Targeted alpha therapy (TAT) drugs have gained a large amount of interest following the success of Xofigo®, based on the α-emitting 223RaCl2, in treating metastatic castration-resistant prostate cancer. The promising performance of Xofigo® has illustrated the need to expand the catalog of α-emitting radionuclides available for use. One such isotope which has drawn a great deal of attention is 211At, having well-suited decay properties for clinical settings, with a moderately-short half-life of 7.2 h and a quantitative α-emission from a simple decay scheme. With only roughly 30 cyclotrons possessing the ability to generate usable quantities world-wide and just seven of them in the US, only one of which is currently a supplier for the US Department of Energy's Isotope Program, the supply of 211At remains limited. Bombardment of natural Bi targets with an α-particle beam in the energy range of 28.5-31 MeV has been adopted as the standard for generating usable quantities of 211At via the 209Bi(α,2n)211At nuclear reaction. Despite the low availability, 211At has been used in a number of clinical trials investigating the treatment of malignant brain tumors, ovarian cancer, and a current study treating advanced hematopoietic malignancies.
In addition, At chemistry in general is one of the few areas left relatively unexplored on the periodic table. This can be attributed to the fact that At's abundance on earth is estimated to be only 0.07 g, the lowest of any naturally occurring element, because At has no stable isotopes. The longest half-life of only ˜8.1 h belongs to 210At, slightly longer lived than 211At. Astatine is the fifth member of the halogen series and the heaviest confirmed member of the metalloids, which allows for a rich and diverse chemistry. As an example, various oxidation states have been observed, At−, At0, At+, At3+, At5+, and At7+, but a detailed description of their chemistry and speciation has been inhibited by the barrier surrounding its limited supply. The electronic structure, complicated by relativistic effects of this large (atomic radius ˜0.45 Å), heavy element (Z=85), undergoes significant spin-orbit-coupling, making predictions of its chemical behavior based on computational models which neglect spin-orbit-coupling problematic. Conversely, including spin-orbit-coupling requires significantly more computational resources and specialized treatment of the models to ensure accuracy of the predictions. Numerous properties of At and its complexes are affected by the inclusion of spin-orbit-coupling in such predictions, which include polarizability, electronegativity, shifts in the vibrational frequency, and changes in the dipole moment, to name a few.
Whether motivated by exploring the frontiers of the periodic table, radiopharmaceutical applications, or understanding At in its own right, a rapid and efficient separation and purification for recovery and isolation of this interesting element is of crucial importance. Historically, two approaches have been utilized to recover 211At from the Bi targets: dry distillation and wet chemical processing. The latter has been shown to generate a more reproducible 211At recovery yield. For an analytical scale separation, where the amount of 211At to be recovered and purified is on the order of 1-10 ng, with macro amounts of Bi (1-10 g) making up the bulk of the matrix, solvent extraction does not lend itself as an efficient means for separation, as it is limited to a single separation stage per contact and requires sophisticated equipment to run in a continuous-flow mode. Chromatography, conversely, can provide a large number of stages in a single column and is inherently run in a continuous-flow mode.
Both Woen et al. (Inorg. Chem. 59 (2020) 6137-6146) and Li et al. (Sci. Rep. 9 (2019) 16960) have recently shown effective chromatography systems for recovering 211At from bombarded 209Bi targets, with yields of 68% using Pre-Filter resin and 95% using tellurium metal powder, respectively. US 2018/0308599 also describes a process of isolating 211At using chromatography. However, these approaches require the system to be converted from a nitrate to a chloride media, which adds a slow, time-consuming step of either evaporation to dryness to remove the nitrate or the approaches require chemical destruction of the nitrate with hydroxylammonium chloride. Thus, a rapid process and more efficient process to recover At is desirable.
According to one aspect of the present disclosure, a process comprises:
(a) contacting a composition comprising astatine and bismuth with nitric acid to form a first solution comprising astatine, bismuth, and nitric acid;
(b) contacting a resin with the first solution so that astatine partitions out of the first solution and into the resin; and
(c) eluting astatine from the resin.
In another aspect, a composition comprises AtO+X−, wherein X is a counterion.
Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure. The process and compounds of the present disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another.
1. A process comprising
(a) contacting a composition comprising astatine and bismuth with nitric acid to form a first solution comprising astatine, bismuth, and nitric acid;
(b) contacting a resin with the first solution so that astatine partitions out of the first solution and into the resin; and
(c) eluting astatine from the resin.
2. The process of clause 1, wherein the resin is impregnated with a solvent.
3. The process of clause 1 or 2, wherein the solvent comprises an organic solvent.
4. The process of any one of the preceding clauses, wherein the organic solvent is polar.
5. The process of any one of the preceding clauses, wherein the organic solvent comprises an optionally substituted C1-C18 alkyl.
6. The process of any one of the preceding clauses, wherein the organic solvent comprises a carbonyl.
7. The process of any one of the preceding clauses, wherein the organic solvent comprises an aldehyde, a ketone, an ester, an amide, a carbonate, a carboxylate, or a carbamate.
8. The process of any one of the preceding clauses, wherein the organic solvent is of the formula C1-C6 alkyl-C(O)—C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is optionally substituted.
9. The process of any one of the preceding clauses, wherein the organic solvent is octanone.
10. The process of any one of the preceding clauses, wherein the organic solvent is 3-octanone.
11. The process of any one of clauses 1-5, wherein the organic solvent is a C1-C18 alkanol.
12. The process of any one of the preceding clauses, wherein the astatine has a D-value partition coefficient in the organic solvent of at least 20.
13. The process of any one of the preceding clauses, wherein the astatine has a D-value partition coefficient in the organic solvent at least 40.
14. The process of any one of the preceding clauses, wherein the astatine has a D-value partition coefficient in the organic solvent at least 60.
15. The process of any one of the preceding clauses, wherein the astatine has a D-value partition coefficient in the organic solvent at least 80.
16. The process of any one of the preceding clauses, wherein the resin is an inert resin.
17. The process of any one of the preceding clauses, wherein the resin is a polymeric resin, a zeolite, a molecular sieve, or a porous glass bead.
18. The process of any one of the preceding clauses, wherein the resin comprises a styrene-divinylbenzene copolymer.
19. The process of clause 18, wherein the benzene does not contain a functional group.
20. The process of any one of the preceding clauses, wherein the astatine is 211At.
21. The process of any one of the preceding clauses, wherein the astatine is 209At.
22. The process of any one of the preceding clauses, wherein the bismuth does not partition into the resin.
23. The process of any one of the preceding clauses, wherein the nitric acid in the first solution is at a concentration of about 1 M to about 10 M.
24. The process of any one of the preceding clauses, wherein the nitric acid in the first solution is at a concentration of about 1 M to about 8 M.
25. The process of any one of the preceding clauses, wherein the nitric acid in the first solution is at a concentration of about 2 M to about 8 M.
26. The process of any one of the preceding clauses, wherein the process further comprises the step of washing the resin after step (b).
27. The process of any one of the preceding clauses, wherein the step of washing is performed by passing an aqueous solution through the resin.
28. The process of clause 27, wherein the aqueous solution comprises an acid.
29. The process of clause 28, wherein the acid is nitric acid, hydrobromic acid, hydrochloric acid, sulfuric acid, or perchloric acid.
30. The process of clause 28 or 29, wherein the concentration of acid is about 1 M to about 10 M.
31. The process of any one of the preceding clauses, wherein the process recovers ≥85% of the astatine from the mixture
32. The process of any one of the preceding clauses, wherein the process recovers ≥90% of the astatine from the mixture.
33. The process of any one of the preceding clauses, wherein the process recovers ≥95% of the astatine from the mixture.
34. The process of any one of the preceding clauses, wherein the astatine after step (c) has a purity of ≥90%.
35. The process of any one of the preceding clauses, wherein the astatine after step (c) has a purity of ≥95%.
36. The process of any one of the preceding clauses, wherein the astatine after step (c) has a purity of ≥99%.
37. The process of any one of the preceding clauses, wherein the step of eluting is performed by contacting the resin with a second organic solvent.
38. The process of clause 37, wherein the second organic solvent comprises acetone or a C1-C18 alkanol.
39. The process of clause 38, wherein the second organic solvent comprises ethanol.
40. The process of any one of clauses 37-39, wherein the second organic solvent is miscible in the first organic solvent.
41. The process of any one of the preceding clauses, wherein steps (a), (b), and (c) are performed in less than about 1 hour.
42. The process of any one of the preceding clauses, wherein steps (a), (b), and (c) are performed in less than about 30 minutes.
43. The process of any one of the preceding clauses, wherein steps (a), (b), and (c) are performed in less than about 15 minutes.
44. The process of any one of the preceding clauses, wherein steps (a), (b), and (c) are performed in less than about 10 minutes.
45. The process of any one of the preceding clauses, wherein steps (a), (b), and (c) are performed in less than about 20% of the half-life of the astatine.
46. The process of any one of the preceding clauses, wherein steps (a), (b), and (c) are performed in less than about 15% of the half-life of the astatine.
47. The process of any one of the preceding clauses, wherein steps (a), (b), and (c) are performed in less than about 10% of the half-life of the astatine.
48. The process of any one of the preceding clauses, wherein steps (a), (b), and (c) are performed in less than about 5% of the half-life of the astatine.
49. The process of any one of the preceding clauses, wherein the process includes a step of preparing the resin prior to step (b).
50. The process of clause 49, wherein the step of preparing the resin includes contacting the resin with an organic solvent.
51. The process of any one of the preceding clauses, wherein the process further comprises a step of labeling a therapeutic with the eluted astatine.
52. A composition comprising AtO+X−, wherein X− is a counterion.
53. The composition of clause 52, wherein X− is nitrate, a halide, or perchlorate.
54. The composition of clause 53, wherein X− is nitrate.
55. The composition of clause 53, wherein X− is perchlorate.
56. The composition of clause 53, wherein X− is a halide.
57. The composition of clause 56, wherein the halide is chloride.
58. The composition of any one of clauses 52-57, wherein the composition is complexed with an organic solvent.
59. The composition of clause 58, wherein the organic solvent comprises an optionally substituted C1-C18 alkyl.
60. The composition of clause 58, wherein the organic solvent comprises a carbonyl.
61. The composition of clause 58, wherein the organic solvent comprises an aldehyde, a ketone, an ester, an amide, a carbonate, a carboxylate, or a carbamate.
62. The composition of clause 58, wherein the organic solvent is of the formula C1-C6 alkyl-C(O)—C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is optionally substituted.
63. The composition of clause 58, wherein the organic solvent is octanone.
64. The composition of clause 58, wherein the organic solvent is 3-octanone.
65. The composition of any one of clauses 52-64, wherein the astatine is 211At.
66. The composition of any one of clauses 52-64, wherein the astatine is 209At.
67. The composition of any one of clauses 52-66, produced by a process according to any one of clauses 1-51.
68. A composition comprising astatine produced by a process according to any one of clauses 1-51.
69. A process consisting of the steps of any one of clauses 1-51.
70. A process consisting essentially of the steps of any one of clauses 1-51.
Additional features of the present disclosure will become apparent to those skilled in the art upon consideration of illustrative embodiments exemplifying the best mode of carrying out the disclosure as presently perceived.
Astatine (At) may be useful as a radiolabel for therapeutics. However, the natural abundance of At is low. At may be produced by bombarding a bismuth (Bi) metal target with alpha-particles. The produced At must be subsequently isolated from unreacted Bi. Described herein is a process that isolates At from compositions, such as the composition formed from bombarding Bi, using chromatography. In illustrative embodiments, the process described herein dissolves a composition comprising At and subsequently isolates the At from the dissolved mixture. The described process can be performed without the need to convert the media or solution used to initially dissolve the At/Bi composition.
The At described herein may be 209At or 211At and cationic species thereof. For example, the At described in the process herein may be the cationic species AtO+ but will still be referred to as At. Illustratively, the process may include producing the At. The At may be produced by the 209Bi(α,2n)211At nuclear reaction whereby 209Bi metal is bombarded with α-particle. The formed bombarded target may comprise a mixture of At, unreacted Bi, and byproducts.
In some aspects, the At is isolated from the composition comprising Bi and At. Illustratively, the composition is contacted with a solution such as an aqueous solution. In illustrative aspects, the aqueous solution comprises an acid, for example an organic acid or a mineral acid. The mineral acid may be nitric acid. The solution dissolves or substantially dissolves the composition to form a solution comprising At and Bi. In some embodiments, the solution comprises At, Bi, and an acid. In some embodiments, the solution comprises At, Bi, and nitric acid.
In some aspects, the solution has a particular concentration of acid or is adjusted prior to subsequent steps to have a particular concentration of acid. Illustratively, the acid may assist in dissolving the composition. For example, the presence of nitric acid may aid in dissolving a bombarded Bi target.
Illustratively, the acid concentration may be about 1 M to about 10 M, about 1 M to about 8 M, about 2 M to about 8 M, or about 3 M to about 7 M. The concentration of acid may be about 1 M, about 2 M, about 3 M, about 4 M, about 5 M, about 6 M, about 7 M, about 8 M, about 9 M, or about 10 M. The concentration of acid maybe adjusted depending on the partition coefficient in a solvent used in subsequent steps. The ranges described herein are equally applicable when the acid is an organic acid or a mineral acid such as nitric acid.
In some aspects, the At is isolated using chromatography. In illustrative embodiments, the chromatography is performed by using a resin. The resin may be in the form of a resin bed. The resin bed may be in a column. Alternatively, the resin may be used in a bulk process. Illustrative resins include polymeric resins and glass resins. In some embodiments, the resin comprises a zeolite, a molecular sieve, a polymeric resin, or a glass resin. In some embodiments, the resin is porous. In some embodiments, the porous resin is a poly-acrylate resin or a porous glass bead. The resin may be inert. In some embodiments, the resin comprises a styrene-divinylbenzene copolymer. In some embodiments, the benzene of the copolymer does not contain a functional group.
In some aspects, the process includes a step of preparing the resin. This step may occur prior to contacting the resin with a solution comprising At. In illustrative embodiments, the resin may be contacted with a solvent, such as an organic solvent. Illustratively, the step of preparing the resin yields a resin impregnated with a solvent, such as an organic solvent. In some embodiments, the organic solvent is polar. In some embodiments, the organic solvent comprises an optionally substituted C1-C18 alkyl where each hydrogen atom of the C1-C18 alkyl is optionally substituted by a functional group. Optional substituents on C1-C18 alkyl are commonly known in the art and include halogens, hydroxyls, amines, thiols, oxo, ketones, carboxylates, aldehydes, amides, carbonates, carbamates, combinations thereof, and the like. In some embodiments, the organic solvent comprises an aldehyde, a ketone, an ester, an amide, a carbonate, a carboxylate, or a carbamate. In some embodiments, the organic solvent comprises a C1-C18, C1-C12, or C1-C6 alkyl comprising an aldehyde, a ketone, an ester, an amide, a carbonate, a carboxylate, or a carbamate. In some embodiments, the organic solvent is of the formula C1-C6 alkyl-C(O)—C1-C6 alkyl. In some embodiments, the organic solvent is of the formula C1-C6 alkyl-C(O)—C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is optionally substituted. In some embodiments, the organic solvent is octanone. In some embodiments, the organic solvent is 3-octanone. In some embodiments, the organic solvent is a C1-C18 alkanol. Illustratively, the organic solvent may comprise a mixture of the organic solvents described herein.
The term “alkyl” refers to a straight- or branched-chain monovalent hydrocarbon group. In some embodiments, it can be advantageous to limit the number of atoms in an “alkyl” to a specific range of atoms, such as C1-C18 alkyl, C1-C12, alkyl, or C1-C6 alkyl. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. It will be appreciated that an alkyl group can be unsubstituted or substituted as described herein. An alkyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. The term “alk-” may form a prefix with the remainder being a functional group. For example an “alkanol” is an alkyl group substituted with an alcohol.
The term “substituted” means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In some embodiments, “substituted” means that the specified group or moiety bears one, two, or three substituents. For example, two hydrogen atoms on a carbon of an alkyl group may be substituted by an oxo (═O) group to form carbonyl (C═O). In other embodiments, “substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments, “substituted” means the specified group or moiety bears one substituent.
The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine.
In some aspects, the solvent of the impregnated resin is a solvent that provides a D-value partition coefficient for At of at least 10 against an aqueous solution, such as an aqueous solution comprising nitric acid. In illustrative embodiments, At has a D-value partition coefficient in the organic solvent of at least about 20, at least about 40, at least about 60, or at least about 80. Illustratively, the partition coefficient may be measured against an aqueous solution comprising an acid, such as nitric acid. In some embodiments, At has a partition coefficient of at least about 20 or at least about 40 between octanone and an aqueous solution comprising about 2-6 M nitric acid.
In some embodiments, the At composition is loaded onto a resin in a volume of a solution in a ratio to the volume of the resin bed volumes. In some embodiments, the solution comprising At is loaded onto the resin bed at a ratio of up to about 10, up to about 8, up to about 6, or up to about 4 bed volumes. The number of bed volumes used to load the At composition may adjusted by means known within the art to maximize the amount of At partitioned into the resin.
Illustratively, the At may contact a resin and the At may partition into the resin, form a complex, or otherwise form a favorably interaction with the resin. Illustratively, although Bi may contact the resin, Bi will not be retained in or on the resin. Alternatively, the Bi may form weak interactions with the resin such that bound or retained Bi is removed when washing the resin. It should be understood that contact includes any manner of chemical interactions such as ionic or non-covalent interactions. It should be further understood that partitioning into the resin includes partitioning into an interior space of the resin as well as contacting the surface of the resin and forming a favorable interaction to retain the At to the resin.
After the step of contacting with the solution containing a mixture comprising At, the resin may be washed. The step of washing may include washing the resin with an aqueous solution. In some embodiments, the aqueous solution comprises an acid. In some embodiments, the aqueous wash solution comprises an acid at a lower concentration than the acid concentration used to dissolve the At/Bi composition. For example, if the acid concentration is about 6 M in the aqueous solution that dissolves the At/Bi composition, the acid concentration in the wash solution may be less than about 6 M, for example about 2 M. In some embodiments, the concentration of acid is less than about 10 M, less than about 8 M, less than about 6 M, or less than about 4 M. In some embodiments, the concentration of acid is up to about 8 M, up to about 6 M, or up to about 4 M. In illustrative embodiments, the acid used in the wash steps is the same acid, for example nitric acid, as the acid in the previous steps.
Alternatively, the acid may be a different acid. For example, the acid may be HClO4, HCl, HBr, or H2SO4. Illustratively, changing the acid used in the wash step may change the counterion of the isolated At recovered by the eluting step.
In some embodiments, the step of washing the resin is measured as ratio of bed volumes. For example, the resin may be washed with a solution having a volume of at least about 2, at least about 3, at least about 4, at least about 5, or at least about 6 bed volumes. In illustrative embodiments, the resin may be washed sequentially with an aqueous solution containing an acid and an aqueous solution free of an acid. The washing steps may be adjusted by means known in the art to include additional or fewer washing steps of aqueous solutions.
The process includes a step of eluting the At from the resin. Illustratively, the step of eluting dissociates the At from the resin to allow for the At to be collected. The eluting step may be performed by contacting the resin with an organic solvent. In some embodiments, the organic solvent is the same solvent that impregnates the resin. In some embodiments, the organic solvent in the eluting step is miscible with the solvent that impregnates the resin. In some embodiments, the organic solvent comprises an optionally substituted C1-C18 alkyl where each hydrogen atom of the C1-C18 alkyl is optionally substituted by a functional group. Optional substituents on C1-C18 alkyl are commonly known in the art and include halogens, hydroxyls, amines, thiols, oxo, ketones, carboxylates, aldehydes, amides, carbonates, carbamates, combinations thereof, and the like. In some embodiments, the organic solvent comprises an aldehyde, a ketone, an ester, an amide, a carbonate, a carboxylate, or a carbamate. In some embodiments, the organic solvent comprises a C1-C18, C1-C12, or C1-C6 alkyl comprising an aldehyde, a ketone, an ester, an amide, a carbonate, a carboxylate, or a carbamate. In some embodiments, the organic solvent is of the formula C1-C6 alkyl-C(O)—C1-C6 alkyl. In some embodiments, the organic solvent is of the formula C1-C6 alkyl-C(O)—C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is optionally substituted. In some embodiments, the organic solvent is octanone. In some embodiments, the organic solvent is 3-octanone. In some embodiments, the organic solvent is a C1-C18 alkanol. In some embodiments, the solvent comprises ethanol.
Illustratively, the process described herein recovers at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the At from the composition comprising At. In some embodiments, the process recovers about 80% to about 99%, about 85% to about 99%, or about 90% to about 99% of the At from the composition comprising At.
Illustratively, the eluted At has a purity higher for At than the composition comprising At prior to the chromatograph step. In some embodiments, the eluted At has a purity of at least about 90%, at least about 95%, or at least about 99%.
The process described herein may be performed in less than about 1 hour, less than about 30 minutes, less than about 15 minutes, or less than about 10 minutes. Illustratively, the process is performed in less time compared to a comparative process that requires a step of dissolving an At/Bi composition in an nitric acid solution, evaporating the nitric acid solution, and reconstituting the residue in hydrochloric acid prior to chromatography or compared to a comparative process that requires destruction of t nitrate prior to chromatography. The process described herein isolates At in a particular percentage of its half-life. In some embodiments, the process is performed in less than about 20%, less than about 15%, less than about 10%, or less than about 5% of the half-life of At such as 211At.
In some embodiments, the process may further include labeling a therapeutic with the eluted At. This may be done directly with the column fraction of eluted At or may include concentrating the fraction containing At and suspending or dissolving the At in a solution used for the labeling step.
In another aspect, a composition comprises the salt AtO+X−, wherein X− is a counterion. The counter ion may be the conjugate base of an aqueous acid used in the process described herein or may be the conjugate base of any suitable acid. In some embodiments, X− is nitrate, a halide, or perchlorate. In some embodiments, X− is nitrate. In some embodiments, X− is a halide. Suitable halides include fluorides, chlorides, or bromides. In some embodiments, X− is perchlorate. In some embodiments, the At of AtO+ is 211At or 209At.
Materials:
Nitric Acid (67-70% Aristar® Plus, HNO3) was purchased from BDH chemicals; 3-octanone (ACS Grade ≥96%) was purchased from EMD Millipore Corp.; 1-octanol (Lab grade) was purchased from Ward's Science; and ethanol (≥99.5% 200 proof) was purchased from EMD, and all were used as received. Deionized (DI) H2O was obtained from an ELGA LabWater Purelab Flex ultrapure laboratory water purification system operated at 18.2 MΩ cm at 25° C.
Bismuth-207 was purchased from Eckert & Ziegler Isotope Products (Valencia, Calif.) as a Bi(NO3)3 solution with ˜0.24 μCi per mL and roughly 48 μM total Bi concentration in 4 M HNO3.
Methods:
Quantitative analysis for Bi was performed utilizing inductively-coupled plasma mass spectrometry (ICP-MS) with a Thermo Fisher Scientific iCAP RQ mass spectrometer. Semi-quantitative analysis of 207Bi and quantitative analysis for 211At was performed via gamma (γ)-ray spectroscopy using a calibrated Canberra Model GC2020 high-purity germanium detector (HPGe) with a relative efficiency of 20.0% and an active detector volume of ˜115 cm3 and InSpector™ 2000 digital signal analyzer (DSA, Canberra Industries Inc., Meriden, Conn.) along with Genie-2000 software. The detector has an energy resolution of 1.0 keV at 122 keV and 1.98 keV at 1300 keV. Relevant nuclear data were obtained from Browne and Firestone. All calibrations were determined with a 152Eu standard γ-ray source traceable to the National Institute of Standards and Technology (NIST) purchased from Eckert & Ziegler Isotope Products. The 207 Bi was tracked directly using the 1064 keV γ-ray. The 211At was tracked directly using the 76.9 keV, 79.9 keV, 89.8 keV, and 92.3 keV X-rays and 687 keV γ-ray. The impurities, 66167Ga, were identified by half-life analysis (see SI) and were tracked directly using the 833 keV and 1039 keV γ-rays for 66Ga and the 185 keV and 300 keV γ-rays for 67Ga.
At-211 Production:
Astatine-211 was produced in two separate runs by the 209Bi(α,2n)211At nuclear reaction via 28.8 MeV α-particle bombardment (˜0.9 barn cross section)[7] of a natural Bi metal target (isotopically pure 209Bi, metal purity ≥99.997% purchased from Goodfellow) for 9-10 h with an average beam current of 2.4-3.2 pμA on the K150 cyclotron at Texas A&M. The Bi metal targets were about 9.4 g or 1.0 g in mass with a racetrack oval shape (6.985×1.27 cm), capped with half circles (radii 0.635 cm) on either end with an estimated thickness of 950 μm or 100 μm, which was housed in an aluminum frame (6061 Al alloy, 95% Al) in contact with a support block cooled by recirculated water chilled to 15° C. The target was held at a 10° angle from the beam to maximize coverage of the target, while minimizing the loss of beam to the Al housing. The bombarded targets were dissolved in either 11.2 M or 8 M HNO3, resulting in final HNO3 concentration of roughly 6 M. This solution was then sampled and the production yield was determined for 211At at the end of bombardment. 211At and 207Bi to a lesser extent, are highly radioactive and were handled under ALARA principles in laboratories equipped to handle radioactive materials appropriately, a radiological biosafety cabinet was employed.
Partitioning
A series of extractions from HNO3 at various concentrations into several organic solvents were investigated. First, simple straight-chain alcohols, 1-octanol and 1-decanol, were used to extract 211At from 1-3 M HNO3, as shown in
AtO++NO3−
To test this further, a less polar solvent, diisopropyl ether, and a more polar solvent, methyl isobutyl ketone, were investigated. The 211At extraction into diisopropyl ether was in the range of the 1-decanol, with the 207Bi continuing to remain in the aqueous phase (D-value ≤0.05). 211At behaved significantly different in the methyl isobutyl ketone system compared to the other solvent systems studied, displaying a strong HNO3 dependence. The 211At extraction into methyl isobutyl ketone was slightly higher from that of 1-octanol in 1 M HNO3, while the D-values increase by a factor of roughly 1.7× and 2.4× when the HNO3 concentration is increased to 2 and 3 M, respectively. The 207Bi, on the other hand, showed similar behavior as the other systems studied, with very low D-values, ≤0.05. A second ketone, 3-octanone, with a polarity similar to 1-octanol was then tested to determine if solvation effects of the more polar methyl isobutyl ketone was the driving force for the extraction or if the carbonyl functional group of the ketones were playing a major role. As with methyl isobutyl ketone, 211At extraction into 3-octanone appears to be similar to that of 1-octanol in 1 M HNO3, while the D-values increase by a factor of roughly 1.2× and 1.8× when the HNO3 concentration is increased to 2 and 3 M, respectively. Again, the 207Bi remained in the aqueous phase (D-value ≤0.05). The enhanced extraction of AtO+ by ketones over alcohols has also been demonstrated by employing DFT calculations, which showed the free energy of binding for acetone to be 4.6 kcal mol−1 stronger than that for isopropyl alcohol.
The overall behavior of 211At extraction in both the 3-octanone and methyl isobutyl ketone systems was similar, showing a linear relationship between 211At D-values and the initial HNO3 concentration in the aqueous phase between 1-3 M HNO3, while the slope of the methyl isobutyl ketone system was roughly 50% steeper than that of the 3-octanone system. The direct correlation between D-values of 211At into both methyl isobutyl ketone and 3-octanone as a function of HNO3 concentration may indicate an interaction between the ketone and At metal center. Currently, the nature of such an interaction is not completely clear. Density functional calculations show a strong donor-acceptor interaction between the empty π* orbital of the AtO+ and the ‘sp2’ O lone pair of the acetone. The NBO analysis of the AtO+_isopropanol indicates its spa O lone pair donates 0.11 fewer electrons to AtO+ than the sp2 O lone pair orbital in AtO+_acetone. This interaction is 4.6 kcal:mol stronger than the corresponding interaction of the AtO+ with the ‘sp3’ O lone pair of isopropyl alcohol, while the solvent corrected Gibbs free energy of binding is still larger for AtO+_acetone than for AtO+_isopropanol by 2.1 kcal/mol. Thus, ketones show strong binding to AtO+, which leads to better extraction. At the H2O-organic, interface, the organic molecules will have their polar end (oxygen) in (at) the H2O layer. The AO+ and NO3− will be solvent separated in the H2O layer so the early interaction of these species with respect to extraction of AtO+ will be the binding of AtO+ with the oxygen of the organic molecule. The movement of the AtO+ into the organic layer will necessarily need to be accompanied by the NO3−.
Extraction Chromatography:
Amberchrom® CG300M porous beads with a pore volume of 0.7 mL g−1 and a particle size of 50-100 μm slurry in 20% ethanol was purchased from Sigma-Aldrich. Amberchrom® CG300M is a styrene-divinylbenzene copolymer with no functional group on the benzene ring. Prior to use, the beads were dried at 80° C. for a minimum of 24 h to remove any solvent from the pores. The dried resin was then impregnated with either 1-octanol or 3-octanone by soaking the beads in the organic solvent for no less than 24 h. Thermogravimetric analysis (TGA) was performed on the impregnated resin, as well as the dried resin, using a TA Instruments TGA 5500 at a heating rate of 10° C. min−1 under N2 flow. The impregnated resin was then packed into a 2-mL Kontes® Flex-Column® with a bed volume (BV) of 0.5 mL and an inner diameter (ID) of 0.7 cm. An excess of organic solvent was maintained in the column above the bed of the impregnated resin to prevent evaporation of the solvent from the pores Immediately before the extraction chromatographic separation, the excess solvent was drained from the column.
The general chromatography procedure is as follows. The load solution, a 0.5-5 mL solution spiked with 13±1.3 μCi to 9.8±0.98 mCi of 211At in 2-6 M HNO3, was passed through the column in 0.5 mL aliquots, next four 0.5-mL aliquots of 2 M HNO3 were passed through the column, followed by a 0.5-mL aliquot of H2O, and finally three to five 0.5-mL aliquots of ethanol. The elution of each fraction was expedited by manually applying pressure to the headspace of the column with a syringe. In all cases, fractions were collected every 0.5 mL and each fraction was analyzed by γ-ray spectroscopy. Total organic carbon analysis (TOC) using a Shimadzu TOC-VWP analyzer was conducted on fractions eluted from a column packed with 3-octanone impregnated resin (BV ˜0.5 mL) following the general chromatography procedure; however, no radioactive species were present.
Column Characterization:
The loading of the impregnated Amberchrom® CG300M resin with either 1-octanol or 3-octanone was determined by TGA, as shown in
To determine if the organic solvent leached from the pores during the chromatography process, total organic carbon (TOC) analysis was performed on fractions of 6 M HNO3, 2 M HNO3, and H2O eluents which had been successively passed through an extraction chromatography system packed with beads impregnated with 3-octanone to achieve a BV of 0.5 mL.
A small amount of 3-octanone was observed in the first two fractions, 1.4% and 0.9% of the total, respectively, while the subsequent fractions were at or below baseline. The initial leaching of 3-octanone in the first two fractions of 6 M HNO3 may be due to residual solvent in the interstitial space between beads, rather than solvent sorbed in the pores. This indicates that very little leaching of the organic solvent is removed from the pores of the resin during the extraction chromatography process. There is very little bleeding of 211At prior to intentional elution of the nuclide, which major indicates extraction of 211At into the impregnated solvent and the solvent with the extracted 211At remains in the pores. Other extraction chromatography systems which are based on silica scaffolding show a higher tendency toward leaching of the organic phase and require the addition of multicomponent solvent systems to improve the hydrophobic character of the stationary phase.
Extraction Chromatography:
In order for 211At to be utilized in a pharmaceutical setting, it will need to be purified from both the nonradioactive natural Bi, and any radiochemical contaminants generated in its production. As mentioned earlier, the short half-life of 211At (t1/2, ˜7.2 h) necessitates rapid chemistry to achieve separation from the host matrix, Bi metal in this case. To begin with, a 1-octanol extraction chromatography system with a BV of 0.5 mL was tested with a small spike of the Run 1 dissolved bombarded target solution (˜13 μCi of 211At) in 2 M HNO3. As shown in the chromatogram in
Currently, the exact mechanism for 211At adherence to the resin is unclear, but it seems there is an interaction of AtO+ with the resin backbone. The Amberchrom® CG300M resin is based on a polystyrene divinylbenzene polymer. When utilized as a support for thin films of extractant ligands sorbed to the surface, as with extraction chromatography of metal ions, the backbone is thought of as inert with respect to the metal species of interest. One reason for the retention of the AtO+ species on the resin could be interactions of the AtO+ molecules to defects in the polymer, which were generated in the manufacturing of the resin. The hypothesis of the 211At interacting with defects in the polymer chain, as opposed to the bulk functionality of the resin, the phenyl group in the case of Amberchrom® CG300M, is the very small amount of 211At retained. That is to say, roughly 10 μCi of 211At was retained by the resin, which translates to 2.4×10−14 mol, many orders of magnitude less than the phenyl groups present. If a strong interaction occurs with the phenyl groups and 211At, the expected result would be to have near quantitative retention of the 211At. On the other hand, if some interaction with defects is occurring, these defects would only need to represent a very small fraction of the resin, <<0.01% (w/w %).
Next, a second extraction chromatography system impregnated with 3-octanone instead of 1-octanol was tested with a small spike of the Run 1 dissolved bombarded target solution (˜μCi of 211At) also in 2 M HNO3 (see
Following the increased elution yield with the 3-octanone system, the acidity of the load solution was increased to 6 M HNO3 (chromatogram shown in
The activity of the spike was then increased to roughly 1 mCi of 211At and the elution profile of 3-octanone impregnated resin was examined as a function of nitric acid concentration.
211At
207Bi
66Ga/67Ga
211At
207Bi
66Ga/67Ga
211At
207Bi
66Ga/67Ga
The separation was further scaled up with a 5-mL aliquot of the Run 1 dissolved target solution (˜4.1 mCi of 211At in ca. 6 M HNO3).
Finally, the amount of 211At was increased to approximately 9.8 mCi, as shown in
The speciation of the 211At in dissolution solution, mainly HNO3; extracted in the impregnated resin, mainly 3-octanone; and eluted in the strip, primarily ethanol, has not been experimentally determined, as the small amount of At present, resulting from the short half-life, prevent traditional spectroscopic techniques from being employed. At(III), as AtO+, is the dominant species in the aqueous solution. A strong donor-acceptor interaction between the empty π* orbital of the AtO+ and the ‘sp2’ O lone pair of the ketone was calculated and is believed to be the driving force of the efficient extraction of AtO+ out of HNO3 into the 3-octanone. Thus, AtO+ is likely the dominant species in the ethanol strip.
The entire process, from the addition of the first 0.5-mL load aliquot to eluting the fifth and last strip fraction, took less than 20 min despite the slow nature of manual addition of eluent and collection of fractions. Supposing the solutions were fed through the column with a pump, set to the modest speed of 2 mL min−1, the process of recovering ≥95% of the 211At would take less than 5 min. As was discussed earlier, the source of the affinity between the AtO+ and the resin is currently unknown, which prevents a detailed description being given for why the scaled-up separation yield was much higher than its smaller counterpart. However, if the conjecture that an interaction with defects in the resin is occurring, it is not unreasonable to conclude all the exposed defect sites on the resin were saturated in the scaled-up separation. Once the sites were saturated, the majority of the 211At was extracted into the solvent filling the pores, which was eluted by dissolving the 3-octanone into the ethanol strip. This process of recovering high purity 211At, in near quantitative yields, directly from nitric acid represents a significant advance in At separations.
This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Ser. No. 63/003,335 filed on Apr. 1, 2020, the entire disclosure of which is incorporated herein by reference.
This invention was made with government support under DOE-Office of Science DE-SC0020958. The government has certain rights in the invention.
Filing Document | Filing Date | Country | Kind |
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PCT/US2021/025156 | 3/31/2021 | WO |
Number | Date | Country | |
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63003335 | Apr 2020 | US |