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Journal of Radioanalytical andNuclear ChemistryAn International Journal Dealing withAll Aspects and Applications of NuclearChemistry ISSN 0236-5731 J Radioanal Nucl ChemDOI 10.1007/s10967-014-3439-9

Development of multiple-elution cartridge-based radioisotope concentrator devicefor increasing the 99mTc and 188Reconcentration and the effectiveness of99mTc/99Mo utilisationVan So Le, Nabil Morcos & Zac Bogulski

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Development of multiple-elution cartridge-based radioisotopeconcentrator device for increasing the 99mTc and 188Reconcentration and the effectiveness of 99mTc/99Mo utilisation

Van So Le • Nabil Morcos • Zac Bogulski

Received: 4 August 2014

� Akademiai Kiado, Budapest, Hungary 2014

Abstract A self-shielded, sterile and cartridge-based

radioisotope concentrator device coupled to 99mTc/188Re

generators to increase the 99mTc/188Re-concentration of the

generator eluate was developed based on new aminoalkyl-

functionalized silica sorbent which conditionally catches

and release 99mTc/188Re to concentrate the daughter

nuclide of the generator eluates. The cartridge can be used

for multiple elutions with an overall concentration factor of

[100 and daughter nuclide recovery yield of[85 %. This

device can be used for 10 days extension of 99mTc-gener-

ator life-time, saving about 20 % of the generator activity

and for ‘‘early’’ generator-elution programs, under which

the generator is eluted at an optimized build-up time for

increasing the effectiveness of 99mTc/99Mo utilisation.

Keywords 99Mo/99mTc-generator � Radioisotope-

concentrator � 188Re

Introduction

99mTc is used in approximately 85 % of diagnostic imaging

procedures in nuclear medicine world-wide. 188Re is

important radio-therapeutic radionuclide. The expansion of99mTc and 188Re application depends on the generator

availability. However, the cost-effective utilisation of99mTc and 188Re generators and the quality of the generator

eluates are controlled by the 99mTc and 188Re generator

operation/elution management, which is determined by the99mTc and 188Re concentration in the generator eluate. The

injection dose activity of 99mTc- and 188Re-based radio-

pharmaceuticals delivered in 1 mL solution (99mTc- or188Re- concentration, MBq/mL) is an important factor in

determining the quality of 99mTc based SPECT imaging

diagnosis or 188Re-based radiotherapy, respectively. Gen-

erally 99mTc and 188Re eluates are produced from the

generators in fixed volume and the 99mTc and 188Re con-

centration of the eluates decreases with the life time of the

generators due to radioactive decay of parent nuclides99Mo and 188W, respectively. Consequently, the useful life

time of the generator is also a function of available 99mTc

and 188Re concentration of the eluate. Moreover, the 99mTc

also decays to 99Tc during his build-up from the decay of99Mo. This process not only reduces the effectiveness of99mTc/99Mo activity utilisation (i.e. a large quantity of99mTc activity is wasted and the generator is non-eco-

nomically exploited), but also it makes the specific activity

(SA) of 99mTc continuously decreased. The low SA may

cause the labelling quality of 99mTc eluate is degraded.

This means that the elution of the generator at a shorter

buildup time of the daughter nuclide will result in its better

labelling quality and more effectiveness of 99mTc/99Mo

activity utilisation. In contrast, the 99mTc elution performed

at shorter build up time (‘‘early’’ elution) will result a lower99mTc yield and thus yields an eluate of lower 99mTc-

concentration. These facts show that a high labelling

quality solution of clinically sufficient 99mTc concentration

could be achieved if the generator eluate obtained at an

‘‘early’’ elution is further concentrated by a certified

radioisotope concentrator device. Obviously, the radioiso-

tope concentrator may not only has positive impact on the

extension of useful life time of the generators, but also is

capable to increase the effectiveness of 99mTc and 99Mo

V. S. Le � N. Morcos � Z. Bogulski

Cyclopharm Ltd, Lucas Heights, Nsw, Australia

V. S. Le (&)

MEDISOTEC, Gymea, Nsw, Australia

e-mail: vansole01@gmail.com

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DOI 10.1007/s10967-014-3439-9

Author's personal copy

utilisation by performing the early elutions of the generator

at any time before maximal build-up of 99mTc. This fact

has been proved with the performance of the radioisotope

concentrator device developed at Cyclopharm Ltd, which is

reported in this article.

Experimental

Materials and methods

99mTc-generator was supplied from ANSTO (Australia).

Functional sorbent and strong cation exchange in silver

form were provided by MEDISOTEC and IC-Ag resin was

purchased from ALTECH Associates Aust Pty Ltd.

Radioactivity of 99Mo and 99mTc was measured using

Capintec radioisotope dose calibrator. Gamma-ray spec-

trometric assays were performed using an Ortec gamma-

ray spectrometer coupled with HpGe detector, which was

calibrated using a standard 152Eu radioisotope solution.

Radioisotope concentration process

A multi-elution, radioisotope concentrator device [1–3], in-

line eluted via evacuated-vial and through disposable

sterile filters was developed to increase the concentration

of 99mTc in the elution of aged commercial 99mTc gener-

ators. A self-shielded radioisotope concentrator device

(Fig. 1) was created based on a newly developed sorbent/

concentrator column which selectively retains 99mTcO4-

ions. 99mTc concentration is performed in two steps. First, a

standard elution of the generator through a tandem of: (1) a

competitive ion-selective (CIS) column (Silver-form of

strong cation exchange resin or IC-Ag resin) and (2) a

sorbent (Isosorb-FS-01) concentration column of the con-

centrator is performed with 5 or 10 mL saline. The Cl- and

MoO42- ions are retained on CIS column by forming a

stable AgCl and Ag2MoO4 precipitates, while 99mTcO4-

ions retained on the Isosorb-FS-01 sorbent by an anion

exchange reaction. 99mTc is then eluted from the concen-

trator column with \1.0 mL saline into an evacuated vial

through a Millipore filter and is ready for injection. The

design of the device in form of a disposable cartridge was

optimised to make elution process effective, simple, sterile

and radiation safe. Disposable cartridge was designed for

5–10 elutions.

The early elutions were also performed at the 6 h build-

up times to evaluate the effective utilisation of 99mTc

generator achieved with an early elution regime, for which

the 99mTc-yield ratio (Ry) factor was used as described in

the following sections. Gentech 99mTc generators of

110 GBq activities eluted with 10 mL saline was chosen to

test our radioisotope concentrator device.

Design of Concentrator Device [4, 5]

In general, the performance of the concentration process is

characterized with the concentration factor n,

n ¼ c2=c1

For a concentration process of solute recovery yield (k),

the following mass balance is established:

V2 � c2 ¼ k � c1 � V1

Relating the above equations, the following is derived:

n ¼ c2

c1

¼ k � V1

V2

where, V1 and V2 are the solution volumes before and after

concentration, respectively. c1 is the solute concentration in

the solution before the concentration and c2 is the solute

concentration in the solution after the concentration using a

given concentration process. In individual case of 99mTc

concentration, c1 is the 99mTc radioactivity concentration in

the eluate eluted from the 99mTc generator and c2 is the99mTc radioactivity concentration in the 99mTc solution

concentrated using a given concentration process.

All the chromatographic column concentration pro-

cesses are described by the following basic equations.

V1 ¼ Vm þ KS � S

where S ¼ mc � S and KS ¼ KW= S�

If V2 is given as a designed value, the concentration

factor (n) is evaluated based on the above equations.

Assuming the dead volume of the concentration column

Vm � V2), the concentration factor (n) is assessed for the

designing of the concentrator column as follows:

Fig. 1 Radioisotope concentrator device with standard accessories

a and the radioisotope concentrator device coupled with 99mTc

generator for in-line elution/concentration of 99mTc eluate b

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n ¼ k � V1

V2

¼ k � Vm

V2

þ KS �S

V2

� �� �¼ k � KS �

S

V2

� �

where, KS (mL/m2) and KW (mL/g) are the area and weight

distribution coefficients of the solute (99mTcO4-) in a given

sorbent-solution system, respectively; S is the surface area

of the sorbent loaded in the column (m2); mc is the weight

of sorbent loaded in the column (g); S is the specific sur-

face area of the sorbent (m2/g).

Results and discussion

Use of radioisotope concentrator for increasing

the generator life time

As a result obtained from our project, the 99mTc eluate

was concentrated more than 10-fold with a 99mTc

recovery yield of [85 % using this radioisotope concen-

trator device. The increase in 99mTc concentration in the

eluate enhances the utilisation of technetium in Technegas

generator-based lung perfusion (3.7–9.25 GBq/mL) and

other SPECT (740–1,110 MBq/mL) imaging studies. 10

or 20 repeated elutions were successfully performed with

each cartridge coupled to the 10 or 5 mL saline solution-

eluted generators, respectively. So, each cartridge can be

effectively used for 10 days in the hospital environment

for radiopharmaceutical formulation. This fact also shows

that when a bolus 99mTc-solution is needed to be con-

centrated, the concentration factor n = 50 can be

achieved. The useful lifetime of the 99mTc generator

(Table 1) was significantly extended from 10 to 20 days

for the generators of 11.1–111 GBq activity, respectively.

This means that about 20 % of the generator activity is

saved by extending the life time of the generator as

Fig. 2 Gamma-ray spectra of99mTc-solutions: a, Spectrum of

unprocessed 99mTc-generator

eluate; b, Spectrum of

concentrated 99mTc-eluate

Table 1 Effect of radioisotope concentrator on 99mTc-generator useful life

Radioactivity

of generator, GBq

Life time of generator useful for clinical

SPECT imaging (days)

Life time of generator useful for the Cyclomedica

Technegas Generator (days)

Without 99mTc

concentration

With post-elution

concentration of 99mTc

Without 99mTc concentration With post-elution

concentration of 99mTc

3.7 1 6 0 1

11.1 4 10 0 4

18.5 6 12 0 6

37.0 9 15 1 9

111.0 14 20 4 14

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shown in Fig. 4b. The 99Mo impurity in the 99mTc solu-

tion eluted from the Gentech generator was totally elim-

inated by this radioisotope concentrator device (Fig. 2).

Use of radioisotope concentrator in optimisation

of the generator elution to increase 99mTc-activity yield

and effectiveness of 99Mo utilisation [5, 6]

The radioisotope concentration process not only has posi-

tive impact on the extension of useful life time of the

generators, but also is capable to increase the effectiveness

of 99mTc and 99Mo utilisation by performing the early

elutions of the generator at any time before maximal build-

up of 99mTc.

The 99mTc activity yield of the generator can be

increased by performing an optimal regime of multiple

‘‘early’’ elutions (the generator is more frequently eluted)

combined with a process of 99mTc-eluate concentration.

The method for evaluation of the effectiveness of early

elution regime in comparison with a single elution

performed at maximal build-up time of the generator is

described as follows. For this evaluation, 99mTc-yield ratio

(Ry) is set up and calculated based on quotient of the total

of eluted 99mTc-elution yields (or 99mTc-activity produced/

used for scans) in all i elutions (Ei is the index for the ith

elution) divcan be increased by performing an optimal ided

by the maximal 99mTc-activity (A99mTcðMaxÞ which would be

eluted from the generator at maximal build-up time tMax:

Ry ¼Xi¼n

i¼1

A99mTcðEiÞ

,A99mTcðMaxÞ ð1Þ

Starting from the basic equations of radioactivity build-

up/yield A99mTc Maxð Þ� �

and time (maximal build-up time,

tMax) for attaining the maximal activity build-up yield of

daughter nuclide radioactivity growth-in in the radionu-

clide generator system, the equation for calculation of the99mTc-yield ratio (Ry) is derived as follows:

The decay scheme of 99Mo/99mTc system used in the

calculation processes is present as follows.

Fig. 3 Kinetics of radioactive

decay/99mTc-activity build-up in

the generator eluted with an

early elution regime: a, 99Mo-

activity; b, 99mTc-activity build-

up from beginning; c, 99mTc-

activity growth after first

elution; d, 99mTc-activity

growth/eluted at 6-h elutions; e,99mTc-SA in the system of99mTc-radioactivity build-up

from beginning

Fig. 4 a, Effectiveness of99mTc activity utilisation of the

generator eluted with an early

elution program compared with

that normally eluted at the time

point of maximal 99mTc-build-

up (The dashed line is

calculated using Eq. 8 and the

solid black circles are

experimental results); b,

Recovery of residual 99mTc-

activity of expired generators

versus their originally calibrated

activities

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Radioactivity of 99mTc nuclides in the generator:

A99mTc ¼ k99mTc � N0;Mo � b1 �kMo

k99mTc � kMo

� �

� ðe�kMot � e�k99mTctÞð2Þ

The maximal build-up time (at which the maximal99mTc-activity build-up/yield in 99Mo/99mTc generator

system is available):

tMax ¼ ½lnðk99mTc�=k99MoÞ�=ðk99mTc � k99MoÞ ð3Þ

Numbers of Tc atoms at build-up time t:

NTc ¼ N99Tc þ N99mTc ¼ N0;Mo � NMo

¼ N0;Mo � ð1� e�kMotÞ ð4Þ

Specific activity of carrier-included 99mTc in the 99mTc

generator system or 99mTc-eluate is calculated by combi-

nation of Eqs. 2 and 4 as follows:

SA99mTc ¼A99mTc

NTc

¼ 6:02213� 108

�k99mTcb1 ekMot � ek99mTct

� �k99mTc

kMo� 1

� � 1� ekMotð Þ

ðGBq=lmolÞ ð5Þ

99mTc-yield ratio (Ry) calculation for multiple early elution

regimes

The Ry value is calculated based on quotient of the

total 99mTc-elution yields eluted (or 99mTc-activity pro-

duced/used for scans) in all i elution numbers (Ei is the

index for the ith elution) divided by the maximal 99mTc-

activity A99mTc Maxð Þ� �

which would be eluted from the

generator at maximal build-up time tMax. The total 99mTc-

elution yields eluted in all i elutions is the sum of 99mTc-

radioactivities at different elution number i A99mTc Eið Þ� �

.

This amount is described as follows.

Xi¼n

i¼1

A99mTcðEiÞ ¼ k99mTc �Xx¼i�1

x¼0

hN0;Mo � e�kMoxtb � b1

� kMo

k99mTc � kMo

� �� ðe�kMotb � e�k99mTc

tbÞi

ð6Þ

The maximal 99mTc-activity build-up/yield in99Mo/99mTc generator system described using Eqs. 2 and 3

is as follows.

A99mTcðMaxÞ ¼ k99mTc � N0;Mo � b1 �kMo

k99mTc � kMo

� �

� ðe�kMotMax � e�k99mTctMaxÞ ð7Þ99mTc-yield ratio (Ry) is derived from the above Eqs. 6,

7 as follows.

Ry ¼

Pi¼n

i¼1

A99mTcðEiÞ

A99mTcðMaxÞ¼

Px¼i�1

x¼0

½e�kMoxtb � ðe�kMotb � e�k99mTctb Þ�

ðe�kMotMax � e�k99mTctMax Þ

ð8Þ

i is the number of the early elutions needed for a

practical schedule of SPECT scans. The build-up time

(tb) for each elution is determined as tb = (tMax/i) x is

the number of the elution which have been performed

before starting a 99mTc-build-up process for each con-

secutive elution. At this starting time point no residual

Tc atoms left in the generator from a preceding elution

is assumed (i.e. 99mTc-elution yield of the preceding

elution is assumed 100 %).

The results of the evaluation based on the Eqs. 2, 5, and

8 are described in Figs. 3 and 4a. As shown in Fig. 4a, the99mTc yield of the generator eluted with a early elution

regime of build-up/elution time \6 h increases by a factor

[2.

Table 2 Effectiveness of 99mTc elution performed with an early elution regime compared with that normally eluted at the time point of maximal99mTc-build-up

Elution time 8 AM Day 1 Day 3 Day 6

Early elution regime of

6 h 99mTc-buid-up time

(4 elutions/day)

99mTc-concentration (MBq/mL) 15,170.0 7,400.0–5,735.0 4,440.0–3,515.0 2,109.0–1,628.0

Total yield of generator elutions

per day (MBq)

15,358.7 25,289.5 15,540.0 7,292.7

Elution at maximal 99mTc-

build-up time (tMax = 22.86 h)

(One elution/day)

99mTc-concentration (MBq/mL) 3,071.0 2,331.0 1,435.6 673.4

Total yield of generator elution

per day (MBq)

15,358.7 11,655.0 7,178.0 3,370.7

Generator activity at calibration day (day 1, 8:00 AM) is 19.425 GBq 99Mo or 17.0 GBq 99mTc; Solvent is 5 mL saline; Generator is coupled

with Ultralute concentrator device; Final concentrated 99mTc solution volume is 1.0 mL

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With the utilization of 99mTc concentrator device which

give a final 99mTc-solution of 1.0 mL volume, the experi-

mental results reported in Table 2 using a *20 GBq

generator as an example confirmed that the concentration

and the yield of 99mTc solution eluted with a 6-h elution-

regime is much better than that achieved with the elution

regime performed at the maximal build up time (22.86 h).

The effectiveness of this early elution mode was also

confirmed experimentally in the prior-of-art of 68Ga/68Ge

generator [7].

Conclusions

We conclude that the radioisotope concentrator device

functioned well and is robust in operation. This device will,

to some extent, mitigate the global 99mTc crisis. The

extension of the 99mTc-generator life time can save about

20 % of the generator activity. 99mTc concentrator device

also allows performing an optimal regime of multiple

‘‘early’’ elutions, under which the generator will be eluted

at the time before establishment of radioactive decay

equilibrium in the 99mTc/99Mo system. This elution regime

will increase the 99mTc activity use and specific activity of

the 99mTc eluate by a factor of[2. All these features of the99mTc concentrator device benefit the economic use of the

generator for users, the improved quality of labelling/scan

for radiopharmacies, the reduced residual radiation dose of99Tc for patients, and the lowered cost of scan for patients.

Thus there is an increase in the effectiveness of 99Mo

utilisation.

References

1. Le VS, McBrayer J, Morcos N (2014) A radioisotope concentrator,

PCT International Publication Number WO2014/063198A1, http://

patentscope.wipo.int/search/en/detail.jsf?docId=WO2014063198&

recNum=1&office=&queryString=ALLNAMES%3A%28Le%2C

?Van?So%29&prevFilter=&sortOption=Pub?Date?Desc&max

Rec=7. Accessed 8 August 2014

2. Le VS, Morcos N, McBrayer J, Bogulski Z, Buttigieg C, Phillips G

(2013) J Label Compd Radiopharm 56(Suppl 1):S190

3. Le VS, Morcos N (2013) J Nucl Med 54(S2):609

4. Le VS, Le MK (2013) Australian Patent AU2013903629, 20

September 2013

5. Le VS, Do ZH, Le MK, Le V, Le NT (2014) Molecules. doi:10.

3390/molecules19067714

6. Le VS (2014) 99mTc Generator Development: up-to-date 99mTc-

recovery technologies for increasing the effectiveness of 99Mo

utilization. Sci Technol Nuclear Installations. doi:10.1155/2014/

345252

7. Le VS (2013) Rec Res Can Res 194:43–75

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