Optimization of Cation Exchange for the Separation of Actinium-225 from Radioactive Thorium, Radium-223 and Other Metals.

Actinium-225 (225Ac) can be produced with a linear accelerator by proton irradiation of a thorium (Th) target, but the Th also underdoes fission and produces 400 other radioisotopes. No research exists on optimization of the cation step for the purification. The research herein examines the optimization of the cation exchange step for the purification of 225Ac. The following variables were tested: pH of load solution (1.5-4.6); rinse steps with various concentrations of HCl, HNO3, H2SO4, and combinations of HCl and HNO3; various thorium chelators to block retention; MP50 and AG50 resins; and retention of 20-45 elements with different rinse sequences. The research indicated that HCl removes more isotopes earlier than HNO3, but that some elements, such as barium and radium, could be eluted with ≥2.5 M HNO3. The optimal pH of the load solution was 1.5-2.0, and the optimized rinse sequence was five bed volumes (BV) of 1 M citric acid pH 2.0, 3 BV of water, 3 BV of 2 M HNO3, 6 BV of 2.5 M HNO3 and 20 BV of 6 M HNO3. The sequence recovered >90% of 225Ac with minimal 223Ra and thorium present.

Development of separation technology for the removal of radium-223 from targeted thorium conjugate formulations. Part I: purification of decayed thorium-227 on cation exchange columns.

Targeted thorium conjugates (TTCs) are being explored as a potential future platform for specific tumor targeting pharmaceuticals. In TTCs, the alpha emitting radionuclide thorium-227 (227Th) with a half-life of 18.697 d is labeled to targeting moieties, such as monoclonal antibodies (mAbs). The amount of daughter nuclide radium-223 (223Ra, t1/2 = 11.435 d) will increase during manufacture and distribution, and so a technology for purification is required to assure an acceptable level of 223Ra is administrated to the patient. Since 223Ra is the only progeny of 227Th with a long half-life (days), the progenies of 223Ra will have a very limited stay in the formulation once 223Ra is removed. The focus in this study has, therefore, been on the removal of 223Ra. In this study, the sorption and separation of 223Ra (radium(II)) and 227Th (thorium(IV)) on cation exchange columns has been evaluated as a purification method of decayed 227Th (i.e. prior to radiolabelling of a mAb and formation of TTC). The goal is to minimize the sorption of 227Th and maximize the sorption of 223Ra. Statistical experimental design with formulation and process parameters, including buffered formulations comprising citrate and acetate, at various concentrations and pH, presence of free radical scavenger and chelator, and resin amount have been evaluated for impact on the purification process. The studies have been interpreted by the aid of multivariate data analysis. The correlations between design of experimental variables and sorption are summarized by regression models. The predictive accuracy of radionuclide sorption was given by standard deviation and 95% confidence intervals originating from statistical cross validation. Experimental results and statistical models for citrate-buffered formulations verified reproducible and acceptable sorption levels of 223Ra and 227Th under selected conditions. For acetate-buffered formulations, prediction of 227Th sorption was influenced by complex variable relationships and hence a risk of obtaining irreproducibility. Fine-tuned variable levels showed, however, variable combinations predicting high sorption of 223Ra (>90%) and low sorption of 227Th (<3%) also for the acetate-buffered formulations. The optimal separation conditions should be decided based on tuning the variables levels for 223Ra in the citrate-buffered formulations, while for acetate, the optimal separation should be based on tuning variable levels for 227Th sorption. The ionic strength of the formulation also seemed to affect the radionuclide sorption. Labeling of an antibody-chelator conjugate with purified 227Th (i.e. preparation of TTC) was successful in the selected citrate-buffered formulations tested.

Development of separation technology for the removal of radium-223 from targeted thorium conjugate formulations. Part II: purification of targeted thorium conjugates on cation exchange columns.

Tumor targeting pharmaceuticals will play a crucial role in future pharma pipelines. The targeted thorium conjugate (TTC) therapeutic platform could provide real benefit to patients, whereby targeting moieties like monoclonal antibodies are radiolabelled with the alpha-emitting radionuclide thorium-227 (227Th, t1/2 = 18.7 days). A potential problem could be the accumulation of the long-lived daughter nuclide radium-223 (223Ra, t1/2 = 11.4 days) in the drug product during manufacturing and distribution. Therefore, the level of 223Ra must be standardized before administration to the patient. The focus in this study has been the removal of 223Ra, as the other progenies will have a very limited stay in the formulation. In this study, the purification of TTCs labeled with decayed 227Th has been explored. Columns packed with a strong cation exchange resin have been used to sequester 223Ra. The separation of TTC from 223Ra has been evaluated as influenced by both formulation and process parameters with a design of experiments (DOE) study; including citrate or acetate buffer, pH, buffer concentration, presence or absence of pABA + EDTA, resin amount and sodium chloride concentration. The aim was to achieve a separation with high sorption of 223Ra and accompanying low TTC sorption. The results were analyzed by multivariate analysis. Four regression models of TTC and 223Ra sorption from citrate and acetate buffered formulations were developed. The predictive accuracy of sorption in the four statistical models was given by standard deviations and confidence intervals. The TTC sorption in citrate and acetate buffered formulations was affected by the identical variables and the variation in TTC sorption was comparable for the two models. However, the DOE variables had a significantly stronger impact on the 223Ra sorption in citrate buffered formulations than the 223Ra sorption in acetate buffer. An optimal separation with a TTC sorption below 25% and 223Ra sorption above 90% can be achieved in both citrate and acetate buffered formulations. Stability studies of radiochemical purity (RCP) indicated that the measured 227Th values may be partly due to free 227Th and not TTC, but the results indicate that TTC stability may be controlled by optimizing formulation parameters. Hence, the sorption data and the regression models presented must be reviewed and further explored with regard to what is known about the stability of the TTC in the different buffered formulations.

An efficient chelator for complexation of thorium-227.

We present the synthesis and characterization of a highly efficient thorium chelator, derived from the octadentate hydroxypyridinone class of compounds. The chelator forms extremely stable complexes with fast formation rates in the presence of Th-227 (ambient temperature, 20min). In addition, mouse biodistribution data are provided which indicate rapid hepatobiliary excretion route of the chelator which, together with low bone uptake, supports the stability of the complex in vivo. The carboxylic acid group may be readily activated for conjugation through the ɛ-amino groups of lysine residues in biomolecules such as antibodies. This chelator is a critical component of a new class of Targeted Thorium Conjugates (TTCs) currently under development in the field of oncology.

Development of separation technology for the removal of radium-223 from decayed thorium-227 in drug formulations. Material screening and method development.

Targeted thorium conjugates are currently being investigated as a new class of alpha-radiopharmaceuticals. The natural decay of thorium-227 ((227)Th) results in the ingrowth of radium-223 ((223)Ra). Consideration must, therefore, be given to define acceptable limits of (223)Ra in the drug product at the time of dose administration. By effective sequestration of (223)Ra, we aim to improve the radiochemical purity and extend the effective user window of drug products containing (227)Th. (223)Ra is the first progeny of (227)Th and the only one with a long half-life (days). We have, therefore, focused on the removal of this specific species since the progenies of (223)Ra will have a very limited lifetime in the formulation once (223)Ra is removed. In this study, we investigated a multitude of materials for their ability to reduce the (223)Ra level by: (1) passive diffusion or (2) by cartridge filtration on gravity columns. In addition, we probe the compatibility of these materials in the presence of antibody trastuzumab to assess the level of protein binding and estimate the quenching of radiolysis by binding of radionuclides. A screening matrix of organic and inorganic materials was established, i.e. strontium and calcium alginate gel beads, distearoyl phosphatidylglycerol (DSPG) liposomes, ceramic hydroxyapatite, Zeolite UOP type 4A and cation exchange resins AG50W-X8 and SOURCE 30S. First, passive diffusional uptake of (223)Ra by suspended materials present in the formulation was measured as a decrease in sample radioactivity after separation. Second, selected materials were packed on gravity columns in order to evaluate the efficiency of column separation versus diffusional adsorption. The retention of (223)Ra and (227)Th were characterized by measuring the radioactivity in the eluate and on the columns. Finally, the compatibility between trastuzumab, as a selected model antibody, and suspensions of the binding materials was analyzed during storage of the drug product in the presence of adsorbent. The formation of H2O2 was evaluated to measure the influence of radionuclide binding material on radiolysis in the formulation. All the materials bound (223)Ra by passive diffusional uptake ranging from 31% to 95% with DSPG liposomes demonstrating superiority at 95% efficiency. All materials suitable for assessment by gravity column filtration bound (223)Ra almost quantitatively (∼100%) and with minimal variation (relative standard deviation <1%). The uptake was significantly higher compared to passive diffusional uptake. Alginate gel beads, ceramic hydroxyapatite and SOURCE 30S reduced the antibody concentration in solution to 40-50% while the Zeolite UOP type 4A, AG50W-X8 resin and DSPG liposomes showed ≤10% reduction of antibody concentration. Ceramic hydroxyapatite significantly reduced H2O2 formed by radionuclide initiated radiolysis.

Evaluation of Candidate Theranostics for 227Th/89Zr Paired Radioimmunotherapy of Lymphoma.

227Th is a promising radioisotope for targeted α-particle therapy. It produces 5 α-particles through its decay, with the clinically approved 223Ra as its first daughter. There is an ample supply of 227Th, allowing for clinical use; however, the chemical challenges of chelating this large tetravalent f-block cation are considerable. Using the CD20-targeting antibody ofatumumab, we evaluated chelation of 227Th4+ for α-particle-emitting and radiotheranostic applications. Methods: We compared 4 bifunctional chelators for thorium radiopharmaceutical preparation: S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 2-(4-isothicyanatobenzyl)-1,2,7,10,13-hexaazacyclooctadecane-1,4,7,10,13,16-hexaacetic acid (p-SCN-Bn-HEHA), p-isothiacyanatophenyl-1-hydroxy-2-oxopiperidine-desferrioxamine (DFOcyclo*-p-Phe-NCS), and macrocyclic 1,2-HOPO N-hydroxysuccinimide (L804-NHS). Immunoconstructs were evaluated for yield, purity, and stability in vitro and in vivo. Tumor targeting of the lead 227Th-labeled compound in vivo was performed in CD20-expressing models and compared with a companion 89Zr-labeled PET agent. Results: 227Th-labeled ofatumumab-chelator constructs were synthesized to a radiochemical purity of more than 95%, excepting HEHA. 227Th-HEHA-ofatumumab showed moderate in vitro stability. 227Th-DFOcyclo*-ofatumumab presented excellent 227Th labeling efficiency; however, high liver and spleen uptake was revealed in vivo, indicative of aggregation. 227Th-DOTA-ofatumumab labeled poorly, yielding no more than 5%, with low specific activity (0.08 GBq/g) and modest long-term in vitro stability (<80%). 227Th-L804-ofatumumab coordinated 227Th rapidly and efficiently at high yields, purity, and specific activity (8 GBq/g) and demonstrated extended stability. In vivo tumor targeting confirmed the utility of this chelator, and the diagnostic analog, 89Zr-L804-ofatumumab, showed organ distribution matching that of 227Th to delineate SU-DHL-6 tumors. Conclusion: Commercially available and novel chelators for 227Th showed a range of performances. The L804 chelator can be used with potent radiotheranostic capabilities for 89Zr/227Th quantitative imaging and α-particle therapy.

89Zr-3,2-HOPO-Mesothelin Antibody PET Imaging Reflects Tumor Uptake of Mesothelin-Targeted 227Th-Conjugate Therapy in Mice.

The mesothelin (MSLN)-targeted 227Th conjugate is a novel α-therapy developed to treat MSLN-overexpressing cancers. We radiolabeled the same antibody-chelator conjugate with 89Zr to evaluate whether PET imaging with 89Zr-MSLN matches 227Th-MSLN tumor uptake, biodistribution, and antitumor activity. Methods: Serial PET imaging with protein doses of 4, 20, or 40 µg of 89Zr-MSLN and 89Zr-control was performed up to 168 h after tracer injection in human tumor-bearing nude mice with high (HT29-MSLN) and low (BxPc3) MSLN expression. 89Zr-MSLN and 227Th-MSLN ex vivo tumor uptake and biodistribution were compared at 6 time points in HT29-MSLN and in medium-MSLN-expressing (OVCAR-3) tumor-bearing mice. 89Zr-MSLN PET imaging was performed before 227Th-MSLN treatment in HT29-MSLN and BxPc3 tumor-bearing mice. Results: 89Zr-MSLN PET imaging showed an SUVmean of 2.2 ± 0.5 in HT29-MSLN tumors. Ex vivo tumor uptake was 10.6% ± 2.4% injected dose per gram at 168 h. 89Zr-MSLN tumor uptake was higher than uptake of 89Zr-control (P = 0.0043). 89Zr-MSLN and 227Th-MSLN showed comparable tumor uptake and biodistribution in OVCAR-3 and HT29-MSLN tumor-bearing mice. Pretreatment SUVmean was 2.2 ± 0.2 in HT29-MSLN tumors, which decreased in volume on 227Th-MSLN treatment. BxPc3 tumors showed an SUVmean of 1.2 ± 0.3 and remained similar in size after 227Th-MSLN treatment. Conclusion: 89Zr-MSLN PET imaging reflected MSLN expression and matched 227Th-MSLN tumor uptake and biodistribution. Our data support the clinical exploration of 89Zr-MSLN PET imaging together with 227Th-MSLN therapy, both using the same antibody-chelator conjugate.

227Th-Labeled Anti-CD22 Antibody (BAY 1862864) in Relapsed/Refractory CD22-Positive Non-Hodgkin Lymphoma: A First-in-Human, Phase I Study.

Background: BAY 1862864 is an α-particle emitting 227Th-labeled CD22-targeting antibody. This first-in-human dose-escalation phase I study evaluated BAY 1862864 in patients with CD22-positive relapsed/refractory B cell non-Hodgkin lymphoma (R/R-NHL). Materials and Methods: BAY 1862864 intravenous injections were administered at the starting 227Th radioactivity dose of 1.5 MBq (2 or 10 mg antibody), and the radioactivity dose escalated in ∼1.5 MBq increments (10 mg antibody) until the maximum tolerated dose (MTD) was reported. The primary objective was to determine the safety, tolerability, and MTD. Results: Twenty-one patients received BAY 1862864. Two dose-limiting toxicities (grade 3 febrile neutropenia and grade 4 thrombocytopenia) were reported in one patient in the 4.6 MBq (10 mg antibody) cohort. The MTD was not reached. Ten (48%) patients reported grade ≥3 treatment-emergent adverse events, with the most common being neutropenia, thrombocytopenia, and leukopenia, each occurring in 3 (14%) patients. Pharmacokinetics demonstrated the dose proportionality and stability of BAY 1862864 in the blood. The objective response rate (ORR) was 25% (5/21 patients) according to the LUGANO 2014 criteria, including 1 complete and 4 partial responses. The ORR was 11% (1/9) and 30% (3/10) in patients with relapsed high- and low-grade lymphomas, respectively. Conclusions: BAY 1862864 was safe and tolerated in patients with R/R-NHL. Clinical Trial Registration numbers: NCT02581878 and EudraCT 2014-004140-36.

Production and Supply of α-Particle-Emitting Radionuclides for Targeted α-Therapy.

Encouraging results from targeted α-therapy have received significant attention from academia and industry. However, the limited availability of suitable radionuclides has hampered widespread translation and application. In the present review, we discuss the most promising candidates for clinical application and the state of the art of their production and supply. In this review, along with 2 forthcoming reviews on chelation and clinical application of α-emitting radionuclides, The Journal of Nuclear Medicine will provide a comprehensive assessment of the field.

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy.

Targeted α therapy (TAT) offers the potential for the targeted delivery of potent α-particle-emitting radionuclides that emit high linear energy transfer radiation. This leads to a densely ionizing radiation track over a short path. Localized radiation induces cytotoxic, difficult-to-repair, clustered DNA double-strand breaks (DSBs). To date, radium-223 (223Ra) is the only TAT approved for the treatment of patients with metastatic castration-resistant prostate cancer. Thorium-227 (227Th), the progenitor nuclide of 223Ra, offers promise as a wider-ranging alternative due to the availability of efficient chelators, such as octadentate 3,2-hydroxypyridinone (3,2-HOPO). The 3,2-HOPO chelator can be readily conjugated to a range of targeting moieties, enabling the generation of new targeted thorium-227 conjugates (TTCs). This review provides a comprehensive overview of the advances in the preclinical development of TTCs for hematological cancers, including CD22-positive B cell cancers and CD33-positive leukemia, as well as for solid tumors overexpressing renal cell cancer antigen CD70, membrane-anchored glycoprotein mesothelin in mesothelioma, prostate-specific membrane antigen in prostate cancer, and fibroblast growth factor receptor 2. As the mechanism of action for TTCs is linked to the formation of DSBs, the authors also report data supporting combinations of TTCs with inhibitors of the DNA damage response pathways, including those of the ataxia telangiectasia and Rad3-related protein, and poly-ADP ribose polymerase. Finally, emerging evidence suggests that TTCs induce immunogenic cell death through the release of danger-associated molecular patterns. Based on encouraging preclinical data, clinical studies have been initiated to investigate the safety and tolerability of TTCs in patients with various cancers.

Atomic Nanogenerators in Targeted Alpha Therapies: Curie's Legacy in Modern Cancer Management.

Atomic in vivo nanogenerators such as actinium-225, thorium-227, and radium-223 are of increasing interest and importance in the treatment of patients with metastatic cancer diseases. This is due to their peculiar physical, chemical, and biological characteristics, leading to astonishing responses in otherwise resistant patients. Nevertheless, there are still a few obstacles and hurdles to be overcome that hamper the broader utilization in the clinical setting. Next to the limited supply and relatively high costs, the in vivo complex stability and the fate of the recoiling daughter radionuclides are substantial problems that need to be solved. In radiobiology, the mechanisms underlying treatment efficiency, possible resistance mechanisms, and late side effect occurrence are still far from being understood and need to be unraveled. In this review, the current knowledge on the scientific and clinical background of targeted alpha therapies is summarized. Furthermore, open issues and novel approaches with a focus on the future perspective are discussed. Once these are unraveled, targeted alpha therapies with atomic in vivo nanogenerators can be tailored to suit the needs of each patient when applying careful risk stratification and combination therapies. They have the potential to become one of the major treatment pillars in modern cancer management.

The potential radio-immunotherapeutic α-emitter 227Th - part II: Absolute γ-ray emission intensities from the excited levels of 223Ra.

At the time of publication, radiopharmaceuticals labelled with thorium-227 are in clinical trials in Europe for the treatment of various types of cancer. In part I of this two-part series the primary standardisation of an aqueous solution of 227Th was reported. In part II, the activity derived from the recommended absolute γ-ray emission intensities have been compared to that from the primary standardisation techniques. This comparison showed a negative bias of 4% in the determined activity per unit mass with an 11% spread in the activities determined for the eight most intense γ-ray emissions (Iγ > 1%) from the 227Th α decay. Using the standardised 227Th, measurements of the characteristic γ-ray emissions from the 223Ra excited states were made using a calibrated HPGe γ-ray spectrometer. This has enabled the absolute intensities of 70 γ ray emissions from the 227Th α-decay to be experimentally determined. A significant improvement over the precision of the recommended normalisation scaling factor has been made, with a value of 12.470 (35) % determined. Typically, the precision of the intensities has been improved by an order of magnitude or greater than current recommended values. The correlation matrices for pairs of the most intense γ-ray emission intensities are presented.

Determination of the activity and half-life of 227Th.

Liquid scintillation samples with 227Th were prepared a few hours after the separation of the progeny. During the measurements, 227Th and its daughters are not in radioactive equilibrium. The counting efficiencies of the individual radionuclides of the decay chain differ from each other and the activity of an individual progeny relative to the activity of 227Th varies with time. Hence, the overall counting efficiency varies with time as well. The counting efficiency εT227h++ of 227Th and its progeny was determined by means of the CIEMAT/NIST efficiency tracing method. The free parameter is derived from the quench-indicating parameter, SQP(E), and from 3H tracer measurements. This makes it possible to compute the efficiency εT227h++ as a function of time. The individual efficiencies of all progeny are to be combined, taking correction factors and activity ratios into account. Thereby, a new, time-dependent correction, namely for the decay during the measurements, is applied. With this method, activity results are obtained that are stable over a long period of time. A least-squares method yields the time of the chemical separation as well as the 227Th half-life, which was also obtained by means of measurements in an ionization chamber. The weighted mean of the two methods (CIEMAT/NIST efficiency tracing and measurements in ionization chambers) was found to be T1/2 = 18.681(9) d.

Measurement of absolute γ-ray emission probabilities in the decay of 227Ac in equilibrium with its progeny.

The emission probabilities of γ rays produced in the 227Ac decay series were determined by high-resolution γ-ray spectrometry of sources with standardised activity. The sources were prepared quantitatively on glass discs by drop deposition of a solution with 227Ac in radioactive equilibrium with its daughter nuclides. Their activity was measured by a primary standardisation technique based on alpha-particle counting at a defined low solid angle. Four laboratories performed γ-ray spectrometry and derived absolute γ-ray intensities. Mean values were calculated and compared with literature data and the currently recommended evaluated data. New values on certain γ-ray emission probabilities are proposed.

The potential radio-immunotherapeutic α-emitter 227Th - part I: Standardisation via primary liquid scintillation techniques and decay progeny ingrowth measurements.

Thorium-227 is a potential therapeutic radionuclide for applications in targeted α-radioimmunotherapy for the treatment of various types of cancer. To provide nuclear medicine departments involved in Phase I clinical trials traceability to the SI unit of radioactivity (Bq), a standardisation of a radiochemically pure 227Th aqueous solution has been performed at the National Physical Laboratory. This was achieved via two primary liquid scintillation (LS) techniques -4π(LS)-γ digital coincidence counting (DCC) and 4π LS counting. These absolute techniques were supported by the indirect determination of the 227Th activity via the measurement of the ingrowth and decay rate of the decay progeny by both ionisations chambers and high purity germanium (HPGe) gamma-ray spectrometry. The results of the primary techniques were found to be consistent, both with each other (zeta score = 1.1) and to the decay progeny ingrowth measurements. An activity per unit mass of 20.726 (51) kBq g-1 was determined for the solution. A procedure has been developed that provided an effective separation of the 227Th from its decay progeny, which was shown by the effective time zero of the 227Th-223Ra nuclear chronometer measured by HPGe gamma-ray spectrometry.

Evaluation of the separation and purification of 227Th from its decay progeny by anion exchange and extraction chromatography.

Thorium-227 is currently undergoing evaluation as a potential radionuclide for targeted cancer therapy, and as such a high chemical purity of the material is required. To establish a reliable procedure for radiochemical isolation of 227Th from the parent 227Ac and decay progeny, which includes the radiotherapeutic 223Ra, the performance of three different separation schemes based on ion-exchange and extraction chromatography have been evaluated. The results suggest that both ion exchange and extraction chromatographic techniques can be successfully used for the separation of 227Th from its decay progeny, however extraction chromatographic resins demonstrate favourable performance in terms of Th recovery and purification from radionuclide impurities.

A Radium-223 microgenerator from cyclotron-produced trace Actinium-227.

The alpha particle emitter Radium-223 dichloride (223RaCl2) has recently been approved for treatment of late-stage bone metastatic prostate cancer. There is considerable interest in studying this new agent outside of the clinical setting, however the supply of 223Ra is limited and expensive. We have engineered a 223Ra microgenerator using traces of 227Ac previously generated from cyclotron-produced 225Ac. Radiochemically pure 223RaCl2 was made, characterized, evaluated in vivo, and the source was recovered in high yield for regeneration of the microgenerator.

Large scale accelerator production of 225Ac: Effective cross sections for 78-192MeV protons incident on 232Th targets.

Actinium-225 and 213Bi have been used successfully in targeted alpha therapy (TAT) in preclinical and clinical research. This paper is a continuation of research activities aiming to expand the availability of 225Ac. The high-energy proton spallation reaction on natural thorium metal targets has been utilized to produce millicurie quantities of 225Ac. The results of sixteen irradiation experiments of thorium metal at beam energies between 78 and 192MeV are summarized in this work. Irradiations have been conducted at Brookhaven National Laboratory (BNL) and Los Alamos National Laboratory (LANL), while target dissolution and processing was carried out at Oak Ridge National Laboratory (ORNL). Excitation functions for actinium and thorium isotopes, as well as for some of the fission products, are presented. The cross sections for production of 225Ac range from 3.6 to 16.7mb in the incident proton energy range of 78-192MeV. Based on these data, production of curie quantities of 225Ac is possible by irradiating a 5.0gcm-2 232Th target for 10 days in either BNL or LANL proton irradiation facilities.

The half-life of ²²7Th by direct and indirect measurements.

Utilising a chemically purified solution the radioactive half-life of (227)Th has been determined indirectly by observation of the ingrowth of (223)Ra using an ionisation chamber (IC) and for the first time by direct observation of the change in activity with time using a high-purity germanium (HPGe) γ-ray spectrometer. The radioactive decay was observed for ~104 days (~5.6 half-lives) by γ-ray spectrometry and approximately 63 days and 72 days (~3.4 and ~3.9 half-lives) using an ionisation chamber (IC). The resulting half-life values - 18.695 (4) days (IC) and 18.683 (20) days (HPGe) - are consistent and detailed uncertainty budgets are presented for the two measurement techniques. A weighted mean of our results of 18.695 (4) days is inconsistent with the most precise published half-life value of 18.7176 (52) days (Jordan and Blanke, 1967). A critical evaluation of literature data has been performed, indicating a paucity of reliable and independent measurements. Selected independent published values have been used to determine a recommended half-life of 18.697 (7) days. A method has been introduced in the course of this work so that the recommended half-life of (227)Th as determined by ingrowth can be modified if a different (223)Ra half-life has been determined, evaluated and adopted.