Production of radioisotopes and radiopharmaceuticals at the Dalat nuclear research reactor

Nuclear Science and Technology, Vol. 4, No. 1 (2014), pp. 46-56

Production of Radioisotopes and Radiopharmaceuticals

at the Dalat Nuclear Research Reactor

Duong Van Dong, Pham Ngoc Dien, Bui Van Cuong, Mai Phuoc Tho,

Nguyen Thi Thu, Vo Thi Cam Hoa

Nuclear Research Institute,

01 Nguyen Tu Luc Street, Dalat City, Vietnam

(Received 5 March 2014, accepted 8 March 2014)

Abstract: After reconstruction, the Dalat Nuclear Research Reactor (DNRR) was inaugurated on

March 20^th, 1984 with the nominal power of 500 kW. Since then the production of radioisotopes and

labelled compounds for medical use was started. Up to now, DNRR is still the unique one in Vietnam.

The reactor has been operated safely and effectively with the total of about 37,800 hrs (approximately

1,300 hours per year). More than 90% of its operation time and over 80% of its irradiation capacity

have been exploited for research and production of radioisotopes. This paper gives an outline of the

radioisotope production programme using the DNRR. The production laboratory and facilities

including the nuclear reactor with its irradiation positions and characteristics, hot cells, production

lines and equipment for the production of Kits for labelling with ^99mTc and for quality control, as well

as the production rate are mentioned. The methods used for production of ¹³¹I, ^99mTc, ⁵¹Cr, ³²P, etc.

and the procedures for preparation of radiopharmaceuticals are described briefly. Status of utilization

of domestic radioisotopes and radiopharmaceuticals in Vietnam is also reported.

Keywords: Radioisotope; Radiopharmaceutical; Labelled KIT, Nuclear Medicine.

I. INTRODUCTION

put forward a limited radioisotope production

programme to support radioisotope application

in medicine, agriculture and industry. For this

objective the core of the present 500-kW

reactor reconstructed from the previous 250-

kW TRIGA MARK II reactor is equipped with

more neutron irradiation channels and with a

neutron trap for improving thermal neutron

flux. In addition, the reactor characteristics are

more useful as far as radioisotope production is

concerned, i.e. of higher excess reactivity, the

cadmium ratio in neutron irradiation channels

being rather high in the thermal neutron trap

and rather low in the fast neutron channels.

The establishment of a laboratory for routine

production of radioisotopes was carefully

considered by balancing the investment

requirement and the production technology of

choice, as well as the radioactive waste

treatment problem and radiation protection.

During the last 30 years of operation, the

DNRR has been successfully used for producing

many

kinds

of

radioisotopes

and

radiopharmaceuticals used in medicine and other

economic and technical fields. Providing about

400Ci per year of radioisotopes including I-131,

P-32, Tc-99m generator, Kit in-vivo and in-vitro,

Sr-46, Cr-51, etc. Each year, about 300,000

patients have been diagnosed and treated by

radioisotopes produced at DNRR that contributed

to push forward the development of nuclear

medicine in Vietnam.

In a developing country of low economic

level, the benefit of establishment of a nuclear

research center with a research reactor of low

power will be recognized by society only when

its contributions to social progress become

evident. This point of view has oriented us to

DUONG VAN DONG et al.

II. PRODUCTION OF RADIOISOTOPE

effective irradiation volume of trap will

increase a factor of 1.5.

AND RADIOPHARMACEUTICALS

A. Production laboratory and facilities

Construction of neutron irradiation positions

Due to the low power of DNRR we must

take into consideration of the irradiation

position construction, core management and

reactor operation mode in order to improve the

neutron flux, to maximize the volume available

for target irradiation and to balance the

formation-decay of activated radionuclides.

For the purpose of augmentation of

thermal neutron flux, the central irradiation

channel (so called neutron trap) was

surrounded by beryllium metal block of

thickness of 1.7 cm and height of 60 cm.

Fig. 1. Neutron plux depletion in target.

The effect of beryllium gave an

improving in flux and quality of thermal

neutron. As cited in Figs. 1 & 2, this neutron

trap has a diameter of 64 mm originally and

has only one guiding tube of diameter of 38

mm in the centre for holding the target

containers. This construction of neutron trap

has been found inconvenient in exhaustive

exploitation of irradiation volume. So it has

been proposed for reconstruction. The design

work is based on the fact of self shielding-

effect of targets and cooling water circulation,

as an example of this, neutron flux depletion in

TeO₂and MoO₃target under reactor irradiation

was noted in Fig. 1.

65cm

Old trap

New trap

Fig. 2. Neutron trap construction for the

optimization of effective irradiation

volume exploitation.

Irradiation techniques

As shown in the case of target sample of

diameter of 2 cm, the neutron flux in its center

dropped about 10 percent. This fact leads us to

design a neutron trap which is composed of

two channels of 24-mm diameter. The

sectional cut of old and new neutron trap was

shown in Fig. 2. With this new construction,

The targets held in the quartz ampoule

were irradiated with thermal neutron either in

the neutron trap at the center of the reactor core

or in the rotary specimen rack. For fast neutron

irradiation, it was carried out in a dry channel

inserted between fuel elements of the reactor

47

PRODUCTION OF RADIOISOTOPES AND RADIOPHARMACEUTICALS AT …

core. Before irradiation, the targets were

purified to remove traces of impurities.

radioisotopes of higher specific radioactivity,

such as ¹³¹I and Mo. Mo with high specific

radioactivity used for ⁹⁹Mo-⁹⁹Tc^mgenerator.

⁹⁹Mo was produced by neutron irradiation of

MoO₃target at the centre of neutron trap, where

thermal neutron flux is of highest value. The

distribution of neutron flux in an irradiation

position is a very important parameter for the

management of target irradiation.

99

Reactor operation schedule

The schedule of reactor operation mainly

depends on the kinds of radionuclide produced

and their role. The formation rate of these

kinds of radionuclides and the required

minimal specific radioactivity of radioisotopes

are indispensable factors to decide on the

option of reactor operation mode. The DNRR

was offered to produce some important

radionuclides for nuclear medicine application.

Among these radioisotopes, ¹³¹I and ⁹⁹Tc^m

isotopes are most highly evaluated. So the

reasonable schedule of reactor operation must

be chosen, taking into consideration of the

production yield and quality of ¹³¹I and ^99mTc

radioisotope products. Basing on the formation

rate under reactor activation and half life of

⁹⁹Mo and ¹³¹I radionuclides a reactor operation

schedule of 130-150 hrs of continuous run

every three weeks has been applied.

Fig. 3. Quartz ampoule and aluminum container

for containing target.

Reactor core management for the irradiation of

targets

The core management plays an

important role in the optimization of research

reactor utilization for production of

radioisotopes. The core management is based

on the nuclear reaction applied to produce a

predescribed radionuclides, the neutron

activation cross section and/or requested

specific radioactivity of a specified radioactive

products. Besides, the neutron flux and

characteristics of irradiation position such as

R_cd, neutron flux distribution were also taken

into consideration.

At the DNRR, the irradiation channel of

lowest cadmium ratio, R_cd=1.90 is used for

fast neutron irradiation to produce the

radionuclide with (n, p) nuclear reaction, such

as ³²S(n, p)³²P. ³²P isotope produced in this

channel is of high specific radioactivity and is

32

used for preparation of injectable P solution.

Meanwhile the rotary specimen rack of highest

cadmium ratio, R_cd= 4.5 is used for production

32

31

of P of low specific radioactivity with P(n,

γ)³²P reaction. This ³²P product was used to

prepare the ³²P applicators for skin disease

treatment. In the neutron trap of highest

thermal neutron flux and of R_cd= 2.93, the (n,

γ) nuclear reaction was applied to produce the

Fig. 4. Annual operation time at DNRR

since 1984 to 2013.

48

DUONG VAN DONG et al.

B. Production laboratory

The main utilization of the DNRR is the

in 1990 with 2 shielded cells ball-joint

manipulators (Fig. 7).

production of radioisotopes for nuclear

medicine, agriculture, sedimentology and other

scientific research. About 90 percent of time is

used for radioisotope production.

An area of 200 sq.m is reserved for a

rather limited programme of isotope

production. The facilities available for the

isotope production consist of one hot cell with

master slave manipulator (Fig. 5).

Fig. 6. ¹³¹I isotope production line equipped

in 2008 with 2 shielded cells.

Fig. 5. Hot cell with master slave manipulator

One ¹³¹I isotope production line

equipped by the IAEA TC Project VIE/0/002

in 1987 with 4 shielded cells, one ¹³¹I isotope

production line equipped in 2008 by the

National Project with 2 shielded cells ball-joint

manipulators (Fig. 6), and five shielded fume

hoods for isotope labelling and -emitted

isotope processing.

Fig. 7. ^99mTc generator production line.

All these facilities are connected with

the existing ventilation system of the reactor.

Equipment for the production of Kits to

be labeled with ^99mTc isotope and for the

quality control of radioisotopes and

radiopharmaceuticals was also supplied by the

National Projects (Figs. 8 and 9).

One ^99mTc generator production line

(using fission ⁹⁹Mo solution) equipped

under the IAEA TC Project No. VIE/6/016

49

PRODUCTION OF RADIOISOTOPES AND RADIOPHARMACEUTICALS AT …

60

65

- Other radioisotopes such as Co, Zn,

⁶⁴Cu, ²⁴Na, ⁸⁶Rb, ⁴⁶Sc, ⁷¹Ge, ⁵⁵Fe, etc., were also

produced in a small amount when requested.

C. Radiochemical processing of activated

targets

Iodine-131:

Iodine-131 is produced from the

irradiated tellurium dioxide in neutron trap.

The target of tellurium dioxide contained in a

welded aluminum capsule, according to the

nuclear reaction as follows:

Fig. 8. Sterile hot cell.

The irradiated tellurium dioxide powder

is transferred to a Vycor distillation vessel and

connected to the iodine-131 tellurium

processing system. The processing furnace is

heated up to 750^oC in order to distill the

iodine-131 over to a charcoal column trap

connected in-line of the distillation system.

The charcoal column trap is rinsed with the de-

ionized water then eluted with sodium

hydroxide 0.05N to form the final product of

iodine-131 solution. The scheme in Fig. 10

shows the flow chart of the operation and

procedures.

Fig. 9. Clean room.

Since the beginning of 1984 (the year of

reactor inauguration) up to now the

radioisotope production at the DNRR has

concentrated on the following radionuclides:

The target used in the production is an

analytical grade material of natural tellurium

as tellurium dioxide obtained from Fluka Inc.

The chemical purity of the target as TeO₂is

>95%. The specification of the target before

being fired in a muffle furnace through

analysis by emission spectrograph should

contain of selenium less than 0.05% and

heavy metals less than 0.1%. After being fired

in the muffle furnace the analysis should give

selenium less than 0.005% and heavy metal

less than 0.1%.

-

³²P in injectable orthophosphate

solution and ³²P applicator for skin disease

therapeutics.

-

¹³¹I in NaI solution.

- Mo-⁹⁹Tc^mgenerator.

99

-

⁵¹Cr in injectable sodium chromate

solution and Cr-EDTA.

50

DUONG VAN DONG et al.

Fig. 10. The flow chart of the operation and procedures of I-131.

Final product specification for use

^99mTc generator:

The final product as sodium iodide, ¹³¹I

solution in NaOH, without reducing agents will

be used as ¹³¹I bulk solution for

Among the two reactions of choice for

production of ⁹⁹Mo parent isotope, the large

investment for use of ²³⁵U(n, fission)⁹⁹Mo

reaction let us to opt for the ⁹⁸Mo(n, ) ⁹⁹Mo

reaction to produce ^99mTc generator.

radiopharmaceuticals

production.

The

specification of the final product is as follows:

In order to separate ^99mTc from its parent

Physical appearance: Colorless solution.

⁹⁹Mo we first used the MEK extraction method.

Radioactivity of ¹³¹I: more than 11.1

GBq (300 mCi) I-131/mL.

The inherent disadvantages of this

method compelled us to start our studies on the

preparation of gel type generators in late 1984

in the framework of the IAEA-CRP on the

“Development of ^99mTc generators using low

power research reactor”. This represents the

state-of-the-art for generator technology and

promises opportunities for both developed and

¹³³I content: less than 0.80% of the ¹³¹I

content at assay time.

pH: more than 11

Radionuclidic purity: ¹³¹I content more

than 99.9%.

Radiochemical purity: Iodidemore than 95%.

51

PRODUCTION OF RADIOISOTOPES AND RADIOPHARMACEUTICALS AT …

developing countries particularly with respect

to eliminating the need for fission ⁹⁹Mo. Two

directions of preparation of gel type generators

were studied:

⁹⁹Mo could be used to produce portable,

chromatographic type ^99mTc- generators which

have a good performance for application in

clinical investigations. Among the established

procedures the column loading procedure was

highly evaluated, because it proved to be

prominent figures for easy and safe operation,

for low cost of technology facilities, equipment

and for the capability to match the traditional

technology of the fission ⁹⁹Mo based ^99mTc-

generator production.

- Preparation

of

chromatographic

generators using zirconium molybdate (ZrMo) or

titanium molybdate (TiMo) column packing

materials synthesized from the neutron irradiated

molybdenum trioxide and the zirconium chloride

and/or titanium chloride, respectively.

- Preparation

of

chromatographic

DNRI had been proposed attending in

these studies program. The commercial

production of PZC generator through the

establishment of national project stage 2006-

2008 for the routine production of ⁹⁹Mo/^99mTc

generator. In this project the ^99mTc-generator

used PZC coming locally synthesis and from

generators using TiMo column packing material

(preformed TiMo) synthesized from the inactive

molybdenum compound and TiCl₄and

subsequently neutron activated in the reactor.

In both modes of preparation we have

carried out studies on three different options of

generators:

99

KAKEN - Japan as the column material, Mo

formed from MoO₃irradiated at DNRR, the

semi-automatic loading and adsorption machine

had studied, designed and installed in the hot

cells available. The generator assembly had also

been designed and fabricated, (Figs. 11, and 12).

- The chromatographic generator using

0.9% NaCl solution as eluant.

- The chromatographic generator using

organic solvent as eluant Solid-Solvent-

extraction).

- The chromatographic generator using dilute

saline as eluant and ^99mTc concentration column.

In the other hand, under the framework

of Forum for Nuclear Cooperation in Asia

(FNCA) program, the PZC based technology

for production of ^99mTc- generator has been

studied at DNRI as well as FNCA member

countries in the past several years.

PZC adsorbent of high performance for

⁹⁹Mo adsorption was easy to synthesize from

isopropyl alcohol (iPrOH) and ZrCl₄.

The procedures and relevant ^99mTc-

generator designs for the preparation of PZC

based ^99mTc- generators were successfully set

up. The columns of from 1.0 gram to 4.0 gram

weight of PZC and from 100 mCi to 500 mCi

Fig. 11. Schema of ^99mTc – Generator

Design of commercial PZC-^99mTc generator

52

DUONG VAN DONG et al.

sulfur. Our glass apparatus for this

production process is shown in Fig. 13. It can

be used for distillation either in the vacuum

or in the N₂gas flow by changing the upper

stopper of the distillation vessel. The

distillation parameters and post-distillation

purification of ³²P solution were adopted as

described in literature.

Fig. 12. The semi-automatic loading machine

In conclusion, it is strongly believed that

ZrMo, TiMo and PZC based generator play an

importance role as alternative technology for

production of ⁹⁹Mo/^99mTc generator from

reaction ⁹⁸Mo(n, γ)⁹⁹Mo. However these

methods were not very appropriate for the low

power research reactor as DNRR. Because of

those reasons, it is necessary to build a new

research reactor with power at least of 10 MW,

and the neutron flux is high enough to research

and produce radioisotopes.

Fig. 13. The glass apparatus for ³²P production

process using nuclear reaction ³²S(n, p)³²P

The ³²P applicators for skin disease

treatment were produced by neutron irradiation

of a soft plate preformed from cloth binder and

a covering mixture of red phosphorus and glue.

After irradiation in the reactor, the radioactive

plate was impregnated with plastic and covered

Phosphorus-32:

³²P isotope was produced according to two

nuclear reactions: ³²S(n, p)³²P and ³¹P(n, )³²P.

with Scotch adhesive.

The mechanical

strength of the preformed plate was not lost

under 75-hour irradiation in a thermal neutron

flux of 5x10¹²n.cm^-2.s^-1. Under this irradiation

a plate containing 65 mg P per square

The first reaction was used for the

production of injectable carrier-free ³²P

solution, the second for that of ³²P –isotope

applicators for skin disease treatment.

32

centimeter gives a radioactivity of 15 mCi P.

First the injectable ³²P solution of

radioactivity of ten mCi scale was produced

from irradiated MgSO₄target using magnesia

as absorbent to separate ³²P isotope from

MgSO₄solution. In the case of Ci scale

production, the large amount of waste

produced from this technology caused

The absorbed dose rate on the surface of the

plate of size 50 x 40 mm²was measured as 110

Rad.min^-1at the center and 75 Rad.min^-1on the

edge. Medical doctors’ experience over ten

years showed that with repeated treatment of

three or five 15-minute applications the

following diseases will be cured: Eczema, skin

cancer, bump scar, etc. At present more than

storage problems.

Recently, we have

32

75 Ci P in applicator form are used annually

introduced the distillation technique to

32

separate P from reactor irradiated elemental

in the country.

53

PRODUCTION OF RADIOISOTOPES AND RADIOPHARMACEUTICALS AT …

Cr-51 isotope:

chromatography techniques for chemical

purity, and the spectrometry and neutron

activation analysis for chemical purity.

The production of ⁵¹Cr isotope was

carried out based on the Szilard-Charmel

reaction using reagent grade K₂CrO₄target.

The chemical separation of recoiled ⁵¹Cr

nuclide was based on the selective adsorption

of this isotope on an inorganic ion exchanger

Si-ZrP (Silica gel supported zirconium -

phosphate) synthesized by us.

Biodistribution

(apyrogenity,

assay,

biological

toxicity)

tests

and

sterility,

physicochemical tests (pH, turbidity) are also

carried out regularly.

Other isotopes were also produced

when requested in small amounts for industrial

and agricultural applications. The methods for

production of these isotopes were selected

from investigation results or different reference

sources.

D. Production of Kits for labelling with ^99mTc:

In furthering the application of ^99mTc

isotope, the local availability of Kits for

labelling with ^99mTc plays an important role.

With IAEA support the basic equipment for the

production of Kits has been installed in our

laboratory. At present many kinds of in-vivo

Kits have been successfully prepared and put

to use in the country, they are Phytate,

Gluconate, Pyrophosphate, Citrate, DMSA,

HIDA, DTPA, Maccroaggregated HSA and

EHDP (1-hydroxy ethylidene-1, 1-disodium-

phosphate).

Fig. 14. HPLC system for QC.

III. LOCAL PRODUCTION VOLUME

AND DEMAND

These types of radioisotopes have

regularly been supplied to more than 25

hospitals in Vietnam two times per month. The

¹³¹1 radioisotope labelled radiopharmaceuticals

such as ¹³¹I-Hippuran; ¹³¹IMIBG have also

been regularly supplied to hospitals.

Radioisotope production rate is shown in Fig.

15 and Table I.

The studies on the preparation of

Radioimmuno-assay Kits and therapeutic

agents and/or radionuclides were also carried

out. The future production of the above

mentioned items is foreseen and planned.

In order to support the application of

^99mTc, ^113mIn, ¹⁷⁷Lu and ¹⁵³Sm radioisotopes in

clinical diagnosis and therapeutics, the

preparation of radiopharmaceuticals in Kit

forms has been carried out. The following Kits

have regularly been manufactured in DNRI:

Phytate, Gluconate, Pyrophosphate, Citrate,

E. Quality control

Radioisotope and radiopharmaceutical

quality control was carried out for all batches

of our products. The gamma spectrum analysis

DMSA,

EHIDA,

DTPA,

HSA

using Ge-Li detector coupled with

a

macroaggregated, HEDP, HmPAO, MIBI,

MDP.

multichannel analyser is used for radionuclide

purity control, the TLC, HPLC and gel-

54

DUONG VAN DONG et al.

Radioimmunoassay Kits: The RIA Kit

domestic market. Other RIA and IRMA Kits

can be supplied to end-users by dispensing

process based on the contract.

production and distribution programme have

also started. T3 and T4 Kits have been selected

locally by end-users with a share of 50% of

Fig. 16. Radioisotopes and Radiopharmaceuticals

produced at the DNRI

Fig. 15. Total activity of radioisotopes produced

at DNRI

Table I. The supply/demand for radioisotopes and diagnostic Kits in Vietnam.

Product

¹³¹I-

Supply

Demand at present

40-50 Ci/month

20-30 Ci/month

Diagnostic

and

therapeutic capsule/solution

^99mTc-Generator

10 generators (200-

500mCi/each)/month

40 generators (200-

500mCi/each)/month

³²P-Solution/

Applicator

Kits for ^99mTc-Labelling

MDP

50 Ci/month

400 Kit/ month

500 Kit/ month

300 Kit/ month

DTPA

200 Kit/ month

DMSA

PHYTATE

Orther

IV. THE APPLICATION OF LOCAL

PRODUCTS IN THE COUNTRY

- There are six centres of PET-CT and

cyclotron in Hanoi Capital and Ho Chi Minh

City.

- Number

of

nuclear

medicine

- Radiopharmaceuticals used in these

centres: Na¹³¹I solution and capsule, Sodium-

departments in Vietnam: 25

These departments almost are located in

the big cities of the country (Fig. 17).

(

^99mTc) pertechnetate (^99mTc-Generator) ¹³¹I-

Hippuran, Sodium-(³²P) orthophosphate, ¹³¹I-

MIBG, In-vivo Kits (MDP, DTPA, DMSA,

- Number of gamma cameras (planar

and SPECT): 22

55

PRODUCTION OF RADIOISOTOPES AND RADIOPHARMACEUTICALS AT …

ordination Meeting, Bandung, Indonesia,

(October 1987).

Phosphon, Glucon, Phytate, MAHSA, EHIDA,

HMPAO, MIBI, MAG-3, etc.).

[2] Radioisotope production and quality control.

Technical Reports Series No. 128. IAFA,

Vienna, (1971).

- Locally manufactured products take

about 50% of total market. In order to get a

higher market share now we increase the

production by loading generations with

[3] Le Van So, Investigation on the silica gel

supported form of micro crystalline zirconium-

phosphate ion exchanger and its applications in

chemical separation.

99

importing raw materials such as Mo and ¹³¹I

solutions.

I.- Preparation, ion exchange properties and

stability of Si-ZrP, J. Radioanal. Nucl. Chem.,

(Articles) 9 (1) 17-30 (1986).

[4] Le Van So, Richard M. Lambrecht,

Development of alternative technologies for a

gel-type chromatographic ^99mTc generator. J.

Labelled Compd. Radiopharm. 35:270 (1994).

[5] Ngo Quang Huy et al, Reactor physics

experimental studies on Dalat nuclear research

reactor, 50A-01-04 Research Project Final

Report, (1990) (in Vietnamese).

[6] Tran Ha Anh et al, Studies on Dalat Nuclear

Reactor Physics and Technique and on

Measures to ensure the safety and efficiency of

the reactor, KC-09-15 Research Project Final

Report, (1995).

[7] Nguyen Nhi Dien, Dalat nuclear research

reactor - status of operation and utilization,

Dalat Sym. -RR-PI-05, Dalat, (2005).

[8] Duong Van Dong, Status of Radioisotope

Production and Application in Vietnam, Dalat

Sym. -RR-PI-09, Dalat, (2009).

Fig. 17. Location of Nuclear Medicine Departments

in Vietnam.

[9] Duong Van Dong, Status of the study on PZC

based Tc-99m generator and potential of its

commercial production in Vietnam, Nihon

Genshiryoku Kenkyu Kaihatsu Kiko JAEA-

Conf, Journal Code: L2150A, page 25-29

(2007).

REFERENCES

[1] Le Van So, Production of ^99mTc isotope from the

chromatographic generator using zirconium-

molydate and titanium-molybdate targets as

column packing materials.

Research Co-

56