Patent application title: METHOD OF PRODUCING HIGH-CONCENTRATED TECHNETIUM-99m SOLUTION IN LARGE QUANTITIES
Akihiro Kimura (Higashi-Ibaraki, JP)
Kaori Nishikata (Higashi-Ibaraki, JP)
Kunihiko Tsuchiya (Higashi-Ibaraki, JP)
Masahiro Ishihara (Higashi-Ibaraki, JP)
Masakazu Tanase (Higashi-Ibaraki, JP)
Saburoh Fujisaki (Higashi-Ibaraki, JP)
Akio Ohta (Higashi-Ibaraki, JP)
JAPAN ATOMIC ENERGY AGENCY
IPC8 Class: AC22B316FI
Class name: Below 300 degrees c using nonmetallic material which is liquid under standard conditions (e.g., hydrometallurgy, etc.) with leaching or dissolving
Publication date: 2013-02-14
Patent application number: 20130036871
A method of producing high concentrated 99mTc solution has the steps
of dissolving 99MoO3 pellet with alkali solution; extracting
99mTc from the dissolved solution with ketone type organic solvent;
separating an ketone type organic phase containing 99mTc and an
aqueous phase; adsorbing and concentrating the separated ketone type
organic phase containing 99mTc after removing impurities, through a
basic alumina column for impurity removal and an acidic alumina column
for adsorption and concentration connected continuously; and eluting
99mTc from the acidic alumina column to which 99mTc is adsorbed
by physiological saline, wherein the alkali solution is 6M-NaOH solution
or 6M-KOH solution.
1. A method of producing high concentrated 99mTc solution comprises
the steps of: dissolving 99MoO3 pellet with alkali solution;
extracting 99mTc from the dissolved solution with ketone type
organic solvent; separating an ketone type organic phase containing
99mTc and an aqueous phase; adsorbing and concentrating the
separated ketone type organic phase containing 99mTc after removing
impurities, through a basic alumina column for impurity removal and an
acidic alumina column for adsorption and concentration connected
continuously; and eluting 99mTc from the acidic alumina column to
which 99mTc is adsorbed by physiological saline, wherein said alkali
solution is 6M-NaOH solution or 6M-KOH solution,
2. The method according to claim 1, wherein an acid alumina prepared by processing alumina with uniform particle diameter in 0.1M-HNO3 for 24 hours or more is used as alumina used for said acidic alumina column.
3. The method according to claim 1, wherein a diameter of said acidic alumina column which adsorbs 99mTc is set to the range of Φ10-14 mm.
4. The method according to claim 1, wherein said ketone type organic solvent is methyl ethyl ketone solution.
5. The method according to claim 4, wherein a diameter of said acidic alumina column which adsorbs 99mTc is set to the range of Φ10-14 mm.
BACKGROUND OF THE INVENTION
 The present invention relates to a method of producing high concentrated technetium-99m (99mTc) solution in large quantities and in a short time, which is used as technetium-99m pharmaceutical products in general.
 99mTc is widely used for the nuclear medicine diagnosis in the world. 99mTc is usually obtained from the generator on which molybdenum-99 (99Mo) which ketone type organic solventis the parent nuclide is adsorbed. In general, 99mTc pharmaceutical products are produced with a small generator or supplied directly from a medicine maker as 99mTc pharmaceutical products in a hospital etc. (For instance, refer to patent literature 1) though 99mTc pharmaceutical products are produced with a large-scale generator in the medicine maker.
 Though 99mTc is generated with β-decay of 99Mo which is the parent nuclide, the enriched uranium is used as a raw material in a conventional 99Mo production method, and 99Mo is extracted through complex processes after irradiating the enriched uranium in a nuclear reactor (hereafter, (n,f) method). Non-patent literature 1 discloses the outline of the method of producing a large amount of 99mTc which exceeds 100 Ci (3.7 TBq) on a commercial basis from the 99Mo produced by 98Mo (n,y) 99Mo reaction (hereafter, (n,y) method). In the method disclosed in the non-patent literature 1, 250 g (specific radioactivity 1 Ci (3.7×1010 Bq)/gMoO3) obtained by irradiating neutrons to molybdenum trioxide is dissolved to KOH solution. The solution is babbled by air under the temperature environment of 90-95° C. to prevent precipitation by reduction, and 99mTc is extracted into methyl ethyl ketone (MEK) by stirring to babble after adding MEK. This extracted solution is moved to an evaporator after separating from the aqueous phase, and the MEK is evaporated to dryness by heating. Remaining 99mTc is dissolved by physiological salt solution to make a product.
 Moreover, the laboratory-scale 99mTc production unit which is a basic production unit for carrying out the method according to the present invention is disclosed in non-patent literature 2. The production unit disclosed in this document is provided with a basic alumina column and an acidic alumina column connected in series with each other at the final stage to extract high quality 99mTc. Wherein, after removing the impurities such as 99Mo in the basic alumina column, and making an acidic alumina column adsorb 99mTc, the MEK is removed from the acidic alumina column by using water, and the 99mTc is eluted with physiological saline.
 [Patent literature 1] JP 2011-105567 A
 [Non-patent literature 1] R. E. BOYD, Radiochimica Acta, 30, and 123-145 (1982).
 [Non-patent literature 2] Sankha Chattopadhyay et al. Appl. Radiat. Isot, 68, 1-4 (2010).
BRIEF SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
 99Mo of the parent nuclide of 99mTc is produced by an (n,f) method in which the nuclear fission of 235U in a nuclear reactor is used. 99Mo having the specific radioactivity above 370 TBqg-1 is obtained in this (n,f) method. However, there are some problems that the nuclear fuel is treated, it is necessary to separate 99Mo from various types of fission products generated voluminously, and the majority of fission products containing uranium becomes the radioactive waste as it is.
 Therefore, the neutron activation method in which the neutron capture reaction of 98Mo in a nuclear reactor is used is adopted as one of the strategies to obtain 99Mo in the present invention. This method adopts the (n,y) method in which neutrons and 98Mo which exists in nature Mo by about 24% are used, and has merits such as little generation of the radioactive waste, easy production process and easy radiation shield. However, There is a fault that the specific radioactivity of 99Mo obtained is less than or nearly equal to 74 GBqg-1 four digits smaller than the (n,f) method. It is, therefore, required to devise to use as a small generator, and its use is limited. As a result, it has been tried to obtain a large amount of high concentrated 99mTc for 99mTc pharmaceutical products supplied from a medicine maker by using the (n,y) method.
 The outline of a (n,y) method of producing a large amount of 99mTc which exceeds 100 Ci (3.7 TBq) in commercial production has been described in non-patent literature 1 mentioned above. However, this method needs a long time for the evaporation operation of MEK which contains 99mTc after extraction. Moreover, some products obtained might be colored, because a certain amount of the aqueous phase component may be incorporated into the products during the phase separation of MEK. Therefore, it is desirable to avoid such evaporation operation.
 An alumina column which has the function to remove the aqueous phase is used in the production unit disclosed in non-patent literature 2 mentioned above. Therefore, the product obtained is not colored, and thus high quality 99mTc solution can be obtained. However, it is still a production unit at the laboratory scale, and cannot obtain a large amount of products. That is, the amount of handling in this production unit is 500 mCi (18.5 GBq) at most. Accordingly, various research and development is requested to produce a large amount of high concentrated 99mTc in a short time.
 An object of the present invention is to provide a method of producing high concentrated technetium-99m (99mTc) solution in large quantities and in a short time, in which the quantity and the concentration of 99mTc produced per unit time is remarkably improved as compared to the prior art, and thus it is possible to put to practical use.
Means for Solving the Problems
 The inventors succeeded to obtain 99mTc with TBq of radioactivity different from GBq of the radioactivity of conventional 99mTc by improving drastically the production method in the Production unit similar to the conventional one, in which the alkali concentration of the solution for dissolving molybdenum trioxide (MoO3) is improved, preferably, the amount of ketone type organic solvent is reduced, which is used at the extraction of 99mTc, more preferably, the acid alumina obtained by processing the alumina with uniform particle diameter in 0.1M-HNO3 for 24 hours or more is used, and more preferably, the diameter of a column in which the acid alumina is filled is set to Φ10-14 mm. Actually, the production method to obtain a large amount of high concentrated 99mTc solution was established by using rhenium (Re) of a homologous element of 99mTc, to which chemical property is similar. As a result, it came to be able to produce high-radioactivity 99mTc with 2.5 TBq (69 Ci) to 36 TBq (966 Ci).
 Specifically, a method of producing high concentrated 99mTc solution according to one aspect of the present invention comprises the steps of:
 dissolving 99MoO3 pellet with alkali solution;
 extracting 99mTc from the solution with ketone type organic solvent;
 separating an ketone type organic phase containing 99mTc and an aqueous phase;
 adsorbing and concentrating the separated ketone type organic phase containing 99mTc after removing impurities through two kinds of alumina columns connected continuously (a basic alumina column for impurity removal and an acidic alumina column for adsorption and concentration); and
 eluting 99mTc from the acidic alumina column to which 99mTc is adsorbed by physiological saline,
 wherein said alkali solution is 6M-NaOH solution or 6M-KOH solution, and whereby the production efficiency is assumed to become maximum while keeping the quality of 99mTc solution the highest.
 In the above-mentioned production method, it is desirable to use acid alumina prepared by processing alumina with uniform particle diameter in 0.1M-HNO3 for 24 hours or more as alumina used for the acidic alumina column.
 In the above-mentioned production method, it is desirable to set a diameter of the acidic alumina column which adsorbs 99mTc to the range of Φ10-14 mm.
 According to a method of the present invention, an amount of the liquid used for dissolution of 99MoO3 pellet can be suppressed to the minimum amount and the efficiency of production be improved by using 6M-NaOH solution or 6M-KOH solution as alkali solution by which 99MoO3 pellet is dissolved.
 In addition, high concentrated 99mTc with 2.5 TBq (69 Ci)-36 TBq (966 Ci), which is greatly different from the conventional unit of GBq is obtained in large quantities and in a short time. That is, it is possible to obtain 99mTc solution of the radioactive concentration equal to 99mTc solution obtained from 99Mo produced by an (n,f) method.
BRIEF DESCRIPTION OF SEVERAL DRAWINGS
 FIG. 1 shows a schematic view of 99Mo/99mTc extraction-separation and concentration system.
 FIG. 2 shows an elution curve of Re with an alumina column.
 FIG. 3 shows the relationship between99mTc radioactivity estimated and recovery yield.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
 The present invention separates and concentrates 99mTc at high efficiency while maintaining the high quality by using a 99mTc production unit in which a conventional method of extracting and separating 99mTc directly from the solution obtained by dissolving 99MoO3 pellets to MEK, and a conventional method of purifying and concentrating 99mTc with an alumina column are combined, and by optimizing the components and the quantities of various liquids used in the production process of 99mTc.
 The design of each system was carried out to put this unit into practical use. The embodiments of this invention will be explained hereinafter. Here, NaOH was used as alkali solution for dissolving 99MoO3 pellet, and methyl ethyl ketone (MEK) was used as solution for extracting 99mTc from the dissolved solution. However, it is possible to use KOH which has a similar function instead of NaOH, and use other ketone type organic solvents such as acetones instead of MEK as explained in the above-mentioned patent literature 1.
 FIG. 1 shows a schematic view of 99Mo/99mTc extraction separation and concentration system according to the present invention. This system comprises mainly 99MoO3 pellet dissolving tank 10, 99mTc extraction tank 20, 99mTc separation tank 30, column 40 for impurity removal, and column 50 for 99mTc concentration. In addition, Each of the tanks and columns has a washing line, etc. to remove impurities which become the obstructions of the antibody labeling of 99mTc pharmaceutical products.
 In 99MoO3 pellet dissolving tank 10 comprised of an Erlenmeyer flask, stirrer, etc. 99MoO3 pellet to which the neutrons are irradiated is dissolved in the alkali solution with stirrer. Moreover, in 99mTc extraction tank 20, 99mTc is extracted directly from 99Mo solution to MEK using an agitator at high efficiency. Next, the obtained MEK phase containing 99mTc is moved to 99mTc separation tank 30 comprised of a separatory funnel, etc. and is separated into an MEK phase containing 99mTc and an aqueous phase of alkali solution to collect only MEK phase containing 99mTc. In column 40 for impurity removal in which the basic alumina is filled, impurities such as 99Mo contained in MEK containing 99mTc are removed. In column 50 for 99mTc concentration in which acid alumina is filled, 99mTc is made to be adsorbed from the MEK phase containing 99mTc , and then the 99mTc is eluted by using a small amount of physiological saline and concentrated.
 Here, acid alumina in which alumina with uniform particle diameter had processed in 0.1M-HNO3 for 24 hours or more was used as the above-mentioned acid alumina in the following tests. The diameter of column 50 for 99mTc concentration in which such acid alumina is filled is desirable within the range of Φ10-14 mm to improve the adsorption efficiency of 99mTc and elute 99mTc efficiently by using a small amount of physiological saline.
1) MoO3 Dissolution Test by NaOH
 The MoO3 dissolution test to determine the solubility condition of the MoO3 pellet to which the neutron was irradiated by NaOH solution was carried out in 99MoO3 pellet dissolving tank 10. First of all, while changing sequentially the concentration of NaOH, the NaOH was mixed with MEK, and stirred for 5 minutes. The concentration of NaOH was determined to 6M in light of the interface state etc. of the aqueous phase and the MEK phase. Though it is desirable that the concentration of this alkali solution is in a higher value such as 7M and 8M to decrease the entire volume and miniaturize the system, It has been understood from the experiment result that 6M is the best because the precipitation is caused after the dissolution when the concentration of the alkali solution exceeds 6M.
 Next, MoO3 was dissolved while changing sequentially the liquid volume of 6M-NaOH to determine an amount of 6M-NaOH necessary to dissolve MoO3. As a result, the ratio of 100 ml to 50 g of MoO3 was suitable.
2) Solvent Extraction Test by MEK
 The solvent extraction to determine 99mTc extraction condition by MEK from the dissolved solution was tested in 99mTc extraction tank 20. The alkali solution and MEK were mixed and stirred for 5 minutes. Here, the liquid volume of MEK was changed sequentially. The aqueous phase and the MEK were separated and collected, and their capacities were measured. As a result, it was confirmed to be able to collect 90% or more of the MEK phase to 6M-NaOH 300 ml at MEK 60 ml. That is, it was possible to separate 99mTc into MEK phase efficiently and concentrate it when the ratio of MEK to 6M-NaOH solution is 5 to 1. The amount of MEK which is necessary can be decreased like this by the optimization of the concentration of NaOH.
3) Rhenium (Re) Elution Test from Alumina Column
 The elution test was carried out by using Re which is a homologous element of 99mTc. Here, Re corresponding to 2.5 TBq (69 Ci)-36 TBq (966 Ci) of radioactivity of 99mTc was used. 30 ml of MEK was mixed with the solution in which Re is dissolved to 150 ml of 6M-NaOH, and the solvent was extracted. The MEK containing Re was passed through a basic alumina column and then through an acidic alumina column, to which Alumina is filled respectively by 5 g. Physiological saline was supplied at a flow rate of about 1 ml/min to the acidic alumina column which Re is adsorbed.
 The Re elution curve is shown in FIG. 2 and the relationship between 99mTc radioactivity estimated and recovery yield is shown in FIG. 3. The result of FIG. 2 is obtained as follows. The alkali solution containing Re which corresponds to 2.5 TBq-36 TBq of radioactivity of 99mTc was extracted by MEK solution respectively for 5 minutes, and after leaving it at rest for 30 minutes, the MEK phase was purified by the basic alumina and Re was made to be adsorbed by the acid alumina. Re adsorbed to the acid alumina is eluted by using physiological saline. In the process, 2 ml or 3 ml of the physiological saline are supplied to the acid alumina, and an amount of Re in the liquid collected is measured by ICP-AES. FIG. 3 shows the result of carrying out the collection work up to total 30 ml. The Re elution rate designated in the ordinate is the ratio (%) of an amount of Re eluted to an amount of Re added in the beginning. Moreover, the graph of FIG. 3 showing the relationship between the 99mTc radioactivity estimated and the recovery yield illustrates how much recovery yield is obtained for each amount of Re which corresponds to 2.5 TBq-36 TBq of radioactivity of 99mTc.
 Based on the elution curve, 3 ml of Initial effluent were thrown away and 12 ml in total from 4 ml to 15 ml of the effluent was recovered. As a result, it was able to be confirmed that Re can be collected in the recovery yield of 80% or more, and 99mTc solution is obtain, in which the concentration of 99mTc, that is, Re corrected, is ten times or more, compared with the original 99Mo solution. In other words, it became possible to recover 2.5 TBq (69 Ci)-50 TBq (966 Ci) of radioactivity of 99mTc by 80% or more.
 The evaporation operation of MEK for extracting 99mTc has required a long time in the prior art. In addition, products might color slightly due to the mixing of the aqueous phase with the MEK phase when the MEK phase and the aqueous phase is separated and recovered. Therefore, to avoid these problems, the coloring phenomenon of the product was prevented by purifying and concentrating MEK containing 99mTc with the alumina column in the present invention. There is a feature that this method can be handily processed in a short time.
 Moreover, though a similar technique to the present invention cannot obtain more than about 18.5 GBq (500 mCi) so far, it was proven that the present invention can be applied to produce a 99mTc product with a large amount of radioactivity from 2.5 TBq (69 Ci) to 36 TBq (966 Ci) by clarifying the adsorption and the elution performance using Re of a homologous element of 99mTc and the same chemical property as 99mTc.
Patent applications by Akio Ohta, Higashi-Ibaraki JP
Patent applications by Kunihiko Tsuchiya, Higashi-Ibaraki JP
Patent applications by JAPAN ATOMIC ENERGY AGENCY
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