DOI: 10.3303/CET25117189 Paper Received: 15 January 2025; Revised: 24 March 2025; Accepted: 10 May 2025 Please cite this article as: Moioli S., Galbiati C., Agnes P., Gabriele F., Bonivento W.M., Simeone M., 2025, Study of Oxygen Isotope Distillation for Applications in Medical Diagnostics, Chemical Engineering Transactions, 117, 1129-1134 DOI:10.3303/CET25117189 CHEMICAL ENGINEERING TRANSACTIONS VOL. 117, 2025 A publication of The Italian Association of Chemical Engineering Online at www.cetjournal.it Guest Editors: Fabrizio Bezzo, Flavio Manenti, Gabriele Pannocchia, Almerinda di Benedetto Copyright © 2025, AIDIC Servizi S.r.l. ISBN 979-12-81206-17-5; ISSN 2283-9216 Study of Oxygen Isotope Distillation for Applications in Medical Diagnostics Stefania Moiolia,*, Cristiano Galbiatib,c, Paolo Agnesc, Federico Gabrieled, Walter Marcello Boniventod, Marino Simeonee aGASP - Group on Advanced Separation Processes & GAS Processing, Dipartimento di Chimica, Materiali e Ingegneria Chimica “G. Natta”, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy bPhysics Department, Princeton University, Princeton, NJ 08544, USA cGran Sasso Science Institute, 67100 L’Aquila, Italy dINFN Cagliari, 09042 Cagliari, Italy eDipartimento di Ingegneria Chimica dei Materiali e della Produzione Industriale, Università degli Studi di Napoli Federico II, Piazzale Tecchio 80, 80125 Napoli, Italy stefania.moioli@polimi.it The production of rare isotopes is difficult and carried out only in few sites in the World, though being of interest. For instance, the production of 18O and 17O is relevant for medical diagnostics, in particular to promote largescale application of breakthrough methods for early diagnostics for cancer, neurodegenerative diseases and lung diseases. 18O and 17O can be produced by cryogenic distillation, operating with a very high number of theoretical stages. On this topic a PRIN 2022 project has been funded by the Ministero dell’Università e della Ricerca, with the aim of designing a distillation plant for increasing the amount of the isotopes of interest in the final product from the natural abundance up to 10%. The project is based on Aria, a major cryogenic distillation infrastructure in Nuraxi- Figus (South Sardinia), where a 350-meter-tall cryogenic distillation column is being installed to purify argon isotopes for dark matter searches. Extending 350 meters underground into a mineshaft of a former coal mine, Aria is today the only facility capable of producing stable light isotopes via cryogenic distillation in the European Union and has the potentiality to become the most powerful production plant of its kind in the world. This work focuses on the study of the cryogenic distillation column for treating a binary mixture of 16O2 and 16O18O with the aim of producing a stream richer in 16O18O. The simulation of the process has been performed and sensitivity analyses on the main operating parameters have been carried out to define the best operating conditions of the column. 1. Introduction Over the past 20 years, significant progress has been made in the research, production and application of stable isotopes. Their importance has increased in nuclear energy, medical diagnostics, and ecological studies. For example, medical applications have advanced with isotopes like 2H, 13C, 15N, 17O, and 18O playing a relevant role in the Nuclear Magnetic Resonance (NMR) for the disease detection and monitoring (Shulman et al., 1984), and in the Positron Emission Tomography (PET) for the effective cancer, cardiac and neurological diagnostics through non-invasive imaging using radioactive tracers (Ter-Pogossian et al., 1980). In the nuclear sector, the use of enriched isotopes such as 235U and 239Pu is needed for nuclear reactor fuels. Recently, 15N has gained attention for its potential use in uranium nitrides as fuel for the fourth-generation nuclear reactors, due to its exceptional thermal and mechanical properties. The isotope separation has been carried out by employing several techniques to exploit the differences in the physical and chemical properties of isotopes, such as mass or boiling points. Among the many considered methods, cryogenic distillation is one of the best for the industrial-scale isotope production due to its efficiency and scalability (Andreev, 2007). It performs the separation of isotopes on the basis of their boiling point differences at extremely low temperatures, though the boiling point differences among different isotopes are 1129 very low. The scalability and the cost-effectiveness of cryogenic distillation have made it an essential technology in the production of stable isotopes, a market that is projected to grow significantly in the coming decade. One of the key projects on cryogenic distillation is Aria (INFN, 2020), that is part of the DarkSide-20k Collaboration. Aria is based on distillation columns initially designed for the purification of Underground Argon (UAr) from sources as the Kinder Morgan’s Doe Canyon wells in Colorado in order to obtain a stream rich in 40Ar (Aaron et al., 2023). The UAr is chosen for its significantly lower 39Ar content compared to the one of atmospheric argon and therefore its higher easiness in increasing the 40Ar content, reducing the radioactive interference in experiments aimed at detecting dark matter (Agnes et al., 2021). DarkSide-20k is an advanced experiment located at the Gran Sasso National Laboratory in Italy (Aalseth et al., 2018), employing Liquid Argon Time Projection Chambers (LAr TPCs) to detect weakly interacting massive particles (WIMPs) through nuclear recoil. The usage of purified and enriched argon in the chambers is to minimize radioactive interference from 39Ar, which would otherwise contaminate the data and reduce the sensitivity of dark matter detection. Aria is today the only facility capable of producing stable light isotopes via cryogenic distillation in the European Union and has the potentiality to become the most powerful production plant of its kind in the world. The facility for the isotope separation is located at the Seruci mine campus in Nuraxi-Figus at Gonnesa, Carbonia in Sardinia (Italy) and is expected to be composed of two distillation columns (Seruci-I and Seruci-II) designed to enhance the mass transfer between the vapor phase and the liquid phase and the separation through an efficient packing. A closed-loop refrigeration system using liquid nitrogen to minimize the thermal losses and to optimize the energy efficiency is employed for cooling. The modules are tested at the Conseil Européen pour la Recherche Nucléaire (CERN) in Geneve (Switzerland) and then installed in the mine well. The height and the diameter of the wells, their configuration with multiple accesses and integrated security systems and the availability of a truckable motorway from the surface to a depth of 500 m are ideal conditions for the safe installation of a plant with unique features in the world (INFN, 2020). The facility has then been thought to be used for the purification of other isotopes in addition to Ar, to set up a production with the aim of satisfying the increasing demand of these species, for instance in medical diagnostics. This work has been carried out within the research project “Production of rare oxygen isotopes with the Aria cryogenic distillation plant for innovative applications in medical diagnostics” and aims at studying the cryogenic distillation column for treating a binary mixture of 16O2 and 16O18O for the production of a stream richer in 16O18O, with a target of 10 % 18O in the product. 2. Isotopes of the molecular O2 16O, 17O and 18O are the three oxygen isotopes present in nature. Their abundances (LibreText Chemistry, 2024) are reported in Table 1. Table 1: Natural abundances [%] of oxygen isotopes Isotope Isotope abundance [%] 16O 99.757 17O 0.038 18O 0.205 The combinations of these isotopes for constituting the molecular oxygen are obtained by considering the probability of formation of these molecules, as the product between the concentrations of the two isotopes constituting the molecule and the normalization of all the molar fractions. The results are reported in Table 2. Table 2: Mole fractions of molecular oxygen isotopes, determined on the basis of the natural abundances of each isotope Molecule Mole fraction 16O2 0.99757 16O18O 0.00205 16O17O 0.00038 18O2 4.21E-06 17O18O 7.81E-07 17O2 1.45E-07 18O2, 17O18O and 17O2 are present in traces. The production of the isotope 18O could be obtained by 16O18O. In this work, the mixture of isotopes has been assumed to be composed of only the two isotopes 16O2, that is the 1130 main one, and 16O18O, that, though being characterized by a much lower amount, is the one with the highest composition excluding 16O2. Considering that the target is 10 % of 18O and that 18O is present in the molecule 16O18O, the distillation column should produce a bottom stream with 20 % of 16O18O on a molar basis. 3. Methodology 3.1 Properties of the binary system The composition of the binary mixture with 16O2 and 16O18O has been normalized by neglecting the molecules present in very low amount and by adding the amount of 16O17O (with a molar fraction equal to 0.00038) to the amount of 16O2. The considered mixture is characterized by a molar fraction of 16O2 and of 16O18O as reported in Table 3. Table 3: Composition of the binary mixture with 16O2 and 16O18O considered in this work Molecule Mole fraction 16O2 0.99795 16O18O 0.00205 Given the very low concentration of the heavy isotope of interest (only 0.2 %) in the feed of the distillation column, the enrichment up to 20 % is very difficult to achieve and is a general characteristic of separation of isotopes. Therefore, a tall distillation column is needed, with a high reflux ratio and a low bottom product flowrate, as the one designed for Seruci-I. 3.2 Simulation of the unit The commercial process simulator ASPEN Plus® V14 has been used for the simulation of the distillation column. It is provided by default in the database with only one molecule of O2, that has been assumed to be representative of the isotope 16O2, the main common one. Another component, representing the 16O18O isotope, has been added to the database, with a different molecular weight because of the different atomic composition and a different vapor pressure. The vapor pressure has been determined on the basis of the value provided by Ancona et al. (1962). The 16O18O isotope is characterized by the same specific heat capacity of the vapor phase and of the liquid phase, the same heat of vaporization and the same liquid molar volume of the the 16O2 isotope (Baraldi, 2024). The Seruci-I column is provided with 28 central modules, each one of height equal to 10.28 m and diameter of 0.71 m, with an internal packing characterized by a Height Equivalent to a Theoretical Plate (HETP) of 10 cm, in addition to be provided with a top module and a bottom module and liquid distributors. The total column height is equal to 349 m and the total number of theoretical stages is 2871. The DSTWU column has been employed for the simulation in this work. It performs a Winn-Underwood-Gilliland shortcut design calculation for a distillation column, with a partial or a total condenser and with a single feed and two products. For the specified recovery of the light and the heavy key components, the minimum number of theoretical stages with the Winn correlation, the minimum reflux ratio with the Underwood correlations, the required reflux ratio for a specified number of theoretical stages or the required number of stages for a specified reflux ratio with the Gilliland method are estimated. In this work, the number of stages has been set equal to the one of the Seruci-I distillation column and the reflux ratio has been determined for different recovery ratios (from 60 % to 99 %) in the bottom product of the heavy isotope of interest. Then, the maximum feed that can be provided on the basis of fluid dynamic performances has been determined and the productivity of the unit has been analyzed. 4. Results and Discussion Firstly, the minimum number of stages (reported in Figure 1a)) required for the separation has been checked. The required binary distillation is possible for every recovery ratio of the heavy isotope 16O18O, because the minimum number of stages is always lower than the number of available ones from Seruci-I. The molar fraction of 16O2 in the distillate product slightly increases as the recovery ratio of 16O18O increases because more 16O18O is recovered in the bottom product (Figure 2). The distillate stream, also for a recovery ratio equal to 60%, is characterized by a molar fraction of the light isotope 16O2 equal to more than 0.999. The molar compositions of the bottom product do not change because of the specification of molar fraction of 16O18O equal to 0.20. 1131 a) b) Figure 1: Variation a) of the minimum number of stages and b) of the reflux ratio as the recovery ratio of 16O18O in the bottom stream varies, obtained with a molar fraction of 20% of 16O18O in the bottom product a) b) Figure 2: Variation of the mole fraction of a) 16O2 and b) of 16O18O in the distillate product as the recovery ratio of 16O18O in the bottom stream varies, obtained with a molar fraction of 20% of 16O18O in the bottom product Figure 3: Variation of the feed flowrate as the recovery ratio of 16O18O in the bottom stream varies, obtained with a molar fraction of 20% of 16O18O in the bottom product 0 500 1 000 1 500 2 000 2 500 3 000 3 500 0.60 0.70 0.80 0.90 1.00 m in im u m n u m b e r o f s ta g e s recovery ratio in B 0 50 100 150 200 250 300 0.6 0.65 0.7 0.75 0.8 0.85 0.9 0.95 0.96 0.97 0.98 0.99 re fl u x r a ti o recovery ratio in B 0.9990 0.9992 0.9994 0.9996 0.9998 1.0000 0.60 0.70 0.80 0.90 1.00 x D 1 6 O 2 recovery ratio in B 0.0000 0.0002 0.0004 0.0006 0.0008 0.0010 0.60 0.70 0.80 0.90 1.00 x D 1 6 O 1 8 O recovery ratio in B 0 10 20 30 40 50 60 70 80 90 100 0.6 0.65 0.7 0.75 0.8 0.85 0.9 0.95 0.96 0.97 0.98 0.99 fe e d f lo w ra te [ k g /d ] recovery ratio in B 1132 a) b) Figure 4: Variation a) of the distillate flowrate and b) of the bottom flowrate as the recovery ratio of 16O18O in the bottom stream varies, obtained with a molar fraction of 20% of 16O18O in the bottom product The reflux ratio, that is much higher than the value usually considered for the separation of traditional systems, significantly increases as the recovery ratio of 16O18O increases, up to more than 300, because of the increased difficulty in the separation (Figure 1b)). Generally, the increase in the reflux ratio causes an increase in the operating costs of the distillation column, mainly related to the condenser duty and to the reboiler duty, because of the higher circulating flowrates. The feed flowrate depends on the maximum circulating flowrates of vapor and liquid inside the column, that increase as the recovery ratio of the heavy isotope increases. As the circulating flowrates inside the column increase, the maximum feed flowrate decreases, as reported in Figure 3. For a recovery ratio of 99% the feed flowrate is lower than half of the one obtained for a recovery ratio of 60%. Therefore, also the productivity varies and the flowrates of the distillate and of the bottom products decrease as the recovery of the isotope 16O18O in the bottom stream increases (Figure 4), for the same molar fraction of 16O18O in the bottom product, equal to 20%. Figure 5: Variation of the number of stages above the feed stage as the recovery ratio of 16O18O in the bottom stream varies, obtained with a molar fraction of 20% of 16O18O in the bottom product The number of theoretical stages above the feed inlet position increases as the recovery ratio of the heavy isotope in the bottom product increases and the feed stage tends to move closer to the bottom of the column (a higher number of theoretical stages above the feed is needed, as reported in Figure 5). A higher section of rectification and a lower section of stripping are needed, with a relevant variation if considering a recovery ratio of 16O18O in the bottom stream equal to 60 % or equal to 99 %. 0 10 20 30 40 50 60 70 80 90 100 0.6 0.65 0.7 0.75 0.8 0.85 0.9 0.95 0.96 0.97 0.98 0.99 d is ti ll a te f lo w ra te [ k g /d ] recovery ratio in B 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.6 0.65 0.7 0.75 0.8 0.85 0.9 0.95 0.96 0.97 0.98 0.99 b o tt o m f lo w ra te [ k g /d ] recovery ratio in B 0 200 400 600 800 1 000 1 200 1 400 1 600 0.6 0.65 0.7 0.75 0.8 0.85 0.9 0.95 0.96 0.97 0.98 0.99 n u m b e r o f s ta g e s a b o v e t h e f e e d recovery ratio in B 1133 An experimental activity on the Seruci-I distillation column is scheduled and it is of interest to compare the results obtained in this work with the experimental points. 5. Conclusions This paper focused on the study of a cryogenic distillation column for producing isotopic mixtures rich in the isotope 18O, with the analyses of the performances of a unit within the Aria Project. In particular, the database of the ASPEN Plus® software has been implemented with the 18O isotope and several simulations of the distillation column have been performed, by analyzing the variation of the main parameters as the recovery ratio of the heavy isotope in the bottom stream varies, for the same purity of the bottom product. The Aria plant can provide an oxygen isotope production, with a potential for the facility to enter the global market. As the research project is being developed, the isotope production capacities could be expanded with Seruci-II, the second column with a larger diameter, that is planned to be built and to start its operation, contributing to the development of the industry focusing on stable isotopes production. Acknowledgments We acknowledge financial support under the National Recovery and Resilience Plan (NRRP), Mission 4, Component C2, Call for tender No. 104 published on 2.2.2022 by the Italian Ministry of University and Research (MUR), funded by the European Union – NextGenerationEU– Project Title “Production of rare oxygen isotopes with the Aria cryogenic distillation plant for innovative applications in medical diagnostics” – CUP E53D23002780006 - Grant Assignment Decree No. 961 adopted on 30.6.2023 by the Italian Ministry of Ministry of University and Research (MUR). References Aalseth C.E., Acerbi P., Agnes P., Albuquerque I.F.M., Alexander T., Alici A., Alton A.K., Antonioli P., Arcelli S., Ardito R., Arnquist I.J., Asner D.M., Ave M., Back O., et al. (the DarkSide collaboration), 2018, DarkSide- 20k: A 20 tonne two-phase LAr TPC for direct dark matter detection at LNGS, The European Physical Journal Plus, 133. 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