EP4073282A2 - Systems and methods for producing elements from mixtures, storage/generation vessels, and storage/generation vessel assemblies - Google Patents
Systems and methods for producing elements from mixtures, storage/generation vessels, and storage/generation vessel assembliesInfo
- Publication number
- EP4073282A2 EP4073282A2 EP20903056.8A EP20903056A EP4073282A2 EP 4073282 A2 EP4073282 A2 EP 4073282A2 EP 20903056 A EP20903056 A EP 20903056A EP 4073282 A2 EP4073282 A2 EP 4073282A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- vessel
- resin
- solution
- column
- mixing vessel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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Classifications
-
- G—PHYSICS
- G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
- G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
- G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
- G21G1/0005—Isotope delivery systems
-
- C—CHEMISTRY; METALLURGY
- C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
- C22B—PRODUCTION AND REFINING OF METALS; PRETREATMENT OF RAW MATERIALS
- C22B26/00—Obtaining alkali, alkaline earth metals or magnesium
- C22B26/20—Obtaining alkaline earth metals or magnesium
-
- C—CHEMISTRY; METALLURGY
- C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
- C22B—PRODUCTION AND REFINING OF METALS; PRETREATMENT OF RAW MATERIALS
- C22B3/00—Extraction of metal compounds from ores or concentrates by wet processes
- C22B3/20—Treatment or purification of solutions, e.g. obtained by leaching
- C22B3/22—Treatment or purification of solutions, e.g. obtained by leaching by physical processes, e.g. by filtration, by magnetic means, or by thermal decomposition
- C22B3/24—Treatment or purification of solutions, e.g. obtained by leaching by physical processes, e.g. by filtration, by magnetic means, or by thermal decomposition by adsorption on solid substances, e.g. by extraction with solid resins
-
- C—CHEMISTRY; METALLURGY
- C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
- C22B—PRODUCTION AND REFINING OF METALS; PRETREATMENT OF RAW MATERIALS
- C22B3/00—Extraction of metal compounds from ores or concentrates by wet processes
- C22B3/20—Treatment or purification of solutions, e.g. obtained by leaching
- C22B3/44—Treatment or purification of solutions, e.g. obtained by leaching by chemical processes
Definitions
- the disclosure generally relates to the isolation of metals as elements for example and assemblies for the storage/generation of metals and in more particular embodiments, to medical radionuclides and more to methods for obtaining materials and performing separations for generating such materials.
- the systems can include: a first vessel housing a first media and either Pb or Bi and/or Th; and a second vessel in fluid communication with the first vessel, the second vessel housing a second media and Ra, wherein the first media is different from the second media.
- Systems for separating Ra from a mixture comprising at least Ra, Pb, Bi, and Th can include a first vessel housing a first media and Th and/or Bi; and a second vessel in fluid communication with the first vessel, the second vessel housing a first media and Pb, wherein the first media is different from the second media.
- Additional systems for separating Ra from a mixture comprising at least Ra, Pb, Bi, and Th can include: a first vessel housing a first media and Th or Bi; a second vessel in fluid communication with the first vessel, the second vessel housing a second media and Pb; and a third vessel in fluid communication with the second vessel, the third vessel housing a third media and Ra, wherein at least one of the first, second, or third medias are different from the other medias.
- Methods for separating Ra from Pb, Bi, and Th are provided, the methods can include: providing a first mixture comprising Ra, Pb, Bi, and/or Th; providing a system that includes: a first vessel housing a first media; and a second vessel in fluid communication with the first vessel, the second vessel housing a second media; exposing the first mixture to the first media within the first vessel to separate the Th and Bi from the Ra and Pb; then, through the fluid communication, exposing the remaining mixture to the second media in the second vessel to associate the Pb or Ra with the second media.
- Methods for separating Ra from Pb, Bi, and Th can also include providing a first mixture comprising Ra, Pb, Bi, and/or Th; providing a system that can include: a first vessel housing a first media; a second vessel in fluid communication with the first vessel, the second vessel housing a second media; and a third vessel in fluid communication with the second vessel, the third vessel housing a third media; and exposing the first mixture to the first media within the first vessel then, through the fluid communication, exposing the first remainder to the second media in the second vessel, then, through fluid communication, exposing the next remainder to the third media in the third vessel, the exposing separating the Th and Bi from the Ra and Pb, and the Ra from the Pb.
- Methods for separating Ra from being associated with a media are also provided.
- the methods can include: exposing the Ra and media to a chelating agent to form a mixture comprising the Ra complexed with the chelating agent.
- Methods for separating Ra from Pb, Bi, and Th are also provided that can include: providing a first mixture comprising Ra and at least Bi and/or Th; separating one or more of Bi and/or Th from the Ra, the separating associating the Bi and/or Th with a first media; and disassociating the Bi and/or Th from the first media to form a mixture comprising the Bi and Th and transferring the mixture to a vessel housing at least Ra and additional Bi and/or Th.
- the system/methods can include providing a mixing vessel in fluid communication with both a bound element source and an acid source.
- the mixing vessel can be operably configured to mix contents within the mixing vessel.
- the systems can include a first multiport valve operably engaged with an exit of the mixing vessel, and a second multiport valve operably engaged with the first multiport valve, the acid source, and a collection vessel.
- Methods for producing free element from a bound element are also provided.
- the methods can include: providing a solution comprising an element bound to a complex; exposing the solution to an acid solution to separate the complex from the element; and removing either the separated element or the complex from the solution to produce a free element.
- the systems can include: a first mixing vessel in fluid communication with a first and a second multiport valve; a manifold of multiport valves in fluid communication with the second multiport valve; a second mixing vessel in fluid communication with at least one of the multiport valves of the manifold; a third multiport valve in fluid communication with an exit of the second mixing vessel; and a metal storage/generation vessel in fluid communication with the third multiport valve.
- the first and second mixing vessels define different volumes.
- the first mixing vessel defines a volume larger than the volume defined by the second mixing vessel.
- Methods for producing a metal storage/generation vessel assembly are also provided.
- the methods can include: homogenizing a resin slurry in a first mixing vessel; supplementing the homogenized resin slurry with a free element to form a homogenized bound element resin slurry; and transferring the homogenized bound element resin slurry to a storage/generation vessel assembly.
- the resin/media alone or in combination with free element of the present disclosure without homogenization will consolidate at the lower portion of the vessel or adhere to other portions of the vessel.
- Homogenizing herein keeps the resin/media alone or in combination with free element distributed throughout the solution of the vessel. This distribution can be uniform and/or without a heterogenous interface.
- Metal storage/generation vessel assemblies are also provided that can include: sidewalls extending between entrance and exit openings to define a vessel volume; inert material proximate the exit opening: and a homogenized bound element resin bed within the vessel, the inert material being between the resin bed and the exit opening.
- Fig. 1 depicts an overall scheme for isolating, freeing, and generating storage/generator vessel assemblies according to an embodiment of the disclosure.
- Fig. 2 represents a more specific scheme also depicting an example storage/generator assembly and the generation of isotopes using the storage/generator vessel assembly according to an embodiment of the disclosure.
- Fig. 3 depicts an example modified triple-column 224 Ra isolation scheme; green cells indicate active flow paths at each step A through E.
- B Secondary wash “b” for C2-C3;
- C Water rinse through C3 to remove H + ions;
- D Ra elution from C3; and
- Fig. 4 is a depiction of Step A: Initial 3-column load of 228 Th stock + wash “a”.
- Fig. 5 depicts gamma spectra obtained following triple-column load/wash routine (see path A in Fig. 4).
- the 228 Th/progeny sample is loaded (A) and washed (B) through all three columns using 6 M FINO3; no activity is observed to break through the three-column stack.
- the AnlXpoiy (defined below in Table 1 ) media (C1 ) shows 228 Th, 212 Bi, and 208 TI adsorbed on the resin beads.
- Fig. 6 depicts gamma spectrum showing a prominent 224 Ra emission in a fraction collected immediately downstream of C2 during the wash “a” sequence. Traces of 212 Bi / 208 TI (unretained on C2), likely generated by the 212 Pb adsorbed on C2, are likewise observed.
- Fig. 7 depicts Step B: C2 + C3 wash “b”.
- Fig. 8 depicts (A) Resin capacity factors ( k ') for Group II divalent cations in nitric acid on Sr Resin. (B) Sr Resin effluent fraction elution profiles for unretained 212 Bi and slightly retained 224 Ra in 2 M HNO3.
- Fig. 9 depicts gamma spectra obtained following double-column load/wash routine (see path B in Fig. 7).
- A The 212 Pb and 224 Ra are washed through C2/C3 using 2 M HNO3; no activity is observed to break through the two-column stack, as 212 Pb is retained on the Sr Resin column (C2) and 224 Ra is retained on the Ra-01 Resin column (C3).
- B Spectrum taken of the Sr Resin column (C2) at the conclusion of the wash “b” step shows pure 212 Pb.
- Fig. 10 is Step C: C3 water rinse.
- Fig. 11 depicts (A) Elution of residual 212 Pb from the 224 Ra-loaded C3 using water. (B) Decay rate of the water wash fractions indicated little to no 224 Ra loss during the water wash step.
- Fig. 12 is Step D: C3 elution of isolated 224 Ra.
- Fig. 13 depicts (A) Assembled radiochromatogram of 224 Ra elute fractions. (B) Monitoring the isolated 224 Ra fraction activity over the theoretical decay rate as a function of time shows that it is radionuclidically pure.
- Fig. 14 is Step E: C1 elution of 228 Th stock with HCI.
- Fig. 15 is (A) Elution of 228 Th, 212 Bi, and 208 TI from the AnlXpoiy (defined below in Table 1 ) resin M1 using 8 M HCI. (B) Spectrum of the AnlXpoiy (defined below in Table 1 ) resin M1 following the HCI elution cycle indicates incomplete 228 Th elution.
- Fig. 16 is fluidic layout schematic of automated triple-column based 224 Ra purification system according to an embodiment of the disclosure.
- Fig. 17 depicts (A) stepper motor driven syringe pump for 228 Th stock solution loading operations. (B) Solenoid-based fluid routing system to drive the triple-column 224 Ra isolation procedure according to embodiments of the disclosure.
- Fig. 18 is gamma spectra of 228 Th elution chromatogram (A) using 1 M HCI on MP-1 M resin (M1 ). 228 Th elution chromatogram (B) using 8 M HCI on same. Dashed line at 10 ml_ indicates the beginning of an applied strip solution of EDTA to remove any residual 228 Th from the column.
- Fig. 19 depicts (A) Load and wash “a” fractions collected from 1 cc TEVA resin effluents in 6 M HNO3. Arrow indicates the location of the absent 228 Th X-ray. 212 Pb, 212 Bi and 208 TI photon peaks are observed to break through the media (the 224 Ra emission is hidden under the 212 Pb peak at ⁇ 240 keV). (B) Analysis of the TEVA resin effluents over time indicate a decay rate consistent with that of 224 Ra; this indicates that 228 Th was well adsorbed on the media during the load/wash “a” steps.
- Fig. 20 depicts gamma spectra of 228 Th elution chromatogram (A) using 1 M HCI on TEVA resin (M1 ). 228 Th elution chromatogram (B) using 8 M HCI on same. Dashed line at 10 ml_ indicates the beginning of an applied strip solution of EDTA.
- Fig. 21 depicts (A) 228 Th activity fractions as a function of 1 M HCI elution volume from TEVA resins of different column internal volumes. (B) Cumulative 228 Th activity yield for same.
- Fig. 22 depicts observed activity decay rate of TEVA resin load fraction (combined loads) for a 1 cc (A) vs. 0.25 cc (B) vessel volume. Dashed line is the theoretical decay rate for 224 Ra. Positive deviation from the 224 Ra curve indicates the presence of 228 Th as TEVA resin column breakthrough.
- Fig. 23 depicts observed activity decay rate of TEVA cartridge 228 Th load fraction for a 2 cc (A), a 1 cc (B), 0.4 cc HML (halfmilliliter) (C) , and 0.2 cc QML (quarter milliliter) cartridge (D).
- Black and grey dashed lines are the theoretical decay rate curves for 224 Ra and 228 Th, respectively. Positive deviation from the 224 Ra curve indicates the presence of 228 Th.
- Fig. 24 depicts observed activity decay rate of TEVA column 228 Th load fraction for a 1 cc hand-packed TEVA resin solid phase extraction (SPE) tube column.
- SPE solid phase extraction
- Fig. 25 depicts cumulative 228 Th activity fractions as a function of 1 M HCI elution volume from machine-packed TEVA resin cartridges of decreasing internal resin volume.
- Cartridge are (A) 2 cc, (B) 1 cc, (C) HML, and (D) QML.
- Fig. 26 is HML (0.41 cc) and QML (0.25 cc) cartridges that were evaluated for 212 Pb removal in the C2 position.
- Fig. 27 is gamma spectra of 228 Th/ 224 Ra solution effluent fractions from C1 + C2 during the load + wash “a” steps in 6 M HNO3.
- Fig. 27C depicts metals speciation comparison i) Pb/Pb-EDTA; ii) Bi/Bi-EDTA; iii) Th/Th-EDTA; and iv) Ra/Ra-EDTA along the same pH spectrum.
- Fig. 27 D i and ii depicts separation of 224 Ra from 212 Bi and 212 Pb using Ra-01 resin column (3 x 50 mm) via protocol listed in Table 6B. Column effluent fraction categories are designated at top. Legend is elapsed days between column run and gamma analysis of fractions. (Right) Select elapsed time series indicates radionuclides present across the separation protocol.
- Fig. 28 depicts (A) load + wash “a” effluent fractions from a 0.25 cc Ra-01 resin showing the elution of 228 Th (arrow), some 212 Pb, and 212 Bi/ 208 TI . (B) effluent fractions from wash “b” showing no observable 228 Th X-rays (arrow). 212 Bi/ 208 TI are observed to wash from the media.
- Fig. 29 is Load / wash “a” column effluent fractions showing 224 Ra elution profile through C1 + C2, wherein C2 is a (A) HML cartridge or a (B) QML cartridge packed with Sr Resin.
- Fig. 30 depicts water wash fractions from the C3 step 3 that was inserted before the 224 Ra elution step.
- Fig. 31 depicts observed activity decay rate of the primary 224 Ra elution fraction from a Ra-01 resin column (C3) loaded with a 228 Th/ 224 Ra solution. Dashed line is the theoretical 224 Ra decay rate.
- Fig. 32 is a speciation diagram for Ra(ll) and Ra(ll)/EDTA complex in 0.05 M EDTA across a range of pH.
- Fig. 33 is a schematic showing the process for loading the 224 Ra from the triple-column method onto a CatlX-based generator column.
- the acidified 224 Ra 2+ solution may then be incorporated into a storage/generator vessel assembly.
- Fig. 34 depicts data acquired upon loading the HCI-acidified, EDTA-dissociated 224 Ra 2+ product onto a strong cation exchange media.
- 224 Ra load fraction (A) and wash fractions (B) plotted vs. elapsed time. Legend indicates the collected fractions (1 mL each) of wash solution delivered through the vessel containing the media. The decay rates indicate that all 224 Ra can be adsorbed onto the media during load/wash steps.
- C Direct counts of the 224 Ra-loaded cation exchange media vs. elapsed time indicates the decay rate of 224 Ra beyond the ⁇ 1.6 day period wherein progeny equilibrium first occurs.
- Fig. 35 is a schematic of a system for producing free isotope according to an embodiment of the disclosure.
- Fig. 36 is a schematic of a system for producing free isotope according to another embodiment of the disclosure, a) 24 Ra bound element elution line from element isolation system; b) acid dispensing line; c) activated charcoal 220 Rn trap; d) 5 mL RezorianTM column w/ Spin plus® PTFE stir bar & hydrophobic Polyethylene (PE) frit; e) three way stopcock valve; f) servo motor (SvM); g) rinse vessel for line; h) vertical magnetic stirrer; i) inverted digital syringe pump (SP) w/ 8 port distribution valve; j) 0.45 pm polyethersulfone (PES) filter; and k) 224 Ra collection vessel.
- PE polyethylene
- Fig. 37 is an image of a portion of the system of Fig. 36 configured as an EDTA precipitation / filtration device, a) activated charcoal 220 Rn trap; b) acid dispensing line from inverted digital SP; c) 5 ml_ RezorianTM column; d) Spinplus® PTFE stir bar; e) hydrophobic PE frit; f) assembled servo motor with attached servo horn (SvM); g) vertical magnetic stirrer; h) three-way stopcock valve; i) 3D printed device mount; and j) line out to inverted digital SP.
- Fig. 38 is an image of pre acidified 224 Ra-EDTA (a), acidified & agitated 224 Ra-EDTA (b), and post acidified & agitated 224 Ra-EDTA solution (c).
- Fig. 39 is an image of a sequence of configurations of a system for producing free isotope according to an embodiment of the disclosure, (a) acidified & agitated 224 Ra-EDTA solution mixing, precipitation, and filtration vessel; (b) 224 Ra collection vessel; (c) filtered EDTA precipitate; (d) free 224 Ra solution; (e) line rinsate reservoir; and (f) in-line membrane filter.
- Fig. 40 is an overall schematic for preparing a storage/generation vessel assembly according to an embodiment of the disclosure.
- Fig. 41 is a system for producing a metal storage/generation vessel assembly according to an embodiment of the disclosure.
- Syringe pump w/ 8-port distribution valve SP
- 4-port and 6-port selector valves V4 or V6)
- AGC assembled generator column
- holding coil to 4-port and 6-port valves HC/V4 or HC/V6)
- excess supernatant coil ESC
- transport line TL
- large mixing vessel LMV
- small mixing vessel SMV
- 3 stopcock manifold servo motor block (SVMB) with three servo motors (SVM1 , SVM2, and SVM3); solenoid-controlled isolation valves (SCIV1 and SCIV2); and N2 gas regulators (R1 and
- Fig. 42 is an image of a system for producing a metal storage/generation vessel assembly according to another embodiment of the disclosure. Labels are identified in Fig. 41 .
- Fig. 43 is an image of a mixing vessel of the system of Figs. 41 and 42 according to an embodiment of the disclosure (LMV) using N2 gas agitation for mixing.
- Five milliliters of settled resin bed in 20 mL deionized water (Dl) can be seen in the vial.
- Figs. 44A and 44B are images a mixing vessel and stirrers of the system of Figs. 41 and 42 according to another embodiment of the disclosure (LMV), using the Multi-Stirrus mixer.
- Fig. 45 is an image of another mixing vessel of the system of Figs. 41 and 42 according to an embodiment of the disclosure (SMV).
- Fig. 46 is an image of a multiport manifold (SM) assembly for use with the systems of Figs. 41 and 42.
- SM multiport manifold
- Fig. 47 is a schematic of a series of manifold configurations for use with the systems of Fig. 41 and 42 according to an embodiment of the disclosure.
- Fig. 48 depict images of a resin slurry in a mixing vessel of the system of Figs. 41 and 42 (LMV) unagitated (A) and agitated (B) with a 2 PSI N2 gas sparge.
- Fig. 49 depicts images of a resin slurry in another mixing vessel of the system of Figs. 41 and 42 (SMV) unagitated (A) and agitated (B) with a 3 PSI N2 gas sparge.
- Fig. 50 is an image of a resin slurry in a mixing vessel of the system of Figs. 41 and 42 (LMV) being homogenously mixed using vane #1 at a Multi-Stirrus mixer setting of 60 RPM.
- Fig. 51 is an image of a resin slurry in a mixing vessel of the system of Figs. 41 and 42 (LMV) being undermixed (A), mixed homogenously (B), and overmixed (C).
- Fig. 52 depicts color contour maps of calculated (left) and empirically determined (right) dry resin masses dispensed as a function of varying flow rates and aspirated volumes. Legend is dry AG MP-50 resin mass (g) delivered.
- Fig. 53 is a schematic of stages of storage/generator vessel assembly preparation according to an embodiment of the disclosure.
- Fig. 54 is an image of a storage/generator vessel assembly according to an embodiment of the disclosure.
- Fig. 55 is an image of a storage/generator vessel assembly according to another embodiment of the disclosure.
- Fig. 56A-56B depict the Thorium -228 decay chain image (56A) and Radium-224 decay and progeny ingrowth curves (56B) over a 1 day interval.
- Fig. 57 depicts a series of a replicate storage/generator vessel assemblies prepared according to embodiments of the disclosure.
- Fig. 58 is a schematic of a system that includes both free isotope preparation and storage/generator vessel assembly preparation according to an embodiment of the disclosure.
- Fig. 59 depicts individual (o) and cumulative ( ⁇ ) 212 Pb fraction recovery relative to the sum eluted activity as a function of 2 M HCI volume loaded onto the 224 Ra generator column data.
- Fig. 60 depicts data indicating some metal ( 224 Ra) breakthrough (BT) from a single storage/generator vessel assembly as a function of ten sequential 212 Pb milking cycles. Each milking cycle was 1 .0 ml_ 2 M HCI followed by 1 .0 mL deionized water (Dl).
- Fig. 61 depicts images of 224 Ra/ 212 Pb storage/generator vessel assemblies and supplemental catch bed cartridges according to embodiments of the disclosure.
- Fig. 62A depicts incremental breakthrough of 224 Ra from different storage/generator vessel assembly configurations across ⁇ 20 mL of 2 M HCI 212 Pb eluent.
- Fig. 62B depicts cumulative 224 Ra breakthrough for the assemblies of 61 B. In this panel, the sacrificial first milking has been omitted from the cumulative plots.
- Fig. 63A depicts fractional 212 Pb elution profiles using 2 M HCI for the four storage/generator vessel assemblies.
- Fig. 63B depicts cumulative 212 Pb activity fraction yields for the assemblies of Fig. 60A.
- FIG. 1 an overall scheme 2 for producing storage and/or generator vessel assemblies is shown that can begin with an element isolation system/module 3 and continue to a free element producing system/module 4 then continue to a generator vessel producing system/module 5.
- Implementations of these systems/modules can be used in the above order given or in different combinations to facilitate desired means.
- single systems/modules can be used or they can be used as combinations of pairs of systems/modules.
- Specific implementations, as directed in Fig. 1 can utilize system/module 3 in combination with system/module 5 without utilizing system/module 4, for example.
- embodiments of the disclosure provide techniques that can be used remotely or hands-free, as well as automated, to allow for the safe and efficient production and transfer of valuable elements such as radioisotopes, for example.
- element isolation system/module 3 can generate an element from another element within a vessel and then isolates same via systems/methods of the present disclosure. As depicted in Fig. 1 , this isolated element can be provided to system/module 4 or system/module 5. Referring to Fig. 2, an example overview of element isolation is shown in the context of Th and Th-progeny. In accordance with the systems and methods of the present disclosure, Ra can be isolated from a mixture of Th and Ra.
- an element upon element isolation as described herein, for example, an element can be produced that is complexed or bound to another material.
- Ra can be isolated as a complex of EDTA.
- System/module 4 can provide a free element, for example a free Ra. In accordance with Fig. 1 , this free element can be provided to system/module 5.
- System/module 5 can be configured to prepare a storage/generator vessel assembly.
- System/module 5 can receive isolated element from system/module 3 or free element from system/module 4.
- free Ra can be provided to system/module 5 and a storage/generator vessel assembly 6 can be prepared that generates Pb and/or Bi.
- the vessel can be configured for the storage of the element and the generation of element-progeny on demand.
- the 224 Ra can be isolated from 228 Th and then provided as a storage/generation vessel assembly 6 as shown.
- this storage/generation vessel assembly 6 can be “milked,” taking advantage of radioisotope decay to produce lead and/or bismuth isotopes as detailed herein as a 224 Ra/ 212 Pb/ 212 Bi generator column.
- the scope of this disclosure is not limited to Th and Th-progeny.
- Additional elements that can be processed/provided using one or more of the systems/modules of the present disclosure can include, but are not limited to: "Mo/ 99m Tc; 1 13 Sn/ 1 13m ln; 44 Ti/ 44 Sc; 52 Fe/ 52m Mn; 68 Ge/ 68 Ga; 72 Se/ 72 As; 1 18 Te/ 1 18 Sb; 82 Sr/ 82 Rb; 134 Ce/ 134 La; 140 Nd/ 140 Pr; 90 Sr/ 90 Y; 188 W/ 188 Re; 166 Dy/ 166 Ho; 194 0s/ 194 lr; 226 Ra/ 222 Rn; 225 Ac/ 213 Bi; 83 Rb/ 83m Kr; 1 13 Sn/ 1 13m ln;
- the generator vessel assemblies can include elements and element progeny, system/module 3 can be configured to isolate element progeny from element/element progeny mixtures, for example.
- the disclosure will define columns by the media present in the columns. This is to be considered media within vessels. Therefore, when an element is retained or bound to a column, it is recognized that the element is bound or retained to media within the column/vessel.
- chelating agents are described as ligands which bind a metal with more than one coordination site, for example, EDTA.
- Organic compounds that coordinate metal ions into circular structures (chelate circles) are considered chelating reagents.
- Most chelating reagents include oxygen, nitrogen, or sulfur atoms in their molecules.
- Chelate structures with five or six member rings form the most stable chelate circle.
- chelating agents possess an organic backbone with functional groups to coordinate to the metal. These functional groups include but are not limited to phosphonates, phosphinates, phosphines, sulfonates, carboxylates, imines, and amines.
- EDTA Ethylenediamine tetraacetic acid
- Phosphonic acid-based chelates may be used as well.
- the entirety or portions of the above can be performed hands-free, automated, and/or remotely, in that users can be separated from potentially toxic or harmful elemental compounds including isotopes through the use of mechanical direction modules.
- the systems and methods of the present disclosure can be performed with mechanical servos and/or pumps including syringe pumps that can be operated and operatively coupled to computer processing circuitry that can be operable to control the pumps, servos, and valves in a predetermined manner or remotely via a computer interface, for example.
- An additional step or procedure that can be accomplished after production of free element can be a system or method for producing a storage/generator vessel assembly as shown in Fig. 1.
- the present disclosure provides systems and methods for the separation of materials that can be used for the acquisition of targets for alpha radiation when performing targeted radioimmunotherapy applications.
- the 212 Pb/ 212 Bi isotope pair shows good promise.
- the parent isotope, 224 Ra must be periodically isolated from 228 Th via radiochemical separation.
- the purified 224 Ra can then be used to prepare 224 Ra / 212 Pb/ 212 Bi generators.
- the present disclosure provides a 224 Ra purification method that can be safer and more efficient than existing prior art methods resulting in reduced personnel dose, reduced labor cost, and reduced preparation time; and may be fully, but at least partially, automated using laboratory fluidics.
- the present disclosure provides systems and/or methods for separating Ra from a mixture comprising at least Ra, Pb, Bi, and Th.
- These vessels can house media.
- C1 can house media M1
- C2 can house media M2
- C3 can house media M3.
- One or all three of these vessels can be in fluid communication via conduits for example.
- Each of the conduits can be controlled via a valve or valves for example.
- a mixture (Th/Ra+ (“+” subsequent progeny can be present) in FINO3) that can provide Ra, Pb, Bi, and Th, can be exposed to vessels C1 -C3 and thereby M1 -M3.
- Each of the Media can be different from one another.
- the media can be (in fluidic introduction order, and as shown in Table 1 ) AnlX-M1 (AG MP-1 M, Bio-Rad, or TEVA resin, Eichrom); 18-crown-6 ether in a 1 -octanol diluent-M2 (Sr Resin, Eichrom); M3 (Ra-01 resin, IBC Advanced Technologies).
- AnlX-M1 AG MP-1 M, Bio-Rad, or TEVA resin, Eichrom
- 18-crown-6 ether in a 1 -octanol diluent-M2 (Sr Resin, Eichrom); M3 (Ra-01 resin, IBC Advanced Technologies).
- HNO3 strong HNO3
- concentrations as low as 0.5 to 1 M or even 2M HNO3 can be utilized as well
- a 3-column wash strong HNO3 can be delivered, and Th + Bi is partially retained in C1 ; Pb retains in C2; Ra retains in C3 (the system configuration of which is shown in Fig. 4 as (A).
- systems of the present disclosure can include a first vessel housing a first media and either Pb or Bi and/or Th (C1 or C2); and a second vessel in fluid communication with the first vessel, the second vessel housing a second media and Ra (C3), wherein the first media is different from the second media.
- systems of the present disclosure can include a first vessel housing a first media and Th and/or Bi (C1 ); and a second vessel in fluid communication with the first vessel, the second vessel housing a second media and Pb (C2), wherein the first media is different from the second media.
- Embodiments of the present disclosure can also include systems having a first vessel housing a first media and Th or Bi (C1 ); a second vessel in fluid communication with the first vessel, the second vessel housing a second media and Pb (C2); and a third vessel in fluid communication with the second vessel, the third vessel housing a third media and Ra (C3), wherein at least one of the first, second, or third medias are different from the other medias.
- a first vessel housing a first media and Th or Bi (C1 ); a second vessel in fluid communication with the first vessel, the second vessel housing a second media and Pb (C2); and a third vessel in fluid communication with the second vessel, the third vessel housing a third media and Ra (C3), wherein at least one of the first, second, or third medias are different from the other medias.
- Methods are also provided that can include providing a mixture having Ra, Pb, Bi, and/or Th; providing the described system having vessel (C1 ) housing the media (M1 ), and vessel (C2 or C3) in fluid communication with vessel (C1 ), with vessel (C2 or C3) housing media (M2 or M3); exposing the mixture to media (M1 ) within vessel (C1 ) to separate the Th and Bi from the Ra and Pb; then, through the fluid communication, exposing the remaining mixture to media (M2 or M3) in vessel (C2 or C3) to associate the Pb or Ra with the M2 or M3 media.
- Th (with Bi) of C1 can be eluted from M1 in strong HCI for dry-down and storage for re-use as desired.
- vessel (C3) can be in fluid communication with vessel (C2), and vessel (C3) can house a media (M3).
- the methods can include exposing the mixture to media (M1 ) within the vessel (C1 ) then, through the fluid communication, exposing the first remainder (that which passes through C1 or is washed through C1 ) to media (M2) in vessel (C2), then, through fluid communication, exposing the next remainder (that which passes through C2 or is washed through C2) to media (M3) in vessel (C3), the exposing separating the Th and Bi from the Ra and Pb, and the Ra from the Pb to sequester the Th and Bi in one vessel, the Pb in another vessel, and the Ra in still another vessel.
- M3 can then be washed with water to remove H + /excess Pb in configuration C.
- Ra can be eluted from M3 (to which it was associated) with dilute EDTA solution (pH adjusted to >7), or a chelating solution with a bonding constant that is higher than that of the M3 resin in C3.
- the Ra is EDTA bound -100% at a pH of -6, and is -50% EDTA bound at pH -5.3. Accordingly, methods of the present disclosure provide for separating Ra from being associated with a media by exposing the Ra and media to a chelating agent to form a mixture comprising the Ra complexed with the chelating agent.
- the Ra/EDTA product solution is not compatible with loading onto a CatlX-based generator column. Adding enough HCI to the Ra/EDTA solution to drop the pH below -2 (Per Fig. 32, Ra is freed from EDTA at pH -4. By pH -2, the EDTA is rendered insoluble and precipitates out, leaving Ra in supernate) can decouple or disassociate the Ra from the EDTA (thereby producing free Ra 2+ ions in solution). The weakly acidified Ra 2+ solution can then be adsorbed onto the CatlX-based generator column.
- the systems and methods of the present disclosure can provide isolated and free a 224 Ra product that can be loaded onto the CatlX generator column.
- Embodiments of the disclosure can be performed without boil-down or acid transposition steps.
- the purified Ra (without 2 12 Pb and 212 Bi progeny) can be handled in a low-dose state for several hours. This can allow for packing the generator column, removing the column from containment, and packing it for shipping before the dosage becomes an issue.
- the present disclosure also provides fluidic systems to perform the methods. This can provide a fluidic platform.
- Table 1 Commercial resins evaluated for the triple-column process to isolate 224 Ra from 228 Th. a.
- Functional group Quaternary amine on macroporous polystyrene divinylbenzene copolymer.
- Functional group Aliquat 336, an organic quaternary amine salt on Amberchrom CG-71 (“Pre-Filter”) polymer support.
- Functional group 18-crown-6 and 1-octanol on Amberchrom CG-71 polymer support.
- Functional group Proprietary; presumed to be a 21-crown-7 (in part) on silica support.
- the prepared 228 Th/progeny stock solution (in 6 M HNO3) can be passed through three columns, each fluidically interlinked.
- the 6 M HNO3 concentration can provide high affinity of Th on the AnIX media (1 ) and high affinity of Pb on the Sr media (M2).
- Th and Bi/TI daughters
- M1 the AnIX media
- Pb the AnIX media
- M2 the Sr media
- Ra the Ra is adsorbed on M3.
- wash “a” comprising 6 M HNO3. This can provide for complete fluid transport of the load solution through the three tandem columns.
- Step A process efficacy is demonstrated by gamma spectra in Fig. 5.
- M1 was an AnlXpoiy. Solutions can be delivered to the three columns at 1 mL/min. The 228 Th/progeny load (A) and initial “wash a” solution (B) triple-column effluent fractions can be collected in test tubes and counted by gamma spectrometer. It was observed that no activity was present from the fractions that has passed through all three columns during the load and wash “a” steps; all activity was adsorbed onto the columns.
- a direct gamma count of the C1 immediately after the completion of the load/wash “a” steps shows the presence of 228 Th, 212 Bi, and 208 TI (Fig. 5 (C)).
- No 212 Pb or 224 Ra gamma peaks are observed on M1 , as these radionuclides have been adsorbed onto M2 and M3, respectively.
- M2 The role of M2 is to adsorb 212 Pb from the 212 Pb / 224 Ra mixture that passes through C1.
- the 18-crown-6 ether extracting agent on the Sr Resin has strong affinity for Pb(ll) ions, and low affinity for Ra(ll) ions and Bi(lll) ions in multi-Molar concentrations of HNO3 (see Fig. 7 and Fig. 8). Consequently, 224 Ra can pass through the Sr Resin and thereby collect onto M3. Any 212 Bi / 208 TI generated by 212 Pb on the M2 is unretained and will pass out of C2 along with 224 Ra to C3. As the 212 Bi / 208 TI is likewise unretained on M3, it will pass to waste while 224 Ra is being loaded.
- Step B C1 can be disconnected from the chain of vessels and remain static until the end of the method, when the adsorbed 228 Th is recovered via a separate elution step as Step E.
- Step E By disconnecting, the fluid communication is simply blocked off, but the conduit associating C1 and C2 can remain.
- Wash “b”, comprising 2 M HNO3, can be passed through C2 and C3 to assure quantitative transfer of Ra from C2 to C3.
- the Pb is strongly bound onto M2 and remains there.
- 2 M HNO3 can be used in this step because it provides the high level of affinity of Pb on the Sr Resin.
- the Ra has a low level of affinity for the Sr Resin (M2) at 2 M HNO3 ⁇ k‘ ⁇ 2, Fig. 8). This is evident by the slight retardation of Ra during the load / wash “b” step shown in Fig. 8 (B). Flere, the 212 Bi trace represents an unretained ion (k' of ⁇ 0.4) passing through the vessel ahead of the 224 Ra passage. Because of this slight Ra / resin affinity, wash “b” can require a volume of ⁇ 10 ml_ to assure complete Ra passage through the Sr Resin column.
- Fig. 9 (A) The wash “b” process data is demonstrated in Fig. 9 (A).
- the C2/C3 effluent fractions show no indication of 212 Pb or 224 Ra breakthrough from the columns.
- Fig. 9 (B) demonstrates that a pure 212 Pb spectrum is observed on the Sr Resin column (C2).
- step C C2 can be disconnected from C3, as M3 now contains the isolated 224 Ra fraction. Again, the disconnection does not remove the conduit connecting vessels C2 and C3, it simply prohibits fluid flow through the conduit. Water can be flushed through the C3 in order to remove the HNO3 from the system. Ra remains strongly bound to M3 during the water flush as Ra affinity for Ra-01 resin generally increases as HNO3 concentration drops. Additionally, the water wash through C3 can result in removal of 212 Pb that may reside on the column. This 212 Pb could be from C2 breakthrough or freshly ingrown 212 Pb produced by the MS- bound 224 Ra. A series of five 1 ml_ water effluent fractions were collected and analyzed by gamma spectroscopy.
- Fig. 11 (A) The removal of 212 Pb from C3 during the water wash is shown in Fig. 11 (A).
- Fig. 11 (B) The rate of activity loss was in agreement with the 212 Pb decay factor (Fig. 11 (B)). This indicates that no 224 Ra was co-eluted with 212 Pb during the water wash.
- Step D the 224 Ra on M3 was eluted using 5 mL of 0.05 M EDTA that had been adjusted to pH 11 using NaOFI. Column effluent fractions were collected, and gamma spectrometry was performed. The resulting radiochromatogram is shown in Fig. 13 (A). In this 224 Ra elution, four milliliters contained the vast majority of the 224 Ra activity (it is hypothesized that higher concentrations of EDTA, or a stronger chelating agent, or a smaller column volume, would result in sharper 224Ra elution peaks.).
- Fig. 13 (B) shows that the rate of activity diminishment of the C3 elution product tracks with the theoretical 224 Ra rate of decay across several orders of magnitude. Importantly, the decay rate data indicates that no 228 Th is present in the 224 Ra product fraction, at least down to -0.1 % of the original activity fraction.
- methods for separating Ra from Pb, Bi, and Th can include separating one or more of Bi and/or Th from the Ra.
- the separating can associate Th and/or some of the Bi with a media (M1 ).
- the method can further include disassociating the Bi and/or Th from the media (M1 ) to form a mixture comprising the Bi and Th and transferring the mixture to a vessel housing at least Ra and additional Bi and/or Th.
- this vessel can be considered a “cow” that through decay generates additional Ra which can be used to initiate step A.
- the Th can be eluted and keep separate from the polymer-based AnIX resin of C1.
- Th was eluted from the AnlXpoiy media (M1 ) using 5 ml_ 8 M HCI.
- Th can be eluted from 1 M to 12M). About 8M will be sufficient if the concentration is sufficient to elute the Bi and/or Th.
- Fig. 15 (A) shows the resulting spectra from these Th elute fractions. The first and second elutions showed most of the recovered Th. Additionally, it was observed that 212 Bi and 208 TI were co-eluted with 228 Th, primarily in the first elute fraction. Complete 228 Th recovery from the AnlXpoiy media (M1 ) was not possible in a 5 mL delivery of 8 M HCI.
- fluidic systems capable of performing the methods of the present disclosure in a fully automated fashion are provided.
- the fluidic system architecture is presented as a schematic in Fig. 16.
- the system was designed with an eye towards operation remotely or in a shielded facility.
- Two digital syringe pumps (SP1 , SP2) are responsible for reagent delivery to the vessels (C1 , C2, and C3); these pumps can be located outside of the shielded zone to eliminate chances of radiolytic or chemical degradation.
- a third syringe pump (SP3).
- This pump can include a stepper motor and a disposable plastic syringe, for example.
- a role of SP3 is to withdraw the 228 Th “cow” solution (the first mixture, for example) into the sample injection loop indicated at the top of Fig. 16 and in Fig.17 (B) (upper left of image).
- the digital syringe pumps located outside of the shielded zone can access the cow solution in the loop and direct it through the columns.
- stepper motor can drive the syringe pump from voltage signals originating outside the shielded zone, and the stepper motor has no integrated circuits within it, the chances of radiolytic degradation of this component is small.
- two of these stepper motors can be irradiated using a 208 R/hr 137 Cs source within a hot cell. The motors received a total dose of -33,700 R over the course of 6.75 days. After removal of the motors from the hot cell, each was tested for functionality; both remained functional.
- the fluids can be routed through a multitude of pathways using Teflon FEP tubing for example and solenoid-actuated valves that feature fluoropolymer wetted surfaces for example (Fig. 18 (B)).
- solenoids are electromagnetically actuated by voltages applied from outside the shielded zone, the potential for radiation-based component failure are low.
- the fluidic system can be routinely utilized in a radiological fume hood (or in a glove box or shielded location using multi-mCi levels of 228Th/224Ra) using 228 Th/ 224 Ra spiked solutions.
- TEVA resin is an extraction chromatographic resin loaded with Aliquat 336, an organic quaternary ammonium salt.
- the load / wash “a” / elute performance of 228 Th on 1 cc TEVA resin columns was evaluated. Load / wash “a” was again performed using 6 M HNO3, and elution was performed at 1 M and 8 M HCI.
- HCI eluents are provided in Table 4. From this table, it can be concluded that the optimal 228 Th elution recovery is obtained from a TEVA resin column, using 1 M HCI as the eluting solution.
- TEVA resin and MP-1 M can have a roughly equivalent ability to adsorb 228 Th from a load solution in a 6 M HNO3 matrix.
- 8 M HCI provides better (but incomplete) 228 Th elution from MP- 1 M relative to 1 M HCI.
- TEVA resin can provide improved 228 Th elution profiles relative to MP-1 M in both 1 M and 8 M HCI.
- 228 Th elution profiles from TEVA resin are better in 1 M HCI vs. 8 M HCI.
- Other column geometries and volumes may be utilized as well.
- Fig. 21 (A) where the 2 28 Th elution profile is plotted (fractions were aged 32 days to allow 2 28 Th progeny ingrowth). The smaller-volume column resulted in earlier
- a 1 cc and 0.25 cc TEVA resin provided roughly equivalent 228 Th elution yields after a 3 mL elution volume in 1 M HCI (Fig. 21 ).
- the 1 cc TEVA resin retained a greater fraction of 228 Th during the load / wash “a” step than the 0.25 cc column volume, as some 228 Th breakthrough was observed (Fig. 22).
- the 1 cc TEVA resin therefore provides a higher purity 224 Ra fraction passing into the remaining fluidic system.
- the measured column load fraction activity values can begin to deviate from the theoretical 224 Ra decay curve at progressively earlier elapsed times as the cartridge bed volume decreases. These observed decay curve deviations can be related to increasing levels of 228 Th in the 224 Ra-bearing column load fractions.
- the 228 Th decay profile can be fitted atop the data points that lay beyond 40 elapsed days. Extrapolation of the curve to the y-intercept provided an estimate of the 228 Th activity fraction present in the 224 Ra-bearing column load effluents. It is observed that the calculated 228 Th activity fraction increases as the TEVA cartridge volume decreases (Fig. 23, grey dashed lines also show this). These calculated 228 Th activity fractions are presented in Table 6A.
- the second cartridge / column performance evaluation was to assess the quality of the 228 Th elution profile.
- the 228 Th was eluted with 10 ml_ of 1 M HCI, delivered at 1 mL/min. Approximately 1 ml_ fractions were collected. The cumulative 228 Th fraction yields are shown for the four TEVA resin cartridge types in Fig. 25 and the TEVA resin in SPE tube column in Fig. 24 (B).
- the 228 Th elution profiles are consistent with the anticipated peak broadening associated with increasing TEVA resin bed volumes. However, even for the largest (2 mL ) TEVA cartridge, the 228 Th recovery was virtually complete after the third fraction.
- the 228 Th cumulative yield for the 1 cc SPE tube is shown in Fig. 24 (B); its yield is likewise virtually complete after 3 mL of eluent.
- the 228 Th elution yields, calculated from the sum of all load / wash / elute fractions, is shown in Table 6A. 228 Th elution yields between 94% and 98% were observed, and this spread is within experimental uncertainty.
- the machine-packed / commercially available TEVA cartridges exhibited 228 Th breakthrough levels that increased with decreasing cartridge bed volume.
- the hand-packed 1 cc SPE tube provided the least degree of 228 Th breakthrough vs. the cartridges.
- the TEVA SPE vessel and cartridges exhibited nearly complete 228 Th elutions after 3 mL of 1 M HCI eluent had been delivered at 1 mL/min.
- Overall, the hand-packed 1 cc SPE TEVA column provided a higher-purity 224 Ra fraction relative to the machine-packed TEVA cartridges.
- the 18-crown-6 ether extracting agent on the Sr Resin column has strong affinity for Pb(ll) ions, and low affinity for Ra(ll) ions and Bi(lll) ions in HNO3. Consequently, 224 Ra is able to pass through the Sr Resin column be collected onto C3, Ra-01 resin).
- the 212 Bi and 208 TI, which passed with 224 Ra through the C2, are likewise unretained on Col. 3, so this dose-causing radionuclide pair is sent to waste while 224 Ra is being loaded.
- the 212 Pb removal by C2, and the transference to waste of 212 Bi / 208 TI following C3 can reduce the radiological dose imparted by 224 Ra progeny.
- the HML (0.41 cc) and QML (0.25 cc) cartridges both from Eichrom, as shown in Fig. 26 may be used for M2.
- the Sr Resinbearing cartridges were loaded into the triple-column system in the C2 slot, and the C1 slot was configured with 1 cc TEVA resin columns. No C3 was installed. Flow rate was 1 mL/min. C1 ⁇ C2 effluent fractions of ⁇ 1 mL each were collected during the column load + wash “a” steps, wherein the load solution was 228 Th in secular equilibrium with 224 RA and its progeny.
- 228 Th/ 224 Ra can be provided as a solution directly through C3, and C3 effluent fractions collected throughout the process.
- C2 can be removed from the triple-column method. Without the presence of C2, both Pb and Ra emerging from the AnIX column may bind onto a Ra-01 column, and Ra separated therefrom. Pb can be selectively removed from the column using a chelator such as EDTA that is adjusted to a pH below the point where Ra(ll)/EDTA complex forms.
- a chelator such as EDTA that is adjusted to a pH below the point where Ra(ll)/EDTA complex forms.
- Ra is not complexed to EDTA below a pH of ⁇ 4.
- Pb(ll) is fully complexed with EDTA above a pH of around 2, with a 50% complexation at a pH around 1.3.
- a solution of EDTA with a pH 3.5 can be provided through the column, which selectively complexed 212 Pb and eluted it from the column while leaving 224 Ra on the column (Pb/EDTA complex is retained at a much lower pH, so at pH 3.5, Pb/EDTA complex is 100% speciated).
- a solution of EDTA with a pH 11 (or a pH greater than ⁇ 6) can be provided to the C3 to remove the Pb-free 224 Ra.
- Fig. 27C depicts metals speciation comparison i) Pb/Pb-EDTA; ii) Bi/Bi-EDTA; iii) Th/Th-EDTA; and iv) Ra/Ra-EDTA along the same pH spectrum.
- Fig. 27 D i and ii depicts separation of 224 Ra from 212 Bi and 212 Pb using Ra-01 resin column (3 x 50 mm) via protocol listed in Table 12.
- Column effluent fraction categories are designated at top. Legend is elapsed days between column run and gamma analysis of fractions. (Right) Select elapsed time series indicates radionuclides present across the separation protocol.
- a water wash can be placed between wash “b” and the 224 Ra elution step.
- the water would be used to remove residual H + ions from the column prior to the introduction of the pH ⁇ 11 224 Ra eluent solution.
- the wash “a” volume is sufficient to assure passage of 224 Ra through C1 and onto C2/C3 (Step A), and the wash “b” volume is sufficient to assure passage of 224 Ra through C2 and onto C3 (Step B).
- the load / wash “a” volumes shown in Fig. 29 are therefore more than adequate to accomplish the Step A objective.
- Fig. 30 (A) The impact of the water wash through the Ra-01 resin is shown in Fig. 30 (A). 212 Pb (retained on the Ra-01 column due to the lack of C2 upstream in this experiment) is removed from the vessel in water. An evaluation of the decay rate of these column effluent fractions indicated that 224 Ra was not present (Fig. 30 (B)). Therefore, indications were that the water wash could be employed to eliminate excess H + ions (preventing EDTA precipitation) and further remove 212 Pb from the Ra-01 resin (thus reducing 224 Ra product dose) without impacting 224 Ra elution yield. Following the water wash, the Ra-01 resin contained isolated 224 Ra. The 224 Ra was eluted using the EDTA solution, and the eluent fraction’s decay rate was monitored to evaluate its radionuclidic purity.
- the 224 Ra source is loaded onto a CatlX resin column (using AG MP-50 resin beads). Therefore, the Ra output from the triple-column method should be amenable to direct loading onto CatlX resin.
- the purified Ra product delivered in dilute EDTA solution (pH adjusted to > 7), will not bind to CatlX resin as a free divalent cation; according to the speciation plots for Ra/EDTA mixtures (Fig. 32), Ra is completely bound to EDTA above pH 7.
- the chelated complex likely progresses from [Ra(EDTA)] ' to [Ra(EDTA)] 2- as the pH increases above 7.
- the Ra/EDTA complex is -50%, and at pH values ⁇ 4, the Ra 2+ cation is completely dissociated from the EDTA complex.
- the system/methods can include providing a mixing vessel in fluid communication with both a bound element source and an acid source.
- the mixing vessel can be operably configured to mix contents within the mixing vessel.
- the systems can include a first multiport valve operably engaged with an exit of the mixing vessel, and a second multiport valve operably engaged with the first multiport valve, the acid source, and a collection vessel.
- element can be Ra, however, as described above, other elements can be processed using these systems and/or methods.
- Methods for producing free element from a bound element are also provided.
- the methods can include: providing a solution comprising an element bound to a complex; exposing the solution to a precipitating solution to precipitate the complex binding the element and produce a free element solution; and transferring the free element solution to a collection vessel.
- the systems/methods can include separating the Ra from a solution comprising Ra and Th to form the solution comprising Ra bound to EDTA.
- the solution of the Ra bound to the EDTA has a pH greater than 11
- the free element solution can include Ra and has a pH less than 4 or even less than 2.
- lowering the 224 Ra/EDTA product solution pH to ⁇ 4 will result in free Ra 2+ cation in solution.
- the schematic shown in Fig. 33 provides a pathway for preparing and binding free Ra 2+ onto a generator column packed with AG MP-50 CatlX resin.
- One milliliter of the isolated 224 Ra product (5 mL) resulting from the triple-column separation can be acidified using 21.7 mI_ of concentrated HCI (0.26 mmoles H + added).
- the acidified solution can be delivered to a MP-50 resin at 0.5 mL/min.
- the data in Fig. 36 (a) shows the activity observed in the column load effluent fraction as a function of elapsed days.
- Fig. 34 indicate that acidification of the isolated 224 Ra product fraction from the triple-column method can provide for quantitative loading of the 224 Ra onto a CatlX media. Accordingly, the triple-column method appears to be well suited to the subsequent 224 Ra/ 212 Pb generator column preparation via a solution acidification step.
- Fig. 35 at least one schematic depiction of the preparation of the free isotope ( 224 Ra 2+ ) is shown.
- the chemical modification chamber or mixing vessel can receive the bound isotope ( 224 Ra/EDTA) eluent directly from the triple-column method (Step D of Fig. 12 above) for example.
- acid can be injected to reduce the solution pH to a point in which the Ra/EDTA complex is eliminated or uncoupled, thereby producing free isotopes ( 224 Ra 2+ ) ions in solution (per Fig. 32).
- a stir bar can be used for mixing of acid into the 224 Ra eluent. If the solution is acidified to ⁇ pH 2, not only does the 224 Ra 2+ dissociate from the Ra/EDTA complex, but the EDTA precipitates from the solution. Once the EDTA precipitate is fully formed, the supernate can be withdrawn from the base of the chemical modification chamber or mixing vessel, through a hydrophobic polyethylene frit for example, thereby removing the precipitated EDTA crystals from the 224 Ra 2+ solution.
- system 100 is shown in Fig. 36.
- system 100 can include a mixing vessel 110 that is in fluid communication with both a bound isotope source 112 and an acid source 114.
- the bound isotope source can be a source as described herein with reference to the separation of elemental Ra from thorium, for example.
- the acid source 114 can be a syringe pump that can be mechanically controlled, for example.
- Mixing vessel 110 can be configured to mix contents therein utilizing, for example, a magnetic mixer such as magnetic mixer 116 that is placed lateral or underneath or about in an operable configuration of mixing vessel 110 that contains magnetic stirrer 130.
- System 100 can also include first and second multiport valves with first multiport valve 118 being operably connected to the exit 124 of mixing vessel 110 and a second multiport valve 120 that can be operably connected to first multiport valve 118 as well as the acid source 114 and a collection vessel 126.
- the element being freed can be Ra such as 224 Ra.
- the element can be freed from a complexing agent such as a chelating agent.
- Example chelating agents can include but are not limited to EDTA.
- the first and second multiport valves can be configured to be operated remotely, and this system can be coupled in tandem with a Ra production system such as that described earlier for isolating Ra from Th.
- mixing vessel 110 can be a 5 ml_ RezorianTM column (Supelco, Bellefonte, PA) fitted with a hydrophobic polyethylene (PE) frit 135 (Scientific Commodities Inc., Lake Havasu City, AZ), a PTFE Spinplus® magnetic stir bar 130 (SP Scienceware, Wayne, NJ), a one-way stopcock valve 118 (Cole-Parmer, Vernon Hills, IL), a 0.45 pm PES filter 131 (Pall, Port Washington, NY), a 12 mL disposable polypropylene syringe 114 (Thermo Fischer Scientific, Waltham, MA), and a “Mu Iti-Sti rrus” magnetic vertical mixer 116 (V&P Scientific, San Diego, CA).
- PE polyethylene
- the 5 mL RezorianTM tube can receive an aliquoted volume of 224 Ra-EDTA solution from the triplecolumn system’s column 3 (C3) 224 Ra elution.
- An inlayed hydrophobic frit positioned at the base of the Rezorian tube) and connected oneway stopcock valve (set to “closed”) were utilized to prevent the 224 Ra- bearing solution from leaking through the bottom port.
- An aliquot of mineral acid can be added the 224 Ra / EDTA solution in the Rezorian tube to lower the pH, thus forming insoluble EDTA that precipitated out of solution.
- the vertical magnetic mixer can be used to create a magnetic field, driving the magnetic stir bar to mix the acid/Ra/EDTA solution and enhance precipitation rate.
- the stopcock valve can be opened and the EDTA- removed 224 Ra supernate can be withdrawn from the Rezorian tube through the hydrophobic frit and into the syringe barrel.
- An additional syringe filter can be added to the line between the syringe barrel and the 224Ra collection vessel to remove any fine EDTA particulates that may have passed through the larger-pored hydrophobic frit.
- FIG. 36 A schematic of the automated in-line EDTA precipitation and filtration system is shown in Figure 36.
- the automated version of the precipitation and filtration system can employ an inverted digital syringe pump 114 (SP, 48,000 steps, IMI Norgren, Littleton, CO) with 8-port distribution valve 120, a three-way stopcock 118 (Cole-Parmer, Vernon Hills, IL) which can be controlled by servo motor (SvM, Dsservo, Dongguan, Guangdong, China), a “Mu Iti-Sti rrus” vertical magnetic spinning device 116, and a 0.45 ⁇ m PES filter connected to a 224Ra collection vessel.
- Port assignments, flow direction, and port designation for the SP are listed in Table 8. Each component in the system is described below in more detail. Operation of the SP, the vertical magnetic mixer, and SvM can be controlled via processing circuitry through a software.
- the processing circuitry can include personal computing system that includes a computer processing unit that can include one or more microprocessors, one or more support circuits, circuits that include power supplies, clocks, input/output interfaces, circuitry, and the like. Generally, all computer processing units described herein can be of the same general type.
- the computing system can include a memory that can include random access memory, read only memory, removable disc memory, flash memory, and various combinations of these types of memory.
- the memory can be referred to as a main memory and be part of a cache memory or buffer memory.
- the memory can store various software packages and components such as an operating system.
- the computing system may also include a web server that can be of any type of computing device adapted to distribute data and process data requests.
- the web server can be configured to execute system application software such as the reminder schedule software, databases, electronic mail, and the like.
- the memory of the web server can include system application interfaces for interacting with users and one or more third party applications.
- Computer systems of the present disclosure can be standalone or work in combination with other servers and other computer systems that can be utilized, for example, with larger corporate systems such as financial institutions, insurance providers, and/or software support providers.
- the system is not limited to a specific operating system but may be adapted to run on multiple operating systems such as, for example, Linux and/or Microsoft Windows.
- the computing system can be coupled to a server and this server can be located on the same site as computer system or at a remote location, for example.
- these processes may be utilized in connection with the processing circuitry described.
- the processes may use software and/or hardware of the following combinations or types.
- the circuitry may use Java, Python, PHP, .NET, Ruby, Javascript, or Dart, for example.
- Some other types of servers that the systems may use include Apache/PHP, .NET, Ruby, NodeJS, Java, and/or Python.
- Databases that may be utilized are Oracle, MySQL, SQL, NoSQL, or SQLLite (for Mobile).
- Communications between the server and client may be utilized using TCP/UDP Socket based connections, for example, as Third Party data network services that may be used include GSM, LTE, HSPA, UMTS, CDMA, WiMax, WiFi, Cable, and DSL.
- Third Party data network services that may be used include GSM, LTE, HSPA, UMTS, CDMA, WiMax, WiFi, Cable, and DSL.
- the hardware platforms that may be utilized within processing circuitry include embedded systems such as (Raspberry Pl/Arduino), (Android, iOS, Windows Mobile) - phones and/or tablets, or any embedded system using these operating systems, i.e., cars, watches, glasses, headphones, augmented reality wear etc., or desktops/laptops/hybrids (Mac, Windows, Linux).
- the architectures that may be utilized for software and hardware interfaces include x86 (including x86-64), or ARM.
- servos for engaging single or multiport valves as well as mechanical or electric switches for engaging valves can be configured according to software and/or hardware to engage/disengage upon achieving and endpoint such as a temperature, a time, a pressure, a volume, etc. Accordingly, much of the systems and methods of the present disclosure can be performed remotely from a processing circuitry interface and/or automatically according to a program.
- the system can be plumbed with 0.02” or 0.03” or 0.04” ID by 1/16” OD fluorinated ethylene propylene (FEP) tubing (IDEX Health & Science, Oak Harbor, WA) connected to polyether ether ketone
- FEP fluorinated ethylene propylene
- PEEK 1 ⁇ 4-28 flangeless nuts with Tefzel® ferrules (IDEX Health & Science, Oak Harbor, WA) or PEEK 10-32 nuts with PEEK conical ferrules (Valeo).
- the automated in-line precipitation and filtration system can utilize the same precipitation vessel described herein with the addition of a teflon cap fitted with tubing lines and an activated charcoal trap to filter 220 Rn emanation from the air space above the 224 Ra-bearing solution.
- the 224 Ra-EDTA solution can be dispensed from the triple column purification system through one of these tubing lines, while the other was used to dispense mineral acid into the 224 Ra-bearing eluent.
- EDTA precipitation rate was enhanced by the use of the vertical magnetic stirrer.
- the three-way stopcock valve with three ports can connect the holding vessel to the digital syringe pump, and to add a rinse vessel line that was used to clear the line of residual 224 Ra-bearing liquid.
- the stopcock valve can be connected to a servo motor (SvM) which is operable between each port.
- SvM servo motor
- the inverted syringe pump with 8-port distribution valve was utilized to aspirate the supernate before dispensing it through the 0.45 pm filter and into the 2 24 Ra collection vessel as shown in Fig. 36.
- a custom holder can be provided to hold the precipitation vessel, servo motor, and vertical mixer in proximity.
- the component bracket was designed with Solidworks2017 (Dassault Systems, Waltham, MA) and 3D printed on a uPrint SE Plus (Stratasys, Eden Prairie, MN).
- FIG. 38 an image of a pre acidified 224 Ra-EDTA solution (a), precipitation forming solution (b), and post precipitation solution (c) is shown.
- the precipitation vessel can be configured from a 5 ml_ Rezorian tube kit with an inlayed 20 pm pore size hydrophobic polyethylene frit at the base, and a Teflon-coated magnetic stir bar. Under magnetic mixing, the acid added to the 224 Ra-EDTA solution reduces the pH , thus causing EDTA to precipitate out of solution while leaving 224 Ra 2+ in the supernate.
- step 1 the servo motor actuated the three-way stopcock valve to 90° and the 224 Ra supernate was aspirated into the inverted syringe pump at a flow rate of 10 mL/min. During this process, the vast majority of the solid EDTA is captured by the frit.
- step 2 the supernate in the syringe was dispensed through a 0.45 pm syringe filter and into the 224 Ra collection vessel (d). The in-line filter was used to remove any small EDTA crystals that may have migrated through the Rezorian tube’s frit.
- step 3 the servo motor actuated the three-way stopcock to 180° to form a singular flow pathway between the rinse vessel, and the SP.
- a 250 pL aliquot of 0.01 M HCI (pH 2) was aspirated through the syringe delivery line and into the SP, carrying any residual 224 Ra-bearing droplets left in the tubing to the syringe.
- the pH 2 rinse solution was dispensed through the 0.45 pm filter and into the 224 Ra collection vessel.
- methods for producing free isotopes can include providing a solution comprising isotope bound to a complex.
- the bound isotope can be in a solution having a pH that is sufficient to bind substantially all of the isotope and/or retain the bound isotope in solution.
- the solution can be adjusted to another pH that decomplexes the isotope from the complex and/or precipitates the complex while leaving substantial amounts of the isotope in solution.
- These example solutions include the Ra bound to EDTA, for example.
- This solution can be exposed to a precipitating solution such as an acidic solution to precipitate the complex binding the isotope and produce a free isotope solution as shown and depicted with reference to the mixing vessels in the previous systems.
- the methods can further include transferring the free isotope solution to a collection vessel.
- the solution of the isotope bound to the complex can have a pH greater than 11.
- the free isotope solution can have a pH less than 2.
- these solutions can be conveyed to and/or from the mixing vessel using pressure differentiation techniques that can include suction or positive displacement, for example.
- the methods can include transferring the free element or Ra through a filter to a vessel.
- Fig. 40 systems and methods are described for producing metal storage/generation vessel assemblies, including particular metals to be stored and/or generated using the vessels. Embodiments of these systems, methods, and assemblies are described with reference to Figs. 40-63B.
- Systems and/or methods for producing a metal storage/generation vessel assemblies are provided.
- the systems can include: a first mixing vessel in fluid communication with a first and a second multiport valve; a manifold of multiport valves in fluid communication with the second multiport valve; a second mixing vessel in fluid communication with at least one of the multiport valves of the manifold; a third multiport valve in fluid communication with an exit of the second mixing vessel; and a metal storage/generation vessel in fluid communication with the third multiport valve.
- the first and second mixing vessels define different volumes.
- the first mixing vessel defines a volume larger than the volume defined by the second mixing vessel.
- Methods for producing a metal storage/generation vessel assembly are also provided.
- the methods can include: homogenizing a resin slurry in a first mixing vessel; supplementing the homogenized resin slurry with a free element to form a homogenized bound element resin slurry; and transferring the homogenized bound element resin slurry to a storage/generation vessel assembly.
- the resin/media of the present disclosure without homogenization will consolidate at the lower portion of the vessel or adhere to other portions of the vessel. Homogenizing herein keeps the resin/media distributed throughout the solution of the vessel. This distribution can be uniform and/or without a heterogenous interface.
- Metal storage/generation vessel assemblies can include: sidewalls extending between entrance and exit openings to define a vessel volume; inert material proximate the exit opening: unbound resin (catch bed) proximate the exit opening wherein the inert material is between the unbound resin and the exit opening; and a homogenized bound element resin bed within the vessel, the inert material and unbound binding resin being between the resin bed and the exit opening.
- an example sequence of events can include homogenizing a resin slurry, metering the resin bed volume to another vessel, and then mixing an element with the slurry mixture, and then transporting the element-loaded slurry to a storage and/or generation assembly 6.
- a system 200 is provided. Within this system are two mixing vessels, a first mixing vessel 210 and a second mixing vessel 212.
- Mixing vessel 210 can be in fluid communication with first and second multiport valves 214 and 216.
- system 200 can further include a manifold of multiport valves 218 which can be in fluid communication with multiport valve 216.
- Mixing vessel 212 can be in fluid communication with at least one of the multiport valves within the manifold 218.
- System 200 can further include a third multiport valve 220 which is in fluid communication with an exit of mixing vessel 212.
- System 200 can additionally include a metal storage generation vessel 6 in fluid communication with multiport valve 220.
- Fig. 42 is a depiction of an implementation of system 200.
- the automated vessel assembly packing system is shown in Fig. 41 and an image of the system in the fume hood is shown in Fig. 42.
- the systems can include a V6 digital syringe pump (SP, 48,000 steps, IMI Norgren, Littleton, CO) with 8-port distribution valve at its head, a 4-port and 6-port Cheminert selector valve (V4 & V6, Valeo, Inc., Flouston, TX), a stopcock manifold (SM, Cole-Parmer, Vernon Hills, IL), three servo motors (SvM, Dsservo, Dongguan, Guangdong, China), several solution holding coils (FIC), two gas regulators (R1/R2) (McMaster-Carr, Los Angeles, CA), and two solenoid-controlled 3-way isolation valves (SCIV, Bio-Chem, Boonton, NJ).
- SP digital syringe pump
- V4 & V6, Valeo, Inc. Flouston, TX
- SM
- Port assignments for the syringe pump (SP), including flow direction, port designation, and tubing dimensions, are listed in Table 9.
- Port assignments for the 4- port valve (V4) and 6-port valve (V6) are listed in Table 10 and Table 11 , respectively. Each component in the system, and their abbreviated terms, will be described in more detail in the sections below. Operation of the SP, V4, V6, SVMB, and SCIVs using processing circuitry.
- the mixing vessels can define different volumes wherein the first mixing vessel can be a larger volume than the second mixing vessel.
- an image of a first mixing vessel configured for N2 agitation for mixing is shown.
- the mixing vessel of Fig. 43 can be considered the first or Large mixing vessel (LMV) and contain a known ratio of CatlX resin to water and is capable of forming a homogeneous suspension of these solid / liquid phases.
- LMVs resin/liquid suspension large mixing vessels
- the first LMV employed N2 gas or air to create a homogeneous resin/water slurry (LMV).
- the vessel was a 50 mL polyethylene centrifuge tube containing a reservoir of MP-50 resin and water at a known solid/liquid volume ratio.
- the LMV had a cap fitted with three holes, through which a N2 gas (inlet) line, a resin slurry aspiration line (outlet), and a N2 gas vent (outlet) port were fixed.
- a stream of N2 gas or air was used to agitate the resin/water mixture in order to obtain a homogeneous slurry while the slurry aspiration line was used to withdraw a metered volume from the LMV.
- An image of the LMV as shown in Fig. 43.
- a first mixing vessel configuration depicts a mixing vessel that can be mechanically stirred, for example.
- FIG. 44A Another LMV was evaluated that defined a 50 mL centrifuge tube and resin/water reservoir configured with a plastic vane placed down its center (Fig. 44A).
- This LMV was in turn positioned onto a base that oscillated in a back-and-forth “washing machine” pattern. The oscillations were driven by a rotating magnetic field using a “Multi- Stirrus” mixer (V&P Scientific, San Diego, CA) that caused angular rotation of the vane, agitating the slurry by turbulent action.
- Two vanes designs of Fig. 44B were evaluated; they were fabricated with holes along the edges, as shown in Fig. 44B.
- the slurry aspiration line was used to withdraw a metered volume from the LMV.
- a second mixing vessel is depicted that is configured for N2 gas or air mixing that includes a gas inlet and outlet, for example.
- This second or small mixing vessel is configured to 1 ) receive the aliquoted volume of MP-50 resin (from the LMV) as a slurry, and 2) contact a 224 Ra-bearing solution with the resin slurry received to obtain a homogeneous distribution of 224 Ra adsorbed to the MP-50 resin.
- the SMV can be defined by a 10 mL polyethylene syringe barrel that was mounted to the V6 valve via a female luer to 1 ⁇ 4 - 28 connector.
- the tube barrel cap custom-machined from Teflon FEP, was fitted with four holes through which a N2 gas or air (inlet) line, a resin slurry dispenser (inlet) line, an excess supernatant coil (ESC) line (inlet/outlet), and a N2 gas or air vent (outlet) port were passed.
- the ESC line with 2.00 ⁇ 0.02 mL inner volume, could be used to aspirate excessive supernatant from the dispensed resin slurry.
- the 224 Ra solution could be introduced into the SMV via the V6 valve; the post-contacted 224 Ra / resin slurry mixture could be aspirated from the SMV via the same valve.
- a stream of N2 gas or air was used to agitate the mixture of resin slurry and 224 Ra solution to affect homogeneous adsorption of 224 Ra onto the resin particles.
- a configuration of the manifold 218 of system 200 is shown that includes the configuration of the multiport valves of the manifold, for example.
- the stopcock manifold (SM) system was constructed from a stack of three 3-way stopcock luer valves (Cole-Parmer). The SM was connected between the V4 and the SMV as a pathway to transport and meter resin for eventual 224 Ra contact in the SMV followed by subsequent column packing.
- a set volume of slurry could be packed and partitioned into a -0.250 mL column bed.
- a custom trimmed high-density polyethylene 5 mL pipette filter (Eppendorf, Hauppauge, New York, USA) was used as a bottom frit to allow water, but no resin, to pass through the bottom port of the SM. A packed bed of resin therefore forms above the frit.
- SM stopcock manifold system
- FIG. 47 A schematic of the SM resin bed metering and partitioning sequence is shown in Figure 47.
- Each of the stopcocks within the manifold can be operably engaged with a servo block motor.
- Fig. 47 again for moving the slurry between the prep slurry and the generator vessel and/or mixing the slurry with elements is shown with manifold configurations as shown in Fig. 47.
- agitation of the slurry is shown with reference to Figs. 48-52 that depicts unagitated and agitated slurry in the first mixing vessel, for example.
- the first method of resin suspension we evaluated employed a stream of N2 gas or air controlled via gas regulator to agitate gravity-settled resin bed causing dispersion of resin beads within the water volume until uniform.
- LMVg gas-agitated LMV
- the regulator was opened at increasing increments of 0.5 pounds per square inch (PSI) followed by 5 minutes of observation to determine if the entire gravity settled resin bed was suspended and became homogenous (i.e., demonstrated no stratification of resin beads with liquid depth). This process was repeated until mixing became overly vigorous. A minimum and maximum PSI was noted for the LMVg and SMV. Images of these vessels in an unagitated and homogeneously agitated state are shown in Fig. 48 (LMVg) and Fig.
- the second method employed a magnetically rotating base (Multi-Stirrus mixer, V&P Scientific, San Diego, CA) to induce an oscillating angular rotation of the LMV.
- the spin vane- agitated assembly was termed “LMVv”.
- Angular rotation of the system was increased at increments of 10 revolutions per minute (RPM) followed by 5 minutes of observation to determine if the entire gravity settled resin bed was suspended and became homogenous. This process was repeated until 100 RPM (the maximum) was reached. A minimum and maximum RPM was noted for each of two vane designs evaluated.
- An image of the LMVv being mixed using vane #1 is shown in Fig. 50.
- a method for forming homogeneous resin suspensions in water was evaluated using N2 gas or air agitation.
- An optimal gas regulator pressure range which provides proportional gas flow rates, was determined to affect good resin suspension formation. Below this range, a partial suspension (a heterogeneous resin suspension) was formed (Fig. 51 (A)). Within this range, a homogenous suspension was formed (Fig. 51 (B)). Beyond this range, resin slurry could be lost or ejected from the LMV (Large Mixing Vessel (gas-agitated resin / water mixture for resin delivery into system) or SMV (Small Mixing Vessel for 224 Ra adsorption onto suspended resin mixture) due to overly vigorous agitation (Fig. 51 (C)). Use of excessive gas flow also enhanced the water evaporation rate, thus eventually altering the resin concentration in the suspension.
- LMV Large Mixing Vessel
- SMV Small Mixing Vessel for 224 Ra adsorption onto suspended resin mixture
- Contour maps of the calculated and empirical data display a similar mass distribution, with a consistent increase in delivered resin mass relative to increasing aspirated volume.
- empirically determined dried resin masses showed a trend of reduced bias as a function of aspirated volume increase for a given flow rate from 0.5 to 3 mL .
- Minimal loss of resin mass per unit volume was observed (less than 7.5%) for aspirated volumes of at least 1 mL for each flow rate.
- a mass of 0.087 grams is needed to pack a 0.250 cm 3 resin bed, based on the determined dry resin density; therefore, aspirated volumes ⁇ 1 mL would not provide sufficient resin mass at any flow rate.
- the aspirated volume of resin slurry was reduced to 1.85 mL (0.161 grams), based on the 0.25 cm 3 inner volume of the SM. This delivered slurry volume will allow an observable slight resin excess without unnecessary overfilling of the SM.
- FIG. 53 an example progression for the preparation of a storage/generator vessel assembly is shown with component label descriptions of the generator column in Table 14.
- the open column body was enclosed with a barbed polycarbonate reducer (314B) connected by silicone tubing (312B) to a female luer-lok / barbed tube coupler (326).
- a barbed polycarbonate reducer (314B) connected by silicone tubing (312B) to a female luer-lok / barbed tube coupler (326).
- the bed of uniformly distributed 224 Ra-sorbed resin (324) was dispensed as a slurry through the inlet tubing (326, 312B, and 314B) and into the column body, packing the column bed.
- a one-way check valve (328) was used to connect the inlet / outlet silicone tubing lines (312A and 312B) by their luer-lok fittings (310 & 326).
- the column body 300 was enclosed within a polyethylene vial prior to column bed packing so as to remove the risk of contamination, and reduce hand dose caused by the previous process (plugging the top with wool, and enclosing the column after the bed was delivered).
- the one-way check valve was installed to provide back pressure, thus preventing the uniform resin bed from deforming during transport.
- this system is configured to be hands-free, as well as remotely and/or operable automatically.
- methods for producing a metal storage generation vessel can include homogenizing a resin slurry in a first mixing vessel, then supplementing the homogenized resin slurry with a metal to form a homogenized bound metal resin slurry and transferring the homogenized bound metal resin slurry to a storage generation vessel.
- these methods can provide for the stable transfer and distribution of these elements into storage and/or generation vessels.
- the storage and generation vessel can include a “catch bed” 320 that includes an unbound or element free resin portion that is proximate the exit of the vessel.
- This resin portion can be above a frit or porous material 318 to alleviate the transfer of resin out of the storage vessel.
- Another frit 322 placed atop the catch bed 320 allows separation of the catch bed 320 from the 224 Ra-sorbed resin bed 324.
- Vessel 6 can have a metal free catch bed 320 that is below a metal and resin distributed bed 324.
- eluent solution can be provided to the intake conduit, and the metal generated can be provided through the eluted out conduit.
- this eluted out conduit can be a decay product of the element or isotope present or provided to the storage and generation vessel.
- Fig. 55 a more detailed view of an implementation of a storage generation vessel is shown with a more detailed description of the dimensions and materials.
- a decay chain image is provided demonstrated the Pb production from an Ra storage/generator vessel assembly according to an embodiment of the disclosure.
- FIG. 57 an example series of storage and generation vessels prepared by the described apparatus are shown. This series was used to evaluate the reproducibility of resin bed deliveries.
- the generator column preparation and packing process time should be minimized to the extent possible, so as to minimize 224 Ra progeny ingrowth. Based on an elapsed time of up to 15 minutes, less than 0.1 % per min of 212 Pb, and 0.01 % per min of 212 Bi, 208 TI, and 212 Po would grow in relative to the initial 224 Ra activity. Minimization of 224 Ra progeny ingrowth during the execution of the column packing process is essential to reduce radiological dose from high energy photons (up to 2.6 MeV from 208 TI).
- the process for minimizing the elapsed time of the automated column packing sequence can be broken into four parts: A) maximization of reagent flow rates, B) reduction in tubing path lengths, C) simplification of the sequence code, and D) reduction in software cycling time.
- the generator column packing system was evaluated through extensive testing to ensure a reproducible column bed with less than 5% variability in resin bed volumes. This was essential, as each generator column was preassembled with only enough empty space for the column bed and the subsequent addition of a barbed end fitting placed atop the column bed. This required that the generator column inserted into the fluidic system receive a consistent volume of resin in a uniform configuration above the felt frit 322 and catch bed 320.
- volumetric analysis was used to evaluate the column beds being packed in each generator column. This was performed to ensure uniform column beds were packed without disturbing the catch bed, and to ensure that there was no entrapment of air bubbles within the resin bed. A resin bed containing trapped air bubbles can significantly alter the flow pathway for the mobile phase through the resin, causing an inconsistent 212 Pb elution recovery
- Table 18 Determined column bed volumes from automatically- packed columns. a. Bed volumes were determined using the column inner diameter
- a tandem EDTA precipitation/filtration module and vessel assembly module is depicted and evaluated.
- the automated precipitation / filtration module can be coupled in tandem for the purpose of reducing the number of electronic components and extraneous process time between steps in the process. By coupling the two systems, only one microcontroller and computer was required to operate both systems. Additionally, this enabled both sets of process steps to be incorporated into a single process sequence which minimized the number of lines of code and system idle time.
- a schematic of the tandem two module system excluding components of the column packing system prior to 224 Ra delivery is shown in Fig. 58. Descriptions of each component are shown in Table 19.
- the overall process can be reduced from the total elapsed time of 16.6 minutes to 8.8 minutes by preforming the system preparation (steps 1 to 5) and remediation (steps 14 to 15) before and after the 224 Ra was delivered.
- the elapsed time of the two module sequence steps performed upon 224 Ra delivery increased only 5.0 minutes (from 3.8 to 8.8 minutes).
- Table 20 Elapsed times for the automated in line EDTA precipitation/filtration and column packing sequence. Non-bolded steps were performed before or after 224 Ra delivery. Bolded steps were performed upon 224 Ra delivery from the triple-column module.
- the EDTA precipitation / filtration system and column packing system were successfully incorporated into a tandem in-line system.
- the 224 Ra yield for the precipitation/filtration step (0.872 ⁇ 0.012) was in agreement with previous evaluation (0.867 ⁇ 0.010), and the generator packing yield of 0.982 ⁇ 0.007 was in agreement with the prior evaluation (0.980 ⁇ 0.010).
- Overall, a cumulative 224 Ra yield of 0.856 ⁇ 0.012 was demonstrated.
- the elapsed time of the process was reduced to 8.8 minutes by reorganizing sequence steps, thereby minimizing ingrowth of 224 Ra progeny (dose to user).
- Table 22 Summary of the elapsed process times for the automated three module process to obtain a 224 Ra-packed generator column when starting from a 228 Th stock solution.
- 224 Ra can be isolated, EDTA-purified, resin-loaded, and packed into a generator column assembly reproducibly, with a mean yield of 0.832 ⁇ 0.029 in a process that takes less than 1 hour with only an additional -0.5 hours to set up and remediate the system.
- performance parameters were assessed, which included: 1 ) the 212 Pb elution profile during milking, and 2) 224 Ra breakthrough from the column.
- the storage/generator vessel assembly demonstrated that -55% of the ingrown elutable 212 Pb was recovered within the first 0.5 mL fraction collected, while -95% was recovered within the first 1 mL.
- 1 mL is sufficient to recover the majority of the elutable 212 Pb, while each additional 0.25 mL fraction will only slightly increase the recovery ( ⁇ 1% gain).
- a decrease in 224 Ra breakthrough was observed between the 1 st milking cycle and 2 nd milking cycle, while a steady 224 Ra breakthrough was noted from the 2 nd to 10 th cycle.
- the 1 st milking cycle is typically discarded (as it represents the 1 st milking after the generator column arrives to the end-user facility), since it grows in stable Pb during transport. Excluding this first milking cycle, the system’s breakthrough is -0.14% per elution cycle. Based on these observed results, a careful assessment of the milking process was performed in an attempt to understand and minimize the 224 Ra breakthrough observed from auto- packed generator columns.
- the distribution coefficient ( K d ) for Ba (a close Ra chemical analogue) on macroporous CatlX resin is estimated to be only -300 mL/g in a 212 Pb elution matrix of 2 M HCI.
- the K d for Pb on the same is -5 mL/g. So, 212 Pb elutes from the column with -60- fold less resin affinity relative to that of Ba (Ra).
- the low CatlX resin affinity of Pb is apparent from the sharp elution from the generator column.
- the Ra 2+ ions at the base of the distributed CatlX bed have a ⁇ 50 ⁇ L resin catch bed ( ⁇ 0.4 mm bed height) to prevent them from co-eluting with 212 Pb.
- the volume of this catch bed may be insufficient to assure a high-purity milked 212 Pb product.
- Respective 212 Pb milking profiles for each of the column configurations were evaluated.
- Each column (with or without the supplemental cartridges described in Table 24) received 2 M HCI at a flow rate of 1 .0 mL/min to milk the in-grown 212 Pb.
- Fractions of ⁇ 0.5 mL were collected for each column elution cycle.
- the results are shown in Figs. 63A and 63Bb.
- 212 Pb elution volume between Columns a and b are virtually identical; the presence of the ⁇ 50 ⁇ L catch bed has no observable impact on 212 Pb elution profiles (which is consistent with the low Kd of 212 Pb on MP-50 resin).
- the 212 Pb yields for Columns a and b after a 1 mL elution volume was ⁇ 88%.
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