Experience with purity tests of 113Sn−113mIn generators

Experience with purity tests of 113Sn−113mIn generators

International Journal of Applied Radiation and Isotopes, 1969, Vol. 20, pp. 717-724. Pergamon Press. Printed in Northern Ireland Experie...

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International

Journal

of Applied

Radiation

and Isotopes,

1969,

Vol.

20, pp.

717-724.

Pergamon

Press.

Printed

in Northern

Ireland

Experience with Purity Tests of S n-“““In Generators 113

LELIO Nuclear

Medicine

Department,

RAYMOND Health

Physics

C. COLOMBETTI

Veterans Administration Palo Alto, Calif. 94304,

C. BARRALL

Department,

Stanford

Hospital, U.S.A.

and ROLAND University,

Stanford

Medical

School,

A. FINSTON

Stanford,

Calif.

94305,

U.S.A.

(Received 19 February 1969) Radioisotope generators of 113mIn have recently become commercially available making possible the routine use of this short-lived nuclide in numerous applications to Nuclear Medicine. It is of great importance to test the eluate from these generators for radionuclidic and chemical purity. The generators under test had a hydrous ZrO, or SiO, bed. The radioactive impurities were measured by gamma-ray spectrometric analysis using NaI(T1) scintillators and Ge(Li) solid state detectors. Calculations showed l13Sn to be the principal source of extraneous patient radiation dose. Because of its long half-life, this radionuclidic impurity may deliver a significant dose in addition to that from 113mIn. The influence of eluant volume on i13Sn breakthrough was also determined. Chemical spot tests and spectrographic analysis were used in searching for stable imimpurities. The principal impurities identified were: aluminum, cadmium, calcium, copper, magnesium, nickel, silicon, zinc, and zirconium. The potential risk to the patient from impurities was quantified and evaluated. EXPBRIENCE

A\‘EC

DES

ESSAIS

DE

PURETB

DES

GENERATEURS

Les gtntrateurs isotopiques de 113mIn se sont recemment introduits dans le commerce, rendant ainsi possible l’emploi de routine de ce nucltide de vie breve en de nombreuses apphcations B la Mtdecine Nucleaire. 11 est de la premiere importance de doser 1’CluC de ces gtntrateurs pour purete radionucltidique et chimique. Les gtnerateurs soumis a l’essai avait un lit de ZrO, ou SiOs hydreux. Les impuretes radioactives furent mesurees par I’analyse spectromttrique des rayons gamma utilisant des scintillateurs NaI(T1) et des detecteurs B l’dtat solide Ge(Li). Les calculs mon&rent que le li3Sn Ctait la source principale de la dose indtsirable de rayonnement sur le patient. A cause de sa longue demi-periode cette impurett radionucleidique peur rendre une dose signifiante en plus de celle du 113mIn. On determina aussi l’influence du volume d’eluant sur la penetration du l13Sn. En cherchant pour les impuretes stables on employa des essais de tache chimique et I’analyse spectrographique. Les principales impure& reconnues furent: aluminium, cadmium, calcium, cuivre, magnesium, nickel, silicium, zinc et zirconium. On a quantilit et CvaluC le risque potentiel au patient provenant des impuretes. OIlbITbI

110

IlPOBEPECE

YlICTOTbI

3JlIOATA

I13

PEIIEPATOPOB

l13Sn

12 113mIn IIe~anao B03MOXHOCTL

nomm~ncb HOpM3JILIlOl-0

IiorsfMepsecmie

pa~Ifon30TonHLIe

PiCIIOJIb30BaHPIR

3TOl'O

717

reHepaTopbr

KOpOTKON4BYIIJW0

113mIn, 1130TOll3

9TO B

AaeT

HnepHOti

718

Lelio G. Colombetti,

Raymond C. Barrall and Roland A. Finston

Me~IlInIIIc. II~OTOM~, npoucpna 3aI0aTa II3 3T1ix rcIIcpaTopoB Ha pa~rIoII30TonIJyI0 II XIJ\lII~ICCII~JO %ICTOTy II3IeeT 6onbIrroe 3IIaycJIIie. ~~ClIl~lTI,IBa~!~iLl~~I’cIICpaTOl,bI I,\,C.JIII uo~IILIii cnoir ZrOz u.xn SiO,. I’a~IioaIITrJnIIbJe npn~ecII onpe;IennnIIc~ ~JJ~~T~~OM~T~~~I~~CIcIlnlaIJaJIII:Johi raniwa-;rystaii JIpJI nOMOIIIn NaI(T1) CnJJHTIJnnRTOpOIl II &(Li) j(eT?KTUI)OlJ TJH?~)~I,IX qaCTIIq. ~IJ~IIC;ICIII~~ nOKa:Ja:IIi, 9TO OCHOBHbIJI IiCTO~IHI?KOH A03 Hapy;IiJJOrO 06;l~YCHIIFI “aIn,OIITa IIII;JI,,‘TCFI l13SII. Kcne3cTbIIc cnoero ~~n5H~oro nepIiosa noJI!-pacnana 3Ta pa~J~ioa3oTonIJan JI~~II~I~~CI, XIOiKCT IIBJIFITbCfI C~7111CCTBCIIIIbIM ~06aBlICHLICM II A0362 n3mtitI. ~InpO;IC.ZCIJO TaIiH(C II~IIIIHIIR Or’,LCMa ~IaCTBOpIITCnH AnII 3~IIOIJ~OBaIIHFI Ha JI~OHII~HOIICIII1O I13Sn. $IH IJLIIIJI.rIOIJIIa CTa6I~InbHbIX 3aI~pFI3HOHIIii JIpIIMCHHJlIlCb XIIhlIl~IN!KIIir ItaIJC:IbJILIir II cnc,liTpo’l’aIXIli~JccIEIIii aIIa;IIi3bI. IjLI.Ui O6Ha~I~~CIII,I CJIO:(jIOIIIIiH OCIIO”HJ,J62 I,~,,h,NXI: anI0\rIiIIIiii, na;IhiIiii, KaJIbnmI. Mezb, MarHIIii, IIIIbcnb. Iipe~~rIIii, I{ITIIIC II qrip~to~~~iii. (~qWCI1 II KOJILI’IeCTBCIIIIO OJIpOnC.rlCIITOKit PIiCIc IEInIlCIJTOIJ OT IJpIIMCCt$.

ERFAHRUNGEN

MIT

REINHEITSVERSUCHEN

VON

n3Sn-n3~‘11n

GENERATOREN

Radioisotopengeneratoren von 113mIn sind in der letzten Zeit auf den Rlarkt gekommcn, sodass die laufende Verwendung dieses kurzlebigen Nuklids in zahlrcichen Fallen in der Kernmedizin moglich wird. Es ist sehr wichtig, das Eluat van diesen Generatorcn auf radionuklidische und chemische Reinheit zu untersuchen. Die untersuchten Generatoren hatten ein wassriges Zr02-oder SiO,-Bett. Die radioaktiven Verunreinigungen wurden durch Gamma-Spektroskopic-Analyse mit Benutzung von NaI(T1) Szintillatoren und Ge(Li) Fcststoffdetektoren gemessen. Berechnungen erwiesen, dass ‘13Sn die Hauptquelle der ausseren Patientenstrahlungsdosis ist. Ihre lange Halbwertzeit befahigt diese radionuklidische Vcrunreinigung eine erhebliche Dosis zusatzlich zu der vom 113mIn zu liefern. Der Einfluss des Eluantenvolumen auf den r13nSn Durchbruch wurde ebenfalls ermittelt. Chemische Fleckproben und spektrographische Analyse wurden bei dcr Suche auf stabile V’erunreinigungen benutzt. Die identilizierten hauptsachlichen V’erunreinigungen waren Aluminium, Kadmium, Kalzium, Kupfer, hlagnesium, Nickel, Silizium, Zink und Zirkonium. Die mogliche Gefahrdung eines Patienten durch V’erunreinigungen wurde quantifiziert und ausgewertet.

INTRODUCTION ABSOLUTE

purity

in

ties

a chemical

product

is very

Even exceptionally pure chemicals may contain as little as one part in lo6 or IO7 of impurities; they are never free of impurities. A radiopharmaceutical has an additional characteristic peculiar to itself. Besides the chemical purity, it is necessary to consider its radionuclidic purity. This is important since, with the passage of a minor long-lived constituent may time, become the predominant radionuclide present. Particular attention should be given when a short-lived radionuclide is produced from the decay of a long-lived parent, as is the case in 1rsSn-113mIn generators(l). When millicurieslevels of short-lived radiopharmaceuticals labeled with 113mIn are administered for diagnostic percentages of the longpurposes, fractional lived parent (113Sn) or other radionuclidic impurities may add greatly to the radiation dose incurred by patients. Non-radioactive impuridifficult,

if

not

impossible,

to

attain.

in

sufficient

toxic,

but

maceuticals hazard

chemical

a generator example,

are degree

However, these

impurities

In

may

chemically in

to

eluate

affect

its physical

research

interfere

AND

no

in the

from

uses,

with

may act as catalysts in reactions, reactions, or may product unexpected chemical effects. METHOD

phar-

as to present it is important

may

properties.

be

present

impurities

since

chemical

may

they

to such small

to patients.

measure and

quantity

usually

for

enzyme chemical physico-

RESULTS

Test for impurities may be divided into several categories: pyrogen and sterility tests (discussed elsewhere) t2), tests for non-radioactive impurities, and tests for radioactive impurities. Two different columns were studied with the 113Sn_113mln

generator

systems:

ZrO,.

generators

were

With the

Five impurity problem

studies of

looking

one for

SiO, studied

is confronted all

elements

and in

all. with

and

Experience with purity tests of 113Sn-113vnIn generators nuclides so as not to bias the results by preconceived notions of expected impurities. Thus, for the detection of non-radioactive impurities, spectrographic analysis was employed, as well as calorimetric spot tests for specific chemical constituents in the eluate. For the detection of radioactive impurities gamma-ray spectrometry with NaI(T1) and Ge(Li) detectors was employed. Non-Radioactive impurities 1. Spectrographic analysis. Emission spectrography requires only a small sample and offers the opportunity of recording the presence of many elements in one single exposure. It also has the ability to detect the presence of unUsing a 3.5-m Hilger expected impurities. spectrograph and carbon arc, samples from both types of generators were run on a monthly basis for a period of four months. 2. Calorimetric spot tests. Very sensitive tests have to be used to detect impurities in the pg per ml range. Suspected non-radioactive impurities techniques. were tested using “spot test” Standard solutions of the elements were used to compare with the color of the lakes developed by eluate samples. The test is based on the (a) Z irconium: formation of a lake, having an orange-brown color, with p-dimethyl-amino-azophenyl arsenic acidt3). Procedure : Impregnate a piece of Whatman No. 1 filter paper with the 0.1 per cent pdimethyl-amino-azophenyl arsenic acid solution and allow to dry in a hood. Place a drop of the unneutralized eluate and one drop each of the zirconium standards (solutions containing 2, 5 and 10 pg per ml) near each other on a piece of this paper. Heat about 150 ml of 1-2 molar hydrochloric acid to 50-60°C. After the drops have dried on the paper, wash it with three 50 ml portions of the warm hydrochloric acid solution. The red color of the paper should fade, leaving orange-brown lake spots where the standard drops and the test drop were placed. Compare intensities of the spots. Zirconium concentration of the ZrO, column eluate will normally be below 2 pug per ml. After a period of disuse, zirconium in the eluate from the column may be higher. It should not exceed 5 pug per ml. 3

719

(b) Silicon : The presence of silicon, as soluble silicates, can be detected by the formation of the silicomolybdate complex, which in turn will react with a solution of benzidine producing a quinnoid having a blue color(4). Procedure: A drop of the eluate solution from the SiO, column generator is placed in a porcelain crucible and mixed with a drop of a solution of ammonium molybdate (5 g in 100 ml of cold water and poured into 35 ml of nitric acid 1:2). Carefully warm over a wire gauze until bubbles form. Let it cool and add a drop of a benzidine solution (0.05 g of benzidine hydrochloride dissolved in 10 ml of concentrated acetic acid and diluted with water to 100 ml). A blue color indicates the presence of silicon. The intensity is compared with colors obtained with silicon standard solutions containing 2, 5 and 10 ,ug per ml. Silicon concentrations in the eluate should not exceed 5 pg per ml. Radionuclidic impurities A pulse height spectrum taken approximately one hour after elution is shown in Fig. 1. The 0.393 MeV photon of 1131nIn and In X-rays are the prominent features of the spectrum. Figure 2 shows a typical spectrum of the eluate also obtained using the NaI(T1) detector but at a post-elution time much greater than the 104-min half-life of 1i3mIn. After several days all 113mIn initially present in the eluate has decayed and the radioactive impurities (rr’?&r, lz3Sn r2sSb) are clearly distinguishable, along with ‘113mIn which arises from and is in equilibrium with the li3Sn impurity present in the eluate. The advantage of using the higher resolution of the Ge(Li) detector is evident in Fig. 3, where an unidentified photon at 0.450 MeV is clearly visible. Detectors were calibrated using National Bureau of Standards point source gamma ray standards. By using many such sources, the detector photopeak area efficiency may be related to the number of photons emitted, for photon energies up to a few MeV. It should be noted that all of the impurities have not been identified and, as a result, the patient dose from the total impurities must be somewhat higher than indicated by the subsequent dose calculations.

Lelio G. Colombetti,

720

Raymond C. Barrall

NaI(TI1

Photon

FIG. 1. Pulse height

spectrum

crystal

energy,

0.16

2.

Pulse

MeV

1crystal

obtained

1 hr after elution.

detector

I.0

0.50 Photon

FIG.

A. Fins&on

detector

of eluate from 113Sn-L13”LIn generator c

No1 (TI

0

and Roland

energy,

MeV

obtained height spectrum of eluate from 11sSn-11sIn generator Radioactive impurities are clearly distinguishable. elution.

6 days

after

Exterience

with @ri&

tests of 1%n-113mIn

721

generators

IO’-

Ge(Li)

crystal

detector

104-

z 6

r

,”

IO’-



c

2

u

IO’-

IO1n

A

Photon

FIG. 3. Pulse

height

spectrum elution,

enerc~y,

1. fictivity

Me’/

obtained of eluate from 113Sn-113T n generator using a detector with higher resolution.

The results of the analyses of two eluated samples are shown in Table 1. Activities were calculated using the number of photons per disintegration shown in column two as given by (shown in LEDERER et ~1.‘~). Contaminants columns three and four) are reported as activity relative to that of the principal radioisotope, rrsmIn, which is normalized to 100. The breakthrough of contaminants for the SD, column is atypically high. The column had not been eluted for several weeks. No significant difference in lr3Sn breakthrough was observed between the two types of generators, on the TABLE

A

of impurities

over a 4-month test period. The average, overall results of rr3Sn breakthrough determinations for the study are: SiO,

columns = 0.027 ZrO, columns = 0.029

j,

113Sn + 113mIn

0.393 0.393

0.64 0.64

117m,c4n

0.158

0.87

1.9 x 10-s

-

0.02 0.24

1.7 x 10-5 1.0 x 10” 4.8 x 10-4

1.08

0.599

elutions

from two

Relative activity at time of elution Photon disint.

llsmSn calculated rz3Sn lz5Sb

per cent (10 elutions)

where percentage refers to the activity of the l13Sn relative to 113mIn at time of elution. One impurity, llgmSn, requires special comment. Internal conversion in this nuclide is so frequent (approx. 100 per cent) as to preclude

(MeV) 113rnI*

0*020 per cent (14 elutions)

4 0.019

relative to that of 113mIn for sample generators

Peak used for analysis

54 days after

SiO,

column

100. a.7 x lo-2

ZrO,

column

100. 1.7 x 10-Z

0.32 0.34 0.44 2.2

x x x x

1OF 10-h 10-a 10-a

722

Lelio G. Colombetti,

Raymond C. Barrall and Roland A. Finston

analysis by gamma spectrometry in a complex mixture of radiations. Rather than neglect this impurity, the quantity present was calculated relative to lr3Sn using the relative capture cross-sections (0.01 vs. 1.3 barns) and relative isotopic abundances (4 per cent vs. 80 per cent) of ll*Sn as compared to 112Sn, and assuming an irradiation time of 3 months. Detailed analysis of several eluates showed little difference in the relative amounts of minor impurities with respect to the principal impurity, l13Sn. Thus, total impurities may be assayed by measuring the rr3Sn + 113mIn several days after elution (via well counter or ion chamber) and then calculating the amounts of minor contaminants.

readings of the aliquots with a kno\vn r’sSn113n61n standard which was in equilibrium. After allowing the samples to decay for 72 hr, the breakthrough of l13Sn was also determined using a well-counter as was previously [email protected]). The ratios of 113Sn-113mIn, as shown in Fig. 4, indicate that an ideal eluting volume should not be more than 8-10 ml. When a larger volume of eluent is used, the ratio of l13Sn activity present in the eluate increases rapidly, because more than 80 per cent of the 113nLIn activity is contained in the first 8-10 ml, while the l13Sn breakthrough remained constant.

Elution

Non-radioactive

volume

t?fect

‘l’he generators were eluted with eight 2-ml aliquots of a HCl solution 0.05 M (pH 1.4-1.8). The amounts of 1137nIn and lr3Sn breakthrough in each aliquot were determined. l13Yn was assayed immediately after the elution operation using an ionization chamber and comparing the

DISCUSSION

OF RESULTS

impurities

Table 2 shows the average concentrations of impurities in several samples of each type of column as determined by spectrographic analysis. There are no known toxic effects for any of these impurities at the levels observed in the eluates. Cadmium is the most hazardous of the

6

I Volume

eluted.

I

ml

in cluatcs. Ratio of ?Sn activit) I:Ic. 4. Ratio, at zero time, of 113Sn-113TrfIn concentrations in first B--l0 present in eluatcs increases rapidly because most of 11srnIn activitv is contained ml, while breakthrough of ““Sn remains constant.

723

Experiencewithpurity tests of 113Sn-113mIngenerators TABLE

2. Average concentrations of non-radioactive impurities in 113Sn-113mIn generators Si02 bed

Hydrous Zr02 bed

.A1 Ca Cd CU

&,Ig Ni Si Zn Zr

No 1

g”“;“’

0.2 3.3 n.d. 0.1 0.1 n.d. 0.05 0.05 2.5

0.04 1.0 0.05 0.5 0.05 0.01 0.1

0.05 0.8

No. 3 n.d.* 0.2 n.d. 0.05 0.1 n.d. 0.02 0.01 06

,cYm:o. n.d. 1.2 0.15 0.1 0.5 n.d. 0.8 0.04 n.d.

2 n.d. 0.4 n.d. 06 0.1 n.d. 1.5 0.05 n.d.

(kg), T is the effective half-life (days), and EF(RBE)n is the effective energy (MeV/dis.) calculated according to the method of ICRP Committe II’@. The biological half-life for calculating T was assumed to be that given by the ICRP for the element and organ in question. If the atoms of impurities are actually bound to the radiopharmaceutical molecules, the biological halflife assumed for the calculation will be in error. Table 3 shows the results of these calculations, TABLE

3. Relative does equivalent/unit of activity for impurities in 113mIn

* n.d. (none detected).

Total body

Liver

Bone

1 410 150 150 680 700

1 680 240 400 1600 570

1 790 240 720 3000 710

113mIn

measured impurities, but it would have to be present in much higher concentrations to be of Similarly, concern. zirconium is lethal in rabbits when injected intravenously in amounts of 150 mg/kg of body weight, but observed concentrations in the generator eluate would not allow doses of that level to occur. The remaining impurities have low toxicity ratings and are present in negligible amounts. Hazards of radionuclidic impurities A wide variety of 113mIn labeled radiopharmaceuticals are in use, each exhibiting a unique distribution and metabolism in the human body. The chemical behavior of tin and antimony radionuclidic impurities present in the radiopharmaceuticals prepared from the eluates has not yet been determined. Thus, several simplifying assumptions were made in order to assess the potential radiation hazard presented by these impurities. First, differences of uptake distribution in the body between 113mIn and the impurities were disregarded. Instead, an idealized assessment of relative hazard was made by calculating the integral dose equivalent (rem) for the special case of a uniform distribution of one unit of activity of each nuclide in each of three selected organs (total body, liver, and bone). The formula for this calculation is D.E.

= 73.8 t

where A is activity

TI

(mCi),

EF(RBE)n

rem

m is the mass of organ

113$, -t 113mIn 117msn 119~~s~

ls3Sn =%b

with the dose from impurities compared in each organ. The relative hazard ranges between 150 x-3000 x , primarily due to the long effective half-life of the contaminant nuclides relative to that of 113nzIn. In the case of iz3Sn, the energetic beta particle contributes most of the energy. In bone, beta particles are assigned a relative damage factor “n” equal to 5. This accounts for its high relative hazard (3000) in bone as compared to 113mIn. The Table illustrates the importance of minimizing longlived radioactive impurities when short-lived isotopes are to be used for diagnosis. For example, if there is as much as 1 ,&X of r1sSn in a mCi dose of 113mIn (O-1 per cent), the patient may receive 4-O-80 per cent more radiation exposure than from 113mIn alone. Relative dose calculations The first column in Table 4 summarizes the overall radio-assay results in terms of the percentages of long lived impurities in the eluates from the two types of generators; llsmIn is normalized to 100. The remaining three columns give the calculated patients’ dose from impurities relative to that of l13Yn. These are obtained by multiplying the relative dose equivalent/unit of activity factors (Table 3) by

L&o G. Colombetti, Raymond C. Barrall and Roland A. Finston

724

TABLE 4. Relative

dose equivalent

Relative activity l13mIn l'3Sn

__~ 113nlIn

1177n~n llgrnSn 123~~

(talc.)

135Sb

Total

2.8 0.6 0.5 0.5 2.6

Total

100. x 10-Z x 10-3 x 10-s x 10-a ‘,: lo-”

CONCLUSION Five 113Sn-113mIn generators have been under test for a period of four months. Three of these generators have a hydrous ZrO, supporting bed and were adquired from two different suppliers. The other two generators have a SiO, column.

in I13nLIn

Relative

dose equivalent

body

Liver

BOW

1100. 19.04 0.142 0,002 0.08 0.148 19.41

100. 22.12 0.142 0.0036 0.150 0.184 22.60

100. 11.48 0,089 0~0007 0.034 0.182 11.79

for impurities

the assay results (Table 4, column 1); again, 113nIn is normalized to 100. l13Sn breakthrough contributes an additional dose of between 11 and 22 per cent over that from llSnLIn alone. Other contaminants are present to such a low degree that together they contribute less than 1 per cent to the patient dose. It should be emphasized that all of the radio-assay results and patient dose calculations are based on data which were normalized to the time of the milking the generators. Should a significant time lag occur between milking and patient administration, corresponding increases in the relative amounts of contaminants per unit of l13”lIn activity will accrue. ‘l’hus, for each 104-min delay in the administration of the radiopharmaceutical, the relative amounts of radionuclidic contamination double and patient radiation dose from contaminants doubles.

from impurities

Non-radioactive impurities were at a low level and in no case did they pose a potential risk for the patient. Breakthrough of radioactive impurities should be monitored frequently to minimize unnecessary radiation exposure to patients. However, one can be assured that not even with those elutions which showed higher concentration of ‘l%n breakthrough was there a potential hazard to patients. The eluate of 113S11-113mIn generators is safe for human USC. REFERENCES 1. 2. 3. 4. 5.

6.

SuBRAhfANIAN G. and MC~FEE J. G. Int. J. nfipl. Radiat. Isotopes 18, 215 (1967). COLOMBETTI I,. G., GOOD\VIND. A. and HINKLEY R. L. J. Roengtend Rad. Ther., in press (1969). FEICL F., KRUM~OLZ P. and RAJzJ”ANx E. Afikrochemie 9, 395 (1931). FEICL F. and KRUMHOLZ I’. Mikrochemie, PreglFestschrif 82 (1929). LEDERER C. M., HOLI.ANDER J. M. and PERLAMN I. Table of Isotopes,6th Edn. \Yiley, New York (1967). Report of I(:RP Committee II on Permissible Dose for Internal Radiation. Hlth Phys. 3, 27

11959).