Techniques for obtaining actinium-225 from radium-226 and related systems and methods

Abstract

Techniques are described for producing radium-225 from a sample containing radium- 226, and milking the sample for actinium- 225, which results in a higher yield of actinium-225 for a given sample in a given period of time compared with conventional approaches. In particular, returning the sample to the reactor while there is still a significant amount of radium-225 in the sample can, over time, produce more actinium- 225 than the conventional approach of milking the sample until the vast majority of radium-225 has decayed into actinium-225.

Description

TECHNIQUES FOR OBTAINING ACTINIUM-225 FROM RADIUM-226 AND RELATED SYSTEMS AND METHODSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 63 / 645,284, filed May 10, 2024, titled “TECHNIQUES FOR OBTAINING ACTINIUM-225 FROM RADIUM-226 AND RELATED SYSTEMS AND METHODS,” which is herein incorporated by reference in its entirety.BACKGROUND

[0002] Actinium- 225 is an isotope of actinium that shows great promise in medical applications due to its favorable decay properties. In particular, decay of actinium-225 (Ac-225) produces short-range, high-energy radiation suitable for use in targeted alpha therapy. Its approximately 10-day half-life is long enough to allow for treatment but short enough that it rapidly decays in the body, the decay products of Ac-225 are safer than those of other isotopes, and each decay of Ac-225 produces four high energy alpha particles, making it a potent source. The current supply of Ac-225 is small, however, and there have been no successful large scale production efforts, which severely limits its use in treatment.SUMMARY

[0003] According to some aspects of the presently disclosed technology, a method for generating actinium-225 isotopes comprises: irradiating a target with a neutron flux for an irradiation period in an irradiation chamber, wherein the target comprises radium- 226; after the irradiation period, storing the target outside of the irradiation chamber for a first accumulation period; after the first accumulation period, performing a first separation to separate a first sample of actinium-227 and actinium-225 isotopes from radium- 226 and radium- 225 isotopes present in the irradiated target that was subject to the first accumulation period; storing the radium-226 and radium-225 isotopes obtained from the first separation for a second accumulation period; performing a secondseparation to separate an actinium- 225 isotope product from the radium-226 and radium- 225 isotopes stored for the second accumulation period.

[0004] According to some aspects of the presently disclosed technology, a method of obtaining actinium- 225 comprises: delivering a sample comprising radium-226 into a fission reactor and leaving the sample in the fission reactor for a first irradiation period; removing the sample from the fission reactor when the first irradiation period ends; milking the sample for actinium over a first milking period, thereby removing actinium- 225 from the sample, wherein when the first milking period begins the sample contains a first number of atoms of radium-225; and subsequent to the first milking period ending, delivering the sample into the fission reactor, or into a different fission reactor, for a second irradiation period, without performing additional milking of the sample between the first milking period and the second irradiation period, wherein when the first milking period ends the sample contains between 60% and 80% of the first number of atoms of radium-225.

[0005] According to some aspects of the presently disclosed technology, a method of obtaining actinium- 225 comprises: delivering a sample comprising radium-226 into a fission reactor and leaving the sample in the fission reactor for a first irradiation period; removing the sample from the fission reactor when the first irradiation period ends; milking the sample for actinium over a first milking period that has a duration that is between 80% and 120% of a duration of the first irradiation period; and subsequent to the first milking period ending, delivering the sample into the fission reactor, or into a different fission reactor, for a second irradiation period without performing additional milking of the sample between the first milking period and the second irradiation period.

[0006] According to some aspects of the presently disclosed technology, a method for generating an actinium-225 product comprises: irradiating a target with a neutron flux for an irradiation period in an irradiation chamber, wherein the target comprises radium-226; after the irradiation period, storing the target outside of the irradiation chamber for a first accumulation period; after the first accumulation period, subjecting the irradiated target to a first separation involving separating a first sample of actinium- 227 and actinium-225 isotopes from radium-226 and radium-225 isotopes, wherein the first separation comprises a first column chromatographic separation step in which the actinium-227 and actinium-225 isotopes are eluted in a first fraction and the radium-226and radium-225 isotopes are eluted in a second fraction; storing the radium-226 and radium- 225 isotopes eluted in the first fraction for a second accumulation period; subjecting the stored radium-226 and radium-225 isotopes to a second separation step to produce the actinium-225 product, wherein the second separation step comprises separating actinium-225 isotopes from radium-226 and radium-225 isotopes using a second column chromatographic separation step in which the actinium-225 product is eluted in a third fraction and the radium-226 and radium-225 isotopes are eluted in a fourth fraction; irradiating a second target formed from the fourth fraction in the same and / or a different irradiation chamber.

[0007] According to some aspects of the presently disclosed technology, a method for generating an isotope product, comprising a daughter isotope from a target comprising parent radium-226, comprises: irradiating the target with a neutron flux for an irradiation period; after the irradiation period, storing the target outside an irradiation chamber for a first accumulation period; performing a first separation on the stored target in which a first sample comprising actinium- 227 and actinium-225 isotopes is separated from radium-226 and radium-225 isotopes; storing the first sample comprising actinium- 227 and actinium-225 isotopes for a second accumulation period; and performing a second separation during and / or after the second accumulation period which a second sample comprising the isotope product comprising the daughter isotope is separated from the first sample.

[0008] According to some aspects of the presently disclosed technology, a method for generating an isotope product, comprising a daughter isotope from a target comprising parent radium-226, comprises: irradiating the target with a neutron flux for an irradiation period; after the irradiation period, storing the target outside an irradiation chamber for a first accumulation period; performing a first separation on the stored target during and / or after the first accumulation period in which a first sample comprising actinium-227 and actinium-225 isotopes is separated from radium-226 and radium-225 isotopes; storing the first sample for a second accumulation period; performing a second separation on the first sample after storage in which a second sample comprising thorium- 227 is separated from the actinium-227 and actinium-225 during and / or after the second accumulation period; storing the actinium-227 and actinium-225 separated from the second sample by the second separation for a third accumulation period; andperforming a third separation on the stored actinium-227 and actinium- 225 separated from the second sample during and / or after the third accumulation period in which a third sample comprising radium-223 is separated from the sample of actinium-227 and actinium-225 that was separated from the second sample.

[0009] The foregoing apparatus and method embodiments may be implemented with any suitable combination of aspects, features, and acts described above or in further detail below. These and other aspects, embodiments, and features of the present teachings can be more fully understood from the following description in conjunction with the accompanying drawings.BRIEF DESCRIPTION OF DRAWINGS

[0010] Various aspects and embodiments will be described with reference to the following figures. It should be appreciated that the figures are not necessarily drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures is represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing.

[0011] FIG. 1A is a schematic of a process of producing Ac-225, according to some embodiments;

[0012] FIG. IB is a schematic decay process for producing daughter isotopes from the decay of Ac-225 and Ac-227, according to some embodiments;

[0013] FIG. 2 is a schematic of a system in which aspects of the present disclosure may be practiced, according to some embodiments;

[0014] FIGs. 3 A and 3B are charts depicting amounts of various isotopes during a process of irradiating and milking a sample comprising radium-226 (Ra-226), according to some embodiments;

[0015] FIG. 3C is a chart depicting the accumulated yield of Ac-225 over time for the example of FIGs. 3A and 3B, according to some embodiments;

[0016] FIG. 3D is a chart depicting amounts of various isotopes during a conventional process of irradiating and milking a sample comprising radium-226;

[0017] FIG. 3E is a chart depicting the accumulated yield of Ac-225 over time for the example of FIG. 3D;

[0018] FIG. 4 depicts a schedule for irradiation and milking for a reactor, according to some embodiments; and

[0019] FIG. 5 is a flowchart of a method of obtaining actinium-225, according to some embodiments.

[0020] FIG. 6 is a flowchart of a method of obtaining actinium-225, according to some embodiments;

[0021] FIG. 7 is a flowchart of a method of obtaining multiple daughter isotopes from a radium sample, according to some embodiments.DETAILED DESCRIPTION

[0022] The inventors have developed technology to improve the generation of Ac- 225, for example for use as a therapeutic radioisotope for clinical treatments. The inventors have also develop techniques for improving the collection of therapeutic daughter isotopes from byproducts of the Ac-225 generation process which may themselves be used as therapeutic radioisotopes for clinical treatments. The technology includes methods for harvesting Ac-225 from an irradiated radium- 226 sample. The contamination of Ac-225 with other actinium isotopes (e.g., Ac-227) is mitigated by purifying the irradiated radium after an initial accumulation period, during which the Ra- 227isotopes decay. Accordingly, the remaining radium- 225 and radium- 226 can be used for producing Ac-225 over the course of a harvesting period(s). According to some aspects of the technology, the harvesting period(s) is coordinated with an irradiation period(s), thereby improving the yield of Ac-225 from the radium-226 starting material.

[0023] As described above, Ac-225 shows great promise as a cancer treatment for numerous reasons, but it does not occur naturally and has historically been difficult to produce pure samples in all but small volumes. For instance, for many years the primary source of Ac-225 has been through decay of thorium- 229 (Th-229), which decays to radium- 225 (Ra-225) via alpha emission, which then beta decays to Ac-225. However, the decay of Th-229 is relatively slow (half-life of 7340 years), so this technique produces a low yield of Ac-225. Other approaches to producing Ac-225 are energetically expensive and require a lot of chemical post-processing, since the reactions create other products that must be separated from the Ac-225.

[0024] One desirable process for producing Ac-225 is by putting a sample containing Ra-226 into an environment rich in neutrons, such as within a fission reactor. Neutrons with sufficient kinetic energy incident on Ra-226 initiate a (n,2n) reaction that converts Ra-226 into Ra-225, which beta decays into Ac-225. After some amount of time has passed, the sample can be retrieved from the reactor, and Ac-225 produced through beta decay of Ra-225 can be separated from the Ra-226 and Ra-225. Since the Ra-225 has a half-life of 14.9 days, Ac-225 is produced from decays of Ra-225 in the sample over a period of many days or weeks. Ac-225 may be extracted from the sample via a chemical process that separates different elements. Generally this process is some type of elution method, often referred to as “milking” the sample, which chemically separates the elements in the sample but does not distinguish between different isotopes of a given element. During the milking process, there may be Ra-225 in the sample that is decaying into Ac-225, such that the milking process extracts Ac-225 as it is produced through this decay process.

[0025] In a conventional milking process, a sample containing Ra-225 is milked for actinium until almost all of the Ra-225 in the sample has decayed into Ac-225, thereby maximizing the yield of Ac-225 produced after a given irradiation period in the reactor. The sample can then be placed back in the reactor (or in another reactor), where more Ra-225 will be produced, then removed and milked for Ac-225, and so forth. These cycles of irradiation and milking therefore periodically yield Ac-225.

[0026] One of the challenges with this process for producing Ac-225 is that radium is extremely expensive (at the time of writing, over US$3 million per gram). Moreover, only a fraction of the radium sample will be converted into Ra-225 even after days or weeks in a reactor. Thus, producing Ac-225 from a radium seed material can be extremely expensive, severely limiting the access of this material for medical applications.

[0027] The inventors have recognized and appreciated techniques for producing Ra-225 from a sample containing Ra-226, and then milking the sample for Ac-225, which result in a higher yield of Ac-225 for a given sample in a given period of time compared with the conventional approach described above. In particular, the inventors have recognized and appreciated that returning the sample to the reactor while there isstill a significant amount of Ra-225 in the sample can, over time, produce more Ac-225 than the conventional approach of milking the sample until the vast majority of Ra-225 has decayed into Ac-225.

[0028] In the conventional approach, there is a relatively small amount of Ra-225 left in the sample when it is returned to the reactor, but according to the techniques described herein, the sample is instead returned to the reactor while there is still a significant amount of Ra-225 in the sample. Because Ac-225 is obtained from decays of Ra-225, the conventional approach is to milk a sample until the majority of Ra-225 has decayed into Ac-225, and that Ac-225 has been extracting through milking. However, in the techniques described herein the sample is counterintuitively returned to the reactor while a majority (e.g., 70-80%) of the Ra-225 that was present at the start of milking still remains in the sample. Because the half-life of Ra-225 is of a similar order of magnitude to the typical irradiation period of a sample, the Ra-225 that is in the sample when it returns to the reactor does decay during irradiation, but much of this Ra-225 is still present when irradiation ends. In addition, more Ra-225 is produced in the sample during this irradiation period, leading to a subsequent milking process in which even more Ac-225 is extracted.

[0029] In at least some cases, the techniques described may produce more Ac-225 contaminated with actinium- 227 (Ac-227) than the conventional approach described above, and may spend comparatively less time producing Ac-225 than the conventional approach, because a smaller fraction of the time is spent milking. However, the present inventors have nonetheless recognized that by performing the techniques described herein, a significant advantage is achieved of producing a comparatively greater amount of Ac-225 for a given sample in a given amount of time, compared with the conventional approach described above. In addition, the techniques described herein result in more Ac-225 produced per gram of Ra-226 in the starting sample compared with the conventional approach. Due to the high cost of radium, this represents a significant advantage over the conventional approach. Furthermore, the techniques described herein allow for more frequent delivery of Ac-225 because of the larger number of milking periods in a given span of time, which is advantageous for medical uses.

[0030] According to some embodiments, the amount of time spent irradiating a sample in a reactor and the amount of time spent milking the sample for Ac-225 may be of similar duration. Since, according to the techniques described herein, the time spent milking is comparatively shorter than the conventional approach in which the sample is milked for Ac-225 until the vast majority of Ra-225 available at the start of milking is no longer present, the time spent irradiating a sample (“irradiation period”) and the time spent milking the sample (“milking period”) may in some cases be of a similar length. In some embodiments, for instance, the milking period may have a duration that is 80% to 120% of the duration of the irradiation period. For example, the irradiation period may be 5 days long, and the milking period may be between 4 days and 6 days long. It may be appreciated that other acts may be performed prior to the irradiation period (e.g., sample loading) and between the irradiation period and the milking period (e.g., sample removal), as these relative times are not intended to limit the length of time such other acts may take. In contrast to the above, a conventional milking period may be around 6-8 times longer than the irradiation period preceding it (e.g., an irradiation period of 5 days, followed by a milking period of 30-40 days).

[0031] Approaches in which the irradiation period and the milking period are the same length, or close to the same length, may be particularly advantageous. It is often the case that reactors, especially research reactors, operate on a fixed schedule so that samples are loaded and removed on a periodic basis (e.g., every 7 days). If the milking period is essentially the same length as the irradiation period (accepting that other acts such as unloading may take place between these periods), and these are as long as the reactor’s periodic schedule, then a sample may be inserted into a reactor at the times that the reactor is scheduled to allow the insertion of samples. For instance, consider a reactor that removes samples every Monday morning and inserts new samples every Monday afternoon. A sample comprising Ra-226 may be inserted on a Monday afternoon, then removed the following Monday morning (such that the irradiation period is around 6.5 days). The sample may then be milked (either immediately after removal, or some hours later, as described further below) for a period of around 6.5 days so that the sample can be inserted back into the reactor on the very next Monday afternoon.

[0032] This type of approach in which the irradiation period and milking period have a length that matches a reactor schedule may have an advantage that production of Ac-225 can be easily compatible with the existing operation schedule of a reactor. An additional advantage is a second sample may be introduced on the same schedule but offset from the first sample. That is, while the first sample is being milked, the second sample is being irradiated, and vice versa. Utilizing two samples in this way maximizes use of the reactor, because there is always a sample in the reactor producing Ra-225 when it is operational. In addition, the total yield of Ac-225 is also increased. This approach could be further extended to more than two samples, if desired.

[0033] According to some embodiments, an amount of Ra-225 in a sample when a milking of the sample ends, may be more than half of the amount of Ra-225 in the sample when the milking of the sample began. As described above, in a conventional approach, a sample may be milked until a relatively small amount (e.g., around 10%) of the Ra-225 that was in the sample when milking began remains in the sample when milking ends. In some embodiments of the techniques described herein, an amount of Ra-225 in a sample when a milking of the sample ends may instead be, for example, 60% to 80% of the amount of Ra-225 in the sample when the milking of the sample began.

[0034] Following below are more detailed descriptions of various concepts related to, and embodiments of, techniques for obtaining Ac-225. It should be appreciated that various aspects described herein may be implemented in any of numerous ways.Examples of specific implementations are provided herein for illustrative purposes only. In addition, the various aspects described in the embodiments below may be used alone or in any combination, and are not limited to the combinations explicitly described herein.

[0035] FIG. 1A is a schematic of a process of producing Ac-225, according to some embodiments. In the example of FIG. 1 A, two different products that may result when neutrons 101 are incident on atoms of Ra-226 (102) are shown. The first type of interaction is an (n, 2n) reaction that converts Ra-226 into Ra-225 (103) and neutrons (104). The threshold kinetic energy of the neutron 101 for this reaction to occur is 6.4MeV. The second type of interaction is an (n, y) reaction that produces radium-227(Ra-227) through neutron capture. The two types of interactions may both take place in an environment rich in neutrons, such as a fission reactor, which contains neutrons of various different energies. It may be noted that the production of Ra-227 through neutron capture more readily occurs with thermal neutrons at lower neutron kinetic energies, whereas the production of Ra-225 requires a fast neutron with kinetic energy above 6.4MeV. However, both of these types of neutrons may generally be present in a fission reactor where a sample of Ra-226 is placed, and as a result Ra-225 and Ra-227 may both be produced in such an environment.

[0036] In the example of FIG. 1 A, when Ra-225 (103) is produced, it beta decays to Ac-225 (105) with a half-life of 14.9 days. The Ac-225 product has a half-life of 9.92 days. Alternatively, when Ra-227 (106) is produced, it Beta decays to Ac-227 (107) with a half-life of 42 minutes. The Ac-227 product has a half-life of 21.8 years.

[0037] One of the challenges with producing Ac-225 in a fission reactor is that both Ac-227 and Ac-225 are produced, yet it is desirable to obtain a pure sample of Ac- 225 for medical uses. In this situation, however, Ac-225 cannot be initially obtained through milking because milking does not distinguish between isotopes of actinium, only between different elements such as actinium and radium. Accordingly, milking of a sample for actinium after removal from an environment in which both Ra-225 and Ra- 227 were produced will yield a mixture of Ac-225 and Ac-227. Since Ac-227 has a much longer half life than Ac-225, waiting for it to decay is also not a suitable solution for producing a pure sample of Ac-225. However, since Ra-227 decays to Ac-227 with a 42 minute half life, once a sample is no longer being irradiated the Ra-227 will be entirely (or almost entirely) converted into Ac-227 within several hours. As such, milking the sample for actinium at this time will yield a combination of Ac-225 and Ac- 227, which can be discarded or used for some other purpose. Subsequent milking of the sample will then yield Ac-225 with a very high level of purity because no additional Ac- 227 will be produced in the sample during this milking period (except for possibly a very small trace amount through decay of residual Ra-227).

[0038] The inventors have further recognized and appreciated that the sample of combined actinium isotopes, Ac-225 and Ac-227, can be further utilized to obtain daughter isotopes of the respective actinium isotopes that are themselves useful fortherapeutic purposes. In particular, bismuth-213 (Bi-213), thorium-227 (Th-227), and radium- 223 (Ra-223) may be obtained from radioactive decay of Ac-225 and / or Ac-227. FIG. IB is a schematic decay process for producing daughter isotopes from the decay of Ac-225 and Ac-227, according to some embodiments. While a mixed sample of Ac-225 and Ac-227 may not be chemically separable, their daughter isotopes may be separated from the mixture of actinium isotopes through conventional separation techniques, such as chromatography techniques that use a stationary phase and a mobile phase to separate components of a mixture based on their differential affinities for the two phases. Chromatography column separation equipment employing commercially available solid phase materials, mobile phase solvents and known techniques can be used in certain embodiments for the various separation and purification steps and processes described herein. As shown in FIG. IB, Ac-225 decays to Bi-213 through a series of a-decay processes. The Ac-225 first decays to francium- 221 (Fr-221) through a first a-emission. The Fr-221 decays to astatine-217 (At-217) through a second a-emission. The At-217 finally decays to Bi-213 through a third a-emission.

[0039] Also as shown in FIG. IB, Ac-227 has two decay channels of a-emission or P-emission. In the first decay channel, Ac-227 decays by an a-emission process into francium-223 (Fr-223). Thereafter, Fr-223 may decay through a-emission or P-emission. When Fr-223 decays through a-emission, it decays into At-219. However, when Fr-223 decays through P-emission, it decays into Ra-223. In the second decay channel, Ac-227 decays by P-emission into Th-227. As shown in FIG. IB, Th-227 may then further decay through a-emission to Ra-223.

[0040] FIG. 2 is a schematic of a system in which aspects of the present disclosure may be practiced, according to some embodiments. In the example of FIG. 2, system 200 includes a portion of a fission reactor 220 and a guide tube 215 that allows for insertion of a capsule 205 into the reactor. Capsule 205 includes a sample that comprises Ra-226 and may be formed from a metal such as titanium. In some embodiments, the sample may initially be composed of, or may consist essentially of, Ra-226. After periods of irradiation in the reactor 220 as described herein, the sample may, at the time of insertion into the reactor, comprise Ra-226 in addition to Ra-225, which was produced from the Ra-226 during prior irradiations.

[0041] In the example of FIG. 2, the guide tube 215 may guide the capsule 205 into the reactor by allowing the capsule to be passed through the seal table 207 and through the guide tube into the reactor. Motion of the capsule 205 is produced by a drive unit 210 coupled to the capsule 205 via cable 211. The capsule 205 may be inserted through the seal table, which separates atmospheric pressure outside the guide tube and reactor from inside the guide tube and reactor where the pressure may be over 2000psi. The capsule may be inserted directly into the guide tube through a thimble or port, or may be inserted into a vessel that is directed into the reactor as described above.

[0042] According to some embodiments, the guide tube 215 may be a flux thimble guide tube, also sometimes called a thimble tube, which is also used for inserting measurement probes and other devices used routinely in commercial fission reactors. However, it may be appreciated that this process of inserting a capsule into a reactor may be different at a research reactor versus a commercial reactor, and as such the example of FIG. 2 may not apply to all implementations.

[0043] FIGs. 3 A and 3B are charts depicting amounts of various isotopes during a process of irradiating and milking a sample comprising radium-226, according to some embodiments. In the example of FIGs. 3 A and 3B, illustrative amounts of Ac-225, Ra- 225, Ac-227 and Ra-227 are shown over time, with the vertical axis representing a number of atoms of the given isotope in the sample. FIG. 3B depicts an initial portion of FIG. 3A, enlarged to show detail and shaded to illustrate different periods of irradiation and milking.

[0044] As shown in FIGs. 3 A and 3B, initially (at time 0) none of the isotopes Ac- 225, Ra-225, Ac-227 and Ra-227 are present in the sample comprising Ra-226. The amount of Ra-226 in the sample in this example would be significantly larger than the scale of FIGs. 3A or 3B, and is not shown. Immediately before the beginning of a first irradiation period 301 (shaded in light gray in FIG. 3B), the sample is delivered into a fission reactor. During the irradiation period 301, Ac-225, Ra-225, Ac-227 and Ra-227 are then produced in the sample via the processes described above in relation to FIG. 1A. As can be seen from FIGs. 3 A and 3B, the relative amounts of Ac-225, Ra-225, Ac-227 and Ra-227 are such that there is generally very little Ra-227 in the sample during irradiation (in part because it decays so quickly to Ac-227), and that Ac-225 is produced during irradiation due to decay of Ra-225 produced during irradiation. Some of this Ac-225 will be lost through its decay into other isotopes while the Ac-225 is still being irradiated in the reactor.

[0045] After irradiation period 301 ends, the sample is removed from the reactor and milked for actinium during milking period 302. As described above, there may be an initial post-irradiation milking period during which the Ac-225 and Ac-227 produced during irradiation period 301 are removed so that they can be discarded or otherwise removed from the sample. This is depicted in FIG. 3A by the rapid drop in the amounts of Ac-225 and AC-227 at the end of irradiation period 301. As may be noted from the relative amounts of Ac-225 and Ac-227 in FIG. 3B, the amount of Ac-227 yielded by this milking is several times greater (e.g., 3-6 times, or at least 5 times greater) than the amount of Ac-225 yielded by this milking. During milking period 302, actinium is separated from other elements in the sample such as, but not limited to: radium, decay products of Ac-225 and Ac-227, and / or other elements.

[0046] After post-irradiation milking period 302 ends, a milking period 303 begins during which the sample is again milked for actinium. Unlike during milking period 302, however, pure (or substantially pure) Ac-225 will be yielded from milking because there is now very little or no Ra-227 or Ac-227 remaining in the sample. During milking period 303, Ac-225 is produced when Ra-225 decays, and any such Ac-225 produced is promptly removed from the sample by the milking process. Consequently, the amount of Ac-225 within the sample during the milking period 303 remains at or close to zero. Since Ac-225 is produced through decay of the Ra-225 present in the sample, during the milking period 303 the amount of Ra-225 decreases

[0047] Subsequent to milking period 303, immediately before the start of irradiation period 304 the sample is returned to the reactor (or delivered into a different reactor). During irradiation period 304, Ac-225, Ra-225, Ac-227 and Ra-227 are produced in the sample via the processes described above in relation to FIG. 1A. Comparing irradiation period 304 to irradiation period 301, it may be noted that the amount of Ra-225 in the sample is higher in irradiation period 304 because there was still a substantial amount of Ra-225 in the sample when it was returned to the reactor. Moreover, the amount of Ra-225 in the sample keeps increasing on each successive irradiation until it reaches a periodic maximum (in FIG. 3 A, at around 4 months). The accumulated yield of Ac-225 over time for the example of FIGs. 3 A and 3B is shown inFIG. 3C, according to some embodiments. In the example of FIG. 3C, the solid line represents the amount of pure (or substantially pure) Ac-225 that is yielded based on the example of FIGs. 3 A and 3B, whereas the dotted line represents the amount of Ac-225 that is mixed with Ac-227 yielded from the post-irradiation milking periods, such as period 302.

[0048] It may be noted in the example of FIGs. 3 A and 3B that the milking period 303 is of a similar length to irradiation period 301. As described above, this differs from the conventional approach, which is depicted in FIG. 3D, in which the milking period 312 is much longer than the prior irradiation period 311 (and subsequent irradiation period 313). The example of FIG. 3D assumes the same initial sample and the same irradiation conditions as the example of FIGs. 3A-3B.

[0049] In the example of FIG. 3D, the milking period (e.g., period 312) are each long enough that the amount of Ra-225 at the end of the milking period is around 10% of the amount of Ra-225 at the start of the milking period. In contrast, in the example of FIGs. 3 A and 3B, the amount of Ra-225 at the end of the milking period 303 is around 75% of the amount of Ra-225 at the start of the milking period 303. This is also true for later milking periods, as shown in FIG. 3A, where generally the amount of Ra-225 at the end of the milking period is around 70-75% of the amount of Ra-225 at the start of the milking period, independent of the absolute amount of Ra-225 present in the sample at the start of the milking period.

[0050] The accumulated yield over time for the example of FIG. 3D is shown in FIG. 3E, according to some embodiments. In the example of FIG. 3E, the solid line represents the amount of pure (or substantially pure) Ac-225 that is yielded based on the example of FIG. 3D, whereas the dotted line represents the amount of Ac-225 that is mixed with Ac-227. As may be seen from FIG. 3E, the conventional approach represented by FIG. 3D produces less pure (or substantially pure) Ac-225 compared with FIG. 3C over the same amount of time (with the exception of a short time window during the first milking period in FIG. 3D). The approach of FIG. 3D does, as noted above, produce less Ac-225 mixed with Ac-227, although since a mixture of Ac-225 and Ac- 227 may still have a valid use this is not necessarily an advantage.

[0051] According to some embodiments, performing multiple milking cycles (where one milking cycle includes one irradiation period followed by one milking period) in a given period of time may yield more Ac-225 than performing a single milking cycle in the same amount of time. For example, the conventional approach shown in FIG. 3D performs one milking cycle in just over 2 months, whereas the improved approach shown in FIG. 3A performs between 4 and 5 milking cycles in the same amount of time. The inventors have determined that the total yield of Ac-225 in a given amount of time may be expected to increase as the number of milking cycles performed in this time increases, with a theoretical upper limit of the gain (being the ratio of Ac-225 yielded in multiple milking cycles to Ac-225 yielded in a single milking cycle over the same time period) estimated in simulations to be 3.78.

[0052] As described above, it may be particularly advantageous to arrange the irradiation period and milking period for a sample comprising Ra-226 so that they align with times at which a reactor is shut down for insertion of samples. FIG. 4 depicts an example of such an approach, according to some embodiments. In some embodiments, FIG. 4 may represent a schedule for irradiation and milking of a sample applied in conjunction with a reactor that shuts down for removal of samples and insertion of samples every 7 days (although the reactor may also shut down for these purposes at other times; the example here just presumes this occurs at least every 7 days). Of course, other suitable time periods may also be utilized in a schedule for irradiation and milking, as FIG. 4 is provided as one illustrative example.

[0053] In the example of FIG. 4, a time period of 14 days is shown, along with an indication of which of four stages is performed during each of these days. In particular, a sample is delivered into the reactor by the start of day 1 and during days 1-6, and for part of day 7, the sample is irradiated in the reactor. Irradiation period 401 therefore has a length of 6.5 days in the example of FIG. 4. Part-way through day 7, the sample is removed from the reactor, retrieved (e.g., removed from a capsule and / or other materials in which it was arranged during irradiation) and an initial waiting period (e.g., several hours) is performed so that the Ra-227 in the sample substantially decays (or fully decays) into Ac-227. Then, also in day 7, an initial process of milking the sample for actinium is performed to remove both Ac-225 and Ac-227 from the sample. Togetherthese processes (removal, waiting, and post-irradiation milking) are performed in period 402.

[0054] In the example of FIG. 4, starting in day 8, the sample is milked for actinium to remove pure (or substantially pure) Ac-225 from the sample. Milking period403, during which this process is performed, starts at the beginning of day 8 and ends part-way through day 14. Milking period 403 therefore has a length of 6.5 days in the example of FIG. 4. Part-way through day 14, after milking period 403 has ended, the sample is reconstituted (e.g., inserted into a capsule and / or arranged with other materials in preparation of its insertion into the reactor) and delivered into the reactor in period404.

[0055] As described above, the type of schedule shown in FIG. 4 may allow for multiple samples to be irradiated and milked in parallel, thereby maximizing utilization of the reactor, which in the conventional approach may not be used to produce Ra-225 during milking of another sample. As one example of irradiating and milking samples in parallel, a second sample may be irradiated and milked using the same schedule as that shown in FIG. 4, but shifted forward or backward 7 days. As such, while the first sample is being irradiated in period 401, the second sample is being milked. Similarly, when the first sample is being milked in period 403, the second sample is being irradiated.

[0056] FIG. 5 is a flowchart of a method of obtaining actinium-225, according to some embodiments. Method 500 may be performed using any suitable sample comprising Ra-226, as described above. For instance, method 500 may be performed using capsule 205, in addition to a suitable fission reactor.

[0057] Method 500 begins in act 502 in which a sample comprising Ra-226 is inserted into a fission reactor. A suitable process for inserting the sample into a reactor is described above in relation to FIG. 2, although any suitable process may be used so long as the sample is placed in a location where it will be bombarded with neutrons. In some embodiments, the sample may be arranged within a capsule or other container. In some embodiments, the sample may be arranged alongside, encapsulated by, or otherwise in proximity to one or more materials that moderate or otherwise change the spectrum of neutrons that are incident on the sample. In some cases, this material maybe a neutron shield to reduce the thermal neutrons incident on Ra-226, which can produce Ra-227 but not Ra-225. However, other materials may also be envisioned.

[0058] In act 504, the sample is left in the reactor for a period of time during which Ra-225 is produced as described in relation to FIG. 1A. Isotopes other than the isotopes described above may also be produced within the sample during this time, though a full discussion of these isotopes is outside the scope of this disclosure.

[0059] In some embodiments, the sample may be left in the reactor in act 504 for a time period greater than or equal to 5 days, 10 days, 15 days, 20 days or 25 days. In some embodiments, the sample may be left in the reactor in act 504 for a time period that is less than or equal to 30 days, 25 days, 20 days, 15 days, or 10 days. Any suitable combinations of the above-referenced ranges are also possible (e.g., the sample may be left in the reactor for a time period of greater than or equal to 5 days and less than or equal to 10 days).

[0060] In act 506, the sample is removed from the reactor. Optionally, the sample is extracted from a capsule or other vessel in which it was placed during act 504. Act 508 is a waiting period performed so that Ra-227 in the sample decays substantially (or completely) to Ac-227.

[0061] In some embodiments, the waiting period of act 508 may be greater than or equal to 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or 11 hours. In some embodiments, the waiting period of act 508 may be less than or equal to 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, or 4 hours. Any suitable combinations of the above-referenced ranges are also possible (e.g., a waiting period greater than or equal to 5 hours and less than or equal to 7 hours).

[0062] In act 510, the sample is milked for actinium. As described above, milking of the sample for actinium comprises any chemical process for separating actinium from other elements within the sample. As a result of Ac-225 and Ac-227 being produced in the sample due to both Ra-225 and Ra-227 being produced, then each decaying via beta decay, milking in act 510 will produce actinium that is a mixture of Ac-225 and Ac-227.

[0063] After act 510 is performed and the actinium obtained discarded or otherwise removed from the sample, milking for actinium is performed in act 512 to obtain pure orsubstantially pure Ac-225. This Ac-225 may be then transported and utilized in a suitable medical procedure, such as targeted alpha therapy.

[0064] In some embodiments, the amount of Ra-225 in the sample when milking of the sample for actinium in act 512 ends is a fraction X of the amount of Ra-225 in the sample when milking for actinium in act 512 begins, where X is greater than or equal to 0.50, 0.55, 0.60, 0.65, 0.70, 0.75 or 0.80. In some embodiments, X is less than or equal to 0.85, 0.80, 0.75, 0.70, 0.65, 0.60, 0.55 or 0.50. Any suitable combinations of the abovereferenced ranges are also possible (e.g., the amount of Ra-225 in the sample when milking of the sample for actinium in act 512 ends is a fraction greater than or equal to 0.60 and less than or equal to 0.80 of the amount of Ra-225 in the sample when milking for actinium in act 512 begins). Such ranges may also be expressed as a percentage rather than a fraction (e.g., the amount of Ra-225 in the sample when milking of the sample for actinium in act 512 ends is greater than or equal to 60% and less than or equal to 80% of the amount of Ra-225 in the sample when milking for actinium in act 512 begins).

[0065] In some embodiments, the time period during which the sample is milked for actinium in act 512 is a fraction Y of the time period during which the sample is irradiated in the reactor in act 504, where Y is greater than or equal to 0.80, 0.85, 0.90, 0.95, 0.98, 1.00, 1.02, 1.05, 1.10, or 1.15. In some embodiments, Y is less than or equal to 1.20, 1.15, 1.10, 1.05, 1.02, 1.00, 0.98, 0.95, 0.90, or 0.85. Any suitable combinations of the above-referenced ranges are also possible (e.g., the time period during which the sample is milked for actinium in act 512 is a fraction greater than or equal to 0.95 and less than or equal to 1.05 of the time period during which the sample is irradiated in the reactor in act 504). Such ranges may also be expressed as a percentage rather than a fraction (e.g., the time period during which the sample is milked for actinium in act 512 is greater than or equal to 95% and less than or equal to 105% of the time period during which the sample is irradiated in the reactor in act 504).

[0066] In act 514, the sample is returned to the fission reactor (or inserted into another reactor) and method 500 returns to act 504. In at least some cases, no further milking is performed after act 512 ends and before act 514 begins. In such cases, the milking process represented by act 512 is the only milking process in method 500between irradiation in act 504, and returning the sample to the reactor in act 514, that produces pure, or substantially pure, Ac-225.

[0067] Milking of the sample in act 510 and 512 may utilize any suitable technology and devices for separating actinium isotopes from isotopes of other elements, including but not limited to radium. As one illustrative example, milking of the sample in act 510 and / or act 512 may comprise operating a cation exchange column such as that described in “Simultaneous Separation of Actinium and Radium Isotopes from a Proton Irradiated Thorium Matrix,” Mastren et al., Sci Rep 7, 8216 (2017). Suitable devices for separation of actinium isotopes from isotopes of other elements are also described, for example, in Aldrich, K. E., et al., “Preparation of an Actinium- 228 Generator,” Inorganic Chemistry 2020, 59 (5) 3200-3206 (2020) and Eddy, M. R., et al., “The Purification of Ac225 using Extraction Chromatographic Resins,” 12th International Symposium on Target Alpha Therapy, February 27 -March 2, 2023, Cape Town, South Africa.

[0068] FIG. 6 is a flowchart of a method, such as the method of FIG. 5, of obtaining actinium- 225 describing embodiments for performing the milking acts in more detail, according to some embodiments. Method 600 may be performed using any suitable target comprising Ra-226, as described above. For instance, method 600 may be performed using capsule 205, in addition to a suitable fission reactor. Prior to the start of method 600, a suitable sample comprising Ra-226 may be formed into a solid target and placed into a capsule, such as capsule 205. In some embodiments, the solid targets comprise Ra(NOa)2, RaCh, Ra(SO4), Ra(OH)2, or Ra metal.

[0069] Method 600 starts at act 602 by irradiating a target, comprising Ra-226, with a neutron flux in an irradiation chamber of a suitable fission reactor. The target comprising Ra-226 is irradiated for an irradiation period during which the neutron flux reacts with the Ra-226 to produce Ra-225 and Ra-227, as described above in connection with FIG. 1A.

[0070] In some embodiments, the irradiation period is between 4 and 14 days. For example, the irradiation period may be approximately 6.5 days.

[0071] In act 604, after the irradiation period, the target is removed from the reactor and stored for a first accumulation period. During the first accumulation period,the products formed through reaction with the neutrons decay. As a result of the nuclear decay processes, Ac-225 and Ac-227 are produced, as shown in FIG. 1A. Accordingly, by the end of the first accumulation period, Ac-225 and Ac-227 are present in measurable quantities.

[0072] In some embodiments, the duration of the first accumulation period is such that practically all or nearly all of the Ra-227 isotopes have decayed. Accordingly, at the end of act 604, the only radium isotopes for which there are measurable quantities in the sample are Ra-225 and Ra-226.

[0073] In act 606, after the first accumulation period, a first sample of Ac-227 and Ac-225 is separated from the Ra-226 and Ra-225 isotopes. The separation may employ suitable column chromatography techniques in certain embodiments. In some embodiments, the column chromatography separation process includes a stationary phase medium and mobile phase solvent(s) and eluant(s) to deliver to and retain radium isotopes on the stationary phase medium in the column while washing and / eluting actinium isotopes from the column with a suitable mobile phase (e.g., a suitable eluent). In other embodiments, the column chromatography separation process includes a column with a stationary phase medium that selectively binds and retains actinium isotopes on the while the radium isotopes are washed / eluted from the column with a suitable mobile phase (e.g., a suitable eluent)' .

[0074] As an example of a column chromatography separation process that includes a stationary phase medium and mobile phase that selectively retains radium isotopes on the stationary phase medium while permitting actinium isotopes to be washed / eluted from the column, a DGA resin medium manufactured by Eichrom Technologies Inc. may be employed. The DGA resin may be a N,N,N’,N’-tetra-n- octyldiglycolamide normal resin or a N,N,N’,N’-tetrakis-2-ethylhexyldiglycolamide branched resin. As a second example, the column chromatography separation process may use a resin based on a mixture of diglycolamide and a phosphine oxide, such as those manufactured by TrisKem International. The diglycolamide and phosphine oxide based resin may be TK-221 or, when based on a branched diglycolamide, TK-222.

[0075] When TK-221 is used as the stationary phase medium, nitric acid or hydrochloric acid may be used to dissolve Ra-226 targets and load them onto thestationary phase medium. Nitric acid or hydrochloric acid may also be employed to elute various species from the stationary phase medium while retaining others. For example, for Ra-226 targets with lanthanide impurities, the nitric acid or hydrochloric acid may be employed as a mobile phase that retains those impurities as well as iron, polonium, and bismuth impurities. The TK-221 particle size may be between 50-100 microns. A second column may be included downstream that uses a crown-ether resin, such as TK-101. The second column may remove additional radium, lead, and / or tin as needed.

[0076] In an exemplary embodiment, a nitric acid and / or hydrochloric acid mobile phase may be used with any suitable column stationary phase media, such as described above (e.g., TK-221 and / or TK-222), for selectively binding actinium. A typical such separation process may start by dissolving the irradiated target in nitric acid. For dissolving typical target materials, nitric acid having a molarity between 2-4 may be used. The dissolved target is then loaded into the column.

[0077] Next, the column with the dissolved target may be washed with 4 molar nitric acid to remove radium, barium, lead, and strontium impurities. After washing, 12 molar nitric acid may be used to elute any residual radium and lanthanides, along with actinium, to obtain a dilute eluate.

[0078] Next, the dilute eluate is subjected to a second column chromatography separation process, using any suitable column stationary phase media, such as described above (e.g., TK-221 and / or TK-222), for selectively binding actinium. In the second separation, 6 molar nitric acid is used to rinse the column to remove lanthanides, 10 molar hydrochloric acid is used to rinse the column to remove bismuth, 0.05 molar nitric acid is used to rinse the column to remove iron and polonium, and finally, to finish the second separation, 0.05 molar hydrochloric acid is used to elute actinium (including actinium-225). The second separation may be repeated two or more times to increase the purity of the resulting eluate.

[0079] A third separation may be used for further radium, lead, strontium, and bismuth removal, if desired. For example, such a third separation may load the actinium eluate from the second separation above into a column containing any suitable column stationary phase media, such as TK-101 described above in a 0.05 molar hydrochloric acid mobile phase. Once loaded, the column may be washed using 0.05 molarhydrochloric acid to collect the purified actinium, while the impurities are retained on the TK-101. If desired, radium and other impurities can be eluted from the column using, for example, a 3 molar nitric acid solution.

[0080] Finally, if nitrates are present, nitrates may be removed as needed using a small anionic resin cartridge.

[0081] Another process which only relies on hydrochloric acid with a suitable DGA resin may be used as an alternative to the nitric and hydrochloric acid process described above to separate radium and actinium. The hydrochloric acid based process involves dissolving the irradiated target in 9 molar hydrochloric acid. To load the dissolved target into the column, a 0.05 molar hydrochloric acid mobile phase may be used. Next, 9-10 molar hydrochloric acid may be used to rinse the column. During rinsing, radium is eluted from the column. Finally, 0.05 molar hydrochloric acid is used to elute actinium from the column.

[0082] A hydrochloric acid based separation using TK-101 resin may also be used. To load the dissolved target onto the column, 0.05 molar hydrochloric acid may be used as mobile phase. Next, 0.05 molar hydrochloric acid may be used to rinse the column. During rinsing, actinium is eluted from the column. Radium may be retained on the column which can subsequently be eluted, if desired, using 3 molar hydrochloric acid.

[0083] If lanthanides need to be removed, actinium purification with a TK-221 containing column may be used. To load the dissolved actinium-containing target onto such column, 0.05 molar hydrochloric acid may be used. Next, 10 molar hydrochloric acid may be used to rinse the column of bismuth, and 0.05 molar nitric acid may be used to rinse the column of iron and polonium. Actinium may then be eluted using 0.05 molar hydrochloric acid. This first pass may be repeated as needed to increase the purity of the actinium. Additionally, a further TK-101 column may be used to further remove any contaminating radium, lead, strontium, and / or barium.

[0084] As described in the above examples, during a column chromatography separation process the target / sample is added to the column containing a suitable stationary phase medium for the desired separation, and then the column may be washed with suitable mobile phase solvent(s) to elute different species off the column at differentstages. The eluate may be collected as separate fractions (e.g., in separate containers). In certain cases, the Ac-227 and Ac-225 isotopes may be eluted from the column in a first fraction. Ra-225 and Ra-226 may be eluted from the column in a second fraction. Depending on the stationary phase medium and mobile phase(s) used, in some embodiments, the radium may instead be eluted before the actinium. However, in other embodiments, the actinium is eluted before the radium.

[0085] Referring again to act 604, in some embodiments, the first accumulation period is between 10 and 14 hours. For example, the first accumulation period may be 12 hours.

[0086] In act 608, the Ra-226 and Ra-225 are stored for a second accumulation period. As substantially all the Ra-227 decayed during the first accumulation period, Ac- 227 will not accumulate during the second accumulation period. The second accumulation period may be in certain embodiments approximately equal in duration to the irradiation period.

[0087] In some embodiments, the second accumulation period is between 39% and 160% the duration of the irradiation period. In some embodiments, the second accumulation period is between 70% and 120% the duration of the irradiation period.

[0088] In act 610, after the second accumulation period, a second sample of actinium-225 isotopes is separated from the radium- 226 and radium-225 isotopes. The second sample of actinium-225 isotopes may be separated using a column chromatography separation process. Unlike the first sample of actinium, from the first separation, which included both Ac-225 and Ac-227 isotopes, the second sample of actinium includes Ac-225 isotopes with little to no detectable levels of Ac-227. Little to no detectable levels of Ac-227 includes samples that have no more than 1 % Ac-227 activity. In some embodiments, the second sample of actinium isotopes will have, 8 mol Ac-225 to less than 1 mol Ac-227.

[0089] In some embodiments, the column chromatography separation process used in act 610 may use the same column having the same stationary phase medium type(s) as used for the first column chromatography separation process of act 606. In other embodiments, the column separation may use a different stationary phase mediumtype(s)than the first column chromatography separation processes suitable and appropriate to purify the Ac-225 from the particular impurities present at this stage of the process. In some embodiments, the radium- 226 and radium-225 isotopes separated in act 610 may be recovered and formed into a new target for another irradiation cycle (act 602) in the irradiation chamber.

[0090] As an example, the column chromatography separation process of act 610may be configured such that the Ac-225 isotopes are eluted in a fraction (referred to here as a “third” fraction to distinguish the first and second fractions referenced above as resulting from the first column chromatography separation process of act 606) and the Ra-226 and Ra-225 isotopes are eluted in a separate “fourth” fraction. Depending on the stationary phase media and the mobile phase solvent(s) used, in some embodiments, the third fraction is eluted before the fourth fraction. However, in other embodiments, the fourth fraction is eluted before the third fraction.

[0091] In some embodiments, the second sample actinium (or multiple second samples, each stored for different accumulation periods) is subjected in act 610 at separation / purification of the actinium a single or in certain embodiments multiple times over the course of the entire second accumulation period. For example, the Ac-225 may be separated from the Ra-225 and Ra-226 by using a column chromatography separation process in samples collected every hour, every two hours, every three hours, every 6 hours, every 10 hours, or on another periodic time scale. As another example, the Ac-225 may be separated from the Ra-225 and Ra-226 using a column chromatography separation process from samples collected at random times or according to an aperiodic time schedule. The aperiodic time schedule may be configured to separate approximately the same quantity of Ac-225 isotopes for each collected sample. Accordingly, near the start of the second accumulation period, the time period between collecting each sample for separation may be shorter than towards the end of the entire second accumulation period.

[0092] In some embodiments, the second accumulation period is between 39% and 160% the duration of the irradiation period. In some embodiments, the second accumulation period is between 70% and 120% the duration of the irradiation period. In some embodiments, the second accumulation period is between 90% and 110% of theirradiation period. In some embodiments, the second accumulation period is between 95% and 105% of the irradiation period.

[0093] In act 612, a second target can be formed from the Ra-226 and Ra-225 resulting from the separation(s) performed in act 610. This second target may then again be irradiated (act 602). During such second (or subsequent) irradiation period(s), the neutron flux will react with the Ra-226 to produce additional Ra-225 and Ra-227.

[0094] In act 614, the second Ac-225 sample purified in act 610 may be further processed if needed or desired to produce a final, clinical grade of Ac-225 isotopes for storage and use as a therapeutic or diagnostic radioisotope. The clinical grade of Ac-225 may be stored in a container for shipping to clinical environments. In some embodiments, at least certain acts of method 600 may be performed in a “hot box” (e.g., a box configured to contain the radioactive samples and shield users or technicians from the radiation). Accordingly, the clinical grade Ac-225 may be removed from the hot box in act 614 for shipment and / or use.

[0095] The inventors have further recognized and appreciated that while the mixture of Ac-227 and Ac-225 extracted in act 606 after the first accumulation period may not be suitable for clinical usage, due to the presence of Ac-227 isotopes, the actinium mixture may be milked to extract other clinically useful isotopes. For example, bismuth-213 (Bi-213), thorium-227 (Th-227), and radium-223 (Ra-223) may be extracted from the mixture of Ac-227 and Ac-225 isotopes.

[0096] FIG. 7 is a flowchart of a method of obtaining one or more daughter isotopes from a radium sample, according to some embodiments. Method 700 may be performed using any suitable sample comprising Ra-226, as described above.

[0097] Acts 702-706 of method 700 may be performed identically as acts 602-606 of method 600 as described previously in certain embodiments

[0098] In some embodiments, during the accumulation period of act 704, the parent isotopes whose decay results in the accumulation of Ac-227 will have fully decayed such that there are no detectable levels of the parent isotopes of Ac-227. For example, where an Ra-226 sample is irradiated by a neutron flux during the irradiation period, the parent isotope of Ac-227 is Ra-227. In some embodiments, the accumulationperiod is between 10 and 14 hours, as described above. Following the accumulation period, the remaining radium isotopes will be Ra-225 and Ra-226. Similarly, the actinium mixture resulting from act 706 will include Ac-227 and Ac-225 isotopes.

[0099] In act 708, a sample of Bi-213 is separated from the sample of Ac-227 and Ac-225 produced in act 706, in some embodiments. The separation of Bi-213 from the mixed actinium sample may comprise a column chromatography separation process as described previously configured or adapted to separate bismuth from actinium and any other undesired impurities. In some embodiments, the bismuth separation may occur at the same facility as the separation of actinium performed in act 706. In other embodiments, the actinium mixture may be packaged in a first facility and shipped to a second facility for milking and separation of the Bismuth isotopes. The second facility may be a treatment facility such as a hospital. Accordingly, milking and / or separation of the Bi-213 in the same facility where patients are treated may provide advantages in maximizing the quantity of Bi-213 when compared to extracting Bi-213 in a separate facility followed by shipping the Bi-213 sample to a remote patient treatment facility.

[0100] In some embodiments, the accumulation time for Bi-213 is between 3 to 12 hours. Accordingly, a sample of Bi-213 may be separated from the sample of Ac-227 after successive accumulation times. For example, after every 4 hours, a Bi-213 sample may be separated from the sample of Ac-227.

[0101] In act 710, after separating the sample of Bi-213, optionally, a sample of Th- 227 is separated from the sample of Ac-227 and Ac-225. In some embodiments, the accumulation time for Th-227 is on the order of months. Accordingly, a sample of Th- 227 can be separated from the sample of Ac-227 and Ac-225 when a patient demands it (assuming sufficient accumulation time) or on a schedule of periodic extractions occurring between 1-6 months. Additionally or alternatively, a sample of Ra-223 is separated from the sample of Ac-227 and Ac-225. The Th-227 and / or Ra-223 may be separately separated from the actinium mixture through respective column chromatography separation processes with resins, mobile phases, and conditions selected to effect the desired separations. Techniques and materials for performing such separations are known to those skilled in the art. In some embodiments, the Th-227 and / or Ra-223 may be separated at the same facility where the actinium mixture wasseparated. Accordingly, in embodiments where the actinium mixture is packaged and sent to a separate facility for producing and purifying the bismuth, the actinium mixture may be received back at the first facility for the subsequent milking and separation of thorium and radium. The received actinium mixture need not be the same actinium mixture that was originally sent to the second facility. Rather, the received actinium mixture may be any actinium mixture prepared in accordance with acts 702-708 and then returned to the facility for processing.

[0102] In some embodiments, method 600 and method 700 may be performed in parallel. Accordingly, acts 602-606 and acts 702-706 may be coextensive and performed as one set of acts on the same sample. Thereafter, acts 608-614 may be performed in parallel with acts 708 and / or 710.

[0103] Having thus described several aspects of at least one embodiment of this invention, it is to be appreciated that various alterations, modifications, and improvements will readily occur to those skilled in the art.

[0104] Such alterations, modifications, and improvements are intended to be part of this disclosure, and are intended to be within the spirit and scope of the invention. Further, though advantages of the present invention are indicated, it should be appreciated that not every embodiment of the technology described herein will include every described advantage. Some embodiments may not implement any features described as advantageous herein and in some instances one or more of the described features may be implemented to achieve further embodiments. Accordingly, the foregoing description and drawings are by way of example only.

[0105] Various aspects of the present invention may be used alone, in combination, or in a variety of arrangements not specifically described in the embodiments described in the foregoing and is therefore not limited in its application to the details and arrangement of components set forth in the foregoing description or illustrated in the drawings. For example, aspects described in one embodiment may be combined in any manner with aspects described in other embodiments.

[0106] Also, the invention may be embodied as a method, of which an example has been provided. The acts performed as part of the method may be ordered in any suitableway. Accordingly, embodiments may be constructed in which acts are performed in an order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments.

[0107] Further, some actions are described as taken by a “user.” It should be appreciated that a “user” need not be a single individual, and that in some embodiments, actions attributable to a “user” may be performed by a team of individuals and / or an individual in combination with computer-assisted tools or other mechanisms.

[0108] Use of ordinal terms such as “first,” “second,” “third,” etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term) to distinguish the claim elements.

[0109] The terms “approximately” and “about” may be used to mean within ±20% of a target value in some embodiments, within ±10% of a target value in some embodiments, within ±5% of a target value in some embodiments, and yet within ±2% of a target value in some embodiments. The terms “approximately” and “about” may include the target value. The term “substantially equal” may be used to refer to values that are within ±20% of one another in some embodiments, within ±10% of one another in some embodiments, within ±5% of one another in some embodiments, and yet within ±2% of one another in some embodiments.

[0110] The term “substantially” may be used to refer to values that are within ±20% of a comparative measure in some embodiments, within ±10% in some embodiments, within ±5% in some embodiments, and yet within ±2% in some embodiments. For example, a first direction that is “substantially” perpendicular to a second direction may refer to a first direction that is within ±20% of making a 90° angle with the second direction in some embodiments, within ±10% of making a 90° angle with the second direction in some embodiments, within ±5% of making a 90° angle with the second direction in some embodiments, and yet within ±2% of making a 90° angle with the second direction in some embodiments.

[0111] Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having,” “containing,” “involving,” and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

[0112] What is claimed is:

Claims

CLAIMS1. A method for generating actinium- 225 isotopes, the method comprising: irradiating a target with a neutron flux for an irradiation period in an irradiation chamber, wherein the target comprises radium-226; after the irradiation period, storing the target outside of the irradiation chamber for a first accumulation period; after the first accumulation period, performing a first separation to separate a first sample of actinium-227 and actinium-225 isotopes from radium-226 and radium- 225 isotopes present in the irradiated target that was subject to the first accumulation period; storing the radium-226 and radium-225 isotopes obtained from the first separation for a second accumulation period; performing a second separation to separate an actinium-225 isotope product from the radium-226 and radium-225 isotopes stored for the second accumulation period.

2. The method of claim 1, further comprising forming a second target formed from the radium-226 and radium-225 isotopes resulting from the second separation step; and irradiating the second target with a neutron flux in the same and / or a different irradiation chamber.

3. The method of claim 1, wherein the second accumulation period and the irradiation period are approximately a same duration.

4. The method of claim 1, wherein the first separation comprises a first column chromatographic separation step in which the actinium-227 and actinium-225 isotopes are eluted in a first fraction and the radium-226 and radium-225 isotopes are eluted in a second fraction.

5. The method of claim 4, wherein the second separation comprise a second column chromatographic step in which the actinium-225 isotopes are eluted in a third fraction and the radium-226 and radium-225 isotopes are eluted in a fourth fraction.

6. The method of claim 5, wherein the second fraction is eluted before the first fraction.

7. The method of claim 5, wherein the first fraction eluted before the second fraction.

8. The method of claim 5, wherein the third fraction is eluted before the fourth fraction.

9. The method of claim 5, wherein the fourth fraction is eluted before the third fraction.

10. The method of claim 5, wherein the first fraction includes actinium- 225 isotopes and actinium- 227 isotopes and the third fraction includes actinium- 225 isotopes without detectable levels of actinium- 227 isotopes.

11. The method of any one of claims 1 to 10, wherein the second separation is repeated multiple times during the second accumulation period.

12. The method of any one of claims 1 to 10, wherein the second accumulation period is between 39% and 160% the duration of the irradiation period.

13. The method of claim 12, wherein the second accumulation period is between 70% and 120% the duration of the irradiation period.

14. A method of obtaining actinium-225, the method comprising: delivering a sample comprising radium-226 into a fission reactor and leaving the sample in the fission reactor for a first irradiation period; removing the sample from the fission reactor when the first irradiation period ends;milking the sample for actinium over a first milking period, thereby removing actinium-225 from the sample, wherein when the first milking period begins the sample contains a first number of atoms of radium- 225; and subsequent to the first milking period ending, delivering the sample into the fission reactor, or into a different fission reactor, for a second irradiation period, without performing additional milking of the sample between the first milking period and the second irradiation period, wherein when the first milking period ends the sample contains between 60% and 80% of the first number of atoms of radium-225.

15. The method of claim 14, wherein the first milking period has a duration that is between 80% and 120% of a duration of the first irradiation period.

16. The method of claim 15, wherein the first irradiation period is between 5 days and 10 days, and wherein the first milking period is between 5 days and 10 days.

17. The method of claim 15, wherein the first milking period has a duration that is between 95% and 105% of a duration of the first irradiation period.

18. The method of any one of claims 14 to 17, wherein the sample is a first sample, and wherein the method further comprises: delivering a second sample comprising radium- 226 into the fission reactor while milking the first sample for actinium over the first milking period; and milking the second sample for actinium while the first sample is irradiated in the fission reactor during the second irradiation period.

19. The method of any one of claims 14 to 17, wherein milking the sample for actinium comprises chemically eluting actinium-225 from the sample.

20. The method of any one of claims 14 to 17, further comprising, prior to milking the sample for actinium over the first milking period, milking the sample for actinium over a post-irradiation time period, thereby removing actinium-225 and actinium- 227 from the sample.

21. The method of claim 20, wherein an amount of actinium- 227 removed from the sample over the post-irradiation time period is at least five times greater than an amount of actinium-225 removed from the sample over the post-irradiation time period.

22. The method of any one of claims 14 to 17, further comprising waiting for a waiting period subsequent to removing the sample from the fission reactor, and removing radium- 227 from the sample during the waiting period.

23. The method of claim 22, wherein the waiting period is between 4 hours and 12 hours.

24. The method of any one of claims 14 to 17, wherein the sample comprising radium- 226 is arranged in a metal capsule, and delivering the sample comprising radium- 226 into the fission reactor comprises delivering the metal capsule into the fission reactor.

25. A method of obtaining actinium-225, the method comprising: delivering a sample comprising radium-226 into a fission reactor and leaving the sample in the fission reactor for a first irradiation period; removing the sample from the fission reactor when the first irradiation period ends; milking the sample for actinium over a first milking period that has a duration that is between 80% and 120% of a duration of the first irradiation period; and subsequent to the first milking period ending, delivering the sample into the fission reactor, or into a different fission reactor, for a second irradiation period without performing additional milking of the sample between the first milking period and the second irradiation period.

26. The method of claim 25, wherein the sample is a first sample, and wherein the method further comprises:delivering a second sample comprising radium- 226 into the fission reactor while milking the first sample for actinium over the first milking period; and milking the second sample for actinium while the first sample is irradiated in the fission reactor during the second irradiation period.

27. The method of claim 25, wherein the first irradiation period is between 5 days and 10 days, and wherein the first milking period is between 5 days and 10 days.

28. The method of any one of claims 25 to 27, wherein the duration of the first milking period is between 95% and 105% of the duration of the first irradiation period.

29. The method of any one of claims 25 to 27, wherein milking the sample for actinium-225 comprises chemically eluting actinium from the sample.

30. The method of any one of claims 25 to 27, further comprising, prior to milking the sample for actinium over the first milking period, milking the sample for actinium over a post-irradiation time period, thereby removing actinium-225 and actinium- 227 from the sample.

31. The method of claim 30, wherein an amount of actinium- 227 removed from the sample over the post-irradiation time period is at least five times greater than an amount of actinium-225 removed from the sample over the post-irradiation time period.

32. The method of any one of claims 25 to 27, further comprising waiting for a waiting period subsequent to removing the sample from the fission reactor, and removing radium- 227 from the sample during the waiting period.

33. The method of claim 32, wherein the waiting period is between 4 hours and 12 hours.

34. The method of any one of claims 25 to 27, wherein the sample comprising radium- 226 is arranged in a metal capsule, and delivering the sample comprising radium-226 into the fission reactor comprises delivering the metal capsule into the fission reactor.

35. A method for generating an actinium-225 product, the method comprising: irradiating a target with a neutron flux for an irradiation period in an irradiation chamber, wherein the target comprises radium-226; after the irradiation period, storing the target outside of the irradiation chamber for a first accumulation period; after the first accumulation period, subjecting the irradiated target to a first separation involving separating a first sample of actinium- 227 and actinium-225 isotopes from radium-226 and radium-225 isotopes, wherein the first separation comprises a first column chromatographic separation step in which the actinium- 227 and actinium-225 isotopes are eluted in a first fraction and the radium-226 and radium-225 isotopes are eluted in a second fraction; storing the radium-226 and radium-225 isotopes eluted in the first fraction for a second accumulation period; subjecting the stored radium-226 and radium-225 isotopes to a second separation step to produce the actinium-225 product, wherein the second separation step comprises separating actinium-225 isotopes from radium-226 and radium-225 isotopes using a second column chromatographic separation step in which the actinium-225 product is eluted in a third fraction and the radium-226 and radium-225 isotopes are eluted in a fourth fraction; irradiating a second target formed from the fourth fraction in the same and / or a different irradiation chamber.

36. The method of claim 35, wherein the irradiation period and the second accumulation period are approximately a same duration.

37. The method of claim 35 or 36, wherein the irradiation period is approximately 6.5 days.

38. The method of any one of claims 35 to 37, wherein the first accumulation period is approximately 12 hours.

39. The method of any one of claims 35 to 38, wherein the second separation step is performed at the end of the second accumulation period.

40. The method of any one of claims 35 to 39, wherein the second separation step is performed prior to competition of the second accumulation period.

41. The method of claim 40, wherein the second separation step comprises a plurality of separation steps performed multiple times over a duration of the second accumulation period.

42. The method of any one of claims 37 to 41, wherein the second accumulation period is between 39% and 160% the duration of the irradiation period.

43. The method of claim 40, wherein the second accumulation period is between 70% and 120% the duration of the irradiation period.

44. The method of any one of claims 35 to 43, wherein the second fraction is eluted before the first fraction.

45. The method of any one of claims 35 to 43, wherein the first fraction is eluted before the second fraction.

46. The method of any one of claims 35 to 43, wherein the third fraction is eluted before the fourth fraction.

47. The method of any one of claims 35 to 43, wherein the fourth fraction is eluted before the third fraction.

48. The method of any one of claims 35 to 47, wherein the first fraction includes actinium-225 isotopes and actinium-227 isotopes, and the third fraction includes actinium-225 isotopes without detectable levels of actinium-227.

49. The method of any one of claims 35 to 48, wherein the first fraction is stored separately from the third fraction.

50. The method of any one of claims 35 to 49, wherein irradiating the second target comprises inserting the second target into the irradiation chamber.51 The method of claim 35-43, further comprising storing the actinium-225 product from the third fraction for use as a clinical source of actinium-225 isotopes.

52. A method for generating an isotope product comprising a daughter isotope from a target comprising parent radium-226, the method comprising: irradiating the target with a neutron flux for an irradiation period; after the irradiation period, storing the target outside an irradiation chamber for a first accumulation period; performing a first separation on the stored target in which a first sample comprising actinium- 227 and actinium-225 isotopes is separated from radium-226 and radium-225 isotopes; storing the first sample comprising actinium-227 and actinium-225 isotopes for a second accumulation period; and performing a second separation during and / or after the second accumulation period which a second sample comprising the isotope product comprising the daughter isotope is separated from the first sample.

53. The method of claim 52, wherein the second sample comprises bismuth-213 isotopes.

54. The method of claim 52, further comprising, after the second accumulation period,storing the first sample comprising actinium-227 and actinium- 225 isotopes for a third accumulation period; and performing a third separation during and / or after the third accumulation period in which a third sample comprising thorium- 227 is separated from the first sample.

55. The method of claim 54, further comprising, after the second accumulation period,: storing the first sample comprising actinium-227 and actinium-225 isotopes for a fourth accumulation period; and performing a fourth separation during and / or after the third accumulation period in which a fourth sample comprising radium-223 is separated from the first sample.

56. The method of claim 52, further comprising, during and / or after the first accumulation period, performing a fifth separation in which a fifth sample comprising actinium-225 isotopes is separated from the irradiated target.

57. The method of claim 56, further comprising forming second target from the radium- 226 and radium- 225 isotopes separated from the fifth sample in the fifth separation.

58. The method of claim 56, wherein the fifth sample comprising actinium-225 isotopes is suitable for use as a clinical source of actinium-225 isotopes.

59. The method of claim 52, wherein the irradiation period is between 5 days and 10 days.

60. The method of claim 59, wherein the irradiation period is approximately 6.5 days.

61. The method of claim 52, wherein the accumulation period is between 10 hours and 14 hours.

62. The method of claim 52, wherein the first accumulation period is approximately12 hours.

63. The method of claim 52, wherein the second accumulation period is between 3 to 12 hours.

64. The method of claim 54, wherein the third accumulation period is between 1 to 6 months.

65. The method of claim 52, further comprising packaging the first sample of actinium-227 and actinium-225 isotopes for shipment and shipping the packaged first sample for analysis and / or purification.

66. The method of claim 65, further comprising receiving a returned shipment of the first sample comprising actinium-227 and actinium-225 isotopes and using the returned shipment of the first sample, in the step comprising storing the first sample comprising actinium-227 and actinium-225 isotopes for the second accumulation period.

67. A method for generating an isotope product comprising a daughter isotope from a target comprising parent radium-226, the method comprising: irradiating the target with a neutron flux for an irradiation period; after the irradiation period, storing the target outside an irradiation chamber for a first accumulation period; performing a first separation on the stored target during and / or after the first accumulation period in which a first sample comprising actinium-227 and actinium-225 isotopes is separated from radium-226 and radium-225 isotopes; storing the first sample for a second accumulation period; performing a second separation on the first sample after storage in which a second sample comprising thorium- 227 is separated from the actinium-227 and actinium-225 during and / or after the second accumulation period; storing the actinium-227 and actinium-225 separated from the second sample by the second separation for a third accumulation period; andperforming a third separation on the stored actinium-227 and actinium- 225 separated from the second sample during and / or after the third accumulation period in which a third sample comprising radium- 223 is separated from the sample of actinium- 227 and actinium-225 that was separated from the second sample.

68. The method of claim 67, further comprising after the step of performing the first separation: packaging at least a portion of the first sample of actinium-227 and actinium-225 isotopes for shipment and shipping the least a portion of packaged first sample for analysis and / or purification; receiving a returned shipment of the first sample comprising actinium-227 and actinium-225 isotopes, optionally for use in the step of performing thesecond separation on the first sample.

69. The method of claim 68, further comprising collecting a fourth sample comprising actinium-227 and actinium-225 isotopes separated during the first separation.

70. The method of claim 68, further comprising forming a second target from the radium- 226 and radium- 225 isotopes separated from the first sample during the first separation.

71. The method of claim 70, further comprising during and / or after the first accumulation period, performing a fifth separation in which a fifth sample comprising actinium-225 isotopes is separated the irradiated target.

72. The method of claim 68, wherein the irradiation period is between 5 days and 10 days.

73. The method of claim 72, wherein the first accumulation period is approximately 12 hours.

74. The method of claim 68, further comprising:storing at least a portion of the first sample for a fourth accumulation period; and during and / or after the fourth accumulation period, performing a sixth separation in which a sixth sample comprising bismuth-213 is separated from the stored first sample.

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