4,4'(5')-di-tert-butylcyclohexano-18-crown ether-6 (Sr resin, using 1-octanol as a diluent), N,N,N,N'-tetraoctyl diethylene glycol amide (TODGA), and N,N,N',N'-tetrapentyl diethylene glycol amide (TPDGA). In another embodiment, the lead-chelating medium for the first ferrule column may be any lead-chelating medium described herein, such as those shown in Table 1.

[0069] According to one embodiment, the medium for the second ferrule column comprises a weak cation exchange medium containing ionizable carboxyl alkyl groups bonded to a silica-based support. For example, according to some embodiments, the weak cation exchange medium may comprise any one or more of CM-silica, BioSuite CM, and Sep-Pak Accell Plus CM. In another embodiment, the weak cation exchange medium for the second ferrule column may be any weak cation exchange medium described herein, such as those shown in Table 1.

[0070] According to one embodiment, the first loading solution for loading lead onto a first ferrule column comprises an inorganic acid. For example, the inorganic acid present in the first loading solution is any one or more of HNO3, HCl, HBr, HCl, and H2SO4. According to some embodiments, the concentration of the first loading solution containing the inorganic acid is 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.

[0071] In one embodiment, a first loading solution is provided to a first cassette column, which contains lead and radium radioisotopes in an aqueous (liquid) form in nitric acid (HNO3). The first loading solution can be contained and stored in a container (i.e., the original container). The concentration of nitric acid in the first loading solution in aqueous form can be in the range of 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 more preferably about 2 M. When the first cassette column is loaded with the first loading solution, the lead radioisotopes in the first loading solution are adsorbed onto the medium of the first cassette column. The radium and / or thorium radioisotopes in the first loading solution pass through the first cassette column and can be recovered and collected in the 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 can be the original container containing the first loading solution, radium and / or thorium, and lead, or it can be a separate container.

[0072] In one embodiment, the first ferrule column is also washed with nitric acid (HNO3). The washing product can be collected in the original container or a separate container. The concentration of nitric acid used in the first washing solution can be 0.1-3 M, more preferably 0.5-2.5 M, more preferably 1.5-2.5 M, and even more preferably 2 M. One or more washes can be performed.

[0073] According to certain aspects, the radium radioisotope passing through the first cassette column (e.g., in waste liquid 102(e)) can be recycled for further use in the generation of lead, for example, by further extraction of lead from a solution containing radium radioisotopes, or by further decaying the collected radium to generate lead radioisotopes, which can then be separated and extracted via the methods and systems described herein. Such systems and methods allow for the generation of lead from radium in solution, which can be a more stable radiodegradation form than radium stored in a storage medium. The recovered radium can be further concentrated to reduce volume and increase the concentration of radium in aqueous form, for example, in nitric acid.

[0074] According to one embodiment, the first eluent for eluting lead radioisotopes from a first cassette column comprises 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 4.5. According to one embodiment, the weak acid comprises any one or more of a carboxyl group, a sulfate group, or a phosphate group, which is in equilibrium with these groups in an acidic form. For example, the weak acid can be a buffer solution, optionally adjusted to a suitable pH. According to one embodiment, the weak acid is prepared from any one or more salts selected from acetate, citrate, and oxalate. The salt forming the counterion can comprise any pharmaceutically acceptable salt, such as sodium acetate and / or ammonium acetate. In one embodiment, the weak acid is prepared from ammonium acetate. According to one embodiment, the concentration of the weak acid in the first eluent can be 0.1-2.0 M, 0.5-1.5 M, 0.75-1.25 M, and / or about 1 M.

[0075] In one embodiment, lead adsorbed onto a first cassette column is eluted with a first eluent containing a weak acid, said weak acid being derived from a salt containing a sodium or ammonium counterion and a carboxyl group (i.e., acetate, oxalate, or citrate). Several types of carboxyl group-containing salts can be used to elute lead from the first cassette column. In one embodiment, the salt is ammonium acetate. The concentration of ammonium acetate in the first eluent can be 0.1-2.0 M, preferably 0.5-1.5 M, more preferably 0.75-1.25 M, and even more preferably 1 M. The pH of the weak acid in the first eluent can be buffered to 1-5.5, preferably 2-5, more preferably 3-5, more preferably 4-5, and even more preferably 4.5. In addition to carboxyl groups, the salt can also contain sulfate or phosphate groups.

[0076] In one embodiment, the first eluent used to elute lead radioisotopes from the first cassette column comprises a dilute inorganic acid. For example, in one embodiment, the first eluent comprises a dilute inorganic acid comprising any one of HNO3, HCl, HBr, HI, and H2SO4. According to one embodiment, the first eluent comprises a dilute inorganic acid with a concentration not exceeding 0.1 M, for example 0.001-0.1 M, and / or 0.01-0.1 M.

[0077] In one embodiment, lead adsorbed onto the first ferrule column is eluted with a higher concentration of inorganic acid. For example, the first eluent may contain a more concentrated inorganic acid, including any one of HNO3, HCl, HBr, HI, and H2SO4. As an example, the concentration of the inorganic acid in the first eluent may be greater than 4 M, for example, 4-10 M, or even greater than 5 M, for example, 5-10 M.

[0078] According to one embodiment, the second loading solution for loading the lead radioisotope onto the second cassette column is a first eluent, which is formed when a first eluent is supplied to the first cassette column to elute the lead radioisotope from the column. For example, the first eluent can flow directly from the first cassette column to the second cassette column as the second loading solution. According to one embodiment, the first eluent flows from the first cassette column to the second cassette column without change. According to another embodiment, the first eluent can be modified to form the second loading solution before loading onto the second cassette column, for example, by adjusting the pH of the solution.

[0079] According to one embodiment, the second loading solution contains a weak acid, such as a weak acid used as a first eluent, which passes through the first ferrule column to form a first eluent. According to one embodiment, the second loading 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 of a carboxyl group, a sulfate group, or a phosphate group, which is in equilibrium with the acidic form of these groups. For example, the weak acid can 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 oxalate. The salt forming the counterion can contain any pharmaceutically acceptable salt, such as sodium acetate and / or ammonium acetate. In one embodiment, the weak acid is prepared from ammonium acetate. According to one embodiment, the concentration of the weak acid in the first eluent can be 0.1-2.0 M, 0.5-1.5 M, 0.75-1.25 M, and / or about 1 M.

[0080] In one embodiment, the second loading solution for loading the lead radioisotope onto the second ferrule column comprises a dilute inorganic acid. For example, in one embodiment, the second loading solution comprises a dilute inorganic acid comprising any one of HNO3, HCl, HBr, HI, and H2SO4. According to one embodiment, the second loading solution comprises a dilute inorganic acid with a concentration not exceeding 0.1 M, for example 0.001-0.1 M, and / or 0.01-0.1 M.

[0081] In one embodiment, the second loading solution may contain a more concentrated inorganic acid, including any one of HNO3, HCl, HBr, HI, and H2SO4. As an example, the concentration of the inorganic acid in the second loading solution may be greater than 4M, for example 4-10 M, or even greater than 5M, for example 5-10 M.

[0082] According to one embodiment, the second cassette column can be further cleaned after loading with the second loading solution and before elution with the second eluent. For example, the second cassette column can be cleaned with a cleaning solution having the same acid used in the second loading solution, but without radioactive isotopes. A second solution can further clean radium and / or thorium radioactive isotopes from the second cassette column, and this cleaning solution can be discarded, or optionally processed and recycled back to the original solution mixture, back to the first cassette column, and / or back to the second cassette column. According to one embodiment, the solution used to clean the second cassette column is dilute HCl. According to some aspects, the concentration of HCl used for cleaning can typically be 0.001-0.1 M, and / or 0.01-0.1 M, but in some embodiments, the concentration can be 0.001-1 M, for example 0.005-0.5 M, or even 0.01-0.25 M.

[0083] According to one embodiment, the second eluent for eluting lead radioisotopes from a second cassette column comprises an inorganic acid. For example, according to one embodiment, the second eluent comprises any one or more of HNO3, HCl, HBr, HI, and H2SO4. According to one embodiment, the concentration of the inorganic acid contained in the second eluent is 0.01-5 M, 0.02-4 M, 0.02-3 M, and / or 0.02-2 M. For example, according to one embodiment, when the second loading solution is a dilute inorganic acid, the second eluent may contain a higher concentration of inorganic acid. According to one embodiment, the concentration of the inorganic acid contained in the second eluent is sufficient to form lead in anionic form in the second eluent. For example, according to some aspects, the lead in anionic form comprises PbCl4. 2- .

[0084] In one embodiment, lead adsorbed onto a second ferrule column is eluted with a second eluent, which is hydrochloric acid (HCl). The concentration of HCl may be 0.01-5 M, preferably 0.02-4 M, more preferably 0.02-3 M, and even more preferably 0.02-2 M (e.g., 0.05 M, 0.5 M, 1 M, or 2 M).

[0085] Additional card sleeve post

[0086] On the other hand, in addition to the first and second ferrule columns described above, the system 100 described herein for separating and purifying lead radioisotopes from aqueous radium and / or thorium radioisotopes may also include additional ferrule columns. In one embodiment, the system further includes a third ferrule column 112, such as... Figure 2 As shown. In one embodiment, the system further includes a third ferrule post 112 and a fourth ferrule post 114, as shown. Figure 2 As shown. According to some embodiments, any residual radium radioisotopes present in the eluent of the second cassette column can be adsorbed onto the resin of the third cassette column, while lead radioisotopes can pass through this cassette column for collection or adsorption onto the fourth cassette column.

[0087] For example, see Figure 2 According to some implementations, system 100 further includes a third ferrule post 114 ( Figure 2 The third cassette column (a Pb-purified column) is connected in series with one or more of the first and second cassette columns. The third cassette column has its own separate inlet 106a, outlet 106b, and its own separate chamber 108 located between the inlet and outlet, which contains the chromatographic medium for the cassette column. According to this embodiment, loading solutions, washing solutions, eluents, etc., can be introduced into the third cassette column at the inlet and from the chamber to the outlet, where the eluent and waste liquid exit the cassette column. Although... Figure 2 Specific radioactive isotopes Pb-212 and Ra-224 have been depicted, but it should be noted that the system and method are not limited to this; other radioactive isotopes of lead can also be separated from radioactive isotopes of radium and / or thorium. Furthermore, Figure 1 The aqueous solution composition shown is exemplary, and other aqueous solution compositions, such as any of those described herein, may also be provided.

[0088] According to certain embodiments, the chamber 108 of the third cassette column 102 contains a chromatographic medium comprising a strong cation exchange medium that (i) preferentially binds to radium or thorium radioisotopes in the presence of a third loading solution 112a containing a second eluent 104c, thereby separating radium or thorium radioisotopes from the third loading solution 112a, and (ii) allows lead radioisotopes in the third loading solution 112a to pass through, thereby forming a third lead-containing solution 112c having lead radioisotopes dissolved therein and having a lower radium or thorium radioisotope content compared to the radium or thorium radioisotope content in the second eluent 104c. In other words, the strong cation exchange medium of the third cassette column can preferentially bind to radium or thorium radioisotopes while simultaneously allowing lead radioisotopes to pass through, thereby further purifying the lead radioisotopes in the solution passing through the cassette column. For example, according to one embodiment, the method may include loading a third cassette column (via a cassette column inlet) with a third loading solution 112a containing a second eluent 104c. The third cassette column has a third chromatographic medium containing a strong cation exchange medium that preferentially binds radium or thorium radioisotopes in the presence of the third loading solution 112a compared to lead radioisotopes, thereby separating the radium or thorium radioisotopes from the third loading solution 112a to form a third lead-containing solution 112c. The third lead-containing solution 112c has lead radioisotopes dissolved therein and a lower radium or thorium radioisotope content compared to the radium or thorium radioisotope content in the second eluent 104c. The third lead-containing solution 112c can be collected and used, for example, for medical purposes involving radionuclides, including radionuclide labeling of radiopharmaceutical compounds for diagnosis and / or treatment.

[0089] According to some embodiments, a cleaning solution 112d may also be provided to the third cassette column after the introduction of the third loading solution 112a and the formation solution 112c. Similar to the third lead-containing solution 112c, the cleaning solution 112d passing through this cassette column may be collected and used, for example, by combining with the third lead-containing solution, or subsequently cleaning the third cassette column. According to one embodiment, the cleaning solution 112d used to clean the third cassette column is HCl. For example, the cleaning solution 112d may contain HCl at a concentration of 0.01-5 M, preferably 0.02-4 M, more preferably 0.02-3 M, and even more preferably 0.02-2 M (e.g., 0.05 M, 0.5 M, 1 M, or 2 M). Alternatively, the third lead-containing solution 112c may be recycled back to the third cassette column for further removal of radioactive isotopes of radium and / or thorium.

[0090] According to one embodiment, the strong cation exchange medium contained in the third ferrule column comprises sulfonic acid groups. According to another embodiment, the strong cation exchange medium comprises sulfonic acid groups bonded to divinylbenzene.

[0091] According to one embodiment, the third loading solution for loading the third cassette column corresponds to the second eluent. For example, according to one embodiment, the second eluent flows from the second cassette column to the third cassette column without modification. According to another embodiment, the second eluent is modified to form the third loading solution before being loaded onto the third cassette column, for example by adjusting the pH of the second eluent to form the third loading solution.

[0092] According to one embodiment, the third loading solution for loading the third ferrule column comprises an inorganic acid. For example, according to one embodiment, the third loading solution comprises any one or more of HNO3, HCl, HBr, HI, and H2SO4. According to one embodiment, the concentration of the inorganic acid in the third loading solution is 0.01-5 M, 0.02-4 M, 0.02-3 M, and / or 0.02-2 M. According to one embodiment, the concentration of the inorganic acid in the third loading solution is sufficient to form lead in anionic form in the third loading solution. According to one embodiment, the third loading solution comprises HCl.

[0093] According to one embodiment, the third lead-containing solution corresponds to the third loaded solution passing through the third ferrule column and has a lower content of radium or thorium isotopes compared to the third loaded solution.

[0094] See you again Figure 2 According to some implementation schemes, system 100 also includes a fourth ferrule post ( Figure 2 The fourth cassette column (a drug product matrix conversion column) 114 is connected in series with one or more of the first, second, and third cassette columns. The fourth cassette column includes its own separate inlet 106a, outlet 106b, and its own separate chamber 108 located between the inlet and outlet, containing the chromatographic medium for the cassette column. According to this embodiment, loading solutions, washing solutions, eluents, etc., can be introduced into the fourth cassette column at the inlet and from the chamber to the outlet, where the eluent and waste liquid exit the cassette column. Although... Figure 2 Specific radioactive isotopes Pb-212 and Ra-224 have been depicted, but it should be noted that the system and method are not limited to this; other radioactive isotopes of lead can also be separated from radioactive isotopes of radium and / or thorium. Furthermore, Figure 1 The aqueous solution composition shown is exemplary, and other aqueous solution compositions, such as any of those described herein, may also be provided.

[0095] According to certain embodiments, the chamber 108 of the fourth ferrule column 114 contains a fourth chromatographic medium comprising a lead complexing medium, which (i) preferentially binds to lead radioisotopes more than radioactive isotopes of radium and thorium in the presence of a fourth loading solution 114a containing a third lead-containing solution 112c, thereby separating the lead radioisotopes from the fourth loading solution, and (ii) elutes the lead radioisotopes in the presence of a fourth eluent introduced into the lead complexing medium, thereby forming a fourth eluent containing lead radioisotopes dissolved in the fourth eluent. For example, a method for separating lead radioisotopes from a fourth loading solution containing a third lead-containing solution may include loading a fourth cassette column 114 (via a cassette column inlet) with a fourth loading solution 114a containing a third eluent 112c, the fourth cassette column containing a fourth chromatographic medium containing a lead complexing medium that preferentially binds lead radioisotopes in the presence of the fourth loading solution compared to radium and thorium radioisotopes, thereby binding the lead radioisotopes to the lead complexing medium and separating them from the fourth loading solution. According to some aspects, by loading the fourth solution onto the fourth cassette column having a lead complexing medium that preferentially binds lead radioisotopes, the lead radioisotopes remain bound to the medium, while the remaining fourth loading solution (containing radium and thorium radioisotopes) that is not bound to the medium passes through the cassette column and is discharged as waste liquid 114(e). The waste liquid can be discarded, or optionally treated and recycled back to the original mixture 110 and / or back to any of the first to third cassette columns for further extraction of lead radioisotopes. According to some embodiments, the method further includes eluting the bound lead radioisotopes from a fourth cassette column with a fourth eluent 114b (introduced via the cassette column inlet), thereby forming a fourth eluent 1114c (flowing out from the cassette column outlet), the fourth eluent containing lead radioisotopes dissolved in the fourth eluent. That is, the fourth eluent is used to elute the bound lead from the lead complexing medium, causing the lead to flow out from the fourth cassette column.

[0096] According to one embodiment, the fourth loading solution used to load the fourth ferrule column has a pH, i.e., pH 4L The fourth eluent has a pH value, i.e., pH 4E ; and pH 4E greater than pH 4L .

[0097] According to some embodiments, a cleaning solution 114d may also be provided to the fourth loading solution after loading the fourth loading solution and before eluting the bound lead with a fourth eluent, thereby further cleaning the radium and thorium radioisotopes and any other impurities from the cassette column. The cleaning solution 114d passing through the cassette column similarly forms waste liquid 114(e), which may be discarded or optionally treated and recycled back to the original mixture 110, and / or back to any of the first to third cassette columns, from which further lead radioisotopes may be extracted, and the cleaning solution may have an aqueous composition similar to the loading solution, but without radioisotopes. According to one embodiment, the fourth cassette column is cleaned with HCl, for example, at a concentration of 0.01-5 M, preferably 0.02-4 M, more preferably 0.02-3 M, and even more preferably 0.02-2 M (e.g., 0.05 M, 0.5 M, 1 M, or 2 M).

[0098] According to one embodiment, the fourth cassette column contains a lead complexing medium of the same type as that in the first cassette column. According to one embodiment, the lead complexing medium contained in the fourth cassette column is an ionicly neutral medium. For example, according to one embodiment, the lead complexing medium may include one or more of a diethylene glycol amide-complexing moiety and a crown ether-complexing moiety. According to one embodiment, the fourth cassette column contains a lead complexing medium that is one or more of the following: 4,4'(5')-di-tert-butylcyclohexano-18-crown ether-6 (Pb resin, using isodecanol as a diluent), 4,4'(5')-di-tert-butylcyclohexano-18-crown ether-6 (Sr resin, using 1-octanol as a diluent), N,N,N',N'-tetraoctyl diethylene glycol amide (TODGA), N,N,N',N'-tetrapentyl diethylene glycol amide (TPDGA). In another embodiment, the lead chelating medium for the fourth ferrule post can be any lead complexing medium described herein, such as those shown in Table 1, and / or can be different from the lead complexing medium provided in the first ferrule post.

[0099] According to one embodiment, the fourth loading solution is the third lead-containing solution. For example, according to one embodiment, the third lead-containing solution can flow from the third ferrule column to the fourth ferrule column without modification. According to another embodiment, the third lead-containing solution can be modified to form the fourth loading solution before being loaded onto the fourth ferrule column.

[0100] According to one embodiment, the fourth loading solution for loading the fourth ferrule column comprises an inorganic acid. For example, according to one embodiment, the fourth loading solution comprises any one or more of HNO3, HCl, HBr, HI, and H2SO4. According to one embodiment, the concentration of the inorganic acid in the fourth loading solution is 0.01-5 M, 0.02-4 M, 0.02-3 M, and / or 0.02-2 M. According to one embodiment, the fourth loading solution comprises HCl.

[0101] According to one embodiment, the fourth eluent for eluting lead radioisotopes from a fourth cassette column comprises 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 comprises any one or more of a carboxyl group, a sulfate group, or a phosphate group, which is balanced with these groups in an acidic form. For example, the weak acid is a buffer solution, optionally adjusted to a suitable pH. According to one embodiment, the weak acid is prepared from any one or more salts of acetate, citrate, and oxalate. The salt forming the counterion can comprise any pharmaceutically acceptable salt, such as sodium acetate and / or ammonium acetate. In one embodiment, the weak acid is prepared from ammonium acetate. According to one embodiment, the concentration of the weak acid contained in the fourth eluent is 0.1-2.0 M, 0.5-1.5 M, 0.75-1.25 M, and / or about 1 M.

[0102] In one embodiment, lead adsorbed onto a fourth cassette column is eluted with a fourth eluent containing a weak acid formed from a salt (i.e., acetate, oxalate, or citrate) having a sodium or ammonium counterion and carrying a carboxyl group. Several types of carboxyl group-containing salts can be used to elute lead from the first cassette column. In one embodiment, the salt is ammonium acetate. The concentration of ammonium acetate in the fourth eluent can be 0.1-2.0 M, preferably 0.5-1.5 M, more preferably 0.75-1.25 M, and even more preferably 1 M. The pH of the weak acid in the fourth eluent can be buffered to 1-5.5, preferably 2-5, more preferably 3-5, more preferably 4-5, and even more preferably 4.5. In addition to carboxyl groups, the salt can also carry sulfate or phosphate groups.

[0103] In one embodiment, the fourth eluent used to elute lead radioisotopes from the fourth cassette column comprises a dilute inorganic acid. For example, in one embodiment, the fourth eluent comprises a dilute inorganic acid, said dilute inorganic acid comprising any one of HNO3, HCl, HBr, HI, and H2SO4. According to one embodiment, the concentration of the dilute inorganic acid contained in the fourth eluent is not greater than 0.1 M, for example, 0.001-0.1 M, and / or 0.01-0.1 M.

[0104] In one embodiment, lead adsorbed onto a fourth ferrule column is eluted with hydrochloric acid (HCl). The concentration of HCl may be 0.01-5 M, preferably 0.02-4 M, more preferably 0.02-3 M, and even more preferably 0.1-2 M (e.g., 0.1 M, 1 M, or 2 M).

[0105] In one embodiment, lead adsorbed onto a fourth ferrule column is eluted with a higher concentration of inorganic acid. For example, the fourth eluent may contain a more concentrated inorganic acid, including any one of HNO3, HCl, HBr, HI, and H2SO4. As an example, the concentration of the inorganic acid in the fourth eluent may be greater than 4 M, for example 4-10 M, or even greater than 5 M, for example 5-10 M.

[0106] According to some embodiments, the fourth eluent can be collected and used for medical purposes with radionuclides, such as radiolabeling radiopharmaceuticals with lead radioisotopes. According to other embodiments, the fourth eluent can be modified, for example by raising or lowering the pH, or by adding other stabilizers.

[0107] According to some embodiments, a method for preparing a radiopharmaceutical includes introducing an unchelated radiopharmaceutical into an aqueous solution containing any of the second to fourth eluents, thereby forming a radiopharmaceutical chelated with a lead radioisotope. According to another embodiment, the radiopharmaceutical comprises a radiation-labeled chelating agent prepared according to the method described above.

[0108] According to another embodiment, the positions of the third and second cassette columns in the system can be switched, such that the third cassette column receives the first eluent from the first cassette column, and the second cassette column receives the third lead-containing solution from the third cassette column (the fourth cassette column receives the second eluent from the second cassette column). In an embodiment of the process with this configuration, the process includes loading the third cassette column with a third loading solution containing the first eluent, the third cassette column having a third chromatographic medium containing a strong cation exchange medium that, in the presence of the loading solution, preferentially binds radium or thorium radioisotopes over lead radioisotopes, thereby separating radium or thorium radioisotopes from the third loading solution, thus forming a third lead-containing solution having lead radioisotopes dissolved therein and having a lower radium or thorium radioisotope content compared to the radium or thorium radioisotope content in the first eluent. The third lead-containing solution is then supplied to the second cassette column as a second loading solution. According to this embodiment, if the fourth cassette column is also used as part of such a system having a second and a third cassette column in reverse order, the process further includes loading the fourth cassette column with a fourth loading solution containing a second eluent, the fourth cassette column having a fourth chromatographic medium containing a lead complexing medium that preferentially binds lead radioisotopes in the presence of the fourth loading solution compared to radioisotopes of radium and thorium, thereby separating the lead radioisotopes from the fourth loading solution, and eluting the bound lead radioisotopes from the fourth cassette column with a fourth eluent, thereby forming a fourth eluent containing lead radioisotopes dissolved in the fourth eluent.

[0109] Detecting purity and yield

[0110] In this invention, the purity of radium can be detected using rapid alpha spectroscopy and by liquid scintillation counting of Ra-224 decay. The yield of radium can be detected using liquid scintillation counting and HPGe γ analysis. The yield of lead can be detected using HPGe γ analysis.

[0111] According to certain embodiments, the yield of lead isotopes processed using system 100 (e.g., the first and second cassette columns, or all four cassette columns) is at least 80%, at least 90%, and / or at least 95%. The radiochemical purity of the lead isotopes processed according to the system described herein (with respect to all parent isotopes) can be at least 95%, for example, 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 Pb-212 (with respect to its parent isotopes) can be at least 95%, for example, at least 99.9%, at least 99.99%, at least 99.999%, at least 99.9999%, and / or at least 99.99999%.

[0112] In some respects, the principle behind these detections is that isotopes of the same element have the same chemical properties, so a radiochemical tracer is introduced into the system to calculate the recovery and detection efficiency [1-3]. It is generally expected that some chemical losses (e.g., detection efficiency, source formulation loss) will occur during the chromatographic steps and during sample analysis, so using an alternative isotope allows for confirmation of the analyte's chemical yield by this method. 2 The common tracer isotope of Pb-212 is Pb-203. Pb-203 offers several advantages, including ease of detection, a more suitable half-life for research and development, and a simpler decay pattern than Pb-212. This allows Pb-203 to be used as a tracer, or as a substitute for Pb-212, in studies of chemical separations (as illustrated in the examples below). Pb-203 and Pb-212 are expected to have the same chemical properties throughout the separation process.

[0113] Example

[0114] The following examples are used to illustrate various aspects of the present invention, but the present invention is not limited thereto.

[0115] Example 1

[0116] Figure 3 A flowchart of one embodiment for separating Pb-212 from a liquid source of Ra-224 is shown, as used in Example 1.

[0117] According to this embodiment, the elution process uses the following column: Primary column (PC): QML Pb resin, 50-100μm, pre-adjusted with 5mL of 2.0M HNO3. The second column (SC): QML CM-silica, 20-45 μm, pre-adjusted with 5 mL of 1.0 M ammonium acetate to pH 4.5. The third column / protective column (GC): QML MP50, 75-150μm.

[0118] The steps in the elution process are as follows: 1) Load the Ra-224 source in 2.0M HNO3 (add 20 mL initially, then 0.5 mL in each cycle) onto the PC. Collect Ra-224 from the PC in the same source container.

[0119] 2) Use 0.5 mL of 2.0 M HNO3 to wash the PC into the Ra-224 source container.

[0120] 3) Remove the Ra-224 source container. Place the PC waste bottle under the PC.

[0121] 4) Wash the PC with 9.5 mL of 2.0 M HNO3. Collect the PC waste liquid in a PC waste bottle.

[0122] 5) Remove the PC waste bottle.

[0123] 6) Add SC under PC.

[0124] 7) Add the SC waste bottle below these columns.

[0125] 8) Transfer Pb-212 from PC to SC containing 10 mL of 1.0 M ammonium acetate at pH 4.5. Collect the eluent in the SC waste bottle.

[0126] 9) Remove the PC.

[0127] 10) Wash SC with 10 mL of 0.01 M HCl. Collect the SC waste liquid in a SC waste bottle.

[0128] 11) Remove the SC waste bottle.

[0129] 12) Add the Pb-212 vial.

[0130] 13) Add GC under SC.

[0131] 14) Using 4.0 mL of 2.0 M HCl, Pb-212 from SC was recovered into a Pb-212 vial via GC.

[0132] Figures 4a-4bThe percentage Pb penetration and radiochemical purity of the Pb-212 product shown in Example 1 vary with percentage Pb recovery. Percentage Pb penetration is the amount of Pb-212 eluted with Ra-224 on the primary column. Pb-212 is then stored with Ra-224 for future emulsification of the Ra-224 source. The radiochemical purity of Pb is relative to Ra-224 and / or Th-228. The radiochemical purity of Pb-212 does not account for the inward growth of Pb-212 decay products. Percentage Pb recovery is the amount of Pb-212 recovered throughout the separation process.

[0133] Example 2

[0134] Figure 5 A flowchart of one embodiment for separating Pb-212 from a liquid source of Ra-224 is shown, as used in Example 2. The flow and parameters used in this embodiment are similar to those in Example 1, except that: (1) PC is switched from Pb-resin to TPDGA, and (2) the cleaning solution used for PC is reduced to 0.25M HNO3.

[0135] According to this embodiment, the elution process uses the following column: Primary column (PC): 1 mL TPDGA resin, 50-100 μm, pre-adjusted with 5 mL 2.0 M HNO3. The second column (SC): QML CM-silica, 20-45 μm, pre-adjusted with 5 mL of 1.0 M ammonium acetate to pH 4.5. The third column / protective column (GC): QML MP50, 75-150μm.

[0136] The steps in the elution process are as follows: 1) Load the Ra-224 source in 2.0M HNO3 (add 20mL initially, then 1.0mL in each cycle) onto a PC. Collect Ra-224 in the same source container.

[0137] 2) Use 1.0 mL of 0.25 M HNO3 to wash the PC into the Ra-224 source.

[0138] 3) Remove the Ra-224 source container. Place the PC waste bottle under the PC.

[0139] 4) Wash the PC with 4.0 mL of 0.25 M HNO3. Collect the PC waste liquid in a PC waste bottle.

[0140] 5) Remove the PC waste bottle.

[0141] 6) Add SC under PC.

[0142] 7) Add the SC waste bottle below these columns.

[0143] 8) Transfer Pb-212 from PC to SC containing 10 mL of 1.0 M ammonium acetate at pH 4.5. Collect the eluent in the SC waste bottle.

[0144] 9) Remove the PC.

[0145] 10) Wash SC with 10 mL of 0.01 M HCl. Collect the SC waste liquid in a SC waste bottle.

[0146] 11) Remove the SC waste bottle.

[0147] 12) Add the Pb-212 vial.

[0148] 13) Add GC under SC.

[0149] 14) Using 4.0 mL of 2.0 M HCl, Pb-212 from SC was recovered into a Pb-212 vial via GC.

[0150] Figures 6a-6b The percentage Pb penetration and radiochemical purity of the Pb-212 product shown in Example 2 vary with percentage Pb recovery.

[0151] Example 3

[0152] Figure 7 A flowchart of one embodiment for separating Pb-212 from a liquid source of Ra-224 is shown, as used in Example 3. The flow and parameters used in this embodiment are similar to those in Example 1, except that the volumes of the loading solution and the washing solution have been optimized to maximize Pb recovery, Ra recovery, and Pb purity.

[0153] According to this embodiment, the elution process uses the following column: Primary column (PC): 1 mL Pb resin, 50-100 μm, pre-adjusted with 10 mL 2.0 M HNO3. The second column (SC): HML CM-silica, 20-45 μm, pre-adjusted with 10 mL of 1.0 M ammonium acetate to pH 4.5. The third column / protective column (GC): QML MP50, 75-150μm.

[0154] The steps in the elution process are as follows: 1) Load the Ra-224 source in 2.0 M HNO3 onto the PC. Collect Ra-224 in the same source container. (Initial source volumes: source A = 24 mL; source B = 58 mL; source C = 87 mL, with the volume increased by 1.0 mL after each cycle).

[0155] 2) Use 1.0 mL of 0.1 M HNO3 to wash the PC into the Ra-224 source.

[0156] 3) Remove the Ra-224 source container. Place the PC waste bottle under the PC.

[0157] 4) Wash the PC with 9.0 mL of 0.1 M HNO3. Collect the PC waste liquid in a PC waste bottle.

[0158] 5) Remove the PC waste bottle.

[0159] 6) Add SC under PC.

[0160] 7) Add the SC waste bottle below these columns.

[0161] 8) Transfer Pb-212 from PC to SC containing 15 mL of 1.0 M ammonium acetate at pH 4.5. Collect the eluent in the SC waste bottle.

[0162] 9) Remove the PC.

[0163] 10) Wash SC with 10 mL of 0.01 M HCl. Collect the SC waste liquid in a SC waste bottle.

[0164] 11) Remove the SC waste bottle.

[0165] 12) Add the Pb-212 vial.

[0166] 13) Add GC under SC.

[0167] 14) Using 4.0 mL of 2.0 M HCl, Pb-212 from SC was recovered into a Pb-212 vial via GC.

[0168] Figures 8a-8b The percentage Pb penetration and radiochemical purity of the Pb-212 product shown in Example 3 vary with percentage Pb recovery.

[0169] List of implementation plans

[0170] The present invention includes embodiments listed below. However, embodiments of the present invention are not limited to those listed below.

[0171] Implementation Scheme 1. A method for separating a lead radioactive isotope from a mixture comprising a lead radioactive isotope and a radium or thorium radioactive isotope, the method comprising: (a) Loading a first cassette column with a first loading solution containing the mixture, the first cassette column containing a first chromatographic medium containing a lead complexing medium that, in the presence of the first loading solution, preferentially binds lead radioisotopes to the lead complexing medium rather than to radioisotopes of radium and thorium, so that the lead radioisotopes bind to the lead complexing medium and are separated from the first loading solution. (b) The bound lead radioisotope is eluted from the first ferrule column with a first eluent, thereby forming a first eluent containing the lead radioisotope dissolved in the first eluent. (c) Loading a second cassette column with a second loading solution containing the first eluent, the second cassette column having a second chromatographic medium containing a weak cation exchange medium that, in the presence of the second loading solution, preferentially binds lead radioisotopes over radium and thorium radioisotopes, so that lead radioisotopes bind to the weak cation exchange medium and separate from the second loading solution; and (d) Elute the lead radioisotope from the second cassette column with a second eluent, thereby forming a second eluent containing the lead radioisotope dissolved in the second eluent. The second loading solution has a pH, i.e., pH 2L The second eluent has a pH value, i.e., pH 2E ; and pH 2L greater than pH 2E .

[0172] Implementation Scheme 2. The method according to Implementation Scheme 1, wherein the first loading solution passing through the first ferrule column is circulated back to the first ferrule column to further bind the lead isotope to the lead complexing medium, or discarded.

[0173] Implementation Scheme 3. The method according to any one of Implementation Schemes 1-2, wherein the second loading solution passing through the second cassette column is recycled back to the first cassette column to further bind the lead isotope to the lead complexing medium, processed and recycled back to the first cassette column to further bind the lead isotope to the weak cation exchange medium, or discarded.

[0174] Implementation Scheme 4. The method according to any one of Implementation Schemes 1-3, wherein the first loading solution has a pH, i.e., pH 1L The first eluent has a pH value, i.e., pH 5. 1E ; and pH 1E greater than pH 1L .

[0175] Implementation Scheme 5. The method according to any one of Implementation Schemes 1-4, further comprising: (e) A third cassette column is loaded with a third loading solution containing a second eluent, the third cassette column having a third chromatographic medium containing a strong cation exchange medium that preferentially binds to radium or thorium radioisotopes in the presence of the third loading solution, thereby separating radium or thorium radioisotopes from the third loading solution, thus forming a third lead-containing solution containing lead radioisotopes dissolved therein and having a lower radium or thorium radioisotope content compared to the radium or thorium radioisotope content in the second eluent.

[0176] Implementation Scheme 6. The method according to Implementation Scheme 5, wherein the third lead-containing solution flowing from the third cassette column is optionally recycled back to the third cassette column, thereby further reducing the content of radioactive isotopes of radium or thorium in the third lead-containing solution.

[0177] Implementation Scheme 7. The method according to any one of Implementation Schemes 5-6, further comprising: (f) A fourth cassette column is loaded with a fourth loading solution containing a third lead-containing solution, the fourth cassette column having a fourth chromatographic medium containing a lead complexing medium that preferentially binds lead radioisotopes in the presence of the fourth loading solution compared to radioactive isotopes of radium and thorium, thereby separating the lead radioisotopes from the fourth loading solution; and (g) The bound lead radioisotope is eluted from the fourth cassette column with a fourth eluent, thereby forming a fourth eluent containing the lead radioisotope dissolved in the fourth eluent.

[0178] Implementation Scheme 8. The method according to Implementation Scheme 7, wherein the fourth loading solution passing through the fourth cassette column is processed and recycled back to the first or fourth cassette column for further separation of lead isotopes, recycled back to the second cassette column for further separation of lead isotopes, or discarded.

[0179] Implementation Scheme 9. The method according to any one of Implementation Schemes 7-8, wherein the fourth loading solution has a pH, i.e., pH 4L The fourth eluent has a pH value, i.e., pH 4E ; and pH 4E greater than pH 4L .

[0180] Implementation Scheme 10. The method according to any one of the foregoing implementation schemes, wherein the type of lead complexing medium contained in the first ferrule column is the same as the type of lead complexing medium in the fourth ferrule column.

[0181] Implementation Scheme 11. The method according to any one of the foregoing implementation schemes, wherein the lead comprises lead-212 or lead-203.

[0182] Implementation Scheme 12. The method according to any one of the foregoing implementation schemes, wherein radium is present in the form of radium-224 or radium-223.

[0183] Implementation Scheme 13. The method according to any one of the foregoing implementation schemes, wherein thorium is present in the form of thorium-228 or thorium-232.

[0184] Implementation Scheme 14. The method according to any one of the preceding implementation schemes, wherein one or both of the first ferrule column and the fourth ferrule column contain a lead complexing medium, said lead complexing medium being an ionicly neutral medium.

[0185] Implementation Scheme 15. The method according to any one of the preceding implementation schemes, wherein one or both of the first ferrule column and the fourth ferrule column comprise a lead complexing medium comprising one or more of a diethylene glycol amide-complexing portion and a crown ether-complexing portion.

[0186] Implementation Scheme 16. The method according to any one of the preceding embodiments, wherein one or both of the first and fourth ferrule columns comprise a lead complexing medium comprising any one or more of the following: 4,4'(5')-di-tert-butylcyclohexano-18-crown ether-6, 4,4'(5')-di-tert-butylcyclohexano-18-crown ether-6 (diluent: 1-octanol), and N,N,N',N'-tetraalkyldiglycolamide, wherein the alkyl group is the same or different linear or branched alkyl group having 2-12 carbon atoms.

[0187] Implementation Scheme 17. The method according to any one of the preceding implementation schemes, wherein the second ferrule column comprises a weak cation exchange medium comprising an ionizable carboxyl alkyl group bound to a silica-based support.

[0188] Implementation Scheme 18. The method according to any one of the preceding implementation schemes, wherein the second ferrule column comprises a carboxymethyl functional group bonded to a silica-based support.

[0189] Implementation Scheme 19. The method according to any one of the preceding implementation schemes, wherein the third ferrule column comprises a strong cation exchange medium containing sulfonic acid groups.

[0190] Implementation Scheme 20. The method according to any one of the preceding implementation schemes, wherein the third ferrule column comprises a strong cation exchange medium containing sulfonic acid groups bonded to divinylbenzene.

[0191] Implementation Scheme 21. The method according to any one of the foregoing implementation schemes, wherein the first loading solution comprises an inorganic acid.

[0192] Implementation Scheme 22. The method according to Implementation Scheme 21, wherein the inorganic acid present in the first loading solution comprises any one of HNO3, HCl, HBr, HI and H2SO4.

[0193] Implementation Scheme 23. The method according to any one of Implementation Schemes 21-22, wherein the concentration of the inorganic acid in the first solution is 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.

[0194] Implementation Scheme 24. The method according to any one of the foregoing implementation schemes, wherein the first eluent comprises a weak acid.

[0195] Implementation Scheme 25. The method according to Implementation Scheme 24, wherein the first eluent comprising a weak acid has a pH in the range of 1-5.5, 2-5, 3-5, 4-5 and / or 4.5.

[0196] Implementation Scheme 26. The method according to any one of Implementation Schemes 24-25, wherein the weak acid comprises any group of carboxylate group, sulfate group or phosphate group.

[0197] Implementation Scheme 27. The method according to any one of Implementation Schemes 24-26, wherein the weak acid comprises any one or more salts selected from acetate, citrate and oxalate.

[0198] Implementation Scheme 28. The method according to any one of Implementation Schemes 24-27, wherein the weak acid comprises ammonium acetate.

[0199] Implementation Scheme 29. The method according to any one of Implementation Schemes 20-28, wherein the concentration of the weak acid is 0.1-2.0 M, 0.5-1.5 M, 0.75-1.25 M, and / or about 1 M.

[0200] Implementation Scheme 30. The method according to any one of the preceding implementation schemes, wherein the first eluent comprises a dilute inorganic acid with a concentration not exceeding 0.1 M.

[0201] Implementation Scheme 31. The method according to Implementation Scheme 30, wherein the first eluent comprises a dilute inorganic acid, said dilute inorganic acid comprising any one of HNO3, HCl, HBr, HI and H2SO4.

[0202] Implementation Scheme 32. The method according to any one of Implementation Schemes 30-31, wherein the first eluent comprises a dilute inorganic acid at a concentration of not more than 0.1 M, 0.001-0.1 M and / or 0.01-0.1 M.

[0203] Implementation Scheme 33. The method according to any one of the foregoing implementation schemes, wherein the second loading solution is the first eluent.

[0204] Implementation Scheme 34. The method according to any one of the foregoing implementation schemes, wherein the first eluent flows from the first ferrule column to the second ferrule column without any change.

[0205] Implementation Scheme 35. The method according to any one of Implementation Schemes 1-33, wherein the first eluent is modified to form a second loading solution before being loaded onto the second ferrule column.

[0206] Implementation Scheme 36. The method according to any one of the preceding implementation schemes, wherein the second loading solution contains a weak acid.

[0207] Implementation Scheme 37. The method according to Implementation Scheme 36, wherein the second loading 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.

[0208] Implementation Scheme 38. The method according to any one of Implementation Schemes 36-37, wherein the weak acid comprises any group of carboxylate group, sulfate group or phosphate group.

[0209] Implementation Scheme 39. The method according to any one of Implementation Schemes 36-38, wherein the weak acid comprises any one or more salts selected from acetate, citrate, and oxalate.

[0210] Implementation Scheme 40. The method according to any one of Implementation Schemes 36-39, wherein the weak acid comprises ammonium acetate.

[0211] Implementation Scheme 41. The method according to any one of Implementation Schemes 36-40, wherein the concentration of the weak acid is 0.1-2.0 M, 0.5-1.5 M, 0.75-1.25 M, and / or about 1 M.

[0212] Implementation Scheme 42. The method according to any one of the preceding implementation schemes, wherein the second loading solution contains a dilute inorganic acid with a concentration not greater than 0.1 M.

[0213] Implementation Scheme 43. The method according to Implementation Scheme 42, wherein the second loading solution comprises a dilute inorganic acid, said dilute inorganic acid comprising any one of HNO3, HCl, HBr, HI and H2SO4.

[0214] Implementation Scheme 44. The method according to any one of Implementation Schemes 42-43, wherein the second loading solution contains a dilute inorganic acid with a concentration of not more than 0.1 M, 0.001-0.1 M and / or 0.01-0.1 M.

[0215] Implementation Scheme 45. The method according to any one of the foregoing implementation schemes, wherein the second eluent comprises an inorganic acid.

[0216] Implementation Scheme 46. The method according to Implementation Scheme 45, wherein the second eluent comprises any one of HNO3, HCl, HBr, HI and H2SO4.

[0217] Implementation Scheme 47. The method according to any one of Implementation Schemes 45-46, wherein the second eluent comprises an inorganic acid at a concentration of 0.01-5 M, 0.02-4 M, 0.02-3 M and / or 0.02-2 M.

[0218] Implementation Scheme 48. The method according to any one of Implementation Schemes 45-47, wherein the concentration of the inorganic acid contained in the second eluent is sufficient to form lead in anionic form in the second eluent.

[0219] Implementation Scheme 49. The method according to any one of Implementation Schemes 45-48, wherein the lead in anionic form comprises PbCl4. 2- .

[0220] Implementation Scheme 50. The method according to any one of Implementation Schemes 45-49, wherein the second eluent comprises an inorganic acid corresponding to HCl.

[0221] Implementation Scheme 51. The method according to any one of the foregoing implementation schemes, wherein the third loading solution is the second eluent.

[0222] Implementation Scheme 52. The method according to any one of the preceding implementation schemes, wherein the second eluent flows from the second ferrule column to the third ferrule column without change.

[0223] Implementation Scheme 53. The method according to any one of Implementation Schemes 1-50, wherein the second eluent is modified to form a third loading solution before being loaded onto the third ferrule column.

[0224] Implementation Scheme 54. The method according to any one of the foregoing implementation schemes, wherein the third loading solution comprises an inorganic acid.

[0225] Implementation Scheme 55. The method according to Implementation Scheme 54, wherein the third loading solution comprises any one of HNO3, HCl, HBr, HI and H2SO4.

[0226] Implementation Scheme 56. The method according to any one of Implementation Schemes 54-55, wherein the third loading solution contains an inorganic acid at a concentration of 0.01-5 M, 0.02-4 M, 0.02-3 M and / or 0.02-2 M.

[0227] Implementation Scheme 57. The method according to any one of Implementation Schemes 54-56, wherein the concentration of the inorganic acid contained in the third loading solution is sufficient to form lead in anionic form in the third loading solution.

[0228] Implementation Scheme 58. The method according to any one of Implementation Schemes 54-57, wherein the lead in anionic form comprises PbCl4. 2- .

[0229] Implementation Scheme 59. The method according to any one of Implementation Schemes 54-58, wherein the third loading solution contains an inorganic acid corresponding to HCl.

[0230] Implementation Scheme 60. The method according to any one of the preceding embodiments, wherein the third lead-containing solution corresponds to the third loading solution passing through the third ferrule column and has a lower content of radium or thorium isotopes compared to the third loading solution.

[0231] Implementation Scheme 61. The method according to any one of the foregoing implementation schemes, wherein the fourth loading solution is the third lead-containing solution.

[0232] Implementation Scheme 62. The method according to any one of the preceding implementation schemes, wherein the third lead-containing solution flows from the third ferrule column to the fourth ferrule column without alteration.

[0233] Implementation Scheme 63. The method according to any one of Implementation Schemes 1-61, wherein the third lead-containing solution is modified to form a fourth loading solution before being loaded onto the fourth ferrule column.

[0234] Implementation Scheme 64. The method according to any one of the foregoing implementation schemes, wherein the fourth loading solution comprises an inorganic acid.

[0235] Implementation Scheme 65. The method according to Implementation Scheme 64, wherein the fourth loading solution comprises any one of HNO3, HCl, HBr, HI and H2SO4.

[0236] Implementation Scheme 66. The method according to any one of Implementation Schemes 64-65, wherein the fourth loading solution comprises an inorganic acid with a concentration of 0.01-5 M, 0.02-4 M, 0.02-3 M and / or 0.02-2 M.

[0237] Implementation Scheme 67. The method according to any one of Implementation Schemes 64-66, wherein the fourth loading solution contains an inorganic acid corresponding to HCl.

[0238] Implementation Scheme 68. The method according to any one of the foregoing implementation schemes, wherein the fourth eluent comprises a weak acid.

[0239] Implementation Scheme 69. The method according to Implementation Scheme 68, wherein the fourth eluent comprising a weak acid has a pH in the range of 1-5.5, 2-5, 3-5, 4-5 and / or 4.5.

[0240] Implementation Scheme 70. The method according to any one of Implementation Schemes 68-69, wherein the weak acid comprises any group of carboxylate group, sulfate group or phosphate group.

[0241] Implementation Scheme 71. The method according to any one of Implementation Schemes 68-70, wherein the weak acid comprises any one or more salts selected from acetate, citrate, and oxalate.

[0242] Implementation Scheme 72. The method according to any one of Implementation Schemes 68-71, wherein the weak acid comprises ammonium acetate.

[0243] Implementation Scheme 73. The method according to any one of Implementation Schemes 68-72, wherein the concentration of the weak acid is 0.1-2.0 M, 0.5-1.5 M, 0.75-1.25 M, and / or about 1 M.

[0244] Implementation Scheme 74. The method according to any one of the preceding implementation schemes, wherein the fourth eluent comprises a dilute inorganic acid with a concentration not exceeding 0.1 M.

[0245] Implementation Scheme 75. The method according to Implementation Scheme 74, wherein the fourth eluent comprises a dilute inorganic acid, said dilute inorganic acid comprising any one of HNO3, HCl, HBr, HI and H2SO4.

[0246] Implementation Scheme 76. The method according to any one of Implementation Schemes 74-75, wherein the fourth eluent comprises a dilute inorganic acid at a concentration of not more than 0.1 M, 0.001-0.1 M and / or 0.01-0.1 M.

[0247] Implementation Scheme 77. The method according to any one of the preceding implementation schemes includes washing one or more lead complexing media in a first cassette column, a lead complexing media in a fourth cassette column, and a weak cation exchange media in a second cassette column with a cleaning solution, thereby further eluting one or more of radium or thorium.

[0248] Implementation Scheme 78. The method according to any one of the foregoing implementation schemes, comprising washing the strong cation exchange medium in the third ferrule column with a cleaning solution to further elute lead.

[0249] Implementation Scheme 79. The method according to any one of the foregoing implementation schemes further includes: (g) A third cassette column is loaded with a third loading solution containing a first eluent. The third cassette column has a third chromatographic medium containing a strong cation exchange medium, which, in the presence of the loading solution, binds radium or thorium radioisotopes more preferably than lead radioisotopes, thereby separating the radium or thorium radioisotopes from the third loading solution, thus forming a third lead-containing solution. This third lead-containing solution contains lead radioisotopes dissolved therein and has a lower radium or thorium radioisotope content compared to the radium or thorium radioisotope content in the first eluent. (h) Provide a third lead-containing solution to the second ferrule column as the second loading solution.

[0250] Implementation Scheme 80. The method according to Implementation Scheme 79 further includes: (i) A fourth cassette column is loaded with a fourth loading solution containing a second eluent, the fourth cassette column having a fourth chromatographic medium containing a lead complexing medium that preferentially binds lead radioisotopes to radium and thorium radioisotopes in the presence of the fourth loading solution, thereby separating the lead radioisotopes from the fourth loading solution; and (j) The bound lead radioisotope is eluted from the fourth cassette column with a fourth eluent, thereby forming a fourth eluent containing the lead radioisotope dissolved in the fourth eluent.

[0251] Implementation Scheme 81. An aqueous solution of a lead radioactive isotope, obtained by any one of the preceding implementation schemes.

[0252] Implementation Scheme 82. A method for preparing a radiopharmaceutical, comprising introducing an unchelated radiopharmaceutical into an aqueous solution containing a fourth wash solution, thereby forming a lead-chelated radiopharmaceutical.

[0253] Implementation Scheme 83. A radiopharmaceutical prepared by the method described in Implementation Scheme 82.

[0254] Implementation Scheme 84. A system for separating a lead radioisotope from a mixture comprising a lead radioisotope and a radium radioisotope or a thorium radioisotope, the system comprising a first ferrule column and a second ferrule column connected in series, each ferrule column having an inlet, an outlet, and a chamber containing a chromatographic medium located between the two, wherein: (a) The chamber in the first cassette column contains a first chromatographic medium comprising a lead complexing medium, which (i) preferentially binds to lead radioisotopes more than radioisotopes of radium and thorium in the presence of a first loading solution containing the mixture, thereby separating the lead radioisotopes from the first loading solution, and (ii) elutes the lead radioisotopes in the presence of a first eluent, thereby forming a first eluent containing lead radioisotopes dissolved in a second solution; (b) The chamber in the second cassette column contains a second chromatographic medium comprising a weak cation exchange medium that (i) preferentially binds to lead radioisotopes more than radium and thorium radioisotopes from a second loading solution containing a first eluent, thereby separating the lead radioisotopes from the second loading solution, and (ii) elutes the lead radioisotopes in the presence of a second eluent, thereby forming a second eluent containing lead radioisotopes dissolved in the second eluent. The second loading solution has a pH, i.e., pH 2L The second eluent has a pH value, i.e., pH 2E ; and pH 2L greater than pH 2E .

[0255] Implementation Scheme 85. The system according to Implementation Scheme 84, wherein the first loading solution has a pH, i.e., pH 1L The first eluent has a pH value, i.e., pH 5. 1E ; and pH 1E greater than pH 1L .

[0256] Implementation Scheme 86. The system according to any one of Implementation Schemes 84-85, further comprising: (c) A third cassette column connected in series with the first and second cassette columns, the third cassette column having an inlet, an outlet, and a chamber containing chromatographic media located between the two, wherein the chamber in the third cassette column contains a chromatographic medium comprising a strong cation exchange medium that (i) preferentially binds to radium or thorium radioisotopes in the presence of a third loading solution containing a second eluent than lead radioisotopes, thereby separating radium or thorium radioisotopes from the third loading solution, and (ii) allows lead radioisotopes in the third loading solution to pass through, thereby forming a third lead-containing solution having lead radioisotopes dissolved therein and having a lower radium or thorium radioisotope content compared to the radium or thorium radioisotope content in the second eluent.

[0257] Implementation Scheme 87. The system according to Implementation Scheme 86 further includes: (d) A fourth cassette column connected in series with the first, second, and third cassette columns, the fourth cassette column having an inlet, an outlet, and a chamber containing chromatographic media located between the two, wherein the chamber in the fourth cassette column contains a chromatographic medium comprising a lead complexing medium that (i) preferentially binds to lead radioisotopes more than radium and thorium radioisotopes in the presence of a fourth loading solution containing a third lead-containing solution, thereby separating the lead radioisotopes from the fourth loading solution, and (ii) elutes the lead radioisotopes in the presence of a fourth eluent introduced into the lead complexing medium, thereby forming a fourth eluent containing lead radioisotopes dissolved in the fourth eluent.

[0258] Implementation Scheme 88. The system according to Implementation Scheme 87, wherein the fourth loading solution has a pH, i.e., pH 4L The fourth eluent has a pH value, i.e., pH 4E ; and pH 4E greater than pH 4E .

[0259] Implementation Scheme 89. The system according to any one of Implementation Schemes 87-88, wherein the type of lead complexing medium contained in the first ferrule column is the same as the type of lead complexing medium in the fourth ferrule column.

[0260] Implementation Scheme 90. The system according to any one of the foregoing implementation schemes, wherein the lead comprises lead-212 or lead-203.

[0261] Implementation Scheme 91. The system according to any one of the foregoing implementation schemes, wherein radium exists in the form of radium-224 or radium-223.

[0262] Implementation Scheme 92. The system according to any one of the foregoing implementation schemes, wherein thorium is present in the form of thorium-228 or thorium-232.

[0263] Implementation Scheme 93. The system according to any one of the preceding implementation schemes, wherein one or both of the first ferrule column and the fourth ferrule column contain a lead complexing medium, said lead complexing medium being an ionicly neutral medium.

[0264] Implementation Scheme 94. The system according to any one of the preceding embodiments, wherein one or both of the first ferrule post and the fourth ferrule post comprises a lead complexing medium, said lead complexing medium comprising one or more of a diethylene glycol amide-complexing portion and a crown ether-complexing portion.

[0265] Implementation Scheme 95. The system according to any one of the preceding implementation schemes, wherein one or both of the first and fourth ferrule columns comprise a lead complexing medium comprising any one or more of the following: 4,4'(5')-di-tert-butylcyclohexano-18-crown ether-6, 4,4'(5')-di-tert-butylcyclohexano-18-crown ether-6 (diluent: 1-octanol), and N,N,N',N'-tetraalkyldiglycolamide, wherein the alkyl group is the same or different linear or branched alkyl group having 2-12 carbon atoms.

[0266] Implementation Scheme 96. The system according to any one of the preceding embodiments, wherein the second ferrule column comprises a weak cation exchange medium comprising an ionizable carboxyl alkyl group bound to a silica-based support.

[0267] Implementation Scheme 97. The system according to any one of the preceding implementation schemes, wherein the second ferrule column comprises a carboxymethyl functional group bonded to a silica-based support.

[0268] Implementation Scheme 98. The system according to any one of the preceding implementation schemes, wherein the third ferrule column comprises a strong cation exchange medium containing sulfonic acid groups.

[0269] Implementation Scheme 99. The system according to any one of the preceding embodiments, wherein the third ferrule column comprises a strong cation exchange medium containing sulfonic acid groups bonded to divinylbenzene.

[0270] Implementation Scheme 100. The system according to any one of the foregoing implementation schemes, wherein the lead complexing medium preferentially binds to lead radioisotopes in the presence of a first loading solution containing an inorganic acid.

[0271] Implementation Scheme 101. The system according to Implementation Scheme 100, wherein the lead complexing medium preferentially binds to lead radioactive isotopes in the presence of an inorganic acid, said inorganic acid comprising any one of HNO3, HCl, HBr, HI and H2SO4.

[0272] Implementation Scheme 102. The system according to any one of Implementation Schemes 100-101, wherein the lead complexing medium preferentially binds to lead radioisotopes in the presence of inorganic acids at concentrations 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.

[0273] Implementation Scheme 103. The system according to any one of the foregoing implementation schemes, wherein the lead complexing medium elutes lead radioisotopes in the presence of a first eluent containing a weak acid.

[0274] Implementation Scheme 104. The system according to Implementation Scheme 103, wherein a 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 4.5.

[0275] Implementation Scheme 105. The system according to any one of Implementation Schemes 103-104, wherein the lead complexing medium elutes lead radioactive isotopes in the presence of a weak acid comprising any group of carboxylate, sulfate or phosphate groups.

[0276] Implementation Scheme 106. The system according to any one of Implementation Schemes 103-105, wherein the lead complexing medium elutes lead radioactive isotopes in the presence of a weak acid comprising one or more salts selected from acetate, citrate, and oxalate.

[0277] Implementation Scheme 107. The system according to any one of Implementation Schemes 103-106, wherein the lead complexing medium elutes lead radioactive isotopes in the presence of a weak acid comprising ammonium acetate.

[0278] Implementation Scheme 108. The system according to any one of Implementation Schemes 103-107, wherein the lead complexing medium elutes the lead radioisotope in the presence of a weak acid at a concentration of 0.1-2.0 M, 0.5-1.5 M, 0.75-1.25 M and / or about 1 M.

[0279] Implementation Scheme 109. The system according to any one of the preceding implementation schemes, wherein a lead complexing medium elutes lead radioactive isotopes in the presence of a first eluent, the first eluent comprising a dilute inorganic acid with a concentration not exceeding 0.1 M.

[0280] Implementation Scheme 110. The system according to Implementation Scheme 109, wherein a lead complexing medium is used to elute lead radioactive isotopes in the presence of a dilute inorganic acid, said dilute inorganic acid comprising any one of HNO3, HCl, HBr, HI and H2SO4.

[0281] Implementation Scheme 111. The system according to any one of Implementation Schemes 109-110, wherein the lead complexing medium elutes lead radioisotopes in the presence of a first eluent, the first eluent comprising a dilute inorganic acid at a concentration not greater than 0.1 M, 0.001-0.1 M and / or 0.01-0.1 M.

[0282] Implementation Scheme 112. The system according to any one of the preceding embodiments, wherein the weak cation exchange medium preferentially binds to the lead radioisotope in the presence of a second loading solution, the second loading solution corresponding to the first eluent.

[0283] Implementation Scheme 113. The system according to any one of the preceding embodiments, wherein the weak cation exchange medium preferentially binds to the lead radioisotope in the presence of a second loading solution, the second loading solution corresponding to a first eluent, the first eluent flowing from the first ferrule column to the second ferrule column without alteration.

[0284] Implementation Scheme 114. The system according to any one of Implementation Schemes 84-112, wherein the weak cation exchange medium preferentially binds to lead radioisotopes in the presence of a second loading solution, the second loading solution corresponding to a first eluent, the first eluent having been modified to form the second loading solution prior to loading onto a second ferrule column.

[0285] Implementation Scheme 115. The system according to any one of the preceding embodiments, wherein the weak cation exchange medium preferentially binds to the lead radioisotope in the presence of a second loading solution, the second loading solution comprising a weak acid.

[0286] Implementation Scheme 116. The system according to Implementation Scheme 115, wherein a weak cation exchange medium preferentially binds a lead radioisotope in the presence of a second loading solution, the second loading solution comprising a weak acid and having a pH in the range of 1-5.5, 2-5, 3-5, 4-5 and / or 4.5.

[0287] Implementation Scheme 117. The system according to any one of Implementation Schemes 115-116, wherein the weak cation exchange medium preferentially binds to lead radioisotopes in the presence of a weak acid, said weak acid comprising any group of carboxylate, sulfate or phosphate groups.

[0288] Implementation Scheme 118. The system according to any one of Implementation Schemes 115-117, wherein the weak cation exchange medium preferentially binds to lead radioisotopes in the presence of a weak acid, said weak acid comprising one or more salts of acetate, citrate and oxalate.

[0289] Implementation Scheme 119. The system according to any one of Implementation Schemes 115-118, wherein the weak cation exchange medium preferentially binds to lead radioisotopes in the presence of a weak acid, said weak acid comprising ammonium acetate.

[0290] Implementation Scheme 120. The system according to any one of Implementation Schemes 115-119, wherein the weak cation exchange medium preferentially binds to lead radioisotopes in the presence of weak acids at concentrations of 0.1-2.0 M, 0.5-1.5 M, 0.75-1.25 M and / or about 1 M.

[0291] Implementation Scheme 121. The system according to any one of the preceding implementation schemes, wherein the weak cation exchange medium preferentially binds to lead radioisotopes in the presence of a second loading solution, the second loading solution containing a dilute inorganic acid with a concentration not exceeding 0.1 M.

[0292] Implementation Scheme 122. The system according to Implementation Scheme 121, wherein the weak cation exchange medium preferentially binds to lead radioactive isotopes in the presence of a second loading solution containing a dilute inorganic acid, said dilute inorganic acid comprising any one of HNO3, HCl, HBr, HI and H2SO4.

[0293] Implementation Scheme 123. The system according to any one of Implementation Schemes 121-122, wherein the weak cation exchange medium preferentially binds to lead radioisotopes in the presence of a second loading solution, the second loading solution comprising a dilute inorganic acid at a concentration not greater than 0.1 M, 0.001-0.1 M and / or 0.01-0.1 M.

[0294] Implementation Scheme 124. The system according to any one of the preceding implementation schemes, wherein the weak cation exchange medium preferentially binds to lead radioisotopes in the presence of a second eluent, the second eluent comprising an inorganic acid.

[0295] Implementation Scheme 125. The system according to Implementation Scheme 124, wherein the weak cation exchange medium preferentially binds to lead radioisotopes in the presence of a second eluent, the second eluent comprising any one of HNO3, HCl, HBr, HI and H2SO4.

[0296] Implementation Scheme 126. The system according to any one of Implementation Schemes 124-125, wherein the weak cation exchange medium preferentially binds to lead radioisotopes in the presence of a second eluent, the second eluent comprising an inorganic acid at a concentration of 0.01-5 M, 0.02-4 M, 0.02-3 M and / or 0.02-2 M.

[0297] Implementation Scheme 127. The system according to any one of Implementation Schemes 124-126, wherein the weak cation exchange medium preferentially binds to lead radioisotopes in the presence of a second eluent containing an inorganic acid, the concentration of which is sufficient to form lead in anionic form in the second eluent.

[0298] Implementation Scheme 128. The system according to any one of Implementation Schemes 124-127, wherein the lead in anionic form comprises PbCl4. 2- .

[0299] Implementation Scheme 129. The system according to any one of Implementation Schemes 124-128, wherein the weak cation exchange medium preferentially binds to the lead radioisotope in the presence of a second eluent containing an inorganic acid corresponding to HCl.

[0300] Implementation Scheme 130. The system according to any one of the preceding embodiments, wherein the strong cation exchange resin preferentially binds to the radioactive isotopes of radium and thorium in a third loading solution, the third loading solution corresponding to the second eluent.

[0301] Implementation Scheme 131. The system according to any one of the preceding implementation schemes, wherein the strong cation exchange resin preferentially binds to the radioactive isotopes of radium and thorium in the second eluent, the second eluent flowing from the second ferrule column to the third ferrule column without alteration.

[0302] Implementation Scheme 132. The system according to any one of Implementation Schemes 84-129, wherein the strong cation exchange resin preferentially binds to the radioactive isotopes of radium and thorium in the second eluent, the second eluent being modified to form a third loading solution prior to loading onto the third ferrule column.

[0303] Implementation Scheme 133. The system according to any one of the preceding implementation schemes, wherein the strong cation exchange resin preferentially binds radioactive isotopes of radium and thorium in the presence of a third loading solution, said third loading solution comprising an inorganic acid.

[0304] Implementation Scheme 134. The system according to Implementation Scheme 133, wherein the strong cation exchange resin preferentially binds radioactive isotopes of radium and thorium in the presence of a third loading solution comprising any one of HNO3, HCl, HBr, HI and H2SO4.

[0305] Implementation Scheme 135. The system according to any one of Implementation Schemes 133-134, wherein the strong cation exchange resin preferentially binds radioactive isotopes of radium and thorium in the presence of a third loading solution, said third loading solution comprising an inorganic acid at a concentration of 0.01-5 M, 0.02-4 M, 0.02-3 M and / or 0.02-2 M.

[0306] Implementation Scheme 136. The system according to any one of Implementation Schemes 133-135, wherein the strong cation exchange resin preferentially binds radioactive isotopes of radium and thorium in the presence of a third loading solution containing an inorganic acid, the concentration of which is sufficient to form lead in anionic form in the third loading solution.

[0307] Implementation Scheme 137. The system according to any one of Implementation Schemes 133-136, wherein the lead in anionic form comprises PbCl4. 2- .

[0308] Implementation Scheme 138. The system according to any one of Implementation Schemes 133-137, wherein the strong cation exchange medium preferentially binds radioactive isotopes of radium and thorium in the presence of a third loading solution containing an inorganic acid corresponding to HCl.

[0309] Implementation Scheme 139. The system according to any one of the preceding implementation schemes, wherein the lead complexing resin of the fourth ferrule column preferentially binds to lead radioactive isotopes in the presence of a third lead-containing solution, the third lead-containing solution flowing directly from the third ferrule column to the fourth ferrule column.

[0310] Implementation Scheme 140. The system according to any one of the preceding implementation schemes, wherein the system includes a conduit for allowing the third lead-containing solution to flow directly to the fourth ferrule column.

[0311] Implementation Scheme 141. The system according to any one of the preceding implementation schemes, wherein the lead complexing resin of the fourth ferrule column preferentially binds to lead radioactive isotopes in the presence of a third lead-containing solution, the third lead-containing solution flowing from the third ferrule column to the fourth ferrule column without alteration.

[0312] Implementation Scheme 142. The system according to any one of Implementation Schemes 84-140, wherein the lead complexing resin of the fourth ferrule column preferentially binds to lead radioactive isotopes in the presence of a third lead-containing solution, said third lead-containing solution being modified to form a fourth loading solution before being loaded onto the fourth ferrule column.

[0313] Implementation Scheme 143. The system according to any one of the preceding implementation schemes, wherein the lead complexing medium of the fourth ferrule column preferentially binds to a lead radioactive isotope in the presence of a fourth loading solution, said fourth loading solution comprising an inorganic acid.

[0314] Implementation Scheme 144. The system according to Implementation Scheme 143, wherein the lead complexing medium of the fourth ferrule column preferentially binds to a lead radioactive isotope in the presence of a fourth loading solution comprising any one of HNO3, HCl, HBr, HI and H2SO4.

[0315] Implementation Scheme 145. The system according to any one of Implementation Schemes 143-144, wherein the lead complexing medium of the fourth ferrule column preferentially binds to lead radioisotopes in the presence of a fourth loading solution, said fourth loading solution comprising an inorganic acid at a concentration of 0.01-5 M, 0.02-4 M, 0.02-3 M and / or 0.02-2 M.

[0316] Implementation Scheme 146. The system according to any one of Implementation Schemes 143-145, wherein the lead complexing medium of the fourth ferrule column preferentially binds to the lead radioisotope in the presence of a fourth loading solution containing an inorganic acid corresponding to HCl.

[0317] Implementation Scheme 147. The system according to any one of the preceding implementation schemes, wherein the lead complexing medium of the fourth ferrule column preferentially binds to lead radioisotopes in the presence of a fourth eluent, said fourth eluent comprising a weak acid.

[0318] Implementation Scheme 148. The system according to Implementation Scheme 147, wherein the lead complexing resin of the fourth ferrule column preferentially binds to lead radioisotopes in the presence of a fourth eluent, the fourth eluent comprising a weak acid and 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.

[0319] Implementation Scheme 149. The system according to any one of Implementation Schemes 147-148, wherein the lead complexing medium of the fourth ferrule column preferentially binds to a lead radioisotope in the presence of a weak acid comprising any group of carboxylate, sulfate or phosphate groups.

[0320] Implementation Scheme 150. The system according to any one of Implementation Schemes 147-149, wherein the lead complexing medium of the fourth ferrule column preferentially binds to lead radioisotopes in the presence of a weak acid comprising one or more salts of acetate, citrate, and oxalate.

[0321] Implementation Scheme 151. The system according to any one of Implementation Schemes 147-150, wherein the lead complexing medium of the fourth ferrule column preferentially binds to a lead radioisotope in the presence of a weak acid, said weak acid comprising ammonium acetate.

[0322] Implementation Scheme 152. The system according to any one of Implementation Schemes 147-151, wherein the lead complexing medium of the fourth ferrule column preferentially binds to lead radioisotopes in the presence of a weak acid at concentrations of 0.1-2.0 M, 0.5-1.5 M, 0.75-1.25 M and / or about 1 M.

[0323] Implementation Scheme 153. The system according to any one of the preceding implementation schemes, wherein the lead complexing medium of the fourth ferrule column preferentially binds to lead radioisotopes in the presence of a fourth eluent, said fourth eluent comprising a dilute inorganic acid with a concentration not greater than 0.1 M.

[0324] Implementation Scheme 154. The system according to Implementation Scheme 153, wherein the lead complexing medium of the fourth ferrule column preferentially binds to lead radioisotopes in the presence of a fourth eluent containing a dilute inorganic acid, said dilute inorganic acid comprising any one of HNO3, HCl, HBr, HI and H2SO4.

[0325] Implementation Scheme 155. The system according to any one of Implementation Schemes 153-154, wherein the lead complexing medium of the fourth ferrule column preferentially binds to lead radioisotopes in the presence of a fourth eluent, said fourth eluent comprising a dilute inorganic acid at a concentration not greater than 0.1 M, 0.001-0.1 M and / or 0.01-0.1 M.

[0326] Implementation Scheme 156. The system according to any one of the preceding embodiments, wherein the system is configured to further elute one or more of radium or thorium by washing with a cleaning solution the lead complexing medium in a first cassette column, the lead complexing medium in a fourth cassette column, and the weak cation exchange medium in a second cassette column.

[0327] Implementation Scheme 157. The system according to any one of the preceding embodiments, wherein the system is configured to include washing the strong cation exchange medium in the third ferrule column with a cleaning solution, thereby further eluting lead.

[0328] Implementation Scheme 158. The system according to any one of the foregoing implementation schemes, comprising: A third cassette column, connected in series with the first and second cassette columns, has an inlet, an outlet, and a chamber containing chromatographic media located between them. The chamber in the third cassette column contains a chromatographic medium comprising a strong cation exchange medium that (i) preferentially binds to radium or thorium radioisotopes more preferentially than lead radioisotopes in the presence of a third loading solution containing the first eluent, thereby separating radium or thorium radioisotopes from the third loading solution, and (ii) allows lead radioisotopes in the third loading solution to pass through, thereby forming a third lead-containing solution having lead radioisotopes dissolved therein and having a lower radium or thorium radioisotope content compared to the radium or thorium radioisotope content in the first eluent. The second cassette column is configured to receive a third lead-containing solution at the second loading solution, and the weak cation exchange resin in the second cassette column preferentially binds lead isotopes in the presence of the third lead-containing solution.

[0329] Implementation Scheme 159. The system according to Implementation Scheme 158 further includes: A fourth cassette column is connected in series with the first, second, and third cassette columns. The fourth cassette column has an inlet, an outlet, and a chamber containing chromatographic media located between them. The chamber in the fourth cassette column contains a chromatographic medium containing a lead complexing medium, which (i) preferentially binds to lead radioisotopes more than radium and thorium radioisotopes in the presence of a fourth loading solution containing a second eluent, thereby separating the lead radioisotopes from the fourth loading solution, and (ii) elutes the lead radioisotopes in the presence of a fourth eluent introduced into the lead complexing medium, thereby forming a fourth eluent containing lead radioisotopes dissolved in the fourth eluent.

[0330] List of cited references: [1] WO 2024 / 05018.

[0331] [2] A Lead-Selective Extraction Chromatographic Resin and its Application to Isolation of Lead from Geological Samples, Horwitz et al., Analtica Chimica Acta 292 (1994) 263-273.

[0332] [3] A Novel Strontium-Selective Extraction Chromatographic Resin, Horwitz et al., Solvent Extraction and Ion Exchange, Vol. 10 (No. 2) (1992).

[0333] [4] Optimized Production, Purification, and Radiolabeling of the 203Pb / 2212Pb Theranostic Pair for Nuclear Medicine, McNeil et al., Nature Scientific Reports, 13 (2023), 10623.

[0334] [5] Chromatographic Generator Systems for Actinides and Natural Decay Series Elements, McAlister et al., Radiochim. Acta, 99 (2011) 151-159.

[0335] [6] Optimized Methods for the Production of High Purity 203Pb Using Electroplated Thallium Targets, Saini et al., J. Nucl. Med. 64 (2023) 1791-1797.

Claims

1. A method for separating a lead radioisotope from a mixture comprising a lead radioisotope and a radium or thorium radioisotope, the method comprising: (a) Loading a first ferrule column with a first loading solution containing the mixture, wherein the first loading solution has a pH, i.e., pH 1L The first cassette column contains a first chromatographic medium comprising a lead complexing medium, which, in the presence of a first loading solution, preferentially binds lead radioisotopes to the lead complexing medium rather than to radioisotopes of radium and thorium, so that the lead radioisotopes bind to the lead complexing medium and separate from the first loading solution. (b) The bound lead radioisotope is eluted from the first ferrule column with a first eluent, thereby forming a first eluent containing the lead radioisotope dissolved in the first eluent, wherein the first eluent has a pH, i.e., pH 1E And pH 1E greater than pH 1L ; (c) Load the second ferrule column with a second loading solution containing the first eluent, wherein the second loading solution has a pH, i.e., pH 2L The second cassette column has a second chromatographic medium comprising a weak cation exchange medium that, in the presence of the second loading solution, preferentially binds lead radioisotopes over radium and thorium radioisotopes, so that lead radioisotopes bind to the weak cation exchange medium and separate from the second loading solution; and (d) Elute the lead radioisotope from the second cassette column with a second eluent, thereby forming a second eluent containing the lead radioisotope dissolved in the second eluent, wherein the second eluent has a pH, i.e., pH 2E And pH 2L greater than pH 2E .

2. The method according to claim 1, further comprising: (e) A third cassette column is loaded with a third loading solution containing a second eluent, the third cassette column having a third chromatographic medium containing a strong cation exchange medium that preferentially binds to radium or thorium radioisotopes in the presence of the third loading solution, thereby separating radium or thorium radioisotopes from the third loading solution, thereby forming a third lead-containing solution containing lead radioisotopes dissolved therein and having a lower radium or thorium radioisotope content compared to the radium or thorium radioisotope content in the second eluent.

3. The method according to claim 2, further comprising: (f) Loading the fourth ferrule column with a fourth loading solution containing the third lead-containing solution, wherein the fourth loading solution has a pH, i.e., pH 4L The fourth cassette column has a fourth chromatographic medium containing a lead complexing medium that preferentially binds to lead radioisotopes in the presence of a fourth loading solution than to radioisotopes of radium and thorium, thereby separating lead radioisotopes from the fourth loading solution. and (g) The bound lead radioisotope is eluted from the fourth ferrule column with a fourth eluent, thereby forming a fourth eluent containing the lead radioisotope dissolved in it, wherein the fourth eluent has a pH, i.e., pH 4E And pH 4E greater than pH 4L .

4. An aqueous solution containing a lead radioactive isotope, obtained by the method according to claim 1.

5. A method for preparing a radiopharmaceutical, the method according to claim 1, and further comprising chelating lead contained in a second eluent with a pharmaceutical composition, thereby forming a lead-chelated radiopharmaceutical.

6. A radiopharmaceutical prepared according to the method of claim 5.

7. A system for separating a lead radioisotope from a mixture comprising a lead radioisotope and a radium radioisotope or a thorium radioisotope, the system comprising a first ferrule column and a second ferrule column connected in series, each ferrule column having an inlet, an outlet, and a chamber containing a chromatographic medium located between the two, wherein: (a) The chamber in the first ferrule column contains a first chromatographic medium comprising a lead complexing medium, said lead complexing medium (i) being present in the mixture and having a pH, i.e., pH 1L In the presence of the first loading solution, lead radioisotopes preferentially bind to radioisotopes more than radium and thorium, thereby isolating lead radioisotopes from the first loading solution, and (ii) in a solution having pH, i.e., pH 1E Lead radioisotopes are eluted in the presence of a first eluent, thereby forming a first eluent containing lead radioisotopes dissolved in a second solution, wherein pH... 1E greater than pH 1L ; and (b) The chamber in the second ferrule column contains a second chromatographic medium comprising a weak cation exchange medium (i) which is derived from a first eluent and has a pH, i.e., pH. 2L The second loading solution preferentially binds lead radioisotopes compared to radium and thorium radioisotopes, thereby separating the lead radioisotopes from the second loading solution, and (ii) elutes the lead radioisotopes in the presence of a second eluent, thereby forming a second eluent containing lead radioisotopes dissolved in the second eluent, wherein the second eluent has a pH, i.e., pH 2E And pH 2L greater than pH 2E .

8. The system of claim 7, wherein the system further comprises: (c) A third cassette column connected in series with the first and second cassette columns, the third cassette column having an inlet, an outlet, and a chamber containing chromatographic media located between the two, wherein the chamber in the third cassette column contains a chromatographic medium comprising a strong cation exchange medium that (i) preferentially binds to radium or thorium radioisotopes in the presence of a third loading solution containing a second eluent than lead radioisotopes, thereby separating radium or thorium radioisotopes from the third loading solution, and (ii) allows lead radioisotopes in the third loading solution to pass through, thereby forming a third lead-containing solution having lead radioisotopes dissolved therein and having a lower radium or thorium radioisotope content compared to the radium or thorium radioisotope content in the second eluent.

9. The method, aqueous solution, radiopharmaceutical, or system according to any one of claims 1 to 8, wherein the lead radioisotope is lead-212 or lead-203, the radium radioisotope is radium-224 or radium-223, and the thorium radioisotope is thorium-228 or thorium-232.

10. The method, aqueous solution, radiopharmaceutical, or system according to any one of claims 1 to 8, wherein the lead complexing medium comprises a diethylene glycol amide-complexing portion and a crown ether-complexing portion.

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