Efficient Separation of Lu from Yb Using Rext-P350@Resin: A Promising Route for No-Carrier-Added ¹⁷⁷Lu Production

Abstract

Due to the nearly identical chemical properties of Lu and Yb, the production of no-carrier-added (NCA) ¹⁷⁷Lu faces significant challenges in their separation. Achieving efficient and streamlined separation of Lu and Yb is crucial for the production of NCA ¹⁷⁷Lu. This study systematically investigated the separation performance of the commercial Rext-P350 extraction resin for Lu and Yb. Static adsorption experiments revealed that, at a solid–liquid ratio of 8 g/L, both Lu³⁺ and Yb³⁺ were nearly completely adsorbed, with saturation adsorption capacities of 25.8 mg/g and 21.5 mg/g, respectively. An increase in the nitric acid concentration in the aqueous phase significantly inhibited adsorption, but the separation factor for Lu³⁺/Yb³⁺ remained above 1.88. The adsorption kinetics followed a pseudo-second-order model (R² > 0.99), with equilibrium reached within 15 min, demonstrating fast adsorption kinetics. Characterization by SEM, FT-IR, and XPS confirmed the chemical coordination between the resin and Lu³⁺/Yb³⁺. Dynamic chromatographic separation experiments showed that the Rext-P350 resin exhibited significantly better separation performance for Lu³⁺/Yb³⁺ compared to 2-ethylhexylphosphoric acid mono-2-ethylhexyl ester (P507) extraction resin. Leveraging the excellent performance of Rext-P350 resin, a two-stage continuous extraction chromatography process was designed, achieving efficient separation of 0.045 mg of Lu³⁺ from 200 mg of Yb³⁺ with a Lu³⁺ purity of 90.9% and a yield of 98.4%. This study provides a feasible separation technique for the purification of NCA ¹⁷⁷Lu.

1. Introduction

Radionuclides are foundational materials in nuclear medicine, playing a crucial role in the early detection, precise localization, and effective treatment of major diseases, such as cancer and cardiovascular conditions [1,2]. Among these, ¹⁷⁷Lu is particularly distinguished by its unique decay properties. With a half-life of 6.64 days, ¹⁷⁷Lu offers an optimal balance between effective therapeutic duration and manageable radiation safety [3]. Its combination of therapeutic beta emissions and diagnostic gamma radiation makes ¹⁷⁷Lu a versatile radionuclide, suitable for both targeted therapy and imaging, providing significant clinical benefits [4,5]. Currently, ¹⁷⁷Lu-labeled compounds, including antibodies and peptide drugs, have demonstrated remarkable efficacy in targeted radionuclide therapy for various malignancies [6,7]. Notable examples include ¹⁷⁷Lu-DOTATATE (Lutathera) and ¹⁷⁷Lu-PSMA-617 (Pluvicto), which have achieved substantial clinical success in the treatment of neuroendocrine tumors and prostate cancer, respectively [8,9,10]. These significant advancements highlight the growing clinical application of ¹⁷⁷Lu, suggesting its potential for expanded use in the near future.

The production of ¹⁷⁷Lu in nuclear reactors can be achieved through two distinct pathways [11,12]. The first, known as the direct or carrier-added method, involves neutron irradiation of ¹⁷⁶Lu via the ¹⁷⁶Lu(n,γ)¹⁷⁷Lu nuclear reaction in medium-to-high energy reactors. In contrast, ¹⁷⁷Lu can also be produced via an indirect route, involving the neutron irradiation of a ¹⁷⁶Yb target through the ¹⁷⁶Yb(n,γ)¹⁷⁷Yb → ¹⁷⁷Lu nuclear reaction in high-flux reactors. The indirect method offers significant advantages over the direct approach for clinical applications, as it results in no-carrier-added (NCA) ¹⁷⁷Lu with a higher specific activity (>2.96 TBq/mg) and negligible levels of the long-lived by-product ^177mLu (T_1/2 = 160.4 days) [13,14]. However, the effective separation of ¹⁷⁷Lu from ¹⁷⁶Yb remains a formidable challenge. This difficulty arises primarily from the nearly identical physicochemical properties of Lu³⁺ and Yb³⁺, which have minimal differences in their ionic radii (85.8 pm and 84.8 pm, respectively). Furthermore, the substantial concentration disparity between ¹⁷⁶Yb and ¹⁷⁷Lu (>10³:1) complicates the separation [12,15,16]. The separation process must also be rapid to allow sufficient time for multi-step radiolabeling, long-distance transport, and clinical use of the radiopharmaceuticals, adding an additional layer of difficulty. Importantly, in industrial-scale production, the separation process must be adaptable for remote automated operation to ensure safe and continuous production within a radioactively shielded facility [17,18,19].

Various separation techniques have been developed for the purification of NCA ¹⁷⁷Lu, such as electrochemical methods, solvent extraction, and chromatography [20]. It has been reported that Yb³⁺ can be reduced to Yb²⁺ by the electrochemical method under specific conditions and extracted by the amalgamation process, whereas Lu lacks this property, thereby enabling the effective separation of Lu³⁺ and Yb²⁺ [21,22]. However, despite various advancements in the electro-amalgamation process, which have to some extent simplified workflow and operational complexity, it has not yet been successfully scaled for commercial production. The primary challenges persist in the environmental risks associated with mercury usage and the difficulties in mercury recovery. Additionally, the electrochemical process requires high operational precision and specialized equipment, which increases both operational costs and complexity. Solvent extraction exhibits advantages such as high processing capacity, low production costs, ease of automation, and scalability, making it one of the most commonly used techniques for individual rare earth elements large-scale industrial separation [23,24]. However, existing extractants exhibit a relatively low separation factor for Lu and Yb, necessitating multistage extraction processes to achieve effective separation. Furthermore, solvent extraction processes often rely on hazardous solvents and typically require extensive post-processing steps for solvent recovery and waste disposal.

Ion-exchange chromatography stands out as one of the most promising approaches. It is well-suited for continuous automated operation and remote control, making it an ideal technology for the large-scale production of NCA ¹⁷⁷Lu [25]. Within ion-exchange chromatography, the difference in complexation constants of the complexing agent with Yb and Lu is crucial for the effective separation of the two elements [26]. α-Hydroxyisobutyric acid (α-HIBA) is a commonly used complexing agent for the separation of Lu/Yb in ion-exchange chromatography. However, it has a low separation factor of only 1.55 for Lu/Yb, which often results in significant Yb contamination in the Lu³⁺ fraction due to “peak tailing” of Yb [3,27]. While ethylenediaminetetraacetic acid (EDTA) or diethylenetriaminepentaacetic acid (DTPA) offer higher separation factors for Lu/Yb, their low solubility limits their practical use [28,29]. Additionally, the complexing agents present in the ¹⁷⁷Lu obtained through ion exchange chromatography require additional steps for removal, further complicating the process [30]. Therefore, the development of chromatographic separation methods with higher separation factors and simplified procedures is key to achieving efficient Lu/Yb separation.

Extraction chromatography methods for the separation of rare earth elements have been developed by integrating ion-exchange chromatography and solvent extraction techniques [31,32]. This approach leverages the high selectivity of solvent extraction, coupled with the multi-stage separation efficiency and operational simplicity of ion-exchange chromatography. As a result, it has found increasing application in the separation and purification of lanthanide elements, offering significant advantages in terms of both selectivity and process efficiency [33,34]. LN-series resins, based on extractants such as Di-(2-ethylhexyl)phosphoric acid (P204) and 2-ethylhexylphosphoric acid mono-2-ethylhexyl ester (P507), have already been applied in the separation of ¹⁷⁷Lu from ¹⁷⁶Yb [35,36]. Based on P507 extraction resin (LN2), Horwitz et al. proposed a promising conceptual flowchart for the separation of ¹⁷⁷Lu from a 300 mg neutron-irradiated ¹⁷⁶Yb-enriched target [37]. The process involves three main steps: the preliminary removal of ¹⁷⁶Yb, the initial purification of ¹⁷⁷Lu, and the further purification of ¹⁷⁷Lu. Additionally, after each step, the ¹⁷⁷Lu fractions are concentrated, and their acidity is adjusted using N,N,N’,N’-tetraoctyldiglycolamide (DGA) resin. However, the overall process is relatively complex, which presents challenges in the design of automated systems and may result in a reduction in ¹⁷⁷Lu yield. To enhance the performance of extraction chromatographic processes, Zhuo et al. developed a self-synthesized resin M18II, which demonstrated improved separation efficiency compared to LN2 [38]. More recently, Li et al. introduced novel P507-impregnated covalent organic frameworks (COFs) and COF-derived microporous carbon materials for ¹⁷⁷Lu separation and purification. These materials exhibited excellent stability under strong acidic and high-radiation conditions [39,40]. Additionally, a functional core-shell SiO₂@COF material has been developed for the separation of no-carrier-added ¹⁷⁷Lu. This material improves the separation process by simultaneously impregnating two extractants, P507 and C272, which helps reduce the required concentration of elution acid during the separation [41]. Nevertheless, due to the inherent limitations of P507-based systems, these materials offer limited improvement in the separation efficiency between Lu and Yb. Therefore, the development of more efficient ¹⁷⁷Lu separation and purification technologies remains an urgent need.

In this work, the commercially available Rext-P350@Resin, impregnated with mixed phosphoric acid ester extractants, was used for the selective separation of Lu/Yb, with the aim of developing a more efficient and simplified process for the separation and purification of NCA ¹⁷⁷Lu. Static adsorption experiments were conducted to evaluate the resin’s selectivity, adsorption kinetics, and saturation adsorption performance for Lu and Yb. The interactions between the resin and the Lu/Yb were further characterized using SEM, FT-IR, and XPS. Dynamic elution experiments were performed to determine the optimal acidity for Lu/Yb separation. Finally, a continuous separation process was developed and validated through dynamic elution testing. This work provides valuable insights into the separation and purification of NCA ¹⁷⁷Lu, which has significant medical applications.

2. Experimental Section

2.1. Reagents and Materials

Yb(NO₃)₃·5H₂O and Lu(NO₃)₃·6H₂O with a purity of 99.99% were purchased from Shanghai Adamas Reagent Co., Ltd., Shanghai, China. HNO₃ (65.0–68.0%, GR) and NaOH (≥96.0%) were obtained from Sinopharm Chemical Reagent Co., Ltd., Shanghai, China. The Rext-P350@Resin, manufactured by Beijing Realkan Separation Technologies Co., Ltd., Beijing, China, is an extraction chromatographic resin composed of a polystyrene-divinylbenzene copolymer matrix, impregnated with a dialkyl phosphates mixture (50 wt% of the resin). The resin has a particle size distribution of 200–400 mesh. The same specification of extraction chromatographic resin impregnated with P507 extractant was also provided by this company. The standard solutions of Lu and Yb were bought from the National Center of Analysis and Testing for Nonferrous Metals and Electronic Materials, Beijing, China. All other reagents used in this work were purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai, China. All chemicals and reagents were purchased from commercial sources and were used without further purification.

2.2. Instrumentation and Analysis Methods

The concentrations of elements in the aqueous sample were determined by an inductively coupled plasma-atomic emission spectroscopy instrument (ICP-OES, iCAP PRO, ThermoFisher, Bremen, Germany). The concentration of H⁺ in the aqueous sample was quantified through acid–base titration. Fourier transform infrared spectroscopy (FT-IR) of Rext-P350@Resin before and after adsorption of Lu and Yb was measured using INVENIO R (Bruker Corporation, Karlsruhe, Germany) in the wavenumber range of 400–4000 cm⁻¹. Scanning Electron Microscope (SEM) images were obtained with a HITACHI Regulus 8230 (Hitachi High-Tech Corporation, Tokyo, Japan). In addition, the X-ray photoelectron spectra (XPS) of the samples were measured by AXIS Supra+ (Kratos Analytical (SHIMADZU), Kyoto, Japan).

2.3. Batch Sorption Experiments

The adsorption and separation performance of Rext-P350@Resin for Lu and Yb was evaluated through static sorption experiments. These experiments were conducted in a thermostatically controlled air shaker at 25 °C with a shaking frequency of 300 rpm. The Lu and Yb feed solutions were prepared by dissolving specific amounts of Yb(NO₃)₃·5H₂O and Lu(NO₃)₃·6H₂O in deionized water. Unless otherwise specified, the concentrations of Yb and Lu in the aqueous samples were maintained at 1 mmol/L, with an H⁺ concentration of 0.04 mol/L. During the adsorption experiment, the solid-to-liquid ratio (S/L) of Rext-P350@Resin to the feed solution was set at 8 g/L, and the contact time was 30 min. The Rext-P350@Resin was used directly without any pretreatment. The effects of various parameters on the adsorption of Lu and Yb by Rext-P350@Resin were studied, including the solid-to-liquid ratio (ranging from 2.0 to 10.0 g/L), the concentrations of Lu and Yb in the aqueous phase (ranging from 0.42 to 2.84 mmol/L), HNO₃ concentration (ranging from 0.04 to 2.0 mol/L), and the contact time (ranging from 0 to 30 min).

The sorption efficiency (E%), equilibrium sorption capacity (Q_e, mg/g), distribution coefficient (K_d, mL/g), separation factor (SF), recovery rate (R%), and decontamination factor (DF) were calculated according to the following equations:

$$E\%={\displaystyle \frac{C_i-C_e}{C_i}}\times \mathrm{100\%}$$

(1)

$$Q_e=(C_i-C_e)\times {\displaystyle \frac{V}{m}}$$

(2)

$$K_d={\displaystyle \frac{C_i-C_e}{C_e}}\times {\displaystyle \frac{V}{m}}$$

(3)

$$SF={\displaystyle \frac{K_d(Lu)}{K_d\left(Yb\right)}}$$

(4)

$$R\%={\displaystyle \frac{m_{elute}}{m_i}}\times \mathrm{100\%}$$

(5)

$$DF={\displaystyle \frac{\left[m_i\right(Yb\left)\right]/[m_i(Lu\left)\right]}{\left[m_{elute}\right(Yb\left)\right]/[m_{elute}(Lu\left)\right]}}$$

(6)

where C_i and C_e are the initial and equilibrium concentrations of the element in the aqueous solution, respectively, V is the volume (mL) of the aqueous solution, and m is the mass (g) of the solid sorbents. m_elute and m_i represent the mass of the element loaded onto the resin and the mass recovered in the eluted fractions during dynamic separation, respectively.

2.4. Lu/Yb Chromatography Separation Experiment

To achieve optimal chromatographic performance, the resin must be effectively wetted. The resin was mixed with 1.0 mol/L HNO₃ at a solid-to-liquid ratio of 1:2 in a sealed 500 mL blue-cap reagent bottle at room temperature for 1 h to ensure thorough wetting. Afterward, the mixture was degassed using an ultrasonic water bath for 2 min to minimize the entrainment of air bubbles during the wetting process. The fully wetted resin was then packed into a glass column. The column was kept under continuous flow, allowing the resin to settle under the influence of the water stream. Any floating resin particles were promptly removed during this process. Once the resin had been packed to the desired bed height, the column was flushed with deionized water at a flow rate of 28.0 mL/min for 2 h. Finally, the column was preconditioned with three bed volumes of 0.1 mol/L HNO₃ at a flow rate of 5.0 mL/min, resulting in a chromatographic column ready for separation.

A comparison of the chromatographic separation performance of Rext-P350@Resin and P507 extraction resin for Lu and Yb was conducted under identical conditions. The dimensions of the chromatographic column used were 16 mm × 20 cm, and the resin bed height was 18 cm. A 10 mL solution of 0.10 mol/L HNO₃ containing Yb (1.50 mg) and Lu (0.015 mg) was introduced into the column at a flow rate of 2 mL/min. To ensure complete transfer of Yb and Lu onto the column, the storage bottle was subsequently rinsed three times with equal volumes of 0.10 mol/L HNO₃. Elution of Yb and Lu was carried out using 1.50 mol/L HNO₃ at a flow rate of 5 mL/min. The eluates were collected in 60 mL centrifuge tubes, and the concentrations of Yb and Lu in the collected fractions were determined using ICP-OES. Furthermore, the influence of varying HNO₃ concentrations on the separation efficiency of Yb and Lu using the Rext-P350@Resin column was evaluated, maintaining all other experimental conditions as previously described.

The continuous chromatographic separation of Lu and Yb was conducted using two identical chromatographic columns packed with Rext-P350@Resin (26 mm × 50 cm), with a resin bed height of 48 cm. A 20 mL solution of 0.10 mol/L HNO₃ containing 200 mg of Yb and 0.045 mg of Lu was introduced into the column at a flow rate of 3.0 mL/min. This was followed by the addition of three equal volumes of 0.10 mol/L HNO₃ to ensure complete loading of Lu and Yb onto the column. Subsequently, Yb was eluted from the column using 1.63 mol/L HNO₃ at a flow rate of 20 mL/min or 28 mL/min, and Lu was eluted from the column using 4.2 mol/L HNO₃ at a flow rate of 28.0 mL/min. The eluates were collected in pre-weighed 60 mL centrifuge tubes, and the concentrations of Lu and Yb in the collected samples were determined using ICP-OES.

3. Results and Discussion

3.1. Adsorption Properties of Rext-P350@Resin Toward Lu and Yb

To check the separation and loading ability of Rext-P350@Resin toward Lu and Yb from an aqueous solution under various environmentally relevant conditions, the effect of S/L ratio, Lu and Yb concentrations, HNO₃ concentration, and contact time on the adsorption properties were investigated. As shown in Figure 1a, when the S/L ratio of the Rext-P350@Resin and the feed solution is 2.0 g/L, the E% of Lu and Yb are 46.2% and 37.9%, respectively, and the E% of Lu and Yb increases with the S/L ratio. When the S/L ratio between the resin and the feed solution reaches 8 g/L, Lu and Yb are almost completely adsorbed. The results preliminarily prove that Rext-P350@Resin has good adsorption ability for Lu and Yb. To determine the adsorption capacity of Rext-P350@Resin for Lu and Yb, adsorption isotherm experiments were conducted with Lu and Yb concentrations. The maximum sorption capacities were found to be 25.8 mg Lu/g Rext-P350@Resin and 21.5 mg Yb/g Rext-P350@Resin (Figure 1b), which is comparable to the adsorption capacity of P507-impregnated COF-derived carbon materials [39,40]. Additionally, the adsorption isotherm results indicate that Rext-P350@Resin has a higher affinity for Lu than for Yb.

Before the chromatographic separation of ¹⁷⁷Lu and ¹⁷⁶Yb, the irradiated ¹⁷⁶Yb₂O₃ target needs to be dissolved in a HNO₃ solution. After dissolution, the acidity should be adjusted to match the acid tolerance of the resin, allowing for the effective loading of Lu and Yb onto the resin. HNO₃ solution is also used as the eluent during the chromatographic separation process. During both the adsorption and elution stages, the resin must maintain strong adsorption and separation capabilities to ensure the effective separation of Lu and Yb. Therefore, it is crucial to determine the adsorption and separation performance of Rext-P350@Resin for Lu and Yb under different HNO₃ concentrations. As shown in Figure 1c, the E% of Lu and Yb decreases as the HNO₃ concentration increases from 0.04 mol/L to 2.0 mol/L. This decrease is likely due to changes in the surface charge of Rext-P350@Resin and the competitive interaction between H⁺ and Lu/Yb. When the HNO₃ concentration in the feed solution reaches 2.0 mol/L, the E% for Lu and Yb are 16.2% and 10.7%, respectively. Notably, within the studied range of HNO₃ concentrations, the separation factor of Rext-P350@Resin for Lu and Yb remains above 1.88, demonstrating superior separation performance compared to P507 and P204 extraction resins [35]. The superior separation factor of Rext-P350@Resin is anticipated to enhance the efficiency of the chromatographic separation process and shorten the separation process.

The adsorption capacities of the Rext-P350@Resin for Lu and Yb as a function of contact time are shown in Figure 1d. After 5 min of adsorption, the loading capacities of the Rext-P350@Resin for Lu and Yb were 19.5 mg/g and 17.8 mg/g, respectively. After 15 min, the adsorption reached equilibrium, with Lu and Yb adsorption capacities of 20.0 mg/g and 18.5 mg/g, respectively. These results indicate that Rext-P350@Resin exhibits rapid adsorption kinetics for both Lu and Yb. Moreover, the adsorption kinetics of Lu and Yb exhibited very similar behavior. The adsorption processes of both fit better with the pseudo-second-order kinetics model, which is usually regarded as the process dominated by chemical adsorption, indicating that there is a strong adsorption between Rext-P350@Resin and Lu/Yb.

3.2. Characterization of Rext-P350@Resin Before and After Adsorption of Lu and Yb

SEM, FT-IR, and XPS characterizations were conducted on Rext-P350@Resin before and after the adsorption of Lu and Yb to analyze the interaction mechanisms between the resin and these metal ions. As shown in Figure 2a, the uniform distribution of P and O elements observed in the EDS mapping before adsorption suggests that the extractant was homogeneously impregnated on the resin matrix, which is crucial for maximizing the surface area available for interaction with target ions. After Lu adsorption (Figure 2b), the even distribution of Lu on the resin surface, as revealed by EDS mapping, demonstrates the effectiveness of Rext-P350@Resin in absorbing Lu. In addition, the Rext-P350@Resin retained its intact spherical morphology after Lu adsorption, indicating that the resin possesses good mechanical strength. The FT-IR spectra of Rext-P350@Resin exhibit peaks at 1193 cm⁻¹ and 1027 cm⁻¹, corresponding to the stretching vibrations of P = O and P-O-C, respectively (Figure 2c). After the adsorption of Yb and Lu, the P = O stretching vibration shifts to 1165 cm⁻¹ and 1167 cm⁻¹, respectively, while the P-O-C stretching vibration shifts to 1134 cm⁻¹. These shifts in the FT-IR spectra before and after adsorption confirm the coordination interactions between the extractant and the Lu/Yb.

To further investigate the adsorption mechanism of Rext-P350@Resin towards Lu/Yb, XPS analysis was performed (Figure 2d–f). Compared to the XPS spectra of pristine Rext-P350@Resin, the spectra of Rext-P350@Resin after loading with Lu/Yb exhibit two new pronounced characteristic peaks, confirming the presence of Yb and Lu on the resin surface post-adsorption. In addition, taking Rext-P350@Resin-loaded Lu as an example, the high-resolution spectra of O1s and P2p show significant differences compared to those of the pristine Rext-P350@Resin. The high-resolution spectra of O1s and P2p for Rext-P350@Resin and Rext-P350@Resin-loaded Lu also present great differences. The high resolution of P2p XPS spectra consists of two main peaks corresponding to the P 2p1/2 (130.3 eV) and P 2p3/2 (129.4 eV). Meanwhile, the high resolution of O1s XPS spectra can be split into two individual characteristic peaks at 533.3 and 532.3 eV, which are assigned to P = O and P-O-C, respectively. After the adsorption of Lu, the characteristic peaks of P 2p shift to higher binding energies, while O 1s shifts to lower binding energies, likely due to the bonding of Lu with the P = O group of the extractant within the Rext-P350@Resin. These observations further demonstrate that the adsorption of Yb and Lu by Rext-P350@Resin is a chemical process.

3.3. Dynamic Elution Separation of Lu/Yb by Rext-P350@Resin

Static adsorption experiments indicate that Rext-P350@Resin demonstrates superior separation capability for Lu/Yb, with a separation factor of Lu/Yb higher than that of P507 extraction resin. However, the dynamic chromatographic separation of Lu/Yb is influenced by multiple factors, leading to a significant difference from actual separation performance. Consequently, the dynamic elution separation of Lu/Yb using Rext-P350@Resin was further evaluated and compared to the P507 extraction resin column under identical conditions. As shown in Figure 3a, using 1.50 mol/L HNO₃ as the eluent, both Lu and Yb loaded on the P507 extraction resin were effectively eluted, with Yb being eluted prior to Lu. According to

Table 1. The recovery rates (%) and separation performance of Lu/Yb during the dynamic elution process using P507 extraction resin and Rext-P350@Resin.

Resin	Elution	Fractions Collected (mL)	RYb (%)	RLu (%)	DF
P507 extraction resin	1.5 M HNO3	1400–2500	2.95	94.7	32.0
Rext-P350@Resin	1.5 M HNO3	1150–2100	0.50	94.4	190.5
Rext-P350@Resin	1.6 M HNO3	900–1800	1.24	97.9	79.2
Rext-P350@Resin	1.8 M HNO3	650–1300	2.58	96.9	37.5

, in the fractions collected between 1400 mL and 2500 mL from the P507 extraction resin column, the R% of Lu reached 94.7%, while the residual Yb content was 2.95%, resulting in a DF value of 32.0. In contrast, Rext-P350@Resin exhibited a more effective dynamic elution separation for Lu/Yb, with narrower elution peaks for both Yb and Lu (Figure 3b). In the fractions collected between 1150 mL and 2100 mL, the R% of Lu was 94.4%, the residual Yb content was 0.50%, and the DF value reached 190.5, significantly higher than that of the P507 extraction resin. The smaller fraction volumes collected during dynamic separation with Rext-P350@Resin suggest a substantial reduction in eluent consumption and a shorter separation time.

The impact of using 1.6 mol/L and 1.8 mol/L HNO₃ as eluents on the chromatographic separation of Yb and Lu by Rext-P350@Resin was further evaluated. As shown in Figure 3c,d and Table 1, increasing the eluent acidity led to a significant reduction in the elution peak widths for both Lu and Yb, thereby decreasing the required volume of eluent and shortening the overall separation time. This is particularly advantageous in the production of NCA ¹⁷⁷Lu, where minimizing waste liquid and expediting separation are critical. However, the increase in eluent acidity comes at the cost of reduced resolution between the Lu and Yb peaks, with the DF values corresponding to 1.6 mol/L and 1.8 mol/L HNO₃ decreasing to 79.2 and 37.5, respectively. Therefore, to balance these competing demands, 1.6 mol/L HNO₃ was selected as the optimal eluent for the continuous chromatographic separation process of Lu/Yb in this study.

3.4. Lu/Yb Continuous Chromatographic Separation Process by Rext-P350@Resin

In order to further validate the feasibility of continuous chromatographic separation of Lu/Yb using Rext-P350 resin, a continuous chromatographic separation process for Lu and Yb was designed based on Rext-P350 resin, as shown in Figure 4. The process involves a two-stage separation for Lu/Yb, as detailed below: (1) The Lu/Yb solution to be separated is fully loaded onto the first chromatographic separation column. (2) The first elution solution is used to continuously elute Yb until the Lu fraction begins to elute. At this point, elution is stopped, and the eluate obtained during this process is collected for Yb recovery. (3) The second elution solution (4.2 M HNO₃) is then used to continuously elute Lu. The Lu fraction is passed through a 1.5 mol/L sodium hydroxide solution at the same flow rate for pH adjustment, and is then directly loaded onto the second chromatographic column. When Lu is completely eluted from the first chromatographic column and loaded onto the second column, the elution from the first column and the sodium hydroxide flow are stopped, and the second chromatographic separation begins. The separation process in the second stage is consistent with the first stage, resulting in the final Lu and Yb fractions.

Based on the process flow outlined in Figure 4, a series of separation experiments for Lu/Yb were conducted, and the results are shown in Figure 5. The two-stage chromatographic separation process effectively achieved the separation of Lu and Yb. When Yb was eluted with 1.63 mol/L HNO₃ at a flow rate of 20 mL/min, the Lu fraction obtained from the two-stage separation process exhibited a Lu purity of 86.7% with a recovery of 94.2%. By increasing the Yb elution flow rate to 28 mL/min, the separation time for Lu/Yb was significantly reduced. Under these conditions, the final Lu fraction achieved a purity of 90.9% and a recovery of 98.4%. These results confirm the feasibility of using Rext-P350 resin for the two-stage continuous chromatographic separation of Lu/Yb, and provide a practical reference for the production of NCA¹⁷⁷Lu from 200 mg-scale ¹⁷⁶Yb targets.

Overall, this study demonstrates the potential application of Rext-P350@Resin in the separation and purification of NCA ¹⁷⁷Lu. However, several considerations must be addressed when transitioning to industrial-scale production. Specifically, the impact of radiation on resin stability is a critical factor, particularly regarding the resin’s reusability. Over time, radiation exposure may cause degradation of the resin, leading to a reduction in both its capacity and selectivity. Additionally, the ability to achieve remote operation and automation of the process is of paramount importance. This will not only enhance production efficiency, but also mitigate safety risks associated with the production process. It is also worth noting that while the current process yields high-purity ¹⁷⁷Lu, further optimization is still required to meet the stringent standards for clinical use. This may be achieved by extending the column length, reducing the elution flow rate, or selectively collecting higher-purity Lu fractions. Therefore, our future work will focus on addressing these technical challenges through systematic investigation and process refinement. These efforts aim to establish a robust and scalable production route for NCA ¹⁷⁷Lu, thereby supporting its broader application in nuclear medicine.

4. Conclusions

This work focuses on the application of the commercially available Rext-P350 extraction resin for the separation of Lu and Yb, aiming to provide a viable solution for the purification of NCA ¹⁷⁷Lu. A comprehensive evaluation was conducted to assess the static adsorption characteristics of Rext-P350 resin for Lu and Yb, as well as the feasibility of dynamic elution separation. The results revealed that the resin exhibits superior adsorption capacity and selectivity, with a higher affinity for Lu compared to Yb. Specifically, the resin’s saturated adsorption capacities were 25.8 mg/g for Lu and 21.5 mg/g for Yb, with a Lu/Yb separation factor consistently exceeding 1.88. Notably, adsorption equilibrium was reached within 15 min, and the process adhered to a pseudo-second-order kinetic model. Characterization through FT-IR and XPS confirmed that the resin interacts with Lu and Yb through coordination, with chemical adsorption being the predominant mechanism. In dynamic elution tests, Rext-P350 resin demonstrated superior separation performance compared to P507 extraction resin under identical conditions. Building on these findings, a two-stage continuous extraction chromatography process using Rext-P350 resin was developed for Lu/Yb separation. This process achieved a Lu purity of 90.9% and a yield of 98.4%, thereby providing a robust technical framework for the production of NCA ¹⁷⁷Lu.