US3785990A - Method of manufacturing a generator which produces radio-isotopes and has an improved elution efficiency,and generator obtained by this method - Google Patents

Abstract

IT HAS BEEN FOUND THAT THE ELUTION EFFICIENCY OF GENERATORS WHICH PRODUCE RADIOACTIVE ISOTOPES AND CONTAIN AL2O3 AS THE ADSORBENT MAY BE GREATLY IMPROVED. THE IMPROVEMENT IS OBTAINED BY PROVIDING THE ADSORBENT OF THE GENERATOR WITH AN OXIDANT BEFORE FIRST USE OF THE GENERATOR. THE OXIDANT MUST HAVE A STRONG AFFINITY FOR THE SUBSTRATE. SUITABLE OXIDANTS ARE CHROMATES AND DICHROMATES.

Description

- US. Cl. 252301.1 R

United States Patent 3,785,990 METHOD OF MANUFACTURING A GENERATOR WHICH PRODUCES RADIO-ISOTOPES AND HAS AN IMPROVED ELUTION EFFICIENCY, AND GENERATOR OBTAINED BY TI-HS METHOD Harm Martinus Benjamins, Koos Kortenoeven, and Helena Panek-Finda, all of van Houtenlaau, Weesp, Netherlands No Drawing. Filed Feb. 29, 1972, Ser. No. 230,502 Claims priority, application Netherlands, Mar. 2, 1971, 7102716 Int. Cl. C09k 3/00 4 Claims ABSTRACT OF THE DISCLOSURE It has been found that the elution etiiciency of generators which produce radioactive isotopes and contain A1 0 as the adsorbent may be greatly improved. The improvement is obtained by providing the adsorbent of the generator with an oxidant before first use of the generator. The oxidant must have a strong aflinity for the substrate. Suitable oxidants are chromates and dichromates.

The invention relates to a method of manufacturing a generator which produces radioisotopes.

Radionuclides having a half-life of a few hours to a few days are used in medicine for diagnostic purposes. To prevent the occurrence of radiation damage in the tissues as far as possible, preferably radionuclides are used which are pure gamma radiators. The optimum gamma lines lie between 100 and 400 kev.

In addition to Sr and In especially Tc is being increasingly used. This radio-active technetium isotope may be used for the above indicated purpose as such but it is also suitable to label other substances such, for example, as albumins.

The radioisotope suitable for medical use is obtained inter alia from a generator, which frequently is referred to as a cow or milker. The radioisotope then is marketed in the form of the generator. The user may withdrawn the desired radioisotope from the generator respectively. Such instantaneous production is of great practical importance because of the rapid decay of a suitable radioisotope.

An isotope generator is obtainable by filling a container provided with an inlet and an outlet with an adsorbent material to which a radioactive parent isotope is then applied. If desired, the generator may be provided with seals which permit sterile use of the generator (Netherlands patent application No. 6,607,699, PHN. 1670). A frequently used adsorbent is A1 0 Generally an adsorbent largely consisting of A1 0 is used in producing the aforementioned Tc generator.

The radioactive parent isotope present on the adsorbent by its decay produces the daughter isotope, which is of interest for medical purpose, with the emission of radiation. In the Tc generator radioactive molybdenum in the form of a molybdate is used as the parent isotope. The Tc produced from M0 by radioactive decay will mainly be in the form of the pertechnetate.

In the operation of the generator a washing liquid or eluent is admitted at the top through the inlet. The eluent traverse the adsorbent and carries along the radioactive daughter isotope present. The eluent together with the radioactive daughter isotope dissolved in it leaves the generator at the bottom and is collected in a receiver which if desired may be rigidly secured to the generator proper. The parent isotope is hardly, or not at all, displaced over the adsorbent by the eluent. A suitable eluent is an isotonic salt solution such, for example, as a 0.9% common salt solution.

Several tests have been carried out with the aforedescribed isotope generator. From the various test it has been found that the efliciency of a generator which con tains an adsorbent mainly consisting of A1 0 greatly fluctuates and under certain conditions may be very low. The term efiiciency is used herein to mean the ratio between the amount of radioactive daughter isotope actually obtained at elution and the amount of radioactive daughter isotope which could theoretically have been obtained.

The fluctuations in the efliciency of the generator and the low level of efliciency may be read from Table I of German Offenlegungsschrift (pre-published German patent application) No. 1,929,067 which gives data about the yield of a Tc generator. According to this Offenlegungsschrift the efiiciency of an isotope generator may be increased if in the use of the generator a washing agent is used which contains an oxidant. Such a washing agent may simply be prepared by adding, for example,

sodiumhypochlorite to an isotonic solution and acidifying the mixture.

We have found that the use of the washing agent suggested in the aforementioned Olfenlegungsschrift has the following disadvantages:

(I) The stated increase in etficiency is not yet optimal at the first elution(s) of the generator. This means that in the period during which the generator has its highest activity and is of greatest interest to the user no maximal improvement in efficiency is achieved.

(2) The use of a washing liquid which contains an oxidant may result in an eluate containing this oxidant. This greatly reduces the usability of the eluate, for a liquid containing for example, chlorine cannot be used as an injection preparation without further processing. The necessary working up of the eluate implies a reduction of radioactivity and the loss of the sterility of the eluate, which effects both are disadvantageous.

(3) The presence of oxidants in the washing liquid (eluent) and eluate results in that inlet and outlet reedles become seriously effected.

The proposed step of improving the efiiciency has to be taken by the user of the generator himself.

We have now found a new method of manufacturing an isotope generator which contains an adsorbent mainly consisting of A1 0 The generator made by the method according to the invention has a high efiiciency and does not have the aforementioned disadvantages.

Before going into particulars of the new process according to the invention it would appear to be desirable for a good understanding first to expound the knowledge we have gained of the problems inherent in a generator, on which knowledge the present invention is based.

From tests we have a correlation between the efficiency fluctuations and the low efficiency level of a generator containing A1 0 as an adsorbent and on the other hand the amount of radiation produced by the generator. More particularly it has been found that the efficiency fluctuations increase and a tendency to very low values of the efficiency occurs if the radioactivity produced by a generator exceeds from about 100 mCi. The level of the radioactivity at which this phenomenon occurs depends to a certain extent on the manner in which the generator has been manufactured and on the dimensions of the generator. For example, in a To generator a reduction in efiiciency from 65-80% to about 25-50% is produced when the radioactivity of the generator exceeds about 100-450 mCi. Although hitherto it has not been possible to explain phenomenon fully, we have evolved the hypothesis that in that part of the generator in which the radioactivity exceeds the above-mentioned values the radiation produces a chemical and physical change in the generating system which comprises the absorbent, the parent isotope and the daughter isotope, the whole in the aqueous environment of the eluent. These changes are such that transport of the radioactive daughter isotope through the adsorbent is no longer possible or at least is highly retarded. The further investigation was directed to the finding of means of counteracting the degeneration of the generator system due to strong radiation.

Surprisingly it has been found that the said degeneration may be greatly reduced or even prevented if at least at the regions in the generator in which there is strong radiation the generator system it brought into an oxidizing condition.

More particularly the invention relates to a method of manufacturing an isotope generator in which a container provided with an inlet and an outlet is filled with an adsorbent mainly consisting of A1 to which a radioactive parent isotope is applied, and the invention is characterized in that even before first use of the generator the adsorbent is brought to an oxidizing condition by the application of an oxidant.

The oxidant to be used according to the invention preferably should have a strong aflinity to the A1 0 adsorbent, for it is important that when the generator manufactured by the method according to the invention is used the washing agent used should not remove the oxidant from the adsorbent, but on the contrary it forms part of the substance of the invention that the oxidant is fixed as securely as possible in the region of the radiation field, i.e. of the parent isotope.

A person skilled in the art may readily select from the large assortment of available oxidants a substance having the required aflinity for A1 0 We have achieved very good results with the use of chromates and dichromates, particularly alkali metal chromates and dichromates.

The application of the oxidant may be effected by a known method. Preferably a solution of the oxidant is used. If desired, the solvent may be removed from the adsorbent, for example by drawing off at a reduced pressure. When water or an aqueous salt solution is used as the solvent it need not be removed from the adsorbent.

The amount of oxidant to be applied depends on various factors. Some of these factors are the radioactivity level and the shape of the generator, the position of the parent isotope on the adsorbent, the concentration of the oxidant in the solution used and the nature of the oxidant.

By means of comparatively simple tests a person skilled in the art may himself determine the amount of oxidant which provides satisfactory results in a given situation. It should be borne in mind that for a satisfactory effect it is necessary for the substrate material to be provided with the oxidant as effectively as possible in and about the region in which the parent isotope is present.

Consequently, when the parent isotope is readily accessible, for example when the parent isotope is present in the upper layer of the adsorbent, as is usual, it is sufficient to apply a small amount of a concentrated solution of an oxidant.

When the parent isotope is not taken up in the upper layer of the adsorbent a larger amount of a solution of an oxidant is desirable.

Tests carried out with a Tc generator which had been manufactured by the method according to the invention and in which an aqueous potassium dichromate solution was used as the oxidant have shown that satisfactory results are obtained if at least 3 mg. of potassium dichromate dissolved in a few milliliters of water is present.

Finally it should be noted that when sterile generators according to the invention are manufactured the treatment with the oxidant may be effected either before or after sterilization.

The invention will now be illustrated by the following example.

4 EXAMPLE Containers provided with an inlet and an outlet, which in the art are generally referred to as cartridges, were filled with an A1 0 adsorbent and then processed in the following manner.

(1) Treatment with a molybdate solution containing radioactive M0.

The pH of the solution was 1 to 2.

(2) Washing with ml. of an isotonic salt solution. (3) If required sterilization at C. for 20 minutes.

The generators obtained by the above, known method were then treated with an aqueous salt solution in which potassium dichromate had been disolved. The amount of potassium dichromate and the volume of the salt solution were varied within wide limits, as will be seen from the following Table I. As a reference, a generator without potassium bichromate has been inserted into Table I.

TABLE I [Survey of some manners of pretreatment of generators] Sterilization before or after the Generator Treatment with dichromate according to dichromate number the invention treatment (1 (reference).

6 mg K2C1207 in 5 ml. of salt solution.. After.

Do. 12 mg. K201701111 5 ml. of salt solution-. Do. do Do. 12 mg. K2Cr2O in 60 ml. of salt solution.-- Do. -rln Do. 6 mg. KzCrz0 in 5 ml. of salt solution... Before.

n Do. 12 nag. K2OrzO1 in 5 ml. of salt solution- Do. n Do. 12 mg. K2Clz07 in 60 ml. of salt solution... Do. d0 Do. 6 mg. KzC12O7 in 5 ml. of salt solution. Do. -do Do. 6 mg. KzOr2O in 3 ml. of salt solution Do. 16- ..rln Do. 17 6 mg. K2Cr2O7 in 1 ml. of salt solution D0. 18.-. do Do. 3 mg. K2CrzO in 5 m1. Do. 0 Do. Do. D0. of salt solution"--- Do. D0. of salt solution-. Do. Do. 1 mg. KzClzO1 in 3 ml. of salt solution... Do. 28.-- 1 mg. K2Cr2O in 3 ml. of salt solution. Do. 29..- 1 mg. K2CrzO7 in 1 ml. of salt solution Do. 30.... -do Do.

The operation of the generators obtained by the method according to the invention was tested by eluting them in the usual manner and determining the yields of radioactive daughter isotope in the eluates obtained.

The efiiciencies obtained are listed in Table II.

TABLE II [Elution eflleiencies of a number of Te generators as a function of the pretreatment (compare Table 1)] Generator Elution number (see Table 1) 1st 2d 3d 4th 7th 12th TABLE IIContinued Between each two successive elutions there was a time interval of at least 22 hours.

Table II shows that the elution efficiency of the generators 25 to 30 which contain a comparatively small amount of oxidant is appreciably lower than that of the generators 1-24 which contain larger amounts of oxidant. The reference generator without oxidant gives a very poor yield.

The table shows that at the twelfth elution the difierences in elution efliciency are substantially eliminated. This may readily be explained by considering that at the twelfth elution the radioactivity of the generators, which initially was 300 mCi, had fallen to an extent such that the limit value below which the influence of the radiation on the etficiency is absent or at least greatly reduced is passed.

What is claimed is:

1. In the method of manufacturing an isotope generator in which a container provided with an inlet and outlet is filled with an adsorbent consisting mainly of A1 0 to which adsorbent a radioactive parent isotope is applied, the improvement which comprises bringing the adsorbent to an oxidizing condition by applying to the adsorbent an oxidant which is strongly bound to the adsorbent prior to the first elution.

2. The method of claim 1 wherein the oxidant is a chromate or dichromate.

3. The method as claimed in claim 2 characterized in that the A1 0 adsorbent to which molybdenum containing Mo has been applied as a parent substance is treated with an aqueous which contains at least 3 mg. of potassium dichromate.

4. An isotope generator obtained by the method of claim 1.

References Cited UNITED STATES PATENTS 3,468,808 9/1969 Arino 252--301.1 3,561,932 2/1971 Gruverman et a1. 23-312 3,664,964 5/1972 Haney et a1. 252-364 CARL D. QUARFORTH, Primary Examiner R. L. TATE, Assistant Examiner US. Cl. X.R.

23-252 R; 250106 T; 424l UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,785,990 (PHN 5464) Dated January 15, 1974 Inventofls) MARTINUS BENJAMINS ET AL It 15' certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as ,shown below:

' Column 1, line 8, after "Netherlands" insert assignor to U.S,. Philips Corporation, New York,

Column 6, line l2, after."aqueous" insert "solution".

Signed and sealed this 16th day of July 1974.

(SEAL) Attest: I

GIBSON JR. c. MARSHALL DANN g t ng Officer Commissloner of Patents UNITED STATES PATENT OFFICE 7 CERTIFICATE OF CORRECTION Patent No. 3,785,990 (PHN 5464i Dated Januarv 15, 1974 Inventofls) MARTINUS BENJAMINS ET AL It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 8, after "Netherlands" insert assignor Column 6, line 12, after "aqueous" insert "solution".

Signed and sealed this 16th day of July 1971 (SEAL) Attest:

M. GIBSON JR. c. MARSHALL DANN g ting Officer Commissioner of Patents