Recovery Profiles of Molybdate Solutions Through Varying Dowex-1 Resin Amounts, and Translation to Mo99/Tc99m Separation

The influence of molybdenum concentration and resin amount on the retention of molybdenum in 5M NaOH on Dowex-1 columns with successive elutions of saline and tetrabutylammonium bromide (TBAB) was investigated. Studies were performed with 45, 75, 125, 175, or 250 mg of resin and at 100 and 250 mg/mL molybdenum concentrations. Initial pass-through molybdenum recoveries from the column were 97.8% at 100 mg/L and 97.8% at 250 mg/mL (n=3 at each resin amount). Molybdenum breakthrough into TBAB solvent was low for all five resin amounts. Values for the 100mg/mL solution were 0.33 – 3.73 ppm, representing 0.0002 0.0014% of the original molybdenum load; and were 0.96 11.27 ppm for the 250 mg/mL solution, equivalent to 0.0002 – 0.0027%. Breakthrough into TBAB is generally higher with higher resin amounts for both the 100 mg/ml and 250 mg/mL molybdenum concentrations. The resin can be used for high molybdenum loads, with care taken to optimize the relative resin-solute amounts.


Introduction
We and collaborators are developing linear accelerator technology for a viable long-term production alternative for the current ageing medical isotope reactor production of molybdenum-99 (Mo99), and in line with the global transition to technologies that are more environmentally sustainable (Canadian Light Source, 2012;International Atomic Energy Agency, 2013;Kobes et al., 2010;Mang'era et al., 2011;Natural Resources Canada, 2012;Prairie Isotope Production Enterprise, 2010;Uvarov et al., 1998).As the target material for accelerator production is an isotope of molybdenum and the conversion, the radioactive product Mo99 product is intrinsically of low-to-medium specific activity, and the high relative molybdenum chemical loads mean that the traditional alumina column used separation of the daughter radionuclide technetium-99m (Tc99m) from Mo99 is not viable.Capacity of alumina is limited to 2-20 mg Mo/g alumina (Chattopadhyay & Das, 2008;Dash et al, 2013).Solvent-solvent extraction and solid-phase affinity chromatography (including use of Dowex TM -1 resin) are two techniques that have been applied to successfully separate technetium-99m (Tc99m) and molybdenum-99m (Mo99) from stocks of low-specific activity Mo99 of the type that is obtained by linear accelerator production (International Atomic Energy Agency, 1995;Kanpp & Mirzadeh, 1994).In Dowex TM -1 separations, Mo99 is not retained appreciably by the resin and the procedure involves quantitative pass-through of the molybdenum and retention of the Tc99m.The Tc99m is subsequently recovered, usually with the solvent tetrabutyl ammonium bromide (TBAB), and it is critical for clinical use that minimal Mo99 breakthrough into the TBAB eluate is seen.
Publications that report separations utilizing Dowex TM -1 resin have usually employed very similar parameters, including concentration of solvent base (NaOH) used to dissolve molybdenum (Chattopadhyay & Das, 2008;Chattopadhyay et al., 2008;Morley et al., 2012).The goal of this investigation is to evaluate the Dowex TM -1 system under various parameters that would be applicable to the very low specific activity Mo99 relevant to linear accelerator production technology.We spiked the molybdenum mixtures with Tc99m and report on Tc99m extraction efficiency.We extrapolate on the implications for product quality of any molybdenum retention on the To determine the elution profile of Tc99m into TBAB, after passing the 250 mg/mL molybdenum solution was separately passed through the lowest (45 mg) and the highest Dowex TM -1 amounts (250 mg) and the Tc99m eluted using 10mL of TBAB in 15 aliquots, initially in 0.5 mL aliquots during the first 5 mL volume and then 1 mL aliquots for the latter 5 mL solvent.

Results and Discussion
Table 1 shows elution recoveries and retentions of molybdenum on Dowex TM -1 columns following the three steps of the separation.Percentages of residual molybdenum retained on the column after Step 1 that are then eluted in Step 2, and residual after Step 2 that are then eluted in Step 3 are also provided.Table 1 shows that the molybdenum recoveries are high after the solution is run through Dowex TM -1 in Step 1, with the amount of the stock molybdenum retained on the column at less than 4% in all cases.The saline washes in Step 2 effectively reduce the retained molybdenum to < 2% in all cases (highest retained is 1.9% at 100 and 250 mg/mL), with the relative percentages washed off variable between 9 -76 % of the small amounts on the column after Step 1.The magnitude of molybdenum recovered in the wash is higher with higher amounts retained on the column after Step 1. Logically, the washed-out portion at Step 2 seems to have been loosely retained on the column.Although there is some pattern showing higher molybdenum retention with increasing resin amounts after Step 1, the apparently more effective subsequent wash with saline in Step 2 means that after Step 2, especially with the 250 mg/mL molybdenum concentration a consistent residual content on the column of 1.4 ± 0.3% is obtained for all samples at this concentration.
For clinical products in which the key process is the separation of Tc99m from Mo99 and where Tc99m purity is the key parameter, the relative amount of radioactive Mo99 to the Tc99m ("Mo99 breakthrough") constitutes the principal radionuclidic impurity, and relative amount of total molybdenum mass (all isotopes, radioactive and non-radioactive) eluted into the Tc99m extract constitutes the principal chemical impurity.The effectiveness of Step 3 separation is therefore crucial in a clinical setting prior to use of the extracted Tc99m product.Compendial limits for Mo99 breakthrough are 0.15 kBq of Mo99/1 MBq of Tc99m at the time of use of the clinical preparation (USP, 2012).We performed tests where both the 100 mg/mL and 250 mg/mL molybdenum solutions were spiked with Tc99m-pertechnetate and the resulting solutions were extracted through three Dowex TM -1 amounts (45, 125, and 250 mg).The amounts of chemical molybdenum in the 15 TBAB aliquots collected in the Tc99m-spiked elution study were measured using ICP-OES assays (Table 3).A clear difference is observed in the elution profiles for the two resin amounts, with the full amount of molybdenum eluted in the first 0.5 mL for the 45 mg Dowex TM -1 column while for the 250 mg Dowex TM -1 column, more TBAB solvent was required for full elution.It is notable, nevertheless that even for 250 mg resin, all the molybdenum was eluted within the standard 5 mL of TBAB volume.Chemical and radionuclidic molybdenum impurities in the final eluted Tc99m therefore appear to be concentrated in early aliquots, while the desired Tc99m product elutes at a more delayed profile.This elution differential allows for and could, if necessary, be exploited in difficult separations to optimize higher ratios of Tc99m to molybdenum in elutions, by discarding a small early fraction in the elution that would proportionately carry the highest impurity concentration.Avg.Molybdenum Concentration (ppm) 0.5 10.44 5.532 1.0 0 0.234 1.5 0 0.011 2.0 0 0.128 2.5 0 0.027 3.0 0 0 3.5 0 0 4.0 0 0 4.5 0 0.032 5.0 to 10.0 in 1 mL aliquots 0 0 Note.Molybdenum concentrations of 15 TBAB aliquots collected after passing 10mL of TBAB through two different amounts of Dowex TM -1 resin columns, to extract the components of a Tc99m-spiked 250mg/mL molybdenum solution passed through the column (n=2, 0.5mL aliquots for first 5mL and 1.0 aliquots for second 5mL).
The molybdenum extraction results in Table 3 are consistent with the Tc99m extraction profiles in Table 2 with respect to higher amounts of Dowex TM -1 resin leading to a poorer elution profile of the solute during TBAB extraction of the column.The 250 mg Dowex TM -1 column requires more TBAB to run through the column before all the molybdenum is removed.As far as satisfying molybdenum breakthrough requirements, the higher amounts of TBAB used do not create issues by increasing molybdenum breakthrough into the final product as overall molybdenum in the 15 aliquots for the 10 mL TBAB solvent volume are similar to the values obtained when only using 5 mL of TBAB.We would therefore prefer to adopt the higher amount of TBAB to elute the Dowex TM -1 column.

Conclusion
These experimental results show that high initial molybdenum recoveries and low molybdenum impurity elutions in the final TBAB solvent are obtained at the different concentrations tested of the parent sodium molybdate solution.The amounts of Dowex TM -1 used in the columns has no significant effect for amounts up to 175 mg but a significant change is noticed when Dowex TM -1 amounts reach 250 mg.These results indicate that the concentration of molybdenum in the sodium molybdate load solution is not as critical as the amount of Dowex TM -1 resin used in the column.It is recommended that amounts of Dowex TM -1 resin be kept at or lower than 175 mg for similar sets of separation parameters.
Fig he Tc99m in so different Dow

Table 1 .
Average percent of molybdenum retained on a Dowex TM -1 column and subsequent distribution of retained molybdenum