Paper presented at 10SPLG, August 11-14, 2008, Angra dos Reis. Brazil

1. ENRICHMENT OF HEAVY OXYGEN ISOTOPES.
Gheorghe VĂSARU
National Institute for Research and Development of Isotopic
and Molecular Technology, Cluj-Napoca, ROMANIA
Aleea Tarniţa Nr. 7, Apt. 11, 400659 Cluj-Napoca , ROMANIA
e-mail: gvasaru@hotmail.com
I. Applications and needs of oxygen isotopes
Oxygen is a mixture of three stable isotopes:
(0.205 at. %), respectively.
16
O (99.757 at. %), 17O (0.038 at. %) and
18
O
Stable isotopes of oxygen have a wide range of applications in almost every natural and
physical science. The most notable uses of oxygen isotopes are in the fields of agronomy,
marine biology, environmental science, nutrition, biochemical research, medical diagnostics
and medical therapy. All three stable oxygen isotopes have medical applications:
16
O is used in the production of radioactive 13N which is used for Positron Emission
Tomography (PET)1/ imaging and myocardial perfusion.
17
O can be used as a tracer in the study of cerebral oxygen utilization. Compounds labeled
with 17O (nuclear spin I = 5/2) are used in Nuclear Magnetic Resonance (NMR) experiments.
Researches are currently exploring the use of 17O to provide improved lung images.
18
O is a key isotope because it is the raw material for cyclotron production of radioactive
isotope 18F (T½ = 110 min) used to produce 2-[18F] fluoro-2-deoxyglucose (18FDG)) - a very
important a tracer in PET.. To produce these scans 18FDG is needed. The synthesis of 18FDG
involves the production of 18 F in a cyclotron using 18O(p,n)18F nuclear reaction. Highly 18O
enriched water (95-97 at. % H218O) is used as favorite target material The major source for
the 18O for this reaction is highly 18O enriched water (95-97 at. %), The 18FDG is then
injected into patient´s bloodstream, being absorbed by body tissues, coloring diseased areas.
The PET scan is then performed on the patient.
Millions of these FDG-PET medical procedures are performed annually to investigate a
range of diseases in various human organs. 18O enriched water, (10%), is also used in medical
research for energy expenditure studies. This research measures the amount of food that is
being metabolized by a person and is often used in cholesterol research.
Demand for highly enriched 18O skyrocketed with the breakthrough of PET scans, in which
the compound is used by doctors to view soft tissue and bone images as well as respiratory
research for energy expenditure studies. This research measures the amount of food that is
being metabolized by a person and is often used in cholesterol research.
_____________________
1/
PET is an imaging technique which assists in the diagnosis of many diseases in areas
such as oncology, neurology and cardiology. PET allows the physician to examine the
whole patient at once, by producing pictures of the functions of the human body
unobtainable by other imaging techniques. . These images show body metabolism and
other functions rather than simply the gross anatomy and structures revealed by
conventional X-rays, CT or MRI scans.

2. PET is one of the most rapidly expanding areas of medical diagnosis. PET is routinely used in
determining the extent of tumor metastases, utilizing an analog of glucose in which the
hydroxyl group at the two positions is replaced by a radioactive fluorine atom. This
compound, 2-[18F] fluoro-2-deoxyglucose (FDG), is taken up in tissues in an amount very
similar to glucose, but is retained in the tissue unlike normal glucose, which is rapidly
metabolized largely to water and carbon dioxide. This retention of the radioactivity allows
visualization of tumors, which metabolize glucose to a greater extent than normal tissue. In
research studies, the glucose utilization of the tumors can be quantified. Due to the 110 min.
of 18F, this compound must be distributed from the regional centers. All of these centers
utilize enriched 18O to produce the fluoride used to make 18FDG. 18F is reacted with agents to
produce the radioactive drug used in medical diagnostic studies.
PET research studies have various applications that include cardiology, oncology, neurology,
pharmacology, and neuropsychology and cognitive neuroscience. (Sigma-Aldrich)
The PET scanning with the radiopharmaceutical (18FDG) is now generally accepted as a
method for measuring glucose metabolism
Demand for highly enriched 18O skyrocketed with the breakthrough of PET scans, in which
the compound is used by doctors to view soft tissue, and bone images as well as respiratory
and circulation functions. PET scans provide a more precise color image of the body in order
to diagnose tumors and other critical organ problems.
18
O is also used as a tracer for several biomedical applications. The two primary applications
are the study of organism energy expenditure and organ specific utilization of glucose.
With the growing demand for PET scans as a diagnostic tool for physicians, 18O water has
become increasingly important. This application accounts for the vast increases in world-wide
consumption of 18O:
H2O of 95 % 18O  PET ; 18O  18F
Production:
35 kg/an in 1997
600 – 1000 kg/an in 2004 of 120 – 200 mil. USD/y
D2O of 10 at.% 18O  Organisms energetic consumption studies
2. Separation of Heavy Isotopes of Oxygen
Research on the separation of stable isotopes and the investigation of their properties was
started 70 years ago. Up to 1955, however, research on the separation of the stable isotopes of
oxygen was limited to a laboratory scale.
In subsequent years (1955 – 1965) interest in these isotopes increased considerably. In many
laboratories throughout the world, complex investigation were started to develop effective
methods for their extraction and use in various field of science, industry and agriculture. In a
number of countries, specialized scientific research institutes were established.
Numerous studies in many countries have shown that distillation and chemical exchange are
the most promising methods for extracting the stable isotopes of oxygen. Starting in 1965, 18O
has been produced in yearly amounts within the range of several hundred grammas
New results obtained in biological and medical investigations with 18O as well as the success
in developing methods for measuring isotope composition (MS, NMR, spectrometry, etc.,)
have led to a new and greatly increased spectrum of isotope use.
The problem has therefore arisen of producing isotopes and labeled compounds in amounts of
hundreds of kg at considerably lower price.

3. In this connection in the last 40 – 45 years, attention has been focused on increasing the scale
of existing methods. In this period some very effective methods have been established for
enriching 17O and 18O. For example,
18
O - by low-temperature distillation of nitrogen oxide:
USA: 1,5 kg/y 18O (at concentrations of 95-98%);
USSR: 2,5 kg/y 18O (90%);
- by water distillation:
Israel, with a capacity of: 3 – 4 kg/y 18O (99%);
Germany);
- by cryogenic distillation of oxygen:
( Daniels, W.R. et al., England).
Principal methods of separation of oxygen isotopes in current use (1979):
16
O – Distillation NO, H2O at 99.98 – 99.99 at.% ; 1000s kg/y
17
O - Distillation NO, H2O at 20 – 40 at.%; 2 -5 kg/y
- Thermal Diffusion O2 at 96 at.%; 0.01 kg/y
18
O - Distillation NO, H2O, D2O at 90 – 99.99 at.%; 0.2 – 0.4 kg/y
At LANL large quantities of ICON’s are produced by low temperature distillation of
carbon monoxide and nitric oxide. The enrichment form, and price per gram of oxygen
isotopes are given below:
Isotope form, Enrichment Gram isotope/unit
Price ($/g of isotope)
-
Oxygen-16, 99.98%
Oxygen gas
Water
1.43/lt
0.888/g
Oxygen-17, 20-50%
Oxygen gas
Water
0.303 - 0.607/lt
0.179 - 0.358/g
Oxygen-18, 5-10%
Water
5%
10%
0.045 - 0.09
Oxygen-18, 90-99%
Oxygen gas
Water
1.45 - 1.59/lt
0.810 - 0.891/g
1.85
1.35
370.60
228.20
23.10
149.90
106.50
In Soviet Union (now Russia) the researches about distillation at low temperatures of NO has
been performed by Asatiani et al., in Tbilisi (1965, 1967) [49-50].. Using a two columns
cascade an enrichment of 18O at 90 at. % has been obtained. Later, (1977), an industrial pilot
plant for the distillation of nitric oxide has been constructed. The plants consisted of a profiled
stepped cascade formed of terraced separation columns with a total length of 40 m (diameter
and length of columns: 57 mm and 15 m; 32 mm and 13 m; 15 mm and 12 m respectively).

4. Distillation has been performed at a pressure a little above atmosphere. The production of 18O
was of several kg/y, at an enrichment of 85-90 at. %.
In 1977, a nitric oxide distillation plant at low temperature produced 3.8 kg/y of 18O at
concentration of 95 at. %).
In USA, the first three stages low temperature distillation of NO has been realized in 1965 by
Mc. Inteer et al. (cascade length: 57.5 m.; column diameters: 52.5 mm.,23.6 mm., 17.3 mm.,
respectively.). After a repeated rectification in a column of 5.8 m length and 10.9 mm in
diameter, has been attained concentrations of 98.2 at. % 18O and 8.3 at. % 17O respectively)
The first researches for enrichment of 18O by water distillation has been performed by
Dostrovsky in Israel [54}. The industrial plant for production of oxygen isotopes by water
distillation (of natural isotopic concentration) and thermal diffusion, has been constructed at
Weizmann Institute [1,55]. It consisted of two sections. The first, consisting of 27 columns
(inner diameter of 100 ÷ 17 mm., each with a length 0f 10 ÷ 15 m. Thermal diffusion section
consisted of 104 columns with an inner diameter of 12 mm and length of 1.5 m. The
production of this plant was of 5.5 kg/y oxygen at concentration of 98.5 at. % 18O and 0.9
kg/y of 20 at. % 17O respectively. Thermal diffusion section facilitated enrichments of 99.9
at. % 18O and 96 at. % 17O, respectively.)
In 1967, in the Karlsruhe nuclear research center (Germany) has been operated a waterdeuterated plant for enrichment of 17O and 18O. The research activity has been performed in
collaboration with norvey scientists [1,56]. The enrichment attained was 99.8 at % H 218O
and 99 at. % H217O respectively. The 18O has been obtained by rectification of molecular
oxygen. The separation factor was greater than in the case of water but smaller than for nitric
oxide.
In UK, Prochem Co. constructed a plant for production of 18O by rectification of molecular
oxygen [6] it consisted from columns with diameters of 37,5 ÷ 18,5 mm and 11 m length.
This plant permitted an enrichment of 25 at. % 18O.
In the period of 1960, for separation of oxygen isotopes has been proposed the exchange
chemical reaction NO – water: N16O + H218O <=> N18O + H216O of which elementary
separation factor was of only 1.02 [60]
After the discovery of the 17O and 18O isotopes, numerous attempts were made to obtain
oxygen containing materials enriched in these isotopes. These processes include fractional
distillation of water, of liquid oxygen, of carbon monoxide, of nitric monoxide or organic
liquids, thermal diffusion of oxygen, electrolyses of water, membranes, chemical exchange
reactions and laser methods.
Of all these processes only few have been found promising as methods of obtaining
considerable amounts of highly enriched oxygen isotopes. There are:
- fractional distillation of water,
- distillation of water combined with thermal diffusion of oxygen gas,
- cryogenic distillation of nitric oxide,
- fractional distillation of carbon monoxide and
- thermal diffusion of oxygen.
The latter process has yielded the highest concentration of 18O obtained, over 99.5 %. As a
consequence, however, of the low throughput of thermal diffusion columns this method is not
particularly suitable for the production of 17O and 18O in quantities of gram per day.

5. Process Materials. Water, oxygen and nitric oxide were considered as process materials. The
use of oxygen, instead water, involved a larger capital investment and offered few
compensating advantages. Nitric oxide was potentially attractive because of the relatively
large differences in the vapor pressures of its isotopic species. The equilibrium distillation of
water was tentatively selected as the method of producing high purity 17O.
.. The low temperature distillation of carbon monoxide has been used at Harwell (UK) for
many years and reasonable production of both 18O and 13C have been achieved. Dostrovsky et
al., have been studying the enrichment of oxygen isotopes by the fractional distillation of
water for over 10 years.
Fractional distillation of water has been a favorite process since early days of interest in 18O.
The first attempt at a relatively large scale production was made in 1936 by Huffman and
Urey who obtained some hundreds of grams of water enriched 5 times with respect to 18O.
Fractionating columns for 18O has also been constructed by Brodsky and co. and later by
Baertschi and Kuhn. After World War II, large quantities of 18O water of about 1.5 %
concentration became available in USA, presumably as a by- product of heavy water
production.
Industrial Pilot Plant for the production of
18
O
AIEA-Leipzig, 1977, Asatiani et al.
The growing demand for enriched 18O for scientific research with labeled atoms poses a
problem of industrial production. At the present, the distillation of nitric oxide at low
temperatures is the most economical and effective separation method. This process has very
good prospects for industrial production of both 18O and 15N as a consequence of the large
isotope shift in the vapor pressure associated with these isotopes.
The plant consists of a profiled tapered cascade formed of tapered separation columns with a
total length of 40 m. The plant has a condenser, and the cascade steps are connected by
intermediate evaporators. Distillation is performed at a pressure a little above atmospheric.
The plant produces several kg/year of 18O at an enrichment of 90 - 95 at. %. At the same time
it allows the production of NO enriched with 15N.
Production: ISI (Tbilisi, Georgia) NO distillation ----- 30 kg/y
Production of 17O and 18O by countercurrent distillation of reactor-grade heavy water
AIEA-Leipzig, 1977, D. Staschewski
Heavy water produced by electrolysis and distillation is a unique source for the extraction of
heavy oxygen isotopes. The pre-enrichment of these isotopes in reactor grade D2O (enriched
up to 1.4 at .% 18O and 0.12 at. % 17O by Norsk Hydro) was directly utilized in the Karlsruhe
separation plant, consisting of 4 distillation units with a total of 44 columns. The steamheated columns, mostly 12 m high, and 100, 34 or 12 mm in diameter contained the wellknown packing of oxidized phosphor bronze wire gauze. The pre-stage units yield products
enriched up to 20 at. % 18O and 1 at. % 17O which was fed to an intermediate cascade where
the final upgrading of 18O toward absolute isotopic purity and enrichment of 17O to a level of
10 at. % take place. Unlike these units the distillation facility for high concentrated 17O was
run with H2O as the holdup. Consequently the intermediately product enriched in 17O (
D217O) was converted by electrolysis into H217O. Electrolysis cells are also used to produce
chemical pure 18O2 gas from D218O for various syntheses.
The Karlsruhe separation process was a countercurrent distillation of heavy water at an
average temperature of 74oC and a pressure of 200 torr at the top of each column.

6. The considerable delay in the columns in water distillation places a serious limit upon the
speed of isotope enrichment. To produce high-grade 17O with a reasonable time, the input of
isotopes has to be increased by a more efficient basic unit. For this purpose a new basic
cascade consisting in an arrangement of 16 columns, consuming daily a total of 4000 kg of
steam has been take into consideration. A continuous feed flow of 800 liters of D 2O yearly
would yield a bulk isotope transport of 11 kg of 18O and 0.7 kg of 17O which are obtained as
separate products. The intermediate product enriched to 4 at. % 17O is to be fed immediately
to the present main cascade, where a second intermediate product enriched to 40 at. % 17O
would be available in steady-state operation which could be upgraded, after conversion, to
very high enrichment in the H2O distillation unit.
Osiashvili E.D. et al: Production of 18O- labeled water … Leipzig TC-90, 1977.
O isotopes have a wide applications in the various fields of science and technology. The
distillation of nitric oxide at low temperatures is the most effective and widespread method
for separating oxygen isotopes. In this case nitric oxide is enriched simultaneously with the
important oxygen and nitrogen isotopes.
However, oxygen isotopes in the form of nitric oxide have no practical application. For
scientific research and for solving some tasks in modern technology , oxygen isotopes in the
form of water are required. Water with changed isotope content is also an initial substance for
the synthesis of many compounds labeled with oxygen isotopes. In this purpose the reduction
of nitric oxide with hydrogen in the presence of various catalysts ( cobalt, nickel, platinum) is
performed.
D. Halliday et al. – The Use of SI in Medicinal Chemistry, (1978)
18
O was first produced commercially at the Weizmann Institute in Israel from the distillation
of water [54] and this method has subsequently been developed in combination with thermal
diffusion to have a capability of producing 18O at 99.9 at,% and 17O at 96 at.% [55].
At the Nuclear Research Centre at Karlsruhe (Germany) 17O and 18O was separated by
distillation of heavy water. This work was carried out in collaboration with Norsk-Hydro,
capitalizes on the fact that there was enrichment of heavy oxygen isotopes in the Norwegian
manufacture of heavy water [23]. In this plant, the feature of which has been described [56],
18
O was produced at 99.9 at.%. Intermediate product was converted into H 2O and fed to a
distillation unit in order to produce useful enrichments of 17O (approaching 30 at. %). Water16
O (depleted in both 17O and 18O) was produced at 99.99 at. % 16O.
The separation of 16O,
Alamos (USA).
17
O and
18
O by cryogenic distillation of nitric oxide was used at Los
Cryogenic distillation of oxygen is an effective method of producing 18O economically at
lower enrichments (25 at. %). The method is limited by the fact that 16O in the feedstock is
present as 16O and 18O. By randomization of the molecular species, for example by heating,
higher enrichments could be attained [26]. The technique provides a ready source of depleted
material (16O2).
Leipzig 1977. Many interesting developments are to be expected in the applications of stable
isotopes of oxygen, particularly 18O. For this purpose is necessary the increasing availability
of this isotope at lower cost. Fortunately, for many applications in the life sciences, it is not
necessary to use very pure 18O. Enrichment to 90 % or even 75 % is high enough in most
cases. When using 18O, however, care has to be taken because of the tendency of this isotope

7. to undergo exchange reactions. Activation analysis seems to be a very promising method for
the determination of this isotope.
18
O also has important applications in connection with the study of cells and tissues by NMR
methods, e.g. for the investigation of the nature of water in normal and cancerous cells.
Steps :
- Determination of elementary separation factor for distillation of different compounds
containing oxygen. For practical purposes: NO, O2 and water
- Elaboration of technological processes which use these compounds.
- The first paper relative to simultaneously production of 15N, 17,18O was of Clusius and
Schleich) (1958, 1961) [47-46]
Leipzig 1977: Summary Report
In recent years there has been a pronounced increase in the use of stable isotopes in the life
sciences, particularly oxygen isotopes. This is due to the increased availability of these
isotopes in a wider variety of useful chemical forms and the increase in the sensitivity,
selectivity and reliability with which these isotopes can be analyzed by mass spectrometry,
optical emission spectroscopy, nuclear magnetic resonance spectroscopy and other methods.
Current status and present problem. Substantial progress has been made in the recent years in
developing methods for separation of stable isotopes of oxygen. Until 1977, the principal
methods of separation of 16O, 17O in current use was distillation of NO, H2O, (enrichment of
product: 99.98-99.99 at. % for 16O and 20-40 at. % for 17O at a world production of 1000s,
respectively 2-5 kg/y)..For the 18O - distillation of NO,.H.O,.D2O at enrichments of 90-99.99
at. % and a production of 15-20 kg/y.
Despite the fact that separation methods for oxygen isotopes are fairly well advanced, it is still
of interest to consider how costs may yet be further reduced. The main possibilities are (1) the
further optimization of process in existing plants, (2) the design of new separation plants,
perhaps based on new compounds and additives, and (3) increasing the scale of production.
The separation of oxygen isotopes is best carried out in large industrial-type units serving a
wide geographical area.
3. Commercial Heavy Oxygen Isotopes Producers in the World:
ICON - Los Alamos National Laboratory (LANL).
LANL pioneered the process of stable isotope production using the cryogenic distillation
separation method in the late 1960’s.: 17O and 18O was produced by cryogenic distillation of
nitric oxide at ICON plant.
At LANL large quantities of ICON’s are produced by low temperature distillation of carbon
monoxide and nitric oxide.
Production: ICON, Los Alamos National Laboratories, USA:
NO distillation -------------------------- 13 kg/y
ICON 2001 - Lease agreements has been signed between the Department of Energy, the Los
Alamos Commerce and Development Corp. and Spectra Gases of New Jersey. These will
pave the way for a private company to begin producing the potentially life-saving stable
isotopes of 17O and 18O for the U.S. market. Production will occur at the Laboratory's ICON
facility. ICON stands for isotopes of carbon, oxygen and nitrogen.

8. The company plans to upgrade some of the equipment at the ICON facility before beginning
production of carbon and oxygen isotopes. 17O and 18O will be produced by cryogenic
distillation of nitric oxide, while 13C will be produced from carbon monoxide.
LANL developed isotope separation using NO distillation technology. ISOTEC acquired
the technology for commercial use. Sigma–Aldrich purchased the ISOTEC
facility in 2001 from Matheson Gas Products.
Sigma–Aldrich reported that all nitric oxide has been removed from column N6
and that NO distillation has ceased at the ISOTEC facility.
Conclusion: Successful research has shown that kilogram quantities of the isotopes of oxygen
(ICONS) will be needed for clinical applications concerned specific diagnostic tests and organ
dysfunction. As compounds labeled with oxygen become less expensive and commercially
available, it is expected that biomedical applications of these isotopes will increase.
R. DeWitt – Enriched Isotope Applications: Biomedical Field, 1979 (ICON)
Enriched isotope applications in the biomedical field could require isotopes in gram to
kilogram quantities. For the stable isotopes now available in large quantity at reasonable cost,
such as the isotopes of oxygen, large clinical applications are either in the process of being
established or are in the development stage.
The recent proliferation of particle accelerators in hospitals, universities, and
radiopharmaceutical firms, along with widespread acceptance of the clinical use of
accelerator-produced radionuclides, can greatly accelerate the increased need from gram to
kilogram quantities of enriched stable isotopes of oxygen.
Note: By definition, a stable isotope is one with very long half-life (greater than 1010 yr). That
stable isotopes are often used as feed material (enriched isotope targets) to prepare radioactive
isotopes by nuclear transmutation.
Oxygen isotopes are found in varying amounts in human body, the amount of which depends
in general, upon their concentrations in local soli, food, and atmosphere. They are of interest
because of their essential role in the life process.
Principal methods of separation of oxygen isotopes in current use (1979):
16
O – Distillation NO, H2O at 99.98 – 99.99 at.% ; 1000s kg/y
17
O - Distillation NO, H2O at 20 – 40 at.%; 2 -5 kg/y
- Thermal Diffusion O2 at 96 at.%; 0.01 kg/y
18
O - Distillation NO, H2O, D2O at 90 – 99.99 at.%; 0.2 – 0.4 kg/y
Cambridge Isotope Laboratories (CIL).
CIL (U.S.): 18O - water distillation plant located in Xenia, Ohio. The expanded plant produces
250 Kg/y of 18O used for the production of FDG in the PET industry and in other medical
research.
CIL Xenia Ohio USA CIL has been producing 18O - water for the
PET community
since 1996.
December 18, 2002 Groundbreaking Ceremony for CIL Isotope Separations, Inc.
Another 18O Facility Expansion
In January 2000, CIL announced construction of the world's largest isotope separation facility
for the production of highly enriched 18O.
CIL has made this commitment in order to provide a solution for the current shortage of 18O water. Increasing demands for highly enriched (96 at. %) 18O water have come from the
international PET community and for 10 at. % 18O - water from the metabolic research

9. community. By building this new facility, CIL hopes to ensure that ample supplies of 18O will
be available for all important research needs and diagnostic efforts for the foreseeable future.
Production: CIL (Cambridge Isotope Laboratories), Xenia, Ohio, USA:
Water distillation ---------------------- 250 kg/y
Global Scientific Technologies (GST).
GST, is a St. Petersburg, Russia - based manufacturer of 18O used to produce PET
radiopharmaceuticals. GST is one of the world’s largest producers of 18O .
GST is main producer of 18O - water. GST was established in 1995. Situated in Sosnovy Bor
town, near Saint- Petersburg, Russia. The company is standing for developing of global
scientific research. GST have a great experience in producing 18O - water. GST is one of the
world's leaders in producing 18O - water used in PET. GST is close connected with leading
Russian Physical and Medical Institutions, such as Institute of Human Brain, Central
Radiological Institute, V.G. Khlopin Radium Institute (Saint- Petersburg) , Russian Research
Centre Kurchatov Institute, Central President's Moscow Hospital, Backulev Cardiological
Center. GST has been working for a long time with ISONICS Corporation (USA, Colorado).
Global Scientific Technologies CMR-GST is one of the world leaders in production 18O
enriched water. Situated in Sosnovy Bor Town near St.Petersburg, Russia. 18O - water used in
cyclotron target for production of 18F labeled compounds for PET. Everywhere it obtained the
highest appreciation for quality and the highest yield for FDG (Fluorodeoxyglucose). The 18O
- water has more 97.0 at. % isotope enriched 18O.
Current production quality control of provided on plant's laboratories in Sosnovy Bor. Final
quality control and issue of Quality Certificate made in Moscow independence laboratories of
Kurchatov Institute and Moscow State University.
Production of 18O - water is made over 10 years and annual volume reaches 80 kg. And
supplied to head's PET centers of US, Europe and Asia.
.
Separation of mixture H216O and H218O carried out in a series of distillation columns. Each
column consists of cube-evaporator and self-column with special packing, condenser, and
upper reservoir. Steam lift up in the column and interact with water which floating down the
packing in film form. At that stage occurs mass exchange process. When steam is getting
depleted and steaming down water enriches with high boiling point compound H 218O.
Enriched water till 97 at. % 18O - water passes stage of purification of deuterium
(normalization) till such physics-chemical parameters that meet requirements of using in PET
centers.
In the heart of method purification lies decomposition of water on 18O and hydrogen, with
next purification of 18O and synthesis of 18O - water from 18O and purified hydrogen, received
from natural water.
Main parameters of enriched 18O - water are tested routinely during the production process.
The quality of each final batch of 18O - water tested in independence laboratories that have
international certification. For each batch independents laboratories make new quality
certificate and signed by heads of this laboratories.
The isotope content on a gas was determined by mass spectrometer ionization impact МИ1201В. Accuracy for 18O is ± 0.2 at. %, for enriched higher than 80 at. %.
4. ISOTEC (US).
Was the first commercial company to build and maintain cryogenic distillation columns for
the separation of 18O. ISOTEC is also the first commercial company to build and maintain

10. thermal diffusion columns for the production of noble gases and oxygen isotopes. It
continually explores alternative separation methods such as laser separation and chemical
exchange. ISOTEC is the largest commercial producer of 18O – water and gas by cryogenic
distillation of nitric oxide since 1985 at concentrations up to > 99 at. %.
ISOTEC has the world’s largest 18O production capacity, and has been enriching 18O by
cryogenic distillation of nitric oxide since 1985.
ISOTEC has started construction of additional 18O capacity to greatly increase its total
production of 18O isotope to meet worldwide demand.
ISONICS Corporation (Nasdaq:ISON).
Is the world’s second largest supplier of 18O.
18
O represents ISONICS single largest product line and is used in medical cyclotrons to
produce the primary radioisotope currently used in PET. Due to its ability to identify and
localize areas of high metabolic activity, PET has been demonstrated to be one of the most
powerful tools in the fight against many types of new and recurrent cancers. The demand for
18
O continues to grow rapidly as the number of approved clinical procedures increase and
insurance reimbursement treatment remains favorable. As the tight supply situation currently
existing is likely to persist for the next several years, ISONICS will continue its aggressive
efforts aimed at quickly increasing its production capacity.
6. ROTEM Industries Ltd. (Israel)
Is the world largest manufacturer of 18O - enriched water, an intermediate bulk material used
in a cyclotron water target in the production of 18F labeled compounds for PET diagnostics in
nuclear medicine.
The process used for the enrichment of the 18O and 17O isotopes of oxygen is water
fractional distillation
Use is made of the very slight difference in the vapor pressure of the isotopic forms of water.
Fractional distillation is carried out in a series of distillation columns, each filled with a
special, proprietary packing endowing it with a very high separation power.
The enrichment is carried out in stages, enabling ROTEM to offer water of any desired
enrichment level , from 2 at. % to 95 at. % .
After distillation, which enriches the water also with deuterium oxide, a normalization step
takes place, where the water is electrolyzed and the resulting 18O gas is reacted with electronic
grade hydrogen to re-form water of extremely high quality.
For the 95 at. % 18O - water, mostly intended for PET, a further purification process
combining ultra - filtration, distillation and terminal heat-sterilization is carried out in a
controlled environment to produce sterile and non-pyrogenic water.
ROTEM Industries Ltd., Israel 18O output was increased to 120 kilograms in 2003 and
250 kilograms in 2005.
Production: ROTEM Industries , Israel:
Water distillation ----------------------250 kg/y
7. MARSHALL ISOTOPES Ltd. (Israel)
The technology used in the plant is the fractional distillation of water; main products - the
95% and the 10% 18O-enriched water, respectively.
MARSHALL ISOTOPES Ltd. (Israel) founded in 1998. Production:
2000 … 30 kg/y
2002 … 60 kg/y

11. 2004 … 100 kg/y
Every company whose core business is technology devotes considerable resources to R&D.
Marshall Investments profit and loss statement does not contain this item, because the
company's technology know-how is held by Prof. Michael Epstein, formerly of the Weizmann
Institute of Science.
Production: MARSHALL ISOTOPES, Israel:
Water distillation ------------------ 100 kg/y
Huayi Isotope Co. (HIC), China
Huayi Isotope Co. (HIC), located near Shanghai in China, is one of the largest 18O
manufacturers in Asia , with a yearly capacity of 100 kg and offers the nuclear medicine
community the highest quality greater than 98 at.% 18O - enriched water for use in the
production of radiotracer 18F (FDG), and 10 at. % single water or double-labeled water for
metabolism studies of body energy expenditure while in full compliance with GMP standards
and certified by ISO-9001:2000 and ISO-14001.
SRICI, China
Shanghai Research Institute of Chemical Industry (SRICI) is the world leader in the
separation of 15N isotope and China leader in the separation of 18O for medical applications
and the production of stable isotope labeled compounds. In 2002 SRICI took cognizance of
the extensive need of the Positron Emission Tomography (PET) and began the research on
separating 18O. SRICI constructed its first 18O water distillation plant in China. This plant
meets advanced world standards and now has an annual production capacity of 50 Kg, and
probably has been expanded to 100 Kg per year from 2006. With his breadth of experience
and expertise in stable isotopes, SRICI is very sure of itself to satisfy the growing global
needs of the PET community for consistently high quality product delivered on time at a fair
price. The product type of SRICI is 18O - water (18O > 95 %).
SRICI's 18O Milestones:
- 1957 - SRICI's beginning of the research on the separation of heavy (deuterium) water
-1959 - Success in the research, and get the heavy (deuterium) water which abundance is
99.999 %
- 2000 - SRICI's beginning of the research on the separation of heavy ( 18O) water
- 2002 - Success in the research on the water distillation of heavy ( 18O ) water and get the
heavy (18O ) water which abundance is 10.0 % + (deuterium)
- 2003 - SRICI build up the China first manufacture of the heavy ( 18O) water
- 2004 (April) - SRICI's manufacture get the certified heavy (18O) water, which abundance is
99.0 % + (18O)
- 2004 (June) - SRICI's certified heavy (18O) water, which abundance is 95.0 % + (18O) is
successfully used in PET, and distributed to worldwide community
- 2004 (August) - SRICI's capacity is up to 50 Kg/y heavy (18O) water, which abundance is
95.0 % + (18O)
2005 (Jan) - SRICI's certified heavy (18O) water, which abundance is 97.0 % + (18O) is
distributed to worldwide community.
Production of stable isotopes by membrane method
Separation of Water Isotopomers by Porous Hydrophobic Membrane
(Institute of Nuclear Chemistry and Technology, Warsaw, Poland)

12. Water enriched with its natural isotopes plays an important role in research and technology.
Heavy water (HDO, D2O) is used in nuclear technology and research and the increasing
market demand is expected in future if nuclear fusion will be used for energy production.
Water enriched in 18O is used in research and medicine in trace experiments, as is
water enriched in 17O. Recently there appears to be significant market demand for increased
production of heavy oxygen (18O). Its role is becoming more important as large amounts of
heavy oxygen is used for production of 18F for PET scanning.
The method of separation of water isotopomers proposed in the project is thermal
evaporation through a porous hydrophobic membrane (membrane distillation). The unit
separation factor for the process was determined in experiments carried out with a laboratory
apparatus, equipped with PTFE flat sheet membranes. The experiments showed the membrane
process is characterized by higher separation factors than distillation of water. Since
distillation is now the only commercial method for heavy oxygen production the proposed
process has particular importance. In some cases the method can be also applied for a
production of heavy water. Preliminary engineering calculations based on cascade theory
showed many advantages of membrane permeation. Employing the system of two
countercurrent cascades combined in series results in savings in stage number, reflux ratio,
and energy demand. The technical and economic evaluation of permeation as compared to
other enrichment methods showed the competitiveness of membrane process. The process
was experimentally tested with different multistage systems.
The method can be applied for a separation of isotopes of hydrogen and oxygen in
natural water. It can be used separately or in combination with other separation processes.
18
O is widely used in research of mechanisms of catalytic reactions. Double-labeled
water with 18O and D is employed in metabolism studies to measure energy expenditure and
the total body water composition in human subjects especially when subjected to extreme
conditions, e.g. during surgical operations, persons under treat, etc. To increase precision of
measurements triple-labeling is sometimes employed (18O, 17O and D). In contrast to other
oxygen isotopes 17O possesses a magnetic moment, which allows easy detection using NMR.
Over the past few years the world has witnessed a continuously increasing demand for
enriched oxygen isotopes, especially 18O, due to a large consumption of H218O by positron
emission tomography (PET, a new medical diagnostic technique used principally for tumor
detection). PET uses short-lived positron emitters, like 11C, 13N, 15O and 18F incorporated into
bio-chemically active tracer molecules absorbed preferentially by the tumor. The subsequent
radioactive decay monitored by sophisticated position sensitive detectors permits to tumor or
target organ to be mapped at high resolution

13. Production of stable isotopes by membrane method
Production of heavy oxygen ( 18O)
(Institute of Nuclear Chemistry and Technology, Warsaw, Poland) 2
•
Several different target materials are used for a production of these isotopes (Table 1), among
them water enriched in 18O.
Nuclide
11C
13N
15O
18F
Table 1. TARGET SYSTEM
Half-period [min]
Reaction
14N (p, a) 11C
20.4
16O (p, a) 13N
9.97
15N (p n) 15O
2.07
18O (p, n) 18F
109.8
Target material
Nitrogen gas (natural)
Water (natural)
Nitrogen gas (15N - enriched)
Water (18O – enriched)
Heavy oxygen water (H218O) is used as a target material for production of the short lived
radioisotope 18F used in PET scanning. 18F is obtained efficiently using the
nuclear reaction: 18O (p, n) 18F, induced in small PET cyclotrons (~11 MEV). As 18F and the
other product isotopes in Table 1 are short-lived, the cyclotrons are installed directly in
hospitals or clinics. A typical tomography centre comprises specialized cyclotron for short lived
positron isotope production, a laboratory for the synthesis of labelled tumor-specific
compounds, and a positron tomograph.
In the 1990’s at Institute of Nuclear Chemistry and Technology, Warshaw, the new method
of heavy oxygen enrichment in natural water was elaborated. The method based on
permeation through porous, hydrophobic membrane, called membrane distillation produces
higher separation factors than distillation of water. Unit separation factors in membrane
process were determined in the experiments carried out with a simple laboratory apparatus
equipped with flat sheet PTFE membrane .
The application of double system of counter-current cascades connected in series resulted in
reduction of number of stages, reflux ratio, energy consumption.
Technological and economical evaluation of permeation in comparison with other methods
used for oxygen isotope enrichment showed the competitiveness of membrane process.
The method proposed in patents [1-5] can be used separately or in combination with other
separation processes.
Note: The experiments showed the separation factors of membrane permeation process are
markedly higher than those obtained for distillation of water.
Since the distillation is the main process used for heavy oxygen enrichment the membrane
process is of particular importance.
Preliminary engineering calculations based on the separation cascade theory showed the
advantages of membrane permeation.
The methods of heavy oxygen enrichment are very expensive and very often difficult
in their technological accomplishment. Effective processes as thermal diffusion or chemical
isotope exchange are characterized by low kinetics. NO distillation exhibits a large separation
factor , however it is disadvantageous because of high price of feed material, its
toxicity, difficulty with handling and inconveniently low process temperatures.
A comparison of heavy oxygen enrichment methods is given in Table given below:
---------------------------------------------------------------------------------------------------------Process
Unit separation factor Energy consumption Apparatus Industrial hazard
per 1 kg H218O [GJ]

14. --------------------------------------------------------------------------------------------------------Water
Distillation
1,0032
4-8
Simple
Safe
Normal carbon
steel
Water
Permeation
1,005 - 1,04
1 - 12
Simple
Safe
Normal carbon
steel, plastics
NO
Distillation
Complicated,
NO – toxic
special materials, substance
corrosion hazard
----------------------------------------------------------------------------------------------------------1,0406
-
Separation methods of 18O taken into consideration:
NO Cryogenic distillation – explosion peril
Thermal Diffusion – no feasible
Water Distillation – Yes
SILEX technology
18
O is used in several different fields, including scientific research, geology and medical
imaging. By far the biggest demand for 18O is for PET medical imaging. The market for this
application is currently approaching US $ 100 m and is rapidly growing.
18
O is currently produced via old and inefficient distillation techniques. The potential for
highly efficient production with SILEX technology could result in significant economic value
for the company.
SILEX – Australia
Stable Isotope Program, with the primary focus on silicon and oxygen enrichment. .
The design and construction of a prototype oxygen enrichment facility include a laser system,
foto-reactor vessel and associated gas handling system.
The prototype facility under construction in 2004, enrichment tests will be conducted in the
first half of 2005.
This facility could then be potentially modified to produce initial commercial quantities of the
18
O isotope used primarily in PET medical imaging.
The world market for 18O is currently estimated to be worth approximately US$ 50M/y (not
including demand for milit. LIDAR appl.)
Method of concentrating 18O with laser
Japanese Patent 1991
A method of concentrating 18O with laser which comprises adding optionally a hydrocarbon
to a saturated acyclic ether (except dimethyl ether) or a saturated cyclic ether as a starting
material containing 18O and laser beams are applied thereto for causing selective photolysis of
18
O, and separating a product containing 18O from the products of said photolysis. The
concentrated 18O can be used as a tracer or the like.

15. Photochemical separation of isotopes
CA Patent 1122567 by Andreas Ch. Vikis
A method for photochemical separation or enrichment of isotopes of 13C and 18O employing
123.58 nm resonance radiation of Kr of selected band-width and degrees of self-absorption in
order to excite selectively to the AlII v' = 13 state, 13C16O, 12C18O, or both 13C16O and 12C18O
simultaneously, in a mixture of isotopic CO molecules where the 12C16O isotopic molecule
is in a large excess. The electronically excited isotopic CO molecules react with a second
reactant to yield isotope enriched final products which can be separated; for example, ground
state CO as second reactant yields CO2 and C3O2 products.
8. Medical Isotopes, Inc., Pelham, NH, US
Supply 18O enriched water at 97%; 95% and 10% respectively to the medical community.
18
O enriched water at 95% and the 97% is used for PET.
The 10% 18O - water is used in patients for metabolic studies.
18
O enriched water, 10% is used in medical research for metabolic studies. This research
measures the amount of food that is being metabolized by a person and is often used in
cholesterol research.
9. American Elements
American Elements is a manufacturer and supplier specializing in the stable (non-radioactive)
isotopes of numerous elements and their oxide and fluoride compounds marketed under the
trademark AE Isotopes™, including oxygen (18O). Isotopes from American Elements are nonradioactive materials with numerous applications and properties.
18
O has been used extensively to study human metabolism by measuring metabolic energy
output in research involving obesity, heart disease, osteoporosis and diabetes. 18O can be
traced through the body using mass spectrometry.
Final Remarques
The capacity of these commercial producers is not always directly available. These producers
isolate 18O by distillation of water or nitric oxide using large, steady state distillation columns.
Commercial quantities are however, produced by fractional distillation of water or cryogenic
distillation of nitric oxide or carbon monoxide.
Development of a variety of isotope separation processes is an important R&D activity,
because there is no one isotope separation process which is economically superior to all others
for every isotope. The best method of separation can be chosen only after an evaluation of the
chemical and physical properties of nuclides involved, the degree of separation desired, the
scale of the operation, the capital investment, the energy consumption, and the operating and
maintenance costs for each competing separation process. The availability of a variety of
isotope separation methods also allows the option of combination two or more processes for
a more economical isotope production.
This paper presented succinctly the various methods and units used for separation of heavy
stable isotopes of oxygen. More information can be find in our paper: “Separation of Heavy
Oxygen Isotopes – A Selected Bibliography”. It is a comprehensive compilation of references
from the scientific and technical literature on the separation of heavy oxygen isotopes. The
references are arranged chronologically according to the leading author.
Appendix:

16. Some general considerations on methods for separating stable iotopes, (ISOTEC, 1990).
In the case of oxygen, current production methods are distillation and gaseous thermal
diffusion and in R & D area, MLIS (Molecular Laser Isotope Separation), IEX (Ion
Exchange) and CHEMEX (Chemical Exchange)
Distillation is an economical technique for separation of many light isotopes. Industrially
distillation is used to separate the isotopes of oxygen.
Gas-phase thermal diffusion is currently used for the separation of noble gas isotopes. TD
plants generally have low capital cost. TD is a versatile process for producing small quantities
of isotopes. The main disadvantage of this technology is that it has a high product unit costs
due to a small production rate per column and large electrical consumption. There is ni
significant economy of scale in TD plants.
Chemical exchange is used for separation of oxygen isotopes. Since chemical exchange
processes use conventional chemical process equipment they can be easily scaled. The
elementary separation factors are usually better than distillation for the same isotope.
Generally, chemical exchange processes have a good economy of scale. However, the
processes require expensive chemical refluxing unless thermal or electro-chemical refluxing
is possible. Often the systems require the use of highly toxic and corrosive gases.
Molecular laser isotope separation (MLIS) is actually a group of related processes utilizing
laser induced photochemical reactions which can be made isotopic selective by precise
adjustment of the laser wavelength. Potential MLIS processes have been discovered for the
isotopes of oxygen. LIS is achieved by irradiating one of the isotopic components (usually the
rare one) so that it is selectively excited. The excitation then drives this particular isotope to
react and form products that are enriched in it. MLIS research has demonstrated isotope
separation factors higher than 8000 for one step. Also laser technology has been steadily
improving output power while the cost/kW has been decreasing. This situation indicates a
promising future for this type of process. Two significant problems with many MLIS schemes
is that the feed materials are often expensive compare to feeds used in other processes and
that the reaction products often requires expensive chemical conversions to arrive at desired
product form.