Advantages and disadvantages of nuclear reactions used in reactors or cyclotrons, in addition to a theoretical study based on photodisintegration on natural indium for 111Ag production

Khaled M. El-Azony· Nader M. A. Mohamed · Dalal A. Aloraini

Abstract Production routes were recorded on available reactions for 111Ag production from nuclear reactors or cyclotrons using a natural palladium target based on 110Pd(n, γ) and 110pd(d, n) reactions, respectively. natCd(γ,x) based on 110Cd(γ, p) has also been studied as a prospective reaction for the production of 111Ag. Unfortunately, these nuclear reactions are difficult to utilize because,in some cases,they reduce the specific activity of 111Ag. This is a consequence of the stable silver isotopes produced in high concentrations. These isotopes include 107,109Ag and, in other cases, the high impurity of silver radioisotopes, such as 110m,106m,105Ag, that are produced during parallel nuclear reactions. Due to a scarcity of data regarding the(γ,α)reaction,the gamma reaction on natural indium for 111Ag production based on the 115In(γ, α)reaction was calculated. The natIn(γ, α) reaction satisfies the criteria as a possible reaction to produce 111Ag with a sufficient yield and purity as consequence of the high 115In(95.7%) abundance as an enriched form and a relatively soft background caused by the parallel nuclear reactions.

Keywords Silver-111 · Nuclear data · Natural cadmium ·Natural palladium · Natural indium

1 Introduction

Silver has long been recognized as an antimicrobial and therapeutic metal, frequently used for the treatment of a number of superficial wounds, bruises, and mild burns[1, 2]. The incorporation of silver into several pharmaceuticals is a common commercial in medical applications[3-7].Several radionuclides,including165Dy,169Er,198Au,166Ho,177Lu,32P,186Re,153Sm,89Sr,182Ta170Tm, and90Y,have been used as therapeutic agents as a consequence of the linear energy transfer(LET)property resulting from beta particle decay [8-10]. Recently, radionuclide theranostic concepts in nuclear medicine have demonstrated that gamma-ray decay or positron emission, as well as beta particle emission, can be used for both diagnostic and therapeutic purposes [11-13]. Referring to111Ag as a radionuclide (t1/2= 7.45 d), it has β-- particle emission(Emax= 1.04 MeV)[14]and γ-rays at energies of 245 keV(1.3%) and 342 keV (6.7%) suitable for detection [15];consequently,it has theranostic properties[16]owing to its characteristic decay state, as shown in Table 1. The length of beta emitting in tissue ranged from one to ten millimeters based on the quantity of energy emitted; consequently, it is ideal for medium to large tumors [17]. In addition, the decay of111Ag produces low gamma rays,allowing simultaneous SPECT imaging. The combination of diagnostic and therapeutic uses in the same isotope enables parallel therapy as well as in vivo dose monitoring[18]. Furthermore, the relatively long half-life of111Ag is compatible with the biological half-lives of antibodies;consequently, this isotope is attractive for application in radio-immunotherapy [19, 20].111Ag has been produced using a variety of nuclear reactions based on nuclear reactors [21, 22] and cyclotrons [23-25]. Thermal neutron irradiation of natural palladium targets produces anintermediate of111Pd radionuclide via a110Pd(n, γ)111Pd reaction and then the short-lived111Pd (t1/2= 23.4 min)decays to111Ag [21, 22]. Unfortunately, the cross section of the110Pd(n,γ)reaction is small(0.34 b)[26,27],and the presence of six stable palladium isotopes permits the numerous simultaneous nuclear reactions that reduce the purity and activity of111Ag. Deuteron-induced reactions have been studied to produce111Ag by110Pd(d, n) andnatPd(d, x) [23-25] resulting in an inescapable co-production of110mAg (t1/2= 249.83 d) in both reactions in addition to the presence of many silver radioisotopes produced due to a variety of nuclear reactions occurring on natural palladium. The yields of photonucleon reactions with different multiplicities that occur on a natural mixture of cadmium isotopes were measured in order to produce111Ag via anatCd (γ, p) reaction based on the112Cd (γ, p)reaction using Bremsstrahlung as a gamma-ray source with an endpoint energy of 55 MeV [28].

Table 1 Main decay data for the silver radioisotopes

As a result, photon-induced reactions were emphasized as electromagnetic radiation with a moderate energy of roughly (20-25) MeV that perturbs the nucleons in the target nucleus, causing the product particles to be released[29,30],and evidence for the regular threshold dependence of photon-induced reactions was observed. For the emission of alpha particles, reactions occur at the sum of the reaction threshold (Eth) and the Coulomb barrier (Bc). For many decades, researchers have investigated the (γ, α)reaction for light targets. However, literature data for medium-weight and heavy targets are limited. Cross sections of electro- and photonuclear reactions were studied on58Ni and60Ni targets[31,32].The product yields of(γ,α)reactions with antimony targets have been reported[33].The yield of117In in the121Sb(γ,α)reaction has also been reported to be close to 0.8% of the (γ, n) yield, which is much greater than that obtained by Volkov et al., 1980[31]. The yield of the (γ, α) reaction was found less than that of the (γ, p) reaction by a factor of 20, i.e., roughly 10-4of the rate of the (γ, n) reaction [28]. Due to contradictory results in the literature,as well as a general lack of reliable evidence,it can be concluded that there is a need to investigate the relative yields of bremsstrahlung-induced reactions, particularly in the case of (γ, α) reactions to heavy targets such as natural indium for the production of111Ag.

This work evaluates111Ag production methods based on accessible nuclear reactions, taking into consideration the target selection that provides the lowest cost,largest yield,and best purity, by evaluating nuclear data for all feasible nuclear reactions.

2 Production route

The criteria for producing111Ag as a theranostic radioisotope are based on reaction selection, which achieves high radionuclidic purity with high specific activity via projectile type,energy,and isotopic abundance in the target, as well as high chemical purity via chemical separation methods,as shown in Table 2.Although several nuclear reactions,including nuclear reactors vianatPd(n,γ)reactions [21, 22] and cyclotrons via232Th(p, f) andnatPd(d, n) reactions [16, 34], are used for111Ag production, an additional factor associated with the type of nuclear reaction is the chemical separation route. This is governed by yield, purity, and separation duration. The separation yield of111Ag based on the (n, γ) reaction was performed with a yield of 80-82% and a suitable chemical purity for use in nuclear medicine,where the palladium concentration was measured to be 1-2 μg [21, 22]. Unfortunately,111Ag was produced with low specific activity due to the high concentration of stable isotope109Ag product(90 GBq/mg at 24 h irradiation time and 5 × 1013n cm-2s-1neutron flux) [21]. According to the literature, two nuclear reactions,232Th(p, f) and110Pd(d, n), were used in the cyclotron to produce111Ag. Although the activity of111Ag produced in the(p,f)reaction is very significant,the fission reactions produce several radionuclides,resulting in a high proportion of radioactive impurities and the difficulty of separating111Ag with high purity, as well as a separation method that requires significant time. Furthermore, a110mAg long-lived radioisotope (t1/2= 249.83 d) with a relatively high ratio of 0.1% (0.518 GBq) could not be separated. Deuterium reactions have been studied on the110Pd(d,n)111Ag[36],but these routes are limited by the small110Pd deuterium capture cross section and the unavoidable co-production of the110mAg. In the medical context, typical111Ag radiotherapeutic doses range from 3700 to 7400 MBq (100 to 200 mCi) per patient [24, 37].The properties of the nuclear reactions are discussed individually below.

2.1 natPd(n,x)111Ag reaction

Natural palladium was irradiated in a nuclear reactor[21, 22]. The111Ag activity concentration in the irradiated target was determined using Eq. (1):

where A is the activity concentration of111Ag by Becquerel(disintegration per second), Nnetis the net area under the peak of 695 keV, while ε is the absolute efficiency of the detector at the given gamma energy, Iγis the branching ratio (7.1%) of the given gamma energy, and t is the measurement time. The quantity of produced stable109Ag isotope (μg) may be calculated by using the Avogadro number to estimate the number of radionuclides (N) in109Pd by knowing its activity (A) measured by Eq. (1) at a gamma energy peak of 88 keV,which has a branching ratio(Iγ) of 3.6%. Because both activity A and the half-life of109Pd(13.7 h)are known,Eq. (2)can be used to determine the number of radionuclides for109Pd.

Table 2 Comparison of 111Ag production methods based on the type of nuclear reaction used(reactor or cyclotron)and the separation method based on separation yield and chemical and radionucleudic purity

2.2 natPd(d,x)111Ag reaction

where Ntis the surface density of the target atoms,Nbis the number of bombarding particles per unit time, Tγis the photopeak number count, εdis the efficiency of the detector, εγis the gamma-ray intensity, εtis the dead time of measurement,which is the ratio of live time to real time,λ is the decay constant, tbis the time of irradiation, tcis the time of cooling, and tmis the time of acquisition.The data obtained from cross section reactions play a very important role in the production of radionuclides by cyclotrons,as described earlier[38,39].In order to be able to determine the yield with a good accuracy, one needs to know the full excitation functions.Therefore,the estimated yield of a product within a certain energy range,that is,the target thickness, may be determined using Eq. (5):

where Y is the yield of the activity concentration of the product by Becquerel, H is the enrichment (or isotopic abundance) of the target nuclide, M is the mass number of the target element,σ(E)is the cross section within a certain energy range,ρ is the density of the target material,and x is the projectile distance traveled through the target material.

2.3 Photonuclear reactions

Experimental photonuclear reaction data are typically collected by directly recording the number of particles released or by measuring the residual nuclear activity. In the case of energies that exceed the multi-particle emission threshold, more than one combination of emitted light particles may associate the same number of neutrons produced or may contribute to the same residual nucleus. The experimental data collection recorded for the (γ, n) cross section may contain charged particles released at the same time as a single neutron emission, that is, (γ, 1n) ＋(γ,1np) ＋(γ, n2p)….etc., which depend on the incident photon energy. Continuous bremsstrahlung spectra are generated by impacting the target with an electron beam from the accelerator (initially betatrons and synchrotrons,and now,linear accelerators).The photon energy spectrum is continuous, and the yield of the reaction Y(Eo) can be measured as in Eq. (6): [28]

where Eγis the photon energy, σ(Eγ) is the reaction cross section, W is the bremsstrahlung energy-dependent photon flux, E0is the endpoint energy of the bremsstrahlung spectrum relative to the electron beam energy, Ethis the threshold energy, and NRis the standardized coefficient.Adjusting the E0by simple changes allows the measurement of the yield curve, and then the use of the ‘‘unfolding’’ technique achieves a cross section for the photonuclear reaction. The benefit of bremsstrahlung measurements is the high photon beam intensity, which introduces the possibility of achieving sufficient statistics even with very limited cross section reactions. However,this technique has many challenges [28]. It is necessary to know more regarding the bremsstrahlung spectrum for all electron energies. Then, γ-analysis of the residual nucleus is performed after irradiation of the target by bremsstrahlung at varying endpoint energies [28-30]. From the γ-lines, the photonuclear reaction cross sections were calculated. The photon charged particle reaction cross sections, σ(γ, p)and σ(γ,α),respectively, are insufficient and limited in the literature and do not contain photon fission reactions.

2.3.1natCd(γ,x)111Ag reaction

The RM-55 microtron (55 MeV) was used for the irradiation experiments, as illustrated in Fig. 1. A tungsten braking converter(2.2 mm tungsten thickness)was used to generate bremsstrahlung radiation.The CdO target powder occupied an area of 6.3 cm2[28].The cadmium target was placed directly behind the braking target. The gamma radiation dose was monitored with the aid of a Faraday cylinder. The target is irradiated for a known duration and then transported for gamma-ray spectrum measurement by the Hp-Ge detector. The reaction yield (Y) was calculated using Eq. (7):

Fig. 1 Photodisintegration of natural cadmium [28]

2.3.2natIn(γ,x)111Ag reaction The following equation governs the activity A(t) of a produced radioisotope when a target is irradiated in a nuclear radiation flux: [40]:

where a and M are the abundance and atomic mass of the nuclide, m is the mass of the element in the target.

The analysis assumes that a natural indium target is exposed to a bremsstrahlung radiation beam produced by an electron accelerator at the energy distributions provided in Ref.[41],particularly at the endpoint energy of 24 MeV for the production of111Ag through the (γ, α) reaction.Indium has two naturally occurring stable isotopes,113In and115In, with natural abundances of 0.0429 and 0.9571,respectively. As a consequence of the (γ, α) reaction, the undesirable stable109Ag is produced alongside the radioisotope111Ag. The109Ag production is based on the abundance of113In on the natural indium target. Figure 2 illustrates the (γ, α) reaction cross sections of the two isotopes, and the threshold energy for both nuclides is approximately 10 MeV.The effective cross section can be calculated as follows:

Fig. 2 (γ,α) reaction cross sections of In-113 and In-115 [wwwnds.iaea.org]

where σ(E) represents the reaction cross section of energy E and φ(E) represents the energy-dependent flux. In this case,the bremsstrahlung radiation was calculated using the following equation:

3 111Ag production routes

Three nuclear reaction pathways were used by the nuclear reactor, cyclotron, and microtron RM-55, respectively, to produce111Ag as a β--emitter in a no-carrieradded form:

The production methodology involves work in many different directions, such as nuclear data, irradiation technology, chemical separation, and product quality control.

3.1 Production of 111Ag by natPd(n,x) reactions

Scheme 1 Irradiation scheme of natural palladium target by thermal neutrons for the production of 111Ag radionuclide

Palladium involves six stable isotopes of natural abundance; therefore, different radionuclides are produced by their activation using thermal neutrons in the nuclear reactor, as shown in Scheme 1. Activation of natural palladium targets by thermal neutrons produced111,111mPd as an intermediate radionuclide, as shown in the first nuclear reaction pathway. Nuclear data were obtained from literature data [42-46]. Scheme 1 shows that111Ag can be produced by pathway(1)accompanied by103Pd and109Pd.In the case of103Pd, it decayed to103Rh via electron capture, which could be easily separated chemically.However, the parallel reaction for the production of111Ag using natural palladium is the neutron capture of108Pd to form109Pd, which eventually decays by β-emission into stable109Ag. This reaction also limits the final specific activity of111Ag due to the high concentration of109Ag.Therefore,111Ag is produced as a carrier, according to the data provided in Table 3 [21, 47]. An increase in the irradiation time from 24 to 960 h contributes to a decrease in the specific activity of111Ag from 90 to 24 GBq/mg due to an increase in109Ag resulting from the decay of the high109Pd activity level based on a high natural abundance of108Pd (26.46%) and a high neutron cross section reaction(8.68 b).According to Alberto et al.,1992[21],the average yield of109Pd is 1630 MBq at 3 × 1013n cm-2s-1of neutron flux for 26 h of irradiation time, followed by 72 h of cooling to produce 100 MBq of111Ag(1 μg of Ag).The specific activity of111Ag was enhanced by decreasing the amount of109Ag, which could be accomplished by decreasing the cooling time and rapid chemical separation of111Ag from109Pd after EOB. However, the enriched110Pd could be used instead of the natural palladium to achieve a high specific activity for the production of111Ag carrier-free. However, this type of nuclear reaction is not preferred because of the high target price.

3.2 Production of 111Ag by natPd(d, x) reactions

There are two long-lived states of the111Ag radioisotope: the ground state (t1/2= 7.45 d) and the excited state of111mAg (t1/2= 64.8 s), which decays to111gAg by IT(99.3%). Excitation studies have been performed to determine the potential to produce111Ag (theranostic applications) using deuteron-induced reactions onnatPd[23,25,48-51].The meta-stable and ground-state of111Ag are occupied by the beta decay of meta-stable and ground-state of111Pd (t1/2= 5.5 h and 23.4 min, respectively.Experimental excitation functions have been studied using deuteron-induced reactions on natural palladium [23, 25],which have encountered difficulties in111Ag production with high purity due to a variety of nuclear reactions that are synchronized with the main reaction (d,n),as shown in Table 4. Side nuclear reactions depend on the projectile energy (deuteron energy) to reach the reaction threshold energy and the abundance of each isotope. Table 4 reveals that111Ag production uses anatPd(d,x) reaction based on a110Pd(d,n) reaction as a direct nuclear reaction. However,there are parallel reactions to106m,105,104,103Ag production that also consume the products of the105Pd(d,n),104Pd(d,n),103Pd(d,n), and102Pd(d,n) reactions, respectively.104,103Ag does not pose a problem because of their short half-lives and decay by electron capture and positron emission to yield stable104Pd and103Rh isotopes, which can be easily separated by chemical methods. The experimental cross section data for105,106m,110m,111Ag indicated the presence of their cross sections with high values within the deuteron energy range of 5-25 MeV [25, 51]. Halflives of110mAg,106mAg and105Ag are longer than the111Ag half-life and are thus difficult to separate chemically.In the literature, experimental data for integral physical yields are rare and have only been found in Ditroi et al.[23], as shown in Fig. 3.

Table 3 Activities and quantities of 109Ag and 111Ag formed by the irradiation of 0.1 g natural palladium using 5 × 1013 n/cm2/s [21, 46]

Furthermore, as shown in Table 5,111Ag can be produced indirectly vianatPd(d,x)on the basis of a110Pd(d,p)reaction to produce111Pd, which decays by beta emission to111Ag.The deuteron-induced reaction for108Pd via(d,p)produces109Pd, which decays by beta emission to stable109Ag, reducing the specific activity of111Ag.Although the cross section values for the production of109Pd vianatPd(d,p)are high[23],there is no documented existence of109Ag in the literature.

3.3 Production of 111Ag based on natCd(γ,x)reactions

Figure 4 indicates that the maximum cross sections of(γ, n) and (γ, p) reactions on natural cadmium within the gamma energy range of 15-20 MeV are 200-250 mb[52].Table 6 provides the threshold energies for various photon reactions to cadmium isotopes,which clarified that both(γ,n) and (γ, p) reactions begin within the energy range of 7-11 MeV, whereas the photon energy produced and required for the reaction to occur is within the range of 15-20 MeV, which is greater than the threshold energies for these reactions. Therefore, the generated γ-ray energy was able to produce all the radionuclides established in Table 6 [28, 30, 53, 54], as verified by the relative yield measurements for these radionuclides [28].111Ag is difficult to produce throughnatCd(γ, x) reactions because of simultaneous nuclear reactions that produce105,107,109,110m,112,113,115Ag based on the direct reactions(γ, p) cadmium isotopes at the same γ-energy used. In contrast, there are parallel reactions based on indirect reactions such as108Cd(γ, n) and110Cd(γ, n) which produce107Cd and109Cd. These two isotopes which decay by electron capture to107Ag and109Ag stable isotopes. These two Ag isotopes decrease the specific activity of111Ag.The literature has not definitively indicated the presence of silver isotopes, whether long-lived radioactive, such as105Ag,110mAg, or stable silver isotopes such as107Ag and109Ag, and concentrations can influence the specific activity of111Ag.

3.4 Production of 111Ag based on natIn(γ,x)reactions

Table 7 indicates that111Ag may be produced by thenatIn(γ, x) based on the115In(γ, α) reaction when the photon energy is greater than the sum of the two energies of the threshold and the Coulomb barrier (14.1 MeV). Other channels,such as the(γ,n)and(γ,p)reactions,are opened at threshold energies of 9 and 6.8 MeV, respectively, less than that required for the(γ,α)reaction,to produce114mIn(t1/2= 49.51 d) and the stable114Cd isotope, which can be easily separated by chemical methods. Parallel nuclear reactions produce a stable isotope of109Ag, a radionuclide of112mIn (t1/2= 20.56 min) and a stable isotope of112Cd,based on the reactions of113In(γ, α), (γ, n), and (γ, p),respectively. Fortunately,113In has a small abundance(4.3%) compared to115In (95.7%), so the109Ag concentration produced will not be a concern, as in other nuclear reactions.

Figure 5 shows the energy distributions of bremsstrahlung radiation, as quoted in the energy range of interest. The integrations in Eq. (5) for the effective cross section of113In and115In were calculated using the data in Figs.4 and 5(0.00532 and 0.00432 barns,respectively).In addition, the bremsstrahlung radiation flux in the range of concern was assessed, producing 10.37% of the overall bremsstrahlung radiation, as summarized in Table 8.

The bremsstrahlung photon flux in the range of interest will be 5.7 × 1013cm-2s-1if the electron accelerator is set to 10 μA [40, 41]. Substituting the evaluated results in Eq. (2), the interaction rates for both nuclides per gram of target (6.94 × 107and 1.24 × 109s-1, respectively) are calculated,as shown in Table 8.Since the(γ,α)reactions of113In and115In produce109Ag and111Ag, respectively, the rate of109Ag production to the rate of111Ag production is approximately 1: 18. The generated activity of111Ag was calculated as a function of irradiation time by substituting the interaction rate of115In in Eq. (1), as shown in Fig. 6.

Table 4 Deuterium induced reactions on natural palladium via natPd(d, x) reactions

Fig. 3 Integral yields for the natPd(d,xn)111,110m,106m,105,104,103Ag reactions [23]

4 Conclusion

This study confirms that the available nuclear reactions,which rely on natural targets to minimize production costs using Pd and Cd targets by thenatPd(n, x),natPd(d, x), andnatCd(γ, x) reactions, based on the110Pd(n, γ),110Pd(d, n),and112Cd(γ, n) reactions, respectively, to produce111Ag have several issues. Some reactions have a poor specific activity due to the high quantities of109Ag stable produced,while others have a low yield of111Ag because of the existence of radio-silver isotopes such as105,106mAg. The calculated data indicated that111Ag may be produced using thenatIn(γ,x)reaction based on the115In(γ,α)reaction as a promising reaction according to the achieved results of approximately 800 MBq111Ag per gram of indium metal target during 12 days of irradiation time.The ratio of109Ag production to111Ag production is roughly one to 18,implying that111Ag may be produced with a high specific activity.

Fig.4 Bremsstrahlung gamma-ray spectrum as in the solid curve and cross section [σ(γ, x) = σ(γ, n) ＋σ(γ, p) ＋…] (the dashed curve)for the reaction of the natural cadmium target according to data obtained from [40]

Table 5 Nuclear data obtained by activation via natPd(d,x) reactions to produce radioactive palladium isotopes

Table 6 Reaction yields and threshold energies for natCd(γ, x) reactions based on experimental measurements

Table 7 Threshold energies(Eth) and Coulomb barrier (Bc)for the natIn (γ, x) reactions

Fig.5 Distributions of bremsstrahlung radiation in the range from 10 to 24 MeV

Table 8 Data and calculation results of irradiating natural indium metal in an electron accelerator operated at 10 μA

Fig.6 The generated activity of Ag-111 as a result of irradiating 1 g of natural indium metal in electron accelerator operated at 10 μA

AcknowledgementsThis research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through a fast-track research funding program.

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Authors contributionAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Khaled Mohamed El-Azony, Nader M.A. Mohamed and Dalal A. Aloraini. The first draft of the manuscript was written by Khaled Mohamed El-Azony, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

FundingOpen access funding provided by The Science,Technology& Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB).