# Highly Enriched Uranium-Free Medical Radioisotope Production Methods: An Integrative Review
## 2 Materials and Methods  
This study aims to identify which radioisotopes used in medicine have recently received interest from the scientific community and the methodologies used in their production. Thus, this research has two guiding questions: \"What alternative, HEU-free methods have been recently used to produce medical radioisotopes?\" and \"What medical radioisotopes can be produced by these alternative technologies?\".  
The literature review was performed in January 2022 on the databases Virtual Health Library (VHL) [32], Science Direct [33], and Scopus [34], with the following search strings: \"radiopharmaceutical production\" OR \"radioisotope production\". The search filters used were the following: peer-reviewed papers; English-written; available electronically; and published from 2010 to 2021. By using these filters, 91 papers were selected on VHL, 604 on Science Direct, and 294 on Scopus, resulting in 989 papers. After removing duplicate papers, this number was reduced to 927 unique papers. After a preliminary analysis, it was observed that, rather than reporting their own experimental radioisotope production, many of these publications only cited the productions from other works (eventually comparing them to their own simulation results) or estimated radioisotope reaction cross-sections, without informing the production itself. Since filtering this situation is non-trivial, once it involves context awareness, the 927 selected papers were manually analyzed. From this analysis, papers that did not report their own experimental radioisotope production, or did not present explicit radioisotope activity--in units of Bq or Ci--thick target yields, or saturation yields (which could be used to calculate the activity), were excluded. Using this methodology, from the 927 papers, 48 were selected [35; 36; 37; 38; 39; 40; 41; 42; 43; 44; 45; 46; 47; 48; 49; 50; 51; 52; 53; 54; 55; 56; 57; 58; 59; 60; 61; 62; 63; 64; 65; 66; 67; 68; 69; 70; 71; 72; 73; 74; 75; 76; 77; 78; 79; 80; 81; 82], and their data are presented in Tables A1-A4, in chronological order. In particular, in Tables A2-A4, experimental results are reported with the same precision (number of decimal digits) informed by their respective authors. Moreover, quantities calculated from these results were rounded according to the number of significant digits.  
With regard to the amount of radioisotope produced, all data collected from these papers were converted to activities at the end of the bombardment in order to present all results in the same physical unit. Each selected article presented the information differently, because the production technology used was not the same, or because different types of measurements were conducted.  
Most of the selected studies utilizing cyclotron accelerators presented their production results in one of three ways: thick target yield, saturation yield, or activity at the end of the bombardment. In order to compare the production with studies that utilized other accelerator technologies or physical processes, all measurements or calculated results presented in these papers were converted to activities at the end of the bombardment, by using Equations (1) and (2) [83]:  
\[\mathrm{A_{EOB}} =\frac{\mathrm{TTY}i}{\lambda}(1-e^{-\lambda t}), \tag{1}\] \[\mathrm{A_{EOB}} =\mathrm{SY}i(1-e^{-\lambda t}), \tag{2}\]  
where \(\mathrm{A_{EOB}}\) is the activity at the end of the bombardment [MBq], \(t\) is the irradiation time [h], TTY is the thick target yield [MBq/Ah], \(\lambda\) is the decay constant of the produced radioisotope [h\({}^{-1}\)], \(i\) is the beam current [A], and SY is the saturation yield [MBq/A].  
Some authors performed experimental activity measurements hours after the end of the bombardment. In those cases, the \(\mathrm{A_{EOB}}\) was estimated with Equation (3) using the measurement activity \(\mathrm{A_{T}}\), the time after irradiation T [h], and the decay constant \(\lambda\).  
\[\text{A}_{\text{EOB}}=\frac{\text{A}_{\text{T}}}{e^{-\lambda\text{T}}}. \tag{3}\]