CA1113257A

CA1113257A - Method of producing radioactive technetium-99m

Info

Publication number: CA1113257A
Application number: CA322,216A
Authority: CA
Inventors: Hampar L. Karageozian
Original assignee: Individual
Current assignee: Individual
Priority date: 1978-03-14
Filing date: 1979-02-23
Publication date: 1981-12-01
Also published as: IT7920973A0; GB2016796B; FR2420190B3; GB2016796A; JPS54133295A; DE2909648A1; FR2420190A1; IT1166691B

Abstract

ABSTRACT
The invention relates generally to a method for producing radioactive isotopes. More specifically, the invention relates to an improved chromatographic extraction method whereby Technetium-99m of high yield and high purity is produced. Technetium-99m which has a half life of six hours, is produced by the spontaneous radioactive decay of Molybdenum-99, which has a half life of 67 hours. The user then separates the desired amount of Technetium-99m from the Molyb-denum-99 as his needs require. Prior art separation methods are either non-specific or relatively inef-ficient. Additionally, with most of the prior art methods, Technetium-99m is produced in the form of an aqueous solvent whereas production in a solventless, i.e. dry particulate form, would be more desirable for purposes of flexibility in the preparation of diagnos-tic reagents of desired radioactive concentration.
According to the present invention, Technetium-99m is produced in a dry particulate form of high yield and high purity. The method of the present invention com-prises the steps of eluting an adsorbant chromato-graphic material containing Molybdenum-99 and Techne-tium-99m with a neutral solvent system comprising an organic solvent containing from about 0.1 to less than about 10% water or from about 1 to less than about 70% of a solvent selected from the group consisting of aliphatic alcohols having 1-6 carbon atoms and separating the solvent system from the eluate whereby a dry, particulate residue is obtained containing Technetium-99m, said residue being substantially free of Molybdenum-99.

Description

3'ZSi7 TECHNICAL FIELD
~ he invention relates generally to a method ror producing radioactive isotopes. More specifioally, the lnventlon relates to an improved chromatographic extrac-tion method whereby Technetium-99m o~ high yield and high purity is produced. ~-BACKGROUND OF PRIOR ART
~echnetium-99m which has a half life o~ six 10 hours, is produced by the spontaneous radioactive decay ~ -o~ Molybdenum-99, which has a hal~ e o~ 67 hours.
High purity Technetium-99m is u~ed primarily as a rad~o-lsotope ln medioal research and diagnosis. Sinoe the isotope ~ought to be used has suoh a short hal~ e, it is common practice to ship the users of ~echnetium-g9m Molybdenum-99, ~he user then separates the desired amount o~ Technetium-99m from the Molybdenum-99 as his needs require A variety o~ methods are disolosed in the prior art ror separating ~echnetium-99m ~rom Molybdenum-99.
These prior art methods are quite dif~erent rrom the ;~ method d$sclosed~herein, ;~ One of these prior art methods~ as exempli~ied by U.S. Patent No. 3~436J354, is based on liquid-liquid extraotion prinoiplesJ whereby Molybdenum-99 and Technetlum-99m are partitioned between two lmmis-cible liquids by con~tant agitation. ~his process is non-~peci~ic and in order to extract high purity Technetium-99m several repeated extractions are neces-3 sary; ~urthermore it allows chemically labile organio , ~ .
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solvents to be exposed to stron~ mineral aclds and alkalies, which results in the chemical de~radatlon o~
the organic phase ancl contamination o~ the Techne-tium-99m.
A second prior art method, as examplified by U.S. Patents Nos. ~,519,385 and ~,890,244, utilizes principles of precipitation and physical separation o~
the precipitated Molybdenum-99 from the soluble Tech-netium-99m by filtration or centrifugation.
A third prior art method as illustrated by U.S. Patent No. 3~382,152, a paper by J. J. PinaJian "International Journal o~ Applied Radiation and Isotopes"
17, 664, 1966 and another paper by J. ~. Allen "International Journal of Applied Radiation and Isotopes"
16, 334, 1965, eaoh use principles of ion exchange chromatography. In this process an ion exchange column i~ ~irst preconditioned with an acid solution. ~hen an acidi~ied solution of Molybdenum-99 is loaded onto the column. The column is again conditioned by using an organic solvent before it i8 ready for elution with an acidi~ied salt solution or an acidified organic solvent. The shortcomings o~ this process are (1) the ~everal preconditioning ~teps that are neces~ary, (2) the unavailability o~ usable 1'echnetium-99m on the fir~t day of operation because of radionuclldic Molybdenum-99 contamination and chemical alumina con-tamination, (3~ possible degradation of the organic solvent because o~ acid expo~ure and (most impor-tantly) (4) because o~ the relatively low yields o~
Technetium-99m, e.g.~ 65-75% yields of Technetium-99m which may be contaminated with radioactive iodine.
The ~ourth prior art method, a~ illustrated by U.S. Patent No. ~,468S808, utilizes chemical re-actions between Molybdenum_99 and zirconium oxide, ~5 thus allowing Technetium-99m to be eluted ~rom the column using ionic solutions or using an organic ~olvent, A ~urther drawbac~ o~ some of the ~oregoing methods is that the Technetium-99m i8 produced in the ~orm of an aqueous solvent whereas production in a ,: :

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;, solventless, i.e. dry pQrticulate form, would be more desirable ror purposes o~ ~lexibility in the prepara-tion o~ diagnostic reagents o~ desired radioactive concentration. It would be desirable to have a method for producing Technetium-99m in dry, particulate form :in high yield and purity, i.e., free ~rom contamination with Molybdenum-99.
BRIEF SUMMARY OF INVENTION
I have now discovered a method of producing Technetium-99m in a solventless, i.e., dry5 particulate form of high yield and high purity.
me invention herein described relates to a method for producing Technetium-99m in a dry, particu-late form comprising eluting an adsorbant chromato-graphic material containing Molybdenum-99 and Tech-netium-99m with a neutral solvent system comprising an organic solvent containing from about 0.1 to less than about 10~ water or ~rom about 1 to less than about 7 ~
of a solvent selected ~rom the group consistin~ of all-phatic alcohols having 1-6 carbon atoms and separatlng the solvent ~ystem from the eluate whereby a dry, particulate residue is obtainecl containing Technetium-99m, said residue being substantially free of Molybdenum-99.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a high yield process for producing high purity Technetium-99m in dry, particulate form. The process involves selectlvely eluting a Technetium-99m composition from a chromato-graphic column containing a mixture of Technetium-99m and Molybdenum-99 (the parent of ~eohnetium-99m) with a neutral solvent system comprising an organic solvent containing a second solvent, as described in more de-tall below. The solvent system containing the Techne-tium-99m is then separated from the eluate to leave a dry, particulate residue containing Technetium-99m.
The resulting Technetium-99m may then be used for diag-nostic techniques by combining it with suitable carriers, e.g. saline at a desired concentration.

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-~ 7 Molybclenum-99 is obtained ~rom conventional sources such as by irradiatin~ a molybdenum compouncl or by usln~ rission product molybdenum Use~ul molyb-den~m-containing compound~ include molybdenum tri-oxide, molybdic acid, sodium molybdate, ammoniummolybdate, molybdenum metal dissolved in an acid to form a salt and the like.
A conventional chromatographic container, e.g.
a column, i9 used in this invention. The chromato-graphic container should be made of a material which isinert to the solvent system, e.g. stainless steel, glass, polypropylene, teflon or any other organic solvent~
resistant material.
Chromatographic packing material which may be used in this invention are those adsorbant materials which allow selective elution o~ Technetium-99m. That is, the chromato~raphic material must have the property of selectively retainin~ Molybdenum-93 and other radio-nuclidic impurities while allowing Technetium-99m to ~0 be removed in the solvent system. Specific chromato-graphic packing material~ which may be used in this invention include activated aluminum oxide, both neutral, basic and acidic ~orms, i.e. aluminum oxide particles coated with a thin layer of aluminum oxycarbonate;
aluminum oxide, i.e., alumina, aluminum hydroxide and magnesium aluminum silicate. Other column paclcing materials which may be used include aluminum silicate, barium hydroxide, bentonite, calcium oxide, magnesium hydroxide, and ~erric oxide. The pre~erred column pack-~o ing material is activated aluminum oxide.
The neutral solvent system is selected sothat it will selectively and pre~erentially elute the - Technetium-99m and leave the Molyb~enum-99 in the chromatographic column. The solvent system comprises an organic solvent and a second solvent. Organic solvents which may be used in the present invention include acetone, methyl ethyl ketone, diethyl ketone, ethyl acetate and mixtures thereof. The pre~erred organic solvents are the ketones and preferably methyl .: . , . ' ,: , .

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The second solvent may be wate~, in an amount ranging ~rom about 0.1 to less than about 10% and preferably about 1 to about 7~, or an aliphatic alco-hol containin~ 1-6 carbon atoms in an amount ranging between about 1 to less than about 70~ and pre~erably l~rom about 10 to about 5 ~. Typical examples of ali-phatic alcohols which may be used in thls invention include methanol, ethanol, isopropyl alcohol, butanol and h0xanol and pre~erably ethanol.
I have discovered that the second solvent discussed above is critical to the present invention.
As illustrated by the Examples, the use o~ the second solvent in the solvent system remarkably increases yield and purity o~ the eluted Technetium-99m. The use of excess second solvent results in an eluate con-taminated with Molybdenum-99 In carrying out the invention, a measured amount o~ a neutral a~ueous solution containing Molyb-denum-99 is dispersed in a chromatographic column con-tainin~ a suitable chromatographic packing material, e.g. activated chromatographic grade aluminum oxide.
In order to achieve the highest recovery of Techne-tium-99m by this method, the Technetium-99m should be in its highest oxidation state. Therefore, it is pre-ferred to add a suitable amount of conventional chemical oxidizing agent to the aqueous solution containing Molybdenum-99 prior to dispersing it on the column.
Oxidizing agents which may be used include sodium hypochlorite, hydroge~ peroxide and the like.
The chromatographic column is then eluted with the neutral solvent system hereinbe~ore described.
The elution may be assisted by positive pressure exerted at the top of the column, as by an inert pressurized gas, or by applying a reduced pressure on the lower end o~ the chromatographic column.
The resultant eluate, containing the solvent system and Technetium-99m is then pre~erably ~iltered through a conventional sterile filter e.g. 0.22 - 0.45 .

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~ 7 ~ o re~ove all bacterial contamination. The solvent sy~tem is then ~eparated from the Technetium-99m by any suitable conventional means and pre~erably by evapora-tion e.g. conventional vacuum or heating methods may be used. A~ter the solvent system has been removed, the Technetium-99m remains as a dry, particulate residue.
The resultant residue may be recovered in any convenient manner, e~g. by redissolving in the desired amount of a suitable liquid, such as, for example, saline. The recovered Technetium-991n is then used as desired ~or medical, diagnostic or other uses.
As is apparent ~rom the ~oregoing, the present method allows Technetium-99m to be prepared in a con-sistent, desired concentration. This is in comparison to the prior art methods wherein the eluate ~rom a given chromatographic column is obtained in steadily decreasing concentrations as the Molybdenum-99 decays.
The exact chemical ~orm of the technetium compound pro-duced by the herein described method is not completely lmown. Knowledge of the exact compound, however, is not important because the Technetium-99m obtained by the practice of this invention is in usable ~orm. In addition, it should be noted that ordinary precautions ~r protection against radiation should be used in the carrying out of this invention.
The following examples are given for the pur-pose o~ illustrating the invention and are not intended to limit the scope o~ this invention.
In the following examples, the indicated so-lutions of radioactive molybdenum si~ ts were introducedonto the indicated chromatographic column containing the indicated chromatographic packing material. On the indicated day in 7- or 8-day cycles, the indicated sol-vent system was used to elute the column. The resultant eluate was in a~l cases clear and colorless. The eluate made in each example was then evaporated to dryness. The residue (containing Technetium-99m) was then dissolved in saline (isoton~c) to ~orm clei~r, colorless solutions. The yields and purity for each ,.~,.. .. . . . . .. . . .
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~ 7 sample is reported. Purity in each in~tance was deter-mined by USP Standard XIXs which requires a purity of no more than 1 n~crocurie of molybdenum-99 per millicure of Technetium-99m.
~~MPLE I
Chromatographic column - Glass Column packing - 6 grams activated alumi-num oxide Column load - 0.1 ml sodium molybdate aqueous ~iolution contain-ing 1 ~ by weight sodium hypo¢hlorite and having 50 millicuries of activity Solvent system - 20 ml portions of anhy-drou~ methyl ethyl ketone (for each day's elution) 15 The results are shown in Table 1 below.
Table 1 Yield ~%) Dav of Week Technetium-99m Pass USP XIX `
1 96 yes 2 81 yes yes 6 68 yes 7 57 yes As seen in Example I, the purity of the Technetium-99m i8 good, but the yield decrea es to almost one-half by the end of the first week of elu-tion.
EXAMPLE II
Example I was repeated, except the solvent sys-

3 tem con~ained 1~ water. The results are shown in ~able ::
2 below.
able 2 YieId (~) Pass USP XIX
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1 99 yes 2 95 yes 9~ yes 6 95 yes 7 94 yes .
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i'7 Table 2 ~ ont'd ) Yield (~) Da~ o~ eekTe hnetiu_~2m Pass USP XIX
~ 94 yes As seen ~rom the Example II, the yield re-mains above 90~ for all elutions in the presence of a minor amount of water in the solvent system.
EXAMPLE III
Example I was repeated, except the chromato-graphic column was made of polypropylene and the sol-vent system consisted o~ two 10 ml portions of MEK
saturated with water (approximately 12.5~). The re-sults are shown in Table 3 below.
Table Yield (~) Day o~ Week Technetium-99m Pass USP XIX
1 97 yes 2 99 yes 5 9~ yes 6 115 no The ~orego~ng example demonstrates that when an excessive amount o~ water is used in the solvent system, the yields are high, but contamination results.
EXAMPLE IV
Example III was repeated,except the column load contained 80 millicuries of activity and the solvent system consisted of 20 ml portions of MEK containing 3% water. The results are shown in Table 4 below.
Table 4 3 Yield (%) Day o~ Week ~ Pass USP XIX
1 95 yes 2 91 ye~
yes ~5 6 91 yes 7 94 yes 8 96 yes EXAMPLB V
Example IV was repeated except the column . . . .
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i 7 g lo~d consisted o~ 0.5 ml o~ sodium molyddate solution containing ten percent by volurne sodium hypochlorite and having 300 millicuries of activity and the solvent s~stem consisted Or 20 ml portions of MEK containing 2~ water, The results are shown in Table 5 below.
Table 5 Yield (~) Da~ of Week Technetium-9~ Pass USP XIX
1 98 yes 2 97 yes 94 yes 6 95 yes 7 96 yes 8 96 yes The ~oregoing Example shows that increasing the level of activity in the column load does not alter ~ `
the consistent and high yield levels o~ Technetium-99m.
EXAMPLE VI
Example V is repeated, except 5~ water is used in the solvent system. The results are shown in Table 6 below.
able 6 Yield (%) D~ f Week Technetium-99m Pass USP XIX
1 96 yes 2 96 yes 92 yes 6 93 yes 7 91 yes 8 92 ,ye~
EXAMPLE VII
Example II was repeated, except the solvent system contained 7% water. The results are shown in Table 7 below, Tabl 7 Yield (~) Da;y o~ Week ~echnetlum ~ Pass USP XIX
1 92 yes 2 92 yes : .
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Table_7 (Cont'd.) Yield (%) Day o~ Week Te _netium-99m Pass USP XIX
5 90 yes 6 9~ yes 7 89 yes For the following Examples, a molybdenum/
Technetium-99m test solution was prepared by ~irst pre-paring a molybdenum solution by dissolving 12.0 grams of molybdenum trioxide in 20 ml of 6N sodium hydroxide solution. 2ml o~ ~ hydrogen peroxide was added and the solution was made up to 30 ml using purified ~ater, 5.5 ml of Technetium-99m solution containing 100 millicuries of activity was then added to 5 ml of the molybdenum solution to form the test solution.
EXAMPLE VIII
Chromatographic column - polypropylene Column packing - 6 g. alumina Column load - 0.5 ml of test solution containing 4.5 milli-curies of activity Solvent system - 20 ml portion o~ MEK
containing 10~ ethanol Elution of the column gave greater than 99 re¢overy of Technetium-99m with a negative determina-tion (less than 2 micrograms) of molybdenum.EXAMPLE IX
Example VIII was repeated, except isopropyl alcohol was used instead of ethanol. Elution o~ the ~lumn gave greater than 99% recovery of Technetium-99m 3 with a negative determination (less than 2 miorograms) of molybdenum.
EXAMPLE X
Example VIII was repeated, except the solvent system consisted of acetone containing approximately ~5 8~water. Elution of me column gave greater than 98 recovery of Technetium-99m with a negative determina-tion (less than 2 micrograms) of molybdenum.
EX~MP~E XI
Example VIII was repeated~ except 5 columns .

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1~ /7 (A-E) were used, each column containing 6 grams of activated alumlna, basic and 0.2 ml o~ test solution.
Each of the columns was eluted with 25 ml of the indi-cated solvent. The results are shown in Table ~ below, Table 8 Solvent Molybdenum level o umMEK/ethanol(v/v) in eluate A 50/50 less than 2 ~g B ~0/70 less than 2 ~g C 20/80 more than 2 ~g D 10/90 more than 2 ~g ~-E 0/100 more than 2 ~g This Example demonstrates that levels of alcohol less than about 70% do not allow excessive molybdenum to pass through the column.

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Claims

1. A method for producing Technetium-99m in a dry, particulate form comprising eluting an adsorbant chromatographic material containing Molybdenum-99 and Technetium-99m with a neutral solvent system compris-ing an organic solvent selected from the group con-sisting of acetone, methyl ethyl ketone, diethyl ketone, ethyl acetate and mixtures thereof and (a) about 0.1 to less than about 10% water or (b) from about 1 to less than about 70% an aliphatic alco-hol having 1-6 carbon atoms and separating the sol-vent system from the eluate whereby a dry, particulate residue is obtained containing Technetium-99m, said residue being substantially free of Molybdenum-99

2. The method of Claim 1 wherein the chromato-graphic material is activated aluminum oxide.

3. The method of Claim 1 wherein the organic solvent is methyl ethyl ketone.

4. The method of Claim 1 wherein the aliphatic alcohol is ethanol.

5. The method of Claim 1 wherein the solvent system is separated by evaporation.