An improved internal Cu3As-alloy cyclotron target for the production of 75Br and 77Br and separation of the by-product 67Ga from the matrix activity

Int. J. AppL Radiat. lsot. Vol. 35, No. I0, pp. 927-931, 1984 Printed in Great Britain. All rights reserved

0020-708X/8453.00+0.00 Copyright ~ 1984,PergamonPress Ltd

An Improved Internal Cu3As-alloy Cyclotron Target for the Production of 75Br and 77Br and Separation of the By-product 67Ga from the Matrix Activity G. B L E S S I N G and S. M. Q A I M lnstitut t-fir Chernie 1 (Nuklearcheraie), Kernforschungsanlage Jfilich GmbH, D-5170 Jfilich, F.R.G. (Received 26 March 1984; in rerised form I1 May 1984)

The use of Cu3As-alloyin high current irradiations in an internal target system for the production of 75Br via the 75As(3He,3n)r~Br reaction and nBr via the 7SAs(,,,2n)nBr process has been optimized. Radiobromine is separated from the irradiated alloy by thermochromatography and is of high chemical purity. The major radionuclidic impurity in 7~Bris VSBr(5--8~ at EOB). Batch yields amount to 200 mCi 7SBr (EOB) and 48 mCi 77Br (EOB). A wet chemical method based on cation-exchange chromatography followed by solvent ektraction was developed to separate ~TGa(formed via the eSCu(,,,2n)e~Ga reaction) from the matrix activity. The final product is chemically pure but contains 2.3~ ~Ga as radionuclidic impurity. The batch yield amounts to 9 mCi S~Ga(at 100 h after EOB). The process is of interest only in combination with the production of r~Br where STGais formed as a by-product.

Introduction The methods used for the production of medically important radioisotopes 75Br [t~/~-- 1.65 h; //+ (75.5~), EC (24.5~); E./ 286 keV (91.6~)] and 7'Br [h/2--57h; EC (99.3~0), t ÷ (0.7~); ET: 239keV (22.8~), 521 keV (22.1~)] have been reviewed (cf. Refs l and 2). It was concluded t:) that the major processes for the production of 7SBr entail the 7SAs(3He, 3n)7~Br (Jfilich) and ~SSn(p, 2n)75Br (Groningen) reactions. Large scale production of nBr was achieved by spallation of Mo (Los Alamos) and the ~SAs(`', 2n)7~Br reaction (Hammersmith, Jfilich). To some extent the 7sSe(p, 2n)nBr reaction was also used (BNL). In order to use arsenic as target material for the production of both 75Br and nBr, a Cu3As-ailoy was developed °~ which is capable of withstanding high beam currents. Details of production using this alloy and irradiations mainly in an external target system were described. We now report on some further optimizing experiments relevant to the production of both 7SBr and "Br using an internal target system. In all the production runs, involving both 3He- and ,,-particle irradiations, strong matrix activity originating from nuclear reactions on copper was found. In particular in `'-particle irradiations of the alloy, 67Ga [h,~ = 78.3 h; EC (100~); ET: 93 keY (38.0~),

185keY (23.6~), 300keY (19.0~)], an important medical radioisotope, was formed in appreciable amounts via the SSCu(,,, 2n)STGa reaction. For the production of this radioisotope several routes have been suggested, e.g. protons on " Z n , STZn and UZn (cf. Refs 4--8), deuterons on "a'Zn, ~Zn and 67Zn (cf. Refs 5, 6, 9-12), `'-particles on Zn (cf. Refs 10, 13, 14), 3He-particles on Cu (cf. Ref. 6) and `'-particles on Cu (cf. Pet's 5, 6, I0, 15). In practice, however, proton and deuteron induced reactions on zinc, which give relatively high yields, are commonly used. The details of the production processes using highly enriched ~Zn, 67Zn or ~*Zn as target material have been well investigated and the radioisotope is even commercially available. The 3He- and ~t-particle induced reactions as such are less useful, since they lead to low yields of 67Ga. However, since in our 77Br-production runs 67Ga is formed as a by-product via the ~SCu(`', 2n)STGa reaction, involving no extra effort with regard to targetry and irradiation time, and would go to waste if not chemically separated, we attempted to recover it from the matrix activity. Targetry The experimental details relevant to the preparation of the Cu~As-alloy with the optimum composition of As (31~) and Cu (69~0) have been

927

(3. BI.ESSlNGand S. M. Q~dM

928

described previously.(3) The preparation of the target (Cu3As-alloy layer on Cu-backing) has now been improved and optimized for irradiations with internal beams. The alloy is ground, the powder is micronized and a suspension in organic solvent is made. The target material is then allowed to sediment on a polished copper backing sheet (7.7 x i.0 crn), melted in hydrogen atmosphere in an oven at 900°C, and then cooled down to 20°C within 2 min to minimize arsenic losses. The thickness of the layer was determined using a micrometer. If necessary, the sample was ground and controlled with a calibrated inductive thickness gauge. In contrast to the earlier method involving the welding of alloy pieces on Cu-backing and subsequent grinding to achieve the required thickness, the present method has the advantage that the thickness of the layer can be better controlled. About 10/~m thick alloy layers are needed to cover the optimum energy ranges for the production of both 75Br and 77Br (E~M~= 36---*25 MeV for 7~Br and E~ = 28---, 14 MeV for 7VBr). Previously the Cu-backing used was flat; now we use a Cu-sheet in the form of a wedge. The wedged target is soldered on a target holder made of copper. A sketch of the system is given in Fig. l(a). The target holder fits into -the internal target assembly()6) at our compact cyclotron CV28 and is cooled at the back by flowing water. The wedged target has two advantages over the fiat form used previously.~) Firstly, the angle between the beam path and the Cu3As-alloy layer has "~

been increased from 3.2 -~to 6.2 °, as a result of which somewhat thicker alloy layers can be tolerated, without increasing the 76Br-impurity level in 7~Br. Secondly, it is possible to incorporate a thermoclement in a cavity in the middle of the wedge. Previously we had experienced some difficulties in the adjustment of internal beams of 3He- and ~-particles on the target (see yield data given below). The use of a thcrmoelement eliminated this difficulty. The power density experienced by the thermoelemcnt is proportional to the beam intensity incident in the middle of the target. The relative variation in the power density registered as the beam moves along the length of the target is shown in Fig. l(b). It is thus possible to adjust the beam. Irradiations are performed with beam currents of up to 120~A. An autoradiographic profile of the beam incident on a wedged target (with thermoelement) is shown in Fig. l(c). A microscopic analysis of irradiated targets showed no significant radiation damage effects at the end of a 6 h irradiation.

Production of 7SBr and 77Br Production of 7SBr is carried out routinely by irradiations of the above mentioned targets with 36 MeV 3He-particles at beam currents of up to 100#A for periods up to 2h. In the case of 77Br, irradiations are performed with 28 MeV ~-particles at beam currents of up to 120/~A for periods up to 6 h.

Q

Thermocoupte voLtage

'

g

Target holder

A Target Length I I

,, : L _ .

6.2* ~' -

,

.

Oizm)

Beam angle Cavity for thermoetement Cu-backing [wedged}

Beam current t .~.

5 cm

'-~

•

.-

Q

eam

Fig. 1. (a) Sketch of the target and target holder used for irradiations with internal beams. The target consists of a thin layer of Cu3As-alloy on a wedged Cu-baddng. A thermoelernent placed in a cavity in the middle of the target allows the adjustment of the beam. (b) Relative power density experienced by the thermoelement as the beam moves~along the length of the target. Beam is considered to be adjusted when the maximum power density is registered. (c) Autoradiographic profile of the beam incident on the target.

929

A Cu3As-alloy cyclotron target for production of 7s'rTBrand 6?Ga The target holder together with the target is removed from the internal target assembly °6) automatically. The target is then desoldered from the target holder in a hot cell and transferred to an automated distillation apparatus where radiobromine is separated by thermochromatography and taken up in 1 mL H20, as described earlier. (3)Production of TSBrvia this method has been performed in our laboratory now more than 40 times and that of nBr more than 100 times.

Yields For the Cu3As-alloy with an As-content of 31% the theoretically expected thick target yield of 7SBr over the energy range of E~., --- 36-* 25 MeV amounts to 2.4mCi/#Ah, and that of "Br over E= = 28---, 14 MeV to 0.13 mCi/pAh (cf. Ref. 3). The experimental yields obtained in a large number of production runs using our old flat target system are shown in Fig. 2 as a function of the integrated current (~Ah). The data showed large scatters and were attributed to the lack of beam adjustment, especially in the case of 3He-irradiations. Using the wedged target, with beam adjustment through thermoelemerit, a more consistent set of yield values have been achieved: 1.4 + 0.2 mCi/pAh in the case of 7SBr a n d 0.080 + 0.015 mCi/pAh for "Br, over the dose ranges shown in Fig. 2. These experimental thick target yields are still appreciably lower than the theoretical values. There appears to be three possible reasons for the discrepancy.

T

(i) Low As-content in the alloy. As discussed previously(3) the eutectic mixture of the Cu3As-alloy has an As-content of 21%. The alloy used as target material, however, has an initial As-content of 31%. During the melting of the alloy layer on Cu-backing at 900°C (see above) some As is lost by evaporation. A gravimetic analysis of As-content showed that this loss is much higher in the case of a thin ahoy layer (needed in internal target system) than that for a relatively thick layer (required for external irradiations). It is estimated that the decrease in yield due to this effect amounts up to 20%. (ii) Radiation damage effects. These may lead to losses of radiobromine. This source of discrepancy, however, is expected to be small since the power density effective at the target amounts to only ,-, 400 W era-2. The negligible dependence of the yield on the integrated current as well as the absence of any significant contamination of the internal target assembly appear to support this assumption. (iii) Loss of radiobromine during thermochromatographic separation. The yield of the separation process was found to lie between 85 and 90%. The overall experimental thick target yields of both 7SBr and "Br amount to 55-60% of the respective theoretical values. A 1.6 h irradiation with 36 MeV 3He-particles at 100/~A leads to a batch yield of about 200 mCi 7SBr (at EOB). The chemical proeessing takes about 1 h, so that about 130 mCi 7SBr is available at the start of the labelling work. A 6 h irradiation with 28 MeV :t-particles at 100 p A gives about 48 mCi ?TBr (at EOB).

~SAs(3He,3n)~

Rat forget (without t~oelement)

E3~: 36~251',teV

-I

°%- - _ _ -~ . . . . . . . . . . . . . .

~/'///////'/////////'///~

o

o~

°oo

t

,

0

=

o

nBr- yie[cls

=

*

W~dged target (vith thermoetment)

~|o oo o,' O0

~SBr-yie[ds

"~-yietds : 0

.

. . . . . . . . . . . .

: ®

9. . . . . . . .

(~

o

~SAs(a.2n)

(~)

T;Br

~ = 28~%HW

'= 0.'I c~

g

•

E (.

0.01

1L

•

•

•

......

"__-..'J .....

I 0

I 100

i 200

•

.____

ql

eo

eo

3.,__..'_,

t 3OO

........

i ~0 Integrafed

-'__"

i 500 current

I 6O0

I 7OO

600

(l~Ah)

Fig. 2. Thick target yields of 7SBrand "Br as a function of the integrated current in production runs. The open and dosed circles describe the experimental yields obtained using a fiat target (without thermoelement). The broken lines show the lower and upper limits of those data. The shaded areas depict the consistent set of yield values obtained using a wedged target (with thermoelemcnt).

G. BLESSING and S. M.

930

Purity The radionuclidic purity of 7SBr and :TBr samples was checked using Ge(Li) detector 7-ray spectroscopy. As described previously (3~ the major impurity in ~SBr was 7SBr; its content varied between 5 and 8?/0 (at EOB). ~Br is also a positron emitter; it is in fact the limiting factor in the use of rSBr since its longer half-life may cause higher radiation doses to the patient, depending on the pharmaceuticals. A small amount of ~SZn(0.01%) was also detected both in "Br and rTBr. In "Br no other impurity was found. Radiochromatographic analysis, similar to the one described earlier, o) showed that the separated radiobromine in neutral aqueous solution exists > 95% as :SBr- or rTBr-. Since in internal irradiations thin Cu~As-alloy layers are used and are spread over a larger area of the Cu-backing than that in irradiations with external beams, it is likely that during the thermochromatographic separation of radiobromine the evaporation of other elements is enhanced. A thorough investigation on the chemical impurities present in the separated radiobromine samples was therefore carried out. The total contents of Cu, Sn, Pb, Ca and Si were determined via atomic absorption spectroscopy and found to be on the average 0.25, 0.10, 0.06, 0.4 and 0.07/zg, respectively. The As-content was estimated via neutron activation analysis as well as via optical emission spectroscopy in conjunction with inductively coupled plasma, and found to be about 2 #g. The latter technique was also used for the determination of Se-content. It could not be detected positively and an upper limit of 1/~g was given.

Separation of 6~Ga A wet chemical method was developed to separate 67Ga from the matrix activity left after the thermochromatographic separation of radiobromine. The

QAIM

separation scheme is based on a combination of several conventional chemical and radiochemical separation methods for gallium described in the literature. The alloy with Cu-backing was treated for several hours with 12 mL of 65% HNO3 and 9 mL H20. Sn (from solder) was converted to SnO: and did not dissolve. After filtration the solution was neutralized with 4oraL NH,OH (25% NH3-solution), whereby arsenic was converted to AsO~-, copper to [Cu(NH3)4] 2+ and radiozinc to [Zn(NH~h] 2+. The solution chemistry of gallium (cL Ref. 17) suggests that the radiogallium occurs probably as [Ga(OH)4]-. On addition of NH4CI and MgCI2 arsenic was precipitated as Mg(NH4)AsO~.6HzO and lead (from solder) as PbClz, both of which were centrifuged off. The pH of the filtrate was then adjusted to about 10 and further separation was achieved through cationexchange chromatography. For this purpose a 40 × 2.5 cm ~ column packed with Dowex 50 W × 8 (50-100 mesh) resin was used. The column was eluted first at 60°C with a 5% solution of NH,CI and then with a 10% solution of aq-NH3 to convert the resin to O H - form at pH .,. 14. Thereafter the above mentioned filtrate was transferred to the column and elution started with water at a flow rate of 0.7-1.0mL/min. 67Ga was eluted, presumably as [~Ga(OH)4]-, whereas Cu and Zn remained on the column. In order to remove those elements from the column, elution with dilute HCI was performed. A typical elution curve is shown in Fig. 3. Cationexchange chromatography has also been used previously (cf. Refs 15, 18) for separating 6~Ga from the irradiated zinc and copper targets. In those methods, however, elution was done by HCI only: copper and zinc were eluted first and 6~Ga later. In our method of elution from the alkaline medium followed by acidic medium the 6~Ga appears first; it is of some advantage for subsequent processing.

Cation-exchange chromatography

X3o

[Cu(NH3);] z÷ [ 65ZnINHt ); ]/+ l~Cm(0tl k ]-

{DOWEX

f

Eluant ~'- 8z0

IH i

o

10 :

~lGa Ino corrier-od~l)

g l

~s

lo

zs

3o

.

3s

Preetutio~ I

0

[<

I

I

~5

6O

I

I

9O

|

Etuant I-- HCt I *sZn (no r.orrier-oddKI)

i

8"~ l0 Z

5 0 WX8 f ~ - l O O mesh)

~0

t,5 SO 85 Fraction number

I i i fit 1~ Etuted ~0tume (mr)

,." Cuz m~rix 12791

\,i'.\ s\/ 90

95

lO0

105

ilO

its

RO

L I

I

I

I

Fig. 3. Eludon curves for 67Ga, eSZn and Cu (matrix) from a 40 x 2.5 cm ~b column of Dowex 50 W x 8 (50-100mesh) at a flow rate of 0.?~l.OmL/min. Initial dution was done from the alkaline medium, followed by elution with HCI. Volume of each fraction was 3.0 ml. 67Ga and eSZn were determined radiometrically, and Cu gravimetrically. The tailing effects are due to a heavy loading of the column.

A CujAs-alloy cyclotron target for production of 7s'rTBrand 67Ga Although the cation-exchange chromatography led to a complete separation of 67Ga from the matrix activity, a further separation step using solvent extraction was introduced in order to (a) concentrate the 67Ga activity in a small volume of the solvent, (b) to get rid of the excessive salts and, (c) to obtain 67Ga as citrate, a form in which the radioisotope is needed for medical applications. The fractions containing 6~Ga (from 13 to 43 of Fig. 3) were collected (total volume 90 mL), neutralized with HCI and the HCI concentration in the mixture adjusted to 5.5M. Thereafter, 67Ga was extracted twice in 20 mL diisopropyl ether (of. Refs 6, 7, 19). Back extraction of 67Ga in the aqueous phase was achieved by shaking the organic phase with a small volume of a 4% solution of sodium citrate buffered at pH 6. The separation of 67Ga is started about 100 h after the end of irradiation to allow shorter-lived matrix activity to decay. The dissolution of the alloy and the Cu-backing takes several hours. Thereafter, the separation is rather fast and can be completed within about 2 h.

931

;,-ray spectroscopy. The major impurity was ~Ga[tl:z = 9.3 h, formed via the 63Cu(~t, n)~Ga reaction] and amounted to 2.3%. Furthermore, :sSe (0.1%) and 6~Zn (0.01%) were also found. The chemical impurities present in the final 67Ga-citrate solution were detected via optical emission spectroscopy in conjunction with inductively coupled plasma. The total contents of Cu, Mg and Pb were found to be about 1/ag and those of As, Sn and Fe about 2/zg. Zn and Se could not be detected and an upper limit of 1/~ g was given. Acknowledgements--It is a pleasure to thank Professor G.

Stfcldin for his active support of this work. We are grateful to the crew of the Compact Cyclotron CV 28 for some advice on the optimization of the internal target system and for performing numerous irradiations. Mr H. Rosezin helped considerably in experimental work. Our thanks are due to the Zentralabteilung ffir Chemische Analysen of the KFA Jfilich for carrying out chemical analysis of the 75'77Br and ~TGa samples.

References Yields

The thick target yield of 67Ga in 3He-particle induced reactions on copper was calculated using the excitation functions reported by Bryant et a13'°~ and Golchert et al., ~z~ and in :-particle induced reactions from the data of Bryant et al. ~2°~Considering that the abundance of 65Cu in natural copper is 30.9% and that the Cu-content in the alloy used as target material is about 69%, for the 6SCu(3He, n)67Ga reaction the theoretical yield over the energy range of E~,~= 36--,8 MeV amounts to about 5/~Ci//tAh. Due to this expected low-yield value the separation of 67Ga from targets irradiated with 3He-particles (75Br-production) is of little use and was not pursued. The 6~Cu(~, 2n)67Ga reaction on the other hand has relatively high cross sections and the expected thick target yield over the energy region E~ -- 28--* 10 MeV amounts to about 100/zCi//~Ah. Thus, for a 6 h irradiation of the alloy with 28 MeV :,-particles at a beam current of 100/zA a batch yield of about 60mCi 67Ga (EOB) could be expected. After performing the above chemical separation procedure about 9 mCi 6~Ga was obtained at 100 h after the end of irradiation (-'- 22 mCi at EOB). The overall experimental yield thus amounts to about 37% of the theoretically expected value. The losses are presumably due to chemical processing. The batch yield is at least an order of magnitude smaller than those via the proton and deuteron induced reactions on enriched zinc isotopes. As mentioned above, the present method of production is of interest only in combination with the production of ~Br where 67Ga is obtainecL as a by-product. Purity

The radionuclidic purity of 67Ga samples separated at 100 h after the end of irradiation was checked via

1. StScklin G. Int. J. AppL Radiat. Isot. 28, 131 (1977). 2. Qaim S. M. and Stfcklin G. Radiochim. Acta 34, 25 (1983). 3. Blessing G., Weinreich R., Qaim S. M. and Sttcklin G. Int. J. AppL Radiat. lsot. 33, 333 (1982). 4. Hupf H. B. and Beaver J. E. Int. J. Appl. Radiat. lsot. 21, 75 (1970). 5. Krasnov N. N., Dmitriyev P. P., Konstantinov I. O., Konjakin N. A., Ponomarev A. A., Ognev A. A., Romanchenko A. E. and Tuyev V. M. Proc. Conf. on the Uses of Cyclotrons in Chemistry, Metallurgy and Biology, Oxford, 1969. (Ed. Amphlett C. B.) p. 159

(Butterworths, London, 1970). 6. Dahl J. R. and Tilbury R. S. Int. J. Appl. Radiat. [sot. 23, 431 (1972). 7. Brown L. C., Callahan A. P., Skidmore M. R. and Wilson T. B. Int. J. AppL Radiat. Isot. 24, 651 (1973). 8. Little F. E. and Lagunas-Solar M. C. Int. J. Appl. Radiat. lsot. 34, 631 (1983). 9. Gruverman I. J. and Kruger P. Int. J. AppL Radiat. Isot. 5, 21 (1959). 10. Helus F. and Maier-Borst W. Proe. Syrup. on Radiopharmaceuticals and Labelled Compounds, Copenhagen, 1973. Vol. I, p. 317 (IAEA, Vienna, 1973). 1!. Steyn J. and Meyer B. R. Int. J. Appl. Radiat. Isot. 24, 369 (1973). 12. Neirinckx R. D. Int. J. AppL Radiat. Isot. 27, 1 (1976). 13. KopeckS, P. and Mudrov~i B. Int. J. AppL Radiat. Isot. 26, 323 (1975). 14. Nagame Y., Unno M., Nakahara H. and Murakami Y. Int. J. AppL Radiat. lsot. 29, 615 (1978). 15. Silvester D. J. and Thakur M. L. Int. J. AppL Radiat. lsot. 21, 630 (1970). 16. Stellmaeher W., Kogler W., Cremer H., Bolten W. and Blessing G. J. Labelled Compd. Radiopharm. 19, 1355 (1982). 17. Moerlein S. M. and Welch M. J. Int. J. NucL Med. BioL 8, 277 (1981). 18. Neirinckx R. D. and Van der Mcrwe M. J. Radiochem. Radioanal. Left. 7, 31 (1971). 19. Brown L. C. Int. J. AppL Radiat. lsot. 22, 710 (1971). 20. Bryant E. A., Cochran D. R. F. and Knight J. D. Phys. Rev. 130, 1512 (1963). 21. Golchert N. W., Sedlet J. and Gardner D. G. Nucl. Phys. A152, 419 (1970).