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A facile method for electrochemical separation of 181−186Re from proton irradiated natural tungsten oxide target
Applied Radiation and Isotopes 154 (2019) 108885
Contents lists available at ScienceDirect
Applied Radiation and Isotopes journal homepage: www.elsevier.com/locate/apradiso
A facile method for electrochemical separation of irradiated natural tungsten oxide target
181−186
Re from proton
T
Rubel Chakravartya,b,∗, Sudipta Chakrabortya,b, Sachin Jadhava, K.C. Jagadeesana, S.V. Thakarea, Ashutosh Dasha a b
Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400 094, India
H I GH L IG H T S
Re radioisotopes were produced by proton bombardment on natural tungsten oxide target. • Anelectrochemical process based on selective deposition of Re on platinum electrode was developed. • The Re radioisotopesseparation free from tungsten impurities could be obtained with > 80% yield in normal saline medium. • The suitability of Re radioisotopes for preparation of radiopharmaceuticals was demonstrated. • 181−186
A R T I C LE I N FO
A B S T R A C T
Keywords: 186 Re DMSA Electrochemical separation HEDP High specific activity Radiolabeling Theranostics
Routine availability of high specific activity 186Re would provide a significant boost to the development of potent theranostic radiopharmaceuticals. In the present study, 181−186Re was produced by proton bombardment (12 MeV, average beam intensity 180 nΑ) for 60 h on natural tungsten oxide target. A facile electrochemical method has been developed for radiochemical separation of Re radioisotopes from irradiated target material. The overall yield of the process was > 80% and Re radioisotopes could be separated in a form suitable for preparation of radiopharmaceuticals.
1. Introduction ‘Theranostics’ is now the buzzword in nuclear oncology. With rapid advancement in this field, the present day radiopharmaceuticals research is focussing predominantly on development of novel agents which can be used for personalized diagnosis and treatment of various types of cancer (Ballinger, 2018; Kelkar and Reineke, 2011). This approach not only guides clinical decision making for optimal cancer treatment but can also be utilized to objectively examine the therapeutic response in order to improve the survival and quality of life of individual patients. Owing to the rapid increase in cancer burden and large variability observed in cancer patients, the need for production of newer radiometals for use in preparation of theranostic radiopharmaceuticals has grown much more than ever before (Cutler et al., 2013; Park and Kim, 2013). This essentially requires development of improved production methods and efficient radiochemical separation routes for obtaining the radiometals with high radionuclidic purity and
∗
in a form suitable for preparation of radiopharmaceuticals. Rhenium-186 has the potential to stand alone as an intrinsically theranostic radiometal due its excellent nuclear decay characteristics: has relatively long half-life (3.72 d) which allows investigation of slower in vivo processes through radiolabeling of biomolecules with longer in vivo circulation, emits medium energy β− particle (Eβmax = 1.07 MeV) which is appropriate for treatment of wide variety of tumors and accompanying γ emission at 137 keV (9% abundance) which is suitable for single photon emission computed tomography (SPECT) imaging (Cutler et al., 2013). Being a group 7 congener of Tc, this radioisotope shares remarkably similar chemical behavior with 99m Tc (the ‘work-horse’ of diagnostic nuclear medicine) and therefore, 99m Tc radio-complexation knowledge can often be applied to 186Re for formulation of a host of theranostic radiopharmaceuticals (Cutler et al., 2013). Nevertheless, the dissimilarities in substitution kinetics and redox chemistry of Tc and Re need to be taken into consideration for preparation of new radiopharmaceuticals with 186Re.
Corresponding author. Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India. E-mail addresses: [email protected], [email protected] (R. Chakravarty).
https://doi.org/10.1016/j.apradiso.2019.108885 Received 8 April 2019; Received in revised form 30 August 2019; Accepted 3 September 2019 Available online 04 September 2019 0969-8043/ © 2019 Elsevier Ltd. All rights reserved.
Applied Radiation and Isotopes 154 (2019) 108885
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Fig. 1. (A) Pelletized natural tungsten oxide target prepared for irradiation, (B) schematic diagram of the set up for electrochemical separation (not drawn to scale).
Generally, 186Re available in the market is produced via 185Re (n, γ) Re reaction in a nuclear reactor (Cutler et al., 2013). Despite feasibility of large-scale production in the medium flux research reactor facilities in the world, the specific activity of 186Re produced by this route is low and is therefore inadequate for preparation of target specific radiopharmaceuticals (Moustapha et al., 2006). Alternatively, 186 Re can be produced in an accelerator with high specific activity by proton/deuteron bombardment on W targets via 186W (p, n) 186Re or 186 W (d, 2n) 186Re reactions (Ali et al., 2018). In the past, several studies have been reported on the measurement of the excitation functions for the radionuclides produced by natW(p,d; x) nuclear processes and physical yields were deduced towards production of high specific activity 186Re (Ali et al., 2018; Balkin et al., 2016; Bonardi et al., 2010; Lapi et al., 2007; Zhang et al., 1999, 2001). However, regular production of 186Re by accelerator based approaches have not yet commenced, probably, due to unavailability of a viable methodology for radiochemical separation of 186Re from bulk W target to obtain the radionuclide in a form suitable for preparation of radiopharmaceuticals. Development of a suitable radiochemical separation technology for routine availability of high specific activity 186Re would have tremendous impact in theranostic research. Herein, we report the development of a simple and efficient electrochemical pathway for radiochemical separation of Re radioisotopes (181−186Re) from proton irradiated natural tungsten oxide target. The conditions of achieving selective electrodeposition of 181−186Re on an inert electrode were optimized and the separation process was demonstrated. Detailed quality control studies were carried out to evaluate the efficacy of the separation process and establish the suitability of radiochemically separated Re radioisotopes towards preparation of radiopharmaceuticals.
supply with 100 V compliance, 1.2 nA current resolution, a maximum current of 2 A and > 1013 Ω input impedance was used. High purity germanium (HPGe) detector coupled with multichannel analyzer (Canberra Eurisys, France) with a 1.5 keV resolution at 1333 keV and useable energy range from 121 keV to 2 MeV was used for identification and quantification of radionuclides present. A standard 152Eu reference source (1 mL aqueous solution in a glass vial containing 3.86 kBq activity as on April 1, 2019) was used for energy and efficiency calibration of the HPGe detector. Radioactivity measurements in PC and TLC studies were carried out by using a well type NaI(Tl) scintillation counter (Mucha, Raytest, Germany) using suitable window settings. Inductively coupled plasma-atomic emission spectroscopy (ICP-AES) of decayed samples was carried out using ICP-AES JY-238 spectrometer, Emission Horiba Group, France.
186
2.2. Production of irradiated target
181−186
Re and radiochemical processing of the
Natural tungsten oxide was used for production of 181−186Re via W (p, xn) 181−186Re reaction. For preparation of the target, natural tungsten oxide powder was pressed into a grooved aluminum holder to form a pellet of 10 mm diameter with surface density of 11.53 mg/mm2 (Fig. 1A). The irradiation was carried out using an incident proton beam of 12 MeV with average beam intensity of 180 nΑ for 60 h at Bhabha Atomic Research Centre-Tata Institute of Fundamental Research (BARC-TIFR) Pelletron Facility, Mumbai. After the end of irradiation, the target was cooled for 6 h, in order to allow decay of shortlived radioisotopes. Subsequently, the target was dissolved in 10 mL of 2 M NaOH solution with gentle heating on a hot plate. The resulting solution was evaporated to near dryness and reconstituted in 10 mL of 0.5 M NaOH solution. A known volume of the radioactive solution was withdrawn and diluted in deionized water in order to maintain the final volume at 1 mL. The γ-spectrum of the sample prepared was recorded in HPGe detector by keeping it at an appropriate position such that the dead time of the detector was ≤2%. nat
2. Experimental 2.1. Materials and equipments Platinum metal wires of high purity (> 99.99%) were procured from Hindustan Platinum Limited, India. Tungsten (VI) oxide powder (of 99.995% purity on trace metals basis), stannous chloride, meso-2,3dimercaptosuccinic acid (DMSA) and 1-hydroxyethylidenediphosphonic acid tetrasodium salt (HEDP) were purchased from SigmaAldrich, Germany. All other chemicals were of analytical grade and obtained from S.D. Fine Chemicals, India. Paper chromatography (PC) strips and flexible silica plates for thin layer chromatography (TLC) were obtained from Whatman Ltd., England. In electrochemical separation studies, a direct current (DC) power
2.3. Electrochemical set up The electrochemical separation process involved selective electrodeposition of Re radioisotopes (181−186Re) from the radioactive solution obtained after radiochemical processing. The radioactive solution obtained after radiochemical process of the irradiated target was directly transferred to the electrochemical cell and used as the electrolyte. A schematic diagram of the electrochemical cell is given in Fig. 1B. The electrodes used were made of high purity platinum wires. The 2
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2.5. Demonstration of the electrochemical separation process After optimization of the electrochemical parameters, the separation process was demonstrated in a shielded facility. The irradiated target was radiochemically processed as described in Section 2.2 and the alkaline radioactive solution was directly transferred in the electrochemical cell. The electrodeposition process was carried out under the optimized conditions by application of a potential of 7 V for 30 min. After the electrodeposition process, the cathode containing the 181−186 Re deposit was withdrawn without switching off the power supply and washed with 5 mL of acetone. Subsequently, the 181−186Re deposit on the cathode was stripped in 1 mL of saline solution adopting the procedure described in Section 2.4 and used for quality control studies.
2.6. Quality control of
Fig. 2. γ-spectra of the irradiated target after radiochemical processing and prior to electrochemical separation procedure.
181−186
Re
Radionuclidic purity measurement of the electrochemically separated solution was carried out using a calibrated HPGe detector coupled with multichannel analyzer. The γ-spectrum of the final product was compared with that of the irradiated target solution to investigate the efficacy of the electrochemical separation process. The radiochemical purity of 181−186Re in the form of ReO4− ions was determined by PC using normal saline as the mobile phase as per the reported procedure (Chakravarty et al., 2009). In order to detect the presence of stable tungsten and rhenium isotopes in the final product, it was allowed to decay for 2 months and ICP-AES analysis was carried out. This study would aid towards analyzing the degree of effectiveness of the electrochemical separation process and also provide an idea regarding the specific activity of 181−186Re obtained (Balkin et al., 2017). The utility of electrochemically separated 181−186Re toward radiopharmaceutical formulation was ascertained by radiolabeleing studies with HEDP and DMSA ligands as per the procedure reported by us earlier with 188Re (Chakravarty et al., 2009). Radio-TLC studies were performed with the radiolabeled complexes by developing the chromatograms in normal saline and acetone media and the radiolabeling yields were determined as per the reported procedure (Chakravarty et al., 2009).
electrochemical cell consisted of a glass container (24 × 40 mm, 20 mm ID) with a teflon cap. The electrodes (length 50 mm and diameter 1.5 mm) were fitted 5 mm apart on the teflon cap. The teflon cap and the electrodes were fitted on the mouth of the glass vial. Vertical raising or lowering of the electrodes was carried out along with the teflon cap. The platinum electrodes were adjusted parallel to each other, connected to the power supply using small screws embedded into the teflon cap which were in contact with the electrode. A provision for passing inert gas through a glass tube, dipped into the electrolysis solution, was provided. A small hole (∼2.5 mm) was provided in the teflon cap for venting off any gases, that may be formed. 2.4. Optimization of parameters for electrodeposition of electrode
181−186
Re on Pt
The radioactive solution was transferred in the electrochemical cell and electrodeposition was performed at different applied potentials for 1 h. Subsequently, the pH of the electrolyte was varied by addition of HCl or NaOH solution and electrodeposition of 181−186Re was carried out at the optimal potential for 1 h. In order to optimize the time required for the electrodeposition process, the procedure was repeated at the optimal applied potential and pH of the electrolyte for different time intervals. In each of these studies, 181−186Re deposited on the cathode was subsequently stripped in 1 mL of 0.9% (w/v) NaCl (normal saline) solution. For this purpose, the cathode containing the 181−186Re deposit was transferred to a new electrolytic cell containing 1 mL of normal saline solution, without switching off the power supply. The polarity of the electrode was reversed after inserting a new Pt electrode and electrolysis was carried out on application of 15 V potential for 30 s. The yield of 181−186Re was estimated by comparing the activity obtained after the stripping step with the total activity of 181−186Re taken in the electrochemical cell prior to the electrodeposition process.
3. Results 3.1. Radiochemical processing of the irradiated target and γ-ray spectrum analysis After radiochemical processing, the γ-ray spectrometry of the radioactive solution (Fig. 2) revealed the presence of six different Re radioisotopes (181Re, 182mRe, 182Re, 183Re, 184Re and 186Re). By analysis of the γ-ray spectrum, the activities of the Re isotopes obtained after radiochemical processing were estimated (Table 1). In addition to the Re radioisotopes, trace quantities of 187W and 183Ta were also detected in the radioactive solution (Fig. 2).
Table 1 Activities of Re radioisotopes estimated by γ-ray spectrum analysis. Radioisotope
a
181
19.9 12.7 64.0 1680.0 912.0 89.2
Re Re 182 Re 183 Re 184 Re 186 Re 182m
a b
T½ (h)
a
Principal γ-ray energy used for the estimation [keV (% abundance)]
b
Activity after radiochemical processing of the irradiated target (MBq)
b
365.80 (56.6) 1222.03 (24.8) 229.54 (26.0) 162.28 (23.3) 903.85 (37.9) 137.27 (9.4)
0.28 0.52 12.14 0.16 0.19 0.82
0.23 0.43 10.14 0.13 0.16 0.68
Data from Chu et al. (1998). Extrapolated to the end of bombardment. 3
Activity after electrochemical separation (MBq)
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Table 2 Electrodeposition yield of
181−186
Re at different pH of the electrolyte.
pH of the electrolyte
Electrodeposition yield (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
18 ± 3 23 ± 5 25 ± 7 19 ± 4 11 ± 3 7±2 6±1 7±1 17 ± 4 33 ± 3 67 ± 5 83 ± 4 84 ± 2 83 ± 5
N = 3.
3.3. Demonstration of the electrochemical separation process In order to demonstrate the electrochemical separation process under the optimized conditions, the total radioactivity obtained after radiochemical processing of the irradiated target (as indicated in Table 1) was used. After performing the electrodeposition process under the optimized conditions in a shielded facility, the Pt cathode containing the 181−186Re deposit was withdrawn without switching off the power supply. If the power supply was switched off before lifting up the electrode from the electrolyte solution, there was significant (20–30%) loss of activity due to dissolution of the deposit in the alkaline electrolyte. Subsequently, the electrode surface was washed in acetone. This process led to < 2% loss of 181−186Re. Finally, 181−186Re deposit could be quantitatively stripped in 1 mL of saline solution and used for further studies. The yields of the Re radioisotopes obtained after electrochemical separation are shown in Table 1. The overall decay corrected yield of Re radioisotopes obtained in saline solution was (82.79 ± 1.04) %. The electrochemical separation process is fast and it could be completed within 1 h. 3.4. Quality control of
181−186
Re
After electrochemical separation of 181−186Re, the γ-ray spectrum of the radioactive solution was recorded in HPGe detector coupled with multichannel analyzer (Fig. 4). In addition to 186Re, other radioisotopes of Re such as 181Re, 182mRe, 182Re, 183Re, 184Re were also present in the radioactive solution. However, peaks corresponding to 187W and 183Ta were not seen in the γ-spectrum of the separated product (Fig. 4). The radiochemical purity of 181−186Re in the form of ReO4− was 98.6 ± 0.3% (N = 5) as determined by paper chromatography (Fig. 5).
Fig. 3. Optimization of parameters for selective deposition of Re on Pt cathode by variation in (A) applied potential, (B) time of electrodeposition.
3.2. Optimization of parameters for electrodeposition of electrode
181−186
Re on Pt
The applied potential is the most important factor that influences the separation of Re from W. From the optimization study, it was found that the maximum electrodeposition of 181−186Re was achieved at an applied potential of 7 V (Fig. 3A). The pH of the electrolyte plays a crucial role in the electrodeposition process. The maximum electrodeposition yield of 181−186Re was obtained when the pH of the electrolyte was ≥12 (Table 2). Consequently, the radioactive solution after the radiochemical processing step (i.e. after dissolution of the irradiated target) could directly be utilized as the electrolyte without further pH adjustments. Also, a minimum of 30 min of electrolysis was required to achieve maximum electrodeposition yield (Fig. 3B). After electrodeposition, 181−186Re could be quantitatively retrieved in 1 mL of saline solution.
Fig. 4. γ-spectra of the electrochemically separated product. 4
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Fig. 5. Typical paper chromatographic pattern of the electrochemically separated product (181−186Re) developed in saline medium.
ICP-AES analysis of the decayed samples indicated that the level of stable tungsten and rhenium isotopes was below detectable limit (< 0.01 μg/mL). From this observation, it could be concluded that the specific activity of 181−186Re obtained after the electrochemical separation process was very high and almost equal to the theoretical value for the no-carrier-added (NCA) radioisotopes. In order to examine the suitability of 181−186Re obtained by electrochemical separation for radiopharmaceutical formulation, complexation was done with DMSA and HEDP. When radio-TLC was performed using saline as solvent, free ReO4− ions as well as the radiolabeled complexes migrated to the solvent front, whereas hydrolyzed rhenium remained at the origin (Fig. 6A). On the other hand, in radio-TLC developed using acetone as solvent, the radiolabeled complexes remained at the point of application and uncomplexed ReO4− ions moved towards the solvent front (Fig. 6B). In this case, if hydrolyzed rhenium (ReO2) is present, it will also remain at the origin. By combining the results of both the TLCs, the radiolabeling yields of 181−186 Re-DMSA and 181−186Re-HEDP were estimated to be 98.2 ± 0.4% and 98.5 ± 0.6% (N = 5), respectively. 4. Discussion Fig. 6. Typical radio-TLC patterns of 181−186Re-DMSA and developed in (A) saline, (B) acetone media.
Over the last several years, there has been numerous reports on evaluation of production cross-sections of 186Re via charged particle induced reactions [186W (p, n) 186Re or 186W (d, 2n) 186Re] on tungsten target (Ali et al., 2018; Balkin et al., 2016; Bonardi et al., 2010; Cutler et al., 2013; Khandaker et al., 2017; Lapi et al., 2007; Moustapha et al., 2006; Richards et al., 2015; Shigeta et al., 1996; Zhang et al., 1999, 2001). In order to exploit the suitable nuclear characteristics of 186Re in preparation of radiopharmaceuticals for use in cancer theranostics, it is important to separate the radioisotope from the irradiated bulk component. A variety of methods based on dry distillation, thermochromatography, solvent extraction, ion exchange chromatography and adsorption on alumina column have been reported for radiochemical separation of high specific activity 186Re from the irradiated target (Fassbender et al., 2013; Mastren et al., 2017; Moustapha et al., 2006; Novgorodov et al., 2000; Richards et al., 2015; Shigeta et al., 1996; Zhang et al., 2001). Most of these processes involve multiple separation steps which are difficult to execute during large scale separations in shielded hot cells. In view of this limitation, prospects of using electrochemical separation route for availing high specific activity 186Re
181−186
Re-HEDP
from the irradiated target holds significant promise and therefore exploited in the present study. This strategy has earlier been established by our group in preparation of clinically important radionuclide generators for use in nuclear medicine (Chakravarty et al., 2008, 2009, 2010, 2012; Dash and Chakravarty, 2014). Electrochemical separation strategy exploits the difference between the formal electrode potentials of the different radionuclide ions dissolved in the electrolyte medium (Chakravarty et al., 2012; Dash and Chakravarty, 2014). The radionuclide of interest can be selectively electrodeposited on an electrode surface under the influence of controlled applied potential. This elegant technique is amenable for separation of miniscule quantity of the desired radionuclide (of high specific activity) from the bulk target material in a single step. Additionally, the process is not susceptible to radiation damage inflicted by the radionuclides dissolved in the electrolyte medium. The present 5
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for ICP-AES analyses of the decayed samples. Thanks are due to Dr. Ajay Singh and Dr. K. P. Muthe of Technical Physics Division, Bhabha Atomic Research Centre for their help in preparation of the target used for irradiation. Mr. Ramu Ram of Radiopharmaceuticals Division, Bhabha Atomic Research Centre is gratefully acknowledged for his help in the irradiation experiments.
study involved selective electrodeposition of Re radioisotopes from the irradiated WO3 target dissolved in alkaline medium on an inert platinum cathode. Platinum electrode was chosen for this study as it would not lead to addition of chemical impurities due to dissolution of the electrode material during the electrodeposition or stripping processes. The presence of such chemical impurities in high specific activity 186Re would negatively impact in subsequent radiolabeling studies. Owing to low hydrogen overvoltage and high discharge potential of the ions of tungsten, they cannot be electrodeposited from aqueous electrolyte media on a Pt electrode (Chakravarty et al., 2009). In fact, tungsten electrodeposition is generally performed from its molten salts (Liu et al., 2013). On the other hand, aqueous electrochemistry of Re is well established and this phenomenon has been exploited in selective electrodeposition of Re from sodium tungstate solution (Chakravarty et al., 2009; Hahn et al., 2007; Salakhova et al., 2012; Vargas-Uscategui et al., 2013). The electrochemical reduction of perrhenate ions in aqueous alkaline medium is as per equation (1).
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ReO4− + 7e +8H2O = Re + 8OH− Eo = −0.584 V (Salakhova et al., 2012) (1) The Re deposit could be finally stripped in saline solution, which is desirable from the perspective of radiopharmaceutical preparation. Since natural tungsten oxide target was bombarded with proton beam in the present study, a variety of Re radioisotopes were produced via natW (p, xn) 181−186Re reaction (Lapi et al., 2007; Zhang et al., 1999). It is pertinent to mention here that an optimized irradiation parameter (energy window) and use of enriched 186W target shall provide 186Re with high radionuclidic purity. Optimization of irradiation parameters has already been reported earlier via excitation function measurements using natural tungsten target (Ali et al., 2018; Bonardi et al., 2010; Lapi et al., 2007; Zhang et al., 1999) and hence not repeated in the present study. When enriched target is irradiated under the optimized conditions, this innovative and simple electrochemical separation strategy shall be useful for isolation of 186Re from the irradiated target for use in preparation of theranostic radiopharmaceuticals. 5. Conclusions The objective of developing a simple, clean and fast method for radiochemical separation of high specific activity 186Re from proton irradiated tungsten target has been successfully accomplished. Adopting the efficient electrochemical pathway reported in the article, 181−186 Re radioisotopes produced by proton bombardment on natural tungsten oxide were selectively separated from bulk target and obtained in a form suitable for preparation of radiopharmaceuticals. This electrochemical separation strategy would be useful to produce high specific activity 186Re on a large scale, enough for preparation of clinically relevant doses of theranostic radiopharmaceuticals, on the cyclotrons with high intensity proton or deuteron beams. The electrochemical separation technique can also be explored for the separation and purification of other medically important radionuclides produced in cyclotrons and thus serves as a model for future possibilities. Acknowledgements This work was done as a part of International Atomic Energy Agency – Coordinated Research Project (IAEA-CRP F22053) on ‘Therapeutic Radiopharmaceuticals Labelled with New Emerging Radionuclides (67Cu, 186Re, 47Sc)’. The authors are grateful to Dr. P. K. Pujari, Associate Director, Radiochemistry and Isotope Group, Bhabha Atomic Research Centre for his valuable support to the Isotope Program. The authors are thankful to all staff members at BARC-TIFR Pelletron facility who were involved in the proton irradiation. Analytical Chemistry Division, Bhabha Atomic Research Centre is gratefully acknowledged 6
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Zhang, X., Li, Q., Li, W., Sheng, R., Shen, S., 2001. Production of no-carrier-added 186Re via deuteron induced reactions on isotopically enriched 186W. Appl. Radiat. Isot. 54, 89–92. Zhang, X., Li, W., Fang, K., He, W., Sheng, R., Ying, D., Hu, W., 1999. Excitation functions for natW(p,xn) 181-186Re reactions and production of no-carrier-added 186Re via 186W (p,n) 186Re reaction. Radiochim. Acta 86, 11–16.
Shigeta, N., Matsuoka, H., Osa, A., Koizumi, M., Izumo, M., Kobayashi, K., Hashimoto, K., Sekine, T., Lambrecht, R.M., 1996. Production method of no-carrier-added 186Re. J. Radioanal. Nucl. Chem. 205, 85–92. Vargas-Uscategui, A., Mosquera, E., Cifuentes, L., 2013. Analysis of the electrodeposition process of rhenium and rhenium oxides in alkaline aqueous electrolyte. Electrochim. Acta 109, 283–290.
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Applied Radiation and Isotopes journal homepage: www.elsevier.com/locate/apradiso
A facile method for electrochemical separation of irradiated natural tungsten oxide target
181−186
Re from proton
T
Rubel Chakravartya,b,∗, Sudipta Chakrabortya,b, Sachin Jadhava, K.C. Jagadeesana, S.V. Thakarea, Ashutosh Dasha a b
Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400 094, India
H I GH L IG H T S
Re radioisotopes were produced by proton bombardment on natural tungsten oxide target. • Anelectrochemical process based on selective deposition of Re on platinum electrode was developed. • The Re radioisotopesseparation free from tungsten impurities could be obtained with > 80% yield in normal saline medium. • The suitability of Re radioisotopes for preparation of radiopharmaceuticals was demonstrated. • 181−186
A R T I C LE I N FO
A B S T R A C T
Keywords: 186 Re DMSA Electrochemical separation HEDP High specific activity Radiolabeling Theranostics
Routine availability of high specific activity 186Re would provide a significant boost to the development of potent theranostic radiopharmaceuticals. In the present study, 181−186Re was produced by proton bombardment (12 MeV, average beam intensity 180 nΑ) for 60 h on natural tungsten oxide target. A facile electrochemical method has been developed for radiochemical separation of Re radioisotopes from irradiated target material. The overall yield of the process was > 80% and Re radioisotopes could be separated in a form suitable for preparation of radiopharmaceuticals.
1. Introduction ‘Theranostics’ is now the buzzword in nuclear oncology. With rapid advancement in this field, the present day radiopharmaceuticals research is focussing predominantly on development of novel agents which can be used for personalized diagnosis and treatment of various types of cancer (Ballinger, 2018; Kelkar and Reineke, 2011). This approach not only guides clinical decision making for optimal cancer treatment but can also be utilized to objectively examine the therapeutic response in order to improve the survival and quality of life of individual patients. Owing to the rapid increase in cancer burden and large variability observed in cancer patients, the need for production of newer radiometals for use in preparation of theranostic radiopharmaceuticals has grown much more than ever before (Cutler et al., 2013; Park and Kim, 2013). This essentially requires development of improved production methods and efficient radiochemical separation routes for obtaining the radiometals with high radionuclidic purity and
∗
in a form suitable for preparation of radiopharmaceuticals. Rhenium-186 has the potential to stand alone as an intrinsically theranostic radiometal due its excellent nuclear decay characteristics: has relatively long half-life (3.72 d) which allows investigation of slower in vivo processes through radiolabeling of biomolecules with longer in vivo circulation, emits medium energy β− particle (Eβmax = 1.07 MeV) which is appropriate for treatment of wide variety of tumors and accompanying γ emission at 137 keV (9% abundance) which is suitable for single photon emission computed tomography (SPECT) imaging (Cutler et al., 2013). Being a group 7 congener of Tc, this radioisotope shares remarkably similar chemical behavior with 99m Tc (the ‘work-horse’ of diagnostic nuclear medicine) and therefore, 99m Tc radio-complexation knowledge can often be applied to 186Re for formulation of a host of theranostic radiopharmaceuticals (Cutler et al., 2013). Nevertheless, the dissimilarities in substitution kinetics and redox chemistry of Tc and Re need to be taken into consideration for preparation of new radiopharmaceuticals with 186Re.
Corresponding author. Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India. E-mail addresses: [email protected], [email protected] (R. Chakravarty).
https://doi.org/10.1016/j.apradiso.2019.108885 Received 8 April 2019; Received in revised form 30 August 2019; Accepted 3 September 2019 Available online 04 September 2019 0969-8043/ © 2019 Elsevier Ltd. All rights reserved.
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Fig. 1. (A) Pelletized natural tungsten oxide target prepared for irradiation, (B) schematic diagram of the set up for electrochemical separation (not drawn to scale).
Generally, 186Re available in the market is produced via 185Re (n, γ) Re reaction in a nuclear reactor (Cutler et al., 2013). Despite feasibility of large-scale production in the medium flux research reactor facilities in the world, the specific activity of 186Re produced by this route is low and is therefore inadequate for preparation of target specific radiopharmaceuticals (Moustapha et al., 2006). Alternatively, 186 Re can be produced in an accelerator with high specific activity by proton/deuteron bombardment on W targets via 186W (p, n) 186Re or 186 W (d, 2n) 186Re reactions (Ali et al., 2018). In the past, several studies have been reported on the measurement of the excitation functions for the radionuclides produced by natW(p,d; x) nuclear processes and physical yields were deduced towards production of high specific activity 186Re (Ali et al., 2018; Balkin et al., 2016; Bonardi et al., 2010; Lapi et al., 2007; Zhang et al., 1999, 2001). However, regular production of 186Re by accelerator based approaches have not yet commenced, probably, due to unavailability of a viable methodology for radiochemical separation of 186Re from bulk W target to obtain the radionuclide in a form suitable for preparation of radiopharmaceuticals. Development of a suitable radiochemical separation technology for routine availability of high specific activity 186Re would have tremendous impact in theranostic research. Herein, we report the development of a simple and efficient electrochemical pathway for radiochemical separation of Re radioisotopes (181−186Re) from proton irradiated natural tungsten oxide target. The conditions of achieving selective electrodeposition of 181−186Re on an inert electrode were optimized and the separation process was demonstrated. Detailed quality control studies were carried out to evaluate the efficacy of the separation process and establish the suitability of radiochemically separated Re radioisotopes towards preparation of radiopharmaceuticals.
supply with 100 V compliance, 1.2 nA current resolution, a maximum current of 2 A and > 1013 Ω input impedance was used. High purity germanium (HPGe) detector coupled with multichannel analyzer (Canberra Eurisys, France) with a 1.5 keV resolution at 1333 keV and useable energy range from 121 keV to 2 MeV was used for identification and quantification of radionuclides present. A standard 152Eu reference source (1 mL aqueous solution in a glass vial containing 3.86 kBq activity as on April 1, 2019) was used for energy and efficiency calibration of the HPGe detector. Radioactivity measurements in PC and TLC studies were carried out by using a well type NaI(Tl) scintillation counter (Mucha, Raytest, Germany) using suitable window settings. Inductively coupled plasma-atomic emission spectroscopy (ICP-AES) of decayed samples was carried out using ICP-AES JY-238 spectrometer, Emission Horiba Group, France.
186
2.2. Production of irradiated target
181−186
Re and radiochemical processing of the
Natural tungsten oxide was used for production of 181−186Re via W (p, xn) 181−186Re reaction. For preparation of the target, natural tungsten oxide powder was pressed into a grooved aluminum holder to form a pellet of 10 mm diameter with surface density of 11.53 mg/mm2 (Fig. 1A). The irradiation was carried out using an incident proton beam of 12 MeV with average beam intensity of 180 nΑ for 60 h at Bhabha Atomic Research Centre-Tata Institute of Fundamental Research (BARC-TIFR) Pelletron Facility, Mumbai. After the end of irradiation, the target was cooled for 6 h, in order to allow decay of shortlived radioisotopes. Subsequently, the target was dissolved in 10 mL of 2 M NaOH solution with gentle heating on a hot plate. The resulting solution was evaporated to near dryness and reconstituted in 10 mL of 0.5 M NaOH solution. A known volume of the radioactive solution was withdrawn and diluted in deionized water in order to maintain the final volume at 1 mL. The γ-spectrum of the sample prepared was recorded in HPGe detector by keeping it at an appropriate position such that the dead time of the detector was ≤2%. nat
2. Experimental 2.1. Materials and equipments Platinum metal wires of high purity (> 99.99%) were procured from Hindustan Platinum Limited, India. Tungsten (VI) oxide powder (of 99.995% purity on trace metals basis), stannous chloride, meso-2,3dimercaptosuccinic acid (DMSA) and 1-hydroxyethylidenediphosphonic acid tetrasodium salt (HEDP) were purchased from SigmaAldrich, Germany. All other chemicals were of analytical grade and obtained from S.D. Fine Chemicals, India. Paper chromatography (PC) strips and flexible silica plates for thin layer chromatography (TLC) were obtained from Whatman Ltd., England. In electrochemical separation studies, a direct current (DC) power
2.3. Electrochemical set up The electrochemical separation process involved selective electrodeposition of Re radioisotopes (181−186Re) from the radioactive solution obtained after radiochemical processing. The radioactive solution obtained after radiochemical process of the irradiated target was directly transferred to the electrochemical cell and used as the electrolyte. A schematic diagram of the electrochemical cell is given in Fig. 1B. The electrodes used were made of high purity platinum wires. The 2
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2.5. Demonstration of the electrochemical separation process After optimization of the electrochemical parameters, the separation process was demonstrated in a shielded facility. The irradiated target was radiochemically processed as described in Section 2.2 and the alkaline radioactive solution was directly transferred in the electrochemical cell. The electrodeposition process was carried out under the optimized conditions by application of a potential of 7 V for 30 min. After the electrodeposition process, the cathode containing the 181−186 Re deposit was withdrawn without switching off the power supply and washed with 5 mL of acetone. Subsequently, the 181−186Re deposit on the cathode was stripped in 1 mL of saline solution adopting the procedure described in Section 2.4 and used for quality control studies.
2.6. Quality control of
Fig. 2. γ-spectra of the irradiated target after radiochemical processing and prior to electrochemical separation procedure.
181−186
Re
Radionuclidic purity measurement of the electrochemically separated solution was carried out using a calibrated HPGe detector coupled with multichannel analyzer. The γ-spectrum of the final product was compared with that of the irradiated target solution to investigate the efficacy of the electrochemical separation process. The radiochemical purity of 181−186Re in the form of ReO4− ions was determined by PC using normal saline as the mobile phase as per the reported procedure (Chakravarty et al., 2009). In order to detect the presence of stable tungsten and rhenium isotopes in the final product, it was allowed to decay for 2 months and ICP-AES analysis was carried out. This study would aid towards analyzing the degree of effectiveness of the electrochemical separation process and also provide an idea regarding the specific activity of 181−186Re obtained (Balkin et al., 2017). The utility of electrochemically separated 181−186Re toward radiopharmaceutical formulation was ascertained by radiolabeleing studies with HEDP and DMSA ligands as per the procedure reported by us earlier with 188Re (Chakravarty et al., 2009). Radio-TLC studies were performed with the radiolabeled complexes by developing the chromatograms in normal saline and acetone media and the radiolabeling yields were determined as per the reported procedure (Chakravarty et al., 2009).
electrochemical cell consisted of a glass container (24 × 40 mm, 20 mm ID) with a teflon cap. The electrodes (length 50 mm and diameter 1.5 mm) were fitted 5 mm apart on the teflon cap. The teflon cap and the electrodes were fitted on the mouth of the glass vial. Vertical raising or lowering of the electrodes was carried out along with the teflon cap. The platinum electrodes were adjusted parallel to each other, connected to the power supply using small screws embedded into the teflon cap which were in contact with the electrode. A provision for passing inert gas through a glass tube, dipped into the electrolysis solution, was provided. A small hole (∼2.5 mm) was provided in the teflon cap for venting off any gases, that may be formed. 2.4. Optimization of parameters for electrodeposition of electrode
181−186
Re on Pt
The radioactive solution was transferred in the electrochemical cell and electrodeposition was performed at different applied potentials for 1 h. Subsequently, the pH of the electrolyte was varied by addition of HCl or NaOH solution and electrodeposition of 181−186Re was carried out at the optimal potential for 1 h. In order to optimize the time required for the electrodeposition process, the procedure was repeated at the optimal applied potential and pH of the electrolyte for different time intervals. In each of these studies, 181−186Re deposited on the cathode was subsequently stripped in 1 mL of 0.9% (w/v) NaCl (normal saline) solution. For this purpose, the cathode containing the 181−186Re deposit was transferred to a new electrolytic cell containing 1 mL of normal saline solution, without switching off the power supply. The polarity of the electrode was reversed after inserting a new Pt electrode and electrolysis was carried out on application of 15 V potential for 30 s. The yield of 181−186Re was estimated by comparing the activity obtained after the stripping step with the total activity of 181−186Re taken in the electrochemical cell prior to the electrodeposition process.
3. Results 3.1. Radiochemical processing of the irradiated target and γ-ray spectrum analysis After radiochemical processing, the γ-ray spectrometry of the radioactive solution (Fig. 2) revealed the presence of six different Re radioisotopes (181Re, 182mRe, 182Re, 183Re, 184Re and 186Re). By analysis of the γ-ray spectrum, the activities of the Re isotopes obtained after radiochemical processing were estimated (Table 1). In addition to the Re radioisotopes, trace quantities of 187W and 183Ta were also detected in the radioactive solution (Fig. 2).
Table 1 Activities of Re radioisotopes estimated by γ-ray spectrum analysis. Radioisotope
a
181
19.9 12.7 64.0 1680.0 912.0 89.2
Re Re 182 Re 183 Re 184 Re 186 Re 182m
a b
T½ (h)
a
Principal γ-ray energy used for the estimation [keV (% abundance)]
b
Activity after radiochemical processing of the irradiated target (MBq)
b
365.80 (56.6) 1222.03 (24.8) 229.54 (26.0) 162.28 (23.3) 903.85 (37.9) 137.27 (9.4)
0.28 0.52 12.14 0.16 0.19 0.82
0.23 0.43 10.14 0.13 0.16 0.68
Data from Chu et al. (1998). Extrapolated to the end of bombardment. 3
Activity after electrochemical separation (MBq)
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Table 2 Electrodeposition yield of
181−186
Re at different pH of the electrolyte.
pH of the electrolyte
Electrodeposition yield (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
18 ± 3 23 ± 5 25 ± 7 19 ± 4 11 ± 3 7±2 6±1 7±1 17 ± 4 33 ± 3 67 ± 5 83 ± 4 84 ± 2 83 ± 5
N = 3.
3.3. Demonstration of the electrochemical separation process In order to demonstrate the electrochemical separation process under the optimized conditions, the total radioactivity obtained after radiochemical processing of the irradiated target (as indicated in Table 1) was used. After performing the electrodeposition process under the optimized conditions in a shielded facility, the Pt cathode containing the 181−186Re deposit was withdrawn without switching off the power supply. If the power supply was switched off before lifting up the electrode from the electrolyte solution, there was significant (20–30%) loss of activity due to dissolution of the deposit in the alkaline electrolyte. Subsequently, the electrode surface was washed in acetone. This process led to < 2% loss of 181−186Re. Finally, 181−186Re deposit could be quantitatively stripped in 1 mL of saline solution and used for further studies. The yields of the Re radioisotopes obtained after electrochemical separation are shown in Table 1. The overall decay corrected yield of Re radioisotopes obtained in saline solution was (82.79 ± 1.04) %. The electrochemical separation process is fast and it could be completed within 1 h. 3.4. Quality control of
181−186
Re
After electrochemical separation of 181−186Re, the γ-ray spectrum of the radioactive solution was recorded in HPGe detector coupled with multichannel analyzer (Fig. 4). In addition to 186Re, other radioisotopes of Re such as 181Re, 182mRe, 182Re, 183Re, 184Re were also present in the radioactive solution. However, peaks corresponding to 187W and 183Ta were not seen in the γ-spectrum of the separated product (Fig. 4). The radiochemical purity of 181−186Re in the form of ReO4− was 98.6 ± 0.3% (N = 5) as determined by paper chromatography (Fig. 5).
Fig. 3. Optimization of parameters for selective deposition of Re on Pt cathode by variation in (A) applied potential, (B) time of electrodeposition.
3.2. Optimization of parameters for electrodeposition of electrode
181−186
Re on Pt
The applied potential is the most important factor that influences the separation of Re from W. From the optimization study, it was found that the maximum electrodeposition of 181−186Re was achieved at an applied potential of 7 V (Fig. 3A). The pH of the electrolyte plays a crucial role in the electrodeposition process. The maximum electrodeposition yield of 181−186Re was obtained when the pH of the electrolyte was ≥12 (Table 2). Consequently, the radioactive solution after the radiochemical processing step (i.e. after dissolution of the irradiated target) could directly be utilized as the electrolyte without further pH adjustments. Also, a minimum of 30 min of electrolysis was required to achieve maximum electrodeposition yield (Fig. 3B). After electrodeposition, 181−186Re could be quantitatively retrieved in 1 mL of saline solution.
Fig. 4. γ-spectra of the electrochemically separated product. 4
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Fig. 5. Typical paper chromatographic pattern of the electrochemically separated product (181−186Re) developed in saline medium.
ICP-AES analysis of the decayed samples indicated that the level of stable tungsten and rhenium isotopes was below detectable limit (< 0.01 μg/mL). From this observation, it could be concluded that the specific activity of 181−186Re obtained after the electrochemical separation process was very high and almost equal to the theoretical value for the no-carrier-added (NCA) radioisotopes. In order to examine the suitability of 181−186Re obtained by electrochemical separation for radiopharmaceutical formulation, complexation was done with DMSA and HEDP. When radio-TLC was performed using saline as solvent, free ReO4− ions as well as the radiolabeled complexes migrated to the solvent front, whereas hydrolyzed rhenium remained at the origin (Fig. 6A). On the other hand, in radio-TLC developed using acetone as solvent, the radiolabeled complexes remained at the point of application and uncomplexed ReO4− ions moved towards the solvent front (Fig. 6B). In this case, if hydrolyzed rhenium (ReO2) is present, it will also remain at the origin. By combining the results of both the TLCs, the radiolabeling yields of 181−186 Re-DMSA and 181−186Re-HEDP were estimated to be 98.2 ± 0.4% and 98.5 ± 0.6% (N = 5), respectively. 4. Discussion Fig. 6. Typical radio-TLC patterns of 181−186Re-DMSA and developed in (A) saline, (B) acetone media.
Over the last several years, there has been numerous reports on evaluation of production cross-sections of 186Re via charged particle induced reactions [186W (p, n) 186Re or 186W (d, 2n) 186Re] on tungsten target (Ali et al., 2018; Balkin et al., 2016; Bonardi et al., 2010; Cutler et al., 2013; Khandaker et al., 2017; Lapi et al., 2007; Moustapha et al., 2006; Richards et al., 2015; Shigeta et al., 1996; Zhang et al., 1999, 2001). In order to exploit the suitable nuclear characteristics of 186Re in preparation of radiopharmaceuticals for use in cancer theranostics, it is important to separate the radioisotope from the irradiated bulk component. A variety of methods based on dry distillation, thermochromatography, solvent extraction, ion exchange chromatography and adsorption on alumina column have been reported for radiochemical separation of high specific activity 186Re from the irradiated target (Fassbender et al., 2013; Mastren et al., 2017; Moustapha et al., 2006; Novgorodov et al., 2000; Richards et al., 2015; Shigeta et al., 1996; Zhang et al., 2001). Most of these processes involve multiple separation steps which are difficult to execute during large scale separations in shielded hot cells. In view of this limitation, prospects of using electrochemical separation route for availing high specific activity 186Re
181−186
Re-HEDP
from the irradiated target holds significant promise and therefore exploited in the present study. This strategy has earlier been established by our group in preparation of clinically important radionuclide generators for use in nuclear medicine (Chakravarty et al., 2008, 2009, 2010, 2012; Dash and Chakravarty, 2014). Electrochemical separation strategy exploits the difference between the formal electrode potentials of the different radionuclide ions dissolved in the electrolyte medium (Chakravarty et al., 2012; Dash and Chakravarty, 2014). The radionuclide of interest can be selectively electrodeposited on an electrode surface under the influence of controlled applied potential. This elegant technique is amenable for separation of miniscule quantity of the desired radionuclide (of high specific activity) from the bulk target material in a single step. Additionally, the process is not susceptible to radiation damage inflicted by the radionuclides dissolved in the electrolyte medium. The present 5
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for ICP-AES analyses of the decayed samples. Thanks are due to Dr. Ajay Singh and Dr. K. P. Muthe of Technical Physics Division, Bhabha Atomic Research Centre for their help in preparation of the target used for irradiation. Mr. Ramu Ram of Radiopharmaceuticals Division, Bhabha Atomic Research Centre is gratefully acknowledged for his help in the irradiation experiments.
study involved selective electrodeposition of Re radioisotopes from the irradiated WO3 target dissolved in alkaline medium on an inert platinum cathode. Platinum electrode was chosen for this study as it would not lead to addition of chemical impurities due to dissolution of the electrode material during the electrodeposition or stripping processes. The presence of such chemical impurities in high specific activity 186Re would negatively impact in subsequent radiolabeling studies. Owing to low hydrogen overvoltage and high discharge potential of the ions of tungsten, they cannot be electrodeposited from aqueous electrolyte media on a Pt electrode (Chakravarty et al., 2009). In fact, tungsten electrodeposition is generally performed from its molten salts (Liu et al., 2013). On the other hand, aqueous electrochemistry of Re is well established and this phenomenon has been exploited in selective electrodeposition of Re from sodium tungstate solution (Chakravarty et al., 2009; Hahn et al., 2007; Salakhova et al., 2012; Vargas-Uscategui et al., 2013). The electrochemical reduction of perrhenate ions in aqueous alkaline medium is as per equation (1).
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ReO4− + 7e +8H2O = Re + 8OH− Eo = −0.584 V (Salakhova et al., 2012) (1) The Re deposit could be finally stripped in saline solution, which is desirable from the perspective of radiopharmaceutical preparation. Since natural tungsten oxide target was bombarded with proton beam in the present study, a variety of Re radioisotopes were produced via natW (p, xn) 181−186Re reaction (Lapi et al., 2007; Zhang et al., 1999). It is pertinent to mention here that an optimized irradiation parameter (energy window) and use of enriched 186W target shall provide 186Re with high radionuclidic purity. Optimization of irradiation parameters has already been reported earlier via excitation function measurements using natural tungsten target (Ali et al., 2018; Bonardi et al., 2010; Lapi et al., 2007; Zhang et al., 1999) and hence not repeated in the present study. When enriched target is irradiated under the optimized conditions, this innovative and simple electrochemical separation strategy shall be useful for isolation of 186Re from the irradiated target for use in preparation of theranostic radiopharmaceuticals. 5. Conclusions The objective of developing a simple, clean and fast method for radiochemical separation of high specific activity 186Re from proton irradiated tungsten target has been successfully accomplished. Adopting the efficient electrochemical pathway reported in the article, 181−186 Re radioisotopes produced by proton bombardment on natural tungsten oxide were selectively separated from bulk target and obtained in a form suitable for preparation of radiopharmaceuticals. This electrochemical separation strategy would be useful to produce high specific activity 186Re on a large scale, enough for preparation of clinically relevant doses of theranostic radiopharmaceuticals, on the cyclotrons with high intensity proton or deuteron beams. The electrochemical separation technique can also be explored for the separation and purification of other medically important radionuclides produced in cyclotrons and thus serves as a model for future possibilities. Acknowledgements This work was done as a part of International Atomic Energy Agency – Coordinated Research Project (IAEA-CRP F22053) on ‘Therapeutic Radiopharmaceuticals Labelled with New Emerging Radionuclides (67Cu, 186Re, 47Sc)’. The authors are grateful to Dr. P. K. Pujari, Associate Director, Radiochemistry and Isotope Group, Bhabha Atomic Research Centre for his valuable support to the Isotope Program. The authors are thankful to all staff members at BARC-TIFR Pelletron facility who were involved in the proton irradiation. Analytical Chemistry Division, Bhabha Atomic Research Centre is gratefully acknowledged 6
Applied Radiation and Isotopes 154 (2019) 108885
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