Production and purification of 43Sc and 47Sc from enriched [46Ti]TiO2 and [50Ti]TiO2 targets

The radioscandium isotopes, 43Sc and 47Sc, compose a promising elementally matched theranostic pair that can be used for the development of imaging and therapeutic radiopharmaceuticals with identical structures. This study aimed to investigate the production of high radionuclidic purity 43Sc from enriched [46Ti]TiO2 targets and 47Sc from enriched [50Ti]TiO2 targets and establish a target recycling technique. Enriched [46Ti]TiO2 targets were irradiated with 18 MeV protons, and enriched [50Ti]TiO2 targets were bombarded with 24 MeV protons. 43Sc and 47Sc were purified using ion chromatography attaining recovery yields of 91.7 ± 7.4% and 89.9 ± 3.9%, respectively. The average radionuclidic purity for 43Sc was 98.8 ± 0.3% and for 47Sc 91.5 ± 0.6%, while the average recovery of enriched titanium target material was 96 ± 4.0%. The highest apparent molar activity for [43Sc]Sc-DOTA was 23.2 GBq/µmol and 3.39 GBq/µmol for [47Sc]Sc-DOTA. This work demonstrates the feasibility of using enriched recycled [46Ti]TiO2 and [50Ti]TiO2 targets to produce high purity 43Sc and 47Sc as an elementally matched theranostic isotope pair.


Reagents
All chemicals used were analytical or trace metal grade unless otherwise stated.Water was obtained from a deionized 18.2 MΩ-cm Milli-Q System (Millipore, Billerica, MA).Hydrochloric acid (HCl, 37% by weight, 99.999%), ammonium bifluoride (NH 4 HF 2 , 99.999%), and 28% ammonia solution (NH 4 OH, 99.999%) were purchased from Sigma-Aldrich (St. Louis, MO).Nitric acid (HNO 3 , 67-70% by weight, 99.999%) was purchased from Fisher Scientific (Hampton, NH, USA).Enriched 46 Ti and 50 Ti were provided by the National Isotope Development Center, USA.The isotopic percentage, provided by the National Isotope Development Center, is given in Table S3 in supplemental information and the Certificates of Analysis in Table S4.The titanium cover foil with 4N5 purity and tantalum coin backing with 3N8 purity were purchased from ESPI Metals (Ashland, OR, USA).All periodic table analytical standards (mix 101, 103, 104, 5% HNO 3 , 10 mg/L) and SG-iTLC plates were purchased from Agilent Technologies (Santa Clara, CA, USA).Analytical-grade N,N,N′,N′-tetra-2-ethylhexyldiglycolamide (branched DGA) resin was purchased from Eichrom Technologies (Lisle, IL) and empty 1 mL SPE fritted columns, 0.2 µm additional frits, and column adaptors were purchased from Sigma-Aldrich (Supelco, Sigma-Aldrich, St. Louis, MO).DOTA was purchased from Macrocyclics (Plano, TX, USA).The Micro Deluxe Phantom™ with the Micro Deluxe Cold Rod Insert™ was purchased from Data Spectrum Corporation (Durham, NC, USA).Conical 15 mL screwcap perfluoroalkoxy alkane (PFA) digestion vessel, 6 mL Octagonal Body Vial, and PFA 10 mL volumetric flasks were purchased from Savillex (Eden Prairie, MN).Millipore Sigma MF-Millipore Mixed Cellulose Ester Membranes with 0.22 µm pore size were purchased from Fisher Scientific (Hampton, NH, USA).The 68 Ga was eluted from Eckert and Ziegler 68 Ge/ 68 Ga generator using 0.1 M HCl and was concentrated on an Agilent Bond Elute SCX cartridge, where 68 Ga was recollected in 250 µL 5 M NaCl/0.1 M HCl.All glassware was cleaned in a 20% HNO 3 bath overnight before use.

Target preparation and irradiation conditions
The 2-mm thick tantalum (Ta) target coins and target material preparation were carried out as previously reported by Loveless et al. 17 .Briefly, the TiO 2 material was kept at 250 °C in an oven for at least 24 h before bombardment.Approximately 100 mg targets were pressed in a FTIR pellet 10-mm evacuable die (Specac, Kent, UK) by increasing the applied pressure in 1-ton increments per minute up to 5 tons, then held at 5 tons for 15 min using a Carver model 3664 hydraulic press (Carver, INC, Wabash, IN, USA).The pellet was removed and placed into the divot of a 2 mm Ta coin.Targets were irradiated on a TR-24 cyclotron (Advanced Cyclotron Systems, Inc., Richmond, BC, Canada) using a 90° coin target holder (Advanced Cyclotron Systems, Inc., Richmond, BC, Canada) 20 .For 43 Sc production using [ 46 Ti]TiO 2 , targets were bombarded with 18 MeV protons at 20 µA for 1.5 h.For 47 Sc production using [ 50 Ti]TiO 2 , targets were bombarded with 24 MeV protons at 20 µA for 4 or 8 h.The theoretical predicted activity was calculated based on the cross section measurements retrieved from EXFOR shown in Fig. S1 [21][22][23] .Cross sections for additional co-produced radiocontaminants are presented in the supplemental information Fig. S2.

Digestion of TiO 2
The irradiated target material was removed from the Ta coin and added to a 15-mL screwcap PFA digestion vial with 300 mg of NH 4 HF 2 .The vial was capped and placed into a furnace at 250 °C for 2 h.After digestion, the vial was removed and allowed to cool before adding 5 mL of concentrated HCl.The vial was heated in a silicone oil bath at 160 °C for 45 min.The dissolved solution was transferred into a 10 mL PFA volumetric flask and diluted www.nature.com/scientificreports/ to 10 mL, using 1 mL additions of 9 M HCl, rinsing the digestion vial in the process for a final concentration of 10.5 M HCl.

Purification
Approximately 150 mg of branched DGA resin was added to an empty SPE column with frits on either side of the resin bed.The column was conditioned with a syringe pump at 2 mL/min with the following solutions: 20 mL of 7 M HNO 3 , 20 mL of 1 M HNO 3 , 20 mL of Milli-Q water, 20 mL of 0.1 M HCl and 20 mL of 9 M HCl.Air was pushed through after each solution.Following column conditioning, the dissolved target was loaded onto the column through a 10 mL syringe, which was either pushed manually or by using a syringe pump with the flow rate set to 2 mL/min (collected in Flow-Through (FT) tube).The column was then washed with 20 mL of 9 M HCl (Elution 1 (E1)), followed by 10 mL of 7 M HNO 3 (Elution 2 (E2)), 3 mL of 1 M HNO 3 (Elution 3 (E3)), and three separate, 3 mL additions of 0.1 M HCl (Elution 4-6 (E4-6)) as shown in Fig. S3.Each of the eluents was collected in individual Falcon tubes.The E4 fraction was evaporated to dryness using a Smart Evaporator (BioChromato) before being reconstituted with 200 μL 0.1 M HCl and used for further studies.The evaporation conditions used a 5 mL PFA vial, heated at 100 °C in an Al bead bath under vacuum without the use of N 2 .

Target material recycling
The FT and E1 fractions were combined and diluted to 500 mL with Milli-Q water in a 1 L glass beaker.The beaker was wrapped with plastic wrap and the solution was heated to 80 °C for 1 h and then allowed to cool.
While stirring, the solution was adjusted to pH 8 with 1 mL additions of 28% ammonium hydroxide, until the TiO 2 precipitated as a white cloudy solution.The solution/precipitate was left to settle overnight at room temperature and then vacuum filtered using a 0.22 μm mixed cellulose filter paper on a low vacuum.After the filter paper was dried, the TiO 2 was collected into a clean, dry beaker and placed into a vacuum furnace at 250 °C for at least 24 h before the next bombardment.

Gamma-ray spectroscopy
Gamma-ray spectroscopy was used for isotope identification, to determine radionuclide yields and radionuclidic purity using a Canberra GC2018 High Purity Germanium detector (HPGe), interfaced with a DSA = 100 multichannel analyzer (Meriden, CT, USA).Data acquisition and analysis were performed using Genie 2000 software (Canberra).A 1. where A 1 is the activity calculated from the HPGe acquisition, N p is the net peak area in each photopeak, λ is the decay constant of radioisotope of interest, ε is the detector efficiency of the photopeak, t 1 is the real-time of HPGe acquisition, D r is the average dead time of the instrument, I γ is the branching ratio of the γ-ray of the radioisotope, A o is the activity at the end of bombardment, and t o is the time passed between the end of bombardment and the time of acquisition 24 .Measurements were taken for a minimum of 500 counts under each photopeak and a deadtime no larger than 5%.

Inductively coupled plasma mass spectrometry (ICP-MS)
Elemental analysis was performed on Agilent Technologies 7800 ICP-MS (Santa Clara, CA, USA) with Agilent software, ICP-MS MassHunter v4.3.A 20 µL aliquot from each fraction from the separation was diluted to 10 mL with 2% HNO 3 to determine the elements present, in triplicate.The dissolved target solution and the flow-through collection had a secondary dilution step where 400 µL of the first ICP-MS sample was diluted to 10 mL in 2% HNO 3 .Multi-element standards in 2% HNO 3 were used for calibration of 0.1, 0.5, 1, 5, 10, 100, 200, 400, 600, 800, and 1000 ppb for the calibration curve and prepared in 10 mL volume from a 10 µg/mL stock.
Elements selected for monitoring are given in the supplemental information Table S5.

Apparent molar activity
To determine apparent molar activity (AMA), a DOTA titration was performed using 43 Sc or 47 Sc, after which, the half-maximum effective concentration (EC 50 ) for complete complexation was determined by taking the best-fit values of a transform of the log(µmol) versus percent radiolabeled, performed using Prism 8 software.Then, the average activity added was divided by EC 50 multiplied by 2, shown in Eq. (3) below.
(1) www.nature.com/scientificreports/Details of the titration are provided in the supplemental information; section i of the supplemental and Table S6.Analysis of the samples was performed via instant thin-layer chromatography by spotting 1 µL of sample on an iTLC-SG paper and developing in 1 M citrate buffer.An Eckert & Ziegler AR2000 TLC scanner (Berlin, Germany) was used for TLC analysis.

Phantom imaging
A phantom composed of poly(methyl methacrylate) with rod diameters between 1.2 and 4.8 mm was used for imaging studies.Complete details of the phantom dimensions are provided in supplemental information Fig. S5.The preparation process for the phantoms containing 18 F, 43 Sc, or 68 Ga involved diluting each radioactive solution to 20 mL with Milli-Q water (MQ).Subsequently, 18 mL of the diluted solution was added to the phantoms to achieve a radioactivity of 3.72 ± 0.06 MBq (100.6 ± 1.7 µCi).The phantoms were scanned for 30 min on the UAB small animal GNEXT PET/CT scanner (GNEXT PET/CT, Sofie Biosciences, CA, USA), with an energy window of 350-650 keV, followed by a 5-min CT scan at a voltage 80 kVp, current 150 μA, and 720 projections.Images were reconstructed using a 3D-OSEM (Ordered Subset Expectation Maximization) algorithm (24 subsets and 3 iterations, with random, attenuation, and decay correction).Additionally, the 18 F and 43 Sc were reconstructed with the same number of total decays as the 68 Ga scan (1693 s for 18 F and 1614 s for 43 Sc).The images were processed using the description by Bunka et al. 25 .Image analysis was performed using VivoQuant software (VivoQuant 4.0, Invicro Imaging Service and Software, Boston USA), where one representative transversal section was used and analyzed at the different depths of the phantom.The resulting intensity plots of each phantom were exported to Origin * 2022 (OriginLab), where the full-width at half-maximum (FWHM) was processed for each slice, and an arithmetic mean and standard deviation were obtained 25,26 .All three radionuclides' FWHM were compared for all visibly distinguishable rods.The 43 Sc FWHM were statistically compared to 18 F and 68 Ga FWHM using either one-way ANOVA, on rods 4.8, 4.0 and 3.2 mm, or to 18 F only using t-test statistics for 2.4 and 1.6 mm rods.

Digestion and separation yields
Targets were readily dissolved in a pressurized PFA digestion vial before isolating the radioscandium nuclides from co-produced radiovanadium and the titanium starting material.The two-step dissolution process took a total of 3 h.A representative separation profile for 47 Sc is depicted in Fig. 1 and supplemental information Table S7 show the results of the separation, where the total average 43 Sc and 47 Sc recovery yields were 91.7 ± 7.4% and 89.9 ± 3.9%, respectively, with the majority in the E4 fraction.The co-produced 48 V was removed before the elution of the 43 Sc and 47 Sc as shown in the gamma ray spectra in Fig. 2. The decay corrected activity at the end of bombardment for a 1.5 h run using 46 Ti and a 4 h run using 50 Ti was 510 MBq (13.8 mCi) for 43 Sc and 52.17 MBq (1.42 mCi) for 47 Sc (supplemental information Table S7).
The radionuclides were measured by gamma-ray spectroscopy using their characteristic γ-rays presented previously in Table S2.The identification of the radionuclides is shown in the HPGe spectra in Fig. 2. Each photopeak is labeled with their corresponding radionuclide.The spectra shown in panels a and c in Fig. 2 represent the dissolved target solution of either production whereas panels b and d are for the purified material.
HPGe analysis was used to determine the final activity and the radionuclidic purity of 43 Sc and 47 Sc decay corrected to end of bombardment.Table 1 is the average activity produced of all radioscandium nuclides and the radionuclidic purity for [ 46 Ti]TiO 2 and [ 50 Ti]TiO 2 bombardments, decay corrected to end of bombardment.The quantification of the longer-lived 46 Sc, 47 Sc, 48 Sc were measured at later time points (≥ 1 day for 47 Sc and 48 Sc and ≥ 4 weeks for 46 Sc), after the shorter lived radioisotopes ( 43 Sc and 44 Sc) have decayed.The average radionuclidic purity for 43 Sc from enriched targets was 98.8 ± 0.3%.The average radionuclidic purity for 47 Sc from enriched targets was 91.5 ± 0.6%.ICP-MS was conducted to assess the elution and presence of trace metal contaminants including Cr, Mn, Ni, Fe, Cu, W, and Zn throughout the separation with results shown in Fig. 3.
The following elements are shown to be removed before the elution of 47 Sc: Cr, Mn, and Ni.Fe, Cu, W and Zn are shown to be significantly reduced before the product collection, < 15 ppb.All other elements measured were below the limit of detection (< 15 ppb for E3-6 and < 50 ppb for other eluted fraction).The elements monitored during analysis were based on the Certificate of Analysis in supplemental information Table S4.Additionally, continued recycling of the target resulted in improved purity as both rinse fractions E2 and E3 were not included during the recycling process, therefore any impurities in those elutions were not reintroduced into the next cycle.This is shown in Table 2, where the trace metal analysis of purified 47 Sc is compared to

Recycling yields
The average recovery from the recycling process was 96 ± 4% (n = 5), showing a high recovery of the target material.The recovery over several run cycles is presented in supplemental information Fig. S6 for [ 46 Ti]Ti and [ 50 Ti] Ti by ICP-MS analysis.Furthermore, Table 3 demonstrates the high target material recovery as the production yields from the same recycled targets, either [ 46 Ti]TiO 2 and [ 50 Ti]TiO 2 , remain consistent.

Apparent molar activity
The radioisotopes 43 Sc or 47 Sc were used to radiolabel DOTA at various concentrations with the % complex versus DOTA concentration represented in Table S6.An scan of an iTLC of a 100% radiochemical yield of [ 47 Sc]  Sc-DOTA and one scan with free [ 47 Sc]Sc control is shown in Fig. S4.The apparent molar activity curve is shown in Fig. S7.The estimated apparent molar activity (AMA) was improved when the target material from later recycling cycles was used.The 43 Sc AMA was 5.92 GBq/µmol (160.3 mCi/μmol) for the second target cycle and improved to 23.2 GBq/µmol (628 mCi/μmol) for the 6th cycle.The 47 Sc AMA was 1.26 GBq/µmol (34.0 mCi/ μmol) for 3rd cycle and was 3.39 GBq/µmol (91.7 mCi/μmol) for 6th cycle.

Phantom imaging
A phantom comparison was performed for two purposes: as a proof-of-concept comparison to reported literature and to assess the image quality of our produced 43 Sc compared to the clinically used 18 F and 68 Ga and reported literature.All phantoms were prepared and imaged in the same manner, the 18 F and 43 Sc were reconstructed under two parameters: where the first reconstruction included the entire 30 min scan and the second reconstruction used shorter time frame (1693 s for 18 F and 1614 s for 43 Sc) for the same total decays of either isotope to match the total decays of the 30 min 68 Ga scan.These images are shown in Fig. 4. A qualitative assessment of Fig. 4 suggests that 43 Sc has a favorable imaging quality and slightly improved resolution over 68 Ga for both reconstructions.Table 4 shows the numerical expression of the image difference using FWHM for all visibly distinguishable rods.
The resulting FWHM corroborates the qualitative analysis of the resolution quality of these radionuclides, both for phantom scanned for the same time or reconstructed for the same total decays.The quantitative resolution results also illustrates that the order of resolution from highest to lowest is: 18 F > 43 Sc > 68 Ga.
Both 18 F and 43 Sc transversal slice images were acquired from the same position.Both of the 43 Sc scans were significantly different to the 68 Ga scan at the 4.0 mm (p = 0.0004 for full 30 min scan and 0.003 for normalized) and 3.2 mm (p = 0.0009 for full 30 min scan and 0.001 for normalized).Both of the 43 Sc scans were also significantly different from the 18 F scan on the 2.4 mm rod (p = 0.034 for the 30-min scan and p = < 0.0001 for the normalized).All other comparisons were not statistically significant.

Discussion
The production of elementally matched theranostic pairs is highly sought after but commonly requires the use of expensive enriched material.Developing a target recycling method is often essential to offset the cost of enriched material.The work presented here demonstrates a reproducible purification and recycling route for 43 Sc and 47 Sc production starting from enriched 46 Ti and 50 Ti, respectively.
The radioactivity decay corrected to end of bombardment yields presented in Table S5 are in close agreement with the theoretical calculations and recent literature 17,26 .For 43 Sc, 510.7 ± 21.8 MBq (13.8 ± 0.59 mCi) were produced, while the theoretical yield amount to 514.3 MBq (13.9 mCi) for a 1.5 h bombardment.In the case of 47 Sc, 52.17 ± 2.3 MBq (1.3 ± 0.1 mCi) were produced versus 49.6 MBq (1.3 mCi) theoretical for a 4 h bombardment (n = 3 for each).The optimization of the separation proposed by Loveless et al. was achieved by adopting three improvements 17 .First, an additional wash of 3 mL of 1 M HNO 3 was added, which improved the radioscandium purification by removing additional impurities (Cr, Fe, Cu and Zn are present in this elution as shown in Fig. 3) and reducing the final elution volume 17,26 .Next, the use of a SPE fritted tube instead of a BioRad column improved the time and reproducibility of the purification 17,26 .The SPE fritted tube columns were adapted for the use of a syringe pump that allowed for constant flow rates, which reduced flow rate variability.Lastly, the presence of HF in the dissolved target solution would decrease the radioscandium affinity to BDGA resin; thus, the TiO 2 with NH 4 HF 2 was heated for 2 h to ensure complete removal of the HF before addition of concentrated HCl 24,27 .These improvements allowed for shorter evaporation time as the collected volume was decreased from 10 to 3 mL for either the 43 Sc or 47 Sc while maintaining an effective separation of the radioscandium from titanium target material and 48 V species 17 .
The irradiated targets for 43 Sc were dissolved 30 min after end of bombardment to allow decay of the shortlived radio contaminates (such as 13 N and 15 O) to reduce the dose to personnel.The radiochemical purity of 43 Sc was 98.8%, with 44g Sc, the other PET radionuclide, being the highest impurity at 1.01%.These results are in agreement with the reported radionuclidic purity from Domnanich et al. 26 .
The irradiated targets for 47 Sc were dissolved the following day to allow for the decay of short-lived radiocontaminates and 43 Sc and 44g Sc produced from other Ti isotopes present in the target material.The advantage of using enriched [ 50 Ti]TiO 2 can be observed in the HPGe analysis as the percent of 47 Sc at end of bombardment is 91.5 ± 0.6% whereas reported radionuclidic 47 Sc purity for nat Ti targets, after which 43 Sc and 44g Sc has substantially decayed, 28 h after end of bombardment, was 43% 17 .
The production of 46 Sc, which is the radioscandium contaminate of concern as its half-life is 83 days and the longest lived radioscandium isotope, was determined to be < 2% of all total radioscandium for 47 Sc production, an indication of the efficiency of using enriched target material.The production yields of 46 Sc and other radioscandium isotopes could be reduced with the use of higher purity enriched [ 50 Ti]TiO 2 .Ideally, the percentages of [ 47 Ti]Ti and [ 49 Ti]Ti should remain consistently low, as both titanium isotopes are routes for 46 Sc production, as shown in supplemental information Fig. S2.
The ICP-MS results indicated the presence of trace metal contaminates within the target material, which is in alignment with the certificate of analysis shown in Table S4, with Cr, Mn at < 100 ppm and Fe, Cu, Zn, W, and Pb having some of the largest starting concentrations.The larger concentrations of Fe, Zn, and W are of concern as they will likely compete with radioscandium for complexation sites [28][29][30] .The separation is shown to be effective at removing these metals before eluting the desired radioscandium, as seen in Fig. 3.The majority of the contaminates were removed with the washes of 9 M HCl, 1 M and 7 M HNO 3 .The overall separation process indicates the removal of the trace metal contaminates and high recovery of Ti species in flow through and E1 via ICP-MS analysis.The high target recovery yield of 96% provides a steady life cycle of the target material to help balance the cost of the enriched material.The percent recovery is also in accordance with the reported Domnanich et al. 26 target recycling for nat TiO 2 (97.6%).Furthermore, the yields of activity produced in subsequent irradiations of the same target remained consistent, validating the constant quality of the target material up to eight target cycles The target recycling method here also resulted in a purification of the target material.As shown in the trace metal analysis of the purified 47 Sc and the increasing AMA of both 43 Sc and 47 Sc, the target material was gradually purified during each cycle.This procedure shows high reproducibility of the target life cycle, from target collection to 43 Sc and 47 Sc purification and increased purity of the recycled target material after each use.
An additional characterization of the produced 43 Sc and 47 Sc is the measured AMA of the complex formation with DOTA.The separation and target purification from repeated recycles is shown to be effective for the removal of trace contaminants that may compete with 43 Sc or 47 Sc and is shown with the increased AMA after each target recycling 11 .
The PET images of the 18 F, 43 Sc and 68 Ga were employed to validate 43 Sc PET imaging resolution, considering two scenarios: 30 min static scan and scans reconstructed and normalized to the total decays of the 68 Ga scan.The image resolution of 43 Sc was quantified and compared to that of 68 Ga, revealing a smaller FWHM at all visibly distinguishable rods.This suggests a higher resolution, particularly evident at the 3.2 mm rod diameter, which represents the smallest distinguishable rod on the 68 Ga scan.Additionally, the resolution order remained consistent, with 18 F having the highest resolution and the smallest FWHM value at each rod, while 68 Ga exhibited the lowest resolution and largest FWHM values.The significant differences between the FWHM data confirms our hypothesis of decreasing resolution order of 18 F > 43 Sc > 68 Ga.These results are in line with expectations, as higher positron energies result in a decreased resolution, which can already be observed by qualitative evaluation of the PET phantom images.The resulting 1.85 FWHM of 18 F for the 2.4 mm rod is in agreement with literature values of 1.9 mm 31 .Comparing the FWHM of 18 F and 43 Sc on the next smaller rod size also corroborates that 18 F has a higher resolution in comparison to 43 Sc but as this resolution difference is demonstrated using a small animal PET scanner, it may have little impact in clinical practice using human scanners.These results indicate that 43 Sc has favorable characteristics for PET imaging.
Future studies will continue the characterization of the proton induced nuclear reactions on enriched 47 Ti for production of 44 Sc and on enriched 48 Ti for production of 47 Sc.Although there are limited reports on the production of 44g Sc from titanium targets, the major challenge lies in the co-production of the metastable state 44m Sc (IT: t 1/2 : 58.6 h) during this production process 19 .However, there has been interest in utilizing 44m Sc as an in vivo generator for longer-lived targeting moieties like antibodies [32][33][34] .
Additionally, further analysis of the recycled TiO 2 targets and proof-of-concept studies using 43 Sc and 47 Sc as a theranostic matched pair in targeted imaging and treatment will be explored.Further enhancement of the target design to increase production is desirable.The first improvement in the design revolves around augmenting the target thickness, thereby ensuring the capture of the entire excitation function under the energy of 24 MeV.The second design modification involves tailoring the target to accommodate higher energy cyclotrons (30 MeV).Theoretical predictions regarding 47 Sc production, based on the 24 MeV design and the same enriched [ 50 Ti] TiO 2 and 4 h bombardment parameters in this work, would yield 5.8 mCi of 47 Sc.The predicted radionuclidic purity for both 46 Sc and 47 Sc is 4.1% and 90.2%, respectively.The 30 MeV target design would increase the 47 Sc yields to 11.6 mCi with a radionuclidic percentages of 46 Sc and 47 Sc at 6.2% and 90.1%, respectively.Although the percentage of 46 Sc increases, it's noteworthy that the 47 Sc yields nearly double while maintaining a comparable level of purity.Investigation of the cross sectional data for the 50 Ti(p,p+α) 46 Sc at 30 MeV can help guide the ideal bombardment parameters, such as irradiating a 28 or 29 MeV, to decrease the 46 Sc production.It's important to acknowledge that the utilization of higher enrichment levels (> 83%) of [ 50 Ti]TiO 2 also holds potential.This is contingent upon the condition that the percentages of 47 Ti and 49 Ti remain equal or lower to reduce 46 Sc and 48 Sc when operating within energies of 30 MeV or below.

Conclusions
This work demonstrates the feasibility of utilizing enriched [ 46 Ti]TiO 2 and [ 50 Ti]TiO 2 for the production of high purity 43 Sc and 47 Sc using 18 or 24 MeV protons.The enrichment of 83% [ 50 Ti]TiO 2 yielded 91% radionuclidic purity of 47 Sc at the end of bombardment, after the decay of short lived 43,44g Sc while the 96% enriched [ 46 Ti]TiO 2 yielded 98% pure 43 Sc at the end of bombardment.The reported separation technique removed radio and trace https://doi.org/10.1038/s41598-023-49377-7

Figure 1 .
Figure 1.The elution profile of the 47 Sc separation from enriched [ 50 Ti]TiO 2 targets, shown as a percentage of activity in the eluted fraction in comparison to the total starting activity.The fractions representing the 47 Sc are black and the fractions representing the 48 V are represented in solid gray.

Figure 2 .
Figure 2. The gamma-ray spectra of the dissolved irradiated [ 46 Ti]TiO 2 target (a).The gamma-ray spectra of the purified 43 Sc elution (b).The gamma-ray spectra of the dissolved irradiated [ 50 Ti]TiO 2 target (c).The gamma-ray spectra of the purified 47 Sc elution (d).Each photopeak is labeled with the corresponding radionuclide.

Figure 3 .
Figure3.ICP-MS elemental analysis results for detectable trace metal contaminates found in the corresponding fractions (x-axis) during the purification of 47 Sc.The element concentration range on the left y-axis is for Cr, Mn, Ni, and Cu.The element concentration range on the right y-axis is for Fe and Zn. https://doi.org/10.1038/s41598-023-49377-7www.nature.com/scientificreports/

Table 1 .
The calculated radionuclide purity of produced 43 Sc and 47 Sc at EOB.

Table 2 .
Trace metal analysis of collected 47 Sc from recycled 50 Ti targets.S.D., standard deviation.

Table 3 .
Production yields from single targets.
a 9 h bombardment.

Table 4 .
The full-width half maximum for 18 F, 43 Sc and 68 Ga 18 .a Reconstructed to match the total decays of the 68 Ga scan (5.74E9 total decays).