Defining Processing Times for Accelerator Produced

molecules

Article Deﬁning Processing Times for Accelerator Produced 225Ac and Other Isotopes from Proton Irradiated Thorium

Jonathan Fitzsimmons 1,* , Justin Griswold 2 , Dmitri Medvedev 1, Cathy S. Cutler 1 and Leonard Mausner 1 1 Isotope Production Laboratory, Collider-Accelerator Division, Brookhaven National Laboratory, Upton, NY 11973, USA; [email protected] (D.M.); [email protected] (C.S.C.); [email protected] (L.M.) 2 Isotope and Fuel Cycle Technology Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA; [email protected] * Correspondence: jﬁ[email protected]; Tel.: +1-631-344-4453

Received: 20 February 2019; Accepted: 18 March 2019; Published: 20 March 2019

Abstract: During the purification of radioisotopes, decay periods or time dependent purification steps may be required to achieve a certain level of radiopurity in the final product. Actinum-225 (Ac-225), Silver-111 (Ag-111), Astatine-211 (At-211), Ruthenium-105 (Ru-105), and Rhodium-105 (Rh-105) are produced in a high energy proton irradiated thorium target. Experimentally measured cross sections, along with MCNP6-generated cross sections, were used to determine the quantities of Ac-225, Ag-111, At-211, Ru-105, Rh-105, and other co-produced radioactive impurities produced in a proton irradiated thorium target at Brookhaven Linac Isotope Producer (BLIP). Ac-225 and Ag-111 can be produced with high radiopurity by the proton irradiation of a thorium target at BLIP.

Keywords: Isotope production; Actinium-225; Silver-111; MCNPX; Thorium; proton irradiation; ﬁssion products; Sr-82; critical process parameter

1. Introduction Typically, it is best to commence isotope purification as soon as possible after the End of Bombardment (EOB), to minimize losses due to decay. However, in some cases a cooling-off period is introduced to maximize the decay of shorter-lived radioimpurities and achieve the desired radionuclidic purity. To achieve the desired product quality, the United States Food & Drug Administration (FDA) requires that critical process parameters be identified, then monitored or controlled [1]. Both experimental and computational approaches can be used to determine optimal radiopurity, and establish optimal processing and irradiation times for a desired radioisotope. In this manuscript, the production of strontium-82 from a rubidium chloride target is used to illustrate the concept of optimal processing times and critical process parameters. The optimal processing times for Actinum-225 (Ac-225) from a thorium target, and subsequent fission products Silver-111 (Ag-111), Rhodium-105 (Rh-105), Astatine-211 (At-211), and Ruthenium-105 (Ru-105) produced in the thorium target are examined. It should be noted that two independent subcategories of radiopurity are discussed in this manuscript: radioisotopic purity and radionuclidic purity. Radionuclidic purity is defined as the absence of other radionuclides. Radioisotopic purity is defined as the absence of other radioisotopes of the same element [2]. Strontium-82 (Sr-82) is produced by the nuclear reaction Rubidium-85 (Rb-85) (p,4n) Sr-82, and Rb-87 (p,6n) Sr-82, and the isotope is purified using ion exchange chromatography [3–6]. The purified Sr-82 is used in a generator to produce Rb-82 for myocardial imaging [7]. Curie levels of Sr-82 have been produced in 14–21 days proton irradiations with a proton energy between 40–90 MeV. During the

Molecules 2019, 24, 1095; doi:10.3390/molecules24061095 www.mdpi.com/journal/molecules Molecules 2019, 24, 1095 2 of 10

production of Sr-82, other strontium isotopes are coproduced, such as Sr-85 (T1/2= 64.849 days) and Sr-83 (T1/2= 32.41 h), which can impact the radioisotopic purity. Sr-85 decays to a stable Rb-85, which does not contribute to a radiation burden. Sr-83 decays to a radioactive Rb-83, which has a half-life of 86.2 days. The presence of Sr-83 complicates the purification of Sr-82, which is focused mainly on the separation of Sr-82 from stable and radioactive Rb isotopes. If the processing occurs too soon after the End of Bombardment (EOB), the Sr-83 would be present in the Sr-82 product and the Sr-83 would decay to Rb-83, contaminating the injectable Rb-82 product from the generator [7]. To eliminate this problem, it is critical that a separation of Sr-82 from Rb-83 is carried out at least ten days after the EOB. This allows the Sr-83 to decay away and not be present in the purified Sr-82, providing acceptable levels of radioisotopic purity. The United States Department of Energy Isotope Program is producing Ac-225 from a high energy proton-irradiated thorium-232 target. In addition to various isotopes of actinium, the irradiation generates over 400 other isotopes, including fission products and other actinides. Some of the fission products have potential utility for imaging and therapy in nuclear medicine (Table1). The purpose of this paper is to begin to evaluate the optimal processing times for the isotopes listed in Table1, to achieve the highest possible radiopurity.

Table 1. Medical isotopes of interest coproduced during the proton irradiation of Thorium-232 (Th-232). Decay information from National Nuclear Data Center (nndc.bnl.gov).

Isotope T1/2 Emission Application Ref. Ac-225 10.0 d 5.830 MeV α Alpha therapy, Generator for Bi-213 [8,9] Rh-105 35.36 h 567.2 keV β, 318.9 keV γ Radiotherapy [10] Ru-105 4.44 h 1193 keV β, 129 keV γ Generator for Rh-105 [11] Ag-111 7.45 d 1036.8 keV β, 342.13 keV γ Radiotherapy [12] At-211 7.214 h 5.8695 MeV α Alpha therapy [13]

2. Results When possible, yields of relevant isotopes in this study were determined experimentally from previous irradiations, like those described in Griswold et al., 2016 [14]. In some cases, relevant isotopes were unable to be detected via gamma spectroscopy, either due to short half-lives or the absence of high intensity γ rays. MCNP6-generated cross sections were used to determine the radioactivity of relevant isotopes of ruthenium, rhodium, palladium, silver, astatine, and radon, produced during the 192 MeV proton irradiation of Th-232.

2.1. Ac-225 Radiopurity When Ac-225 is produced through a high energy proton bombardment of Th-232, significant quantities of Ac-226 (t1/2 = 29.37 h) and Ac-227 (t1/2 = 21.772 y) are coproduced. For a ten day irradiation of Th-232, at 192 MeV incident proton energy and 150 µA of current, approximately twice as much Ac-226 activity is generated as Ac-225 activity (Table2). Decay from the coproduced Ra-225 (t1/2 = 14.9 d) is included in the yield shown in Table2, and the method for determining the experimental effective cross section is shown elsewhere [14]. The radiopurity of Ac-225 from this process is highly dependent on irradiation time, and on the time from the End of Bombardment to the final actinium purification. As the time from the End of Bombardment to the final actinium purification is increased, the radioisotopic purity of Ac-225 increases due to the faster decay of Ac-226 compared to the decay of Ac-225; reaching a maximum value of 99.3% at about nine days. After nine days, the radioisotopic purity continually decreases, as the Ac-225 activity decreases relative to the longer-lived Ac-227 activity. Figure1 shows the radioisotopic and radionuclidic purity of Ac-225 against time, for a seven day period between the EOB and the final purification. The effect of time between the EOB and the final purification is clearly shown in Figure2. Molecules 2019, 24, 1095 3 of 10

Table 2. Radioactive quantities of actinium isotopes produced in a proton irradiated thorium target Molecules 2018, 23, x 3 of 10 producedMolecules 2018 at the, 23, x Brookhaven Linac Isotope Producer (BLIP). Parameters for calculations:3 of a10 1 g Thorium-232 target (450 mg cm−2); proton irradiation at 192 MeV; 150 µA for ten days. Final separation Table 2. Radioactive quantities of actinium isotopes produced in a proton irradiated thorium target Table 2. Radioactive quantities of actinium isotopes produced in a proton irradiated thorium target is sevenproduced days post at Endthe Brookhaven of Bombardment Linac Isotope (EOB). Producer (BLIP). Parameters for calculations: a 1 g produced at the Brookhaven Linac Isotope Producer (BLIP). Parameters for calculations: a 1 g Thorium-232 target (450 mg cm-2); proton irradiation at 192 MeV; 150 µA for ten days. Final separation Thorium-232 target (450 mg cm-2); proton irradiation at 192 MeV; 150 µA for ten days. Final separation is seven days post End of Bombardment (EOB). Activity (mCi) is seven Nuclidedays post End of BombardmentT1/2 (EOB). EOB Final Separation Activity (mCi) Nuclide T1/2 Activity (mCi) NuclideAc-225 T 10.01/2 dEOB 206.91 Final 127.37 Separation EOB Final Separation Ac-225Ac-226 10.0 29.37 d h206.91 433.01 8.21 127.37 Ac-225 10.0 d 206.91 127.37 Ac-226Ac-227 29.37 21.772 h y433.01 0.42 0.42 8.21 Ac-226 29.37 h 433.01 8.21 Ac-227 21.772 y 0.42 0.42 Ac-227 21.772 y 0.42 0.42

140 100 90 120 80 100 100 Ac-225 Activity 70 60 80 60 Ac-226 Activity 50 60 40

Radioisotopic 40 Purity (%)

Radioisotopic Purity (%) Activity (mCi) Purity 30 Activity (mCi) 40 Purity 30 20 20

10 Radioisotopic/Radionuclidic

10 Radioisotopic/Radionuclidic 0 0 0 102030405060 Time from Separation (d)

Figure 1.FigureExperimentally 1. Experimentally calculated calculated radionuclidic radionuclidic and and radioisotopicradioisotopic purity purity of ofActinum-225 Actinum-225 (Ac-225) (Ac-225) at Figure 1. Experimentally calculated radionuclidic and radioisotopic purity of Actinum-225 (Ac-225) at BLIP. Radioisotopic purity includes only the Ac-225, Ac-226, and Ac-227 activity. Radionuclidic BLIP. Radioisotopicat BLIP. Radioisotopic purity includes purity includes only the only Ac-225, the Ac-225, Ac-226, Ac-226, and and Ac-227 Ac-227 activity. activity. Radionuclidic Radionuclidic purity purity includes the activity of the previously mentioned actinium isotopes and the decay progeny includespurity the activity includes ofthe the activity previously of the previously mentioned mentioned actinium actinium isotopes isotopes and the and decay the decay progeny progeny generated generated by Ac-226 and Ac-227 over time. Irradiation parameters are specified in the caption for by Ac-226generated and Ac-227 by Ac-226 over and time. Ac-227 Irradiation over time. parameters Irradiation areparameters speciﬁed are in specified the caption in the for caption Table for2. Time 0 Table 2. Time 0 is the time corresponding to the end of processing (seven days after EOB). is the timeTable corresponding 2. Time 0 is the totime the corresponding end of processing to the end (seven of processing days after (seven EOB). days after EOB).

100

96 96 7 days 5 days 94 5 days 94 3 days 1 day 92

90 Radioisotopic purity (%) Radioisotopic 90 Radioisotopic purity (%) Radioisotopic 0 102030405060 Time from Separation (d)

Figure 2. Radioisotopic purity of Ac-225 as a function of time from final chemical purification. The four curves depict the various durations between the EOB and the final purification. These values represent the radioisotopic purity of Ac-225, only considering all actinium isotopes (radioisotopic purity from Figure1). Molecules 2018, 23, x 4 of 10

Figure 2. Radioisotopic purity of Ac-225 as a function of time from final chemical purification. The four curves depict the various durations between the EOB and the final purification. These values represent the radioisotopic purity of Ac-225, only considering all actinium isotopes (radioisotopic Molecules 2019, 24, 1095 4 of 10 purity from Figure 1).

2.2. Ag-111 Radiopurity

SignificantSignificant quantities of Ag-111Ag-111 (t(t1/21/2 == 7.45 7.45 d) d) are are also also produced in the high energy protonproton irradiationirradiation ofof thorium.thorium. The total experimental yield of Ag-111 includes the decaydecay ofof shorter-livedshorter-lived fissionfission isobarsisobars suchsuch asas Pd-111Pd-111(t (t1/21/2 = 23.4 min) and Rh-111Rh-111 (t(t1/21/2 == 11 11 s). s). These These isotopes isotopes will will be in the processprocess waste after after Ac Ac separation. separation. As As shown shown in inTable Table 3,3 greater, greater than than 1 Ci 1 Cieach each of Ag-111, of Ag-111, Ag-112, Ag-112, Pd- Pd-112,112, and and Ag-113 Ag-113 are areproduced produced in a in ten a tendays days irradiation irradiation of a of 1 ag 1(450 g (450 mg mg cm cm−2) thorium−2) thorium target, target, at 192 at 192MeV MeV incident incident proton proton energy energy and and 150 150 µAµ Abeam beam current. current. However, However, if if a a decay decay period period is introduced between the EOB and finalfinal Ag purification,purification, the radioisotopicradioisotopic purity of Ag-111 increases from 30% to >99%>99% in seven days, due toto thethe decaydecay ofof thethe short-livedshort-lived AgAg isotopes.isotopes. RadioisotopicRadioisotopic purity is shownshown against time after aa sevenseven daysdays processingprocessing periodperiod post-EOBpost-EOB inin FigureFigure3 3..

TableTable 3.3.Radioactive Radioactive quantities quantities of silverof silver and and palladium palladium isotopes isotopes produced produced in a proton in a irradiatedproton irradiated thorium targetthorium produced target produced at the BLIP. at Parameters the BLIP. Parameters for calculations: for calculations: a 1 g Thorium-232 a 1 g targetThorium-232 (450 mg target cm−2 );(450 proton mg irradiationcm-2); proton at 192irradiation MeV; 150 at µ192A forMeV; 10 days.150 µA Final for separation10 days. Final is seven separation days post-EOB. is seven days post-EOB.

ActivityActivity (mCi) (mCi) Nuclide T1/2 Nuclide T1/2 Final EOBEOB Final Separation Separation Ag-105 41.29 d 0.02 0.02 Ag-110mAg-105 249.7641.29 d d 2.04 a 0.02 2.000.02a Ag-111Ag-110m 7.45249.76 d d 1132.412.04a a 590.412.00a Ag-112Ag-111 3.13 h7.45 d 1407.911132.41a 590.41 4.73 a Pd-112Ag-112 21.04 h3.13 h 1019.221407.91 4.024.73 Ag-113 5.37 h 1239.17 0.00 Pd-112 21.04 h 1019.22 4.02 a Derived from experimentally measured cross sections. Ag-113 5.37 h 1239.17 0.00 a Derived from experimentally measured cross sections.

600 100 Radioisotopic purity 90 500 80 400 70 60 300 50 40 200 30 Activity (mCi) 100 20 10 Activity purity (%) Radioisotopic 0 0 0 102030405060 Time from Separation (d)

Figure 3. MCNP6 and experimentally calculatedcalculated radioisotopic purity of Ag-111. Calculations assume silver puriﬁedpurified fromfrom Ac-225Ac-225 wastewaste streamsstreams andand irradiationirradiation parameters speciﬁedspecified in the caption for TableTable3 3..

2.3. Rh-105 Radionuclidic Purity

Both Rh-105 (t1/2 = 35.36 h) and Ru-105 (t1/2 = 4.44 h) are coproduced in the high energy proton irradiation of thorium. Although Curie quantities of Ru-105 (this includes decay of shorter-lived Molecules 2018, 23, x 5 of 10

2.3. Rh-105 Radionuclidic Purity Molecules 2019, 24, 1095 5 of 10 Both Rh-105 (t1/2 = 35.36 h) and Ru-105 (t1/2 = 4.44 h) are coproduced in the high energy proton irradiation of thorium. Although Curie quantities of Ru-105 (this includes decay of shorter-lived

ﬁssionfissionproducts products Tc-105 Tc-105 (t (t1/21/2 == 7.6 min)min) andand Mo-105Mo-105 (t(t1/21/2 == 35.6 35.6 s)) s)) are are generated as shown in Table4 4,, thethe shortshort half-lifehalf-life limitslimits thethe practicalitypracticality ofof usingusing Ru-105Ru-105 producedproduced throughthrough thisthis methodmethod asas aa Rh-105Rh-105 generator.generator. Using Using the the same same irradiation irradiation parameters parameters as as mentioned mentioned for forother otherisotopes isotopesabove, above,Rh-105 Rh-105with with highhigh radioisotopic radioisotopic purities purities can can be be achieved. achieved. The The radioisotopic radioisotopic purity purity quickly quickly declines declines with with the Rh-105the Rh- half-life,105 half-life, as shown as shown in Figure in Figure4, due 4, in due part in topart the to presence the presence of the of longer-lived the longer-lived Rh-99 Rh-99 and Rh-102. and Rh-102.

TableTable 4. 4.Radioactive Radioactive quantities quantities of of ruthenium, ruthenium, rhodium, rhodium, and and palladium palladium isotopes isotopes produced produced in in a a protonproton irradiatedirradiated thorium thorium target target produced produced at at the the BLIP. BLIP. Parameters Parameters for for calculations: calculations: aa 11 gg Thorium-232Thorium-232 target;target; protonproton irradiation irradiation at at 192 192 MeV; MeV; 150 150µ µAA for for ten ten days. days. Final Final separation separation is is seven seven days days post-EOB. post-EOB.

ActivityActivity (mCi) NuclideNuclide T1/2T1/2 EOBEOB Final Final Separation Separation Ru-97 2.83 d 17.08 3.08 Ru-97 2.83 d 17.08 3.08 Rh-99Rh-99 16.116.1 d d 0.93 0.93 0.69 0.69 Pd-100Pd-100 3.633.63 d d 0.60 0.60 0.16 0.16 Rh-100Rh-100 20.820.8 h h 0.80 0.80 0.21 0.21 Rh-101Rh-101 3.33.3 y y 0.01 0.01 0.01 0.01 Rh-102 207.3 d 0.31 0.31 Ru-103Rh-102 39.247207.3 d d 218.52 0.31 193.11 0.31 a Ru-105Ru-103 4.4439.247 h d 1265.42218.52 193.11 0.00a Rh-105Ru-105 35.364.44 h h 1469.291265.42 0.00 61.31 a Ru-106Rh-105 371.835.36 d h 1469.29 21.08 61.31 20.80 Ru-106a Derived from371.8 experimentally d 21.08 measured cross sections. 20.80a aDerived from experimentally measured cross sections.

70 100 90 60 80 50 70 Radioisotopic purity 40 60 50 30 40

Activity (mCi) 20 30 Activity 20

10 purity (%) Radioisotopic 10 0 0 0246810 Time from Separation (d)

FigureFigure 4. 4.MCNP6 MCNP6 andand experimentallyexperimentally calculatedcalculatedradioisotopic radioisotopic purity purity of of Rh-105. Rh-105. CalculationsCalculations assumeassume rhodiumrhodium puriﬁed purified from from Ac-225 Ac-225 waste waste streams streams and and irradiation irradiation parameters parameters speciﬁedspecified inin thethe caption caption for for TableTable4 .4.

Molecules 2019, 24, 1095 6 of 10 Molecules 2018, 23, x 6 of 10

2.4. At-211 Radiopurity As shown in Table5 5 and and FigureFigure5 ,5, At-211 At-211 is is also also generated generated through through the the high high energy energy proton proton irradiation of thorium. However, However, the seven days processingprocessing period employed for the other nuclides discussed in this paper is not approp appropriateriate for At-211 production duedue toto its 7.21 h half-life. For the sake of discussion, the values generated in Table 5 5 and and displayeddisplayed inin FigureFigure5 5employ employ a a one one day day processing processing period instead of a seven day processing period. Using the same irradiation parameters described for the other nuclides above but employing the one day decaydecay period yields a total At-211 activity of less than 2.52.5 mCi,mCi, andand aa radioisotopic radioisotopic purity purity of of ~85%. ~85%. This This includes includes contributions contributions from from the the decay decay of Rn-211of Rn- (t2111/2 (t=1/2 14.6 = 14.6 h) toh) At-211.to At-211.

Table 5.5. Radioactive quantities of various astatine and ra radondon isotopes produced in a proton irradiated thorium target produced at the BLIP. ParametersParameters forfor calculations:calculations: a 1 gg Thorium-232Thorium-232 target; proton µ irradiation at 192 MeV; 150150 µAA forfor oneone day.day. Activity (mCi) Nuclide T1/2 Activity (mCi) Nuclide T1/2 EOBEOB Final Final Separation Separation At-207At-207 1.811.81 h h 1.09 1.09 0.00 0.00 At-208At-208 1.631.63 h h 1.25 1.25 0.00 0.00 At-209At-209 5.425.42 h h 2.79 2.79 0.13 0.13 At-210 8.1 h 2.76 0.36 Rn-210At-210 2.48.1 h h 2.76 2.67 0.36 0.00 At-211Rn-210 7.2142.4 h h 2.67 6.48 0.00 2.42 Rn-211At-211 14.67.214 h h 6.48 5.60 2.42 1.79 Rn-211 14.6 h 5.60 1.79 4.0 90 Radioisotopic purity 3.5 80 3.0 70 60 2.5 50 2.0 40 1.5 30 Activity (mCi) 1.0 20 Activity 0.5 10 Radioisotopic purity (%) Radioisotopic 0.0 0 0 0.5 1 1.5 2 2.5 3 Time from Separation (d)

Figure 5. MCNP6 and experimentally calculatedcalculated radioisotopic purity of At-211. Calculations assume astatine purified puriﬁed from Ac-225 waste streams and irradiationirradiation parameters specified speciﬁed in the caption for Table5 5..

3. Discussion 3.1. Considerations for the Processing Time for Ac-225 3.1. Considerations for the Processing Time for Ac-225 Ac-225 (t1/2 = 10 d), Ac-226 (t1/2 = 29.37 h), and Ac-227 (t1/2 = 21.772 years) are coproduced Ac-225 (t1/2 = 10 d), Ac-226 (t1/2 = 29.37 h), and Ac-227 (t1/2 = 21.772 years) are coproduced during during a proton irradiation of a Th target. Chromatography cannot separate Ac-226 and Ac-227 a proton irradiation of a Th target. Chromatography cannot separate Ac-226 and Ac-227 from Ac-225, so the optimal processing time becomes a critical parameter to produce the highest radioisotopic purity of Ac-225. Varying the incident proton energy upon the thorium target also impacts this ratio,

Molecules 2019, 24, 1095 7 of 10 from Ac-225, so the optimal processing time becomes a critical parameter to produce the highest radioisotopic purity of Ac-225. Varying the incident proton energy upon the thorium target also impacts this ratio, but at lower incident proton energy the Ac-226/Ac-225 ratio worsens [14]. Note also that longer irradiations improve this ratio, as the Ac-226 production saturates after about five days, while Ac-225 levels continue to increase. The decay chains of Ac-225, Ac-226, and Ac-227 are illustrated in Figure6. The Ac-226 decay chain has two major paths, one through the longer-lived Ra-226 (ε, 17%) and the other through Th-226 (β−, 83%). Due to the difference in half-lives, the ratio of Ac-226 to Ac-225 quickly decreases after the EOB. If actinium purification begins immediately after the EOB, the process could require an additional separation step to separate daughters of Ac-226 from the Ac-225 product, depending on the required radionuclidic purity. As seen in Table2, the shorter half-life and higher cross section result in a higher amount of Ac-226 (433 mCi) produced during the irradiation compared to Ac-225 (207 mCi). Using the irradiation parameters mentioned in the above sections, Ac-225 produced at BLIP achieves 95% radionuclidic purity in three–four days after final actinium purification (Figure1, Figure2 and Table2). Consider a scenario where processing starts shortly after the EOB to remove fission products and bulk thorium, using previously reported methods [15]. In such a case it is important to monitor the radionuclidic purity of the Ac-225 after final actinium purification as Ac-226 and Ac-227 decay daughter products grow in. An additional purification could be carried out after the initial purification, to increase the shelf-life by ensuring that Ac-226 and Ac-227 daughter products are separated. Alternatively, a cooling-off period can be used to reduce Ac-226 activity through decay, but this could result in a substantial amount of Ac-225 also lost to decay. Over time, the Ac-227 to Ac-225 ratio will increase in the purified Ac-225 product and will lead to a decrease in the Ac-225 radioisotopic purity. The end of processing and radiopurity should be evaluated for different beam energies and irradiation times. The DOE Isotope Program is preparing a Drug Master File (DMF) on accelerator produced Ac-225, to support future Ac-225/Bi-213 radiopharmaceutical Investigational New Drug (IND) applications to the FDA.

3.2. Considerations for the Processing Time for Ag-111 Ag-111 obtained from a proton irradiated Th target would contain radioactive impurities of Ag with long half-lives (Ag-105 t1/2 = 41.29 d, Ag-110m t1/2 = 249.76 d) and short half-lives (Ag-112 t1/2 =3.13 h, Ag-113 t1/2 =5.37 h). The radioisotopic purity of Ag-111 is shown in Figure3 and Table3. To reduce impurities, purification should be completed after the EOB (Figure3). Waiting for the decay of the impurities would result in an increase in radioisotopic purity, but also the loss of about half of the Ag-111 produced. Separation of Ag-111 from one of the waste streams of Ac-225 processing could be initiated, but introducing a separation step would be critical to remove ingrown daughters of short-lived Ag isotopes. Purification methods have been developed that could purify the Ag-111 from the Ac-225 waste streams [16]. Long-lived impurities (Ag-105, Ag-110m) could hinder the medical use of Ag-111 purified from Ac-225 waste streams.

3.3. Considerations for the Processing Times for Rh-105, Ru-105, and At-211 Direct purification of Rh-105 from the Ac-225 waste streams would result in >98% radioisotopic purity immediately after rhodium purification and decrease quickly with the half-life of Rh-105, as shown in Figure4. Therefore, dedicated production approaches from the method described above for Rh-105 would result in acceptable radioisotopic purity for a short period. Direct purification of At-211 from the Ac-225 waste streams produced in the high energy proton irradiation of thorium is not practical due to its short half-life. Higher yields have been achieved through other production methods [17]. Molecules 2019, 24, 1095 8 of 10 Molecules 2018, 23, x 8 of 10

FigureFigure 6. 6.Ac-225, Ac-225, Ac-226,Ac-226, and Ac-227 decay decay chains chains [18]. [18 ].

4. Materials4. Materials and and Methods Methods MCNP6MCNP6 was was used used to to calculate calculate thethe theoreticaltheoretical cross sections sections of of the the radionuclides radionuclides not not previously previously detecteddetected in in the the proton proton irradiated irradiated thorium thorium targets.targets. Th Thee conditions conditions used used for for the the radiopurity radiopurity calculations calculations 2 forfor Ac-225 Ac-225 at at BLIP BLIP were: were: target target density density 450450 mg/cmmg/cm2, ,proton proton irradiation irradiation at at192 192 MeV, MeV, 150 150 µAµ Afor for ten ten days,days, seven seven days days shipping/processing shipping/processing time (except for for At-211 At-211 as as outlined outlined above), above), cross cross sections sections for for Ac-225,Ac-225, Ac-226, Ac-226, and and Ac-227 Ac-227 were were published published previouslypreviously [14]. [14]. All All other other experimental experimental cross cross sections sections usedused in in the the calculations calculations described described inin thisthis workwork werewere determined in in aa similar similar method method from from previous previous irradiationsirradiations but but are are currently currently unpublished. unpublished.

5. Conclusions5. Conclusions Ac-225,Ac-225, Ag-111, Ag-111, and and Rh-105 Rh-105 cancan bebe producedproduced at high radionuclidic radionuclidic purity purity levels levels from from a proton a proton irradiatedirradiated thorium thorium target. target. Further Furtherstudies studies maymay need to to be be performed performed to to continue continue to to optimize optimize critical critical parametersparameters such such as as irradiation irradiation and and processing processing time,time, to deliver deliver medical medical radionuclides radionuclides with with the the highest highest puritypurity possible possible from from thorium thorium targets targets irradiated irradiated withwith high energy protons. protons. Author Contributions: Jonathan Fitzsimmons organized, reviewed data and analysis, wrote and edited Authormanuscript Contributions: and figures.J.F. Justin organized, Griswold reviewed performed data MCNP6 and analysis, calculations, wrote prepared and edited figu manuscriptres, edited, and reviewed figures. J.G. performed MCNP6 calculations, prepared figures, edited, and reviewed the manuscript. D.M. reviewed and the manuscript. Dmitri Medvedev reviewed and edited manuscript. Cathy S. Cutler and Leonard Mausner edited manuscript. C.S.C. and L.M. reviewed the manuscript. reviewed the manuscript. Funding: This study was supported by funding provided by the Department of Energy, Office of Nuclear Physics, subprogramAcknowledgments: Isotope Development The authors would and Production like to thank for Ariel Research Brown and for comments Applications: on the Core manuscript. research (ST-50-01-03), and BLIP research (ST-50-01-02). Acknowledgments: The authors would like to thank Ariel Brown for comments on the manuscript.

Molecules 2019, 24, 1095 9 of 10

Conﬂicts of Interest: The authors declare no conﬂict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

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Sample Availability: Accelerator produced Ac-225 is available through the Department of Energy, Ofﬁce of Nuclear Physics, subprogram Isotope Development and Production for Research and Applications and can be ordered from the National Isotope Development center and they can be contacted at: Call: (865) 574-6984, Fax: (865) 574-6986, email: [email protected] or online at: https://www.isotopes.gov/catalog/product.php? element=Actinium&type=rad&rad_product_index=87.

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