82Sr production from metallic Rb targets and development of an 82Rb generator system

Appl. Radial. ht. Vol. 44, No. 6, pp. 917-922, 1993 Copyright

Printed in Great Britain. All rights reserved

82Sr Production Development

from Metallic Rb Targets and of an *‘Rb Generator System

M. R. CACKETTE, TRIUMF,

0883-2889/93 $6.00 + 0.00 1993 Pergamoo Press Ltd

0

T. J. RUTH*

4004 Wesbrook

and J. S. VINCENT

Mall, Vancouver,

Canada

V6T 2A3

(Received 31 January 1992; received for publication 3 December 1992) A complete procedure for producing %/Rb generators is described. %r was produced by bombarding metallic rubidium targets with 60 MeV protons with beam currents as high as 80 pA. The experimentally determined cross section for a thick target (6148 MeV) agrees with the literature value of 100 mb. Production rates of about 0.2 mCi/pA-h with a 1.8 g/cm2 target were achieved. The %ir was separated from the target by dissolving the rubidium metal in n-butanol then separating the strontium isotopes on a Chelex-100 column. A SnO, generator system was built from readily available components. Factors affecting generator design, performance and limitations included SnO, particle size, column length and eluant flow-rate.

Production

Introduction The use of ‘*Rb (‘; = 76 s), eluted from the parent ?Sr(tf = 25 d) finds increased clinical application in positron emission tomography for the diagnosis of myocardial disease (Gould, 1991). A special issue of this journal (Waters and Coursey, 1987) contained 13 papers dealing exclusively with *2Sr production, generator technology and medical evaluations. Within the last five years the clinical demand for 82Sr has increased to 2.5 Ci/mo and it is expected to double by 1995 (Holmes, 1991). The demand has encouraged continued technical development to improve s2Sr production. This paper seeks to contribute to that effort by describing a high level s2Sr production scheme (> 1 Ci/target) and some generator developments that have not appeared previously in detail. Specifically, we will discuss:

Target containers were prepared from stainless steel (SS-316) to enclose a hole measuring 2.22 cm in diameter, 1.3 cm thick and covered with 0.13 mm thick stainless steel windows and assembled by TIG welding. A male connector (Swagelok) was welded into the side of each target which provided a means to leak check and fill the target frame with molten rubidium (99.9%, Strem Chemicals), The 1.80 g/cm2 targets were irradiated in the TRIUMF solid target facility of beam line 2C (Cackette et al., 1991). Protons with an incident energy of 60 MeV and a current of 30-80 PA bombarded the target until the desired integrated current was reached. The diameter of the beam was about 5 mm. The targets were set aside for one week to allow for decay of short-lived species.

1. Safe production of 82Sr from metallic rubidium with a 60 MeV proton beam having peak currents up to 80 PA. 2. A scheme for processing targets containing many curies of radio-strontium and radiorubidium. 3. Construction of 82Sr-82Rb generators for research applications and measurement of their performance characteristics.

Irradiated targets were transferred into a hot cell, then placed inside a glass vessel and immersed in 100mL of n-butanol (BDH Inc). The vessel (see Fig. 1) was sealed then purged with argon (Linde, Union Carbide) followed by heating to about 50°C to melt the Rb. The target window was punctured remotely by lowering a shaft tipped with two tungsten prongs. When all the Rb had reacted with the butanol, the liquid was transferred to a round bottom flask. Excess 1 N HCl was added to hydrolyse the butoxide, and the solution was heated to dryness, redissolved in water and evaporated to dryness (Weinreich, 1991). The resulting residue containing the radio-strontium and radio-rubidium isotopes was dissolved in a pH 10 buffer solution (0.1 N NH,OH/NH,Cl, BDH Inc). This mixture was added to a Chelex-100 column

Experimental All reagents were reagent grade unless otherwise specified. *Author for correspondence. 917

Processing

M. R. CACKETTE et

918

al

Generator

Shaft

/

Ar inlet

Ar exit

\

Tip Reaction vessel

J

Thermocouple

n-butanol

Heater

-

7-3 _______

Scale 0

(cm) 5

10

Fig. 1. Simplified schematic diagram of the glass vessel and tool used to dissolve Rb metal targets. A housing (not shown) surrounds the vessel and shaft. (also not shown) allows the shaft to he forced window to puncture it. The two halves of the are sealed during dissolution of the

A screw drive into the target reaction vessel target.

(0.6cm dia, 10 cm long, 100-200 mesh, Bio-Rad) which retained the strontium isotopes while allowing the rubidium isotopes to pass through to waste storage (Brihaye et al., 1987). The *2Sr was eluted from the Chelex column with 6 N HCl. Production rates were determined by assaying product and waste solutions using a standard Ge(Li) detector-multichannel analyser (MCA) system calibrated for energy and efficiency against standard gamma ray sources (Amersham). When gamma ray peaks were well separated, pulse height analysis was performed by a simple integration routine built into the MCA. Otherwise the spectrum was processed by a PC version of the program GAMANAL (Gunnick and Nidas, 1972).

Generator bodies consisted of a column end fitting (Swagelok) containing a 25 pm frit (Swagelok), attached to both ends of a 6mm i.d., 25mm long tube (see Fig. 2). All wetted components are SS 316. Generators were prepared by removing one column end fitting then inserting about 3 g of dry SnO, (sieved to 75-212 pm) into the partially assembled generator body. The generator was then back-washed to remove air pockets and the slurry vibrated at 60 Hz until no further settling of the SnOz grains was observed. The generator was reassembled then leak tested to 90 psi. The generator was loaded with radioactive strontium using a modified version of the procedure described by Brihaye et al. (1987) as follows: A 100 mL sample of 0.1 N NH,OH/NH,Cl buffer was added, followed by 150 mL of 2 N NaCl at a flow rate of 1 mL/min, then the s2Sr solution in pH 7.4 Tris buffer in 10 mL at a flow rate of 0.016 mL/min and a final washing of 1 L of 1% NaCl at a flow rate of 1 mL/min. A typical generator contained about 200 mCi of *%r. Depleted uranium with a wall thickness of 3 cm provided shielding for shipping the loaded generators. The radiation field at 50 cm, with this shielding was < 10 mR/h. Prior to shipping, each generator was tested for elution yield, breakthrough and bolus volume as described by Guillaume and Brihaye (1984). In addition, a fourth test was devised to produce a one dimensional map of the distribution of 82Sr along the length of the column. A shielded 5 cm dia Nal(TI) detector (Bicron) was positioned behind two lead bricks, separated by about 0.5 mm (see Fig. 3). The generator body was placed on the carriage of a syringe pump (Harvard Apparatus Inc.) and moved at a constant rate of 0.1 mm/s past the slit. Pulses from the NaI detector were recorded by a MCA in multi-scalar mode. Samples of SnO, were received from the International Tin Research Institute (ITRI Middlesex, U.K.) and Squibb Diagnostics (Princeton, NJ). The Sn02 particles supplied by Squibb ranged from 75-150 pm (100-200 mesh) while the ITRI sample of Sn02 was split into two fractions, a 75-212 pm (70-200 mesh) fraction and another fraction consisting of particles < 75 pm but larger than the 25 pm pores of the frits. Identical generators (6 mm dia x 25 mm long) were prepared from each of the three types of SnO, following the procedure described. Testing for yield, elution profile and breakthrough followed the procedures described by Guillaume and Brihaye (1984). The volume of saline eluted before S2Sr breakthrough occurred was measured by connecting 10 L reservoirs containing 0.9% NaCl 150 cm above the generator, and allowing gravity to elute the generator. Contributions to back-pressure were identified for the generators described above by attaching a pressure gauge (Wika, model 51640) to the input tubing of the generator. The back-pressure

919

“*SrProduction from Rb metal and “Rb generator development D.U.

shielding

S.S. cladding

Tin dioxide

Generator

-S.S. tubing

Scale I I

1

I

I

I

I

I

I

/

0 Fig.

2. Schematic

diagram

(cm) I I

I I

1 I

1

f

I

I

**Sr/“*Rb generator shielding.

was recorded at about a dozen different flow rates for each combination of generator dimension, tubing dimension and particle size. Teflon tubing (General Valve Corp.) was used for all tests. Two inside diameters of tubing were tested, 0.75 and 1.5 mm. The elution rate was programmed into the syringe pump and was verified periodically by collecting effluent into a graduated cylinder. Results and Discussion Targets We initially began to produce ‘*Sr by irradiating 2.0 g/cm* RbCl targets (Mausner et al., 1987). However after 17 targets, this method was abandoned due to low yields and numerous target failures. We found that the salt fused and retreated from the beam strike area when the beam current exceeded 10 PA in a 5 mm dia beam spot. The resulting ablation reduced

t

10

5

of an assembled

I

including

depleted

uranium

(D.U.)

the target thickness, and hence the yield. We also experienced target failures due to corrosion of the SS 316 windows by the molten salt. Both problems were exacerbated at higher beam current. Metallic rubidium has advantages over RbCl as a target material but also carries some risks and complications. The solid targets are irradiated under water, both for cooling and to adjust proton energy. Because Rb metal reacts violently with water, several targets were destroyed under water to simulate failure under irradiation conditions. The hydrogen released during this test is dissipated without difficulty into the exhaust system. Table 1 lists five typical bombardments at TRIUMF in 1991, using 60 MeV protons with peak currents up to 80 PA. The yields represent a significant improvement over previous reports where RbCl was the target material (Mausner et al. 1987). Zaitseva et al. (1991) have measured %r production cross sections from

920

M. R.

CACKETI’E et al. Table

I. **Sryields

for a series of production irradiations illustrating the stability of the target system

Target

fiA-h

Hours

Al2 Al4 Al5 A16 A17

4400 15193 I5603 8140 1599

216 600 528 288 48

Average beam current (PA) 18 29 26 28 33

Average UOSS

Yield Ki) 0.92 2.7 2.6 1.6 0.37

sections (0) 102 91 89 90 92

6 4 -

natural rubidium. Their average reported cross section for the energy thickness of our target, 61-48 MeV, is 100 k lOmb, in good agreement with the present results.

2

3 -

Processing

2 I -

1.5 1.0 .5

Distance in mm Fig. 3. A cut away schematic diagram of a generator is shown at the top of the figure. The graphs below it show the distribution of 82Sr inside a generator as saline is eluted. When the generator is new (labelled 0 L) the activity is confined to a narrow band at the top of the generator (0 mm). As more and more saline elutes (labelled 3.3 L, 5 L, etc), the activity spreads along the SnO, column.

The chemical processing was performed in a hot cell under an Ar atmosphere until the rubidium was safely dissolved in n-butanol. Care must be exercised during this step because of the flammability of butanol (flash point 35°C) and the heat generated during dissolution of the rubidium metal. A thermocouple within the reaction vessel measured the temperature (Fig. 1). The reaction rate was controlled by adjusting the height of the tips of the target opener which varied the rate at which n-butanol contacted the rubidium metal. About 1 L of hydrogen was produced during dissolution and was vented from the hot cell through the argon exit line (Fig. 1). It should be noted that the butanate solution is very corrosive to stainless steel and common plastics and was thus confined to either glass or teflon. When the butanate solution was transferred from the reaction vessel to the round bottom flask, at least one third of the radio-strontium isotopes was left behind. About 90% of the missing radiostrontium isotopes (30% of total) was recovered by rinsing the target frame and reaction vessel with 0.1 N HCl. It is not known whether the *?Srseparated due to precipitation, or adsorption onto the vessel walls. Even after the 0.1 N HCl rinse, about 7-10% of the missing *‘Sr remained adsorbed onto the interior of the target shell. Complete removal was accomplished by etching the interior of target shells with a solution of 6 N HCl, and 1 N SrCl,. The recovered **Sr was used for assaying production yield and not loaded onto generators because of the presence of the carrier strontium. Each time a target was opened, airborne radioactivity was immediately noted in monitors attached to the hot cell exhaust. The most likely source of the radioactivity is either *5Kr (‘4 = 10.7 y), produced by a (p,2pn) reaction on *‘Rb or 12’Xe (1; = 36.4 d) produced by a number of possible reactions with the cesium contamination present in the rubidium metal. A certificate of analysis accompanying the rubidium metal claims that the concentration of the cesium is about 700 ppm. 15Se has been found in r2Sr produced from RbCl targets (Mausner et al., 1987) and there has been

82Sr Production from Rb metal and ‘*Rb generator development speculation as to its origin. Since it was also seen in the present study using rubidium metal targets it must have been produced by a direct reaction with “alRb, and not by reactions with bromine impurities in RbCl as previously suggested (Mausner et al., 1987). We have used a small in-line filter, filled with glass wool to effectively adsorb 75Sefrom the buffered Sr/Rb solution, prior to separation on the Chelex-100 column. The filter is changed after each target is processed. The most important contaminant was 85Sr (‘f = 64.8 d). The (p,xn) reaction on natural rubidium at 48-60MeV produces about 0.4 times as much ‘?.Gras 82Sr at the end of bombardment (EOB). The ratio increases with time due to the longer half-life of “Sr. The ratio of *SSr/*2Srmust not exceed 5.0 if the generators are for human use. This ratio is exceeded about 150 days after EOB. Thus generators can be prepared from the 82Sr for several months after production using natural rubidium targets. The shelf-life for a particular generator would of course depend upon at what time after EOB the generator was prepared. Typically, the quantity of 82Rb available from the generator would be the limiting factor rather than contamination. Table 2 lists the radioactive nuclides found in the waste solution of a typical process. A total of 1664 mCi of 82Srwere recovered from a target which was processed 20 days after EOB. Most of the radioactive waste consisted of *3,84*86Rb isotopes, nearly all of which were found in the 150 mL of effluent from the Chelex 100 column. Condensed vapours were collected with about 92% efficiency from the numerous drying stages by a water cooled Liebig condenser (10 cm). This procedure permitted recovery of the a2Sr in case of accidents and reduced contamination inside the hot cell. Generators

In comparing the three generators buiit from different sources of tin dioxide, the generator constructed from smaller particles of tin dioxide (ITRI) appeared to offer no advantages. However, the back-pressure of this generator was too high to be eluted by our syringe pump. The other generators prepared from 75-212 pm SnO, (ITRI) and 75-150 pm SnO, from Table 2. Radio-nuclides

Nuclide 7k&$. nBr 8’Rb “Rb %Rb %r 8% “Sfl

present in waste solutions

(d$s)

(kk)

y-ray intensity W)

120.00 2.40 86.20 33.00 18.60 28.60 1.35 64.80

279 238 520 881 1077 776 762 514

25.2 23.1 46. I 71 .o 8.8 13.6 29.6 98.0

from target A5

Organic phase (x&i) 2.9 rf: 0.1 6.4 f 0.1 1.5 * 0.1 1.6~0.1 0.64 + 0.06 2.8 f0.1 0.24 f 0.02 1.10 + 0.03

Aqueous phase (ma) 1.8 f 0.9 <0.9 615 f 5 916+4 366 f 7
*“Se does not include the amount trapped on the glass wool filter. t’“Sr is estimated from previous measurements on other targets. “Organic” refers to species present in the condensed butanate vapours. “Aqueous” refers to species not retained on the Chelex100 column. The target was processed 20 days after EOB. A total of 1664 mCi of 82Sr was recovered from the Chelex column.

921

Squibb had similar performance in all tests except the total elution volume. The Squibb generator had a total elution volume of 30 L while the generators prepared from ITRI particles had an elution capacity of 10 L before strontium breakthrough. The reason for this difference is unknown. Measurement of the distribution of *‘Sr on the generator column was a non-destructive quality control test ensuring that the generator had been loaded properly. Experience with many generators has shown that a normal useful life-time elution volume of saline (> 10 L) could be expected without significant strontium breakthrough if the 82Sr distribution remained in a 3-4mm band after the first elution liter. If the ‘*Sr is distributed throughout the generator, breakthrough of strontium isotopes can be expected. Packing the SnO, prior to loading with 82Srwas found to prevent excessive distribution of the 82Sr. The column scanning technique was also used to follow the distribution of 82Sr inside the generator between elutions as shown in Fig. 3. The front of the 82Sr concentration peak moved along the generator with the total volume of saline eluted. However, a narrow radioactivity peak, aligned with the top of the generator column, remained stationary as the front advanced. The resolution of this technique was about 1 mm FWHM. A properly functioning generator is able to adjust the pH of the eluant saline solution to at least pH 6 to minimize Sr breakthrough (Brihaye et al., 1987). Normally this is done by saturating the SnO, with Na + ions, which exchange with H + ions in the saline. However, the SnO, supplied by ITRI had to be first loaded with NH:. Some generator applications require a bolus injection within 10 s or less, a difficult condition to meet. Bolus injection time is proportional to the volume of the bolus, and inversely proportional to the pumping speed. A constraint on pumping speed is the backpressure developed when saline is forced through the generator. The maximum pressure which the syringe pump would deliver was about 150 kPa. In all cases back-pressure was found to be directly proportional to pumping speed except at very low flow rates (< 10 mL/min) where it was nearly constant. However, low flow rates are not commonly used in most applications. With a limit of 150 kPa delivered by the syringe pump, the back-pressure developed by the generator and all intervening tubing must be no more than 2.5 kPa/mL/min. This limitation can be overcome by the use of tubing with a larger diameter or by using only a portion of the bolus from a generator. Factors affecting the bolus volume include the length of the generator column, and the size of the tin dioxide particles. The current generator length was kept as short as possible and particle size chosen to be as large as possible (75-212pm). Ten mL of saline was sufficient to elute the entire bolus from this generator. An elution rate of at least 60 mL/min was required to elute the bolus in 10s or less.

M. R. CACKETTE et al.

922

Conclusion In conclusion using

metallic

the production this target

we believe that the (p,xn) reaction Rb targets is the method of choice for of large quantities of **Sr. Yields from

system approach

theoretical

even at high

beam current. Generators have been constructed from readily available components which proved to be reliable, strong and immune from radiation damage. Acknowledgements-The authors want to acknowledge the assistance of Mr E. Knight for the design and construction of the Rb reactor apparatus. We thank Dr P. A. Cusak and Mrs B. C. Pate1 of the International Tin Research Institute, Middlesex, England for preparing a sample of a-form SnO,. and giving us the details of the procedure. We are indebted to Squibb Diagnostics, and DrWilliam Eckelman for the donation of several SnO, columns. We also thank Jeanne Link for testing our generators and providing helpful suggestions. Financial assistance from the Faculty of Pharmaceutical Sciences of the University of Alberta, the Department of Radiology of the University of Washington, and Nordion International Incorporated are gratefully acknowledged. Support for this project was provided by the National Research Council through TRIUMF.

Guillaume M. and Brihaye C. (1984) The short-lived radionuclide generator. In Radionuclide Generators (Knapp F. F. and Butler T. A., eds), p. 185. American Chemical Society, Washington. Gunnick R. and Nidas J. B. (1972) Automated gamma spectroscopy by computer. UCRL, 51061, 1, I. Holmes R. A. (1991) National Biomedical Tracer Facilify, Planning and Feasibilify Study, p. 14. Society of Nuclear

Medicine, New York. Horoguchi T., Noma H., Yoshizawa

Y., Takemi H., Hasai H. and Kiso Y. (1980) Excitation functions of proton induced nuclear reactions on s5Rb. Appl. Radial. Isot. 31, 141. Mausner L. F., Prach T. and Srivastava S. C. (1987) Production of s*Sr by proton irradiation of RbCl. Appl. Radial. Isot. 38, 181. Thomas K. E. (1987) Strontium Production At Los Alamos National Laboratory. Appl. Radiat. Isot. 38, 175. Waters S. L. and Coursey B. M. (1987) The strontium-82/ rubidium-82 generator. Appl. Radial. Isot. 38, 171. Weinreich R. (1990) Positron emitters from generators. Nuk. Med. 29, 79.’ Zaitseva N. G., Deptula C., Knotec O., Kahn Kim Sen, Mikolaewski S., Mikec P., Rurarz E., Khalkin V. A., Konov V. A. and Popinenkova L. M. (1991) Cross sections for the 100 MeV proton-induced nuclear reactions and yields of some radionuclides used in nuclear medicine. Radiochim. Acta 54, 57.

APPENDIX

References Brihaye Cl., Guillaume M., O’Brien Jr H. A., Raets D., de Landsheer Ch. and Rigo P. (1987) Preparation and evaluation of a hydrous tin(IV) oxide ‘*Sr/“Rb medical generator system for continuous elution. Appl. Radiat. Iso!. 38, 213. Cackette M., Dougan H., Lenz J., Ruth T. J. and Vincent J. S. (1991) A radioisotope production facility using 70-120 MeV protons. J. Label. Compds Radiopharm. 30, 109. Gould K. L. (1991) PET perfusion imaging and nuclear cardiology. J. Nucl. Med. 32, 579.

SnO, was prepared by the International Tin Research Institute (ITRI), Middlesex, England as follows: An 80 mL sample of 99% SnCl, was added drop-wise to 2000 mL of H,O. The pH was first adjusted to 9 by adding concentrated NH,OH and then to 7 by adding concentrated HNO,. The supematant was decanted, then the solid gelatinous product washed in 2000 mL distilled water, centrifuged and decanted again. This step was repeated until testing with AgNO, indicated the absence of chloride ions in the supernatant (at least three times). The gel was dried at 105°C in air, then broken into smaller particles by adding water and drying again. The yield is about 100 g.