See

discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/278322910

Pharmaceutical grade sodium [99mTc]

pertechnetate from low specific activity 99Mo
using an automated 99Mo/99mTc-TCMautosolex generator
ARTICLE in JOURNAL OF RADIOANALYTICAL AND NUCLEAR CHEMISTRY NOVEMBER 2014
Impact Factor: 1.03 DOI: 10.1007/s10967-014-3211-1

CITATION

READS

15

15 AUTHORS, INCLUDING:
Sankha Chattopadhyay

Luna Barua

Variable Energy Cyclotron Centre

Variable Energy Cyclotron Centre

38 PUBLICATIONS 285 CITATIONS

6 PUBLICATIONS 27 CITATIONS

SEE PROFILE

SEE PROFILE

Kakali De
Indian Institute of Chemical Biology
32 PUBLICATIONS 134 CITATIONS
SEE PROFILE

Available from: Sankha Chattopadhyay

Retrieved on: 11 November 2015

J Radioanal Nucl Chem (2014) 302:781790

DOI 10.1007/s10967-014-3211-1

Pharmaceutical grade sodium [99mTc] pertechnetate from low

specific activity 99Mo using an automated 99Mo/99mTc-TCMautosolex generator
Sankha Chattopadhyay Luna Barua Sujata Saha Das Anirban De
Umesh Kumar Arpit Mitra Tapas Mallick Madhusmita Md. Alam Nayer
Samarendu Sinha Bharat Ratna Sarkar Shantanu Ganguly Kakali De
Malay Kanti Das M. G. R. Rajan

Received: 30 April 2014 / Published online: 8 June 2014

Akademiai Kiado, Budapest, Hungary 2014

Abstract Performance study of a computer controlled

automated closed cyclic module for the separation and
recovery of 99mTc from low specific activity (n, c) 99Mo
using methyl ethyl ketone (MEK) solvent extraction technique named 99Mo/99mTc-TCM-AUTOSOLEX (Technetium automated solvent extraction) Generator is described.
The entire system is automated and controlled by a userfriendly PC based graphical user interface that actually
supervises process via an embedded system based electronic controller. The average yield of separation of 99mTc
was above 85 % and 99Mo breakthrough in 99mTc pertechnetate was \0.002 %. The sodium pertechnetate
obtained was a clear solution having pH 67, Radiochemical (RC). Purity [99 %, MEK content \0.1 % (v/v),
Al and Mo content \10 lg/ml. R. C. Purity of 99mTc-

S. Chattopadhyay (&)  L. Barua  S. S. Das  U. Kumar 

Madhusmita  Md. A. Nayer  M. K. Das
Radiopharmaceuticals Laboratory, Board of Radiation & Isotope
Technology (BRIT), Variable Energy Cyclotron Centre (VECC),
1/AF, Bidhan Nagar, Kolkata 700 064, India
e-mail: sankha@veccal.ernet.in; sankha@vecc.gov.in
A. De  T. Mallick
Variable Energy Cyclotron Centre, 1/AF, Bidhan Nagar,
Kolkata 700 064, India
A. Mitra  M. G. R. Rajan
Radiation Medicine Centre, BARC/BRIT, Parel,
Mumbai 400012, India
S. Sinha  B. R. Sarkar  S. Ganguly
Regional Radiation Medicine Centre, Variable Energy Cyclotron
Centre, 1/AF, Bidhan Nagar, Kolkata 700 064, India
K. De
Nuclear Medicine Department, Indian Institute of Chemical
Biology, Jadavpur, Kolkata 700032, India

radiopharmaceuticals studied was not less than 96 %. BioQuality control studies confirm that sodium pertechnetate
obtained was sterile and pyrogen free. Imaging studies in
animals and humans with limited radiopharmaceuticals
show that the quality of 99mTc-pertechenate obtained in the
present module was good enough to do clinical study.
Keywords 99mTc separation  Computer controlled
automated module  Solvent extraction  Purification 
High purity technetium-99m

Introduction
99m

Tc is the most widely used isotope in nuclear medicine

today [13]. Over 30 million studies were performed
worldwide with technetium-99m annually [47]. The
excellent nuclear characteristics of 99mTc enable high
quality images with low radiation doses to patients. Its
chemical characteristics make it very versatile for making
different chemical compounds, so that it can be used to
target different organs and lesions required for different
diagnostic procedures. Many kits are available on the
market to make easily all these compounds in clinics.
Technetium-99m is generally obtained from 99Mo99mTc
generator where 99Mo decays by b- emission (87.5 %)
with a half-life of 66 h to 99mTc. Molybdenum-99 is
produced in most cases using highly enriched 35U targets
through fission reactions using thermal neutrons 235U (n, f)
99
Mo. In this case very high specific activity can be achieved.
Alternative routes can be also used as the neutron activation
of 98Mo by the 98Mo(n, c) 99Mo nuclear reaction [811] and
there are also proposals for production of 99Mo through
100
Mo (p, x) 99Mo or 99mTc directly through 100Mo (p, 2n)

123

782

J Radioanal Nucl Chem (2014) 302:781790

Fig. 1 Chemical processing

unit

99m

Tc, in a cyclotron to meet the worldwide shortage of

Tc [12, 13]. In these latter cases, the achievable Mo
specific activity is lower than in the case of the fission
production route.
There are several methods for routine separation of
99m
Tc from 99Mo depending on the Mo specific activity.
The most popular one is the alumina column chromatography. The capacity of adsorption of molybdenum 20 mg/g
of alumina restricts its use to high specific activity 99Mo
such as the one obtained by thermal fission of 235U [8].
There are also zirconium molybdate gel column chromatography utilizes medium specific activity (n, c) 99Mo [14],
ion exchange technique based on exchange of 99mTc
[1518] and solvent extraction technique based on extraction of 99mTc with methyl ethyl ketone (MEK) for low
specific activity (n, c) 99Mo [1921].
The 20082010 crisis in fission-produced 99Mo supplies
have given an impetus to consider and foster the practice of
distribution of separated (or eluted) 99mTc. The latter can
come from 99Mo of different specific activities and that
would be a tremendous advantage for securing sustainable,
diversified sources of 99mTc. There is clearly scope for
renaissance of separation technologies applicable to 99Mo
and 99mTc, and which will also help reduce the unduly high
dependence on fission produced 99Mo.
Solvent extraction technique based on extraction of
99m
Tc with MEK offer many advantages for the efficient
production of 99mTc [8]. These include low cost per unit
activity and the ability to use low specific activity 99Mo,
yielding a high radioactive concentration of 99mTc and
providing high radiochemical and radionuclidic purity of
the resulting Na99mTcO4 solution [13, 20, 22].
99m

123

Technetium-99m is obtained in many hospital radiopharmacies in India using the BARC/BRIT (Bhabha
Atomic Research Centre/Board of Radiation & Isotope,
India) MEK solvent extraction system. The method had
the merits of early adaptability in India, compatibility with
the low specific activity of 99Mo produced via the (n, c)
process from natural Mo as molybdenum oxide in our
research reactors. The inherent drawbacks of this system
include daily manual handling of radiological hazard 99Mo
solution, manual separation of organic and aqueous layers,
evaporation of the inflammable solvent MEK by heating
(chances of contamination with aldol induced impurities
due to overheating) and necessitating a terminal sterilization. Though it is being practiced, the method is not
desirable in hospital set up as the MEK being inflammable
solvent, the evaporation of MEK by heating is hazardous
and causes environmental pollution [23]. In addition, the
automation enhances safetyradiological and pharmaceutical bothas well as the capacity to handle much
larger quantity of Mo-99. Klopper et al. [21] has
attempted first to make an automated system for separation of 99mTc using MEK extraction method. The system
was crude and needs more sophistication for use in hospital radiopharmacy.
To solve the above mentioned problems, an automated
computer controlled closed cyclic module for separation
and recovery of 99mTc from low specific activity 99Mo has
been developed. Its working principle and advantages are
explained in the following sections with a discussion of the
process chemistry. Quality control of the final product is
then presented followed by images obtained in both rats
and humans showing that the quality of 99mTc-pertechenate

J Radioanal Nucl Chem (2014) 302:781790

783

Fig. 2 Schematic diagram of the chemical process

obtained in the present module was good enough to do

clinical study.

Experimental
Materials
All chemicals were from commercial sources and were of
AR/GR grade unless otherwise specified. Aluminium
oxide, active basic (100200 mesh), Brockman grade-1
(Prabhat Chemicals, Mumbai, India) were used for preparing the purification column. Molybdenum-99 produced
from the irradiation of natural MoO3 by the 98Mo (n, c)
99
Mo reaction. Molybdenum-99 so obtained formulated as
[99Mo]Na2MoO4 in 5 N NaOH (150 mg Mo/ml:
1.112.22 GBq/ml) was obtained from the Radiochemical
Section, Radiopharmaceutical Division, Bhabha Atomic
Research Centre (BARC) and Board of Radiation & Isotope Technology (BRIT), Mumbai, India. Valves used for
fluid transfer and for controlling vacuum were Burkett twoand three-way PEEK solenoid valves. All the tubing
(PEEK material) and valves were made sterile by washing
with 70 % ethyl alcohol.
The system is comprised of (i) a chemical processing
unit and (ii) a control unit.
(i)

Chemical processing unit

The chemical processing unit (Fig. 1) according to the

present work was made of two major components: an

extraction vessel to extract 99mTc in organic phase (MEK)

and a purification system to remove MEK solvent from
99m
Tc-pertechnetate. The extraction vessel (extractor) is
confined in a lead shielded assembly which is connected
with a conductivity cell at the bottom of the extraction
vessel and is used to extract daughter radionuclide, 99mTc
in organic solvent (MEK) from parent radionuclide, 99Mo
in NaOH solution. The purification system consist of a
basic alumina column to remove traces of Mo/alkali and a
MEK evaporator to remove MEK from the product. Both
are mounted on the front side of the purification assembly.
The solenoid valves to control the process flow are
mounted on the back side of the purification assembly. The
whole assembly is housed in a lead shielded box. The MEK
solvent evaporator is a pear shaped glass flask fitted with
three tubes at the top: through one tube 99mTc in MEK is
introduced into the flask, through the second tube MEK
evaporates out and gets collected in MEK trap under vacuum and the third one is for introduction of saline for
reconstitution of 99mTc in saline and collection of product
as sodium pertechnetate through a 0.22 lm filter. A temperature controlled water bath (7580 C) was used to
evaporate MEK from 99mTc under reduced pressure. Air
lines are connected with 0.22 lm filter to get sterile air in
the system.
(ii)

Control unit

The control unit consists of an embedded system based

hardware interface, a control-software and a PC based
system. The architecture followed has been a modified and

123

784

J Radioanal Nucl Chem (2014) 302:781790

customized version, and constitutes an embedded controller operated by a Visual Basic based graphical user interface (GUI), developed in-house for the automatic operation
of the chemical processing unit. The unit basically employs
a 16-bit microcontroller with associated digital circuitry
and appropriate driver interfaces to operate the relays that
in turn actuate the solenoid valves responsible for the
process. The GUI is, in essence, supervisory software to set
the timing sequences and monitor the states of the valves,
conductivity detector, pump and temperature controlled
heater during the chemical processing operation. The entire
system of automation includes a user-friendly PC based
GUI that actually controls the process via an embedded
system based electronic controller. The time settings for
the actuator sequences are user-settable and features such
as START, TERMINATE, WAIT/RESUME allow smooth
control over the system. Apart from setting and command
interfacing for the system, the controller unit provides
monitoring over the actuators and sending status information to the GUI. An additional feature of time-stamped data
logging for the actuator states is also built in the GUI for
diagnostic purposes. The computer (PC) communicates
with the controller via RS-232 protocol. The communication module of the controller unit processes the command
strings that is sent from the PC and directs the controller to
act accordingly. The relay actuation module interfaces the
controller to the process. This actually operates on a set of
relays that in turn actuates the valves, heater and pump
according to the sequence, maintaining the custom timings.
The entire design guarantees electrical isolation between
the digital controller circuitry and the power signals.

Table 1 Typical data for the recovery of Na99mTcO4 from

(11.1 or 18.5 GBq)
99

Before starting the separation/extraction and purification

operation, the following preparations were completed:
(i)

(ii)

(iii)

5 g of basic alumina was loaded to a glass column

with a G-2 sintered disc at the bottom, and a G-2
sintered disc was also placed on the top. The
column was sealed with butyl rubber stopper and
aluminium cap. The basic column thus prepared
was placed inside the lead shielded jacket with
proper lead lid.
Sodium molybdate-99Mo solution (on the first day
of loading activity) in 5 N NaOH solution (30 ml)
was kept in a container inside the lead pot near the
solvent extractor.
The pear-shaped MEK evaporation vial (MEK
evaporator) was washed with 70 % ethyl alcohol
and then with sterile saline solution before starting
the separation program.

123

Mo

99m
Tc
growth
time (h)

99m
Tc
expected
(GBq)

99m
Tc
obtained
(GBq)

99m
Tc
yield
(%)

11.1

96

10.7

10.3

85

8.7

24

7.7

7.4

96

6.8

24

6.0

5.7

94

5.4

22

4.7

4.2

90

4.2

24

3.7

3.2

87

18.5

96

17.8

15.7

88

14.4

24

12.7

10.9

86

11.4

22

9.9

9.4

95

9.0

22

7.8

7.4

95

7.0

24

6.2

5.3

85

Mo
activity
(GBq)
11.1 GBq

18.5 GBq

Table 2 Quality control test results of

99m

99m

Tc-radiopharmaceuticals

99m
Tc in 2 ml
saline(GBq)

R. C.
Purity (%)

Tc-MDP

0.68

99

Tc-DTPA

1.86

96

Tc-ECD

1.21

95

Tc-MIBI

0.68

96

Tc-DMSA

0.50

99

Tc compound

Tc-Mebrofenin

0.75

96

99m

99

TcO4-

(iv)
Preparation

99

(v)

30 ml MEK was kept in another vial beside the

molybdate solution.
10 ml saline vial and a vacuum product vial
connected through a 0.22 lm membrane filter
were placed in the respective port.

Operation of the automated module

After completion of preparation steps, the computer and the
control unit were switched on and the formal procedures like
temperature setting of the heater and time settings for the
actuator sequences were followed to initiate the automatic
process including transfer of 99Mo activity, extraction of
99m
Tc, separation, purification and collection of 99mTc. As
soon as the start command was given the operation got
started in sequential manner (Fig. 2). At the beginning of the
operation, i.e., in Step 1, the heater of the water bath was
switched on. In Step 2, the vacuum pump was switched on to
create vacuum for suction of the liquids (alkaline solution of
99
Mo/99mTc and MEK) to the solvent extractor. In this step,

J Radioanal Nucl Chem (2014) 302:781790

785

Fig. 3 Renogram of a rat with

99m
Tc-DTPA

MEK and 99Mo activity were transferred to the extractor.

Vigorous mixing of the organic and aqueous solution took
place to extract 99mTc in MEK from aqueous molybdate
solution in this step. In Step 3, the extractor system was made
atmospheric for settling of the aqueous and organic layer
where MEK remains at the top and aqueous alkaline layer at
the bottom. In Step 4, the alkaline layer containing 99Mo was
first transferred to the 99Mo storage vial through conductivity
transducer cell via a solenoid valve after receiving the signal
of the conductivity and then MEK (containing 99mTc) layer
was transferred to the evaporation vial through basic alumina
column via another solenoid valve when the conductivity
detector was not sensing. In Step 5, MEK was removed by
evaporation under reduced pressure and that was collected in
an ice cold trap. In Step 6, 99mTc residue was reconstituted
with saline and collected in a sterile, vacuum vial after
passing through a 0.22 lm membrane filter.

Radionuclide analyses
Radionuclide activities were determined by using a calibrated HPGe detector (Eurisys M, Caen, France) coupled to

a PC-based multi channel analyzer (ORTEC, Oak Ridge,

TN, USA). The detector had a 30 % efficiency relative to a
300 9 300 NaI (Tl) detector and an energy resolution of
1.74 keV at the 1,332 keV c-peak of 60Co. The levels of
99
Mo and 99mTc were determined by quantification of the
different c-lines of the respective radioisotopes at
739.6 keV (12.1 %) and 140.51 keV (89 %). The recovery
of the separated 99mTc was determined by using a calibrated dose calibrator (ISOMED 50, Hans Walischmiller
GmbH, Dresden, Germany).

Quality control tests of Na[99mTc]TcO4

Chemical purity
MEK, molybdenum and aluminium contents in the final
radioactive TcO4- solution were determined by turbidity/
color tests using iodoform, potassium thiocyanate and
chromazural-S tests, respectively, as per BRIT, Mumbai,
India monograph.
MEK identification test 200 ll of 1 N NaOH, 200 ll of
0.1 N iodine, 50 ll of the test solution and 150 ll distilled

123

786

J Radioanal Nucl Chem (2014) 302:781790

Fig. 4 Bone scan of a patient

with 99mTc-MDP

water were taken in a test tube. The turbidity produced

in the sample was compared with that of the standard
(0.1 % v/v).
Molybdenum identification test 50 ll of the test sample,
50 ll of 10 % KCNS and 10 % SnCl2 were taken in a test
tube. The orangered colour produced in the sample was
compared with that of the standard (10 ppm).
Aluminium identification test 10 ll of the test sample,
30 ll of acetate buffer and 10 ll of chromazural-S were
taken in a test tube. The reddish pink colour produced in
the sample was compared with that of the standard
(10 ppm).
The pertechnetate obtained was checked for clarity, pH,
R. C. Purity and 99Mo breakthrough. The efficacy of
labeling specific compounds was assessed using locallyproduced standard radiopharmaceutical kits (BRIT, Mumbai, India), such as 99mTc-MDP, 99mTc-MIBI, 99mTcDTPA, 99mTc-DMSA, 99mTc-mebrofenin and 99mTc-ECD.
R. C. Purity was evaluated by thin layer chromatography
(Silica gel 60, Merck) using a Ray Test TLC scanner
(Model No. BGO-V-detector) and GINAs software provided with the scanner.

123

Labeling of

99m

Tc-radiopharmaceuticals

2 ml of the Na[99mTc]TcO4 solutions obtained after separation were added separately to the freeze-dried kit vials of
MDP, MIBI, DTPA, DMSA, mebrofenin and ECD. The
99m
Tc-MDP, 99mTc-DTPA and 99mTc-DMSA preparation
vials were kept at room temperature for 10 min before use.
The 99mTc-MIBI and 99mTc-mebrofenin preparation vials
were kept in a boiling water bath for 10 and 5 min,
respectively for the completion of the labeling reactions.
The 99mTc-ECD preparation vial was kept for 30 min at
room temperature before use.
Quality assessment of the

99m

Tc-radiopharmaceuticals

The R. C. Purities of 99mTc-MDP, 99mTc-DMSA, 99mTcDTPA were evaluated by developing the thin layer chromatography strips (10 cm 9 1 cm), spotted with the samples, in MEK solvent and saline. The R. C. Purity of 99mTcMIBI was evaluated by developing the thin layer chromatography strip (10 cm 9 1 cm), spotted with the sample, in 95 % ethanol and saline The R. C. Purity of 99mTc-

J Radioanal Nucl Chem (2014) 302:781790

Fig. 5 Renogram of a patient with

787

99m

Tc-DTPA

mebrofenin was evaluated by developing the thin layer

chromatography strips (10 cm 9 1 cm), spotted with the
samples, in 85 % methanol and 20 % saline.
The R. C. Purity of 99mTc-ECD was evaluated by
developing the thin layer chromatography strips
(10 cm 9 1 cm), spotted with the samples, in ethyl acetate
and saline.

37 C for 14 days to observe the growth of aerobic and

anaerobic bacteria. Similarly, 1 ml of the Na[99mTc]TcO4
sample was also inoculated in soyabean casein digest
medium and maintained at 2225 C for 14 days to detect
fungal growth. The bacterial endotoxin test was performed
in accordance with USP XXV. The test was based on the
formation of gel clot in the sample by limulus amoebocyte
lysate (sensitivity: 0.125 EU/ml) reagent.

Sterility and bacterial endotoxin analysis

Scintigraphic imaging on normal rats
Sterility tests were performed according to the Indian
Pharmacopoeia (IP 1996 and IP addendum 2005) protocol.
In this test, 1 ml of the Na[99mTc]TcO4 sample was inoculated in fluid thioglycollate medium and incubated at

Imaging studies were performed on normal (male Sprague

Dawley rat, 200250 g) rats at Thakurpukur Cancer
Research centre (Regional Radiation Medicine Centre,

123

788

J Radioanal Nucl Chem (2014) 302:781790

Fig. 6 Hepatobilary function

study of a patient with 99mTcMebrofenin

VECC, Kolkata) under dual-head gamma camera (GE

Hawkeyes). The animals were injected via the femoral vein
of urethane-anaesthetised rats with a bolus containing
99m
Tc-radiopharmaceutical (18.5 MBq, 500 ll). They were
placed in a typical position for planar imaging under a
small field of view experimental gamma camera, suitable
for both planar and tomographic imaging. Image data were
obtained and analyzed using a gamma camera (GE
Hawkeyes) fitted with a low energy high-resolution all
purpose collimator using both static and dynamic procedures of the Xeleris (Functional Imaging) Workstation
system. For bone scan image was taken after 230 h post
injection. DTPA renogram was taken for 24 min dynamic
study. All the animal experiments were carried out in strict
compliance with the relevant national laws relating to the
conduct of animal experimentation.

Scintigraphic imaging on patients

Institutional Ethical Committee permission in accordance
with the guidelines provided by Indian Council of Medical
Research (ICMR) and Helsinki Declaration of 1975, as

123

revised in 2000 and patients consent was taken prior to

initiation of the human studies. For bone scan about
740925 MBq of 99mTc-MDP was injected in adult
patients and image was taken after 230 h post injection.
For thyroid scan 185259 MBq Na[99mTc]O4 was injected
and scan was taken for 1520 min. DTPA renogram was
taken by injecting 370444 MBq 99mTc-DTPA to a adult
patient for 24 min dynamic study. Hepatobilary scan study
was obtained by injecting 222259 MBq 99mTc-mebrofenin to an adult patient.

Results and discussion

The solvent extraction system and method were found to be
well suited for the low specific activity 99Mo, usually
obtained by the neutron irradiation of the readily available
and inexpensive oxide of natural molybdenum (MoO3).
This extraction technique may also used for separation of
99m
Tc from any types of low specific activity Mo. The
present work is directed towards an automated computer
controlled generator system based on solvent extraction
technique which provides serial online extraction of 99mTc

J Radioanal Nucl Chem (2014) 302:781790

as H[99mTc]TcO4 in MEK from aqueous alkaline (n, c)

Na2[99Mo]MoO4 solution and subsequent purification
through a basic alumina column and final recovery of
99m
Tc in normal saline. Basic alumina purifies 99mTc in
MEK by holding traces of 99Mo solution and sodium
hydroxide. MEK was evaporated under reduced pressure
and was collected in an ice cold trap. Technetium-99m
residue left in the evaporator was reconstituted with normal
sterile saline as Na[99mTc]TcO4 and collected in a sterile
vacuum vial after passing through 0.22 lm membrane filter
to obtain pharmaceutical grade 99mTc.
11.118.5 GBq of low specific 99Mo activity in 30 ml
5 N NaOH was extracted with 30 ml MEK. Nine batches
of 99Mo-Moly (Batch size: 11.1 or 18.5 GBq) were processed to recover pharmaceutical grade 99mTc using TCMAUTOSOLEX module. Fifty-two extractions of 99mTc
were attempted. Average yield of separation of 99mTc was
above 85 % (Table 1). 99Mo breakthrough in 99mTc pertechnetate was \0.002 %. The pertechnetate obtained was
clear solution, pH 67, radiochemical purity [99 %, MEK
content \0.1 % v/v, Al and Mo content\10 lg/ml. The R.
C. Purities of all 99mTc-radiopharmaceuticals were above
95 % (n = 10 for each radiopharmaceuticals) (Table 2).
The quality of pertechnetate solution obtained from this
generator system was found to meet all the requirements of
99m
Tc pertechnetate injection as specified in various pharmacopeia [24, 25]. The whole operation was carried out in
a closed cyclic system under aseptic and sterile conditions.
99m
Tc was collected after online filtration through 0.22 lm
filter. Pre-tested certified sterile reagents, vehicles, tubing
connection were used in the study. Several batches of the
product were made and found to pass the sterility and
bacterial endotoxin tests. Animal imaging studies with
99m
Tc-DTPA and 99mTc-MDP (three studies in each case)
were carried out to check the quality of 99mTc-pertechnetate obtained in the present module. Image with 99mTcDTPA is shown in the Fig. 3. Limited patient studies were
carried out with 99mTc-MDP, 99mTc-DTPA, 99mTc-mebrofenin and 99mTc-pertechnatate radiopharmaceuticals (at
least 10 studies in each case). Images with 99mTc-MDP,
99m
Tc-DTPA and 99mTc-mebrofenin are shown in the figures (Figs. 4, 5, 6). Imaging studies with all the radiopharmaceuticals confirm that the quality of 99mTcpertechnetate obtained in the present module is good
enough to formulate radiopharmaceuticals.
The process has several advantages
(i)

The whole chemical process is automated by

solenoid valve, hence there is little chance of
exposing the operator to radiation dose. The
overall assembly along with the electrical solenoid
valves can be conveniently used in hospital
radiopharmacy.

789

(ii)
(iii)

(iv)

(v)

(vi)

The used MEK after extraction may be reused for

next extraction, excluding the disposal problem.
As the organic and aqueous phase separation is
controlled by a conductivity detector there is very
less chance of MEK remaining in the aqueous
layer.
As the aqueous layer containing 99Mo after 99mTc
extraction is unloaded from the solvent extractor a
fresh loading of 99Mo/99mTc may be done for
another extraction and purification of 99mTc at the
same day. The absence of volume restriction
improves the versatility of the system.
The controller has been configured to include 16
actuators but the design modularity allows a scope
for extension without any major hardware
modifications.
The software provides online display of communication status and a time-stamped background log
of the actuator information that helps in easier
maintenance.

In summary the system simplifies the operation to a

greater extent by minimizing manual intervention while
enforcing strict adherence to embedded protocol, eliminating chance of wrong procedure. This is supplemented
with a failsafe approach at several levels of its design and
the economics of the system advocates high potentiality for
its application in nuclear medicine centre. The new generator system was developed with primary aim for separation of 99mTc from reactor produced low-medium
specific activity 99Mo. This process may also be used for
separation of 99mTc directly produced from 100Mo by (p,
2n) reaction in a cyclotron.
Conclusion
The presented automated module is simple to operate and
can be used to separate 99mTc radioisotope from low specific activity molybdenum. The studies made with patients
showed the good properties of the final product. As the
MEK is condensed back in the process, the module is ecofriendly in nature. Hence it can be concluded that the
module for separation of 99mTc from low specific activity
molybdenum-99 advocates high potentiality for application
in nuclear medicine centers.
Acknowledgments The authors gratefully acknowledge Dr. A. K.
Kohli, Chief Executive, Board of Radiation and Isotope Technology
(BRIT), Mumbai, India, Dr. D. K. Srivastava, Director, Variable
Energy Cyclotron Centre (VECC), Kolkata, India, Shri S. Saha, Head,
PSI, VECC and Shri G. Pal, Head, MED, VECC for their support. The
authors would like to acknowledge the International Atomic Energy
Agency (IAEA) for the support. The authors also acknowledge Shri S.
S. Sachdev, Senior General Manger, BRIT, Mumbai, Shri A. C. Dey,

123

790
Deputy General Manager, BRIT, Mumbai, Dr. S. Sarkar, Scientific
Officer, BRIT, Mumbai and Shri H. Shimpi, Scientific Officer, RMC,
BARC, Parel, Mumbai for their encouragement and valuable
suggestions.

References
1. Arano Y (2002) Recent advances in 99mTc radiopharmaceuticals.
Ann Nucl Med 16:7993
2. Bandoli G, Tisato F, Dolmella A, Agostini S (2006) Structural
overview of technetium compounds (20002004). Coord Chem
Rev 250:561573
3. Liu S (2008) Bifunctional coupling agents for radiolabeling of
biomolecules and target-specific delivery of metallic radionuclides. Adv Drug Deliv Rev 60:13471370
4. Verbeek P (2008) Report on molybdenum-99 production for nuclear
medicine 20102020. State of the art, Association of Imaging Producers & Equipment Suppliers (AIPES) report, November 2008.
https://www.oecd-nea.org/med-radio/docs/200902_AIPESMoly
SupplyReport.pdf
5. Radioisotopes in medicine (2008) Foresight of the use of reactor
isotopes until 2025. Technopolis report, December 2008. http://
www.technopolisgroup.com/resources/downloads/life_sciences/
EN_Radioisotopes_in_Medicine_final.pdf
6. Eckelman WC (2009) Unparalleled contribution of technetium99m to medicine over 5 decades. JACC Cardiovasc Imaging
2:364368
7. Srivastava SC (1996) Is there life after technetium: what is the
potential for developing new broad-based radionuclides? Semin
Nucl Med 26(2):119131
8. Boyd RE (1982) A molybdenum-99: technetium-99m generator.
Radiochim Acta 30:123145
9. Boyd RE (1987) Technetium generators: status and prospects.
Radiochim Acta 41:5963
10. Molinski VJ (1982) A review of 99mTc generator technology. Int
J Appl Radiat Isot 33:811819
11. Matyskin AV, Ridikas A, Skuridin VS, Sterba J, Steinhauser G
(2013) Feasibility study for production of 99mTc by neutron
irradiation of MoO3 in a 250 kW TRIGA Mark II reactor. J Radioanal Nucl Chem 298:413418
12. Guerin B, Tremblay S, Rodrigue S, Rousseau JA, DumulonPerreault V, Lecomte R, Lier JEV, Zyuzin A, Lier EJV (2010)
Cyclotron production of 99mTc: an approach to the medical isotope crisis. J Nucl Med 51(4):13N
13. Pillai MRA, Knapp FF Jr (2012) Molybdenum-99 production
from reactor irradiation of molybdenum targets: a viable strategy
for enhanced availability of technetium-99m. Q J Nucl Med Mol
Imaging 56(4):385399

123

J Radioanal Nucl Chem (2014) 302:781790

14. Evans JV, Moore PW, Shying ME, Sodeau JM (1987) Zirconium
molybdate gel as a generator for 99mTcI: the concept and its
evaluation. Appl Radiat Isot 38:1923
15. Chattopadhyay S, Das MK, Sarkar SK, Saraswathy P, Ramamoorthy N (2002) A novel 99mTc delivery system using (n, c)
99
Mo adsorbed on a large alumina column in tandem with
Dowex-1 and AgCl columns. Appl Radiat Isot 57:716
16. Chattopadhyay S, Das MK, Sarkar BR, Ramamoorthy N (2002)
Separation of pertechnetate from molybdate by anion-exchange
chromatography: recovery of 99mTc from (n, c) 99Mo and suitability for use in central radiopharmacies (CRPh). Radiochim
Acta 90:417421
17. Chattopadhyay S, Saha Das S, Das MK, Goomer NC (2008)
Recovery of 99mTc from Na2 [99Mo]MoO4 solution obtained from
reactor-produced (n, c) 99Mo using a tiny Dowex-1 column in
tandem with a small alumina column. Appl Radiat Isot
66:18141817
18. Morley TJ, Dodd M, Gagnon K, Hanemaayer V, Wilson J,
McQuarrie SA, English W, Ruth TJ, Benard F, Schaffer P (2012)
An automated module for the separation and purification of
cyclotron-produced 99mTcO4-. Nucl Med Biol 39(4):551559
19. Chattopadhyay S, Saha Das S, Barua L (2010) A simple and rapid
technique for recovery of 99mTc from low specific activity (n, c)
99
Mo based on solvent extraction and column chromatography.
Appl Radiat Isot 68(1):14
20. Chattopadhyay S, Barua L, De A, Saha Das S, Kuniyil R,
Bhaskar P, Pal SS, Sarkar SK, Das MK (2012) A computerized
compact module for separation of 99mTc-radionuclide from
molybdenum. Appl Radiat Isot 70(11):26312637
21. Klopper JF, Van Heerden PDR, Moller UD, Baards WP (1974) A
simple automated system for the routine production of 99mTc by
methylethylketone extraction. Afr Med J 48:998
22. Rabinson DG (1972) Impurities in 99mTc-sodium pertechnetate
produced by methylethylketone extraction. J Nucl Med
13(5):318320
23. Ramamoorthy N, Shivarudrappa V, Bhelose A (eds) (2000)
Hospital radiopharmacy practices. Radiopharmaceutical Committee (RPC) & Board of Radiation and Isotope Technology
(BRIT), Mumbai
24. United States Pharmacopeial Convention. (2005) Official monographs: USP 28, sodium pertechnetate Tc99m injection, United
States Pharmacopiea (USP) 28-National Formulary (NF) 23
25. British Pharmacopoeia Commission (2008) British pharmacopoeia, The Stationery Office, Norwich, UK. http://www.pharma
copoeia.org.uk/