Materials and processes for producing radioisotopes

Abstract

The present disclosure generally relates to materials, processes, generators, and / or systems for producing radioisotopes. The present disclosure also generally relates to ceramic materials containing radioisotopes suitable for use in radioisotope generators. The present disclosure also generally relates to processes, generators, and / or systems for producing and capturing radioisotopes. The present disclosure also generally relates to the preparation of radioisotope solutions for use in radiopharmaceutical and / or other clinical applications.

Description

[Technical field]

[0001] The present disclosure generally relates to materials, processes, generators, and / or systems for producing radioisotopes. The present disclosure also generally relates to ceramic materials containing radioisotopes suitable for use in radioisotope generators. The present disclosure also generally relates to processes, generators, and / or systems for producing and capturing radioisotopes. The present disclosure also generally relates to the preparation of radioisotope solutions for use in radiopharmaceutical and / or other clinical applications. [Background technology]

[0002] Radioisotopes have a variety of uses, including medical applications as radiopharmaceuticals, where radioisotopes can effectively deliver lethal radiation directly to cancer cells with little collateral damage to surrounding healthy tissue. However, the clinical uptake of this form of therapy is limited by the availability of suitable radioisotopes, and due to various manufacturing constraints, there is a limited global supply, with the current supply of alpha-emitting radioisotopes worldwide being only sufficient to treat approximately 2000 patients per year. Furthermore, radioisotopes produced by current methods are often contaminated with impurities, including radiochemical impurities that are difficult to filter or remove from the desired radioisotope, which can hinder clinical applications.

[0003] A few radioisotopes, such as lutetium-177 ( 177 Lu) and Actinium-225 ( 225 Ac) are produced for therapeutic / clinical trial use. However, producing these isotopes in clinically useful quantities requires complex operations involving, for example, large particle accelerators or nuclear reactors. Thus, the supply chain for these radioisotopes is cumbersome and expensive and is therefore limited to only a few manufacturing facilities worldwide.

[0004] Lead-212( 212Lead-212 (Pb) is an excellent alpha-emitting radioisotope for radioligand therapy. 212 Current generators for producing radium-224 (Pb) use parent radioisotopes with relatively short half-lives, such as radium-224 ( 224 A column-based generator that uses Ra to convert parent radioisotopes bound to resin-based ion exchange materials or inorganic sorbent salts into radioisotopes. 212 Such resin-based ion exchange and inorganic sorbent-based generators are subject to significant radiolytic damage, which may limit their overall durability and clinical application. Furthermore, the isolated Pb from such resin-based ion exchange and sorbent-based generators 212 The extraction of Pb radioisotopes often requires significant amounts of wash fluids, thus complicating and prolonging the subsequent radiolabeling chemical process. 212 Pb generators require overly complicated loading procedures to immobilize the parent radioisotope that can experience significant yield loss over time and / or expose the user to significant radiation doses due to radiolytic breakdown of the organic materials, such as barium stearate, used to immobilize and contain the parent radioisotope.

[0005] Thus, there is a need for improved materials and processes for producing therapeutic radioisotopes that can enable the production of clinically useful doses of therapeutic isotopes. Summary of the Invention

[0006] The present inventors have undertaken research and development into materials and processes for producing radioisotopes.

[0007] Specifically, the present inventors have developed ceramic materials that can be configured to immobilize radioisotopes that can be used as sources for generating daughter radioisotopes. The present inventors have determined that immobilizing a parent radioisotope on or within a ceramic substrate allows for efficient separation of the gaseous intermediate radioisotopes as they decay and are emitted from the immobilized parent radioisotope, thereby providing downstream benefits including, for example, reduced contamination of the daughter radioisotope by the parent radioisotope.

[0008] In one aspect, an inert ceramic substrate is provided that includes a parent radioisotope immobilized on or within the inert ceramic substrate in an amount effective to produce a medically useful dose of a daughter radioisotope through a sequence of natural decay from the parent radioisotope via a gaseous intermediate radioisotope, at least some of the immobilized parent radioisotope being bound on or near a surface of the inert ceramic substrate as a radioisotope surface layer to allow for effective emission of the gaseous intermediate radioisotope from the inert ceramic substrate.

[0009] In another aspect, there is provided a process for preparing an inert ceramic substrate comprising a parent radioisotope immobilized on or within the substrate in an amount effective to produce a medically useful dose of a daughter radioisotope through a sequence of natural decay from the parent radioisotope via a gaseous intermediate radioisotope, the process comprising the steps of: a) depositing a solution comprising the parent radioisotope species onto a surface of the inert ceramic substrate; and b) heating the inert ceramic substrate to a temperature effective to bond at least some of the parent radioisotope to or near the surface of the inert ceramic substrate forming a heat-treated radioisotope surface layer, thereby allowing the gaseous daughter radioisotope to be effectively emitted from the inert ceramic substrate.

[0010] The present inventors have also developed radioisotope generators and systems for capturing populations of daughter radioisotopes. The radioisotope generators can be configured to accommodate the inert ceramic substrates described herein. According to some embodiments or examples described herein, the efficient emission of gaseous intermediate radioisotopes from parent radioisotopes immobilized within the inert ceramic substrates described herein has enabled the development of radioisotope generators that allow for "line of sight" gravity-assisted collection of daughter radioisotopes with minimal contamination.

[0011] In another aspect, there is provided a radioisotope generator defining a chamber for trapping a population of daughter radioisotopes, the chamber configured to receive within the chamber an inert ceramic substrate as described herein. In another aspect, there is provided a system for producing and trapping a population of daughter radioisotopes, the system comprising: a) a radioisotope generator defining a chamber for trapping a population of daughter radioisotopes, and b) an inert ceramic substrate as described herein received in the chamber. The system may comprise a radioisotope generator as described herein.

[0012] The present inventors have also developed a process for capturing a population of daughter radioisotopes. In another aspect, a process for capturing a population of daughter radioisotopes is provided, the process comprising: a) allowing emission of gaseous intermediate radioisotopes generated through a sequence of natural decay from a parent radioisotope immobilized on or in an inert ceramic substrate as described herein; and b) collecting at least some of the gaseous intermediate radioisotopes for a period of time effective to decay into daughter radioisotopes. The process may comprise a radioisotope generator or system as described herein.

[0013] Other aspects and embodiments related to the present disclosure are described herein. It will be understood that each example, aspect, and embodiment of the present disclosure described herein applies by analogy to each and every other example, aspect, and embodiment, unless specifically stated otherwise. For example, each example, aspect, and embodiment of the inert ceramic substrate described herein may equally apply to one or more of the generators, systems, or processes described herein, and vice versa. The present disclosure should not be limited in scope by the specific examples described herein, which are intended for illustrative purposes only. Functionally equivalent products, compositions, and processes are clearly within the scope of the present disclosure described herein.

[0014] Embodiments of the present disclosure are further described and illustrated below, by way of example only, with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 is a schematic diagram of one embodiment of an inert ceramic substrate containing an immobilized radioisotope. [Diagram 2] FIG. 2 is a schematic diagram of another embodiment of an inert ceramic substrate containing an immobilized radioisotope. [Diagram 3] A) SEM image of a Ta2O5 substrate with thorium radioisotope immobilized on its surface prepared by the process described herein. B) EDX spectrum of the surface of the substrate taken from the boxed area. Evidence of finely dispersed thorium oxide was detected on the surface of the Ta2O5 substrate. [Figure 4] A) SEM image of a Ta2O5 substrate with thorium radioisotope immobilized on its surface prepared by the process described herein. B) EDX spectrum of the surface of the substrate taken from a circular area. Evidence of finely dispersed thorium oxide was detected on the surface of the Ta2O5 substrate. [Diagram 5]A) SEM image of a ZrO2 substrate with thorium radioisotope immobilized on its surface prepared by the process described herein. B) EDX spectrum of the surface of the substrate taken from the boxed area. Evidence of finely dispersed thorium oxide was detected on the surface of the ZrO2 substrate. [Figure 6] A) SEM image of a Ta2O5 substrate with thorium radioisotope immobilized on its surface prepared by the process described herein. B) EDX spectrum and spatial map of thorium distribution. Evidence of finely dispersed thorium oxide was detected on the surface of the Ta2O5 substrate. [Figure 7] In some embodiments, the radioactive decay series for Thorium-228 (Th) comprises a radioisotope of the present disclosure. [Figure 8] FIG. 2 is a diagram of one embodiment of a generator used to generate and capture a population of daughter radioisotopes. [Figure 9] Illustrative valve operating parameters for transporting radiated gaseous intermediate radioisotope from the source chamber to the collection chamber and for collecting the daughter radioisotope products. [Figure 10] Simulated activity of the radioisotopes Thorium-228 (228Th), Radium-224 (224Ra), and Radon-220 (220Rn) in the source chamber over a period of 3000 seconds. [Figure 11] Simulated corresponding activities of the radioisotopes Radon-220 (220Rn) and Lead-212 (212Pb) in the collection chamber over 3000 seconds with 200MBq of Th (in equilibrium with Radium-224 (224Ra)) retained in the source chamber. The time points directly correlate with those shown in FIG. 10. [Figure 12] 1 is a plot showing the simulated total yield of lead-212 (212Pb) in the collection chamber based on the time interval between successive transports of gaseous radon-220 (220Rn) from the source chamber to the collection chamber. Different lines represent different configurations for driving gaseous radon-220 (220Rn) from the source chamber to the collection chamber. [Figure 13] 1 is a plot showing simulated ratios of lead-208 / lead-212 (208Pb / 212Pb) based on the time interval between successive transports of gaseous radon-220 (220Rn) from a source chamber to a collection chamber. Different lines represent different configurations for driving gaseous radon-220 (220Rn) from the source chamber to the collection chamber. [Figure 14A] 13A-13C are simulation plots showing the relationship between the number of radon-220 (220Rn) gas transport events (operating at a 5:1 ratio of pressure-driven gas transport events:high vacuum-driven gas transport events) and the interval between transport events. [Figure 14B] Simulation plot showing the relationship between the number of radon-220 (220Rn) gas transport events (operated at a 5:1 ratio of pressure-driven gas transport events: high vacuum-driven gas transport events) and the total yield (MBq) of lead-212 (212Pb) in the collection chamber. [Figure 14C] Simulation plot showing the relationship between total generator operation time and total yield of lead-212 (in MBq) in the collection chamber based on optimal gaseous radon-220 (220Rn) delivery intervals. [Figure 15] Gamma spectrum of 212Pb captured using a generator containing a tantalum oxide (Ta2O5) substrate containing immobilized thorium-228 (228Th) radioisotope as described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The present disclosure describes various non-limiting embodiments below that relate to research undertaken to develop materials, processes, generators, devices, and / or systems for producing radioisotopes. Surprisingly, it has been found that scalable processes and generators can be provided to reliably produce daughter radioisotopes.

[0017] term In the following description, reference is made to the accompanying drawings that form a part hereof, and in which are shown by way of illustration several embodiments, It is to be understood that other embodiments may be utilized and structural changes may be made without departing from the scope of the present disclosure.

[0018] With respect to the definitions provided herein, unless otherwise stated or implied from the context, the defined terms and phrases include the meanings provided. Unless otherwise stated or apparent from the context, the following terms and phrases do not exclude the meaning that the term or phrase would have acquired by one of ordinary skill in the relevant art. The definitions are provided to help describe certain embodiments and are not intended to limit the claimed invention, as the scope of the invention is limited only by the claims. Further, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular.

[0019] All publications discussed and / or referenced herein are incorporated herein in their entirety.

[0020] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present disclosure and is not to be construed as an admission that any or all of such matters form part of the prior art base or were general general knowledge in the field relevant to the present disclosure prior to the priority date of each claim of this application.

[0021] Throughout this disclosure, unless specifically stated otherwise or unless the context requires otherwise, reference to a single step, composition of matter, group of steps, or group of compositions of matter should be construed to include one and more than one (i.e., one or more) of that step, composition of matter, group of steps, or group of compositions of matter. Thus, as used herein, the singular forms "a," "an," and "the" include plural aspects unless the context clearly indicates otherwise. For example, reference to "a" includes two or more as well as the singular, reference to "an" includes two or more as well as the singular, reference to "the" includes two or more as well as the singular, etc.

[0022] Those skilled in the art will appreciate that the disclosure herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications. The disclosure also includes all of the examples, steps, features, methods, compositions, coatings, processes, and coated substrates referred to or shown herein, individually or collectively, and any and all combinations, or any two or more of said steps or features.

[0023] In describing examples and embodiments, specific terminology is used herein for the sake of clarity. For purposes of description, specific terminology is intended to include at least technical and functional equivalents that operate in a similar manner to achieve a similar result. Additionally, in some cases where a particular embodiment or example includes multiple system elements or method steps, those elements or steps may be replaced with a single element or step. Similarly, a single element or step may be replaced with multiple elements or steps that serve the same purpose.

[0024] The term "and / or" is to be understood as meaning either "X and Y" or "X or Y", and is to be interpreted as explicitly endorsing both meanings or either meaning, for example, "X and / or Y" is to be understood as meaning either "X and Y" or "X or Y".

[0025] Unless otherwise stated, the terms "first," "second," and the like are used herein merely as labels, and are not intended to impose any sequential, positional, or hierarchical requirements on the items to which they refer. Moreover, a reference to a "second" item does not require or preclude the presence of a lower-numbered item (e.g., a "first" item) and / or a higher-numbered item (e.g., a "third" item).

[0026] Where a method / process is recited, and where steps / stages are recited in a particular order (with or without ordering leading letters added for ease of reference), the steps / stages are not to be construed as being chronologically limited to the order in which they are recited, unless otherwise specified or implied by the terms and phrases.

[0027] As used herein, the phrase "at least one of," when used with a list of items, means that one or more different combinations of the listed items may be used, and only one of the items in the list may be required. The items may be specific objects, things, or categories. In other words, "at least one of" means that any combination or number of items from the list may be used, but not all items in the list may be required. For example, "at least one of item A, item B, and item C" may mean item A, item A and item B, item B, item A, item B, and item C, or item B and item C. In some cases, "at least one of item A, item B, and item C" may mean, for example, but not limited to, two of item A, one of item B, and ten of item C, four of item B, and seven of item C, or some other suitable combination.

[0028] As used herein, the term "about," unless stated to the contrary, typically refers to ±10%, for example ±5%, of the specified value.

[0029] When parameters of various characteristics or other values ​​are specified herein for examples or embodiments, these parameters or values, unless otherwise specified, may be adjusted up or down by 1 / 100, 1 / 50, 1 / 20, 1 / 10, 1 / 5, 1 / 3, 1 / 2, 2 / 3, 3 / 4, 4 / 5, 9 / 10, 19 / 20, 49 / 50, 99 / 100, etc. (or may be adjusted up by 1, 2, 3, 4, 5, 6, 8, 10, 20, 50, 100 times, etc.), or may be adjusted within the range of the specified parameter by a rounded approximation thereof, or by a range above or below for any of the variations specified above (e.g., for a specified parameter of 100 and a variation of 1 / 00, the value of the parameter may range from 0.99 to 1.01).

[0030] It will be understood that certain features that are described in this specification in the context of separate embodiments may also be provided in combination in a single embodiment for clarity. Conversely, various features that are described in the context of a single embodiment may also be provided separately or in any subcombination for brevity.

[0031] Throughout this specification, various aspects and components of the invention can be presented in a range format. The range format is included for convenience and should not be construed as an inflexible limitation on the scope of the invention. Thus, a description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range, unless specifically indicated otherwise. For example, a description of a range such as 1-5 should be considered to have specifically disclosed subranges such as 1-3, 1-4, 1-5, 2-4, 2-5, 3-5, etc., as well as individual and partial numbers within the recited range, such as 1, 2, 3, 4, 4.5, and 5, unless an integer is required or implied by context. This applies regardless of the breadth of the disclosed range. Where specific values ​​are required, these are provided herein.

[0032] Throughout this specification the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. The phrase "consisting of" refers to the recited elements and to no other elements.

[0033] As used herein, the term "decay" refers to the natural conversion of a radioactive nuclide into its daughter nuclide, or a different nuclide called its "decay product." The daughter nuclide may be stable or may itself be radioactive and thus undergo further spontaneous decay into a different daughter nuclide. It is understood that these radioactive decay processes occur naturally without the need for human intervention.

[0034] Ceramic substrates for immobilizing radioisotopes. The present inventors have developed a ceramic material that can be configured to immobilize radioisotopes. 212 The parent radioisotope may be a parent radioisotope that is the parent of one or more useful daughter radioisotopes, including those provided in the decay series of Figure 2, such as Pb. The parent radioisotope may be used as a source of a gaseous intermediate radioisotope, which can then be captured and used as a source of daughter radioisotopes using the processes and generators described herein.

[0035] According to at least some embodiments or examples described herein, it has been found that immobilizing the parent radioisotope on or within a ceramic substrate allows for efficient separation of the gaseous intermediate radioisotope as it is emitted from the immobilized parent radioisotope, thereby providing downstream benefits including, for example, reduced contamination of the daughter radioisotope with the parent radioisotope. In one embodiment, an inert ceramic substrate is provided that includes a parent radioisotope immobilized on or within the inert ceramic substrate, for example, on or within a surface of the inert ceramic substrate.

[0036] In one embodiment or example, an inert ceramic substrate is provided that includes a parent radioisotope immobilized on or within the inert ceramic substrate.

[0037] In one embodiment or example, an inert ceramic substrate is provided that includes a parent radioisotope immobilized on or within the inert ceramic substrate, where at least some of the immobilized parent radioisotope is bound on or near a surface of the inert ceramic substrate as a radioisotope surface layer to allow for efficient emission of the gaseous intermediate radioisotope from the inert ceramic substrate.

[0038] In one embodiment or example, the inert ceramic substrate includes a parent radioisotope immobilized on or within the inert ceramic substrate in an amount effective to produce a medically useful dose of a daughter radioisotope through a sequence of natural decay from the parent radioisotope via a gaseous intermediate radioisotope, and at least some of the immobilized parent radioisotope is bound on or near a surface of the inert ceramic substrate as a radioisotope surface layer to enable effective emission of the gaseous intermediate radioisotope from the inert ceramic substrate.

[0039] In another embodiment or example, an inert ceramic substrate is provided that includes a parent radioisotope immobilized on or within the inert ceramic substrate, where at least some of the immobilized parent radioisotope is bound on or near a surface of the inert ceramic substrate as a heat-treated radioisotope surface layer to allow for efficient emission of the gaseous intermediate radioisotope from the inert ceramic substrate.

[0040] In another embodiment or example, an inert ceramic substrate is provided that includes a parent radioisotope immobilized on or within the inert ceramic substrate in an amount effective to produce a medically useful dose of a daughter radioisotope through a sequence of natural decay from the parent radioisotope via a gaseous intermediate radioisotope, and at least some of the immobilized parent radioisotope is bound on or near a surface of the inert ceramic substrate as a heat-treated radioisotope surface layer to allow for effective emission of the gaseous intermediate radioisotope from the inert ceramic substrate.

[0041] In another embodiment or example, an inert ceramic substrate is provided that includes a parent radioisotope immobilized on or within the inert ceramic substrate, where at least some of the immobilized parent radioisotope is bound on or near a surface of the inert ceramic substrate as a radioisotope surface layer having a thickness of about 0.1 nm to about 1000 nm to allow for efficient emission of the gaseous intermediate radioisotope from the inert ceramic substrate.

[0042] In another embodiment or example, an inert ceramic substrate is provided that includes a parent radioisotope immobilized on or within the inert ceramic substrate in an amount effective to produce a medically useful dose of a daughter radioisotope through a sequence of natural decay from the parent radioisotope via a gaseous intermediate radioisotope, wherein at least some of the immobilized parent radioisotope is bound on or near a surface of the inert ceramic substrate as a radioisotope surface layer having a thickness of about 0.1 nm to about 1000 nm, thereby enabling effective emission of the gaseous intermediate radioisotope from the inert ceramic substrate.

[0043] In another embodiment or example, an inert ceramic substrate is provided that includes a parent radioisotope immobilized on or within the inert ceramic substrate, where at least some of the immobilized parent radioisotope is bound on or near a surface of the inert ceramic substrate as a radioisotope surface layer to allow for efficient emission of the intermediate gaseous radioisotope from the inert ceramic substrate, and where the inert ceramic substrate has a porosity (volume % based on the total volume of the inert ceramic substrate) of less than about 10, 5, 2, 1, 0.1, or 0.01.

[0044] In another embodiment or example, an inert ceramic substrate is provided that includes a parent radioisotope immobilized on or within the inert ceramic substrate in an amount effective to produce a medically useful dose of a daughter radioisotope through a sequence of natural decay from the parent radioisotope via a gaseous intermediate radioisotope, at least some of the immobilized parent radioisotope is bound on or near a surface of the inert ceramic substrate as a radioisotope surface layer to allow for effective emission of the gaseous intermediate radioisotope from the inert ceramic substrate, and the inert ceramic substrate has a porosity (volume % based on the total volume of the inert ceramic substrate) of less than about 10, 5, 2, 1, 0.1, or 0.01.

[0045] In another embodiment or example, a metal oxide substrate is provided that includes a parent radioisotope immobilized on or within the metal oxide substrate, where at least some of the immobilized parent radioisotope is bound on or near a surface of the metal oxide substrate as a radioisotope surface layer to allow for efficient emission of the gaseous intermediate radioisotope from the inert ceramic substrate.

[0046] In another embodiment or example, a metal oxide substrate is provided that includes a parent radioisotope immobilized on or within the metal oxide substrate in an amount effective to produce a medically useful dose of a daughter radioisotope through a sequence of natural decay from the parent radioisotope via a gaseous intermediate radioisotope, and at least some of the immobilized parent radioisotope is bound on or near a surface of the metal oxide substrate as a radioisotope surface layer to allow for effective emission of the gaseous intermediate radioisotope from the inert ceramic substrate.

[0047] In another embodiment or example, a metal oxide substrate is provided that includes a parent radioisotope immobilized on or within the metal oxide substrate, where at least some of the immobilized parent radioisotope is bound on or near a surface of an inert ceramic substrate as a radioisotope surface layer to allow for efficient emission of the intermediate gaseous radioisotope from the inert ceramic substrate, and where the metal oxide substrate is an oxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, titanium, or aluminum, or a mixed oxide thereof.

[0048] In another embodiment or example, there is provided a metal oxide substrate comprising a parent radioisotope immobilized on or within the metal oxide substrate in an amount effective to produce a medically useful dose of a daughter radioisotope through a sequence of natural decay from the parent radioisotope via a gaseous intermediate radioisotope, at least some of the immobilized parent radioisotope being bound on or near a surface of the inert ceramic substrate as a radioisotope surface layer to allow for effective emission of the gaseous intermediate radioisotope from the inert ceramic substrate, and the metal oxide substrate is an oxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, titanium, or aluminum, or a mixed oxide thereof.

[0049] In one embodiment, at least some of the immobilized parent radioisotopes are bound on or near the surface of the inert ceramic substrate as a heat-treated radioisotope surface layer to allow for efficient emission of the gaseous intermediate radioisotopes from the inert ceramic substrate. In one embodiment, at least some of the immobilized parent radioisotopes are bound on or near the surface of the inert ceramic substrate as a radioisotope surface layer having a thickness of about 0.1 nm to about 1000 nm to allow for efficient emission of the gaseous intermediate radioisotopes from the inert ceramic substrate. In one embodiment, the inert ceramic substrate has a porosity (volume % based on the total volume of the inert ceramic substrate) of less than about 10, 5, 2, 1, 0.1, or 0.01.

[0050] Types of Radioisotopes Any suitable parent radioisotope may be used, hi one embodiment, the parent radioisotope is an alpha-emitting radioisotope, i.e., capable of emitting an alpha particle (i.e., a helium nucleus), which is thereby transformed into a different atomic nucleus having a mass number decreased by four and an atomic number decreased by two.

[0051] In one embodiment, the parent radioisotope is an isotope of thorium or radium, or a combination thereof. In one embodiment, the parent radioisotope is a thorium radioisotope. The thorium radioisotope is thorium-227( 227 Th), Thorium-228( 228 Th), and thorium-232 ( 232 In one embodiment, the parent radioisotope is radium. The radium radioisotope may be selected from at least one of: 224 Ra and 228 Ra, or a combination thereof.

[0052] In one embodiment, the parent radioisotope is 228 Th. 228 Th has a half-life of approximately 2 years and is commercially available. 228 These and other properties of Th make it an alpha-emitting medical isotope. 212 When immobilized on or within the inert ceramic substrates described herein, according to some embodiments or examples, 228 Th, with a slight gradual disappearance of productivity 212 It can be used as the parent radioisotope in the Pb generator for more than one year. In one embodiment, the gaseous intermediate radioisotope is a radon radioisotope. The radon radioisotope is radon-219( 219 Rn) or Radon-220( 220 In one embodiment, the daughter radioisotope is a lead radioisotope. The lead radioisotope is lead-211 ( 211 Pb) or lead-212( 212 Pb).

[0053] In one embodiment, the parent radioisotope is immobilized on or in the inert ceramic substrate in an amount effective to produce a medically useful dose of the daughter radioisotope via a sequence of spontaneous decay of a gaseous intermediate isotope. As used herein, the term "medically useful" refers to the amount of the daughter radioisotope (e.g., 212 Pb). The parent radioisotope may be provided in an amount effective to produce a medically useful amount (e.g., a preclinically and / or clinically useful amount) of the daughter radioisotope. In one embodiment, the parent radioisotope is provided in an amount effective to produce a medical dose of about 1 to about 1,000 MBq of the daughter radioisotope (e.g., 212 Pb). In one embodiment, the parent radioisotope may be immobilized on or within the inert ceramic substrate in an amount effective to produce a medical dose of at least about 1, 2, 5, 10, 50, 60, 90, 120, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, or 1,000 MBq of a daughter radioisotope (e.g., 212 Pb). In another embodiment, the parent radioisotope may be immobilized on or within the inert ceramic substrate in an amount effective to produce less than about 1,000, 900, 800, 700, 600, 500, 400, 300, 250, 200, 150, 120, 90, 60, 50, 10, 5, 2, or 1 medical dose of the daughter radioisotope (e.g., 212 Pb). In one embodiment, the parent radioisotope may be immobilized on or within the inert ceramic substrate in an amount effective to produce a medical dose of at least about 50, 70, 100, 120, 140, 160, 180, or 200 MBq of a daughter radioisotope (e.g., 212 The parent radioisotope may be immobilized on or within the inert ceramic substrate in an amount effective to produce a medical dose of a daughter radioisotope (e.g., Pb) within the range provided by any two of these upper and / or lower values, e.g., from about 50 MBq to about 200 MBq. 212 The compound may be immobilized on or within the inert ceramic substrate in an amount effective to produce fluorine-containing fluoride (Pb).

[0054] In one embodiment, the parent radioisotope immobilized on or within the inert ceramic substrate is about 1 to about 1500 nm (1 cm of the surface of the inert ceramic substrate). 2 The parent radioisotope is present in an amount effective to provide an activity (in MBq per cm of the surface of an inert ceramic substrate) of at least about 0.01, 0.05, 1, 2, 5, 10, 20, 50, 70, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1200, or 1500 (in MBq per cm of the surface of an inert ceramic substrate). 2 The parent radioisotope may be immobilized on or within the inert ceramic substrate in an amount effective to provide activity (in MBq per cm of the inert ceramic substrate surface). 2 The parent radioisotope may be immobilized on or within the inert ceramic substrate in an amount effective to provide an activity (in MBq per unit mass) in the range provided by any two of these upper and / or lower values, e.g., about 100 to about 1500, about 10 to about 1000, or about 50 to about 500, e.g., about 100. The activity of the parent radioisotope immobilized on or within the inert ceramic substrate may be measured using a suitable radioactivity measuring device or by inference from the amount of daughter radioisotope collected at a distance from the substrate. Activity may also be obtained via suitable simulation and modeling, along with the examples described herein.

[0055] Immobilization of parent radioisotope The radioisotope is immobilized on or within the inert ceramic substrate. In one embodiment, the parent radioisotope is immobilized on or within the surface of the inert ceramic substrate. For example, the parent radioisotope may be immobilized / bound onto the inert ceramic substrate. In one embodiment, the inert ceramic substrate comprises the parent radioisotope immobilized on or within the inert ceramic substrate. The immobilized parent radioisotope may be interspersed on or within the inert ceramic substrate. The immobilized parent radioisotope may be interspersed within the lattice of the inert ceramic substrate. The immobilized parent radioisotope may comprise a radioisotope surface-bound to the inert ceramic substrate. The parent radioisotope may be incorporated or embedded within the surface of the inert ceramic substrate or may be provided as a layer on the surface of the inert ceramic substrate. By immobilizing the parent radioisotope on or within an inert ceramic substrate, for example on or within the surface of an inert ceramic substrate, the intermediate daughter radioisotope, which is gaseous, can be allowed to radiate and diffuse away from the substrate, providing efficient separation of the emitted daughter radioisotope from the immobilized parent radioisotope.

[0056] In one embodiment, at least some of the immobilized parent radioisotopes are bound on or near the surface of an inert ceramic substrate as a radioisotope surface layer to allow efficient emission of the gaseous intermediate radioisotope from the inert ceramic substrate.

[0057] In one embodiment, at least some of the immobilized parent radioisotopes are bound on or near the surface of an inert ceramic substrate as a heat-treated radioisotope surface layer to allow for effective emission of the gaseous intermediate radioisotopes from the inert ceramic substrate. As used herein, the term "heat-treated" radioisotope surface layer refers to a portion of the surface of an inert ceramic substrate that has been heat-treated (i.e., heated) to chemically and / or physically bind the parent radioisotopes on or near the surface. The heat-treated radioisotope surface layer may be obtained by a process that includes a) depositing a solution containing the parent radioisotope species on the surface of the inert ceramic substrate, and b) heating the inert ceramic substrate to a temperature effective to bind at least some of the parent radioisotopes on or near the surface of the inert ceramic substrate, thereby forming a heat-treated radioisotope surface layer to allow for effective emission of the gaseous daughter radioisotopes from the inert ceramic substrate.

[0058] The heat-treated radioisotope surface layer may be obtained by the process described herein under the section heading "Process for preparing an inert ceramic substrate containing an immobilized radioisotope". According to some embodiments or examples described herein, the inventors have determined that the immobilized parent radioisotope within the heat-treated radioisotope surface layer is tightly bound to the surface of the underlying inert ceramic substrate, and that such heat treatment can facilitate chemical exchange of the radioisotope within the atomic lattice at or near the surface of the inert ceramic substrate, forming a radiolytic thin, tightly bound layer at or near the surface of the inert ceramic substrate. Such heat treatment allows little or no parent radioisotope to radiate simultaneously with the gaseous intermediate radioisotope as the lattice is emitted from the inert ceramic substrate. In other words, the parent radioisotope within the heat-treated radioisotope surface layer spontaneously decays into gaseous intermediate radioisotopes that radiate from the tightly bound parent radioisotope on or near the surface of the inert ceramic substrate (i.e., the heat-treated radioisotope surface layer).

[0059] In one embodiment, the binding of the immobilized parent radioisotope on or near the surface of the inert ceramic substrate is such as to allow capture of a population of daughter radioisotopes during use that have a contaminant level of the parent radioisotope, expressed in terms of activity, of less than about 5, 2, 1, 0.1, 0.01 or 0.001% compared to the activity of the daughter radioisotope. One example of a contaminant is a fluororesin produced using an inert ceramic substrate. 212 Pb 228 For example, even if the radioisotope surface layer comes into contact with a collection surface inside the radioisotope generator (e.g., the inner wall of the collection chamber), little or no cross-contamination of the parent radioisotope occurs because the parent radioisotope surface layer is tightly bound.

[0060] The radioisotope surface layer may include immobilized parent radioisotopes distributed uniformly within the layer. The radioisotope surface layer may be located anywhere on the surface of the inert ceramic substrate. The radioisotope surface layer may be a continuous layer on the surface of the substrate. Alternatively, the radioisotope surface layer may be discontinuous with respect to the entire inert substrate surface, e.g., may include two or more sections where the layer does not uniformly and completely cover the surface of the inert ceramic substrate. It will be understood that such discontinuous layer forms are still considered surface layers for purposes of this disclosure. For example, the immobilized parent radioisotopes may be decorated (e.g., interspersed) on or near the surface of the inert ceramic substrate, forming a radioisotope surface layer that allows for effective emission of gaseous daughter radioisotopes from the inert ceramic substrate.

[0061] In one embodiment or example, an inert ceramic substrate is provided that includes a parent radioisotope immobilized on or within the inert ceramic substrate, where the immobilized parent radioisotope is decorated on or near the surface of the inert ceramic substrate as a radioisotope surface layer, allowing for efficient emission of the gaseous intermediate radioisotope from the inert ceramic substrate.

[0062] In one embodiment or example, an inert ceramic substrate is provided that includes a parent radioisotope immobilized on or within the inert ceramic substrate in an amount effective to produce a medically useful dose of a daughter radioisotope through a sequence of natural decay from the parent radioisotope via a gaseous intermediate radioisotope, the immobilized parent radioisotope being decorated on or near a surface of the inert ceramic substrate as a radioisotope surface layer, allowing for effective emission of the gaseous intermediate radioisotope from the inert ceramic substrate.

[0063] In some embodiments, at least some of the immobilized parent radioisotopes forming the radioisotope surface layer are provided as a radioisotope-doped layer within the surface of an inert ceramic substrate, hi one embodiment, at least some of the immobilized parent radioisotopes are bound on or within the atomic lattice of the inert ceramic substrate, forming a radioisotope-doped layer within the surface of the inert ceramic substrate.

[0064] The radioisotope-doped layer may include immobilized parent radioisotope ions, which may be uniformly distributed within the layer. The radioisotope-doped layer may be located anywhere within the surface of the inert ceramic substrate. The radioisotope-doped layer may be a continuous layer within the surface of the substrate. Alternatively, the radioisotope-doped layer may be discontinuous across the entire inert substrate surface, for example, the layer may include two or more sections, where the layer does not uniformly and completely cover the surface of the inert ceramic substrate. The radioisotope-doped layer may include radioisotope ions bound to the inert ceramic substrate. In one embodiment, at least some of the immobilized parent radioisotope ions are interspersed within the interior of the inert ceramic substrate to form a radioisotope-doped layer on the surface of the inert ceramic substrate. In one embodiment, at least some of the immobilized parent radioisotope ions are interspersed within the atomic lattice of the inert ceramic substrate to form a radioisotope-doped layer on the surface of the inert ceramic substrate. In one embodiment, the radioisotope-doped layer comprises a parent radioisotope surface bonded to an inert ceramic substrate. Typically, the parent radioisotope is distributed such that there is a concentration gradient throughout the radioisotope-doped layer (e.g., throughout the depth of the layer), often mediated by the concentration and / or penetration of the radioisotope from the surface of the inert ceramic substrate. It will be appreciated that in this example, the concentration of the parent radioisotope may be higher toward the outer surface of the radioisotope-doped layer and decrease throughout the radioisotope-doped layer as the depth into the inert ceramic substrate increases.

[0065] In one embodiment, at least some of the immobilized parent radioisotopes forming the radioisotope surface layer are provided as one or more solid compound phases of the radioisotope bound on the surface of an inert ceramic substrate. The surface below which the solid compound phases of the radioisotope are bound may comprise a radioisotope-doped layer as described herein. The term "solid compound phase" in relation to a radioisotope is understood to mean any solid form in which the radioisotope may exist stably. The solid compound phase may comprise a crystalline phase or an amorphous phase, or a combination thereof.

[0066] In one embodiment, at least some of the solid compound phases of the radioisotope may comprise one or more crystalline phases of the radioisotope bound on the surface of the inert ceramic substrate. The surface below which the crystalline compound phases of the radioisotope are bound may comprise a radioisotope-doped layer as described herein. The term "crystalline phase" in relation to the radioisotope is understood to mean the radioisotope present in a microscopic structure forming a crystal lattice, e.g., an oxide, that extends in all directions. For example, the immobilized parent radioisotope may assemble into separate crystal lattices and form one or more crystalline phases bound on the surface of the inert ceramic substrate. Alternatively, one or more crystalline phases of the radioisotope ions may be present on the surface, resulting in a radioisotope surface layer that comprises one or more polycrystalline radioisotope phases, i.e., multiple distinct crystalline phases separated by crystalline or amorphous regions of the radioisotope-doped ceramic substrate and / or by regions of the inert ceramic substrate that do not contain the radioisotope (i.e., undoped regions). In one embodiment, the immobilized parent radioisotope is provided as one or more crystalline phases bound on the surface of the radioisotope-doped layer. The crystalline phases may be uniformly distributed on or within the radioisotope-doped layer, for example on a nanometer scale (e.g., as observed by scanning electron microscopy). The one or more crystalline phases of the parent radioisotope may be bound to the lattice of an inert ceramic substrate.

[0067] Alternatively or additionally, at least some of the solid compound phases of the radioisotope may be provided as one or more amorphous phases of the radioisotope bound on the surface of an inert ceramic substrate. The surface below which the amorphous phases of the radioisotope are bound may comprise a radioisotope-doped layer as described herein. The term "amorphous phase" in relation to a radioisotope is understood to mean a radioisotope that exists within a microscopic structure without any regular extended atomic arrangement (i.e. without a defined crystal structure). In one embodiment, the immobilized parent radioisotope is provided as one or more amorphous phases of the parent radioisotope bound on the surface of an inert ceramic substrate. The one or more amorphous phases of the radioisotope may be uniformly distributed on the surface of the inert ceramic substrate, for example, on a nanometer scale (e.g., as observed by scanning electron microscope). The one or more amorphous phases of the parent radioisotope may be bound to the lattice of the inert ceramic substrate.

[0068] In one embodiment, one or more of the solid compound phase, crystalline phase, or amorphous phase are provided as separate particles bound on the surface of an inert ceramic substrate. The surface below which the separate particles are bound may include a radioisotope-doped layer as described herein. The separate particles may be described as a plurality of "islands" bound on the surface of the inert ceramic substrate. Alternatively, or in addition, one or more of the solid compound phase, crystalline phase, or amorphous phase are provided as a layer bound on the surface of the inert ceramic substrate.

[0069] In some embodiments, one or more crystalline phases of the parent radioisotope are provided as a plurality of separate crystalline particles bonded to the surface of the inert ceramic substrate or the radioisotope-doped layer. Alternatively, or additionally, one or more crystalline phases of the parent radioisotope are provided as a crystalline layer bonded to the surface of the inert ceramic substrate or the radioisotope-doped layer. In some embodiments, the separate particles and / or layers may be bonded to the surface of the underlying radioisotope-doped layer or the inert ceramic substrate, e.g., may have a close lattice match with one or more crystalline compound phases present at the surface of the inert ceramic substrate or the radioisotope-doped layer. The lattice mismatch between the separate crystalline particles or layers of the radioisotope and the underlying inert ceramic substrate or the radioisotope-doped layer may be less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1%.

[0070] When present, the layer of the solid compound phase, crystalline phase or amorphous phase may be located anywhere on the surface of the inert ceramic substrate. The layer of the solid compound phase, crystalline phase or amorphous phase may be a continuous layer on the surface of the substrate. Alternatively, the layer of the solid compound phase, crystalline phase or amorphous phase may be discontinuous with respect to the entire inert substrate surface, e.g., the layer may include two or more sections where the layer does not uniformly and completely cover the surface of the inert ceramic substrate.

[0071] In one embodiment, one or more solid compound phases, crystalline phases, or amorphous phases of the parent radioisotope include oxides, hydroxides, oxalates, nitrides, carbides, sulfides, silicates, intermetallic compounds, or combinations thereof of the radioisotopes described herein. In one embodiment, one or more solid compound phases, crystalline phases, or amorphous phases of the parent radioisotope include oxides, hydroxides, fluorides, oxalates, phosphates, nitrides, carbides, sulfides, silicates, intermetallic compounds, or combinations thereof of the radioisotopes described herein. In one embodiment, one or more solid compound phases, crystalline phases, or amorphous phases of the parent radioisotope include oxides, nitrides, fluorides, phosphates, carbides, sulfides, silicates, intermetallic compounds, or combinations thereof of the radioisotopes described herein. In one embodiment, one or more solid compound phases, crystalline phases, or amorphous phases of the parent radioisotope include an oxide, nitride, carbide, sulfide, silicate, or combination thereof of the radioisotope described herein. In one embodiment, one or more solid compound phases, crystalline phases, or amorphous phases of the parent radioisotope include an oxide, phosphate, nitride, carbide, sulfide, or combination thereof of the radioisotope described herein. In one embodiment, one or more solid compound phases, crystalline phases, or amorphous phases of the parent radioisotope include an oxide or hydroxide of the radioisotope described herein, or combination thereof. In one embodiment, one or more solid compound phases, crystalline phases, or amorphous phases of the parent radioisotope are oxides of the radioisotopes described herein.

[0072] In one embodiment, the one or more solid compound phases, crystalline or amorphous phases of the parent radioisotope are thorium dioxide (ThO2) and / or non-stoichiometric thorium oxide (ThO (2+ / -x) ) where x is greater than 0 but less than 0.15.

[0073] The thickness of the radioisotope surface layer, heat-treated radioisotope surface layer, radioisotope-doped layer, solid compound phase, crystalline phase, or amorphous phase may vary depending on, for example, the amount of parent radioisotope loaded onto the surface of the inert ceramic substrate. The radioisotope surface layer, heat-treated radioisotope surface layer, radioisotope-doped layer, solid compound phase, crystalline phase, or amorphous phase may each independently have a thickness of, for example, about 1 to about 1500 of the above (1 cm of the inert ceramic substrate surface). 2 The substrate may have a thickness effective to provide a concentration of the radioisotope in an amount effective to provide an activity (in MBq per unit area).

[0074] In some embodiments, the radioisotope surface layer, the heat-treated radioisotope surface layer, the radioisotope-doped layer, the solid compound phase, the crystalline phase, or the amorphous phase may each independently have a thickness of about 0.1 nm to about 1,000,000 nm (i.e., 1 mm), about 0.1 nm to about 100,000 nm (i.e., 100 μm), or about 0.1 nm to about 1,000 nm (i.e., 1 μm). The radioisotope surface layer, heat treated radioisotope surface layer, radioisotope doped layer, solid compound phase, crystalline phase or amorphous phase may each independently have a thickness (in nm) of at least about 0.1, 0.2, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 30, 50, 100, 150, 200, 300, 400, 500, 700, 900, 1,000, 10,000, 100,000, or 1,000,000. The radioisotope surface layer, heat treated radioisotope surface layer, radioisotope doped layer, solid compound phase, crystalline phase or amorphous phase may each independently have a thickness (in nm) of less than about 1,000,000, 100,000, 10,000, 1,000, 900, 700, 500, 400, 300, 200, 150, 100, 50, 30, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3.5, 3, 2.5, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, 0.2 or 0.1. The radioisotope surface layer, heat treated radioisotope surface layer, radioisotope doped layer, solid compound phase, crystalline phase or amorphous phase may each independently have a thickness (in nm) of at least about 0.2, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18 or 20. The radioisotope surface layer, heat treated radioisotope surface layer, radioisotope doped layer, solid compound phase, crystalline phase or amorphous phase may each independently have a thickness (in nm) of less than about 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3.5, 3, 2.5, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4 or 0.2 nm.The thickness may be in the range provided by any two of these upper and / or lower values, for example, about 0.1 nm to about 1,000,000 nm, about 0.1 nm to about 100,000 nm, about 0.1 nm to about 1,000 nm, about 0.1 nm to about 100 nm, about 1 nm to about 100 nm, or about 1 nm to about 20 nm. According to some embodiments or examples described herein, the thin radioisotope surface layer described herein (including the heat treated radioisotope surface layer / radioisotope doped layer / solid compound phase, crystalline phase or amorphous phase on the inert ceramic substrate described herein) allows for efficient emission of the gaseous intermediate radioisotope from the inert ceramic substrate.

[0075] In some embodiments, the radioisotope surface layer may have a thickness of about 0.1 nm to about 1,000,000 nm (i.e., 1 mm), about 0.1 nm to about 100,000 nm (i.e., 100 μm), or about 0.1 nm to about 1,000 nm (i.e., 1 μm). The radioisotope surface layer may have a thickness (in nm) of at least about 0.1, 0.2, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 30, 50, 100, 150, 200, 300, 400, 500, 700, 900, 1,000, 10,000, 100,000, or 1,000,000. The radioisotope surface layer may have a thickness (in nm) of less than about 1,000,000, 100,000, 10,000, 1,000, 900, 700, 500, 400, 300, 200, 150, 100, 50, 30, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3.5, 3, 2.5, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, 0.2 or 0.1. The radioisotope surface layer may have a thickness (in nm) of at least about 0.2, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20. The radioisotope surface layer may have a thickness (in nm) of less than about 20, 18, 16, 14, 12, 10, 9, 8,, 7, 6, 5, 4, 3.5, 3, 2.5, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, or 0.2 nm. The thickness may be in the range provided by any two of these upper and / or lower values, for example, about 0.1 nm to about 1,000,000 nm, about 0.1 nm to about 100,000 nm, about 0.1 nm to about 1,000 nm, about 0.1 nm to about 100 nm, about 1 nm to about 100 nm, or about 1 nm to about 20 nm.

[0076] In some embodiments, the heat-treated radioisotope surface layer may have a thickness of about 0.1 nm to about 1,000,000 nm (i.e., 1 mm), about 0.1 nm to about 100,000 nm (i.e., 100 μm), or about 0.1 nm to about 1,000 nm (i.e., 1 μm). The heat treated radioisotope surface layer may have a thickness (in nm) of at least about 0.1, 0.2, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 30, 50, 100, 150, 200, 300, 400, 500, 700, 900, 1,000, 10,000, 100,000, or 1,000,000. The heat treated radioisotope surface layer may have a thickness (in nm) of less than about 1,000,000, 100,000, 10,000, 1,000, 900, 700, 500, 400, 300, 200, 150, 100, 50, 30, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3.5, 3, 2.5, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, 0.2, or 0.1. The heat-treated radioisotope surface layer may have a thickness (in nm) of at least about 0.2, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20. The heat-treated radioisotope surface layer may have a thickness (in nm) of less than about 20, 18, 16, 14, 12, 10, 9, 8,, 7, 6, 5, 4, 3.5, 3, 2.5, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, or 0.2 nm. The thickness may be in the range provided by any two of these upper and / or lower values, for example, about 0.1 nm to about 1,000,000 nm, about 0.1 nm to about 100,000 nm, about 0.1 nm to about 1,000 nm, about 0.1 nm to about 100 nm, about 1 nm to about 100 nm, or about 1 nm to about 20 nm.

[0077] In some embodiments, the radioisotope-doped layer may have a thickness of about 0.1 nm to about 1,000,000 nm (i.e., 1 mm), about 0.1 nm to about 100,000 nm (i.e., 100 μm), or about 0.1 nm to about 1,000 nm (i.e., 1 μm). The radioisotope doped layer may have a thickness (in nm) of at least about 0.1, 0.2, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 30, 50, 100, 150, 200, 300, 400, 500, 700, 900, 1,000, 10,000, 100,000, or 1,000,000. The radioisotope doped layer may have a thickness (in nm) of less than about 1,000,000, 100,000, 10,000, 1,000, 900, 700, 500, 400, 300, 200, 150, 100, 50, 30, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3.5, 3, 2.5, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, 0.2, or 0.1. The radioisotope-doped layer may have a thickness (in nm) of at least about 0.2, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20. The radioisotope-doped layer may have a thickness (in nm) of less than about 20, 18, 16, 14, 12, 10, 9, 8,, 7, 6, 5, 4, 3.5, 3, 2.5, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, or 0.2 nm. The thickness may be in the range provided by any two of these upper and / or lower values, for example, about 0.1 nm to about 1,000,000 nm, about 0.1 nm to about 100,000 nm, about 0.1 nm to about 1,000 nm, about 0.1 nm to about 100 nm, about 1 nm to about 100 nm, or about 1 nm to about 20 nm.

[0078] In some embodiments, the solid compound phase, crystalline phase, or amorphous phase may each independently have a thickness of from about 0.1 nm to about 1,000,000 nm (i.e., 1 mm), from about 0.1 nm to about 100,000 nm (i.e., 100 μm), or from about 0.1 nm to about 1,000 nm (i.e., 1 μm). The solid compound phase, crystalline phase or amorphous phase may each independently have a thickness (in nm) of at least about 0.1, 0.2, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 30, 50, 100, 150, 200, 300, 400, 500, 700, 900, 1,000, 10,000, 100,000, or 1,000,000. The solid compound phase, crystalline phase or amorphous phase may each independently have a thickness (in nm) of less than about 1,000,000, 100,000, 10,000, 1,000, 900, 700, 500, 400, 300, 200, 150, 100, 50, 30, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3.5, 3, 2.5, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, 0.2 or 0.1. The solid compound phase, crystalline phase, or amorphous phase may each independently have a thickness (in nm) of at least about 0.2, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20. The solid compound phase, crystalline phase, or amorphous phase may each independently have a thickness (in nm) of less than about 20, 18, 16, 14, 12, 10, 9, 8,, 7, 6, 5, 4, 3.5, 3, 2.5, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, or 0.2 nm. The thickness may be in the range provided by any two of these upper and / or lower values, for example, about 0.1 nm to about 1,000,000 nm, about 0.1 nm to about 100,000 nm, about 0.1 nm to about 1,000 nm, about 0.1 nm to about 100 nm, about 1 nm to about 100 nm, or about 1 nm to about 20 nm.

[0079] Characterization of inert ceramic substrates for the immobilization of radioisotopes. The parent radioisotopes described herein are immobilized on or within an inert ceramic substrate. The term "inert" will be understood to mean that the ceramic substrate is substantially chemically inert, e.g., does not react chemically to any significant extent with the immobilized radioisotopes dispersed on or within the substrate. The inert ceramic substrate may also be substantially unreactive with atmospheric oxygen and water. Additionally, the inert ceramic substrate may include certain robust ceramic materials that make it less susceptible to radiation damage (i.e., structural damage) incurred when the parent radioisotope immobilized therein decays into daughter radioisotopes. For example, the crystallographic properties of the inert ceramic substrate provide a degree of robustness against radiation damage.

[0080] In one embodiment or example, the inert ceramic substrate is an inert metal oxide that the present inventors have identified as being robust and strong with reduced susceptibility to radiation damage. While robust, the inert ceramic substrate is also comprised of a material that does not prevent to a significant extent the emission of gaseous daughter radioisotopes from parent radioisotopes immobilized on or within the inert ceramic substrate as the inert ceramic substrate disintegrates, thereby providing effective separation of the radiated daughter radioisotopes from the immobilized radioisotopes.

[0081] The inert ceramic substrate may be formed from any suitable ceramic material. For example, the inert ceramic substrate may include a suitable ceramic material that may have a chemical affinity for the parent radioisotope to be immobilized, e.g., that supports exchange of the parent radioisotope ions with ions of the ceramic lattice. In some embodiments, the inert ceramic substrate is configured to support one or more crystalline compound phases of the radioisotope.

[0082] The inert ceramic substrate may have a suitable form for insertion into a radioisotope generator, for example, into a source chamber as described herein. In one embodiment, the inert ceramic substrate may be provided as a separate unit, for example, a disk, a plate, a film, a platen, a slab, a tube, a tube section, or a monolith. The unit may have any desired shape, including, but not limited to, a sphere or a hemisphere. In one embodiment, the inert ceramic substrate is a disk. The disk may be configured to be inserted into a radioisotope generator. The disk is not limited to being any particular cross-sectional shape (i.e., spherical, rectangular, etc.), so long as the disk is geometrically substantially planar.

[0083] In one embodiment, the inert ceramic substrate has an aspect ratio (i.e., the ratio of length to width, where length and width are measured perpendicular to one another and length refers to the longest linear distance) of greater than 1.0 to about 10.0, for example, at least about 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0. According to some embodiments or examples described herein, inert ceramic substrates having higher aspect ratios (e.g., greater than 2.0) provide planar geometries that provide a larger radioisotope surface layer area for effective emission of gaseous intermediate radioisotopes.

[0084] The inert ceramic substrate has a porosity effective to allow for immobilization of a quantity of the parent radioisotope, while still allowing for effective emission of the gaseous daughter radioisotope from the inert ceramic substrate surface, thereby providing for effective separation of the emitted daughter radioisotope from the immobilized parent radioisotope. The porosity may be greater at the surface of the inert ceramic substrate. The porosity may facilitate immobilization of a substantial amount of the parent radioisotope. As used herein, the term "porosity" is a measure of the void space in a material, and is the fraction of the volume of voids over the total volume as a percentage of 0% to 100% by volume.

[0085] In some embodiments, the inert ceramic substrate has a porosity of about 0.01% to about 30% by volume, based on the total volume of the inert ceramic substrate. The inert ceramic substrate may have a porosity (in volume % based on the total volume of the inert ceramic substrate) of at least about 0.01, 0.1, 1, 2, 5, 10, 20, or 30. The inert ceramic substrate may have a porosity (in volume % based on the total volume of the inert ceramic substrate) of less than about 30, 20, 10, 5, 2, 1, 0.1, or 0.01. In one embodiment, the inert ceramic substrate has a porosity (in volume % based on the total volume of the inert ceramic substrate) of less than about 10, 5, 2, 1, 0.1, or 0.01. The porosity may be in a range provided by any two of these upper and / or lower values, such as about 10% to about 30% by volume, or about 0.01% to about 5% by volume. The porosity in volume percent can be measured by any suitable technique known to one of skill in the art, including, for example, using standard mercury porosimetry methods and / or optical or electron microscopy analysis of a section of the inert ceramic substrate. According to some embodiments or examples described herein, an inert ceramic substrate having low porosity can provide one or more advantages, including a high yield of daughter isotopes. For example, an inert ceramic substrate having low porosity, and in some cases a morphology that is substantially non-porous (e.g., less than about 1, 0.1, or 0.01 volume percent), allows for more efficient and substantially unhindered emission of gaseous intermediate isotopes from the radioisotope surface layer.

[0086] In relation to porosity, the inert ceramic substrate may have a low surface area, e.g., (m 2 The surface area may be less than about 200, 100, 50, 20, 10, 5, 4, 3, 2, 1 or 0.5 (in g / g). Surface area can be measured using standard ASTM C1274 or using N2 adsorption according to Brunauer-Emmett-Teller (BET) theory applied over the relative pressure range of 0.05 to 0.20 P / P0 at 77K.

[0087] The inert ceramic substrate has a suitable density, for example, to provide a degree of robustness. In some embodiments, the inert ceramic substrate has a density of about 2.0 g / cm 3 ~Approx. 15g / cm 3 The inert ceramic substrate has a density (g / cm) of at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. 3 The inert ceramic substrate may have a density (g / cm) of less than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2. 3 The density may be in the range provided by any two of these upper and / or lower values, for example, about 4 to 13 g / cm. 3 may be also possible.

[0088] The inert ceramic substrate has a suitable thickness. In some embodiments, the inert ceramic substrate has a thickness (in μm) of about 0.001 to about 100,000, about 0.001 to about 10,000, about 0.001 to about 1000, about 0.01 to about 100, about 0.01 to about 100, about 0.01 to about 10, or about 0.1 to about 10, or about 0.005 to about 0.5. The inert ceramic substrate may have a thickness (in μm) of at least about 0.001, 0.002, 0.005, 0.01, 0.015, 0.02, 0.05, 0.1, 0.5, 1, 5, 10, 50, 100, 200, 500, 700, 1000, 5000, 10,000, or 100,000. The inert ceramic substrate may have a thickness (in μm) of less than about 10,000, 10,000, 5000, 1000, 700, 500, 200, 100, 50, 10, 5, 1, 0.5, 0.1, 0.05, 0.02, 0.015, 0.01, 0.005, 0.002, or 0.001. The thickness may be in a range provided by any two of these upper and / or lower values, for example, from about 0.01 μm to about 500 μm. In another embodiment, the inert ceramic substrate may have a thickness (in nm) of at least about 5, 10, 15, 20, 25, 30, 40, 50, 80, 100, 150, 200, 250, 300, 400, or 500. The inert ceramic substrate may have a thickness (in nm) of less than about 500, 400, 300, 250, 200, 150, 100, 80, 50, 40, 30, 25, 20, 15, 10, or 5. The thickness may be in a range provided by any two of these upper or lower values, for example, from about 15 nm to about 100 nm. In one embodiment, the thickness of the radioisotope surface layer is less than the thickness of the underlying inert ceramic substrate.

[0089] The inert ceramic substrate may have a roughened or textured surface. According to some embodiments or examples described herein, it has been found that the roughened or textured surface provides an enhanced surface area that can facilitate loading and immobilizing radioisotopes on or within the inert ceramic substrate. It will be appreciated that such roughening or texturing is understood to mean that the surface of the substrate is engineered (i.e., roughened or textured) and does not include polished metals that may be naturally "dead-flat" or have some form of microscopic roughness. In other words, the surface roughening is achieved by some physical or mechanical treatment of the substrate surface, for example, by polishing the surface using an abrasive powder (e.g., tungsten carbide) on a vibrating table. The surface roughness may include an angular pattern.

[0090] In some embodiments, the inert ceramic substrate has a surface roughness (R t ) (i.e., the height of the peaks relative to the trough of one or more angular peaks produced by the roughening process). The roughened surface has a peak count (R pc The surface roughness may be measured using industry standard ASTM D7127, for example after a polishing process.

[0091] In some embodiments, the roughened surface of the inert ceramic substrate has an increased percent surface area (e.g., at least a 1, 2, 5, 10, 15, or 20% increase in surface area) compared to a corresponding non-roughened, "plain" substrate.

[0092] The inert ceramic substrate is selected from a metal oxide, a metal nitride, a metal carbide, a metal sulfide, or a combination thereof. The inert ceramic substrate is selected from a metal oxide, a metal phosphate, a metal nitride, a metal carbide, a metal sulfide, or a combination thereof. Other suitable ceramic materials include inert intermetallic compounds, such as metal silicides, metal borides, or metal selenides. In one embodiment, the inert ceramic substrate is a metal oxide.

[0093] In one embodiment, the inert ceramic substrate is a metal oxide substrate. The metal oxide substrate may be an oxide of a refractory metal or another transition metal. The metal oxide substrate may be an oxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, titanium, or aluminum, or an alloy thereof. The metal oxide substrate may be an oxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, titanium. In one embodiment, the inert metal oxide substrate is tantalum oxide (Ta2O5). Other metals are also envisioned.

[0094] In one embodiment, the inert ceramic substrate is provided as a layer (e.g., a film supported on an underlying substrate). In one embodiment, the inert ceramic substrate may be provided as a layer on a metal substrate. The inert ceramic substrate layer may be supported on a metal substrate. The metal substrate may provide additional benefits according to some embodiments or examples described herein, including radiation shielding. Additionally, according to some embodiments or examples, the metal substrate may provide stable adhesion for thinner inert ceramic substrates when contacted with, for example, a carrier gas in the source chamber described herein.

[0095] The metal substrate may have a suitable form for insertion into a generator, for example, into a source chamber as described herein. In one embodiment, the metal substrate may be provided as a separate unit, for example, a disk, plate, film, platen, slab, tube, tube section, or monolith. The metal substrate may have any desired shape, including, but not limited to, a sphere or hemisphere. In one embodiment, the metal substrate is a disk or slab. The disk may be configured to be inserted into a radioisotope generator.

[0096] In some embodiments, the metal substrate has a thickness of about 1 mm to about 30 mm. The metal substrate may have a thickness of at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, 30 (in mm). The metal substrate may have a thickness of less than about 30, 25, 20, 15, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0.5 (in mm). The thickness may be in the range provided by any two of these upper or lower values, e.g., about 1 mm to about 10 mm, e.g., about 6 mm. The metal substrate may have a thickness effective to provide a flat surface for the inert ceramic substrate. In some embodiments, a thicker metal substrate may be more suitable for recycling / refurbishment / reuse, e.g., allowing for safer and easier removal of unused radioisotopes from the substrate. Additionally, thicker metal substrates may be easier to create a uniformly roughened surface as described herein according to some embodiments or examples, hi one embodiment, the thickness of the inert ceramic substrate is less than the thickness of the underlying metal substrate.

[0097] In one embodiment, the surface of the metal substrate including the inert ceramic oxide substrate layer is approximately 0.125 cm 2 ~about 50cm 2 The metal substrate with the inert ceramic oxide substrate layer has a surface area of ​​(cm 2The metal substrate with the inert ceramic oxide substrate layer may have a surface area of ​​at least about 0.125, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 cm 2 In some embodiments, the surface area is less than about 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2, 1.5, 1, 0.75, 0.5, 0.25, or 1.25 (at 100%). Ranges may be provided by any two of these upper and / or lower values.

[0098] In one embodiment, the metal of the metal substrate and the inert ceramic substrate (e.g., on the surface of the metal substrate) are the same. In one embodiment, the inert ceramic substrate is a metal oxide substrate and the metal of the metal substrate and the metal oxide substrate are the same.

[0099] In one embodiment, the metal substrate is a refractory or other transition metal. The metal substrate may be tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, titanium or aluminum, or an alloy thereof. The metal substrate may be tantalum, niobium, tungsten, molybdenum, vanadium, zirconium or titanium, or an alloy thereof. In one embodiment, the inert ceramic substrate is a metal oxide and is provided as a layer (e.g., a surface layer) on the metal substrate or its electrode selected from tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, titanium or aluminum, or an alloy thereof.

[0100] In one embodiment, the metal substrate is an anodizable metal. The anodizable metal substrate or its electrode may be selected from tantalum, niobium, titanium, or aluminum, or alloys thereof. The anodizable metal substrate or its electrode may be selected from tantalum, niobium, zirconium, titanium, or aluminum, or alloys thereof.

[0101] In one embodiment, the inert metal oxide substrate is prepared by oxidatively pretreating the surface of a metal substrate. In one example or embodiment, the inert ceramic substrate is a metal oxide substrate layer comprising a metal oxide prepared by anodic polarization of the surface of an anodizable metal substrate. In this example or embodiment, the metal substrate is a metal electrode. Anodic polarization of a metal substrate or its electrode is described herein.

[0102] Alternatively, in another example, the inert ceramic substrate is a metal oxide layer that includes a metal oxide grown by oxidation (e.g., passive or natural oxidation) of the surface of a metal substrate. Oxidation may also be induced by thermally oxidizing the metal substrate in an oxygen atmosphere and / or by subjecting the metal substrate to a more aggressive oxidizing environment (e.g., an atmosphere with elevated oxygen levels).

[0103] The metal substrate may have a roughened or textured surface. The embodiments described above with respect to the roughened or textured surface of the inert ceramic substrate apply equally to the roughened or textured surface of the metal substrate. According to some embodiments or examples described herein, it has been found that the roughened or textured surface of the metal substrate produces a textured metal oxide layer on the surface of the metal substrate, which has enhanced surface area and wettability that facilitates loading and immobilization of radioisotopes. In some embodiments, the rough inert ceramic substrate (e.g., the rough metal oxide substrate) is naturally formed on the roughened surface of the metal substrate, for example, by passive oxidation. Alternatively, the rough inert ceramic substrate (e.g., the rough metal oxide substrate) is produced on the surface of the roughened metal substrate or its electrode via anodic polarization as described herein.

[0104] As an example, a schematic diagram of an inert ceramic substrate containing immobilized radioisotopes is provided in FIG. 1. The inert ceramic substrate includes a metal substrate (101) and a metal oxide layer (102) on the metal substrate. In one example, the metal oxide layer is first prepared by anodization of the metal substrate / electrode. At least some of the radioisotopes are bound on or near the surface of the metal oxide as a radioisotope surface layer (e.g., any one or more of 103, 104, 105, and 107). In one example, some of the immobilized radioisotopes forming the radioisotope surface layer are provided as a radioisotope-doped layer (103) on and / or within the surface of the inert metal oxide, and the radioisotopes (104) are interspersed within the surface of the metal oxide. Alternatively, or in addition, some of the immobilized radioisotopes forming the radioisotope surface layer may be provided as one or more solid compound phases bound on the surface of the metal oxide (e.g., a crystalline oxide phase of the radioisotope (105)) or as an amorphous phase of the radioisotope bound on or within the surface of the inert metal oxide (107), and in some cases may be bound on and / or within the radioisotope-doped layer (103).

[0105] In another example, the radioisotope surface layer is provided as one or more solid compound phases of the radioisotope bound onto the surface of an inert ceramic substrate, as provided in FIG. 2, and the immobilized radioisotope forming the radioisotope surface layer is provided as one or more solid compound phases bound onto the surface of a metal oxide (e.g., a crystalline oxide phase of the radioisotope (105)) or as an amorphous phase of the radioisotope bound on or within the surface of an inert metal oxide (107).

[0106] It will be understood that the radioisotope surface layer need not be a continuous uniform layer covering the entire surface of the metal oxide surface (102) of the inert ceramic substrate (101). For example, referring to FIG. 1, one or more small sections (106) of the metal oxide surface may protrude through the radioisotope doped layer (103) as a result of non-uniform coverage. Alternatively, the radioisotope surface layer may comprise one or more solid compound phases of the parent radioisotope decorated on the surface of the inert ceramic substrate, for example, one or more crystalline oxide phases (105) of the radioisotope bound on or within the surface of the inert metal oxide, or as an amorphous phase (107) of the radioisotope. In both cases, the metal oxide layer is still considered to comprise the radioisotope surface layer described herein, regardless of whether the immobilized parent radioisotope forms a continuous layer or one or more phases / sections decorating the surface of the inert ceramic substrate.

[0107] A process for preparing an inert ceramic substrate containing an immobilized radioisotope. The present disclosure also provides a process for immobilizing a parent radioisotope on or in an inert ceramic substrate. In one aspect or embodiment, there is provided a process for preparing an inert ceramic substrate comprising a parent radioisotope immobilized on or in the inert ceramic substrate, the process comprising: a) depositing a solution comprising a parent radioisotope species on a surface of the inert ceramic substrate; and b) heating the inert ceramic substrate to a temperature effective to immobilize the parent radioisotope on or in the inert ceramic substrate.

[0108] In one embodiment or example, a process is provided for preparing an inert ceramic substrate comprising a parent radioisotope immobilized on or within the inert ceramic substrate, the process comprising: a) depositing a solution comprising the parent radioisotope species onto a surface of the inert ceramic substrate; and b) heating the inert ceramic substrate to a temperature effective to bond at least some of the parent radioisotope to or near the surface of the inert ceramic substrate forming a heat-treated radioisotope surface layer, allowing for effective emission of gaseous daughter radioisotopes from the inert ceramic substrate.

[0109] In a related embodiment or example, there is provided a process for preparing an inert ceramic substrate comprising a parent radioisotope immobilized on or within the inert ceramic substrate, the process comprising: a) depositing a solution comprising the parent radioisotope species onto a surface of the inert ceramic substrate; and b) heating the inert ceramic substrate to a temperature effective to bond at least some of the parent radioisotope to or near the surface of the inert ceramic substrate forming a heat-treated radioisotope surface layer, thereby allowing for effective emission of gaseous daughter radioisotopes from the inert ceramic substrate.

[0110] In a related embodiment or example, there is provided a process for preparing an inert ceramic substrate comprising a parent radioisotope immobilized on or within the substrate in an amount effective to produce a medically useful dose of a daughter radioisotope through a sequence of natural decay from the parent radioisotope via a gaseous intermediate radioisotope, the process comprising: a) depositing a solution comprising the parent radioisotope species onto a surface of the inert ceramic substrate; and b) heating the inert ceramic substrate to a temperature effective to bond at least some of the parent radioisotope to or near the surface of the inert ceramic substrate forming a heat-treated radioisotope surface layer, thereby allowing the gaseous daughter radioisotope to be effectively emitted from the inert ceramic substrate.

[0111] Oxidative pretreatment of inert ceramic substrates. A solution containing the parent radioisotope species is deposited on a surface of an inert ceramic substrate. The surface of the inert ceramic substrate may be provided by oxidatively pretreating the inert ceramic substrate prior to deposition of the radioisotope solution. In one embodiment, the process comprises providing an inert ceramic substrate having a surface previously prepared by oxidative pretreatment as described herein.

[0112] The inert ceramic substrate may be a layer on the surface of a metal. In one embodiment, the inert ceramic substrate layer is a metal oxide layer on the surface of a metal. The metal oxide layer may be prepared by surface modification of the metal. In one embodiment, the metal oxide layer may be prepared by oxidizing the metal (i.e., a reaction in which electrons are removed) to prepare a metal oxide layer on the surface of the metal. The oxidation of the surface of the metal may be passive (i.e., occurring naturally in air), thereby forming a native metal oxide surface layer on the metal, or may be energetically driven by oxidative pretreatment of the metal surface. For example, the oxidation of the surface of the metal may include a chemical reaction with an oxidizing agent to form the inert ceramic substrate as a surface oxide layer on the metal.

[0113] In one embodiment, the metal may be subjected to thermal oxidation (i.e., heating in an oxygen environment) to produce a metal oxide layer. In another embodiment, the metal may be subjected to anodic polarization (also referred to as anodic oxidation) to produce a metal oxide layer. The metal may also be referred to as a metal substrate, as described herein, and the oxidation described herein may produce a metal oxide layer on the surface of the metal substrate. Thus, in one embodiment, the inert ceramic substrate is a metal oxide layer on the surface of a metal substrate. The metal oxide layer may be formed by thermal oxidation or anodic polarization.

[0114] Thermal oxidation is a well-understood process in which a metal (in its zero oxidation state) reacts with atmospheric oxygen at its surface to produce a definable layer of a metal oxide compound. This reaction relies on oxygen migrating to the metal surface along cracks in a pre-existing thin surface oxide film or by diffusion through such a film. Because oxygen diffusion is facilitated by temperature, heating the metal increases both the reaction rate and the thickness of the metal oxide layer produced on the metal's surface. The metal oxide layer may have varying stoichiometry and may be formed initially as an amorphous material (without a defined lattice structure).

[0115] In one embodiment, the metal is heated in the presence of oxygen to a temperature effective to form a layer of metal oxide on a surface of the metal (e.g., an inert ceramic substrate). In one embodiment, the metal is heated in the presence of oxygen to a temperature of from about 100° C. to about 900° C. The metal may be heated in the presence of oxygen to a temperature of at least about 100, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, or 900 (in ° C.). The metal may be heated in the presence of oxygen at a temperature (in °C) less than about 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 380, 360, 340, 320, 300, 280, 260, 240, 220, 200, or 100. The heating temperature may be in a range provided by any two of these upper and / or lower values, for example, from about 200°C to about 900°C, or from about 300°C to about 800°C.

[0116] The metal may be heated in the presence of oxygen from room temperature to the desired heating temperature at a rate of at least 1, 1.5, 2, 2.5, 2, 3.5, 3, 4, 4.5, 5, 6, 7, 8, 9, or 10° C. / min. The heating rate may be in the range provided by any two of these lower values.

[0117] The metal may be heated in the presence of oxygen for a period of time effective to form a layer of metal oxide on the surface of the metal (e.g., an inert ceramic substrate). The metal may be heated in the presence of oxygen for a period of from about 1 minute to about 24 hours. The metal may be heated in the presence of oxygen for a period of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 (minutes), 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours. The metal may be heated in the presence of oxygen for a period of less than about 24, 22, 20, 18, 16, 14, 12, 10, 8, 6, 5, 4, 3, 2 (hours), 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1 (minutes). The heating time may be in the range provided by any two of these upper and / or lower values, for example, from about 10 minutes to about 6 hours. Other heating temperatures and times to those cited herein, including longer heating times, are also contemplated.

[0118] The metal may be subjected to a surface roughening step to provide a textured surface prior to the thermal oxidation step. Roughened surfaces are described herein in relation to inert ceramic substrates. Surface roughening may be achieved by polishing the metal electrode with an abrasive material, e.g., tungsten carbide, as described herein.

[0119] Anodic polarization is an electrochemical process used to produce metal oxide layers with controlled thickness. Anodized metal oxide layers are grown by electrically polarizing a metal as a positive electrode (anode) in an aqueous electrolyte and passing a direct current across the anode-electrolyte interface. The metal oxide layer is formed by oxygen ions diffusing from the electrolyte interface through a pre-existing thin oxide layer to the underlying metal. The thickness of the resulting metal oxide layer depends on the voltage driving this transport. Other properties such as the porosity and density of the oxide layer can often be controlled. According to some embodiments or examples described herein, the inventors have determined that an inert ceramic substrate prepared via anodic polarization of a metal electrode provides a strong and robust substrate for immobilizing radioisotopes thereon or therein, thereby enabling effective separation of the gaseous daughter radioisotopes emitted from the immobilized radioisotopes tightly bound to the inert ceramic substrate.

[0120] In one embodiment, the process comprises anodizing a metal electrode in an electrolyte solution in the presence of a counter electrode to form a metal oxide substrate layer on the surface of the anodizable metal electrode. Thus, in one embodiment, the metal oxide substrate may be a surface layer prepared by anodic polarization of the surface of the anodizable metal electrode.

[0121] The metal may be subjected to a surface roughening step to provide a textured surface prior to anodizing the metal surface. Roughened surfaces are described herein in relation to inert ceramic substrates. Surface roughening may be achieved by polishing the metal electrode with an abrasive material, for example tungsten carbide.

[0122] The metal or anode thereof may be an anodizable metal as described herein in connection with the inert ceramic substrate, including, for example, tantalum, niobium, titanium, vanadium, zirconium, or aluminum, or alloys thereof. In one embodiment, the anodizable metal substrate or electrode thereof is tantalum, and the metal oxide substrate layer is amorphous tantalum oxide, Ta2O5, or a substoichiometric variant thereof, as described herein.

[0123] The anodization may be carried out at a voltage effective to oxidize the surface of the metal electrode to form a metal oxide substrate layer. The anodization may be carried out at a voltage between about 5V and about 120V, which may be measured relative to a platinum or tantalum counter electrode in the same electrolyte solution where the water evolution reaction to hydrogen proceeds or where the reduction reaction of another electrolyte species proceeds (e.g., about 10V to about 100V). The anodization may be carried out at a voltage of at least about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or 120V. The anodization step may be carried out at a voltage less than about 120, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10 or 5V. The anodization may be carried out at a voltage in the range provided by any two of these upper and / or lower values, for example, about 10V to about 50V. The anodization may be carried out at a voltage of about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or 120V.

[0124] The anodization may be carried out for a period of time at a given voltage effective to oxidize the surface of the metal electrode to form a metal oxide substrate layer. The anodization may be carried out for a period of time between about 15 minutes and about 180 minutes. The anodization may be carried out for a period of time of at least about 5, 10, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, or 180 (in minutes). The anodization may be carried out for a period of time of less than about 180, 165, 150, 135, 120, 105, 90, 75, 60, 45, 30, 15, 10, or 5 (in minutes). The anodization may be carried out for a period of time within the range provided by any two of these upper and / or lower values, for example, between about 15 minutes and about 120 minutes.

[0125] The anodization of the metal may be a stepwise anodization process that includes polarizing the metal electrode at two or more voltages, as described above. The stepwise anodization process may include increasing the voltage from about 5 V to about 120 V over a period of about 30 minutes to about 120 minutes. Other suitable voltages and times are described herein in connection with the anodization steps. For example, the anodization sequence may include (i) anodizing the metal electrode at a first voltage of about 5 V to about 15 V, then (ii) anodizing the metal electrode at a second voltage of about 15 V to about 25 V, and (iii) anodizing the metal electrode at a third voltage of about 25 V to about 80 V, or about 20 V to about 40 V. Step (i) may be performed for a period of about 10 minutes to about 20 minutes. Step (ii) may be performed for a period of about 20 minutes to about 40 minutes. Step (iii) may be carried out for a period of about 20 minutes to about 40 minutes. Increasing the voltage in a stepwise manner may provide additional advantages such as a well-controlled thickness of the inert metal oxide substrate layer.

[0126] The metal electrodes may be anodized in any suitable electrolyte solution, for example, the electrolyte solution may be an aqueous solution containing an inorganic acid, such as phosphoric acid (H3PO4), or an organic acid, such as citric acid, tartaric acid, lactic acid, acetic acid, malonic acid, or a mixture thereof.

[0127] In other embodiments, the metal substrate may be subjected to an oxidative pretreatment step.

[0128] An inert ceramic substrate may be used to immobilize parent radioisotopes within the generators described herein for use in capturing populations of daughter radioisotopes.

[0129] In one embodiment, the process includes contacting the surface of the inert ceramic substrate with an aqueous solution including a surfactant prior to depositing a solution including the parent radioisotope species onto the surface of the inert ceramic substrate, which can reduce the surface tension of the deposited solution such that the deposited solution has a sufficiently low contact angle with the surface of the inert ceramic substrate, allowing it to easily wet and spread across the surface without the need for physical agitation. Any suitable surfactant may be used, such as anionic surfactants, nonionic surfactants, or mixtures thereof.

[0130] Preparation and deposition of radioisotope solutions The process involves depositing a solution containing the parent radioisotope species onto the surface of an inert ceramic substrate, which solution may include any liquid effective to keep the parent radioisotope species in solution and allow for efficient loading and distribution of the parent radioisotope species on the surface of the inert ceramic substrate.

[0131] In one embodiment, the solution is an aqueous or alcoholic solution. It will be understood that an aqueous solution will include a certain amount of water. For example, an aqueous solution may include water and one or more water-miscible solvents, such as alcoholic solvents. It will be understood that an alcoholic solution will include a certain amount of alcohol.

[0132] In one embodiment, the aqueous solution includes an alcohol solvent (i.e., is an aqueous alcohol solution). The aqueous solution may include the alcohol solvent in an amount of about 20% v / v to 50% v / v based on the total volume of the aqueous solution. The aqueous solution may include the alcohol solvent in an amount of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70 (in % v / v based on the total volume of the aqueous solution). The aqueous solution may include the alcohol solvent in an amount of less than about 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5 (in % v / v based on the total volume of the aqueous solution). The aqueous solution may include the alcohol solvent in a range provided by any two of these upper and / or lower values, for example, about 20% v / v to 50% v / v based on the total volume of the aqueous solution. The alcohol solvent may be a polar solvent. The polar solvent may be capable of chemically complexing with the radioisotope. The alcohol solvent may be selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, and mixtures thereof. It will be appreciated that the use of a suitable solvent as described herein can reduce the surface tension of the solution such that the solution has a sufficiently low contact angle with the surface of the inert ceramic substrate, allowing it to easily wet and spread across the surface without the need for physical agitation.

[0133] The aqueous solution may further include a surfactant that can reduce the surface tension of the solution so that the solution has a sufficiently low contact angle with the surface of the inert ceramic substrate, allowing it to easily wet and spread across the surface without the need for physical agitation, according to some embodiments or examples described herein. In one embodiment, the surfactant may include an anionic surfactant, a nonionic surfactant, or a mixture thereof. In one embodiment, the surfactant is a polyethoxylated fatty acid ester or an ethoxylated fatty alcohol. The aqueous solution may include the surfactant in an amount of about 1% v / v to about 10% v / v, based on the total volume of the aqueous solution. The aqueous solution may include the surfactant in an amount of at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 5, 6, 7, 8, 9, or 10 (in % v / v, based on the total volume of the aqueous solution). The aqueous solution may contain the surfactant in an amount less than about 10, 9, 8, 7, 6, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1 or 0.5 (in % v / v based on the total volume of the aqueous solution). The aqueous solution may contain the surfactant in a range provided by any two of these upper and / or lower values, for example, from about 1% v / v to 5% v / v based on the total volume of the aqueous solution.

[0134] The radioisotope species may be provided as a water soluble salt or hydrate thereof selected from one or more of hydroxides, halides, nitrates, acetates, sulfates, phosphates, perchlorates, ammonium compounds, and anionic oxometalate compounds. In one embodiment, the radioisotope species is provided in a solvated or complexed cationic form. In one embodiment, the radioisotope species is provided in an anionic oxometalate form (e.g., [ThO(HPO4)3(H 2 PO4)] 5- ) is available.

[0135] In one embodiment, the radioisotope species may be a thorium compound or a radium compound, or a combination thereof. In one embodiment, the radioisotope species is a thorium species. The thorium radioisotope species is 227 Th,228 Th and 232 In one embodiment, the radioisotope species is a thorium species provided as a nitrate or a hydrate thereof, such as thorium nitrate (Th(NO3)4). In one embodiment, the radioisotope species is a radium species. The radium radioisotope species is 224 Ra and 228 In one embodiment, the radioisotope species is a radium species provided as a nitrate salt or a hydrate thereof, such as radium nitrate. The radium radioisotope species may be selected from at least one of its hydrated cations, such as hydrated radium dication (Ra(HO) n 2+ ) may be provided.

[0136] In one embodiment, the radioisotope species is provided in solution at a concentration of about 0.00001 M (mol / L) to about 1 M, about 0.00001 M to about 0.5 M, or about 0.0001 M to about 0.5 M. The radioisotope species may be provided in solution at a concentration of at least about 0.00001, 0.0001, 0.001, 0.002, 0.004, 0.006, 0.008, 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.8, or 1. The radioisotope species may be provided in solution at a concentration (in M) of less than about 1, 0.8, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.05, 0.01, 0.008, 0.006, 0.004, 0.002 0.001, 0.0001 or 0.00001. The concentration of the radioisotope species may be in a range provided by any two of these upper and / or lower values, for example, from about 0.005M to about 0.05M.

[0137] The process may further comprise adding a precipitating agent to the radioisotope solution. The precipitating agent may be added to the radioisotope solution prior to depositing the solution on the surface of the inert ceramic substrate. Alternatively, the precipitating agent may be added to the radioisotope solution after it has been deposited on the surface of the inert ceramic substrate and prior to the heating of step b). The precipitating agent induces precipitation of the radioisotope from the solution prior to the heating of step b), e.g. as a solid amorphous compound of the radioisotope species, e.g. as a hydroxide of the radioisotope species.

[0138] Any suitable precipitating agent may be used. In one embodiment, the precipitating agent is oxalic acid, a hydroxide base (e.g., NaOH, NH4OH, LiOH), or a halide salt. In one embodiment, the precipitating agent is oxalic acid. The concentration of the precipitating agent (e.g., oxalic acid) may be from about 0.01 mM (mmol / L) to about 100 mM. The concentration of the precipitating agent may be at least about 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.5, 1, 2, 3, 5, 10, 15, 20, 30, 50, 60, 80 or 100, 150, 200, 250, 300, 350, 400, 450, or 500 (in mM). The concentration of the precipitant may be less than about (in mM): 500, 450, 400, 350, 300, 250, 200, 150, 100, 80, 60, 50, 30, 20, 15, 10, 5, 3, 2, 1, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.05, or 0.01. The precipitant concentration may be in a range provided by any two of these upper and / or lower values.

[0139] The process may further include increasing the pH of the radioisotope solution to a more alkaline pH. By increasing the pH of the solution, according to some embodiments or examples described herein, the soluble radioisotope species / ions may coalesce into amorphous hydroxides, providing improved binding and immobilization on or within the inert ceramic substrate. In this example, the amorphous hydroxides are then converted to the oxide phase of the radioisotope upon heating as described herein. Examples of suitable additives used to increase the pH include one or more alkaline compounds, including, for example, aqueous ammonium hydroxide. Other solid amine compounds, such as hexamethylenetetramine, may be used. The pH of the solution may be increased prior to heating the inert ceramic substrate, for example, by dripping a suitable solution (e.g., ammonium hydroxide solution) onto the deposited radioisotope solution on the surface of the inert ceramic substrate. Alternatively, the radioisotope solution may be deposited on the surface of the inert ceramic substrate on which a solution having a higher pH (e.g., a more alkaline pH than the pH of the radioisotope solution) has previously been deposited. Alternatively, the pH of the radioisotope solution may be increased prior to deposition onto the surface of the inert ceramic substrate.

[0140] In other embodiments, the process may further comprise lowering the pH of the radioisotope solution to a more acidic pH. According to some embodiments or examples described herein, by lowering the pH of the solution, the soluble radioisotope species / ions remain sufficiently solvated and can be dispersed substantially without agglomeration across the surface of the inert ceramic substrate. In this example, the radioisotope is then exchanged with the lattice ions of the ceramic substrate compound as described herein. Examples of suitable additives used to lower the pH include one or more acidic compounds, including, for example, aqueous nitric acid, perchloric acid, and trifluoroacetic acid.

[0141] The solution containing the radioisotope species may be deposited on the surface of the inert ceramic substrate by any suitable means, for example, by dropping or micropipetting. Once deposited, the inert ceramic substrate may be heated as described herein (e.g., ex-situ deposition and heating). Alternatively, the inert ceramic substrate may be immersed / soaked in the parent radioisotope solution and then heated as described herein (e.g., ex-situ deposition and heating). It will be understood that the amount of solution may be modified depending on the size of the inert ceramic substrate surface, for example, to maximize the output of daughter isotope products. In some embodiments, the inert ceramic substrate is agitated to facilitate the diffusion of the deposited radioisotope solution and / or the mixing of the precipitant and / or alkaline and / or acidic additives described herein.

[0142] Heat treatment of inert ceramic substrates. The process includes heating the inert ceramic substrate to a temperature effective to bind at least some of the parent radioisotope on or near a surface of the inert ceramic substrate, It will be understood that heating the inert ceramic substrate in turn heats the solution deposited on the surface of the inert ceramic substrate.

[0143] In one embodiment, the heating of the inert ceramic substrate forms a heat-treated radioisotope surface layer on the surface of the inert ceramic substrate. In one embodiment, the heating of the inert ceramic substrate forms a radioisotope doped layer within the surface of the inert ceramic substrate. In one embodiment, the heating of the inert ceramic substrate forms one or more solid compound phases, crystalline phases, or amorphous phases of the radioisotope bound on the surface of the inert ceramic substrate. Inert ceramic substrates, radioisotope surface layers, heat-treated radioisotope surface layers, solid compound phases, crystalline phases, and amorphous phases are described herein.

[0144] The heating step may be considered as a thermal treatment of the solution containing the solubilized and / or precipitated radioisotope species, where the radioisotope species are thermally decomposed into parent radioisotopes, which are immobilized on or within the inert ceramic substrate and thus intimately bound thereto. Furthermore, the thermal treatment may facilitate exchange of the radioisotope ions within the atomic lattice of the inert ceramic substrate, as well as migration and scattering of the ions, thereby forming a layer on the surface, as described herein.

[0145] The inert ceramic substrate in step b) may be heated to a temperature effective to bind the radioisotope on or near the surface of the inert ceramic substrate. The heating may be at a temperature effective to convert the radioisotope species in the solution (e.g., dissolved and / or precipitated radioisotope species) to mobile parent radioisotopes that exchange or otherwise chemically interact and are immobilized on or within the inert ceramic substrate. It will be appreciated that heating the solution may also include heating the inert ceramic substrate. The temperature may be selected depending on the radioisotope species. In one embodiment, the heating in step b) is at a temperature of about 100° C. to about 650° C. The heating in step b) may be at a temperature of at least about 100, 200, 220, 240, 260, 280, 300, 320, 325, 340, 360, 380, 400, 450, 500, 550, 600, or 650 (in ° C.). The heating in step b) may be to a temperature (in °C) of less than about 650, 600, 550, 500, 450, 400, 380, 360, 340, 325, 320, 300, 280, 260, 240, 220, 200, or 100. The heating temperature may be in a range provided by any two of these upper and / or lower values, for example, from about 200°C to about 650°C, or from about 300°C to about 500°C, for example, about 325°C.

[0146] The heating temperature may be obtained at a heating rate of at least 1, 1.5, 2, 2.5, 2, 3.5, 3, 4, 4.5, 5, 6, 7, 8, 9, or 10° C. / min. The heating temperature may be obtained at a heating rate of less than 10, 9, 8, 7, 6, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, or 1° C. / min. The heating rate may be in a range provided by any two of these upper and / or lower values.

[0147] The inert ceramic substrate in step b) may be heated for a period of time effective to bind the radioisotope on or near the surface of the inert ceramic substrate. The heating may be for a period of time effective to convert the radioisotope species in the solution to mobile parent radioisotopes that exchange or otherwise chemically interact and are immobilized on or within the surface of the inert ceramic substrate (e.g., as a radioisotope surface layer comprising radioisotope ions tightly bound to the inert ceramic substrate, e.g., as one or more solid compound phases (e.g., amorphous and / or crystalline phases that may be formed following favorable chemical exchange of the radioisotope with the atomic lattice of the inert ceramic substrate).

[0148] In one embodiment, the heating in step b) is for a period of about 10 minutes to about 24 hours. The heating in step b) may be for a period of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 minutes, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours. The heating in step b) may be for a period of less than about 24, 22, 20, 18, 16, 14, 12, 10, 8, 6, 5, 4, 3, 2 hours, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10 minutes. The heating time may be in the range provided by any two of these upper and / or lower values, for example, from about 10 minutes to about 6 hours, or from about 1 hour to about 3 hours. In one embodiment, the heating in step b) may be for a period of about 10 minutes to about 180 minutes. The heating in step b) may be for a period of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 120, 150, or 180 minutes. The heating in step b) may be for a period of less than about 180, 150, 120, 100, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10 minutes. The heating time may be in a range provided by any two of these upper and / or lower values. Other heating temperatures and times to those cited herein are also contemplated, including longer heating times.

[0149] The heating in step b) may be a two-step heating process. In one embodiment, the heating in step b) comprises (i) heating the inert ceramic substrate and the deposited solution at a first temperature for a period of time effective to dry the solution on the surface of the inert ceramic substrate (e.g., to remove / stripulate / evaporate the aqueous or alcoholic solution), and then (ii) heating the inert ceramic substrate containing the residual radioisotopes to a second temperature for a period of time effective to allow the parent radioisotope ions to exchange with and / or chemically interact with the inert ceramic substrate.

[0150] For step (i), the inert ceramic substrate may be heated to a first temperature of about 60°C to about 130°C. The inert ceramic substrate in step (i) may be heated to a first temperature of at least about 50, 60, 80, 100, 110, 120, 130, 140, or 150 (in °C). The inert ceramic substrate in step (i) may be heated to a first temperature of less than about 150, 140, 130, 120, 110, 100, 80, 60, or 50 (in °C). The inert ceramic substrate in step (i) may be heated to a first temperature in the range provided by any two of these upper and / or lower values, for example, about 50°C to about 150°C, or about 80°C to about 120°C, for example, about 85°C. For step (ii), the inert ceramic substrate may be heated to a second temperature of about 200°C to about 650°C. The inert ceramic substrate in step (ii) may be heated to a second temperature of at least about 200, 220, 240, 260, 280, 300, 320, 325, 340, 360, 380, or 400 (in °C). The inert ceramic substrate in step (ii) may be heated to a second temperature of less than about 400, 380, 360, 340, 325, 320, 300, 280, 260, 240, 220, or 200 (in °C). The inert ceramic substrate in step (ii) may be heated to a second temperature in the range provided by any two of these upper and / or lower values, e.g., from about 300 °C to about 500 °C, e.g., about 325 °C. Other heating temperatures are also contemplated.

[0151] For step (i), the inert ceramic substrate may be heated at a temperature for a period of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, and 60 minutes. The heating in step (i) may be for a period of less than about 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10 minutes. The heating time in step (i) may be in the range provided by any two of these upper and / or lower values, e.g., from about 10 minutes to about 60 minutes, e.g., about 30 minutes. In step (ii), the inert ceramic substrate may be heated to a temperature for at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 minutes, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours. Heating in step (ii) may be for a period of less than about 24, 22, 20, 18, 16, 14, 12, 10, 8, 6, 5, 4, 3, 2 hours, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10 minutes. The heating time in step (ii) can be in the range provided by any two of these upper and / or lower values, for example, from about 10 minutes to about 6 hours, from about 1 hour to about 3 hours, or from about 10 minutes to about 180 minutes. Other heating temperatures and times to those recited herein for step (i) and step (ii) are also contemplated, including longer heating times.

[0152] Heating may be carried out using a suitable furnace (e.g., a muffle furnace), kiln, autoclave, microwave reactor, or hot plate. Alternatively, heating may be carried out using spray pyrolysis or spray drying of the solution deposited on a surface-inert ceramic substrate.

[0153] In one embodiment, the heating in step b) includes heating the inert ceramic substrate under pressure, for example in a sealed vessel (e.g., an autoclave or microwave reactor), such that the solution does not substantially evaporate during heating. In one embodiment, the inert ceramic substrate is heated under pressure at a temperature of about 100° C. to about 240° C. The inert ceramic substrate may be heated under pressure at a temperature (° C.) of at least about 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 240, 260, 280, or 300. The inert ceramic substrate may be heated under pressure at a temperature (° C.) of less than about 300, 280, 260, 240, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100. A range may be provided by any two of these upper and / or lower values, for example, from about 100 to about 220. In an embodiment, the inert ceramic substrate may be heated under pressure for a period of 2 hours to about 24 hours. The inert ceramic substrate may be heated under pressure for a period of at least about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 (in hours). The inert ceramic substrate may be heated under pressure for a period of less than about 24, 22, 20, 18, 16, 14, 12, 10, 8, 6, 5, 4, 3, 2, 1, 0.5, or 0.1 (in hours). A range may be provided by any two of these upper and / or lower values, for example, from 0.1 hours to about 18 hours. It is understood that in some embodiments, substantial overpressure is necessary to prevent the solution from evaporating at high temperatures.

[0154] Heating the inert ceramic substrate under pressure may be a two-step process, for example, (i) heating the inert ceramic substrate and the deposited solution under pressure at a first temperature for a period of time effective to cause ion exchange between the radioisotope ions and the ions of the inert ceramic substrate, and then (ii) heating the inert ceramic substrate and the radioisotope species to a second temperature under pressure for a period of time effective for the parent radioisotope to undergo further exchange and / or chemical interaction with the inert ceramic substrate. In some embodiments or examples, the heating under pressure in step (i) may generate small regions of intermediate solid radioisotope compounds on the surface of the inert ceramic substrate, which thermally decompose during the heating under pressure in (ii) to form one or more crystalline phases of the radioisotope bound on the inert ceramic substrate. The heating under pressure in step (i) and / or step (ii) may also facilitate radioisotope ion exchange with the ceramic substrate surface.

[0155] The inert ceramic substrate containing the immobilized parent radioisotope can be used to generate the daughter radioisotope using the processes, systems and generators described below.

[0156] radioisotope generator The present disclosure also provides a radioisotope generator for capturing a population of daughter radioisotopes. In one aspect or embodiment, a radioisotope generator is provided that defines a chamber for capturing a population of daughter radioisotopes, the chamber configured to accommodate an inert ceramic substrate according to any aspect, embodiment or example described herein. As described herein, the inert ceramic substrate accommodated within the chamber may include a parent radioisotope immobilized on or within the inert ceramic substrate in an amount effective to generate (i.e., produce) a medically useful dose of the daughter radioisotope through a sequence of natural decay from the parent radioisotope via a gaseous intermediate radioisotope. It will thus be understood that the chamber housing the inert ceramic substrate produces (i.e., generates) and captures a population of daughter radioisotopes.

[0157] In one embodiment, the chamber includes a collection surface and is configured to accommodate an inert ceramic substrate within the chamber, with a radioisotope surface layer facing the collection surface for collecting at least some of the emitted gaseous intermediate radioisotopes on the collection surface for a period of time effective to decay into daughter radioisotopes.

[0158] The collection surface may be any surface capable of collecting and retaining the radiated intermediate gaseous radioisotope, for example, a removable dish / tray / container. The collection surface may comprise any suitable material. In one embodiment, the collection surface may comprise or consist of a cellulosic material (e.g., cellulose filter paper), a polymeric material (e.g., PTFE), or glass. Alternatively, the collection surface may be an inner wall of a collection chamber as described herein.

[0159] In one embodiment, the chamber may be configured to house an inert ceramic substrate, with the radioisotope surface layer being in line of sight with the collection surface. It will be understood that "in line of sight" communication refers to a configuration in which the collection surface and the radioisotope surface layer are in line of sight with each other at some point in the chamber, without any obstruction (closed valve or retractable seal) therebetween to allow efficient transport of the radiated gaseous intermediate radioisotope. In some embodiments, the chamber may be configured with one or more valves, seals, and / or closures configured to temporarily physically isolate / separate the inert ceramic substrate from the collection surface, for example, when the daughter radioisotopes are extracted from the collection surface. It will be understood that such physical separation of the inert ceramic substrate from the collection surface temporarily obstructs line of sight communication, but that the chamber is configured to provide line of sight communication between the radioisotope surface layer and the collection surface at some point when collection of the radiated radioisotope is occurring. In other words, such a line-of-sight configuration does not preclude the presence of one or more closures, seals and / or valves in the chamber to temporarily physically isolate / separate the inert ceramic substrate from the collection surface, for example, when daughter radioisotopes are being extracted from the collection surface.

[0160] In a related embodiment, the chamber may be configured to house an inert ceramic substrate, with the radioisotope surface facing substantially downward to allow for gravity-assisted collection of at least some of the emitted gaseous intermediates on the collection surface. For example, the chamber may be configured to house the inert ceramic substrate above the collection surface. Again, this does not preclude the presence of one or more closures, seals, or valves present in the chamber to physically isolate / separate the inert ceramic substrate from the collection surface, for example, when the daughter radioisotope is extracted from the collection surface.

[0161] In one embodiment, the radioisotope generator further comprises a carrier gas inlet port configured to introduce a carrier gas into the chamber to facilitate transport of the emitted gaseous intermediate radioisotope from the inert ceramic substrate on the collection surface.

[0162] In one embodiment, the radioisotope generator further comprises a high vacuum pump configured to apply a high vacuum and evacuate the chamber to facilitate transport of the radiated gaseous intermediate radioisotope from the inert ceramic substrate on the collection surface.

[0163] In one embodiment, the radioisotope generator further comprises a fluid delivery system configured to introduce a collection fluid into the chamber to collect the daughter radioisotopes from the collection surface. In some embodiments, the radioisotope generator chamber comprises one or more valves, seals, and / or closures configured to physically isolate / separate the inert ceramic substrate from the collection surface within the chamber, e.g., when the daughter radioisotopes are extracted from the collection surface. In a related embodiment, the radioisotope generator further comprises a collection fluid outlet port configured to transport the collection fluid containing the daughter radioisotopes out of the chamber.

[0164] The radioisotope generator may further comprise a system for washing the daughter radioisotope products from the collection surface into a product container using a suitable collection fluid. For example, the generator may further comprise a fluid delivery system configured to introduce the collection fluid into the chamber to collect the daughter radioisotope deposited on the collection surface. The fluid delivery system may comprise a collection fluid reservoir coupled to a collection fluid inlet port via a collection fluid inlet valve for introducing the collection fluid into the chamber. The fluid delivery system may be controlled by a collection fluid inlet valve operably configured to open intermittently to introduce a series of pulses of collection fluid into the chamber through the collection fluid inlet port.

[0165] The generator may further comprise a collection fluid outlet port configured to transport the collection fluid comprising the daughter radioisotope from the chamber, for example to a product container, which may be controlled by a collection fluid outlet valve and / or pump operably configured to open intermittently to extract the collection fluid comprising the daughter radioisotope from the chamber.

[0166] In one embodiment, the generator is configured, during use, to produce at least one medical (e.g., clinical or full clinical) dose of the daughter radioisotope within a 24 hour period, e.g., at least 1, 2, 3, 4 or 5 medical doses of the daughter radioisotope within a 24 hour period.

[0167] In one embodiment, the generator, during use, generates at least one medical dose of at least about 1, 2, 5, 10, 50, 60, 90, 120, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, or 1,000 MBq of daughter radioisotope (e.g., 212 In another embodiment, the generator may be configured to produce less than about 1,000, 900, 800, 700, 600, 500, 400, 300, 250, 200, 150, 120, 90, 60, 50, 10, 5, 2, or 1 medical dose of at least one daughter radioisotope (e.g., 212 In one embodiment, the generator may be configured to produce at least one medical dose of at least about 50, 70, 100, 120, 140, 160, 180, or 200 MBq of daughter radioisotope (e.g., 212 The generator may be configured to produce at least one medical dose of a daughter radioisotope (e.g., 10 ... 212 Pb).

[0168] In some embodiments or examples, the chamber may comprise a source chamber as described herein configured to receive an inert ceramic substrate and a collection chamber as described herein including a collection surface. The chamber may further comprise one or more closures, seals, and / or valves separating the source chamber and the collection chamber. In one embodiment or example, a radioisotope generator for capturing a population of daughter radioisotopes generated through a sequence of natural decay from a parent radioisotope is provided, the generator comprising: a) a source chamber configured to immobilize the parent radioisotope that decays to emit a gaseous intermediate radioisotope; b) a collection chamber configured to collect the gaseous intermediate radioisotope emitted from the source chamber and hold the gaseous intermediate radioisotope for a period of time effective to decay into the daughter radioisotope; and c) an optional inter-chamber transfer valve separating the source chamber and the collection chamber configured to be operable to transfer the emitted gaseous intermediate radioisotope from the source chamber to the collection chamber.

[0169] In one embodiment, the parent radioisotope is immobilized on or in an inert ceramic substrate as described herein. For example, the source chamber may be configured to accommodate an inert ceramic substrate containing an immobilized radioisotope, as described herein.

[0170] The generator may further comprise a carrier gas inlet port configured to introduce a flow of carrier gas into the source chamber to facilitate transport of the radiated intermediate gaseous radioisotope from the source chamber through the inter-chamber transfer valve to the collection chamber, e.g., to pressurize the source chamber to provide a pressure differential between the source chamber and the collection chamber. The carrier gas inlet port may be controlled by a carrier gas inlet valve operably configured to open intermittently to introduce the carrier gas into the source chamber as a series of pulses.

[0171] The generator may further comprise a high vacuum pump configured to apply a high vacuum on the collection chamber to evacuate the collection chamber to facilitate transport of the radiated gaseous intermediate radioisotope from the source chamber through the inter-chamber transfer valve to the collection chamber, e.g., to evacuate the collection chamber to a high vacuum to provide a pressure differential between the collection chamber and the source chamber. Evacuation of the collection chamber may also facilitate introduction of collection fluid from a collection fluid reservoir to the collection chamber. Evacuation of the collection chamber to a high vacuum may be controlled by a high vacuum valve operably configured to intermittently open to apply a high vacuum to the collection chamber.

[0172] The generator may further comprise a system for d) washing the daughter radioisotope products from the collection chamber into a product container using a suitable collection fluid. For example, the generator may further comprise a fluid delivery system configured to introduce a collection fluid into the collection chamber to collect the daughter radioisotope deposited on the inner walls of the collection chamber. The fluid delivery system may comprise a collection fluid reservoir coupled to a collection fluid inlet port via a collection fluid inlet valve for introducing the collection fluid into the collection chamber. The fluid delivery system may be controlled by a collection fluid inlet valve operably configured to intermittently open to introduce a series of pulses of collection fluid into the collection chamber through the collection fluid inlet port.

[0173] The generator may further comprise a collection fluid outlet port configured to transport the collection fluid comprising the daughter radioisotope from the collection chamber, for example to a product container, which may be controlled by a collection fluid outlet valve and / or pump operably configured to open intermittently to extract the collection fluid comprising the daughter radioisotope from the collection chamber.

[0174] Features of the generator, including aspects, examples and embodiments described under the headings "Process for Producing Daughter Radioisotopes" and "Collection of Daughter Radioisotopes", are described herein, including, for example, in FIG. 8 and associated description herein.

[0175] system The present disclosure also provides a system for producing and capturing a population of daughter radioisotopes generated through a sequence of natural decay from a parent radioisotope, the system comprising: a) a generator; and b) an inert ceramic substrate according to any aspect, embodiment, or example described herein.

[0176] In one aspect or embodiment, there is provided a system for producing and capturing a population of daughter radioisotopes generated through a sequence of natural decay from a parent radioisotope, the system including: a) a radioisotope generator defining a chamber for producing and capturing the population of daughter radioisotopes; and b) an inert ceramic substrate according to any aspect, embodiment, or example described herein contained in the chamber.

[0177] The inert ceramic substrate may be an inert ceramic substrate according to any aspect, embodiment, or example described herein.The radioisotope generator may be a generator according to any aspect, embodiment, or example described herein.

[0178] In one embodiment, the radioisotope generator defines chambers including a source chamber and a collection chamber, each of which are described herein.

[0179] It will be understood that any aspect, embodiment, or example of the radioisotope generator, process, and / or inert ceramic substrate described herein may form one or more aspects, embodiments, or examples of the system.

[0180] Process for producing daughter radioisotopes The present disclosure also relates to processes for capturing a population of daughter radioisotopes. The daughter radioisotopes produced by the processes described herein are generated through a natural decay sequence from a parent radioisotope via a gaseous intermediate radioisotope. An example of a natural radioactive decay sequence relevant to the present disclosure is provided in FIG. 228The Th decay series is shown.

[0181] In one embodiment or example, a process is provided for capturing a population of daughter radioisotopes, the process comprising: a) allowing emission of gaseous intermediate radioisotopes generated through a sequence of natural decay from a parent radioisotope immobilized on or in an inert ceramic substrate according to an aspect, example or embodiment described herein; and b) collecting at least some of the gaseous intermediate radioisotopes for a period of time effective for them to decay into daughter radioisotopes.

[0182] The process may include a radioisotope generator according to any aspect, embodiment, or example described herein, or a system according to any aspect, embodiment, or example described herein.

[0183] In some embodiments or examples, the process involves immobilizing a parent radioisotope in a source chamber and transporting the gaseous intermediate radioisotope to a separate collection chamber where it naturally decays into daughter radioisotopes. Specifically, the inventors have determined that such separation minimizes contamination of the daughter radioisotopes with the parent radioisotope, providing downstream benefits such as a purer clinical product.

[0184] In another aspect or embodiment, there is provided a process for capturing a population of daughter radioisotopes generated through a sequence of natural decay from a parent radioisotope, the process comprising: a) immobilizing in a source chamber a parent radioisotope that decays to emit a gaseous intermediate radioisotope; b) transferring at least some of the gaseous intermediate radioisotope from the source chamber through an inter-chamber transfer valve to a collection chamber, where the gaseous intermediate radioisotope is retained in the collection chamber for a period of time effective for the gaseous intermediate radioisotope to decay into daughter radioisotopes.

[0185] In one embodiment, the inter-chamber transfer valve is opened intermittently to generate discontinuous transfer of radiated gaseous intermediate radioisotope from the source chamber to the collection chamber.

[0186] The processes described herein can be carried out using a radioisotope generator. Referring to Figure 8, one exemplary embodiment of a generator (300) for isolating and capturing a population of daughter radioisotopes is shown. The generator includes an immobilized parent radioisotope source (302) contained therein, e.g. 228 The source chamber (301) is configured to contain Th. The source chamber (301) is configured to allow for the generation of a gaseous intermediate radioisotope where the parent radioisotope is immobilized (302) and radiated inside the base of the source chamber (301). The radiated gaseous intermediate radioisotope may be a pure gas or may be in a carrier gas (307) introduced into the source chamber (301) through a carrier gas inlet port controlled by opening a carrier gas inlet valve (308) (see solid arrow). In one example, the radiated gaseous intermediate radioisotope is 220 Rn. The carrier gas (307) can facilitate the capture of the emitted gaseous intermediate radioisotope.

[0187] The generator comprises a collection chamber (306) as a separate component from the source chamber (301). An inter-chamber transfer valve (304) can be used to transfer the radiated gaseous intermediate radioisotope (303) from the source chamber (301) to the collection chamber (306). The inter-chamber transfer valve (304) is configured to remain open to transfer the radiated gaseous intermediate radioisotope (303) from the source chamber to the collection chamber (306) or to be opened intermittently, for example as a non-continuous flow (e.g. a series of pulses). It will be appreciated that the intermittent opening of the inter-chamber transfer valve (304) moves between a closed state in which the collection chamber (306) is substantially not in gaseous communication with the source chamber (301) (i.e., substantially isolated from one another) and an open state in which the collection chamber (306) and the source chamber are in gaseous communication with one another.

[0188] Transport of the gaseous intermediate radioisotope through the inter-chamber transfer valve (304) may be driven by a pressure differential, as described herein. The pressure differential may be generated by introducing a carrier gas (307) into the source chamber (301). Additionally or alternatively, the pressure differential may be generated by evacuating the collection chamber (306) using a high vacuum pump (309), which may be controlled by a high vacuum valve (310) (see dashed arrow).

[0189] The collection chamber (306) converts the radiated gaseous intermediate radioisotope into daughter radioisotope (305) (e.g., high purity fluorine-containing isotopes) that accumulate on the interior walls of the collection chamber (306). 212The daughter radioisotopes (305) are configured to retain the daughter radioisotopes (305) for a period of time effective to decay into Pb product radioisotopes (Pb product radioisotopes). The daughter radioisotopes (305) can be readily collected, for example, using a collection fluid (311) introduced into the collection chamber (306). A collection fluid inlet valve (312) can be used to control the introduction of the collection fluid (311) into the collection chamber (306), for example, by intermittently opening it to introduce a series of pulses (see dotted arrows) of collection fluid (311) into the collection chamber (306). The collection chamber includes a collection fluid outlet port configured to extract the collection fluid and the daughter radioisotopes. Extraction of the collection fluid through the collection fluid outlet valve can be controlled by a fluid outlet valve.

[0190] The inter-chamber transfer valve (304), carrier gas inlet valve (308), high vacuum valve (310), collection fluid inlet valve (312), and / or fluid outlet valves (not shown) may be electronically controlled solenoid valves. A variety of computer-controlled devices can be utilized to automate and control the timing of the opening of one or more of the valves described herein to automate any suitable aspect of radioisotope production and provide consistent production results with each production cycle.

[0191] A source chamber containing the parent radioisotope The source chamber is configured to accommodate an immobilized parent radioisotope, which decays to emit a gaseous intermediate radioisotope. The source chamber is also configured to facilitate collection of the intermediate gaseous radioisotope. The parent radioisotope may be immobilized on a substrate, which is housed within the source chamber. In one embodiment, the parent radioisotope is immobilized on or within an inert ceramic substrate as described herein. For example, the source chamber may be configured to accommodate an inert ceramic substrate comprising an immobilized radioisotope, as described herein.

[0192] In one embodiment, the parent radioisotope is an alpha emitter, i.e., it decays by emitting an alpha particle (i.e., a helium nucleus), thereby being transformed into a different atomic nucleus having a mass number that is decreased by four and an atomic number that is decreased by two.

[0193] While any parent radioisotope may be used so long as it decays via a gaseous intermediate radioisotope, in one embodiment the parent radioisotope is an isotope of thorium or radium, or a combination thereof. In one embodiment the parent radioisotope is a thorium radioisotope. The thorium radioisotope is 227 Th and 228 In one embodiment, the parent radioisotope is radium. The radium radioisotope may be selected from at least one of: 224 Ra and 228 Ra, or a combination thereof.

[0194] The immobilized parent radioisotope may be provided in an amount effective to generate a gaseous intermediate radioisotope for subsequent decay and collection of the daughter radioisotope (as a product). The parent radioisotope ion may be provided in an amount effective to generate a medically useful amount (e.g., a preclinically and / or clinically useful amount) of the daughter radioisotope. For example, the parent radioisotope ion may be provided in an amount effective to generate a medical dose of at least about 50, 70, 100, 120, 140, 160, 180, or 200 MBq of the daughter radioisotope (e.g., 212 Pb).

[0195] The source chamber may be of any suitable size or configuration capable of accommodating the parent radioisotope immobilized therein. The source chamber may be constructed of a material that is not subject to radiolytic breakdown so as to be unaffected by gamma radiation or the radiated gaseous intermediate radioisotope, e.g., one or more metallic materials such as tungsten, tantalum, lead, stainless steel, including alloys and / or cermet materials containing them. The source chamber may also be constructed of one or more ceramic materials such as cubic zirconia, or polymers (e.g., polyamides) that have a high level of radiation resistance. Such materials are radiolytically stable and are substantially undamaged when in contact with alpha particles emitted during the decay of the immobilized parent radioisotope, or by the gaseous intermediate radioisotope, or by the associated gamma photon flux.

[0196] Discontinuous transport of intermediate gaseous radioisotopes The processes described herein include immobilizing a parent radioisotope in a source chamber and transporting the gaseous intermediate radioisotope to a separate collection chamber where it naturally decays into daughter radioisotopes. According to at least some embodiments or examples described herein, such separation minimizes contamination of the daughter radioisotope with the parent radioisotope and provides downstream benefits such as a safer and / or more active clinical product.

[0197] The gaseous intermediate radioisotope is transferred from the source chamber to the collection chamber via an inter-chamber transfer valve, which in one embodiment may be intermittently opened for a period of time effective to transfer the radiated gaseous radioisotope from the source chamber to the collection chamber.

[0198] In connection with the operation of one or more valves described herein, the terms "intermittently opened" and "intermittently opening" refer to repeatedly opening and closing a valve to generate a discontinuous flow of a medium (e.g., gas or liquid) through the valve. In other words, the valve moves repeatedly between a closed and an open state. For example, in connection with the intermittent opening of an interchamber-to-chamber transfer valve, the valve may be configured in a normally closed position and repeatedly opened to provide an interrupted, discontinuous transfer of radiated gaseous intermediate radioisotope from a source chamber to a collection chamber. The intermittent opening of the valve may include any number of times, for example, at least 2, 5, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2400, 2600, 2800, 3000, 3400, 3800, 4200, 4600, 5000, 5400, 5800, 6200, 7000, 8000, 9000, or 10,000 times of valve opening prior to extraction and collection of the daughter radioisotope from the collection chamber.

[0199] In accordance with at least some embodiments or examples described herein, the inventors have discovered that when an inter-chamber transfer valve is opened intermittently to effect non-continuous transfer of gaseous intermediate radioisotopes from a source chamber to a collection chamber, the radiochemical purity and / or activity yield of collected daughter radioisotopes can be improved.

[0200] When the inter-chamber transfer valves are in their respective open states, the valves are open for a period of time effective to transfer gaseous intermediate radioisotope from the source chamber to the collection chamber. In one embodiment, the inter-chamber transfer valves are in their respective open states for a period of time between about 10 milliseconds and about 500 milliseconds. The inter-chamber transfer valves in their respective open states may be open for a period of time of at least about 10, 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 240, 260, 280, 300, 350, 400, 450, or 500 (in milliseconds). The inter-chamber transfer valves may be open for periods of less than about (in milliseconds) 500, 450, 400, 350, 300, 280, 260, 240, 200, 180, 160, 140, 120, 100, 80, 60, 40, 20, or 10. Each open inter-chamber transfer valve may be open for a period of time within the range provided by any two of these upper and / or lower values, e.g., from about 20 milliseconds to about 90 milliseconds.

[0201] The intermittent opening of the inter-chamber transfer valve may be performed at any suitable interval to achieve optimal non-continuous transfer of the gaseous intermediate radioisotope, for example, the interval between each opening of the inter-chamber transfer valve may be configured to allow sufficient time for the gaseous intermediate radioisotope to grow in concentration in the source chamber between each opening.

[0202] In one embodiment, the inter-chamber transfer valve may be opened intermittently at intervals of about 3 seconds to about 10 minutes after the previous valve opening to provide non-continuous transfer of emitted gaseous radioisotope from the source chamber to the collection chamber. The inter-chamber transfer valve may be opened intermittently at intervals of at least about 3, 4, 5, 6, 8, 10, 15, 30, 60 seconds, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 minutes after the previous valve opening. The inter-chamber transfer valve may be opened intermittently at intervals of less than about 10, 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5 minutes, 60, 30, 15, 10, 8, 6, 5, 4, or 3 seconds after the previous valve opening. The interval after the previous valve opening may be in a range provided by any two of these upper and / or lower values, for example, from about 10 seconds to about 10 minutes, from about 1 minute to about 10 minutes, from about 1 minute to about 5 minutes, for example, about 2 minutes.

[0203] The intermittent opening of the inter-chamber transfer valve may include any number of valve openings, in one embodiment, the inter-chamber transfer valve may be intermittently opened 50 to 10,000 times prior to extraction and collection of the daughter radioisotope from the collection chamber. The inter-chamber transfer valve may be intermittently opened at least 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2400, 2600, 2800, 3000, 3400, 3800, 4200, 4600, 5000, 5400, 5800, 6000, 6200, 7000, 8000, 9000 or 10,000 times prior to extraction and collection of the daughter radioisotope from the collection chamber. The inter-chamber transfer valve may be intermittently opened less than 10,000, 9000, 8000, 7000, 6000, 6200, 5800, 5400, 5000, 4600, 4200, 3800, 3400, 3000, 2800, 2600, 2400, 2200, 2000, 1900, 1800, 1700, 1600, 1500, 1400, 1300, 1200, 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100 or 50 times prior to extraction and collection of the daughter radioisotope from the collection chamber. The inter-chamber transfer valve may be opened a number of times within the range provided by any two of these upper and / or lower values.

[0204] According to some embodiments or examples described herein, the inventors have determined that the overall yield of daughter radioisotopes can be optimized by adjusting the intervals at which the inter-chamber transfer valves are intermittently opened. For example, the intermittent opening of the inter-chamber transfer valves described herein allows for "shot-wise" delivery of gaseous intermediate radioisotopes from the source chamber and "step-wise" accumulation in the collection chamber. Advantages of this "shot-wise" delivery of gaseous intermediate radioisotopes include, for example, that the gaseous intermediate radioisotopes may have less surface area over which they are distributed and from which the daughter radioisotope products must be collected, thus reducing the overall size / footprint of the generator compared to larger generators that rely on continuous delivery and capture of gaseous intermediate radioisotopes from a resin-based ion exchange source chamber. According to at least some embodiments or examples described herein, the gaseous intermediate radioisotopes may be delivered as a series of pulses. 220 Discontinuous transport of Rn (e.g., an irradiated gaseous intermediate radioisotope) produces low levels of stable daughter isotopes. 208 Pb( 228 Th / 212 The final daughter isotope in the natural decay of Pb (see Figure 7). 212 It also allows for the isolation and collection of Pb. 220 Shot-like accumulation and delivery of Rn is possible because it takes less time to accumulate a useful clinical dose in the collection chamber, and then by intermittent opening of the interchamber delivery valve. 212 Pb in the product 208 The Pb level can be reduced. 208 From Pb 212 Since it is not possible to separate Pb chemically, 208 More than Pb 212 Trapping the product with Pb can lead to more efficient radiolabeling of targeting ligands, higher specific activity doses, and ultimately more effective and safer therapeutic agents for use in radiopharmaceuticals (e.g., radioligand therapy).

[0205] The inter-chamber transfer valve may be opened intermittently for intervals effective to provide daughter radioisotopes in the collection chamber having an activity (in MBq) of about 20 to about 500. The inter-chamber transfer valve may be opened intermittently for intervals effective to provide daughter radioisotopes in the collection chamber having an activity (in MBq) of at least about 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 340, 380, 420, 460 or 500. The inter-chamber transfer valve may be opened intermittently for intervals effective to provide daughter radioisotopes in the collection chamber having activities (in MBq) less than about 500, 460, 420, 380, 340, 300, 280, 260, 240, 220, 200, 180, 160, 140, 120, 100, 80, 60, 40, or 20. Ranges may be provided by any two of these upper and / or lower values.

[0206] In one embodiment, the activity of the gaseous intermediate radioisotope in the source chamber is about 5% to 99% of the activity of the parent radioisotope prior to opening of the inter-chamber transfer valve. The activity of the gaseous intermediate radioisotope in the source chamber may be at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 99% of the activity of the parent radioisotope prior to opening of the inter-chamber transfer valve. The activity of the gaseous intermediate radioisotope in the source chamber may be less than 99, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10 or 5% of the activity of the parent radioisotope prior to opening of the inter-chamber transfer valve. The % activity may be in a range provided by any two of these upper and / or lower values.

[0207] In one embodiment, the activity of the gaseous intermediate radioisotope in the source chamber is from about 10 kBq to about 1,000,000 kBq prior to opening of the inter-chamber transfer valve. The activity of the gaseous intermediate radioisotope in the source chamber (in kBq) prior to opening of the inter-chamber transfer valve may be at least about 10, 100, 1000, 10,000, 100,000, 200,000, 300,000, 400,000, 500,000, 600,000, 700,000, 800,000, 900,000 or 1,000,000. The activity of the gaseous intermediate radioisotope in the source chamber (in kBq) may be less than 1,000,000, 900,000, 800,000, 700,000, 600,000, 500,000, 400,000, 300,000, 200,000, 100,000, 10,000, 1000, 100 or 10 prior to opening of the inter-chamber transfer valve. The activity may be in a range provided by any two of these upper and / or lower values, for example, from about 100 kBq to about 500,000 kBq. The activity may be estimated from a theoretical long-term equilibrium activity derivable from the activity of the parent radioisotope on an inert ceramic substrate, as described herein.

[0208] In one embodiment, the inter-chamber transfer valve is opened when a) the activity of the gaseous intermediate radioisotope is at or near a growth rate that is about 20% to about 80% of the maximum growth rate of the gaseous intermediate radioisotope in the source chamber (i.e., the time at which the inter-chamber transfer valve is opened to transfer the gaseous intermediate radioisotope from the source chamber is at or near a point that is about 20% to about 80% of the steepest portion of the temporal growth curve of the gaseous intermediate radioisotope from the parent radioisotope, see FIG. 10). Alternatively, or additionally, the inter-chamber transfer valve is opened when b) the gaseous intermediate radioisotope retained in the collection chamber after the previous transfer has decayed to a point that is about 20% to about 80% of the steepest portion of the temporal growth curve of the gaseous intermediate radioisotope from the parent radioisotope.

[0209] According to some embodiments or examples described herein, the overall yield of daughter radioisotopes is increased by opening the inter-chamber transfer valve only at intervals corresponding to optimal activity of the gaseous intermediate radioisotope in the source chamber, balancing with retaining the previously transferred gaseous intermediate radioisotope in the collection chamber for an optimal period of time to allow it to decay into daughter radioisotopes in terms of maximum growth rate. An example of an interval that utilizes the maximum growth rate of gaseous radioisotope activity in the source chamber is opening the inter-chamber transfer valve for about 1 minute to about 5 minutes, e.g., about 2 minutes, after the previous valve opening.

[0210] Pressure-driven and high vacuum-driven gas transfer events In one embodiment, transport of the radiated gaseous intermediate radioisotope through the inter-chamber transport valve is driven by a pressure difference between the source and collection chambers, which may be provided by a positive pressure applied to the source chamber and / or a negative pressure (i.e., a high vacuum) applied to the collection chamber.

[0211] In one embodiment, a pressure differential is created by pressurizing the source chamber with a carrier gas, and upon opening of the inter-chamber transfer valve, provides a high-pressure driven gas transfer event of the carrier gas containing the radiated gaseous intermediate radioisotope from the source chamber to the collection chamber. In this embodiment, upon opening of the inter-chamber transfer valve, the pressure differential "pushes" the radiated gaseous intermediate radioisotope from the source chamber, through the inter-chamber transfer valve and into the collection chamber.

[0212] In one embodiment, the source chamber may be pressurized with a carrier gas prior to each high-pressure driven gas transport event (e.g., the source chamber is pressurized prior to each high-pressure driven gas transport event). Alternatively, the pressure generated in the source chamber may be effective to provide more than one high-pressure driven gas transport event (e.g., more than one high-pressure driven gas transport event following a single pressurization of the source chamber).

[0213] In one embodiment, the carrier gas is introduced into the source chamber as a flow through a carrier gas inlet port. In one embodiment, the introduction of the carrier gas into the source chamber is controlled by a carrier gas inlet valve that is intermittently opened to introduce a non-continuous flow of the carrier gas into the source chamber. In one embodiment, the carrier gas is introduced into the source chamber through a carrier gas inlet port. In one embodiment, the introduction of the carrier gas into the source chamber is controlled by a carrier gas inlet valve that is intermittently opened to introduce a non-continuous flow of the carrier gas into the source chamber. The source chamber is connected to a carrier gas inlet port configured to introduce the carrier gas into the source chamber through the intermittently opened carrier gas inlet valve. The introduction of the carrier gas into the source chamber may also pressurize the source chamber.

[0214] The carrier gas may include any inert gas that does not react with the radioisotopes (i.e., parent, intermediate and / or daughter radioisotopes) and / or components that are components of the generator. In one embodiment, the carrier gas includes argon, helium, nitrogen, or mixtures thereof. In one embodiment, the carrier gas includes argon.

[0215] In one embodiment, the source chamber may be pressurized with carrier gas (307) to a pressure of about 0.5 bar to about 8 bar (gauge) prior to opening the inter-chamber transfer valve to provide a high pressure driven gas transfer event of carrier gas containing the radiated gaseous intermediate radioisotope from the source chamber to the collection chamber. The source chamber may be pressurized with carrier gas to a pressure of at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 (in bar) prior to opening the inter-chamber transfer valve to provide a high pressure driven gas transfer event of carrier gas containing the radiated gaseous intermediate radioisotope from the source chamber to the collection chamber. The source chamber may be pressurized with carrier gas to a pressure (in bar) less than about 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1 or 0.5 prior to opening the inter-chamber transfer valve to provide a high pressure driven gas transfer event of carrier gas containing the radiated gaseous intermediate radioisotope from the source chamber to the collection chamber. The pressure may be in a range provided by any two of these upper and / or lower values, e.g., about 0.5 bar to about 5 bar, about 0.75 bar to about 4 bar, or about 1 bar to about 2.5 bar, prior to opening the inter-chamber transfer valve to provide a high pressure driven gas transfer event of carrier gas containing the radiated gaseous intermediate radioisotope from the source chamber to the collection chamber (e.g., about 1.7 bar).

[0216] When the carrier gas inlet valve (308) is in each open state, the valve is open for a period of time effective to pressurize the source chamber with a carrier gas flow, for example, from about 10 milliseconds to about 300 milliseconds. The carrier gas inlet valve in each open state may be open for a period of at least about 10, 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 240, 260, 280, or 300 milliseconds. The carrier gas inlet valve in each open state may be open for a period of less than about 300, 280, 260, 240, 200, 180, 160, 140, 120, 100, 80, 60, 40, 20, or 10 milliseconds. Each open carrier gas inlet valve may be open for a period of time in the range provided by any two of these upper and / or lower values, e.g., from about 80 milliseconds to about 140 milliseconds, e.g., about 120 milliseconds.

[0217] In another embodiment, a pressure differential is created by evacuating the collection chamber to a high vacuum, and upon opening the inter-chamber transfer valve, provides a high vacuum driven gas transfer event of the radiated gaseous intermediate radioisotope from the source chamber to the collection chamber. In this embodiment, upon opening the inter-chamber transfer valve, the pressure differential "pulls" the radiated gaseous intermediate radioisotope from the source chamber, through the inter-chamber transfer valve and into the collection chamber.

[0218] In one embodiment, the collection chamber may be evacuated to a high vacuum before each high vacuum driven gas transport event (e.g., the collection chamber is evacuated before each high vacuum driven gas transport event). Alternatively, the high vacuum generated in the source chamber may be effective to provide two or more high vacuum driven gas transport events (e.g., two or more high vacuum driven gas transport events following a single evacuation of the collection chamber).

[0219] Evacuation of the collection chamber to a high vacuum may be provided by a high vacuum pump (309) configured to apply a high vacuum to and evacuate the collection chamber to create a pressure differential. The high vacuum applied to the collection chamber may be controlled by a high vacuum valve (310) that is intermittently opened to evacuate the collection chamber and create the pressure differential.

[0220] The collection chamber may be evacuated to a high vacuum effective to create a pressure difference between the source chamber and the collection chamber. In one embodiment, the collection chamber is evacuated to a high vacuum of about 1 mbar to about 400 mbar before opening the inter-chamber transfer valve to provide a high vacuum driven gas transfer event of the emitted gaseous intermediate radioisotope from the source chamber to the collection chamber. The collection chamber may be evacuated to a high vacuum of at least about 1, 2, 5, 10, 20, 40, 60, 80, 100, 150, 100, 200, 250, 300, 350 or 400 (in mbar) before opening the inter-chamber transfer valve to provide a high vacuum driven gas transfer event of the emitted gaseous intermediate radioisotope from the source chamber to the collection chamber. The collection chamber may be evacuated to a high reduced pressure of less than 400, 350, 300, 250, 200, 150, 100, 80, 60, 40, 20, 10, 5, 2 or 1 mbar prior to opening the inter-chamber transfer valve to provide a high reduced pressure driven gas transfer event of the emitted gaseous intermediate radioisotope from the source chamber to the collection chamber. The high reduced pressure may be in a range provided by any two of these upper and / or lower values, e.g., from about 5 mbar to about 80 mbar, prior to opening the inter-chamber transfer valve to provide a high reduced pressure driven gas transfer event of the emitted gaseous intermediate radioisotope from the source chamber to the collection chamber.

[0221] In one embodiment, the collection chamber may be evacuated to a high vacuum for a period of about 0.5 seconds to about 20 seconds before opening the inter-chamber transfer valve. The collection chamber may be evacuated to a high vacuum for a period of at least about 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, or 20 seconds (in seconds) before opening the inter-chamber transfer valve. The collection chamber may be evacuated to a high vacuum for a period of less than about 20, 18, 16, 14, 12, 10, 8, 6, 4, 3, 2, 1, or 0.5 seconds (in seconds) before opening the inter-chamber transfer valve. The evacuation time may be in a range provided by any two of these upper and / or lower values, for example, from about 0.8 seconds to about 3 seconds.

[0222] In one embodiment, the intermittent opening of the inter-chamber transfer valve comprises at least one sequence of gas transfer events, the at least one sequence of gas transfer events comprising at least one high pressure driven gas transfer event and at least one high vacuum driven gas transfer event of the gaseous intermediate radioisotope from the source chamber to the collection chamber. The one high pressure driven gas transfer event and the at least one high vacuum driven gas transfer event can be performed in any order. The sequence of gas transfer events may also be referred to as a "cycle" or a "production cycle" as described herein.

[0223] In one embodiment, at least one sequence of gas transport events comprises between 2 and 20 high pressure driven gas transport events before or after a high vacuum driven gas transport event. At least one sequence of gas transport events may comprise at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 high pressure driven gas transport events before or after a high vacuum driven gas transport event. At least one sequence of gas transport events may comprise less than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 high pressure driven gas transport events before or after a high vacuum driven gas transport event. The number of high pressure driven gas transport events before or after a high vacuum driven gas transport event in a sequence may be in the range provided by any two of these upper and / or lower values, e.g., 2-10, 2-8, 2-6, or 2-5 high pressure driven gas transport events before or after a high vacuum driven gas transport event. According to some embodiments or examples described herein, a sequence of gas transport events consisting of two or more high pressure driven gas transport events before or after a high vacuum driven gas transport event can achieve optimal yields of daughter radioisotopes in the collection chamber, as shown in FIG.

[0224] The number of high pressure driven gas transport events for any high vacuum driven gas transport event can also be provided as a ratio. In one embodiment, at least one sequence of gas transport events has a ratio of high pressure driven gas transport events to high vacuum driven gas transport events of 1:1 to 20:1. At least one sequence of gas transport events may have a ratio of high pressure driven gas transport events to high vacuum driven gas transport events of at least about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1 16:1 17:1 18:1, 19:1, or 20:1. At least one sequence of gas transport events may have a ratio of high pressure driven gas transport events to high vacuum driven gas transport events of 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or less than 1:1. The ratio of high pressure driven gas transport events to high vacuum driven gas transport events may be in a range provided by any two of these upper and / or lower values, for example, 1:1 to 20:1, for example, 1:1 to 10:1, 1:1 to 8:1, 1:1 to 6:1, or 1:1 to 5:1, for example, 1:1 to 10:1, 1:1 to 8:1, 1:1 to 6:1, or 1:1 to 5:1.

[0225] The sequence of gas delivery events may be repeated any number of times. In one embodiment, the sequence of gas delivery events described herein may be repeated 10 to 2000 times prior to extraction and collection of the daughter radioisotope from the collection chamber. The sequence of gas delivery events described herein may be repeated at least 10, 50, 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 times.

[0226] According to some embodiments or examples described herein, the inventors have determined that the overall yield of daughter radioisotopes in the collection chamber can be increased by transporting the gaseous intermediate radioisotopes through an intermittently opened interchamber transport valve using a combination of high pressure driven gas transport events and high vacuum driven gas transport events. For example, one or more advantages can be provided by using a combination of high pressure driven gas transport events and high vacuum driven gas transport events, including a) the generator does not need to be operated to manage very high gas pressures, and / or b) a large amount of the gaseous intermediate isotope is not lost to the high vacuum system during the high vacuum driven gas transport events, but is retained in the daughter isotope collection chamber. According to some embodiments or examples described herein, increasing the ratio of high pressure driven gas transport events to high vacuum driven gas transport events can increase the overall daughter radioisotope activity in the collection chamber, as shown in FIG. 11.

[0227] The interval between each gas transport event may be about 3 seconds to about 10 seconds after the previous gas transport event, providing for non-continuous transport of emitted gaseous radioisotope from the source chamber to the collection chamber. The interval between each gas transport event of intermittent opening may be at least about 3, 4, 5, 6, 8, 10, 15, 30, 60 seconds, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 minutes after the previous gas transport event. The interval between each gas transport event of the intermittent opening may be less than about 10, 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5 minutes, 60, 30, 15, 10, 8, 6, 5, 4, or 3 seconds after the previous gas transport event. The interval between each gas transport event of the intermittent opening may be in a range provided by any two of these upper and / or lower values, such as from about 10 seconds to about 10 minutes, from about 1 minute to about 10 minutes, from about 1 minute to about 5 minutes, such as about 2 minutes, after the previous gas transport event.

[0228] It will be appreciated that according to some embodiments or examples described herein, only one high pressure driven gas transfer event or one high vacuum driven gas transfer event occurs each time the inter-chamber transfer valve is opened. By way of example only, the intermittent opening may include at least one sequence of gas transfer events consisting of five high pressure driven gas transfer events before or after a high vacuum driven gas transfer event, each gas transfer event being separated by a two minute interval. In this example, every sixth opening of the inter-chamber transfer valve is a high vacuum driven gas transfer event, with each opening of the inter-chamber transfer valve occurring two minutes after the previous valve opening. The sequence may then be repeated any number of times until a desired activity of the daughter radioisotope in the collection chamber is reached, which can then be collected and extracted.

[0229] As described herein, the parent radioisotope decays to emit a gaseous intermediate radioisotope. The gaseous intermediate radioisotope is radon-219 ( 219 Rn), Radon-220( 220 In one embodiment, the gaseous intermediate radioisotope may be: 220 Rn.

[0230] Capture of daughter radioisotopes Upon transfer from the source chamber to the collection chamber, the gaseous intermediate radioisotope is retained in the collection chamber for a period of time effective to naturally decay into daughter radioisotopes. The amount of daughter radioisotopes produced during the decay period may be useful for medical applications. Collection chambers are described herein, including under the "radioisotope extraction" aspects and embodiments of the present disclosure.

[0231] In one embodiment, the process described herein produces a daughter radioisotope in the collection chamber having an activity of about 5% to about 80% of the parent radioisotope immobilized in the source chamber. The process described herein may produce a daughter radioisotope in the collection chamber having an activity of at least about 5, 10, 20, 30, 40, 50, 60, 70 or 80% of the parent radioisotope activity within 24 hours. The process may produce a daughter radioisotope in the collection chamber having an activity of less than about 80, 70, 60, 50, 40, 30, 20, 10 or 5% of the parent radioisotope activity. An activity percent range may be provided by any two of these upper and / or lower limits.

[0232] The daughter radioisotope may be any decay product of the gaseous intermediate radioisotope described herein and depends on the parent radioisotope immobilized in the source chamber, but in some embodiments the daughter radioisotope is a lead or bismuth radioisotope, or a mixture thereof, e.g., lead-211 ( 211 Pb) and / or Bismuth-211(211 Bi ), lead-212( 212 Pb) and / or Bismuth-212( 212 Bi), or a mixture thereof, including their daughter radioisotopes. In one embodiment, the daughter radioisotopes are 212 Pb or 211 Pb, or a mixture thereof.

[0233] The daughter radioisotope can be used as a therapeutic radioisotope in radiolabeled drug applications. The daughter radioisotope can be produced in the collection chamber in clinically relevant quantities. It will be understood that the daughter radioisotope can therefore be a product that can be extracted from the collection chamber, collected, and used as described herein.

[0234] In one embodiment, the process produces at least one medical (e.g., clinical or total clinical) dose of daughter radioisotope within a 24 hour period, e.g., at least 1, 2, 3, 4, or 5 medical doses of daughter radioisotope within a 24 hour period. The process produces at least about 50, 70, 100, 120, 140, 160, 180, or 200 MBq of medical dose of daughter radioisotope (e.g., 212 Pb) may be produced.

[0235] In one embodiment, the process further includes recovering at least some of the daughter radioisotopes from the collection surface or chamber, for example as described herein. Recovery of at least some of the daughter radioisotopes is described herein, including under "Radioisotope Extraction" aspects and embodiments of the present disclosure. The daughter radioisotopes may be recovered from the collection chamber after the required number of cycles of the gas transport event sequence have been performed and / or when the activity of the daughter radioisotopes in the collection chamber has reached a desired level.

[0236] In one embodiment, the recovered daughter radioisotopes can be used in radiopharmaceuticals. For example, the recovered daughter radioisotopes can be conjugated to targeting molecules for use as radiopharmaceuticals, such as in radioligand therapy. Various applications and uses of the recovered daughter radioisotopes are described herein, including under the "Applications" aspects and embodiments of the present disclosure.

[0237] The parent radioisotope, gaseous intermediate radioisotope, and daughter radioisotope used / produced in the present process are described herein. In one embodiment related to the present process, the parent radioisotope is thorium-227 ( 227 Th) and Thorium-228( 228 In one embodiment related to the present process, the gaseous intermediate radioisotope is radon-219 ( 219 Rn) and Radon-220( 220In one embodiment related to the present process, the daughter radioisotope is selected from at least one of lead-211 ( 211 Pb) or lead-212( 212 Pb).

[0238] Collection of daughter radioisotopes The present inventors have developed a process for recovering daughter radioisotopes that have grown and accumulated (e.g., captured / collected) on a collection surface described herein, including when the collection surface is an inner wall of a collection chamber described herein. By introducing a collection fluid to collect the daughter radioisotopes that have accumulated on the collection surface (as a result of the natural decay of the gaseous intermediate radioisotope), the daughter radioisotopes can be extracted from the collection surface in a fluid that can be readily used as a product in clinical radiopharmaceutical applications, such as, for example, radioligand therapy.

[0239] In one aspect or embodiment, a process for recovering a population of daughter radioisotopes from a collection surface in a chamber of a radioisotope generator, the process comprising: a) introducing a collection fluid into the chamber through a collection fluid inlet port to collect daughter radioisotopes deposited on a collection surface; b) extracting a collection fluid containing the daughter radioisotopes from the chamber through a collection fluid outlet port to recover the daughter radioisotopes.

[0240] In one aspect or embodiment, a process for recovering a population of daughter radioisotopes trapped in a collection chamber, the process comprising: a) introducing a collection fluid into the collection chamber through a collection fluid inlet port to collect daughter radioisotopes deposited on an inner wall of the collection chamber; b) extracting a collection fluid containing the daughter radioisotopes from the collection chamber through a collection fluid outlet port to recover the daughter radioisotopes.

[0241] 8, the daughter radioisotopes (305) can be readily collected using, for example, a collection fluid (311) introduced into the collection chamber (306) through a collection fluid inlet port. A collection fluid inlet valve (312) can be used to control the introduction of the collection fluid (311) into the collection chamber (306), for example, by opening it intermittently to introduce a series of pulses of collection fluid (311) into the collection chamber (306).

[0242] A collection chamber to hold the daughter radioisotope The collection chamber is configured to capture gaseous intermediate radioisotopes transferred from the source chamber, for example, via an inter-chamber transfer valve as described herein. The gaseous intermediate radioisotopes are retained in the collection chamber for a period of time effective to naturally decay into daughter radioisotopes. The collection chamber comprises a collection surface (e.g., an inner wall of the collection chamber) for collecting the emitted gaseous intermediate radioisotopes and the daughter radioisotopes. The daughter radioisotopes may be deposited, for example, as small particles, on the collection surface (e.g., an inner wall) of the collection chamber.

[0243] The collection chamber may be made of any suitable material capable of capturing and retaining the daughter radioisotopes. In some embodiments, the collection chamber is made of an inert metal or metal alloy (e.g., stainless steel or anodized titanium alloy), a non-fluorinated polymer (e.g., polyetheretherketone (PEEK)), glass (e.g., borosilicate glass), or a fluoropolymer (e.g., polytetrafluoroethylene, polyvinylidene fluoride). In one embodiment, the collection chamber is transparent.

[0244] The collection chamber includes a collection fluid outlet port located at one end of the collection chamber, for example, at the base of the chamber. In this embodiment, the collection fluid containing the daughter radioisotopes pools at the base of the collection chamber and can be extracted from the collection chamber using gravity by opening the collection fluid outlet port, or by actively drawing fluid through the fluid outlet port using a pump.

[0245] The inner wall of the collection chamber comprises a surface, such as a collection surface described herein. In one embodiment, the inner wall of the collection chamber comprises a hydrophobic surface. Upon contact with the hydrophobic inner surface, the collection fluid forms droplets having a high contact angle (i.e., greater than 120°) on the hydrophobic inner wall surface. Because they form a high contact angle with the inner wall surface, the droplets of the collection fluid easily roll down the inner wall surface due to gravity, and in doing so, the droplets collect daughter radioisotopes (e.g., particles) that have deposited on the inner wall of the collection chamber.

[0246] The hydrophobic surface of the collection chamber may provide a contact angle with the collection fluid of greater than (in degrees) 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, or 175 degrees. The hydrophobic surface of the collection chamber may provide a contact angle with the collection fluid of less than (in degrees) 175, 170, 165, 160, 155, 150, 145, 140, 135, 130, 125, 120, 115, 110, 105, 100, 95, or 90. The contact angle may be in a range provided by any two of these upper and / or lower values.

[0247] In some embodiments, the surface of the inner wall of the collection chamber is configured to optimize the flow of collection fluid to a collection fluid outlet port at the base of the collection chamber. For example, the surface of the inner wall of the collection chamber may be physically textured and / or chemically modified in a manner that facilitates the downward flow of collection fluid toward the collection fluid outlet port. Such physical texturing may include internal 3D profiling within the collection chamber, for example, engraving a grooved or threaded arrangement, which may facilitate the downward flow of collection fluid.

[0248] The daughter radioisotope may be any decay product of the gaseous intermediate radioisotopes described herein, and in some embodiments the daughter radioisotope is a lead or bismuth radioisotope, or a mixture thereof, such as lead-211 ( 211 Pb) and / or Bismuth-211(211 Bi ), lead-212( 212 Pb) and / or Bismuth-212( 212 Bi), or a mixture thereof, including their daughter radioisotopes. In one embodiment, the daughter radioisotopes are 212 Pb or 211 Pb, or a mixture thereof.

[0249] The daughter radioisotope can be used as a therapeutic radioisotope in radiolabeled drug applications. The daughter radioisotope can be extracted from the collection chamber in clinically relevant amounts. It will be understood that the daughter radioisotope can therefore be a product that can be extracted from the collection chamber, collected, and used as described herein.

[0250] In one embodiment, the daughter radioisotopes are captured in the collection chamber by the processes described herein, including under the "Radioisotope Generation and Capture" aspects and embodiments of this disclosure.

[0251] Collection Fluid The process includes introducing a collection fluid into a chamber (e.g., a collection chamber) through a collection fluid inlet port to collect daughter radioisotopes deposited on a collection surface (e.g., an inner wall of the collection chamber). The collection fluid includes any suitable medium capable of collecting the daughter radioisotopes from the collection surface. In some embodiments, the collection fluid does not substantially react with the daughter radioisotopes. It will be understood that the term "fluid" encompasses fluids in their liquid or gaseous states, for example, water or steam.

[0252] In one embodiment, the collection fluid is introduced into the collection chamber as a liquid or a condensable vapor.

[0253] The collection fluid may include an aqueous solution. The aqueous solution may be a biologically compatible aqueous solution. The aqueous solution may include, for example, water, saline, or other pH-neutral elution fluid that is compatible with the protein (e.g., PSMA ligand) that is to be labeled with a radioisotope. By using such a biologically compatible aqueous solution, the daughter radioisotope can be recovered and directly utilized in radiopharmaceutical applications such as radioligand therapy. Other suitable biologically compatible aqueous solutions include, for example, isotonic solutions, buffer solutions, such as acetate buffer, carbonate / HEPES buffer, urea solution, and mixtures thereof.

[0254] According to at least some embodiments or examples described herein, the use of biologically compatible aqueous solutions to collect the daughter radioisotopes can eliminate the need for concentrated acidic solutions, such as hydrochloric acid, that are required in the prior art to recover captured daughter radioisotopes from continuous transport resin-based ion exchange generators. For example, daughter radioisotopes extracted using acidic solutions are not suitable for direct use in radiopharmaceutical applications and must be brought to an appropriate pH level before being put into clinical or preclinical use.

[0255] In one embodiment, the aqueous solution may have a pH of about 6 to about 10. The aqueous solution may have a pH of at least about 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10. The aqueous solution may have a pH of less than about 10, 9.5, 9, 8.5, 8, 7.5, 7, 6.5, or 6. The pH may be in a range provided by any two of these upper and / or lower values.

[0256] In one embodiment, the collection fluid is water. Water may be introduced into the collection chamber as steam, condensable water vapor, and / or liquid water.

[0257] Introduction of collection fluid to collect daughter radioisotopes The collection fluid is introduced into the collection chamber via a collection fluid inlet port. In one embodiment, the collection fluid inlet port is connected to a collection fluid reservoir via a collection fluid inlet valve. The collection fluid reservoir contains the collection fluid for introduction into the collection chamber. The collection fluid reservoir may be made of any suitable material capable of containing the collection fluid, for example, PTFE. The collection fluid reservoir, collection fluid inlet port, and collection fluid inlet valve may collectively form a collection fluid delivery system.

[0258] The collection fluid may be introduced into the collection chamber through an opening configured to spray the collection fluid (e.g., under pressure) into the collection chamber. Alternatively, the collection fluid may be introduced through a spray nozzle, such as an automated spray nozzle. It will be understood that the means of introducing the collection fluid into the collection chamber is not limited to any one particular opening.

[0259] Introduction of collection fluid into the collection chamber via the collection fluid inlet port may be controlled by a collection fluid inlet valve, which may be opened intermittently to introduce the collection fluid into the collection chamber as a series of pulses.

[0260] When the collection fluid inlet valve is in each open state, the valve may be open for a period of between about 10 milliseconds and about 300 milliseconds. The collection fluid inlet valve in each open state may be open for a period of at least about 10, 20, 30 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 240, 260, 280, or 300 milliseconds. The collection fluid inlet valve may be open for a period of less than about 300, 280, 260, 240, 200, 180, 160, 140, 120, 100, 90, 80, 70, 60, 50, 40, 30, 20, or 10 milliseconds. Each open collection fluid inlet valve may be open for a period within the range provided by any two of these upper and / or lower values, for example, from about 20 milliseconds to about 100 milliseconds, or from about 30 milliseconds to about 90 milliseconds.

[0261] The series of pulses provided by the intermittent opening of the collection fluid inlet valve may include any number of valve openings before extracting the collection fluid through the collection fluid outlet port. For example, the collection fluid inlet valve is intermittently opened 1-20 times before the extraction of the collection fluid from the collection chamber. The collection fluid inlet valve may be intermittently opened at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 times before the extraction of the collection fluid from the collection chamber. The collection fluid inlet valve may be intermittently opened less than 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 time before the extraction of the collection fluid from the collection chamber. The number of times the collection fluid inlet valve may be opened may be within the range provided by any two of these upper and / or lower values, for example, 1-10 times, 1-8 times, or 1-5 times before the extraction of the collection fluid from the collection chamber.

[0262] The intermittent opening of the collection fluid inlet valve may occur at any suitable interval to generate a series of pulses (i.e., a non-continuous flow) of collection fluid. In one embodiment, the collection fluid inlet valve may be opened at intervals of about 0.5 seconds to 60 seconds after the previous valve opening to provide for non-continuous delivery of collection fluid to the collection chamber. The collection fluid inlet valve may be opened intermittently at intervals of at least about 0.5, 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 (in seconds) after the previous valve opening to provide for non-continuous delivery of collection fluid to the collection chamber. The collection fluid inlet valve may be opened intermittently at intervals of less than 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 2, 1, or 0.5 (in seconds) after the previous valve opening to provide for non-continuous delivery of collection fluid to the collection chamber. A range may be provided by any two of these upper and / or lower values.

[0263] In one embodiment, the introduction of the collection fluid is driven by a pressure differential across the collection fluid inlet valve. The pressure differential across the collection fluid inlet valve may be created by a positive pressure in the collection fluid reservoir driving the collection fluid through the collection fluid inlet valve. Alternatively, or additionally, the pressure differential across the collection fluid inlet valve is created by a negative pressure in the collection chamber. The pressure differential across the collection fluid inlet valve may be created by a positive pressure in the collection fluid reservoir and a negative pressure in the collection chamber.

[0264] The positive pressure in the collection fluid reservoir may be created by heating the collection fluid reservoir to produce a hot collection fluid having a vapor pressure effective to provide a positive pressure in the collection fluid reservoir. The collection fluid reservoir may be heated to a temperature effective to produce a desired pressure in the collection fluid reservoir. In one embodiment, the collection fluid reservoir is heated to a temperature of about 100° C. to about 140° C.

[0265] The positive pressure in the collection fluid reservoir may be from about 15 kPa to about 400 kPa, or from about 15 kPa to about 250 kPa (gauge). The positive pressure in the collection fluid reservoir may be at least about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 300, 350 or 400 (kPa). The positive pressure in the collection fluid reservoir may be less than about 400, 350, 300, 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 115, 110, 105, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, or 15 kPa. The positive pressure in the collection fluid reservoir may be in a range provided by any two of these upper and / or lower values, for example, from about 60 kPa to about 200 kPa.

[0266] The negative pressure in the collection chamber may be generated by evacuating the collection chamber to a high vacuum prior to the intermittent opening of the collection fluid inlet valve. Evacuation of the collection chamber to a high vacuum may be provided by a high vacuum pump (309) and a high vacuum valve (310) configured to apply a high vacuum to and evacuate the collection chamber to create a pressure differential as described herein.

[0267] In one embodiment, the collection chamber is evacuated to a high reduced pressure of about 1 mbar to about 200 mbar prior to opening of the collection fluid inlet valve. The collection chamber may be evacuated to a high reduced pressure of at least about 1, 2, 5, 10, 20, 40, 50, 60, 80, 100, 150, 100, or 200 (in mbar) prior to opening of the collection fluid inlet valve. The collection chamber may be evacuated to a high reduced pressure of less than 200, 150, 100, 80, 60, 50, 40, 20, 10, 5, 2, or 1 (in mbar) prior to opening of the collection fluid inlet valve. The high reduced pressure may be in the range provided by any two of these upper and / or lower values, for example, from about 5 mbar to about 50 mbar.

[0268] The pressure differential across the collection fluid inlet valve may be from about 15 kPa to about 340 kPa. The pressure differential across the collection fluid inlet valve may be at least about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330 or 340 (in kPa). The pressure differential across the collection fluid inlet valve may be less than about (in kPa) 340, 330, 320, 310, 300, 290, 280, 270, 260, 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 115, 110, 105, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, or 15. The pressure differential across the collection fluid inlet valve may be in a range provided by any two of these upper and / or lower values, for example, from about 50 kPa to about 240 kPa. It will be understood that pressure in kPa can also be provided in bar (i.e., 1 kPa = approximately 0.01 bar). Other pressure differentials are envisioned.

[0269] In one embodiment, the collection chamber is evacuated to a high vacuum and then the collection fluid is introduced through a collection fluid inlet port as described herein. The collection fluid may be introduced into the collection chamber 0.5 to 10 seconds after the collection chamber is evacuated to a high vacuum.

[0270] In one embodiment, the introduction of collection fluid into the collection chamber may include (i) a priming sequence and (ii) a washing sequence. Alternatively, the introduction of collection fluid into the collection chamber may include a single washing sequence.

[0271] For step (i), the priming sequence includes an initial opening of the collection fluid inlet valve to accumulate a volume of collection fluid (e.g., as hot condensate) behind the collection fluid inlet valve (e.g., a fluid bolus). The priming sequence of the collection fluid inlet port may include intermittently opening the collection fluid inlet valve 1-5 times. The collection fluid inlet valve may be opened for a period of time (in milliseconds) as described above.

[0272] For step (ii), the washing sequence involves intermittently opening the collection fluid inlet valve to introduce collection fluid behind the collection fluid inlet valve and in the fluid collection reservoir into the collection chamber as a series of pulses.

[0273] Introduction of the collection fluid into the collection chamber is performed such that the fluid bolus possesses significant momentum and effectively covers the entire surface of the interior wall of the collection chamber after impacting the interior wall. The wash sequence may include intermittently opening the collection fluid inlet valve as described above, for example, 1-20 times prior to extraction of the collection fluid from the collection chamber. The collection fluid inlet valve may be opened for a period of time (in milliseconds) as described above.

[0274] In one embodiment, the collection fluid is a condensable vapor. The condensable vapor can condense (e.g., as many small droplets) on the inner walls of the collection chamber, and the daughter radioisotopes deposited on the inner walls of the collection chamber are collected, for example, by rolling down the walls of the inner chamber under gravity, while collecting minimal daughter radioisotope particles. In one embodiment, the collection chamber is cooled to a temperature effective to condense the condensable vapor on the inner walls of the collection chamber, for example, as many small droplets.

[0275] In one embodiment, the collection fluid is a liquid and a pressurized carrier gas is introduced along with the collection fluid through a collection fluid inlet port to form an aerosol containing multiple droplets (which easily roll down the inner wall surface due to gravity and collect the daughter radioisotopes deposited on the inner walls of the collection chamber).

[0276] In accordance with at least some embodiments or examples described herein, the extraction of daughter radioisotopes described herein can minimize the total volume of collection fluid required to effectively extract the daughter radioisotopes from the collection chamber, and therefore can provide a daughter radioisotope solution having a high specific activity (i.e., radioisotope concentration).

[0277] In another embodiment, the collection fluid is a liquid that is sprayed into the collection chamber through an opening, for example a small orifice.

[0278] The amount of collection fluid introduced into the collection chamber may vary depending on the number of openings of the collection fluid inlet valve used to introduce the collection fluid into the collection chamber (e.g., the number of valve openings in a wash sequence). Other factors that may affect the amount of collection fluid required include the pressure at which the collection fluid is driven into the collection chamber. In one embodiment, about 0.1 mL to about 10 mL, about 0.1 mL to about 5 mL, or about 1 mL to about 3 mL of collection fluid is introduced into the collection chamber prior to extraction.

[0279] Collection fluids and extraction of daughter radioisotopes The process for recovering the daughter radioisotopes described herein includes extracting a collection fluid containing the daughter radioisotopes from a collection chamber through a collection fluid outlet port to recover the daughter radioisotopes. In one embodiment, the extraction of the collection fluid through the collection fluid outlet port is controlled by a collection fluid outlet valve that is intermittently opened to extract the collection fluid containing the daughter radioisotopes from the collection chamber. The collection fluid outlet valve may be an electronically controlled solenoid valve.

[0280] In one embodiment, collection fluid containing the collected daughter radioisotopes accumulates in the lower region / base of the collection chamber above the collection fluid outlet port. In this example, the collection fluid outlet valve can be opened to extract the collection fluid via gravity. Alternatively, the collection fluid may be extracted through the collection fluid outlet port using a pump, for example a peristaltic fluid pump.

[0281] The collection fluid outlet valve and / or pump may be periodically opened to recover the collection fluid and daughter radioisotopes for the intended therapeutic use. For example, the collection fluid including the daughter radioisotopes may be extracted into a container suitable for transport to a radiochemical laboratory or radiopharmacy. For example, the collection fluid outlet port may be configured to transport the extracted collection fluid to various collection systems, such as fraction collectors, glass vials, etc. The collection fluid outlet valve and / or pump may be configured to extract the collected fluid and daughter radioisotopes for downstream medical use, for example. 212 Depending on the desired activity of Pb, it can be controlled to extract a predetermined volume of collection fluid and daughter radioisotope.

[0282] Purpose Applications of the present technology include a variety of applications in the medical, therapeutic, and diagnostic fields, including, for example, radiopharmaceuticals for treating cancer. For example, the nuclear medicine field provides radiolabeling of macromolecules, such as antibodies, that bind with high specificity to antigens expressed on specific cancer cells. Alpha particle emitters (including daughter radioisotopes generated, captured, and collected as described herein) are particularly effective as short-range cytotoxic payloads on such targeted molecular vehicles, thus allowing cancer cell destruction with minimal impact on surrounding healthy tissue.

[0283] In some embodiments, daughter radioisotopes (e.g., 212 Pb) is high radiochemical purity and high specific activity (e.g., low as a result of using the generators and processes described herein). 208 The generators and processes described herein can be used to produce high purity daughter radioisotopes (e.g., high purity 212 Producing uranium chloride (Pb) would allow for the production of this therapeutic isotope on a large scale with wide geographic distribution.

[0284] Daughter radioisotopes produced using the processes and generators described herein, such as 212 Pb can be directly utilized in a variety of clinical applications, including conjugation to targeting molecules / ligands for use in radiopharmaceutical applications such as radioligand therapy. Examples of targeting molecules / ligands include antibodies and / or peptides, such as prostate specific membrane antigen (PSMA) ligands.

[0285] This application claims priority from AU2021 / 902649, filed August 23, 2021, the entire contents of which are incorporated herein by reference. EXAMPLES

[0286] In order that the present disclosure may be more clearly understood, certain embodiments of the invention are described in further detail below by reference to the following non-limiting experimental materials, methodology, and examples.

[0287] Example 1: Loading of parent radioisotopes onto or within inert ceramic substrates Preparation of inert ceramic substrate surfaces by thermal oxidation. An inert ceramic substrate composed of tantalum pentoxide (Ta2O5) coated on tantalum metal was prepared by heating a disk of tantalum metal (30 mm diameter, 6 mm thickness) in a muffle furnace using the following temperature program: from room temperature to 575°C in 100 minutes, held at 575°C for 45 minutes, then allowed to slowly cool naturally. Prior to heating, the tantalum metal disk was uniformly sanded with 240 grit sandpaper (Al2O3 abrasive) to remove machining marks, then rinsed with deionized water and dried using compressed nitrogen.

[0288] An inert ceramic substrate composed of zirconium dioxide (ZrO2) coated on zirconium metal was prepared by heating a disk of zirconium metal (30 mm diameter, 6 mm thickness) in a muffle furnace using the following temperature program: from room temperature to 750°C in 120 minutes, held at 750°C for 300 minutes, then allowed to slowly cool naturally. Prior to heating, the zirconium metal disk was uniformly sanded with 240-grit sandpaper (Al2O3 abrasive) to remove machining marks, then rinsed with deionized water and dried using compressed nitrogen.

[0289] Preparation of inert ceramic substrate surfaces by anodic polarization. The tantalum metal disk was uniformly polished with 240-grit sandpaper (Al2O3 abrasive) to remove machining marks, then rinsed with deionized water and dried using compressed nitrogen. The polished tantalum metal disk was then mounted in an anodization cell such that its polished surface was horizontal and covered with an electrolyte solution of 0.5 M citric acid in deionized water, and its backside was electrically connected to a copper wire. A platinum counter electrode was placed in the citric acid solution above (but not in contact with) the tantalum disk. The two electrodes were connected to a DC power source with the tantalum electrode as the anode (having positive polarity) and the platinum electrode as the cathode (having negative polarity). A constant current of 30 milliamps was applied to the two electrode cell for 15 minutes, then the power source was switched to a constant voltage mode at 10 volts for 30 minutes, after which the voltage was increased to 20 volts for another 30 minutes, and then to 30 volts for another 30 minutes. The anodized disk comprising a Ta2O5 surface on tantalum (i.e., tantalum / Ta2O5 disk) was then removed from the solution, washed with deionized water, and air-dried.

[0290] Preparation of aqueous solutions containing the parent radioisotope Prepare an aqueous solution containing the parent radioisotope for loading onto or into the inert ceramic substrate, with a concentration ranging from 0.5 to 100 millimoles per liter (mM). 232 Th 4+ Add an appropriate amount (0.5-15 mL) of HNO3 with a concentration ranging from 0.001 to 5 moles per liter (M) to 2-150 mg of solid thorium nitrate pentahydrate [ 232 It was prepared in aqueous nitric acid by adding [Th(NO3)4.5H2O].

[0291] In another embodiment, 228 Th 4+ A solution of nitric acid (200-600 μL) with a concentration ranging from 0.001 to 5 moles per liter (M) was added to 2-25 mg of solid thorium nitrate pentahydrate [ 228 Th(NO3)4.5H2O].

[0292] Deposition of aqueous radioisotope solutions onto inert ceramic substrate surfaces. The thorium nitrate solution was applied to the freshly prepared substrate surfaces by dropping the liquid (typically 50-500 μL) onto each Ta2O5 or ZrO2 disk surface with a micropipette. 4+ The solution was left undisturbed on the oxide substrate for a period of time (e.g., 45 minutes) at room temperature. The wetting properties of the Ta2O5 and ZrO2 surfaces were such that minimal or no agitation was required to ensure complete liquid coverage of the substrate surface. Alternatively, the Ta2O5 and ZrO2 disk substrates may be immersed in the thorium solution described above, for example in a microwave reactor, and then heated as described below.

[0293] Optional addition of an aqueous precipitant solution to the parent radioisotope solution In some cases, Ta2O5 or ZrO2 surfaces and Th 4+ After a specified contact period between the solutions, a precipitant was added to the aqueous solution deposited on the surface of the substrate disk. In one example, 40 μL of a 15 mM oxalic acid solution [(COOH)2] was added to the thorium solution on the Ta2O5 surface. After the solution was left for a suitable period (e.g., 5 minutes), the liquid on the disk surface was evaporated by placing the disk on a hot plate (e.g., 85°C, 15 minutes). In other cases, 50 μL of a 5 mM ammonium fluoride solution (NH4F) was added to the thorium solution on the ZrO2 surface or on the Ta2O5 substrate. After the solution was left for a suitable period (e.g., 5 minutes), the liquid on the disk surface was evaporated by placing the disk on a hot plate (e.g., 85°C, 15 minutes).

[0294] Heating an inert ceramic substrate against an aqueous solution of radioisotopes The thorium-loaded tantalum / Ta2O5 and zirconium / ZrO2 disk substrates were placed on a flat refractory tray in a muffle furnace to convert the residual thorium nitrate and thorium (and other thorium precipitate salts, if present) to thorium dioxide (ThO2). The furnace was ramped from ambient temperature to 325°C for 150 minutes, then held at 325°C for 150 minutes, and then allowed to cool naturally. Alternatively, if the Ta2O5 or ZrO2 disk substrates were placed in a microwave reactor and immersed in the thorium solution described above, the substrates may be heated at an appropriate overpressure to an appropriate temperature (e.g., about 100°C to about 300°C) for a period of time (e.g., about 2 hours to about 24 hours), and then removed from the solution, cooled, and washed.

[0295] Example 2: Characterization of inert ceramic substrates containing immobilized parent radioisotopes Energy dispersive X-ray spectroscopy with a scanning electron microscope was used to detect evidence of finely dispersed thorium oxide on the surfaces of both the treated Ta2O5 and treated ZrO2 substrates.

[0296] Figure 3 is a magnified image of a Ta2O5 substrate showing the typical texture of such a polished oxide surface prepared by the heat treatment described herein. This image also shows the patchy nature of thorium deposition when ammonium fluoride (NH4F) is used as the precipitant seen as dark areas under secondary electron detection, such patches likely containing oxyfluoride phases. The EDX spectrum shows a clear thorium x-ray signal from the darker areas, which is not significantly associated with any particle-like features or phases larger than the approximately 0.8 μm spatial resolution of the image, or any features that may have weak connectivity with the oxide surface.

[0297] Figure 4 is a magnified image of a Ta2O5 substrate where NHF was used as the precipitant during the thorium deposition process. The area sampled for EDX analysis is shown along with the resulting x-ray spectrum. A clear thorium x-ray signal is evident, but still not associated with any particle-like features or phases larger than the approximately 0.4 μm spatial resolution of the image, or any features that may have weak connectivity with the oxide surface.

[0298] Figure 5 is an image of a ZrO2 substrate showing the polished oxide surface at very high magnification, along with the area sampled for EDX analysis and the resulting spectrum. A clear thorium signal is evident, but still not associated with any particle-like features or phases larger than the approximately 0.08 μm spatial resolution of the image, or any features that may have weak connectivity with the oxide surface.

[0299] Figure 6 shows a magnified image of a Ta2O5 substrate where oxalic acid (C2O4H2) was used as the precipitant during the thorium deposition process. For this sample, the entire image area was sampled for EDX analysis and a spatial map of the thorium signal was also produced. Clear thorium signals are evident from these, from which it is clear that the deposited thorium is associated with different solids on the substrate surface with different morphologies, including submicron irregularly shaped crystals that appear to be well bound to the substrate surface.

[0300] Example 3: Inert ceramic substrate used 212 Pb generation Immobilized gel prepared according to Example 1 228 The Th-containing tantalum oxide substrate was housed in a radioisotope generator containing a tungsten shroud (50 mm thick, for gamma shielding purposes) that held the inert ceramic substrate in an inverted configuration above the bench surface. A PTFE collecting surface was placed directly underneath the inert ceramic substrate such that the thoriated surface of the substrate was in the line of sight with the collecting surface and left for a predetermined period of time (e.g., 1 hour, 4 hours, 12 hours). 212The Pb radioisotope was then collected. 212 The Pb radioisotope was then washed off the PTFE surface with dilute HCl and placed into a wash fluid vial. 212 The wash fluid vial containing the Pb radioisotope was placed in the ion chamber device and collected. 212 The activity of the Pb radioisotope was measured. 212 Chemical and radiometric assays for Pb radioisotopes showed very low levels of parent isotope contaminants (thorium and radium), as shown in FIG.

[0301] Example 4: Simulation of the transport of a gaseous intermediate from a source chamber to a collection chamber To determine the optimal timing between each delivery of the gaseous intermediate radioisotope, 228 Using a numerical solution to the coupled differential Bateman equations describing the Th decay series, we constructed a series of simulations (see Figure 7 ) to calculate the activity of each isotope in the series at any time under a particular set of conditions.

[0302] Two systems were modeled in parallel: a) one with 228 b) the source chamber contains a chamber in which Th has been in equilibrium for a long period of time with its complete decay series; 220 After long-term equilibrium in the source chamber was established (i.e., a constant 224 After the Ra population is present, all of the 220 Rn was periodically removed and transported to a collection chamber where it immediately began to decay into its various daughters. This process was 220 The Rn transport was simulated 10 to 1500 times with 60 different time intervals. The calculated activities of the isotopes in the decay series in the source and collection chambers are shown in Figures 5 and 6.

[0303] To determine the optimal delivery time and optimal delivery event configuration (i.e., the number of high pressure driven gas delivery events versus high vacuum driven gas delivery events), consecutive 220 Calculated Rn concentration in the collection chamber as a function of the time interval between Rn delivery events 212 Pb activity was plotted in the collection chamber after the start of the next high-pressure-driven gas transport event. 220 It was assumed that there was no loss of Rn. In the case of a high vacuum-driven gas transport event, all of the Rn present in the collection chamber at the start of the high vacuum-driven gas transport event was 220 It is assumed that Rn is lost from the system. 212 The Pb yield is shown in Figure 11. In addition, the simulations show that the shorter the delivery interval, the lower the yield. 208 Pb content 212 It was shown that Pb was produced (Figure 12).

[0304] Example 5: Radioisotope production One embodiment of a generator utilized to generate and capture radioisotopes is provided and shown in FIG.

[0305] The immobilized 228 The inert ceramic substrate containing Th 212 It can be used as a parent radioisotope to generate and capture a population of Pb. The inert ceramic substrate can be 228 Th ( 224 Ra) is emitted from an inert ceramic substrate and separated 220 It can be sealed in a source chamber that spontaneously decays into Rn.

[0306] Emitted 220 Rn can be transferred from the source chamber to the collection chamber via an interchamber transfer valve that is intermittently opened at well-defined time intervals. 220 The selection may be based on several factors, including the activity of Rn. 212 To achieve optimal yields of Pb, the generator was irradiated by a high vacuum-driven gas transport event.220 The Rn can be delivered followed by a series of high pressure driven gas delivery events at defined time intervals.

[0307] Modifying the timing of the inter-chamber transfer valve and the high vacuum valve opening and closing sequence; 212 The yield of Pb can be optimized, for example, by increasing the Pb concentration in the source chamber during each high-pressure driven transport event. 220 Sufficient time must be allowed for Rn to grow. Similarly, before applying high vacuum to the collection chamber when generating a high vacuum driven gas transport event, the collected 220 Sufficient time must be allowed for the Rn to decay in the collection chamber.

[0308] 212 For optimal Pb yield, the source chamber was 220 Delivery of Rn utilizes intermittent opening of the inter-chamber delivery valve including a series (e.g., two or more) high pressure driven gas delivery events at predetermined time intervals, followed by a high vacuum driven gas delivery event to re-equilibrate the pressure within the generator, e.g., in a ratio of 5:1.

[0309] Example 6: Extraction of Lead Radioisotopes Accumulated 212 Pb (or 211 Recovery of the (Pb) product isotopes from the collection chamber in a small volume (less than 5 mL) of metal-free water can be demonstrated by the following example.

[0310] Preparation of the wash fluid reservoir. 90cm 3of deionized water was added by syringe to the PTFE water reservoir via a 1 / 4 inch (BSP) threaded port in the PTFE lid. A 120°C temperature rated polymeric T-piece was then screwed into the port using PTFE tape on the male threads to ensure a tight seal. The top of the T-piece supported an analog pressure gauge attached via a PTFE diaphragm seal (Stubbe). The side arm of the T-piece was connected to a short segment of silicone tubing (8mm OD | 6mm ID) approximately 70mm long. At its other end, this tubing segment was interfaced with the wash fluid solenoid valve using a polymer push-in fitting. The solenoid valve was a type (Gemu-52) with all wetted parts made of fluoropolymer (PVDF body / PTFE seals).

[0311] Preparation of a simulated collection chamber and connecting it to a wash fluid reservoir via a solenoid valve. A simulated radon collection chamber made from borosilicate glass was custom built with very similar internal dimensions to the collection chamber made from (opaque) fluoropolymer, thus allowing visualization of cleaning of the internal chamber walls. The glass chamber was connected to a Gemu-52 selenoid valve with a short segment of silicone tubing (4 mm OD | 2.5 mm ID) approximately 70 mm long. The glass chamber was also connected to a high vacuum line through a second selenoid valve using polyurethane tubing (4 mm OD | 2.5 mm ID), and a custom built digital manometer was integrated into this line. In some cases, a small amount of water-soluble dye (Evans Blue) was introduced into the glass chamber at specific locations using a micropipette, and the dye was dried on the internal glass wall by heating with a heat gun. This allowed better visualization and evaluation of the effectiveness of cleaning under various water delivery conditions.

[0312] The wash water is heated and pressurized. The reservoir was heated to a nominal temperature of 110°C to 120°C as measured by a thermometer in a heated bed surrounding the PTFE water reservoir, while the primary process parameter was the internal pressure as indicated on an analog gauge. Tests were run at pressures ranging from 35 kPa to 230 kPa (relative to atmospheric pressure).

[0313] A sequence of valve openings is performed to deliver wash water under pressure to the collection chamber. The high vacuum line solenoid valve and the pure water line solenoid valve were connected to a custom-built electronic control unit based on an Arduino microcontroller interfaced to a PC. Valve open / close commands and their relative timing were determined using the Arduino software and compiler. The water delivery sequence could be initiated by evacuating the glass chamber to approximately 80 mbar by opening the selenoid valve on the high vacuum line for 2-5 seconds. The high vacuum valve was then closed, followed after 1-5 seconds by several brief openings of the water delivery valve (Gemu-52).

[0314] For reservoir pressures below approximately 75 kPa, the cleaning cycle consisted of two separate sequences, beginning with a priming sequence of two or three openings for 60-90 ms to prime the cleaning fluid and build up a volume of hot condensed water behind the delivery valve, followed by a cleaning sequence involving two to four openings for 30-50 ms to rapidly transfer a pulse of hot water and steam to the glass chamber. For reservoir pressures above approximately 75 kPa, the cleaning cycle consisted of a single sequence of three to six valve openings for 50-75 ms. The water / steam pulse had enough momentum to completely cover all internal surfaces when the driving pressure was above approximately 35 kPa. The optimal sequencing depended on the initial reservoir pressure and the available heating power. In general, water delivery using reservoir pressures above 150 kPa was more consistent and repeatable. The total volume of water delivered to the glass chamber also depends on the initial reservoir pressure, with higher pressures leading to more water vapor delivery, but this can be reduced somewhat by using shorter valve openings.

[0315] Withdrawal of the isotope-containing wash fluid from the collection chamber outlet port. Typical volumes of wash water accumulated in the lower region of the glass chamber ranged from 1.5 to 3.0 mL, depending on the number of water delivery valve openings used in the wash sequence for a particular test; for example, 2.0 mL was delivered by a sequence of four 60 ms openings at a reservoir pressure of 200 kPa(g). Fluid was placed on a barbed port carrying silicone tubing flowing into a proximal mini-peristaltic pump, allowing it to pass through this port each time the peristaltic pump was actuated.

[0316] Example 7: Conjugation of harvested daughter radioisotopes to targeting molecules / ligands for use in radiopharmaceuticals Collected 212Pb can be conjugated to biomolecules such as antibodies, antibody fragments, or peptides by the use of radiometal chelators such as 1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane (TCMC). For example, TCMC-functionalized ligand was dissolved in 80 μL of 0.4 M NaOAc buffer at pH 5 to a final concentration of 1 mM. The ligand solution was prepared by adding 200 MBq of Pb formulated in 4 mL of 0.4 M NaOAc buffer at pH 5 containing 20% ​​ascorbic acid. 212 The mixture was heated at 70° C. for 30 min, followed by removal of any unbound IgG using a Pb-specific resin. 212 Pb or 208 Purified from Pb.

Claims

1. A metal oxide substrate comprising a parent radioisotope immobilized on or within said metal oxide substrate in an amount effective to produce a medically useful dose of a daughter radioisotope through a series of spontaneous decays from the parent radioisotope via a gaseous intermediate radioisotope; A metal oxide substrate, wherein at least some of the immobilized parent radioisotopes are bound on or near the surface of the metal oxide substrate as a radioisotope surface layer, allowing for efficient emission of the gaseous intermediate radioisotopes from the metal oxide substrate.

2. 10. The metal oxide substrate of claim 1, wherein at least some of the immobilized parent radioisotopes are bound on or near the surface of the metal oxide substrate as a heat-treated radioisotope surface layer.

3. 2. The metal oxide substrate of claim 1, wherein the binding of the immobilized parent radioisotope on or near the surface of the metal oxide substrate is such as to allow capture of a population of the daughter radioisotopes, during use, having a parent radioisotope contaminant level, expressed in terms of activity, of less than about 5% compared to the activity of the daughter radioisotope.

4. 10. The metal oxide substrate of claim 1, wherein the metal oxide substrate has a porosity (volume % based on the total volume of the metal oxide substrate) of less than about 10.

5. the parent radioisotope is an alpha-emitting radioisotope; 2. The metal oxide substrate of claim 1, wherein the parent radioisotope is a thorium radioisotope selected from thorium-227 ( 227 Th) or thorium-228 ( 228 Th), and the daughter radioisotope is a lead radioisotope selected from at least one of lead-211 ( 211 Pb) or lead-212 ( 212 Pb).

6. The immobilized parent radioisotope is present in an amount of about 1 to about 1500 (1 cm of the metal oxide substrate surface). ２ 10. The metal oxide substrate of claim 1, wherein the metal oxide substrate is present in an amount effective to provide activity (in MBq per 1000 kJ / g).

7. at least some of the immobilized parent radioisotopes forming the radioisotope surface layer are provided as a radioisotope-doped layer within the surface of the metal oxide substrate; and / or 2. The metal oxide substrate of claim 1, wherein at least some of the immobilized parent radioisotopes forming the radioisotope surface layer are provided as one or more solid compound phases of radioisotope bound on the surface of the metal oxide substrate.

8. At least some of the immobilized parent radioisotopes forming the radioisotope surface layer are provided as a radioisotope-doped layer on the surface of the metal oxide substrate; and / or 10. The metal oxide substrate of claim 1, wherein at least a portion of the immobilized parent radioisotope from the radioisotope surface layer substitutes into the atomic lattice of the metal oxide substrate.

9. The radioisotope surface layer is a continuous or uniform layer that substantially covers the surface of the metal oxide substrate; and / or 2. The metal oxide substrate of claim 1, wherein the immobilized parent radioisotope is non-uniformly distributed on or within the radioisotope surface layer.

10. The method of claim 1, wherein at least a portion of the immobilized parent radioisotopes are distributed on or within the radioisotope surface layer according to a concentration gradient across the depth of the radioisotope surface layer; Preferably, the distribution of the immobilized parent radioisotope according to the concentration gradient across the depth of the radioisotope surface layer is substantially uniform across the surface of the metal oxide substrate; More preferably, the metal oxide substrate according to claim 1, wherein the concentration of the immobilized parent radioisotope decreases along the depth direction of the radioisotope surface layer from the outer surface of the radioisotope surface layer.

11. 10. The metal oxide substrate of claim 1, wherein the radioisotope surface layer, heat-treated radioisotope surface layer, radioisotope-doped layer, solid compound phase, crystalline phase, or amorphous phase each independently has a thickness of from about 0.1 nm to about 1000 nm.

12. The metal oxide substrate of claim 1 , wherein the metal oxide substrate is provided as a disk or a slab.

13. 2. The metal oxide substrate of claim 1, wherein the metal oxide substrate is an oxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, titanium, or aluminum, or a mixed oxide thereof.

14. The metal oxide substrate is made of tantalum pentoxide (Ta ２ O ５ ) or zirconium dioxide (ZrO ２ 14. The metal oxide substrate according to claim 13, wherein

15. 10. The metal oxide substrate of claim 1, wherein the metal oxide substrate is provided as a layer on a metal substrate selected from tantalum, niobium, tungsten, hafnium, molybdenum, vanadium, zirconium, titanium, or aluminum, or alloys thereof.

16. The metal oxide substrate of claim 1 , wherein the metal oxide substrate is produced by oxidatively pretreating the surface of a metal substrate.

17. 1. A process for preparing a metal oxide substrate comprising a parent radioisotope immobilized on or within said metal oxide substrate in an amount effective to produce a medically useful dose of a daughter radioisotope through a sequence of spontaneous decay from said parent radioisotope via a gaseous intermediate radioisotope, said process comprising: a) depositing a solution containing a parent radioisotope species onto a surface of a metal oxide substrate; b) heating the metal oxide substrate to a temperature effective to bond at least some of the parent radioisotopes to or near a surface of the metal oxide substrate forming a heat-treated radioisotope surface layer to allow efficient emission of gaseous daughter radioisotopes from the metal oxide substrate; Preferably, the process is for preparing a metal oxide substrate according to any one of claims 1 to 16.

18. 17. A radioisotope generator defining a chamber for producing and capturing a population of daughter radioisotopes, said chamber configured to accommodate within said chamber a metal oxide substrate according to any one of claims 1 to 16.

19. 1. A system for producing and capturing a population of daughter radioisotopes, comprising: a) a radioisotope generator defining a chamber for producing and capturing a population of daughter radioisotopes; b) a metal oxide substrate according to any one of claims 1 to 16 housed in said chamber.

20. 1. A process for producing and capturing a population of daughter radioisotopes, comprising: a) allowing emission of a gaseous intermediate radioisotope generated through a sequence of spontaneous decay from a parent radioisotope immobilized on or in a metal oxide substrate according to any one of claims 1 to 16; b) collecting at least some of said gaseous intermediate radioisotopes for a period of time effective for them to decay into daughter radioisotopes.

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