AN IMPROVEMENT OF ZIRCONIUM BASED MATERIAL AS AN ADSROBENT FOR (N,γ )
99
Mo/
99mTc GENERATOR
I. Saptiama1, Marlina1, E. Sarmini1, Herlina1, Sriyono1, Abidin1, H. Setiawan1, Kadarisman1, H.Lubis1, A. Mutalib2
1Center for Radioisotope and Radiopharmaceuticals,National Nuclear Energy Agency Puspiptek Area Serpong, Tangerang 15314, Indonesia
2Faculty of Mathematics and Natural Science, Padjadjaran University Jl. Raya Bandung-Sumedang Km.21 Jatinangor Sumedang 45363
A R T I C L E I N F O A B S T R A C T AIJ use only:
Received date Revised date Accepted date Keywords:
99Mo/99mTc generator Zirconium material Adsorption capacity Sodium hypochlorite Yield of 99mTc
99mTc is a widely used diagnostic radionuclide due to its short half-life of 6 hours and its emitted gamma ray atenergy of 140.5 keV ideal for gamma camera. 99mTc as a daughter radionuclide of 99Mo could be obtained from 99Mo/99mTc generator.
The fission product 99Mo/99mTc generators are most commonly used world wide because high specific activity fission 99Mo could be loaded onto small alumina columns with a limited adsorption capacity (2-20 mg Mo/g alumina). Due to many problems in preparing fission product 99Mo, particularly very strict and scarce uranium target supply, very long-life and high radioactivity fission product waste, and very expensive, complicated fission 99Mo processing facility requirements, since several years ago we have been developing (n,γ) 99Mo/99mTc generator using neutron-irradiated natural or enriched MoO3 targets and ZBM loaded chromatography columns that have adsorption capacity up to more than hundreds mg Mo/g MBZ. This paper reports our recent experimental results in improving adsorption capacity of ZBM and performance of (n,γ)99Mo/99mTc generators. The ZBM was synthesized by reacting zirconium (IV) chloride, tetrahydrofurane, isopropyl alcohol, in aquabidest solvent. The reaction mixture was stirred and heated up to 95 °C and then dried for overnight. Subsequently, the ZBM was coated with tetra etil ortho silicate for improving the hardness of material. Adsorption of [99Mo]molybdate into ZBM was carried out by reacting ZBM into [99Mo]molybdate solution at 90 °C to form ZBM-[99Mo]molybdate.
ZBM-[99Mo]molybdate then were packed into generator column, then eluted with 10 x 1 mL of saline followed by 1 x 5 mL of NaOCl solution. The NaOCl solution concentration used were 0.5%; 1%; 3%; and 5% for each column, respectively. This study resulted in ZBM which has99Mo adsorbtion capacity of 167.5 ± 3.4 mgMo/g ZBM, yield eluate of 99mTc up to 70%, and optimum NaOCl concentration for the use of 99mTc-radiopharmaceutical was 0.5%. Therefore, it can be concluded that the synthesized ZBM was able to be used as adsorbent for
99Mo/99mTc generator using neutron irradiated natural molybdenum.
© 2010 Atom Indonesia. All rights reserved
INTRODUCTION
A radionuclide generator of 99Mo/99mTc is a commonly used device for effective separation of a daughter radionuclide of 99mTc from a decaying parent radionuclide of 99Mo. This radionuclide generator is a convenient in-house radionuclide production systems that allow to obtain 99mTc species without existing of on-site reactor or accelerator [1]. 99mTc is the most widely used
Corresponding author.
E-mail address: [email protected]
diagnostic radionuclide in nuclear medicine practice as 99mTc-radiopharmaceuticals due to its short half-life of 6 hours and its emitted gamma ray energy of 140.5 keV ideal for gamma camera of Single Photon Emission Computed Tomography (SPECT) [2,3,4,5]. 99mTc-radiopharmaceuticals are organ specific diagnostics and available to delineate blood flow in organs such as the lung (embolism), heart, and brain to evaluate the functional state of thyroid, liver, kidney, or the hepatobiliary system and to detect tumor and
Atom Indonesia
metastatic growth in bone structures and more specifically, somatostatin receptor-expressing tumors [6]. 99Mo loaded into a generator column can be produced by two different nuclear reactions,i.e. a fission reaction of uranium-235 (
235U (n,f) 99Mo) and neutron activation reaction of molybdenum-98 (98Mo (n,γ) 99Mo) [2]. Various types of 99Mo/99mTc generator systems have been developed over the last few years due to increasing needs of technetium-99m [3].
Curently, many types of preparations of the
99Mo/99mTc generator system have been developed based on the separation techniques, such as use of an electrochemical cell system through selective electrodeposition on an electrode surface under the influence of controlled applied potential to separate
99mTc from the solution consisting of 99Mo, 99Tc and other metal ions [3], a solvent extraction technique based on extraction of 99mTc with methyl ethyl ketone (MEK) from low-medium specific acticity (n,γ) 99Mo [2,7,8], a chromatographic gel type generator that contains molibdenum [9,10,11,12]. and column chromatography with alumina [13,14]. Today, column chromatography system with alumina as an adsorbent, is a popular
99Mo/99mTc generator system in the world.
Adsorption capacity of alumina to molybdate ion is still limited to about 2-20 mg Mo/g alumina [2,3].
The availability of high specific activity of 99Mo, is generally only possibly produced through fission reactions. Nevertheless, separation of 99Mo fission product is a complex processing technology which is highly costly and also generates large quantities of high radiotoxicity and long-life radioactive waste and requires extensive purification prior use.
Furthermore, there are few suppliers of 99Mo fission product from both high and low enriched uranium (HEU/LEU) targets available in the world [3,15].
Production of 99Mo using another technique are also developed in order to reduce the fission- produced 99Mo dependencies. 99Mo can be produced by thermal neutron activation of natural or enriched MoO3 in a nuclear reactor. The advantages of this route include less radioactive waste and by-product simpler post irradiation process. The disadvantage is that the produced
99Mo has low specific radioactivity.
Accordingly, for 99Mo/99mTc generator application, using 99Mo neutron activation is preferred rather than 99Mo fission product. The low specific radioactivity of 99Mo can be overcome with the use of some materials having high adsorption capacity of molybdate ion. Tanase M et al, reported that an inorganic polymer (Poly Zirconium Compound) adsorbent is able to adsorb more than 250 mg Mo of 1 g adsorbent with low activity of
99Mo [16]. The weaknesses of this material was that they were fragile, less hardness, and reducing the 99Mo adsorption capacity if high activity of
99Mo is used.
Since five years ago, Centre for Radioisotopes and Radiopharmaceuticals Technology (CRRT), National Atomic Energy Agency (BATAN) has been developing the synthesis of Zirconium-Based Material (ZBM), as an adsorbent for 99Mo/99mTc generator, using a modified synthesis method that previously developed by Tanase et al[16]. Rohadi et al [17]
reported that the synthesized ZBM was able to absorb 99Mo with capacity up to ~ 183 mg Mo/g ZBM. However, the synthesized ZBM was still fragile and a little amount was dissolved when reacted with [99Mo]-molybdate solution. To increase the hardness of the adsorbent and the 99Mo adsorption capacity, the material was coated with Tetra Etyl Ortho Silicate (TEOS). It appears that in spite of the coated ZBM showed as harder material, its adsorption capacity to absorb 99Mo decreased from 183 to 79.8 mg Mo/g ZBM [18]. The further improvement of a preparation method shows the adsorption capacity increases up to ~ 193 mg Mo/g MBZ [19].
This paper will report our recent improvement on the performance of Zirconium- Based Material (ZBM) as an 99Mo adsorbent and % yield of 99mTc with the addition of sodium hypochlorite (NaOCl) solution from viewpoint of radionuclide generator.
EXPERIMENTAL METHOD
The chemicals used in this experiment were high grade commercial reagents without further purification. Namely molibdenum (VI) oxide (MoO3), zirconium (IV) chloride (ZrCl4), tetrahydrofuran (THF), isopropyl alcohol (iPrOH), sodium hydroxide (NaOH), methanol (CH3OH), and sodium hypochlorite (NaOCl) which were purchased from E Merck. Tetra ethyl ortho silicate (TEOS) which was supplied by Aldrich, and aquabidest (H2O) and saline which were ordered from IPHA-Indonesia. The 99Mo radioisotope was obtained from neutron irradiated MoO3 in the G.A.
Siwabessy nuclear reactor in Serpong.
The equipment used in this study comprised of magnetic stirrer (Acculab ALC-110.4), stirring hot plate (Health magnetic stirrer), furnace (VULCAN A-130), and Single Channel Analyzer (Bioscan). The 99mTc radioactivity was measured using a dose calibrator (ATOMLAB 100 plus) whereas the 99Mo breaktrough was evaluated using a Multi Channel Analysis (MCA-x cooler).
Synthesis of ZBM
First, 0.21 mol of zirconium (IV) chloride powder was added into a mixture of 0.27 mol of tetrahydrofurane and 0.43 mol of isopropyl alcohol in a 100 mL beaker glass. The mixture was stirred for several minutes at room temperature until dissolved. Then 7,6 mL of water and 20 g of tetrahydrofurane were added. The stirring continued and the reaction mixture was heated up to 95 °C. It was dried for overnight. The ZBM precursor granules as reaction product were converted to ZBM by heating for 1 h at specific temperature in the atmosphere. The ZBM was coated with tetra ethyl ortho silicate for improving the hardness of material.
Adsorption of 99Mo into ZBM
Based on the reactor operation schedule, The treatments of 99Mo absorption into ZBM were performed with interval time of 6 months.
Experiment A was performed in February, whereas experiment B in August. The same batch ZBM were used for both experiments on the same treatment of absorption process. 99Mo was obtained by irradiating 5 grams of natural MoO3 target (abundance ratioof 98Mo ~ 23.75 %) through nuclear activation reaction 98Mo (n,γ) 99Mo for 120 h in Central Iradiation Position (CIP) of the G.A.
Siwabesy nuclear reactor, the thermal neutron flux was 1.2 1014 n/cm2s. The irradiated target, was dissolved in 20 ml of 6 M NaOH solution. The solution was spiked to measure radioactivity of
99Mo. 150 mCi of the solution (Aloaded) was transferred from the bulk solution into erlenmeyer flask and then adjust pH up to 7 by adding 1 M HCl and water until 10 ml volume (~ 300 mg of total Mo per 10 ml).
To each solution was added ~ 1.5 grams of ZBM at 90 °C. The mixture was kept for 3 h on water bath. Next, the mixture was decanted to obtained ZBM-[99Mo]-molybdate. 99Mo radioactivity in ZBM-[99Mo]-molybdate (Azbm) was measured by dose calibrator.
Preparation of the column of ZBM
Two ZBM columns (A-1 and A-2) were prepared in experiment A, whereas two ZBM columns (B-1 and B-2) were also prepared in experiment B. After Mo was adsorbed into the ZBM, the ZBM was transferred and packed into a glass column (dia.7 mm; length 50 mm; equipped with cotton wool in the botttom side and fitted with stopcock). The packed ZBM column was washed with 20 mL of saline solution to remove the excess of Mo. To determine the optimization of the yield of 99mTc, it was eluted with saline solution containing four concentration variations of NaOCl
solution,i.e. 0.5%, 1 %, 3%, 5%, and saline solution only
Elution of 99mTc
99mTc was eluted from ZBM-[99Mo]- molybdate columns with various solutions which are shown in Table 1. After 24 h, each column was eluted with 10 x 1 mL of saline at flow rate of 0.7 mL/min followed by elution 1 x 5 mL of NaOCl solution. The fractional elution activities of 99mTc in every 1 mL of the eluate were measured. The 99mTc elution yield was determined by measuring the
99mTc activity using dose calibrator. The 99Mo breakthrough was determined by measuring 99Mo activity at gamma energy of 740 keV and 780 keV using Multi Channel Analyzer. Furthermore, the elution of 99mTc was repeated every day for a week.
Table 1. Various solutions used to elute 99mTc from ZBM columns
ZBM-[99Mo]- molybdate
column
NaCl solution
concentration NaOCl solution concentration
A-1 0.9 % 0.5 %
A-2 0.9 % 3 %
B-1 0.9 % 1 %
B-2 0.9 % 5 %
RESULTS AND DISCUSSION Adsorption 99Mo into ZBM
The adsorption yield of 99Mo to the adsorbent column was determined by equation (2);
%Adsorption yield of Mo99❑ = AZBM Aloaded
x100 %(2) The percentage of 99Mo adsorption yield and 99Mo adsorption capacity of ZBM is shown in Table 2. The adsorption capacity of 99Mo in experiment A and B is significan different (examined by t-test, 95 % confidence level). The adsorption capacity of 99Mo in experiment A is higher than in experiment B. Based on Table 2, it appears that storage time and storage conditions of ZBM main cause of decreasing the quality of ZBM in terms of 99Mo adsorption yield and 99Mo adsorption capacity of MBZ. In order to obtain high
99Mo adsorption yield and 99Mo adsorb capacity,in the future ZBM must be stored in less humidity and the dark container/vial preventing light exposure.
Atom Indonesia
Table 2. Percentage of 99Mo adsorption yield and 99Mo adsorption capacity of MBZ
Parameter Experiment A Experiment B
A-1 A-2 B-1 B-2
Volume of Mo solution (ml) 10 10 10 10
99Mo activity loaded (mCi) 155.6 158.9 160 159.7
pH before adsorption 6 6 6 6
pH after adsorption 1 1 1 1
99Mo Adsorption yield (%) 85.04 84.62 70,36 70.55
99Mo adsorption capacity of MBZ
(mg Mo/g MBZ) 170.37 169.34 164.3 164.74
Hasegawa et al [20] suggested that the mechanism of Mo adsorption into zirconium material occurs through an ion exchange reaction between molybdate ion and chlor ion as depicted in Figure 1.
Zr O Zr O Zr
Cl Cl Cl 99MoO42-
Zr O Zr O Zr
O O O
99Mo O O
99Mo
O O
Fig. 1. Proposed mechanism of Mo adsorption into ZBM
The amount of Mo adsorbed on ZBM depends on the number of Cl atom bound into zirconium atom in the molecule. Substitution reaction between Cl and Mo occurs at the bound Zr-Cl molecules which are close to each other. The mass ratio of the element in the ZBM before [19]
and after 99Mo adsorption was determined using SEM-EDX ( see Table 3 and Figure 2). The decreasing number of Cl atoms significantly was shown after Mo adsorption.
Table 3. Mass element ratio of ZBM
Element Before adsorption of
Mo (%) After adsorption of Mo (%)
Cl 10.7 1
O 38.9 39.3
C 0.6 0.9
Zr 43.9 37.5
Si 5.9 2
Mo - 19.3
Fig. 2. EDX analysis of ZBM after Mo adsorption
During the process of Mo adsorption into ZBM, the pH of molybdate solution decreased from 7 to 1. The ZBM contains -ZrO- and ZrO+Cl- groups are easily hydrolized at high pH or in water.
The formation of hydrochloride resulted from hydrolysis will decrease pH solution or causing acidic solution [21] (see equation (3).
-ZrO+Cl- + H2O -ZrOOH + HCl (3)
Effect of NaOCl concentration variations on
99mTc yield.
Figure 3 shows the yield of 99mTc obtained from the columns eluted with saline or 0.9% NaCl solution and added of NaOCl solution. The concentration of NaOCl solution was varied at 0
%; 0.5 %; 1 %; 3 %; and 5 %. Column elution with saline solution only, resulted in only a little amount of 99mTc. Whereas, column elution with addition NaOCl solution resulted in yield of 99mTc > 70 %.
NaOCl solution has a role as an oxidizing agent to remove solvated electrons resulted from 99Mo emitted β-. The solvated electrons are capable of reducing to insoluble TcO2 that subsequently retained in the column. After the use of NaOCl solution, yield of 99mTc increased up to > 70
%.Optimum yield of 99mTccould be achieved at NaOCl concentration of 3%.
control 0,5% 1% 3% 5%
0 10 20 30 40 50 60 70 80 90
NaOCl concentration
% Yield Tc-99m
Fig. 3. NaOCl concentration vs yield of 99mTc.
Control = saline solution only
Effect of NaOCl concentration variations to elution profile
Figure 4 shows the effect of the use of variations of NaOCl concentration to elution profiles. It appears that elution profiles at fractions of 1 to 4 are quite different between the use of high concentration NaOCl solution (3% - 5%) and that of low concentration (0.5% - 1%). However, elution profiles for all concentration of NaOCl solution are quite similar in the range of fraction 4 to 10. It is plausible the use of high concentration NaOCl (3% - 5%) at the initial step elution will yield high specific radioactivity of 99mTc due to its simultaneous capability of removing solvated electrons and oxidizing low valent 99mTcO2 to
99mTcO4-. When using low concentration NaOCl solution, incomplete removal of solvated electrons occur and reduced 99mTcO2 still remains in the column.However, in general yield of 99mTc from fraction 1 to 10 in every NaOCl concentration variations, gave the same total activity of 99mTc.
1 3 5 7 9 11
0 5 10 15 20
0.5% NaOCl 1% NaOCl 3% NaOCl 5% NaOCl
Fraction
specifc radioactivity of 99mTc (mCi /
Fig. 4. Elution profile of MBZ column eluted with 0.9 % NaCl solution and addition of NaOCl solution
Effect of NaOCl concentration variations to
99Mo breakthrough in 99mTc eluat
99Mo breakthrough associated with radionuclide purity in the 99mTc eluate is one of the most important requirements before labeling radiopharmaceutical kits with 99mTc for clinical uses. The effect of the use of variations of NaOCl concentration to99Mo breakthrough is shown in Fig.5. Based on the data, the highest 99Mo breakthrough in 99mTc eluate due to the 5% NaOCl concentration. The higher NaOCl concentrations used, the higher 99Mo breakthrough resulted. It is presumed that NaOCl in high concentration could break the bonding between Mo and ZBM.
1% 1% 3% 5%
1 10 100 1000
NaOCl concentration breakthrough 99Mo ( µCi 99Mo/mCi 99mTc)
Fig. 5. 99Mo breakthrough profile
A-1 B-1 A-2 B-2
Atom Indonesia
CONCLUSION
The synthesized ZBM could be used as adsorbentof neutron irradiated natural molybdenum in the 99Mo/99mTc generators. Although the present ZBM has lower 99Mo adsorption capacity (167.5 ± 3.4 mg/g ZBM) than earlier study (~193mg/g ZBM), the ZBM yielded eluate of 99mTc up to 70%.
ACKNOWLEDGMENT
The author would like to thank to Siti Darwati as the head of the Center for Radioisotope and Radiopharmaceutical Technology and to all those who have given advise and motivation so that the authors are able to finish this paper.
REFERENCES
1. Anonim. Production of long lived parent radionuclides for generator : 68Ge, 82Sr, 90Sr,
188W.Radioisotope and Radiopharmaceutical series No. 2. IAEA:Austria.
2. Chattopadhyay S, Das SS, Barua L. A simple and rapid technique for recovery of 99mTc from low specific activity (n,gamma) 99Mo based on solid-liquid extraction and column chromatography. Applied Radiation and isotopes 68 (2010) 1-4 .
3. Chakravarty R, Dash A, A novel electrochemical technique for the production of clinical grade 99mTc using (n,gamma) 99Mo.
Nuclear Medicine and Biology. 37 (2010) 21- 28.
4. Jun Byung Jin, et al, Feasibility study on mass production of (n,γ) 99Mo. JAEA research. 2010- 046.
5. M.Mostafa, et al. Labeling of cetriaxone for infective inflammation imaging using 99mTc eluted from Mo/Tc generator based on zirconium molybdate, Applied Radiation and Isotope 68 (2010) 1959-1963.
6. Anonim. Technetium-99m pharmaceuticals : preparation and quality control in nuclear medicine. Springer ( 2007) page 7-8.
7. Taskaev E, Taskaeva M, Nikolov P. Extraction generator fot 99mTc sodium pertechnetate production. Applied Radiation Isotopes Vol 46 No 1 13-16,( 1995)
8. Ambikalmajan Pillai M R, Dash A, Knapp F F. Sustained availability of Tc-99m: Possible path forward. the journal of nuclear medicine, vol.54, No.2, (2013).
9. Davarpanah M R, Nosrati S, Fazlali M, et al.
Influence of drying conditions of zirconium molybdate gel on performance of 99mTc gel generator. Applied Radiation and isotopes 67 (2009) 1796-1801.
10. P. Sara Saraswathy, A.C.Dey , et al. 99mTc generators for clinical use based on zirconium molybdate gel and (n,gamma) produced
99Mo : indian experience in the development and deployment of indigenous technology and processing fasilities. Board of radiation and isotope technology (BRIT) :India
11. Evans, J.V., Moore, P.W, et al. Zirconium molybdate gel as generator for technetium- 99m I. The concept and its evaluation. Appl.
Radiat. Isot. 38 (1987), 19-23.
12. Guzman F M, Romero O C, Velazquez H D.
Titanium molybdate gels as matrix of
99Mo/99mTc generator. J. Nucl. Radiochem.
Sci., Vol 8, No. 1. 2007.
13. Chattopadhyay S, Das M K, et al. A novel
99mTc delivery system using (n,gamma) 99Mo adsorbed on a large alumina column in tandem with Dowex-1 and AgCl column. Applied Radiation and Isotopes 57 (2002) 7-16.
14. Chattopadhyay S, Das M K. A novel technique for the effective concentration of 99mTc from a large alumina column loaded with low specific-activity (n,gamma)-produced 99Mo.
Applied Radiation and Isotopes 66 (2008) 1295-1299.
15. Molinsky VJ, A review of 99mTc generator technology.Int J Appl Radit Isot (1982);33:811-9
16. Tanase M, Tatenuma K, Ishikawa K, et al. A
99mTc generator using a new inorganic polymer adsorbent for ( n, gamma) 99Mo. Applied Radiation and Isotope 48 (1997) 607-611 17. Awaludin Rohadi, Sriyono, Herlina, Sintesis
dan karakterisasi penyerap molibdenum berkapasitas tinggi untuk generator
99Mo/99mTc, Jurnal Radioisotop dan radiofarmaka 13 (2010) 23-32
18. Awaludin Rohadi, Sriyono, Pengaruh perlakuan Tetraorthosilikate terhadap karakteristik material berbasis zirkonium untuk generator radioisotop 99Mo/99mTc. Jurnal Sains dan Teknologi Nuklir Indonesia, Vol. 12, No. 1, Februari (2011), ISSN 1411-3481
19. Saptiama Indra, Sriyono, Herlina, dkk.
Pengembangan material berbasis zirkonium(MBZ) sebagai adsorben pada
generator 99Mo/99mTc. JFN,(2012), 6(2) 114- 119.
20.Hasegawa Y, Nishino M, Et al. A new inorganic adsorbent of (n,gamma) Mo-99 for
the practical Tc-99m generator. Bandung, Indonesia : Japan Atomic Energy Research Institute, (1997). JAERI-Conf 98-015.
21. Le Van So et al. Synthesis, characterization and application of zirconium and titanium inorganic polymer sorbent for the preparation of chromatographic 99mTc and 188Re generators.
IAEA’S Co-ordinated research project report (2007), Daejeon, Korea.
