Reactor production of 32P for medical applications: an assessmentof 32S(n,p)32P and 31P(n,c)32P methods

K. V. Vimalnath • Priyalata Shetty •

A. Rajeswari • Viju Chirayil • Sudipta Chakraborty •

Ashutosh Dash

Received: 22 January 2014

� Akademiai Kiado, Budapest, Hungary 2014

Abstract The article describes a comparative study carried

out on the reactor production of 32P by two different pro-

cesses, namely, 32S(n,p)32P and 31P(n,c)32P with a view to

determine the merits and bottlenecks of each method and

assess the usefulness of 32P obtained from each of the pro-

cesses. In a typical batch, 250 g of elemental sulfur when

irradiated at a fast neutron flux of *8 9 1011 n cm-2 s-1

for 60 days, after chemical processing provided

about 150 GBq(4.05Ci) of 32P having specific activity of

200TBq(5500Ci)/mmole. On the other hand, irradiation of

0.35 g of red phosphorus at a fast neutron flux of

*7.5 9 1013 n cm-2 s-1 for a period of 60 days gave

75 GBq(2.02Ci) of 32P of specific activity 7 GBq(190mCi)/

mol-1. While the specific activity of 32P obtained from32S(n,p)32P is superior to that obtained from the 3lP(n,c)32P

process, the requirement of elaborate target processing steps

involving distillation and purification emerged as a deterrent

that limits its widespread adaptability. Both the production

routes offer 32P of acceptable quality amenable for medical

applications although their specific activity differs.

Keywords 31P(n,c)32P � 32S(n,p)32P � Distillation �Neutron irradiation � Red phosphorus

Introduction

Phosphorus-32 is an attractive and widely used radionuclide

for a variety of therapeutic applications owing to its favorable

nuclear characteristics. Phosphorus-32 is a pure b- emitter

with a maximum energy of 1.71 MeV and decays to stable 32S

with a half-life of 14.26 d days. The mean and the maximum

ranges of b- particles from 32P in soft tissue are 3 and 8 mm,

respectively. The fairly long half-life of 32P provides logistic

advantage for facilitating supply to places distant from the

reactor production site. Widespread applications of 32P have

not only accelerated the progress of radionuclide therapy, but

also offered numerous new therapeutic options. Phosphorous-

32 emerged as the radionuclide of choice for the treatment of

polycythemia vera and leukemia for a distinct subgroup of

elderly patients [1–8]. By virtue of its appropriate nuclear

characteristics, 32P has been identified as a useful radionuclide

for radiosynovectomy [9–14], preparation of radioactive

patches for the treatment of skin cancers [15–21], preparation

of radioactive stent to prevent in-stent restenosis following

coronary angioplasty [22–28] and in palliative care of painful

bone metastasis [29–33].

Phosphorus-32 as a clinically useful radionuclide has its

origin in 1936 at the Berkley cyclotron where E. Lawrence

produced 32P in the cyclotron following 31P(d,p)32P

[r = 0.18 9 10-27 cm2] nuclear reaction [34]. Increasing

clinical demand for 32P of quality amenable for in vivo

therapy led to the abandonment of cyclotron production

route and development of cost effective reactor production

method. There are three 32P reactor production methods

described in literature including 31P(n,c)32P, 32S(n,p)32P

and 36Cl(n,a)32P. In practice, 35Cl(n,a)32P production

method is not followed due to low production yield. The

remaining two options are widely used for the large scale

production of 32P in a cost effective manner [34–39].

Electronic supplementary material The online version of thisarticle (doi:10.1007/s10967-014-3115-0) contains supplementarymaterial, which is available to authorized users.

K. V. Vimalnath � P. Shetty � A. Rajeswari � V. Chirayil �S. Chakraborty � A. Dash (&)

Isotope Applications and Radiopharmaceuticals Division,

Bhabha Atomic Research Centre, Mumbai, India

e-mail: adash@barc.gov.in

123

J Radioanal Nucl Chem

DOI 10.1007/s10967-014-3115-0

Production of 32P following the 31P(n,c)32P route is straight

forward, offers the scope of using inexpensive mononuclidic

natural elemental phosphorus (31P) target material and needs a

very simple chemical treatment after neutron irradiation.

However, the poor thermal neutron capture cross section of

172 mb emerged as the major impediment that resulted low

specific activity product. The concomitant 33P production as a

result of double neutron capture [31P(n,c)32P(n,c)33P] during

target irradiation is negligible owing to the small thermal

neutron capture cross section of 32P. In order to tap the

potential of 31P(n,c)32P process, we have recently evaluated

its effectiveness to avail 32P in palliative care of painful bone

metastasis [32]. While the 32S(n,p)32P route of production

constitutes a successful paradigm of obtaining high specific

activities or no carrier added (NCA) 32P, the requirement of

fast neutron flux as well as low reaction cross-section (0.068

barns) emerged as the major impediment. In order to produce

few hundred MBq of 32P following this route, several hundred

grams of sulfur required to be irradiated. In order to evolve

holistic and long-lasting approaches to ensure sustainable

production of 32P, a thorough assessment of both the pro-

duction route deem worthy of consideration not only to

determine the merits and bottlenecks of each method but also

to evaluate the usefulness of 32P obtained from each of the

production process.

In the current paper, a comparative study on the reactor

production of 32P by two different processes on the basis of

the logistic advantages for production, robustness of the

irradiated target processing, production yield and genera-

tion of radioactive waste, have been reported. This inves-

tigation weighs the pros and cons of both the option, and

decides the quality of 32P that is most appropriate for a

given situation. The present study represents a part of our

on-going efforts to provide 32P of acceptable quality for

radiopharmaceutical applications to meet the domestic

needs and promote the beneficial use of 32P for therapy.

Materials and methods

Materials

Elemental sulfur and red phosphorus used as targets for

neutron irradiation were of greater than 99.9 % purity and

were procured from Sigma-Aldrich Chemicals Private Ltd,

Mumbai, India. All chemicals and reagents used in these

studies were of analytical grade and were procured from

Merck India Ltd, Mumbai, India. Paper chromatography

(PC) strips were purchased from Whatman, UK. Dowex 50

(1 9 8; 100–200 mesh) cation exchange resin was

obtained from Sigma-Aldrich Chemicals Private Ltd,

Mumbai, India. The pH of the solutions was determined

using pH indicator strips procured from Merck India Ltd,

Mumbai, India.

Equipment

A pre-calibrated ionization chamber (Beta-Gamma standard

type 1383A, General Radiological Ltd, England) was used

for the determination of radioactivity content of 32P. A well

type NaI(Tl) scintillation counter (Electronic Enterprises Pvt

Ltd., Hyderabad, India) was used to measure the activity of

chromatography paper strip during radiochemical purity

assay. Shimadzu UV-2401PC UV–Vis Spectrophotometer

(Shimadzu, Kyoto, Japan) with quartz cuvette of 1 mm path

length was used for the spectrophotometric determination of

P. The chemical analysis for the trace level of Al metal was

carried out using inductively coupled plasma-atomic emis-

sion spectroscopy (ICP-ES JY-238, Emission Horiba Group,

France). The radioactivity of 32P was also assayed using a

liquid scintillation counter (Tri-Carb 3100TR Liquid Scin-

tillation analyzer; Perkin Elmer, USA), calibrated for assay

of 32P. HPGe detector coupled with a multichannel analyzer

(MCA) (Canberra Eurisys, France) with a 1.5 keV resolution

at 1,333 keV and range from 1.8 keV to 2 MeV was used for

analysis of gamma emitting radionuclidic impurities.

Neutron irradiated targets were processed in a lead

shielding facility equipped with remote-operating devices,

as described in the supplementary data.

Experimental

Target irradiation

In a typical batch for the production of 32P by 32S(n,p)32P

route, there are 14 neutron irradiated Al container, each

contains 18 g of sulfur were used. Elemental sulfur target

(18 g of natural isotopic composition) was accurately

weighed, melted in a quartz ware and poured into cylin-

drical 1S aluminum container [22 mm (/) 9 44 mm (h)].

After sufficient cooling (solidification) of sulfur, it was

encapsulated by cold-pressure-weld and irradiated in the

Dhruva research reactor of our institution at a fast neutron

flux of *8 9 1011 n.cm-2.s-1 for 60 days. One batch of

radiochemical processing consists of sulfur target of 250 g.

For production of 32P following (n,c) route, about 0.35 g

of red phosphorus was accurately weighed, taken in an

aluminum container [22 mm (/) 9 44 mm (h)], encapsu-

lated by cold-press welding and irradiated in Dhruva

reactor of our institution at a thermal neutron flux of

*7.5 9 1013 n cm-2 s-1 for 60 days.

J Radioanal Nucl Chem

123

Processing neutron irradiated targets

Elemental sulfur

The distillation flask was connected to a receiver to collect

distilled sulfur. The sealed Al containers containing neu-

tron irradiated sulfur were cut open one by one remotely

and transferred to a funnel (receiver) over the distillation

flask. When heated to 120 �C, the irradiated sulfur melt,

becomes fluid and collected in the distillation flask. In

order to perform distillation at reduced pressure, the whole

distillation assembly was connected to a vacuum pump and

pressure in the distillation assembly was reduced to

1–5 mm Hg. The distillation flask was heated to 240 �C

and in this condition, complete distillation of sulfur was

achieved in about 4–5 h. Distilled sulfur was collected in a

receiver and kept for cooling to a period of 6 months for

reuse as target subsequent irradiation. After ensuring

complete distillation of sulfur, vacuum is released and the

distillation flask was cooled. About 250 mL 0.05 N supra

pure HCl was added to the distillation flask and heated to

*60–70 �C. Under this condition, the 32P activity depos-

ited in the flask was leached out and collected as H332PO4.

After sufficient cooling, the content of the flask (H332PO4)

was passed through an ion exchange column containing

cation exchange resin (Dowex 50 9 8 H?, 100–200 mesh).

The use of ion-exchanger column not only removes alu-

minumions but also other cationic impurities from the

product to render it free from cationic impurities. The

eluate containing H332PO4 was collected in a round bottom

flask, excess HCl was removed by evaporation to near

dryness using an infrared lamp and reconstituted in 0.05 M

supra pure HCl to obtain 32P-orthophosphoric acid (H3PO4)

solution of desired radioactive concentration (RAC).

Schematic representation of the distillation set up used for

the processing of neutron irradiated elemental sulfur target

is depicted in Fig. 1.

Elemental red phosphorus

The encapsulated Al container containing 350 mg of neutron

irradiated red phosphorus was cut open and irradiated target

was transferred to a 150 mL three necked round bottom

flask. About 10 mL conc. nitric acid solution (HNO3) was

added slowly through the funnel and heated to dissolve the

red phosphorus till a clear solution was obtained. About

5 mL of concentrated HCl was added to it and heated till near

dryness to expel nitric acid. The residue was then reconsti-

tuted in ultrapure water and heated to near dryness; this step

was repeated three times. Finally, 32P produced as 32P-

orthophosphoric acid (H3PO4) solution was filtered through

a G2 filter assembly and collected in a 150 mL round bottom

flask connected serially. Schematic representation of the set

up used for the radiochemical processing of irradiated ele-

mental red phosphorous target is shown in Fig. 2.

Radiological safeties adopted during the radiochemical

processing of neutron irradiated targets were described in

supplementary data.

Quality control of 32P

Activity measurement

Radioactivity content of 32P obtained from both routes

were measured using a pre-calibrated ion chamber and later

on, after appropriate dilution and sampling, by liquid

scintillation measurements as well. 1 mL of solution con-

taining 32P from the stock dispensed into a 10 mL glass

injection vial, sealed securely and was placed inside a well

type ionization chamber to record the ionization current ‘I’

from which the activity content ‘A’ was calculated using

the equation

A ¼ 1

eMBq

20 mLglass vial P as sodium orthophosphate

in aqueous solution

32

Suction

Sintered Filter

Heating coil

Extractionflask

Resistancefurnace

Neutron irradiated sulfur

Side arm

Heating coil

Vacuumpump

Sulfurreceiving flask

Sulfur

Waste

Sulfurtrap

Condenser

P leacheate32

Suction

Dowex 50ion exchanger

Heatingmantle

Evaporationflask

Suction

Waste

Concentrationflask

IR lamp

Condenser

( S + P)32*

Fig. 1 Experimental set up for the radiochemical processing of irradiated elemental sulfur target

J Radioanal Nucl Chem

123

where ‘e’ is the ionization factor of the ionization chamber

for 32P which is estimated or pre-calibrated as 8.4 9

10-15 A/MBq.

The calibration of ionization chamber was carried out

using 32P solutions whose radioactivity contents were

determined using a liquid scintillation counter (LSC).

While measuring 32P activity in an ion chamber, care was

taken to place the sealed vial containing 32P solution

(1 mL) inside the ionisation chamber with a dedicated

holder in the maximum response position of the measuring

volume.

Specific activity

Concentration of 32P in the radioactive sample was deter-

mined by spectrophotometric method utilizing a working dye

prepared comprising of malachite green, ammonium molyb-

date and tween 20. 12.7 mL working dye solution was pre-

pared by mixing 10 mL of 0.15 % Malachite green, 2.5 mL of

7.5 % Ammonium molybdate solution and 0.2 mL of 11 % of

tween 20. A measured aliquot from 1 M KH2PO4 solution

was suitably diluted to achieve concentration of 13.6 lg

KH2PO4 per mL (5 lL = 0.5 nmol). 100 lL working dye

was utilized in each reaction along with varying PO43- con-

centration (from 0.5 nmole to 5 nmole). A calibration curve

was obtained by using standard solutions having known

concentration of PO43- ions and measuring the optical density

at 620 nm wave length. The unknown sample containing

H332PO4 was measured and concentration of 32P was calcu-

lated from the graph. From the knowledge of activity and

concentration, specific activity of 32P was computed.

Radionuclidic (RN) purity

Radionuclide purity of 32P produced from both routes was

ascertained by half-life determination method. Calculated

amount of solution (approximately 30 lL) containing 32P

activity was measured in liquid scintillation counter for over

5 half-lives of 32P. The half life was calculated from a plot of

activity against time elapsed during radioactive decay.

In order to determine the presence of gamma emitting

radionuclide impurities, gamma ray spectroscopic analysis

of the appropriately diluted fresh 32P samples as well as

decayed samples (20 T1/2 of 32P) were carried out using a

high resolution HPGe detector system coupled to MCA

under appropriate geometrical arrangement. Several spectra

of aliquots drawn from batch control samples were recorded

at regular intervals of time and the RN purity calculated.

Radiochemical (RC) purity

The radiochemical purity of 32P was determined by paper

chromatography. The solvent-mixture of isopropyl alcohol

: water : 50 % trichloracetic acid: 25 % NH4OH in the ratio

75:15:10:0.3 v/v. respectively was prepared. Whatman

3MM paper (30 9 1 cm) was suspended over the solvent

system in chromatography jar for 30 min before spotting.

At the point of spotting, a drop of carrier mixture is placed

prior to analysis, which contains in 5 lL of solution,

phosphorus in the form of orthophosphate (5 lg), pyro-

phosphate (10 lg) and metaphosphate (10 lg). 32P activity

was spotted over the carrier and strip was immersed in the

solvent, monitored till the mobile phase traverse 250 mm

of the strip. The strip was removed, dried, cut into 1 cm

segments and each segment measured in NaI(Tl) scintil-

lation counter to ascertain the activity. A chromatogram

was constructed and radiochemical purity of the radio-

chemical preparation was calculated.

Chemical purity

The trace levels of the metal ion contamination in the 32P

samples were determined by ICP-AES analysis.

Target (Red P)dissolution flaskConc. HNO

Funnel forintroducingreagent

Vaccum orcompressed

air

P - H POin dil. HCl solution

32

3 4

Funnel forintroducingNaOH reagent

100 mLglass vial P as sodium orthophosphate

in aqueous solution

32

Vaccum

3

Heating mantle

G2 Filter

*

Fig. 2 Experimental set up for the radiochemical processing of irradiated elemental red phosphorous target

J Radioanal Nucl Chem

123

Results

32S(n,p)32P production process

Target

Neutron irradiation of elemental sulfur leads to formation of32P by the reaction 32S(n,p)32P. All the radionuclides produced

both by thermal and fast neutrons and their contributions are

described in Table. 1. With a view to diminish the radio

contaminants to an acceptable level, elemental sulphur was

distilled 3 times prior to neutron irradiation.

Processing of neutron irradiated sulfur

The motivation behind the selection of dry distillation

technique for the recovery of 32P from neutron irradiated

sulphur target has been elaborated in supplementary data.

Spurred by the perceived need to obtain high chemical

and radiochemical purity of NCA 32P and to recover the

sulphur target for subsequent irradiation, the scope of

achieving complete volatilization of sulfur is not only an

interesting prospect, but also viewed as the necessity.

While use of dry distillation technique has tangible bene-

fits, the prospect of performing distillation at a lower

temperature is a trustworthy proposition [37–39]. In order

to perform the distillation in a reasonable time, the effect of

negative pressure and temperature was hence considered

worthwhile investigating to arrive at the optimum condi-

tions [38–42]. The influence of negative pressure of the

distillation system on the time required to distill sulfur

applied at a temperature of 240 �C was examined and the

result obtained is illustrated in Fig. 3a. It is seen from the

result that it is possible to achieve complete the distillation

of sulfur when the negative pressure of the system is

maintained at a range of 0.1–1.5 mm of Hg. The role of

temperature of the distillation system maintained at a

constant vacuum of 0.5 mm Hg on the time required to

complete the distillation was studied and the result is

depicted in Fig. 3b. It is seen that working at a temperature

of 240 �C is sufficient to achieve complete distillation of

sulfur within 4 h (Fig. 3b).

Experimentally, it was seen that 4 h distillation at

240 ± 2 �C with a negative pressure of 0.5 mm Hg seems

to be sufficient to drain out the irradiated sulfur totally from

distillation flask to the receiver. In order to recover the

leftover 32P in the distillation flask, 250 mL of water as

well as different concentrations of supra pure HCl were

0.0 0.5 1.0 1.5 2.00

3

6

9

12

Tim

e fo

r co

mpl

ete

dist

illat

ion

of ir

radi

ated

sul

fur

(h)

Vacuum applied (mm Hg)

(a)

170 180 190 200 210 220 230 2400

2

4

6

Tim

e fo

r co

mpl

ete

dist

illat

ion

of ir

radi

ated

sul

fur

(h)

Temperature (°C)

(b)

Fig. 3 Rate of distillation of neutron irradiated sulfur a at different

reduced pressure at a fixed temperature of 180 �C; b at different

temperatures at a constant vacuum of 0.5 mm Hg

0 20 40 60 80 100 1200

1

2

3

4

5

6

7

8

<φ>th = 7.5x10

13

<φ>th = 5.5x10

13

<φ>th = 4.5x10

13

<φ>th = 3.5x10

13

<φ>th = 2.5x10

13

<φ>th = 1.5x10

13

Irradiation time (days)

Spe

cific

Act

iivty

32P

(m

Ci/m

g)

Fig. 4 Specific activity of 32P produced at the end of neutron

irradiation as a function of irradiation time at different thermal

neutron fluxes during the neutron irradiation of red P

J Radioanal Nucl Chem

123

used as leachant and the result obtained is shown in

Table 2.

It is seen from the result that water is ineffective for

quantitative recovery of 32P activity from the distillation

flask. Among the different concentration of HCl used,

0.05 N HCl seems to be the most efficient to recover 32P

activity quantitatively from the distillation flask and thus

prompted its use for subsequent production. Experimen-

tally it was seen that 250 mL 0.05 N HCl with gentle

heating at 80 �C for 3 h was found to be effective for the

quantitative recovery of 32P as H332PO4 from the distillation

flask. In the quest for an effective strategy for the quanti-

tative removal of radioactive cationic impurities from the

leachate, the scope of adapting ion-exchange chromato-

graphic method using a cation exchange resin seemed

sagacious owing to ability to retain cationic impurities

from H332PO4 solution.

Following the procedure described above, several bat-

ches of 32P were prepared. Results of 32P production

carried out from 5 typical batches are presented in

Table 3. The data represents the typical yields of the 32P

in regular batches. The relatively larger variations of yield

from batch to batch are mostly due to the differences in

the reactor irradiation conditions, such as the exact

duration, intervening shut-down, and the variation of fast

neutron flux level due to the power level of the reactor

operation. It was not practicable to normalize the reactor

irradiation conditions in the multi-purpose research reac-

tor. The specific activities of the 32P obtained from dif-

ferent batches were determined following the described

procedure. The specific activity of 32P always remains

[200TBq(5500Ci)/mmol. An important finding observed

from the results of Table 3 is that the specific activity

gradually gets improved as the batch number increases. In

view of the fact that recycled target is used for subsequent

irradiation, the purity of sulfur gradually gets improved

from batch to batch which in turn improve the specific

activity from the previous batch.

(n,c) 32P method of production

In light of the perceived need to obtain 32P having desirable

specific activity and yield, a thorough and systematic

optimization of irradiation parameters and radiochemical

procedures was consider worthwhile investigating.

Target

Stable phosphorus is mononuclidic 31P (abundance:

100 %), there is no direct competing reactions due to other

isotopes of phosphorus. Red phosphorus was chosen as the

target based on the reasons described in supporting data.

0 20 40 60 80 100 120

2

4

6

832

P S

peci

fic A

ctiv

ity b

uild

up

(mC

i/mg)

Irradiation time (days)

Fig. 5 Specific activity of 32P produced at the end of neutron

irradiation as a function of irradiation time at different thermal

neutron fluxes at thermal neutron flux of 7.5 9 1013 n cm-2 s-1

0 5 10 15 20 25 300

5000

10000

15000

20000

25000

30000

P2O74-

polyphosphate

PO43-

Act

ivity

(cp

s)

Migration from the point of spotting (Cm)

(a)

0 5 10 15 20 25 300

5000

10000

15000

20000

25000

30000

35000

40000

polyphosphate P2O74-

Act

ivity

(cp

s)

Migration from the point of spotting (Cm)

PO43-

(b)

Fig. 6 Paper chromatographic pattern of 32P in isopropyl alcohol,

water, 50 % trichloroacetic acid and 25 % NH4OH solvent system

a 32S(n,p)32P route and b 31P(n,c)32P route

J Radioanal Nucl Chem

123

Neutron irradiation

The yield and specific activity of 32P produced via (n,c) route

of production is primarily dictated by the neutron flux and

irradiation time. With a view to achieve optimum specific

activity, irradiation of phosphorus at a neutron flux of

7.5 9 1013 n cm-2 s-1 for a period of 60 days was carried

out. The details of optimization studies carried out are

described in supplementary data and specific activity of 32P

produced at the end of neutron irradiation as a function of

irradiation time at different thermal neutron fluxes during the

neutron irradiation of red P were depicted in Figs. 4 and 5.

Processing of neutron irradiated red phosphorus

The choice of HNO3 to dissolve neutron irradiated red

phosphorous target has been elaborated in supplementary

data. The chemical reactions primarily responsible for the

dissolution of neutron irradiated red phosphorus are

3 P þ 5 HNO3 þ 2H2O ! 3 H3PO4 þ 5 NO "P þ 5HNO3 ! H3PO4 þ 5NO2 " þ H2O

Excess of HNO3 subsequent to dissolution of red

phosphorus target was expelled by addition of conc. HCl

solution till evolution of brown fumes ceases.

HNO3 þ 3HCl! NOCl " þCl2 " þ2H2 "

Nitrosyl chloride (NOCl) further decomposes into nitric

oxide and chlorine.

2 NOCl gð Þ ! 2 NO " þ Cl2 "

Use of HCl for the destruction of excess HNO3 seemed

attractive since the reaction products are gaseous. Excess of

HCl was expelled by heating the solution to near dryness

followed by reconstitution in 5 mL of HPLC-grade water

so as to have minimum extraneous chemical impurities.

Several batches of 32P were produced making use of the

radiochemical processing procedures depicted in experi-

mental section and specific activity of products obtained

from each batches were determined following the descri-

bed procedure. Table 4 shows the results of five different

batches. Analysis of the results reveals that on an average

about *74 GBq (2Ci) of 32P having specific activity

*7 GBq (190mCi)/mmol could be easily produced from

0.35 g irradiated red phosphorus. The differences of yield

from batch to batch were attributed to the variation in the

reactor irradiation conditions.

Quality control of 32P

Recognizing the fact that 32P (32P-orthophosphoric acid)

produced by the two methods are for clinical use, a thor-

ough assessment of their quality is necessary to ensure that

they are of acceptable quality.

Activity measurement

The use of ion chamber for the determination of activity

of 32P solution seems to be an ideal proposition as the

high energy beta particles [Ebmax = 1.709 MeV] emitted

by the radionuclide is capable of producing ionization in

gas filled detectors. Experimentally it was ascertained that

the percentage deviation between activity measurement

values obtained by LSC and ionization current measure-

ment techniques lies within ±3.1 %. Routine determina-

tion of the activity 32P solution was therefore carried out

using well type ionization chamber due to operational

simplicity.

Specific activity

From the knowledge of total PO43- content determined by

colorimetric method as described in the experimental

Table 1 Radionuclide

production by natural sulfur

irradiation with thermal and fast

neutrons

Isotope of S Isotopic

abundance (%)

Activation products formed

Fast neutrons irradiation Thermal neutrons irradiation

Nuclear reaction Half Life Nuclear reaction Half Life

32S 95.02 32S(n,p)32P 14.26 days 32S(n,c)33S Stable33S 0.75 33S(n,p)33P 25.3 days 33S(n,c)34S Stable34S 4.21 34S(n,p)34P 14.4 s 34S(n,c)35S 87.2 days36S 0.02 36S(n,p)36P 5.9 s 36S(n,c)37S 5.05 m

Table 2 Effect of HCl concentration on the recovery of 32P (n = 5)

Sl. no. Extractant used 32P extracted (%)

1 Ultrapure water 41.45 ± 1.25

2 0.001 N HCl 51.41 ± 2.42

3 0.01 N HCl 81.52 ± 2.61

4 0.05 N HCl 89.68 ± 2.37

5 0.1 N HCl 79.82 ± 2.16

6 0.5 N HCl 78.35 ± 2.82

7 1.0 N HCl 79.64 ± 2.91

J Radioanal Nucl Chem

123

section and activity obtained from ion current measure-

ment, specific activity of 32P was computed for each batch

of products obtained from both the routes.

Radionuclidic (RN) purity

Radionuclidic purity of 32P solution obtained from both the

procedures after chemical processing step were [99.9 %.

Gamma ray spectrometric analysis results of decayed sample of32P availed from 32S(n,p)32P show that it is free from gamma

emitting radionuclide impurities. On the other hand, 32P availed

from (n,c)32P route shows the presence of 76As (t1/2 1.097 d),122Sb (t1/2 2.7 d) and 124Sb (t1/2 60.2 d) and their contribution

was 0.034 % (Table 5). Origin of radionuclidic impurities is

described in supplementary data as well as in Table 5.

Radiochemical (RC) purity

Experimentally it was demonstrated that 32P obtained from

both the process possess excellent radiochemical purity

([98 %) and exist as H332PO4. The radiochemical purities

as determined by paper chromatography is elaborated in

supplementary data. Paper chromatography patterns are

shown in Fig. 6.

Chemical purity

The level of metallic ions present as chemical impurity in

the 32P produced from both the process as determined by

ICP-AES was below detectable limit (0.1 mg/L, 0.1 ppm

for all the metal ions) thereby confirming their absence.

Quality control data of the 32P product radiochemical

obtained by both methods is shown in Table 6. It is

pertinent to point out that the qualities of the products

obtained from both the processes are amenable for med-

ical application although their specific activity differs.

The specific activity of 32P obtained from 32S(n,p)32P

method is far superior to that obtained from 31P(n,c)32P

route (Table 6).

Table 3 Yield of 32P produced

by neutron irradiation of 250 g

elemental sulfur

Batch no. Duration of

irradiation (days)

Neutron flux

(n cm-2 s-1)

Yield

[GBq (Ci)]

Specific activity

[TBq(Ci)/mmol]

RC

purity (%)

1 61 8.68 9 1011 147.3 (3.98) 204.7 (5534) 99.3

2 62 8.68 9 1011 149.9 (4.05) 207.4 (5606) 98.5

3 61 8.71 9 1011 144.3 (3.90) 208.2 (5628) 98.5

4 61 8.68 9 1011 138 (3.73) 213.9 (5780) 98.4

5 88 9.02 9 1011 165.4 (4.47) 225 (6081) 99.2

Table 4 Activity of 32P

produced by neutron irradiation

of 0.35 g red phosphorus

Batch

no.

Duration of

irradiation (days)

Neutron flux

(n.cm-2.s-1)

Yield

[GBq (Ci)]

Specific activity

[GBq(mCi)/mmol]

RC purity

(%)

1 70 7.1 9 1013 76.9 (2.08) 7.3 (197.5) 99.5

2 56 7.3 9 1013 74.3 (2.01) 7 (188.7) 99.1

3 77 7.5 9 1013 79.5 (2.15) 7.3 (198.4) 99.4

4 70 7.7 9 1013 78.1 (2.11) 7.2 (195.1) 99.6

5 63 7.8 9 1013 78.8 (2.13) 7.1 (190.9) 99.5

Table 5 Production of

radionuclide impurities during

the neutron irradiation of red

phosphorous

Radio-

nuclide

T1/2 Ebmax energy used

for assay

c peaks used for

assay

Method of formation of the radionuclides

keV % keV % Nuclear

reaction

Natural

abundance (%)

Reaction

cross section

76As 1.09 d – – 559.1

657.1

45

6.2

75As(n,c) 100 4.5 b

122Sb 2.7 d – – 564

692.9

70

3.82

121Sb(n,c) 57.21 5.9 b

124Sb 60.2 d – – 602.7

722.8

97.8

10.9

123Sb(n,c) 42.79 4.1 b

J Radioanal Nucl Chem

123

Discussion

The target for 32S(n,p)32P method is elemental sulfur

consisting of 32S (95.02 %), 33S (0.75 %), 34S (4.21 %) and36S (0.02 %) among which 32S is of interest and utility as

far as production of 32P is concerned. It is pertinent to point

out that the presence of other isotope of S in not a major

deterrent. On the other hand 31P(n,c)32P uses natural

phosphorus which is mononuclidic in 31P. While the use of

natural phosphorus rules out the formation of any other

activation products as radionuclidic impurities, the con-

comitant presence of As and Sb in ppm level lead to the

formation of 76As, 122Sb and 124Sb. Nevertheless, their

contribution is marginal (only 0.034 %). Both the methods

utilize inexpensive natural elemental sulfur as well as

natural red phosphorous. Amount of target required to

produce a given activity level of 32P is much larger in32S(n,p)32P method when compared with 31P(n,c) 32P

method. However, the target used in 32S(n,p)32P method

could be successfully recovered for recycling. The concept

of recycling sulfur target seemed to be attractive as it offers

economic use of precious S and at the same time provides

the scope of enhancing the specific activity of 32P.

The chemical processing of irradiated target in32S(n,p)32P method is not only an elaborate time consuming

distillation technology but also requires sophisticated pro-

cessing equipment as well as reliable trained workforce.

While the distillation method has the advantage of offering32P of high purity can be obtained since no reagents are added

during the separation of 32P from neutron irradiated sulfur,

the demanding requirements for the separation of few

micrograms of 32P from the bulk of 32S make it essential to

have a very high degree of robustness of the operational

systems. This is one of the reasons for most countries to

follow the soft option of purchasing commercially available32P in bulk for therapy. In order to realize the scope of irra-

diating target in the reactor, irradiation volume requirement

for 32S(n,p)32P route process is significantly larger than that

required for 31P(n,c) 32P path. The major advantage of31P(n,c)32P method lies in the simplicity of irradiated target

processing and economy on account of obviating the need for

complicated apparatus and skilled work force. Such target

processing is easy to perform as simple target dissolution

capabilities will suffice.

The most important factor to consider while selecting a

production route is the assessment of the quality of the 32P

which is crucial because it is meant for in vivo use. The

presence of long-lived radionuclidic impurities such as124Sb(T1/2 = 60.2 days) would curtail the useful life of the32P,as the proportion of the impurity in relation to 32P and

the consequent ill effects would increase with time. The

shelf life of 32P obtained from 31P(n,c)32P method would

thus be dictated by the extent of 124Sb contaminant. On the

other hand, for 32P obtained from 32S(n,p)32P route has

longer shelf life as it will be primarily governed by

radioactive decay of 32P alone.

There can be no doubt that 32S(n,p)32P production

method will continue to reign as the preferred option of

accessing higher specific activity 32P with minimum

radionuclide impurities. While the specific activity of 32P

obtained from the 32S(n,p)32P was, predictably, several fold

more compared to that obtained from 31P(n,c)32P method,

the latter was adequate not only for use in patients needing

palliative care of bone pain arising from skeletal metasta-

sis, but also suffice for the preparation of radiation syno-

vectomy agents and radioactive skin patches, with some

surmountable restrictions. At the same time, 32P obtained

from 32S(n,p)32P production method continue to serve for

the applications requiring high specific activity product.

Both the method of production generates negligible quan-

tities of radioactive waste. It is pertinent to mention that

either of the production method is not pitted against each

other, but instead, provide 32P for different purposes. Since

every institution has different scientific and technical

resources, each option will have a place for providing 32P

for a variety of clinical applications.

While the arguments put forth in this paper are not

meant to denounce the need for, or merits of, 32S(n,p)32P

production method, the prospect of utilizing 32P obtained

from 31P(n,c)32P production route for clinical applications

Table 6 Quality control of the H332PO4 produced from two methods

Tests Specifications (n,p) route (n,c) route

Identification Beta spectrum (absorption curve of

maximum energy 1.71 MeV

Matches Matches

Physical appearance Clear, colourless liquid Matches Matches

pH of solution Acidic 2 2

Radionuclidic purity 99.9 % 99.9 % 99.9 %

Radiochemical purity [95.0 % [98 % [98 %

Radioactive concentration C3.7 GBq/mL (100 mCi/mL) C3.7 GBq/mL (100 mCi/mL) C3.7 GBq/mL (100 mCi/mL)

Specific activity Report value 222 TBq (6000 Ci) mmol-1 7.0 GBq (190 mCi) mmol-1

J Radioanal Nucl Chem

123

has been scrupulously examined. However, we do not

believe that 31P(n,c)32P production will replace 32S(n,p)32P

production method used to obtain NCA 32P, and certainly

not in the near future, but will find a role in some area of

medical applications. Thus, production of NCA 32P using32S(n,p)32P route has remained as the procedure par

excellence and will continue to remain for the foreseeable

future.

Our pursuit to assess and evaluate the effectiveness of

two production route is driven mainly by considerations,

namely, (i) Optimum utilization of irradiation positions in

the operating research reactors of our institution; and (ii)

need to augment the production capacity of 32P to meet the

growing demands without addition of new processing

facility. In order to sustain the production and supplies of32P to medical users for the immediate future and for long

term requirement, the prospect of pursuing both the pro-

duction route for different therapeutic applications seemed

very attractive as it would augment the current production32P capacity to a significant level.

Conclusions

An attempt to provide a comparative assessment of two

reactor methods of production of 32P based on experi-

mental findings has been successfully accomplished. While

the quality of 32P obtained from 32S(n,p)32P and 3lP(n,

gamma)32P process are identical, the specific activity dif-

fers significantly. Despite the excitement involved in the32S(n,p)32P production route to obtain 32P of excellent

purity and highest possible specific activity, a major

deterrent to the adaptation of this process, is the require-

ment of elaborate remote handling facilities for target

processing steps involving distillation and purification.

Moreover, the requirement of appreciably larger quantities

of target is also a major disincentive as it will occupy large

irradiation volume in a reactor. The 3lP(n, gamma)32P

method of production is the least intricate and economical

route to access 32P with acceptable radionuclidic purity.

While the specific activity of 32P availed from this path is

significantly lower than that obtained with 32S(n,p)32P

method, it is adequate for use in metastatic bone pain

palliation in terminal cancer patients and radiation syno-

vectomy. Both the routes with favorable production

logistics with negligible generation of radioactive waste

and could be adapted (either alone or together) to access32P for different therapeutic use. The important details

available from this paper would be of considerable value

for other interested producers and countries having opera-

tional research reactors planning to pursue 32P production

strategy to meet their domestic requirement and for export.

Acknowledgments Research at the Bhabha Atomic Research

Centre is part of the ongoing activities of the Department of Atomic

Energy, India and is fully supported by government funding. The

authors expresses their sincere thanks to Dr. Gursharan Singh,

Associate Director(I), Radiochemistry and Isotope Group for his keen

interest, encouragement and administrative support.

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