Sacrificial metal-based radiation decomposition mitigation during chromatographic separation of radioisotopes

Abstract

Provided herein are methods of purifying chemical elements (e.g., radioisotopes) involving the use of sacrificial metal dopants and / or radical scavengers during the chromatographic separation of the desired elements, thereby mitigating unwanted radiation decomposition.

Description

[0001] Priority Statement This application claims priority to U.S. Provisional Application No. 63 / 538,706, filed September 15, 2023, the entire contents of which are incorporated herein by reference for all purposes. Technical Field

[0002] This article provides methods for purifying chemical elements that minimize radiodegradation of the desired element during purification. In particular, this article provides methods for purifying chemical elements that involve the use of sacrificial metal dopants and / or free radical scavengers during the chromatographic separation of the desired element, thereby mitigating unwanted radiodegradation. Background Technology

[0003] Radioactive isotopes such as lutetium-177 (Lu-177) have been found to be used in various diagnostic and therapeutic methods, including for cancer. Current methods for isolating radioactive isotopes subject them to radiation degradation during the isolation process. Therefore, there is a need for improved techniques for purifying radioactive isotopes (such as Lu-177) that minimize radiation degradation. Summary of the Invention

[0004] According to a first aspect of this disclosure, a method for purifying a chemical element includes: subjecting a composition comprising the chemical element and one or more impurities to sublimation, distillation, or chromatography to remove at least a portion of the one or more impurities from the composition to obtain a semi-purified sample; adding a metal dopant to the semi-purified sample; and subjecting the semi-purified sample containing the metal dopant to chromatographic separation to remove the metal dopant and other impurities to obtain a sample fraction rich in the chemical element.

[0005] The second aspect includes the method of the first aspect, wherein the metal dopant includes lanthanides.

[0006] The third aspect includes the method of the first or second aspect, wherein the metal dopant includes lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, or salts thereof.

[0007] The fourth aspect includes a method of any of the foregoing aspects, wherein the metal dopant is chelated.

[0008] The fifth aspect includes the method of any of the foregoing aspects, wherein the amount of the metal dopant added to the semi-purified sample exceeds the amount of the chemical element in the sample.

[0009] The sixth aspect includes a method of any of the foregoing aspects, wherein the method further includes chelating the semi-purified sample containing the metal dopant before the chromatographic separation, and dechelating the sample fraction rich in the chemical element after the chromatographic separation.

[0010] The seventh aspect includes the method of any of the foregoing aspects, wherein the chromatographic separation includes high performance liquid chromatography (HPLC).

[0011] The eighth aspect includes a method of any of the foregoing aspects, wherein the method includes subjecting the sample fraction rich in the chemical element to an additional chromatographic separation step to further enrich the chemical element.

[0012] The ninth aspect includes the method of the eighth aspect, wherein the additional chromatographic separation step includes HPLC.

[0013] The tenth aspect includes a method of any of the foregoing aspects, wherein the method comprises adding a free radical scavenger to the sample fraction rich in the chemical element before or during the additional chromatographic separation step.

[0014] The eleventh aspect includes the method of the tenth aspect, wherein the free radical scavenger is ascorbic acid or a mineral salt thereof.

[0015] The twelfth aspect includes the method of the eleventh aspect, wherein the free radical scavenger is sodium ascorbate.

[0016] The thirteenth aspect includes the method of any one of aspects eight to twelfth, wherein the sample fraction rich in the chemical element is not chelated during the additional chromatographic separation step.

[0017] The fourteenth aspect includes the method of any of the foregoing aspects, wherein the chemical element is a radioactive isotope.

[0018] The fifteenth aspect includes the method of any of the foregoing aspects, wherein the chemical element is lutetium.

[0019] The sixteenth aspect includes the method of the thirteenth aspect, wherein the chemical element is lutetium-177.

[0020] The seventeenth aspect includes the method of any of the foregoing aspects, wherein the one or more impurities include ytterbium.

[0021] The eighteenth aspect includes the method of the seventeenth aspect, wherein the one or more impurities include ytterbium-176.

[0022] The nineteenth aspect includes the method of any of the foregoing aspects, wherein the sublimation, distillation or chromatography removes at least 50% of the one or more impurities from the composition.

[0023] The twentieth aspect includes a method of any of the foregoing aspects, wherein the sublimation, distillation, or chromatography removes at least 80% of the one or more impurities from the composition.

[0024] According to the twenty-first aspect of this disclosure, a method for purifying a chemical element (e.g., a radioactive isotope) includes: subjecting a composition comprising the chemical element and one or more impurities to sublimation, distillation, or chromatography to remove at least a portion of the one or more impurities from the composition to obtain a semi-purified sample; subjecting the semi-purified sample to chromatographic separation to obtain a sample fraction rich in the chemical element; and contacting the sample fraction rich in the chemical element with a free radical scavenger and subjecting the sample fraction and the free radical scavenger to additional chromatographic separation to remove the free radical scavenger and other impurities.

[0025] The twenty-second aspect includes the method of the twenty-first aspect, wherein the method comprises chelating the semi-purified sample prior to the chromatographic separation and dechelating the sample fraction rich in the chemical element after the chromatographic separation.

[0026] The twenty-third aspect includes the method of the twenty-first or twenty-second aspect, wherein the sample fraction containing the free radical scavenger is not chelated during the additional chromatographic separation.

[0027] The twenty-fourth aspect includes the method of any one of the twenty-first to twenty-third aspects, wherein the chromatographic separation includes high performance liquid chromatography.

[0028] The twenty-fifth aspect includes the method of any one of the twenty-first to twenty-fourth aspects, wherein the additional chromatographic separation includes high performance liquid chromatography.

[0029] The twenty-sixth aspect includes the method of any one of aspects twenty-one to twenty-five, wherein the free radical scavenger is ascorbic acid or a mineral salt thereof.

[0030] The twenty-seventh aspect includes the method of the twenty-sixth aspect, wherein the free radical scavenger is sodium ascorbate.

[0031] The twenty-eighth aspect includes the method of any one of aspects twenty-one to twenty-seven, wherein the chemical element is a radioactive isotope.

[0032] The twenty-ninth aspect includes the method of any one of aspects twenty-one to twenty-eight, wherein the chemical element is lutetium.

[0033] The thirtieth aspect includes the method of any one of aspects twenty-one to twenty-nine, wherein the chemical element is lutetium-177.

[0034] The thirty-first aspect includes the method of any one of aspects twenty-first to thirtieth, wherein the one or more impurities include ytterbium.

[0035] The thirty-second aspect includes the method of the thirty-first aspect, wherein the one or more impurities include ytterbium-176.

[0036] The thirty-third aspect includes the method of any one of the twenty-first to thirty-second aspects, wherein the sublimation, distillation or chromatography removes at least 50% of the one or more impurities from the composition.

[0037] The thirty-fourth aspect includes the method of any one of aspects twenty-one to thirty-three, wherein the sublimation, distillation or chromatography removes at least 80% of the one or more impurities from the composition.

[0038] According to the thirty-fifth aspect of this disclosure, the system comprises: a composition including lutetium and one or more impurities; one or more chromatographic resins; and a free radical scavenger and / or a metal dopant.

[0039] The thirty-sixth aspect comprises the system of the thirty-fifth aspect, wherein the metal dopant comprises lanthanide elements.

[0040] The thirty-seventh aspect includes the system of the thirty-sixth aspect, wherein the metal dopant includes lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, or salts thereof.

[0041] The thirty-eighth aspect includes the system of any one of aspects thirty-five to thirty-seven, wherein the one or more chromatographic resins include anion exchange resins, cation exchange resins and / or high-performance liquid chromatography resins.

[0042] The thirty-ninth aspect includes the system of any one of aspects thirty-five to thirty-eight, wherein the free radical scavenger is ascorbic acid or a mineral salt thereof.

[0043] The fortieth aspect comprises the system of the thirty-ninth aspect, wherein the free radical scavenger is sodium ascorbate.

[0044] The forty-first aspect includes a system of any one of aspects thirty-five to forty, wherein the system is contained in a hot chamber. Attached Figure Description

[0045] Figure 1This is a flowchart illustrating an exemplary method for purifying a chemical element as described herein, involving the use of a metal dopant to prevent radiation decomposition loss of the chemical element to be purified. As shown, the method includes subjecting a composition containing the chemical element and impurities to a sublimation, distillation, or chromatographic step to remove a portion of the impurities from the sample, thereby generating a semi-purified sample. This initial purification step is also referred to herein as Stage 1. The method then includes adding a metal dopant to the semi-purified sample and subjecting the semi-purified sample with the metal dopant to chromatographic separation (also referred to herein as Stage 2) to obtain a sample fraction rich in the chemical element. The sample fraction may be subjected to additional chromatographic separation steps for further enrichment of the chemical element.

[0046] Figure 2 This is a flowchart illustrating an exemplary method for purifying a chemical element as described herein, involving the use of a free radical scavenger to prevent radiation decomposition loss of the chemical element to be purified. As shown, the method includes subjecting a composition containing the chemical element and impurities to a sublimation, distillation, or chromatographic step to remove a portion of the impurities from the sample, thereby producing a semi-purified sample. This initial purification step is also referred to herein as Stage 1. The method then includes subjecting the semi-purified sample to chromatographic separation, referred to herein as Stage 2, to obtain a sample fraction rich in the chemical element. The sample may be chelated prior to chromatographic separation (Stage 2) and dechelated after chromatographic separation. The method then involves a free radical scavenger, such as... Figure 2 As shown, a free radical scavenger can be added to a sample fraction rich in chemical elements, followed by chromatographic separation. Alternatively, the free radical scavenger can be present in or added directly to the chromatographic resin, and the sample fraction rich in chemical elements can be added to the resin separately, followed by chromatographic separation. Each of these methods results in the chromatographic separation of the chemical elements from the free radical scavenger and other residual impurities, resulting in the isolation of purified chemical elements.

[0047] Figures 3A-3C Representative diagrams of exemplary systems described herein are shown, including: compositions comprising chemical elements and one or more impurities (represented by C), metal dopants (represented by D), and chromatographic resins. Figure 3A As shown, the system can comprise each of these components, which are separate from each other. Arrows indicate potential steps that can be taken during the use of the system to purify chemical elements. For example, Figure 3A The arrows shown indicate that a dopant can be added to the composition, and then the composition can be added to the chromatographic resin. (As...) Figure 3B As shown, the system may include: a single mixture comprising a composition and a metal dopant, and a separate resin. Such a composition may be added to the resin, as indicated by the arrow. Figure 3CAs shown, the system may include a resin comprising a composition and a metal dopant.

[0048] Figures 4A-4D Representative diagrams of exemplary systems described herein are shown, including: compositions comprising chemical elements and one or more impurities (represented by C), free radical scavengers (represented by S), and chromatographic resins. Figure 4A As shown, the system can comprise each of these components, which are separate from each other. Arrows indicate potential steps that can be taken during the use of the system to purify chemical elements. For example, Figure 4A The arrows shown indicate that a free radical scavenger can be added to the composition, and then the composition can be added to the resin. (As...) Figure 4B As shown, the system may include: a single mixture comprising a composition and a free radical scavenger, and a separate resin. As indicated by the arrows, such a composition may be added to the resin. Figure 4C As shown, the system may include a resin containing a free radical scavenger, and a separate composition. As indicated by the arrow, the composition may be added to the resin. Figure 4D As shown, the system may include a resin comprising a composition and a free radical scavenger.

[0049] Figure 5A , 5B Tables 5C and 5D show the injection activity of the injection solutions with and without lanthanum chelates as shown in Table 1.

[0050] definition Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have the meanings commonly understood by one of ordinary skill in the art. The meaning and scope of terms shall be unambiguous; however, in the event of any potential ambiguity, the definitions provided herein shall prevail over any dictionary or external definition. Furthermore, unless the context requires otherwise, singular terms shall include plural forms, and plural terms shall include singular forms.

[0051] As used herein, the terms “about,” “approximately,” “substantially,” and similar terms are intended to have a broad meaning consistent with that commonly and generally accepted by those skilled in the art to which the subject matter of this disclosure pertains. Those skilled in the art, upon reviewing this disclosure, will understand that these terms are intended to allow for the description of certain features described and claimed, without limiting the scope of these features to precise numerical values ​​or idealized geometries. Therefore, these terms should be interpreted as indicating that no substantial or insignificant modifications or variations to the described and claimed subject matter should be considered within the scope of this disclosure as set forth in the appended claims. In some embodiments, the terms indicate values ​​+ / - 10% of the listed values. For example, “about” or “approximately” can indicate 0.9 to 1.1, and all values ​​included within that range.

[0052] As used herein, the terms “comprise(s)”, “include(s)”, “having”, “has”, “may”, “contain(s)”, and variations thereof are intended to be open-ended transitional phrases, terms, or words that do not exclude the possibility of additional actions or structures. Unless the context clearly indicates otherwise, the singular forms “a”, “and”, and “the” include plural indicators. This disclosure also contemplates other embodiments that “comprise” the embodiments or elements presented herein, “consist of”, and “substantially constitute”, whether or not explicitly stated.

[0053] In the description of the ranges of numbers in this article, each interval number having the same precision is explicitly considered. For example, for the range 6–9, the numbers 7 and 8 are considered in addition to 6 and 9, and for the range 6.0–7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly considered.

[0054] Preferred methods and materials are described below, but similar or equivalent methods and materials may be used in practice or testing in this disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference in their entirety. The materials, methods and embodiments disclosed herein are illustrative only and are not intended to be limiting. Detailed Implementation

[0055] Radioisotopes, or radionuclides, offer valuable strategies for cancer diagnosis and treatment. Lu-177 is a therapeutic diagnostic radionuclide that can be used for both diagnostic testing and therapeutic treatment. In particular, Lu-177 emits low-energy beta particles during its decay, making it suitable for treating cancers, including neuroendocrine tumors, prostate cancer, breast cancer, kidney cancer, pancreatic cancer, and others. Lu-177 also emits two types of gamma rays, which can be used for diagnostic testing. In the coming years, approximately 70,000 patients annually will require carrier-free Lu-177 during their medical treatment. However, methods for purifying radioisotopes such as Lu-177 are hampered by radiodegradation that occurs during purification. This disclosure addresses this and other problems by providing methods for purifying chemical elements that mitigate radiodegradation by adding metal dopants and / or free radical scavengers during the purification process.

[0056] In some respects, this article provides methods for purifying chemical elements. As used herein, the terms “element” and “chemical element” are used interchangeably and refer to a chemical element together with its isotopes and radioactive isotopes. “Radioactive isotope,” “radionuclear material,” or “radioactive isotope” refers to an isotope of an element that contains an unstable combination of neutrons and protons or excess nuclear energy. Excess nuclear energy is emitted from the nucleus in a process called radioactive decay. Given the radioactive nature of radioactive isotopes, any one or more steps of the purification methods described herein can be carried out in a hot chamber.

[0057] In some embodiments, the methods for purifying chemical elements provided herein involve subjecting a composition comprising the chemical element and one or more impurities to sublimation, distillation, or chromatography to remove at least a portion of one or more impurities from the composition. In some embodiments, sublimation, distillation, or chromatography (considered an initial purification step) removes more than 50% of one or more impurities from the composition. In some embodiments, sublimation, distillation, or chromatography removes more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more than 95% of one or more impurities from the composition. In some embodiments, the sample is then subjected to one or more chromatographic separation steps in the presence of a metal dopant and / or a free radical scavenger, which protects the chemical element of interest from radiodegradation.

[0058] In some embodiments, a method for purifying a chemical element includes: subjecting a composition comprising the chemical element and one or more impurities to sublimation, distillation, or chromatography to remove at least a portion of the one or more impurities from the composition to obtain a semi-purified sample; adding a metal dopant to the semi-purified sample; and subjecting the semi-purified sample containing the metal dopant to chromatographic separation to remove the metal dopant and other impurities, thereby obtaining a sample fraction rich in the chemical element. Undesirably, the metal dopant can act as a sacrificial target for radiodegradation, causing significant radiodegradation of the metal dopant while shielding the chemical element from radiodegradation damage. In some embodiments, the amount of radiodegradation shielding (e.g., protection) imparted to the chemical element by the metal dopant depends on the relative amounts of the metal dopant and the chemical element present in the semi-purified sample. The amount of metal dopant added to the semi-purified sample should be adjusted to minimize contamination during chromatographic separation while providing sufficient protection against radiodegradation to the chemical element to be purified. In some embodiments, the amount of metal dopant added to the semi-purified sample exceeds the amount of the chemical element present in the semi-purified sample. In some embodiments, the amount of metal dopant added to the semi-purified sample exceeds the amount of the chemical element present in the semi-purified sample by at least 10%. In some embodiments, the amount of metal dopant added to the semi-purified sample exceeds the amount of the chemical element present in the semi-purified sample by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%.

[0059] Any suitable metal dopant can be used. Generally, the metal dopant should be different from the metal of the desired element to be purified so that the metal dopant can be separated from the element during subsequent chromatographic separation steps. In some embodiments, the metal dopant includes lanthanides. In some embodiments, the metal dopant includes lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, or salts thereof. In some embodiments, the metal dopant is chelated. In some embodiments, the metal dopant is not chelated.

[0060] In some embodiments, the method further includes chelating a semi-purified sample containing a metal dopant prior to chromatographic separation. In some embodiments, chelating the semi-purified sample includes dissolving the sample in an acid, adding a chelating agent, and neutralizing with a base. In some embodiments, the chelated semi-purified sample is then subjected to chromatographic separation to remove the metal dopant (e.g., the chelated metal dopant) from the chelated element and produce a chemically rich sample fraction. In some embodiments, the method then includes dechelating the chemically rich sample fraction. In some embodiments, dechelating the chemically rich sample fraction includes adding an acid to the sample.

[0061] In some embodiments, the method further includes subjecting the chemically enriched sample fraction to an additional chromatographic separation step to further enrich the chemical element (e.g., further remove unwanted impurities). In some embodiments, the chemically enriched sample fraction is not chelated during the additional chromatographic separation step. In some embodiments, no metal dopant is added during the additional chromatographic separation step. In some embodiments, the method includes adding a free radical scavenger to the chemically enriched sample fraction before or during the additional chromatographic separation step.

[0062] In some embodiments, this document provides a method for purifying a chemical element, the method comprising: subjecting a composition comprising the chemical element and one or more impurities to sublimation, distillation, or chromatography to remove at least a portion of the one or more impurities from the composition to obtain a semi-purified sample; subjecting the semi-purified sample to chromatographic separation to obtain a sample fraction rich in the chemical element; and contacting the sample fraction rich in the chemical element with a free radical scavenger and subjecting the sample fraction and the free radical scavenger to additional chromatographic separation to remove the free radical scavenger and other impurities. In some embodiments, contacting the sample fraction rich in the chemical element with the free radical scavenger comprises: adding the free radical scavenger to the sample fraction rich in the chemical element, and then adding the sample fraction rich in the chemical element and containing the free radical scavenger to a chromatographic resin. In some embodiments, contacting the sample fraction rich in the chemical element with the free radical scavenger comprises adding the sample fraction rich in the chemical element and the free radical scavenger to the chromatographic resin separately. In some embodiments, contacting a chemically enriched sample fraction with a free radical scavenger includes adding the chemically enriched sample fraction to a chromatographic resin (e.g., a column) containing (e.g., pre-loaded) a free radical scavenger. In some embodiments, the method includes chelating a semi-purified sample prior to chromatographic separation and dechelating the chemically enriched sample fraction after chromatographic separation. In some embodiments, the sample fraction containing the free radical scavenger is not chelated during additional chromatographic separation.

[0063] In some embodiments, the methods provided herein involve adding a radical scavenger before or during chromatographic separation to protect chemical elements in a sample from radioactive decomposition during purification. In some embodiments, the radical scavenger is added to the sample. For example, in some embodiments, the radical scavenger is added to the sample, and then the sample containing the radical scavenger is added to a resin. In some embodiments, the radical scavenger is added to a chromatographic column (e.g., resin) before, simultaneously with, or after the sample is added to the resin. In some embodiments, the radical scavenger is present in the chromatographic resin, such as in a dried form. As used herein, the term "radical scavenger" refers to a compound that prevents the formation of reactive oxygen species (called free radicals) or removes them from the environment. Radical scavengers are a broad class of compounds, including naturally occurring and synthetic compounds. Non-limiting examples of free radical scavengers include catalase, glutathione, peroxidase, carotenoids (e.g., oxysubunit-carotenoids), superoxide dismutase (SOD), tocopherols (e.g., α-tocopherol / vitamin E), ascorbic acid (vitamin C), β-carotene (vitamin A), selenium, uric acid, bilirubin, albumin, thiols, etc., including their salts (e.g., mineral salts). Generally, the free radical scavenger added prior to one or more chromatographic separation steps should possess sufficient free radical scavenging properties while still being able to separate from the chemical element of interest during chromatographic separation. The amount of free radical scavenger added should be adjusted to provide sufficient protection against radiodegradation while minimizing unwanted residual contamination in the enriched fraction after chromatographic separation. In some embodiments, the free radical scavenger comprises ascorbic acid or a mineral salt thereof. In some embodiments, the free radical scavenger comprises sodium ascorbate.

[0064] For any of the methods provided herein, the presence of one or more impurities in the composition depends on the generation or additional method of the chemical element to be purified. In some embodiments, the Lu-177 to be purified is produced by a neutron capture reaction of ytterbium-176 (Yb-176). Such a neutron capture reaction produces Yb-177, which then rapidly (with a half-life of 1.911 hours) β-decays into Lu-177. Yb-174 impurities are typically present in Yb-176, leading to further Lu-175 impurities in the final product. This process is considered a “support-free” process. The process can be carried out using ytterbium metal or ytterbium oxide. In some embodiments, the purification methods provided herein are particularly useful for purifying Lu-177 from a “support-free” process. Therefore, in some embodiments, the composition comprises Lu-177 and one or more impurities, wherein one or more impurities include ytterbium. In some embodiments, one or more impurities include Yb-176. In some embodiments, one or more impurities include Yb-176 and Yb-174.

[0065] In some embodiments, the method includes subjecting a composition comprising a chemical element and one or more impurities to a sublimation or distillation process. In some embodiments, the sublimation or distillation process is performed before adding a metal dopant and / or a free radical scavenger to the composition. Such an initial sublimation / distillation step removes a relatively large percentage of impurities before chromatographic separation, thereby limiting the amount of impurities entering the chromatographic resin. This improves the recovery rate of the desired chemical element to be purified while reducing the amount of time required for such chromatographic purification. Suitable sublimation and distillation processes, together with the containers (e.g., crucibles) in which such processes can be performed, are described in PCT Publication No. WO 2021202914A1, the entire contents of which are incorporated herein by reference for all purposes. In sublimation, the solid phase of the element is directly converted to a gaseous phase via heating, and the gaseous phase can then be collected for subsequent use. In distillation, the solid is heated to its boiling point (through the liquid phase) and vaporized. The vaporized fraction can then be recovered downstream after condensation of the vapor. For example, ytterbium can be vaporized (and collected downstream for later use), leaving behind lutetium-rich material. Generally, the pressure and temperature of the sublimation or distillation reaction depend on the vapor pressure difference between the chemical element to be purified and one or more impurities.

[0066] In some embodiments, the composition is a solid composition comprising a chemical element and one or more impurities. In some embodiments, the composition is a solid composition comprising lutetium and ytterbium, and the initial purification step includes sublimation or distillation of ytterbium from the composition, leaving a semi-purified composition rich in lutetium. For example, in some embodiments, the method includes a temperature of about 400°C to about 3000°C and about 1 x 10⁻⁶ ppm. -8 Ytterbium is sublimated or distilled from the composition at a pressure of approximately 1520 Torr.

[0067] In some embodiments, the methods provided herein include subjecting a composition comprising a chemical element and one or more impurities to chromatography to remove a portion of one or more impurities from the sample prior to a subsequent chromatographic separation step. In some embodiments, the methods provided herein include subjecting the composition comprising a chemical element and one or more impurities to a sublimation or distillation process to remove a portion of one or more impurities, and subsequently subjecting the resulting semi-purified composition to one or more chromatographic separation steps. During at least one of the one or more chromatographic separation steps, the semi-purified composition may be chelated. As used herein, the terms “chromatography” or “chromatographic separation” refer to any type of chromatography, including, for example, column chromatography, plate chromatography, thin-film chromatography, or high-performance liquid chromatography (HPLC). Generally, chromatography involves separating a mixture into its components by dissolving the mixture in a fluid solvent (e.g., a gas or liquid) called a mobile phase, which carries the mixture through a system comprising a stationary material called a stationary phase. The different components of the mixture have different affinities for the stationary phase and therefore travel through the stationary phase at different rates, thereby allowing the components of the mixture to separate from each other.

[0068] In some embodiments, the chromatography includes ion-exchange chromatography. Ion-exchange chromatography is a chromatographic technique that separates components in a mixture based on their affinity for an ion exchanger. Ion-exchange chromatography includes anion-exchange chromatography and cation-exchange chromatography. In cation-exchange chromatography, the stationary phase is negatively charged, and positively charged molecules are attracted to the stationary phase. For example, the pH used in cation-exchange chromatography may be lower than the isoelectric point (pI) of the molecule of interest, so the molecule is positively charged and attracted to negatively charged ions (anions) on the stationary phase. Alternatively, in anion-exchange chromatography, the stationary phase is positively charged, and negatively charged molecules are attracted to the stationary phase. For example, the pH used in anion-exchange chromatography may be higher than the isoelectric point of the molecule of interest, so the molecule of interest is negatively charged and attracted to positively charged ions (cations) on the stationary phase. Cation exchange or anion exchange chromatography can be carried out by adding a suitable acid or base to a composition comprising a chemical element and one or more impurities to generate a mobile phase having a suitable pH for the desired type of chromatography and resin.

[0069] As an illustrative example, a solution containing a chemical element and one or more impurities can be prepared in dilute HCl (i.e., 0.01-5 N HCl). This can be applied to a solution-filled or dried ion exchange column, and the chemical element (e.g., Lu-177) can be eluted with an additional dilute HCl wash. This is typically described in U.S. Patent No. 7,244,403, where the readily handleable solution is usually a dilute solution of a strong acid (typically HCl). The resin bed can be in the form of a strong anion exchange resin in the column, and contact occurs as the solution flows through the column. In some embodiments, the resin is a strongly basic anion exchange resin with approximately 8% crosslinking. First, an HCl solution is flowed through the column to form an HCl-treated column, then a NaCl solution is flowed through the HCl-treated column to form a NaCl-treated column, and then sterile water is flowed through the NaCl-treated column. These preparatory steps facilitate the elution of a sterile, pyrogen-free product. The resin can then be dried before the application of the lutetium solution. In some embodiments, the anion exchange resin is in powder form, typically having particles with a size of about 100 to about 200 mesh. To accelerate the flow of the solution through the column, a sterile gas pressure can be applied to the top of the column. This can be done by injecting a sterile gas (preferably air) into the upper part of the column to propel the solution of the chemical element (e.g., Lu-177) through the column. The purity of the chemical element recovered by such a process can be higher than that obtained before column chromatography using an anion exchange column.

[0070] In some embodiments, cation exchange resins can be used to purify chemical elements. As an illustrative example, and as generally described by U.S. Patent No. 9,816,156, the method includes: loading a first column filled with cation exchange material with a composition comprising a chemical element and one or more impurities dissolved in a mineral acid; thus exchanging the protons of the cation exchange material with ammonium ions using an NH4Cl solution; and washing the cation exchange material of the first column with water. The outlet of the first column is connected to the inlet of a second column, also filled with cation exchange material. A gradient of water and a chelating agent is then applied to the columns, starting at 100% FLO and decreasing to 0.2 M of chelating agent at the inlet of the first column, to elute lutetium from both the first and second columns. Illustrative examples of chelating agents include, but are not limited to, α-hydroxyisobutyrate [HIBA], citric acid, citrate, butyric acid, butyrate, EDTA, EGTA, and ammonium ions. The method may also include determining a radioactivity dose at the outlet of the second column to identify the elution of a chemical element (e.g., Lu-177). In some embodiments, a first eluent from the outlet of a second column in the container is collected, and then a chelating agent is protonated to deactivate it for forming a complex with a chemical element (e.g., Lu-177). The method may also include: continuously feeding an acidic eluent to the inlet of a final column, loading the final column with cation exchange material, washing away the chelating agent with a dilute mineral acid at a concentration below about 0.1 M, washing the cation exchange material of the final column with mineral acids of various concentrations ranging from about 0.01 to 2.5 M, removing trace amounts of other metal ions from the lutetium solution; and eluting ions from the final column with a high concentration of mineral acid from about 1 M to 12 M. The solvent and mineral acid can be removed from the collected eluent by evaporation.

[0071] In some implementations, chromatography includes HPLC. HPLC is a chromatographic technique that relies on a pump to pass a pressurized liquid solvent containing a sample mixture through a column. The column includes an adsorbent material, such as silica particles, polymer particles, etc. The components of the mixture are separated from each other due to their varying degrees of interaction with the adsorbent material within the column. Compared to conventional low-pressure liquid chromatography, HPLC uses smaller resin sizes and smaller adsorbent particles for the stationary phase, and therefore achieves higher resolving power when separating mixtures.

[0072] Chromatographic separation (e.g., HPLC) can be performed on a suitable column and eluted with a suitable mobile phase, which may vary depending on the method development scenario. For example, the column may be a cation exchange column, an anion exchange column, a reversed-phase column, etc., and the mobile phase can be any suitable mobile phase determined to achieve the separation of the desired components in the sample. The mobile phase can be water-based or organic solvent-based. Illustrative examples include, but are not limited to, water, alcohols, alkanes, ethers, esters, acids, bases, and aromatic hydrocarbons. In various embodiments, the mobile phase may include water, methanol / water, methanol / trifluoroacetic acid / water, and / or methanol mobile phases. In some embodiments, the chromatography uses a stationary phase comprising particles such as silica particles, alumina particles, polymer particles, or (C1-C2) particles. 18 Derived antiphases such as C1-C 18 , phenyl, pentafluorophenyl, C1-C 18 The chromatography is performed using an alkyl-phenyl or polymer-based reversed-phase method. In some embodiments, the chromatography is carried out using a mobile phase consisting of water and 0-40% (by volume) of an organic solvent miscible with water. The organic solvent can be any one or more of methanol, ethanol, propanol, isopropanol, acetonitrile, acetone, N,N-dimethylformamide, dimethyl sulfoxide, or tetrahydrofuran. The solvent may further comprise a mobile phase containing up to 10% (w / w) of an ion-pairing additive, which consists of a cationic and anionic moiety. In some embodiments, the cationic moiety is H... + Li + Na + K + 、Rb + Cs + NH4 + Or C1-C8 tetraalkylammonium. In some embodiments, the anionic moiety is F. - Cl - ,Br - I - Sulfate, hydrogen sulfate, nitrate, perchlorate, methanesulfonate, trifluoromethanesulfonate, (C2-C 18 Alkyl) sulfonate, formate, acetate, (C2-C) 18 Alkyl)carboxylate, lactate, malate, citrate, 2-hydroxyisobutyrate, mandelic acid, diglycolate, or tartrate.

[0073] In some implementations, chromatographic separation can be performed using HPLC at C8 and C6. 18Alternatively, it can be achieved on a phenyl-hexyl reverse phase. In some embodiments, the mobile phase may be water and 3-40 vol% methanol, ethanol, or acetonitrile. Optionally, a buffer solution of 0.01-0.1 mol / L may be used in the mobile phase. Exemplary buffer solutions include sodium acetate (e.g., sodium acetate at pH 4.5), ammonium formate (e.g., ammonium formate at pH 7.00), or ammonium acetate (e.g., ammonium acetate at pH 7.0).

[0074] In some embodiments, the methods provided herein involve chelating a composition and / or a semi-purified sample. For example, in some embodiments, the method includes chelating a composition comprising a chemical element and one or more impurities, and subjecting the chelated composition to chromatography to remove a portion of one or more impurities, thereby obtaining a semi-purified sample. As another example, in some embodiments, the method includes subjecting a composition comprising a chemical element and one or more impurities to sublimation / distillation to remove a portion of one or more impurities, and subsequently chelating the semi-purified sample before performing one or more subsequent chromatographic separation steps. In some embodiments, the sample is chelated during some chromatographic separation steps and not chelated during others. For example, in some embodiments, the method includes performing at least two chromatographic separation steps after removing at least a portion of one or more impurities from a composition comprising a chemical element and one or more impurities by chromatography, sublimation, or distillation, and chelating the sample during a first step of these two chromatographic separation steps, and not chelating the sample during a second step of these two chromatographic separation steps. In some embodiments, the sample is chelated and a metal dopant is added to the sample. For example, in some embodiments, a semi-purified sample is chelated, and then a metal dopant is added to the sample. As another example, in some embodiments, a metal dopant is added to a semi-purified sample, and then the semi-purified sample containing the metal dopant is chelated. In some embodiments, the sample is dechelated after chromatographic separation. For example, in some embodiments, chemically rich sample fractions are dechelated after chromatographic separation.

[0075] In some embodiments, chelating the sample includes: dissolving the sample in an acid to form a dissolution solution, adding a chelating agent to the dissolution solution, and neutralizing with a base to form a chelated solution. In some embodiments, chemical elements, one or more impurities, and / or metal dopants are chelated using such a process. For example, in some embodiments, chemical elements and one or more impurities are chelated using such a process. In some embodiments, chemical elements, one or more impurities, and metal dopants are chelated using such a process. The initial dissolution of lutetium in acid can be carried out using an acid such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, peroxysulfuric acid, perchloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, or any two or more mixtures thereof. The concentration of the acid can be from about 0.01 M to about 6 M. This includes concentrations from about 1 M to about 6 M and from about 2 M to about 6 M. In some embodiments, a chelating agent is then added along with a base (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, NH4+). 4 (OH or alkyl ammonium hydroxide) to neutralize the acid and produce a chelated chemical element. In some embodiments, the concentration of the base is from about 0.01 M to about 6 M.

[0076] In some embodiments, a chromatographic separation step is performed after chelation. In some embodiments, a chromatographic separation step is performed on a semi-purified sample including a metal dopant. In some embodiments, the chemical element in the semi-purified sample is chelated. In some embodiments, the chemical element and the metal dopant are chelated. For example, in some embodiments, the semi-purified chelated sample including the metal dopant is subjected to HPLC after chelation. In some embodiments, the sample is dechelated after one or more chromatographic separation steps. In some embodiments, dechelation includes contacting the sample (e.g., a sample fraction rich in a chemical element) with an acid such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, peroxysulfuric acid, perchloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, or trifluoroacetic acid, or a mixture of any two or more thereof. In some embodiments, dechelation / dechelation is achieved by using HCl (0.01-12 mol / L) at 25°C to 95°C for a period of 5 minutes to 24 hours.

[0077] The methods described herein have been found to be useful for purifying any desired chemical element (e.g., a radioactive isotope). In some embodiments, the chemical element includes lutetium. In some embodiments, the chemical element includes Lu-177. In some embodiments, the chemical element includes Lu-177, and one or more impurities include ytterbium. In some embodiments, the chemical element includes rubidium (e.g., rubidium-82), thallium (thallium-201), fluorine (fluorine-18), iridium (iridium-192), palladium (palladium-103), strontium (e.g., strontium-89), rhenium (e.g., rhenium-186), bismuth (bismuth-213), boron (e.g., boron-10), gadolinium (e.g., gadolinium-157), cesium (cesium-131), yttrium (e.g., yttrium-90), and iodine (e.g., iodine-131, iodine-125). Samarium (e.g., Samarium-153), astatine (e.g., Astatine-211), lead (e.g., Lead-212), radium (e.g., Radium-223), actinium (e.g., Actinium-225), thorium (e.g., Thorium-227), molybdenum (e.g., Molybdenum-99), technetium (e.g., Technetium-99), terbium (e.g., Terbium-149, Terbium-152, Terbium-155, Terbium-161), xenon (e.g., Xenon-133), cobalt (e.g., Cobalt-60), or phosphorus (e.g., Phosphorus-32).

[0078] In some embodiments, the methods provided herein achieve chemical elements with a purity greater than 99% based on isotopes after purification. In some embodiments, the methods provided herein achieve chemical elements with a purity greater than 99.9%, greater than 99.99%, greater than 99.999%, greater than 99.9999%, or greater than 99.99999% based on isotopes after purification. For example, in some embodiments, the methods provided herein achieve purified Lu-177 with a purity greater than 99% based on isotopes. This includes Lu-177 with a purity greater than 99.9%, greater than 99.99%, greater than 99.999%, or greater than 99.9999% based on isotopes. Furthermore, one or more impurities can be collected (e.g., by sublimation, by distillation, or by chromatographic separation) and recycled. For example, in compositions comprising lutetium and ytterbium, ytterbium can be collected and recycled, such as for future generation of Lu-177 by irradiation.

[0079] In some respects, this document provides systems comprising: compositions including chemical elements and one or more impurities; one or more chromatographic resins; and free radical scavengers and / or metal dopants. Such systems provide a method for purifying chemical elements as described herein, while minimizing the radiation decomposition loss of the chemical elements during purification.

[0080] In some embodiments, the chemical element includes lutetium. In some embodiments, the chemical element includes Lu-177. In some embodiments, the system includes the aforementioned chemical elements, such as rubidium (e.g., rubidium-82), thallium (thallium-201), fluorine (fluorine-18), iridium (iridium-192), palladium (palladium-103), strontium (e.g., strontium-89), rhenium (e.g., rhenium-186), bismuth (bismuth-213), boron (e.g., boron-10), gadolinium (e.g., gadolinium-157), cesium (e.g., cesium-131), yttrium (e.g., yttrium-90), and iodine (e.g., iodine-131, iodine- 125), samarium (e.g., samarium-153), astatine (e.g., astatine-211), lead (e.g., lead-212), radium (e.g., radium-223), actinium (e.g., actinium-225), thorium (e.g., thorium-227), molybdenum (e.g., molybdenum-99), technetium (e.g., technetium-99), terbium (e.g., terbium-149, terbium-152, terbium-155, terbium-161), xenon (e.g., xenon-133), cobalt (e.g., cobalt-60), or phosphorus (e.g., phosphorus-32).

[0081] The system may include chromatographic resins suitable for any type of chromatography, such as column chromatography, thin-film chromatography, plate chromatography, etc. In some embodiments, the system includes one or more anion exchange resins, one or more cation exchange resins, and / or one or more high-performance liquid chromatography resins. In some embodiments, the system includes one or more fluids (e.g., gases, liquids) or buffers suitable for different chromatographic types. Suitable chromatographic fluids (e.g., solvents, buffers, water, etc.) have been described above. For example, in some embodiments, the system includes water-based or organic solvent-based fluids, such as fluids containing water, alcohols, alkanes, ethers, esters, acids, bases, or aromatic hydrocarbons.

[0082] In some embodiments, the metal dopant includes lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, or salts thereof.

[0083] In some embodiments, the system includes a chelating agent. In some embodiments, the system includes one or more components for chelating and / or dechelating chemical elements (e.g., radioactive isotopes), including the suitable acids and / or bases described above.

[0084] In some implementations, the system is contained within a hot chamber.

[0085] The invention, which is generally described in this way, will be more readily understood by referring to the following embodiments, which are provided by way of illustration and are not intended to limit the invention.

[0086] Example Example 1 Radiodecomposition losses during chromatographic separation reduce the efficiency of existing purification techniques for radioisotopes such as Lu-177. In particular, high levels of radiodecomposition losses (greater than 25%) are observed during the first chromatographic separation step after the initial removal of most impurities (such as ytterbium) from the sample. Therefore, this paper presents experiments to develop effective strategies to mitigate radiodecomposition losses. Specifically, lanthanum chelates were added to the sample to determine whether the presence of a sacrificial metal dopant would reduce radiodecomposition losses.

[0087] The sample, containing ytterbium (Yb-176) and lutetium (Lu-177), was first subjected to an initial purification step (referred to as Stage 1) to remove most of the ytterbium from the sample. Stage 1 purification could be achieved by sublimation, distillation, or chromatography. Following Stage 1, a lanthanum chelate (50 mg) was added to the sample, and chromatographic separation was performed (referred to as Stage 2). As a control, the sample was subjected to Stage 1 purification and subsequent chromatography (Stage 2) without the addition of the lanthanum chelate. The results are shown in Table 1.

[0088] Table 1. Mitigation of radiodegradation by lanthanum chelates

[0089] As shown, the addition of the lanthanum chelate significantly reduced the radiodecomposition loss observed in Stage 2. Similar injection activities of Injection 1 and Injection 2 (without the radiodecomposition mitigator) and Injection 4 (with the lanthanum chelate) demonstrate a 2.5-fold reduction in radiodecomposition loss in the presence of the lanthanum chelate. Furthermore, the injection activity in row 3, exceeding two-fold, still indicates an approximately 2-fold reduction in radiodecomposition loss. Figure 1 Figures A, 1B, 1C, and 1D show the injection activity of solutions 1, 2, 3, and 4, respectively.

[0090] To confirm that the lanthanum chelate did not contaminate the final purified sample, Lu-177 was collected after stage 2 and analyzed by IPC-MS. The results showed that high levels of lanthanum were not present in the purified product. The first experiment showed that lanthanum was present in the purified Lu-177 product at less than 10 parts per billion (ppb), and the second experiment demonstrated that lanthanum was present in the purified Lu-177 product at only 58 bbp.

[0091] In summary, these results demonstrate that sacrificial metal dopants such as lanthanum mitigate radiation decomposition losses during chromatographic separation of Lu-177 without causing significant levels of contamination in the purified product.

[0092] Example 2 In some methods for purifying radioisotopes (such as Lu-177), multiple chromatographic separation steps are used. Radiation loss can occur during any of these separation steps, and therefore this paper investigates additional techniques to mitigate radiation loss.

[0093] In some of the methods presented herein, an initial purification step (Stage 1), such as chromatography, distillation, or sublimation, is performed to remove most impurities from the sample. The sample is then subjected to chromatography (Stage 2). Additional chromatographic steps (Stage 3) can be performed to further enrich the desired chemical elements. Example 1 demonstrates that adding a metal dopant (such as a lanthanum chelate) before Stage 2 effectively mitigates radiodegradation. However, radiodegradation losses are also observed during Stage 3. To mitigate this loss, the free radical scavenger sodium ascorbate is added to the sample after Stage 2 and before Stage 3 chromatography. A direct comparison was made between samples containing sodium ascorbate and samples not exposed to sodium ascorbate during Stage 3 chromatography. The results are shown in Table 2.

[0094] Table 2. Mitigation of radiodegradation by sodium ascorbate

[0095] As shown, sodium ascorbate provides significant protection against radiodegradation. Similar comparisons of injectable activities (such as injections 2 and 3 without radiodegradation mitigators, and injection 6 with sodium ascorbate) show a 1.5-2 fold reduction in radiodegradation loss in the presence of sodium ascorbate during stage 3 purification.

Claims

1. A method for purifying chemical elements, the method comprising: a) subjecting a composition comprising the chemical element and one or more impurities to sublimation, distillation or chromatography to remove at least a portion of the one or more impurities from the composition to obtain a semi-purified sample; b) Add a metal dopant to the semi-purified sample; as well as c) subject the semi-purified sample containing the metal dopant to chromatographic separation to remove the metal dopant and other impurities, thereby obtaining a sample fraction rich in the chemical element.

2. The method according to claim 1, wherein, The metal dopants include lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, or salts thereof.

3. The method according to claim 2, wherein, The metal dopant is chelated.

4. The method according to claim 1, wherein, The amount of the metal dopant added to the semi-purified sample exceeds the amount of the chemical element in the sample.

5. The method of claim 1, further comprising chelating the semi-purified sample containing the metal dopant prior to the chromatographic separation, and dechelating the sample fraction rich in the chemical element after the chromatographic separation.

6. The method of claim 1, further comprising subjecting the sample fraction rich in the chemical element to an additional chromatographic separation step to further enrich the chemical element.

7. The method of claim 6, further comprising adding a free radical scavenger to the sample fraction rich in the chemical element prior to the additional chromatographic separation step.

8. The method according to claim 6, wherein, During the additional chromatographic separation step, the sample fraction rich in the chemical element is not chelated.

9. The method according to claim 8, wherein, The chemical element is lutetium.

10. The method according to claim 1, wherein, The chemical element is a radioactive isotope.

11. The method according to any one of claims 1-10, wherein, The one or more impurities include ytterbium.

12. A method for purifying a chemical element, the method comprising: a) subjecting a composition comprising the chemical element and one or more impurities to sublimation, distillation or chromatography to remove at least a portion of the one or more impurities from the composition to obtain a semi-purified sample; b) subject the semi-purified sample to chromatographic separation to obtain a sample fraction rich in the chemical element; as well as c) Contacting the sample fraction rich in the said chemical element with a free radical scavenger and subjecting the sample fraction and the free radical scavenger to additional chromatographic separation to remove the free radical scavenger and other impurities.

13. The method of claim 12, further comprising chelating the semi-purified sample prior to the chromatographic separation, and dechelating the sample fraction rich in the chemical element after the chromatographic separation.

14. The method according to claim 12, wherein, During the additional chromatographic separation, the sample fraction containing the free radical scavenger is not chelated.

15. The method according to claim 12, wherein, The chemical element is lutetium.

16. The method according to claim 12, wherein, The chemical element is a radioactive isotope.

17. The method according to any one of claims 12-16, wherein, The one or more impurities include ytterbium.

18. A system comprising: a) A composition comprising lutetium and one or more impurities; b) One or more chromatographic resins; as well as c) Free radical scavengers and / or metal dopants.

19. The system according to claim 18, wherein, The metal dopants include lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, or salts thereof.

20. The system according to claim 18 or claim 19, wherein, The system is contained within a hot chamber.

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