Note: Descriptions are shown in the official language in which they were submitted.
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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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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ethyl ketone.
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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~ 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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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
~ . .
1 99 yes
2 95 yes
9~ yes
6 95 yes
7 94 yes
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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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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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(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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