Introduction

Radionuclide therapy using radiopharmaceuticals has been in existence for nearly 70 years and offers benefits to cancer patients, in particular, patients suffering from thyroid disorder. Radioisotopes of current interest for these applications include 90Y (T 1/2 = 64 h) 131I (T 1/2 = 8 days), 153Sm (T 1/2 = 46.5 h), 166Ho (T 1/2 = 26.8 h), 177Lu (T 1/2 = 6.71 days), 186Re (T 1/2 = 90.6 h), and 188Re (T 1/2 = 16.7 h). Radioisotopes having short physical half-lives ranging from a few hours to a few days are quite useful for radionuclide therapy, and radionuclide generators represent an efficient means for making short lived therapeutic radionuclides more widely available throughout the developed and developing countries. A major advantage of generator produced radionuclides is that they have very high specific activity and can be used for the preparation of radiopharmaceuticals that target low density sites.

Yttrium-90 (Eβmax = 2.28 MeV) is a therapeutic radioisotope of enormous interest, and several established radiopharmaceuticals with this isotope are currently in use [1–4]. Yttrium-90 is a pure β − particle emitter that can be prepared by the irradiation of 89Y in a nuclear reactor or by the decay of 90Sr (T 1/2 = 28.8 years) [5]. Strontium-90 is a major fission product and owing to the long physical half-life, a single batch can be used indefinitely. However, because of the long half-life, the technology required for fabrication of 90Sr/90Y generators is considerably different from that used for other generators such as the 68Ge/68Ga, 99Mo/99mTc and 188W/188Re generator systems. The 90Sr cannot be left in the column matrix for longer time, because of denaturation resulting from energy deposition of the high energy β − particles from decay of parent and daughter radionuclides, which often results in 90Sr breakthrough in the eluate. Yttrium-90 used for therapy should be of very high radionuclidic purity (>99.998%), as the contaminant 90Sr is a bone seeker with a maximum permissible body burden (MPBB) of only 74 kBq (2 μCi). Currently, 90Y is separated by using a combination of several separation techniques such as precipitation, solvent extraction and ion exchange chromatography, or by using ion selective resins [6–10].

In this paper we present the separation of 90Y from 90Sr via colloid formation of 90Y and filtration by membrane filter and glass wool. Quantitative elution of 90Y is achieved by 0.1 M HCl.

Experimental

Materials and methods

All the chemicals used in the experiments were of analytical reagent grade and were purchased from E. Merck (Germany). Yttrium oxide powder and Strontium carbonate was product of Johnson and Mathey. Commercially available EDTMP was obtained from Dojin Laboratories (Kumamoto, Japan). Whatman 3 MM chromatography paper was used for ascending paper chromatography studies. Membrane filters were obtained from Millipore USA. Strontium-90 was purchased from Amersham UK.

Production of, strontium-85 and yttrium-90

Known Quantities of yttrium oxide/strontium carbonate targets were sealed in quartz ampoules and cold welded into aluminum cans. The irradiations were carried out inside the core of the 10 MW swimming pool type Pakistan Research reactor-I (PARR-I) for up to 120 h at a neutron flux of ~1.5×1014 cm−2 s−1. The irradiated material was dissolved in concentrated hydrochloric acid, evaporated and taken in distilled water. These radionuclides were used for yield determinations.

Activity measurement

Yttrium-90 samples were measured in an ionization chamber (Capintec CRC 15R, USA) when used at the mega Becquerel (MBq) level and with a beta counter, when used at lower levels. The 90Sr was also measured by beta counter. The 85Sr (T 1/2 = 65.2 days and γ peak 514 keV 99.3%) was measured by gamma spectrometry on an HpGe solid detector. The HpGe spectrometric system was calibrated using standard calibration radioactive sealed sources.

Filtration of 90Y colloid by glass wool

Approximately 10 mCi of the radioactive solution was taken in 1 M HCl. The pH of solution was adjusted to 12 with concentrated NaOH and filtered slowly through a small glass wool column (1 cm φ × 4 cm) The glass wool then washed with 0.1 N NaOH (15 mL). 0.1 M HCl was then slowly passed through glass wool column. The resulting filtrate was shown to contain only 90Y as evidenced by a half-life measurement (Fig. 1).

Fig. 1
figure 1

Decay of Yttrium-90 (half-life = 64 h)

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Filtration of 90Y colloid by membrane filter

Approximately 10 mCi of the radioactive solution was taken in 1 M HCl. The pH of solution was adjusted to 12 with concentrated NaOH and filtered slowly through a membrane filter (0.22 μm). The membrane filter then washed with 0.1 N NaOH (15 mL). 0.1 M HCl was then slowly passed through membrane filter. The resulting filtrate was shown to contain only 90Y as evidenced by a half-life measurement. Similarly the chloride solution of 90Sr in equilibrium with 90Y was neutralized with NH4OH and passed through Millipore membrane filter. Washing was performed by 1 M NH4OH. Removal of 90Y was achieved by 0.1 M HCl.

Preparation of 90Y-EDTMP

EDTMP was dissolved in distilled water or dilute NaOH. 90Y chloride solution was added to the EDTMP solution. The pH was adjusted to 8.

Paper chromatography

Five microlitre (μL) of the test solution was spotted at 2 cm from one end (bottom end) of Whatman 3 MM chromatography paper strips (14 × 2 cm). The strips were developed in pyridine/ethanol/water (1:2:4), dried, cut into 1 cm segments and the activity was measured. Some times strips were scanned by 2π Scanner (Berthold, Germany).

Results and discussion

The present investigation was planned to study the retention of carrier free 90Y colloid in filtration process with glass wool column and membrane filters. The Millipore bacteria filter is effectively impermeable to particles of colloid size, and by the constant area and uniform pore size of the filters, it would be expected to obtain more quantitative results.

Various experiments were carried out for the separation of 90Y from 90Sr using colloid formation behavior of 90Y in basic pH range. When the acidic solution of 90Sr/90Y was treated with NaOH and passed through a small glass wool column, more than 95% 90Y was retained on glass wool, which was further washed with 0.1 M NaOH. The 90Y was extracted in 0.1 M HCl. Radionuclidic purity was determined by half life measurement (Fig. 1), which confirms the half life of 64 h of extracted isotope. The contamination of parent was less than 0.0001%. Table 1 shows the recovery of 90Y from 90Sr/90Y mixture using a small glass wool column. The glass wool column was reused after washing with 30 mL of deionized water. Similarly when the colloid was passed through membrane filter more than 99% 90Y was retained which was also recovered by 0.1 M HCl. The contamination of 90Sr was less than 0.0001%. New membrane filter was used for each experiment. Similar experiments were carried out using reactor produced 90Y and 85Sr to determine the purity and yield of separation. Table 2 shows the recovery of 90Y from 90Sr/90Y mixture using membrane filters.

Table 1 The recovery of 90Y from 90Sr/90Y mixture using a small glass wool column
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Table 2 The recovery of 90Y from 90Sr/90Y mixture using membrane filters
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Similar results were also obtained when first experiment was performed by neutralization of stock solution of 90Sr/90Y in HCl by NH4OH. However when the stock solution of 90Sr/90Y in NH4OH was again passed through Millipore filter paper or glass wool after 1 week equilibrium time, the retention of 90Y was insignificant. The equilibrium mixture of 90Sr/90Y was acidified with HCl and again precipitated with addition of NH4OH. The basic solution was passed through the Millipore filter or glass wool. More than 90% activity of 90Y was retained, which was finally extracted in 0.1 M HCl. It was concluded that for recovery of 90Y from 90Sr by colloid formation, the acidic solution of 90Sr/90Y shall be freshly precipitated by NH4OH. Presence of NH4Cl has significant effect on the retention of 90Y on membrane filter. After third neutralization cycle the retention of 90Y colloid was very low, since NH4Cl dissolves the Y(OH)3.

On the other hand, in case of NaOH multiple separations of 90Y from 90Sr were performed successfully. The stock solution of 90Sr kept in 0.1 NaOH can be used many times for the separation of colloidal 90Y by filtering through glass wool or Millipore filter. Nearly 3 mL 0.1 M HCl was required for extraction of 90Y from glass wool column or Millipore filter. Various separation techniques reported in the literature [6–10], use multiple steps to achieve high purity 90Y needed for medical applications, while few are cumbersome and not suitable for remote handling. Ion exchange chromatography is frequently used 90Y isolation technique, however due to radiation damage of resin, high level of 90Sr breakthrough occurs. Inorganic adsorbent supported generator system gives low yields of 90Y, while solvent extractions suffer contamination from organic components and incomplete separation from parent radionuclide. 90Sr/90Y generators based on supported liquid membrane and electrochemical deposition require two stages to obtain highly pure 90Y suitable for preparation of radiopharmaceuticals [6]. The method described in this paper gives high yields of 90Y and it can easily be adopted by using spent Tc-99 m generator body for remote handling needed for safety of operator and environment [11].

It was also observed that the adsorption of 90Y in basic solution was quite high when the 90Sr solution was left in a glass vial for the growth of 90Y. However it can be easily extracted after keeping it in boiling water bath for few minutes.

The separated 90Y via colloid formation was used for the labeling of EDTMP. Labeling efficiency of 90Y-EDTMP was more than 98%. Figure 2 show the chromatographic and behavior of 90Y-EDTMP.

Fig. 2
figure 2

Paper chromatography pattern of the 90Y-EDTMP complex and 90YCl3 in pyridine:ethanol:water (1:2:4)

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Conclusion

The separation of 90Y from 90Sr via colloid formation is simple, but not suitable for hospital radiopharmacy. Such procedure can be adopted in radiochemistry lab, where Curie level 90Y may be separated and supplied to its users. Stock solution of 90Sr can be kept in 0.1 M NaOH for growth of 90Y colloid, which can be retained on glass wool or membrane filter and finally extracted by using 0.1 M HCl for labeling purposes.