Mo-99 2016 T OPICAL M EETING ON
M OLYBDENUM -99 T ECHNOLOGICAL D EVELOPMENTS EPTEMBER 11-14, 2016
T HE R ITZ -C ARLTON
S T . L OUIS , M ISSOURIGenerator of Highly Concentrated Pure 99mTc from Low Specific
Activity 99Mo Produced by Reactor and/or Electron Linear Accelerator
K. Tatenuma, A. Tsuguchi, Y. Suzuki, K. Ishikawa
Kaken Inc.
1044 Hori, Mito, Ibaraki 310-0903, JapanandS. Sekimoto, T. Ohtsuki
Kyoto University, Research Reactor Institute2-1010 Asashiro-nishi, Kumatori, Sen-nan, Osaka 590-0494, JapanABSTRACT
Technetium-99m (99mTc) extraction from 99Mo using the newly developed Technetium
Master Milker (TcMM) process was examined. This process combined activated carbon(AC) and/or alumina (AL), with or without an ion exchange resin (IER). It was found thatthe chemical yield and purity of the 99mTc produced using the TcMM process were
90-95% and 6N (99.9999 %), respectively, even in a short time (<30min.) at room
temperature. Therefore, this process is capable of generating high quality 99mTcO4(pertechnetate), which means that the process satisfies the requirements of thepharmaceutical affairs act as a practical 99mTc generator, even with an activity level in therange from a few tens of kBq to TBq. Conclusively, it was shown that 99mTc can besupplied domestically and further locally on demand by the TcMM process after
production of 99Mo by the 98Mo(n,γ) and/or 100Mo(γ,n) reactions, using a neighboring
reactor and/or an electron linear accelerator without enriched uranium (HEU and LEU),
and furthermore, the advanced use for diagnosis can be available everywhere in theworld.
Keywords: Molybdenum-99, Technetium-99m, Technetium Master Milker (TcMM), reactor,bremsstrahlung photon, electron linear accelerator, (n,γ) reaction, (γ,n) reaction,
activated carbon, activated alumina, ion exchange resin11. Introduction

Shortage in the supply of 99Mo owing to the shutdown of reactors used for its production is a
global problem now. Since 99Mo is an indispensable source of 99mTc, which is used in nuclear
medicine to make treatments and diagnoses using techniques such as scintigraphy and single
photon emission computed tomography (SPECT), a stable supply of 99Mo is most essentialand important. Therefore, production of 99Mo using nuclear reactors and/or accelerators hasbeen investigated [1–3]. For the practical use of 99Mo/99mTc, both a stable supply of 99Mo andseparation and purification of the 99mTc are required. To separate 99mTc from 99Mo produced by
nuclear reactors and/or accelerators, methods based on sublimation, solvent extraction, andion-exchange column chromatography have been examined and developed [2, 4–6]. However,according to the pharmaceutical affairs act, the extraction method using organic materials, thegel method using heavy metal elements, and the sublimation method can not be suitable andnot be approved as 99mTc separation methods.
In this study, we developed a new method, the “technetium master milker (TcMM)” process,for separating 99mTc from 99Mo and purifying the extracted 99mTc. The TcMM process wasapplied to low specific activity (LSA) 99Mo, and the subsequent yield of 99mTc was evaluated.
Consequently, we proposed a practical 99mTc generating process and system (99mTc generator)
from 99Mo produced in a reactor and/or accelerator.
2. Experiment
2.1 Preparation of 99Mo2.1.1 Using a reactor

The 99Mo was generated by the 98Mo(n,γ) reaction of natural isotopic Mo oxide (natMoO3; 99.9%
purity, made by Taiyo-Koukou Co., Tokyo, Japan) pellets, which were sintered from natMoO3powder (20 g per pellet) using the spark plasma sintering (SPS) method [7] at 550 °C for 10 min
under a compressive force of 10-15 kN. Each natMoO3 pellet, with a theoretical density (TD) of
80-85%, had a diameter of about 20 mm and a thickness of 16-17 mm. The pellets wereirradiated by neutrons in a nuclear reactor (JRR-3 at the Japan Atomic Energy Agency,maximum neutron flux: 8.7-9.6× 1013 n/cm2/s). The neutron irradiation of 15 MoO3 pellets,
sintered by the SPS method, with a total weight of 293.4 g (195.6 g Mo), lasted for 7 days. The
generated 99Mo had an activity of 2.99× 1012 Bq with a specific activity of 1.48× 1010 Bq/g forthe natMo immediately after irradiation. The irradiated MoO3 pellets were dissolved in 679 mL of6 M NaOH solution, which was adjusted to 1 L by adding water. Subsequently, the Mo solution
was prepared with a concentration of 200 g of Mo/L with neutral pH.
2.1.2 Using an accelerator

The 99Mo was generated by the 100Mo(γ,n) reaction of natural isotopic Mo oxide (natMoO,99.99% purity, made by Kojundo Chemical Laboratory Co. Ltd., Japan) pellets, which weresintered from natMoO3 powder (1.6–1.7 g per pellet) using the SPS method at 520-550 °C for 5
min under a compressive force of 5–6 kN. Each natMoO3 pellet, with TD of 83-89%, had a2

diameter of about 10 mm and a thickness of 5 mm. The pellets were stacked between gold foils(10 mm diameter × 0.02 mm thickness), which were used as a fluence monitor forbremsstrahlung photons. Each pellet stacked between the gold foils was enclosed in a quartz
tube. The stacked samples in the quartz tube were irradiated by bremsstrahlung photons
generated by a 2-mm-thick platinum converter and cooled with running tap water. The
generated 99Mo immediately after irradiation had a total activity of 1.59× 107 Bq with a specificactivity of 1.37-3.48× 106 Bq/g for the natMo and 1.43-3.62× 107 Bq/g for the 100Mo. Eachirradiated natMoO3 pellet was dissolved in 6 M NaOH of 3.8 mL with weak heating and theresulting Na2MoO4 solution with neutral pH was adjusted to 10 mL by adding water.
2.2 TcMM (Technetium master milker)
The TcMM process based on a newly discovered phenomenon, a general activated carbon (AC)has a peculiar characteristics to be able to adsorb 99mTc preferentially and completely, wasdeveloped to separate 99mTc from 99Mo, and consisted of six steps. The TcMM process wasapplied to the irradiated natMoO3 pellets, and the six steps for 99mTc separation from the irradiatednatMoO3 pellets were as follows, in which high purity common reagents were used:(1) Dissolution of irradiated natMoO3 pellets
The irradiated natMoO3 pellets including 99Mo were dissolved in a molar equivalent NaOH
solution with weak heating. The resulting Na2Mo(99Mo)O4 solution had neutral pH and a fixedvolume of 1.0 L was obtained by adding water.
(2) Adsorption of 99mTc in the ACThe Na2Mo(99Mo)O4 solution with a maximum volume of 1.0 L was poured into an ACcolumn packed with activated carbon (4.5 g) at a flow velocity of 100 mL/min for 10 min toadsorb 99mTc onto the AC column. In a flow velocity ranging from 10 mL/min to 200 mL/min,
the AC column worked sufficiently because a trace amount of 99mTc was preferentially andcompletely adsorbed to the activated carbon in comparison to an enormous amount of Mo.
(3) Removal of Mo(99Mo) contaminants from the AC
The Mo(99Mo) contaminant, which usually remains in the holes of the activated carbon particles
during the second step, was removed by sequential water treatments. Firstly, 100 mL of water
was flushed through the column at a rate of 50 mL/min to wash Mo out from the AC column.
Secondly, 30 mL of 6.0 M NaOH was flushed through at a rate of 10 mL/min to remove Mo;
and thirdly, 25 mL of water was flushed through at a rate of 10 mL/min to remove remaining
Mo and any NaOH.
(4) Elution of 99mTc from the AC
In order to elute 99mTc collected in the AC column, 85 mL of water was flushed through the ACcolumn at a rate of 10 mL/min and all the 99mTc adsorbed on the AC column was eluted as aweak alkaline solution.
(5) Removal of Na+ ion in the eluted alkaline 99mTc solution
The solution was flushed through 5 cc of strong acid in an ion exchange resin (IER) and 6 g ofactivated alumina (AL). The Na+ ion in the eluted 99mTc solution was captured by the IER
3

column and the 99mTc was caught in the AL column.
If the IER column was not used, the TcMM process was performed with a combined AC-AL
column system with AL 12 g .
(6) Elution of 99mTc
Highly pure 99mTc was recovered from the AL column by flowing 10-20 mL of saline (0.9%NaCl solution) at a rate of 10 mL/min through the column. The resulting 99mTc had aconcentration of 50-100 times that of the initial Mo (99Mo) solution.
The TcMM 99mTc generator system is shown in Fig. 1 and the TcMM process is outlined in Fig.
2. The columns made by polypropylene (PP) or polyethylene (PE) resin were packed with AC
and AL for the AC-AL process (Fig. 2 (a)) with an additional IER column for the AC-IER-ALprocess (Fig. 2(b)). The AC, AL, and IER can be described as follows.

10TBq type, AC-IER-AL columns

TcMM Flow line

Fig. 1 TcMM System

4	rradiated Mo(99Mo)O3�
! Dissolution by NaOH�

	rradiated Mo(99Mo)O3�

Mo(99Mo+99mTc) stock solution
pH neutral�! Dissolution by NaOH�

6M-NaOH
H 2O

Mo(99Mo+99mTc) stock solution
pH neutral�recovery& reuse

99mTc adsorption

recovery& reuse

6M-NaOH
H 2O& elution�

99Mo sol.

99mTc adsorption& elution�

Alkali removal�
IER column(5cc)

99Mo sol.

Salinerinserinse

Salinerinse

AC column(4.5g)

wasteAC column(4.5g)

Alkali removal &99mTc purification�
AL column(12g)

99mTc purification�

rinse

AL column
(6g)

waste
99mTc sol.

99mTc sol.

(b) AC-IER-AL Process(a) AC-AL Process

Fig. 2 TcMM Process
Activated carbon (AC)In order to collect 99mTc present in a highly concentrated Na2Mo(99Mo)O4 solution, the ACcolumn was utilized by packing 4.5 g of AC in the column. The inside diameter and length of thecolumn was 15.2 mm and 66 mm, respectively. Shirasagi-charcoal was used as the palm shellraw material, (particle size of 0.30-0.85 mm, made by Japan-Environment Chemicals Co., Osaka,Japan).
Activated alumina (AL)The AL column was utilized to adsorb and purify the 99mTc collected from the Mo(99Mo)
solution by removing trace amounts of natMo(99Mo) and radioactive niobium as well as otherimpurities generated from the molybdenum stable isotopes. The column was made by packing
6 g of AL with an IER column or 12 g of AL without an IER column. The column had an inside
diameter of 15.2 mm and lengths of 33 mm and 66 mm. The AL was made by MP
Biochemicals (Santa Ana, CA, USA) with a particle size of 0.063-0.20 mm and a pH of 4.3(acid alumina).
Ion exchange resin (IER)
A strong acid type IER was used to remove Na+ from the 99mTc solution in the AC column with5 mL of water containing a small amount of NaOH. The column had an inside diameter of 15.2mm and a length of 28 mm. The IER was the DIAION SK H 1B made by Mitsubishi Chemical
Co. with a particle size of 0.15 mm with pre-conditioning by HCl.
5

2.3 99mTc purity and quality
The TcMM process was applied to 99Mo produced by a reactor and an accelerator. Theradiopharmaceuticals of 99mTc are explained below.
A NaCl concentration meter with measurement accuracy of 0.02% (TOA DKK
MM-60R/CT-57101B, Tokyo, Japan), pH meter (TOA DKK RM-31P/ELP035) and Ge
semiconductor detector (ORTEC GMX-20190-P-PLUS, Oak Ridge, TN, USA) were used,
respectively, to measure the NaCl concentration, pH, and radioactivity and radiochemical purityof the collected 99mTc solution.
Several analytical methods were performed to confirm the chemical form and quality of the99mTc recovered from the TcMM process. The analytical methods used were thin layer
chromatography with γ-ray detector (γ-TLC, γ-mini GITA Star, Raytest, Strubenhardt,Germany), Cellulose Acetate film Electrophoresis (CAE), Reversed Phase-High Performance
Liquid Chromatography, (RP-HPLC, Hitachi-L2130/Ratest-GABI Star, Tokyo, Japan andStrubenhardt, Germany with a Unison US-C18 column), and SPECT (Triumph SPECT4/CT,TriFoil Imaging Inc., Chatsworth, CA, USA) by labeling experiments using the conventional99m
Tc generators. Radiopharmaceutical kits of MAG3 (mercaptoacetylglycylglycylglycine),HM-PAO (hexamethylpropyleneamine oxine), MIBI (methoxyisobutylisonitrile), MDP(methylene diphosphonate), and Tetrofosmin, which were purchased from Nihon Medi-Physics
and Fujifilm RI Pharma (Tokyo, Japan) were also used. Detail on the TcMM process conditions
can be found in ref [8].
3. Results and discussion
Initial radioactivity of 99Mo was at the TBq level. The 99mTc milking was performed once a day
and this milking was repeated 10 times. As a result, the collection rate of 99mTc was 93.5% onaverage.
The recovery rate of 99mTc was not influenced by the radioactivity of 99Mo or 99mTc in the
1× 104-2× 1012 Bq range, and a recovery rate of 90-98% was stably obtained. The production
time of 99mTc was approximately net 30 min per batch influenced by the liquid volume of theMo(99Mo) solution.
The radiochemical purity of the collected 99mTc was 99.9999-99.99999% on average. The Mo(99Mo) solution had many radioactive impurities such as radioactive niobium (92mNb, 95Nb, and96
Nb generated from Mo stable isotopes) and other radionuclides (60Co, 187W, 198Au, etc.)
generated from trace elements impurities in the natMoO3 pellets. However, the 99mTc solution
collected and purified by the TcMM process was free from such impurities including 99Mo asshown in Fig. 3. However, these radioactive impurities were not found in the 99mTc solution
collected by the TcMM process developed in this study. The 83-85% of radioactive Nb wasdistributed in the AC column and residual radioactive Nb was distributed in the IER and ALcolumns.

6Detected nuclides
99Mo, 99mTc,187W, 92mNb, 24Na,

Detected nuclides

198Au, 134Cs, 124Sb, 60Co, 86Rb

99mTc
99Mo

99mTc

1.7-1.8e+12 Bq
1.7-1.8e+12 Bq

purity: 7N799Mo

TcMM processa) Mo(99Mo) solution
50h elapsed after irradiation stop

99mTc

ND <5e+4 Bq
1.6-1.7e+12 Bqb) Collected 99mTc solution: 4th milking

Fig	 3 γ-spectra of (n,γ)99Mo and 99mTc collected by TcMM process.
Radiochemical purity of 99mTc was confirmed by measuring for a long time after 99mTc decay.

The γ-TLC and CAE analyses showed that the collected 99mTc exhibited a single peak atretention values (Rf) similar to those of 99mTcO4- (pertechnetate), Furthermore, a single form of99m
TcO4- was confirmed, as well as the form of 99mTc made from fission-99Mo by enricheduranium.
The labeling experiments using radiopharmaceutical kits of 99mTc-tetrofosmin, 99mTc-MIBI,
99m
Tc-HMPAO, and 99mTc-MAG3 of the 99mTc collected from the TcMM process showed TLC,
RP-HPLC, and CAE profiles similar to those of 99mTc-labeled radiopharmaceuticals preparedwith 99mTc solutions eluted from the conventional 99Mo/99mTc generator system. The results
mentioned above are explained in detail in a previous study [8-9].
Based on the results of the above experiment, 293.4 g of natMoO3 pellets (195.6 g as natMo, 47.1
g as 98Mo) were irradiated with neutrons for 7 days, and the activity of 99Mo produced was
2.99× 1012 Bq in total just after irradiation, which corresponds to a specific activity of 1.48× 1010
Bq/g for natMo. In Japan, this value is equivalent to the amount of 99mTc required in a few days.
The results of the TcMM process applied to 99Mo produced using an electron linear accelerator
was shown in our recent work [10] in detail, and will be briefly discussed here.
The chemical yield of 99mTc ranged from 83 to 99% over the four runs of the TcMM usingnat
MoO3 pellets irradiated with bremsstrahlung photons. In particular, the activity of 99Mo in thesolution collected by the TcMM process was below the detection limit of g-ray spectrometry.
This was confirmed by the g-ray spectra of the natMoO3 solution before the TcMM process andthe solution collected by the TcMM process. 99mTc of >99.9999% purity was obtained in 0.9%
saline solution at neutral pH by using the TcMM process. The radioactive impurities in (γ,n)
reaction were also found (Fig. 4). The assembly of a TcMM process with an electron linear
accelerator system was proposed based on the results [10].
7[Detected NUclides] 99Mo(99mTc)
90Nb, 91mNb, 92mNb, 95Nb, 95mNb, 96Nb

Linac-(γ,n)99Mo
natMoO pellet Irradiated
3by Linac

2.00E+06

Nuclides generated in
Linac-irradiation natMoO3

1.80E+06

25MeV

1.60E+06

30MeV[main nuclear reactions]
97Mo(γ,p)96Nb
96Mo(γ,p)95mNb&95Nb
94Mo(γ,pn)92mNb
92Mo(γ,p)91mNb
92Mo(γ,pn)90mNb

Bq/g(pellet)

1.40E+06

35MeV

1.20E+06
1.00E+06
8.00E+05
6.00E+05
4.00E+05
2.00E+05
0.00E+00

Nb- 95m Mo- 99

Nb- 95

Nb- 96 Nb- 92m Nb- 90

NuclidesNb- 91m

Fig. 4 Linac-(γ,n)99Mo and impurity nuclides generated

Finally, the TcMM conditions of the AC-AL column process and/or the AC-IER-AL column
process are summarized in Table-1. AC-AL process and AC-IER-AL process are nearly similar,
but the 99mTc concentration rate using IER can be obtained higher than that of AC-AL process.
By using the TcMM system, a highly concentrated pure 99mTc of kBq-TBq from a low specificactivity 99Mo can automatically be collected in a short time (<30min.), furthermore that can also
be utilized as a 99mTc concentrator.
The role of the TcMM process developed in this work is shown as Kaken 99Mo-99mTc Processin Fig. 5.

8

Table-1 TcMM conditions
TcMM type(TcMM process)

TcMM 10T(AC-AL)TcMM<IER> 10T(AC-IER-AL)

amounts of 99Mo

kBq-10TBq

kBq-10TBq

Mo solution

200g(Mo)/L200g(Mo)/LAC column

LH2c-AC 4.5g,
Flow rate of Mo sol. 100mL/min
6M-NaOH 30mL
99mTc elute H 0 85mL
2LH2c-AC 4.5g,
Flow rate of Mo sol. 100mL/min
6M-NaOH 30mL
99mTc elute H O 85mL
2IER column-----DIAION(SK1B H) 5cc

AL column

MP-acid AL 12g
Saline 20mL

MP-acid AL 6.0g
Saline <10mL

99mTc milking time

≤30min≤30minvolumeconcentration rate
radiochemical purity

20mL
50 folds>99.99%≤10mL	
00 folds or more
>99.99%wastes per batch

Liquid: 250 mL
Solid: 17g

Liquid: 250 mL
Solid: 16g

99mTc collected

99Mo-99mTc Domestic & Local Production on demand
99Mo production [Reactor or Accelerator]
99Mo

Natural or Enriched isotope MoO3 or Mo[by Reactor] 98Mo(n,γ)99Mo[by Linac] 100Mo(γ,n)99Mo

Low Specific Activity 99Mo
LSA-99Mo 0.1-1Ci/g(Mo)LSA-99Mo
99mTc Master Milker [TcMM]
99mTc

PatentedConcentration & purification of 99mTc
by activated carbon(AC) & alumina(AL)! 99mTc milking performance:
Bq-10TBq within 30min.
! Mo(	9Mo) specific activity andconcentration: without restriction.
! 99mTc purity in saline: >6N! milked 99mTc concentration:
kBq-TBq/mL! 99mTc chemical form: TcO4-Small AC-(IER)-AL
kBq-10GBq

TcMM
GBq-10TBq

Fig. 5 Kaken 99Mo-99mTc Process

999mTc generator

AC-(IER)-AL
99mTc pharmaceutical

4. Conclusions

To separate 99mTc from 99Mo and to purify the 99mTc, the TcMM process was developed
and presented in detail. Using the TcMM process, 99mTc was separated and purified from1× 104 ~ 2× 1012 Bq of 99Mo, which was produced by a reactor and/or accelerator. TheTcMM process produced highly pure 99mTc (radiochemical purity of >99.99%) with achemical yield of 90% on average. The activity of 99Mo in the solution collected by theTcMM process was extremely low. The TcMM process also produced high quality
99m
TcO4- (pertechnetate) to satisfy the pharmaceutical affairs act. It was found that 99mTc
can be supplied domestically and locally on demand by the TcMM process after
production of 99Mo by the 98Mo(n, γ) in reactor and/or 100Mo(γ,n) reactions in electronlinear accelerator.

Acknowledgements
The authors wish to express their gratitude to Mr. Jaewoong Jang and Dr. Mitsuru Uesakaof Tokyo Univ., Dr. Masashi Yamamoto and Dr. Eiji Tanabe of Accuthera Inc., Dr.
Takahiro Tadokoro of Hitachi Ltd., and Mr. Kari Anderson of Abilene Christian
University for their great support on this study.

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