Niobium as Preferential Material for Cyclotron Target Windows

: The present work promotes and validates the benefits of using niobium instead of Havar ® as the material for the target windows in most routine irradiations in cyclotrons. Calculation of the material activation and measurements of the contamination of the transferred target liquids show major improvements with the use of niobium. Also, the data of the daily routine productions at our production center are presented, proving that Havar ® is not mandatory unless large target currents and/or pressures are required


Introduction
The use of niobium in cyclotron targetry is well established and has long been proven effective; this metal provides consistent advantages due to its chemical inertness, good thermal conductivity and high melting point, among other factors [1].Also, niobium has a low activation cross-section for both protons and thermal neutrons, producing thus far less activation when compared to other suitable options-A characteristic particularly relevant for periodic maintenance tasks.Finally, the activation of niobium reduces drastically after a reduced cooling time, an advantage usually not provided by other materials such as silver.
Similar considerations are valid when considering the material for target windows.However, in this case, it is also mandatory to present improved mechanical strength, even with minimum thickness.For this particular reason, Havar ® , over the years, he become the standard solution for target windows working at high currents and pressures.Unfortunately, this choice came at the expense of harmful consequences since (i) Havar ® -like any steel alloy-presents a multitude of components and, therefore, several radiocontaminants; and (ii) its irradiation results in intense long-term activation.
As biomedical cyclotrons have been developed throughout recent decades for the optimized production of 18 F, with their main goal of the synthesis of 18 F-FDG borne in mind, these machines usually provide protons with a fixed energy of around [16][17][18][19] MeV, depending on the manufacturer.Although such an energy range is suitable for the production of 18 F, it is too high for the production of medically emergent radioisotopes (e.g., 68 Ga) [2].The use of thicker target windows as degraders to reduce the initial energy of the beam on the target has therefore become frequent, with Havar ® becoming much less adequate with larger thicknesses due to its inferior thermal conductivity leading to increased heat load.Moreover, the many (both cold and radioactive) metallic contaminants released from Havar ® during irradiation-and leaching, especially, into liquid target material-are additionally prohibitive for radiolabeling processes involving radiometals, therefore making it mandatory to use a distinct material for target windows.
It is within this particular and more contemporary scenario that niobium naturally became considered as an alternative for target windows, not only because of the previously Instruments 2024, 8, 33 2 of 9 mentioned advantages but also because the target cavity is usually already made of niobium.Its use for target windows therefore avoids the addition of new materials and/or contaminants-either cold or radioactive-within further processes.Furthermore, unlike Havar ® , there is no longer a need for it to be treated as long-term radioactive waste since its activation decays massively after only 2-3 months.The eventual production of 93 Mo is the only exception [3], depending on the incident proton energy.Moreover, niobium is also more affordable and less dangerous (e.g., it contains no beryllium, unlike Havar ® ).
This work presents the benefits of using niobium for target windows, presenting those benefits in terms of the handling of radioactive waste and reduction of transferred radiocontamination, while simultaneously presenting performance data for reliable daily routine use with several thicknesses and distinct production routes.

Methods and Results
At the Institute of Nuclear Sciences Applied to Health (ICNAS) of the University of Coimbra, the cyclotron and radiochemistry laboratory operates daily for the production of radiopharmaceuticals for both routine productions and R&D activities based mainly on the radioisotopes 11 C, 13 N, 18 F, 61 Cu, 64 Cu, 68 Ga and 89 Zr.These latter are produced thanks to two cyclotrons from the manufacturer IBA, namely, the Cyclone 18/9 model, delivering 18 MeV protons and 9 MeV deuterons, and the Kiube Variable Energy cyclotron, delivering protons with energy ranging from 13 to 18 MeV.The cyclotron target systems used are either gaseous or liquid and require target windows made of aluminium, titanium, niobium or Havar ® .Table 1 presents calculations for the cumulated production yields for the radioisotopes with half-lives greater than 2 weeks produced in these target windows of different materials with distinct thicknesses and irradiated at either 13 or 18 MeV.Some of these radioisotopes are even produced though several nuclear reaction routes (e.g., 57 Co is produced via the 59 Co(p,p2n) 57 Co, 56 Fe(p,γ) 57 Co, 57 Fe(p,n) 57 Co, 58 Fe(p,2n) 58 Co, 58 Ni(p,2p) 57 Co and 60 Ni(p,α) 57 Co reactions).The cumulated production yields were obtained using excitation curve fits from cross-section data available in the EXFOR database [4].The last column of Table 1 also presents an estimation of the activity produced for each of these radioisotopes after a period of one month, considering our particular routine schedule of irradiations.Since the half-lives considered are much larger than the time between consecutives irradiations, the decay between irradiations was neglected.For the few exceptions for which the half-life exceeds 2 weeks but is still less than the time unit considered-i.e. one month -(e.g., 48 V), a factor of 0.5 was applied as a rough approximation to account for the decay within the one-month duration.These monthly estimations were used to calculate the cumulative activity produced in the target windows, considering a 30-year-long operation cycle followed by another 30-year-long period of cooling as a practical example.The production and accumulation of radioactivity during this first 30-year cycle of routine production behaves similarly to an irradiation cycle, reaching saturation according to the half-life of the radioisotope in question, with the difference being that those calculations were conducted with a unit time of one month to make use of the monthly production yield calculated.The results obtained for the materials used as target windows are presented in Figure 1 and Table 2.It is possible to see that most of the overall activity resulting from such activation comes from Havar ® , whereas niobium foils produced far less activation.Complementarily, Figure 2 enables us to have a closer look at the decay rates for these materials, confirming that Havar ® is still the most relevant radioactive waste for the first decade of cooling time.Niobium only becomes relevant because of the presence of the long-lived 93 Mo, which is almost exclusively produced when irradiating niobium at 13 MeV (Table 1) and therefore almost avoided at larger initial energies.Moreover, another relevant parameter to consider consists of the quantification of any radiocontaminants removed from the target window during irradiation and then transferred together with the irradiated liquid target.This is of particular interest as it can significantly affect the subsequent radiosynthesis.One of the most illustrative examples is the production of 68 Ga from liquid targets since the very sensitive radiolabeling conditions make the use of Havar forbidden [34,35].Also, for the synthesis of 18 F-based com- Moreover, another relevant parameter to consider consists of the quantification of any radiocontaminants removed from the target window during irradiation and then transferred together with the irradiated liquid target.This is of particular interest as it can significantly affect the subsequent radiosynthesis.One of the most illustrative examples is the production of 68 Ga from liquid targets since the very sensitive radiolabeling conditions make the use of Havar forbidden [34,35].Also, for the synthesis of 18 F-based compounds, the presence of radiometallic impurities was proven to affect the synthesis yields negatively [36,37].Proofs of the non-negligible presence of these radiocontaminants rely on their accumulation in both the recovery vial for the irradiated enriched water and the QMA cartridge; therefore, they become long-term radioactive wastes.Figure 3 presents the high-purity germanium (HPGe) detector analysis performed on water irradiated under standard conditions for the production of 18 F using Havar ® foil for 30 min.It shows that the presence of the expected radiometalic contaminants actually increases with the aging of the Havar foil.
pounds, the presence of radiometallic impurities was proven to affect the synthesis yields negatively [36,37].Proofs of the non-negligible presence of these radiocontaminants rely on their accumulation in both the recovery vial for the irradiated enriched water and the QMA cartridge; therefore, they become long-term radioactive wastes.Figure 3 presents the high-purity germanium (HPGe) detector analysis performed on water irradiated under standard conditions for the production of 18 F using Havar ® foil for 30 min.It shows that the presence of the expected radiometalic contaminants actually increases with the aging of the Havar foil.The same occurs when producing 13 N with a Havar ® window.In this case, these radiocontaminants are even present in the final product vial (FPV), albeit, naturally, in quantities far lower than those required to comply with the radionuclidic purity specification requirement of the European Pharmacopoeia [38].Table 3 presents the activities of the radiometallic contaminant present in the FPV and confirms that the ageing of the Havar ® target windows also results in increasing amounts of these contaminants.The same occurs when producing 13 N with a Havar ® window.In this case, these radiocontaminants are even present in the final product vial (FPV), albeit, naturally, in quantities far lower than those required to comply with the radionuclidic purity specification requirement of the European Pharmacopoeia [38].Table 3 presents the activities of the radiometallic contaminant present in the FPV and confirms that the ageing of the Havar ® target windows also results in increasing amounts of these contaminants.Figure 4 presents gamma-spectrometry analysis performed with a HPGe detector on the FPV of 13 N-NH 3 productions using either 35 µm thick Havar ® foil or 125 µm thick niobium foil as the target windows.The analysis was performed after a cooling period of more than 24 h to allow both 13 N and 18 F to decay.For this particular example of the production of 13 N, the thickness of niobium was increased to 125 µm so that the target window would simultaneously behave as a degrader (energy reduced down to 16.1 MeV [34]) in order to minimize the co-production of 15 O via the 16 O(p,pn) 15 O reaction down to acceptable values.Target currents up to 40 µA are used with a consistent end-ofsynthesis (EOS) yield at of 1.4 GBq/µAh (i.e., up to 20 GBq at EOS). Figure 4 shows that it is not possible to detect these radiometallic contaminants when using niobium, whereas these are easily detectable when using Havar ® as the target window material.
window would simultaneously behave as a degrader (energy reduced down to 16.1 MeV [34]) in order to minimize the co-production of 15 O via the 16 O(p,pn) 15 O reaction down to acceptable values.Target currents up to 40 µA are used with a consistent end-of-synthesis (EOS) yield at of 1.4 GBq/µAh (i.e., up to 20 GBq at EOS). Figure 4 shows that it is not possible to detect these radiometallic contaminants when using niobium, whereas these are easily detectable when using Havar ® as the target window material.As previously demonstrated in [36,37], one can expect that the use of niobium windows would allow for an improvement in the yield of sensitive synthesis through the reduction of radiometallic contaminants.We unfortunately do not possess such proof so far as we still use Havar ® for the production of 18 F.However, we already successfully implement niobium windows-with different thicknesses according to the production route-in most of our targets, i.e., not only in liquid targets developed for the production of radiometals (e.g., 68 Ga, 64 Cu, 61 Cu, 89 Zr) but also for the production of 13 N (Table 1).For instance, proton currents up to 75 µA are usually used for the production of 61 Cu [2], and currents of up to 90 µA are also successfully used when producing 68 Ga [39].Our daily experience shows that niobium can successfully be used as a material for target windows in daily, reliable irradiations, as long as the helium cooling system maintains its long-term stability and performance [39,40].

Conclusions
The several advantages of niobium-ranging from low activation to chemical in- As previously demonstrated in [36,37], one can expect that the use of niobium windows would allow for an improvement in the yield of sensitive synthesis through the reduction of radiometallic contaminants.We unfortunately do not possess such proof so far as we still use Havar ® for the production of 18 F.However, we already successfully implement niobium windows-with different thicknesses according to the production route-in most of our targets, i.e., not only in liquid targets developed for the production of radiometals (e.g., 68 Ga, 64 Cu, 61 Cu, 89 Zr) but also for the production of 13 N (Table 1).For instance, proton currents up to 75 µA are usually used for the production of 61 Cu [2], and currents of up to 90 µA are also successfully used when producing 68 Ga [39].Our daily experience shows that niobium can successfully be used as a material for target windows in daily, reliable irradiations, as long as the helium cooling system maintains its long-term stability and performance [39,40].

Conclusions
The several advantages of niobium-ranging from low activation to chemical inertness, among other examples-make it a suitable choice as a material for target windows.The only exception seems to be very large currents and/or pressures, for which Havar ® remains the gold standard.Our calculations of material activation and the results of our comparison of the contamination of the irradiated transferred solutions prove our central claim.Moreover, our particular daily production routine has successfully demonstrated the potential of niobium as a material for target windows [2,39].

Figure 1 .
Figure 1.Activity present in the different target materials over time (initial 30 years of routine irradiations followed by 30 years of cooling time).

Figure 1 .
Figure 1.Activity present in the different target materials over time (initial 30 years of routine irradiations followed by 30 years of cooling time).

Figure 2 .
Figure 2. Activity present in the different target materials over a cooling period preceded by 30 years of routine irradiations.

Figure 2 .
Figure 2. Activity present in the different target materials over a cooling period preceded by 30 years of routine irradiations.

Figure 3 .
Figure 3. Activity measured for the radioisotopes present in the irradiated water when using Havar ® foil as a function of the accumulated integrated target current in the foil (with N being the number of samples in each case).

Figure 3 .
Figure 3. Activity measured for the radioisotopes present in the irradiated water when using Havar ® foil as a function of the accumulated integrated target current in the foil (with N being the number of samples in each case).

Figure 4 .
Figure 4. HPGe spectra of FPVs of 13 N-NH3 productions after a 24 h cooling period when using either (i) a 35 µm thick Havar ® foil (top) or (ii) a 125 µm thick niobium foil (middle) as target windows.(iii) A background spectrum (bottom) is also presented for direct comparison.

Figure 4 .
Figure 4. HPGe spectra of FPVs of 13 N-NH 3 productions after a 24 h cooling period when using either (i) a 35 µm thick Havar ® foil (top) or (ii) a 125 µm thick niobium foil (middle) as target windows.(iii) A background spectrum (bottom) is also presented for direct comparison.

Table 1 .
Radioisotopes with half-lives greater than 2 weeks produced by proton irradiation at 18 and 13 MeV in the different target windows.

Table 1 .
Radioisotopes with half-lives greater than 2 weeks produced by proton irradiation at 18 and 13 MeV in the different target windows.

Table 2 .
Activity of the radioisotopes with half-lives greater than 2 weeks produced after 30 years of daily irradiations and after 30 years of cooling time.

Table 2 .
Activity of the radioisotopes with half-lives greater than 2 weeks produced after 30 years of daily irradiations and after 30 years of cooling time.

Table 3 .
Radioisotopes present in the FPV of 13 N-NH3 productions using a 35 µm thick Havar ® foil as a target window.

Table 3 .
Radioisotopes present in the FPV of 13 N-NH 3 productions using a 35 µm thick Havar ® foil as a target window.