Production of Rhodium-105

Radiotherapeutic research which uses ¹⁰⁵Rh requires a route for the production of high specific activity ¹⁰⁵Rh. Unfortunately, this radionuclide is not readily available to researchers (primarily due to the relatively stringent conditions and requirements in the isotope production and separation).

Rhodium-105 can be produced in a reactor by several routes, see Figure 1; the simplest of which is via a (2n, γ) reaction from a ¹⁰³Rh target. Unfortunately, this does not yield ¹⁰⁵Rh of high specific activity. ¹⁰⁵Rh is also a product (about 1 per cent) of the fission of ²³⁵U. However, the most commonly used method for the production of nocarrier-added ¹⁰⁵Rh is the indirect (n, γ) reaction using ruthenium metal as the target to produce ¹⁰⁵Ru, which then decays to ¹⁰⁵Rh. Significant byproducts from the production are ⁹⁷Ru (T_1/2 = 2.89 days), ¹⁰⁶Ru (T_1/2 = 39.27 days), ¹⁰⁵Pd (stable) and ¹⁰⁶Pd (stable). The use of enriched ruthenium metal (¹⁰⁴Ru > 99 per cent) as the target material minimises the radionuclidic impurities from ruthenium and increases the production yield of ¹⁰⁵Rh by five-fold.

A procedure proposed by Troutner and colleague has previously been used for the preparation of 5 to 150 millicuries of no-carrier-added ¹⁰⁵Rh at the University of Missouri Research Reactor (MURR) (9). The separation of ¹⁰⁵Rh from its ¹⁰⁵Ru parent was based on a combination of procedures previously described by Kobayashi and Morris (10, 11). An irradiated metal target of enriched ¹⁰⁴Ru is dissolved in alkaline solution in a reaction vial and oxidised to RuO₄ using chlorine gas. The RuO₄ is then removed from the solution by distillation (b.p. 108°C) into a series of hydrochloric acid (HCl) and sodium hydroxide (NaOH) traps. The ¹⁰⁵Rh remains in the reaction vial and is converted to a mixture of Cl^- complexes by the addition of HCl solution and heating. However, the major disadvantage of this process is the use of chlorine gas, which is a corrosive material (in the presence of water) and a highly toxic gas which requires a very effective trapping system. These disadvantages have somewhat discouraged the scale-up of this procedure for the production of higher quantities of ¹⁰⁵Rh. In addition, the subsequent distillation of the oxidised product RuO₄, which is a highly toxic volatile chemical, also requires extreme precautions and a cumbersome trapping system. Although the system can be designed to trap both distilled RuO₄ and excess chlorine gas by the use of a series of HCl and NaOH solutions, the amount of liquid used in the traps would increase the volume of the radioactive waste, which mainly contains ¹⁰³Ru (T_1/2 = 39.27 days). This would be a major disadvantage when scaling-up production.

A new separation procedure is reported here using magnesium oxide, MgO, as the adsorbent to purify no-carrier-added ¹⁰⁵Rh in quantities of 10 to 100 mCi. The method eliminates the use of chlorine gas and the distillation of ruthenium tetraoxide, and has thus significantly increased the feasibility for scale-up (12).

Production of ¹⁰⁵Ru and ¹⁰⁵Rh

Rhodium-105 was produced in quantities of 5 to 100 mCi at MURR using isotopically enriched ¹⁰⁴Ru (99.08 per cent, natural abundance: 28.2 per cent). The thermal and epithermal capture cross-sections of ¹⁰⁵Ru are 0.47 barns and 6 barns, respectively, while the burn-up thermal cross-section of ¹⁰⁵Ru toward the formation of ¹⁰⁶Ru is 0.3 barns. Rhodium-105 is produced from the radioactive decay of the ¹⁰⁵Ru intermediate (T_1/2 = 4.44 hours) both during and after the irradiation. The irradiation samples were prepared by accurately weighing the target material into clean quartz vials, which were then sealed under vacuum. The sealed quartz vials were encapsulated in high purity aluminum capsules and loaded into reflector positions within the MURR reactor for 72 hour irradiations at neutron fluxes of 8 × 10¹³ n cm^-2s^-1. The irradiated samples were allowed to decay for more than 12 hours and processed in a dedicated glove box. For shorter irradiations, natural ruthenium metal and potassium ruthenate were used as target materials for process development. Ruthenium metal samples were prepared in quantities of 1 to 10 mg and sealed in high purity polyethylene vials (of diameter 11 mm and length 23 mm). These vials were embedded in Styrofoam cylinders to cushion shock and placed in high density polyethylene containers known as “rabbits” for neutron irradiation for up to 1 hour in the pneumatic tube facility at MURR. The activities of the ¹⁰⁵Rh produced from these irradiations were in μCi quantities (less than 0.5 mCi).

Separation and Purification of ¹⁰⁵Rh

The irradiated ruthenium metal was placed into the ¹⁰⁵Rh glovebox and transferred into a reaction vial which was connected to a trapping system containing HCl and NaOH solution. Sodium hypochlorite (NaOCl) (4 ml, 5 per cent) was added into the reaction vial and the mixture was stirred at room temperature for 30 minutes. About 2 ml of 2 M NaOH solution was added into the vial after the ruthenium target was dissolved. While stirring, 100 μl of 0.1 M magnesium chloride solution was carefully added into the ruthenium solution. The magnesium hydroxide suspension was then filtered through a 0.45 μm Teflon filter. After washing twice with water, the magnesium hydroxide precipitate and adsorbed ¹⁰⁵Rh were dissolved with 0.5 M HCl in a new reaction vial. About 1 ml of NaOCl solution was added to the new vial and the ¹⁰⁵Rh solution was stirred for 5 minutes. The ¹⁰⁵Rh was re-precipitated on hydrous MgO on the addition of 1 ml of 5 M NaOH. The re-precipitated ¹⁰⁵Rh and MgO were filtered, washed with water, and dissolved with 2 ml of 0.5 M HCl solution. This ¹⁰⁵Rh solution was mixed with 1 ml of 4 M NaCl solution in a clean reaction vial and boiled for approximately 30 minutes. After cooling, the ¹⁰⁵Rh solution was passed through a cation exchange column to remove Mg²⁺. The final pH of ¹⁰⁵Rh solution, as measured with pH paper, was ca. 1.

Radioactivity Measurements

Aliquots of the sample were taken throughout the process and analysed to assess the recovery and radionuclidic purity of the ¹⁰⁵Rh. Gamma spectra were obtained using an intrinsic hyperpure germanium (HPGe) spectrometer attached to a 4000 channel analyser. All fractions for spectral analysis were prepared as 10 ml solutions in glass scintillation vials.

Trace quantities of ¹⁰³Ru in the ¹⁰⁵Rh product processed from the enriched, irradiated ruthenium target were determined on the HPGe detector after the decay of ¹⁰⁵Rh. Ruthenium decontamination factors were calculated by comparing the initial ratio of ¹⁰³Ru:¹⁰⁵Rh prior to chemical separation to the ratio of ¹⁰³Ru:¹⁰⁵Rh in the final ¹⁰⁵Rh sample after the separation.

Results

The radionuclide production resulting from the irradiation of an enriched ruthenium target in a reflector position in the MURR is shown in Figure 2.

The average perturbed neutron flux at this position is about 6.5 × 10¹³n cm^-2s^-1. Ruthenium-105 reaches maximum activity after the first 20 hours of irradiation due to its short decay half-life (T_1/2 = 4.4 hours). Its decay product, ¹⁰⁵Rh, gradually builds up and approaches saturation activity after 140 hours.

One important factor, which needs to be considered in the production, is that the product, ¹⁰⁵Rh, has very high neutron cross-sections (thermal: σ_th = 16,000 barns and epithermal: σ_epi = 17,000 barns) and thus will tend to capture a neutron to form ¹⁰⁶Rh, a short-lived radionuclide with T_1/2 = 30 seconds. Thus, ¹⁰⁶Rh is produced in fairly high quantity and the actual production yield of ¹⁰⁵Rh becomes significantly lower than the theoretical calculation which does not take into account such an “isotope burn-up” process.

The short-lived ¹⁰⁵Ru and ¹⁰⁶Rh, produced during the production process of ¹⁰⁵Rh, are allowed to decay before the irradiated samples are radiochemically processed. The maximum activity of ¹⁰⁵Rh is obtained about 14 hours after the end of irradiation (EOI), see Figure 3. This is, indeed, ideal “timing”, since the short-lived and high dose rate radionuclides, such as ¹⁰⁵Ru, ¹⁰⁶Rh and ³¹Si (2.62 hours, from irradiation of the quartz vial) are decaying and approaching their minimum quantities. The radiochemical separation of the samples can then usually begin 12 to 20 hours after the EOI.

Hydrous MgO adsorbed or co-precipitated rhodium(III) with very high efficiency. Rhodium-105 was collected and concentrated with a small quantity (typically ∼500 μg) of solid MgO/ Mg(OH)₂ which was then readily separated from the alkaline solution containing radioactive ruthenate. Both natural and enriched ¹⁰⁴Ru metal targets were used to develop the MgO separation procedure, and the distillation procedure which uses chlorine gas was used as a control for comparison of method efficiency. A decontamination factor of 11,300 was obtained from this control procedure (distillation) using chlorine gas as the oxidant and a natural ruthenium target. The decontamination factor from the procedure employing hydrous MgO averaged 16,600 for both natural and enriched ruthenium targets, for over 3 trials each. Total ¹⁰⁵Rh recovery averaged above 85 per cent from either procedure.

Discussion

The solution chemistry of ruthenium is complicated since, in most cases, ruthenium is present as more than one chemical species (13). Therefore it is necessary to use a multi-step separation procedure to remove these various ruthenium species. The use of MgO to separate the ¹⁰⁵Rh from the Ru (ruthenate) solution followed by a re-precipitation and column separation step for purification of ¹⁰⁵Rh seems to be a good choice. The decontamination factor obtained from this procedure was as good or better than that of the distillation procedure (control).

This new procedure is superior to the distillation procedure in terms of simplicity and the radionuclidic purity of the isolated ¹⁰⁵Rh. In addition, this procedure can be readily scaled up to processing multi-curie quantities of ¹⁰⁵Rh, because the use of hazardous materials, such as chlorine gas and volatile ruthenium tetraoxide, is avoided.

One important concept that this paper is intended to address is that there are always isotopie carriers and radiochemical contaminants present in a “pure” or “no-carrier-added” sample, which are produced during the currently available separation methodologies. Because of the trace quantity of the “no-carrier-added” radionuclide (the concentration for 10 mCi of ¹⁰⁵Rh in 5 ml solution is about 2 × 10^-11 M), the major components or elements present in the product may not be the specific radionuclides of interest. The ratio of ruthenium:rhodium at the end of a 72-hour irradiation is calculated to be around 200,000, from a comparison of the number of atoms of ¹⁰⁵Rh produced during the irradiation and the total number of ruthenium atoms available. The theoretical ratio of ruthenium:rhodium in the ¹⁰⁵Rh sample separated from a ruthenium target using the MgO adsorption method is in the region of ∼ 12, assuming a decontamination factor of 16,600 is achieved.

In other words, in the separated ¹⁰⁵Rh sample, the major metal element is ruthenium, rather than rhodium, even though nearly 100 per cent of the ruthenium has been chemically removed.

Additionally, it is probably worth mentioning that the ¹⁰⁵Rh is recovered as a mixture of chloroaquorhodium (III) complexes. In dilute HCl solution where chloride [Cl^-] is less than 1 M, there is a mixture of RhCl₄(H₂O)₂^-, RhCl₅(H₂O)^2- and RhCl₆^3-. RhCl₃(H₂O)₃ may also exist in the solution (14).

It has been reported that at high temperature (> 50°C and at a high concentration of chloride ([Cl^-1] = 1.5—3 M), the above reaction is effectively unidirectional toward the formation of RhCl₅(H₂O)^2- and RhCl₆^3- which may undergo aquation by the release of chloride to form neutral or cationic species when reaction conditions are changed (14). It is difficult, in most cases, to directly use the processed ¹⁰⁵Rh for radiolabelling due to its unknown speciation. The problem of converting all rhodium chloroaquo complexes to one chemical form for the subsequent radiosynthesis with bifunctional ligands or proteins – in order to obtain a uniform product with high efficiency – remains.

Conclusion

Rhodium-105 can be produced in quantities and purities suitable for radiotherapy research using a novel separation method based on MgO adsorption. The contamination from residual ruthenium does not apparently cause a problem for the practical use of ¹⁰⁵Rh. Ruthenium removal is less an issue than making sure all the rhodium is in the same chemical form.

This adsorption method eliminates the use of chlorine gas and the production of ruthenium tetraoxide, and thus is desirable for use in large-scale isotope production. This will lead to the potential availability of ¹⁰⁵Rh in multicurie quantities. However, at present no clinical trials are underway or are planned.