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SEPARATION OF HEAVY OXYGEN ISOTOPES. A SURVEY Gheorghe VASARU National Institute for Research and Development of Isotopic and Molecular Technologies, Cluj-Napoca, ROMANIA [email protected]

Separation of heavy oxygen isotopes a survey

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SEPARATION OF HEAVY OXYGEN ISOTOPES. A SURVEY

Gheorghe VASARUNational Institute for Research and Development

of Isotopic and Molecular Technologies, Cluj-Napoca, [email protected]

Oxygen isotopes

• Oxygen is a mixture of three stable isotopes:

• 16O (99.757 at. %), • 17O (0.038 at. %) and • 18O (0.205 at. %), respectively.

Applications and needs of oxygen isotopes

• 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:

16O

• 16O is used in the production of radioactive 13N which is used for Positron Emission Tomography (PET) imaging and myocardial perfusion.

17O

• 17O 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.

18O

• 18O is an important precursor for the production of fluorodeoxyglucose (FDG) used in PET. Generally, in the radiopharmaceutical industry, enriched water (H2

18O) is bombarded with hydrogen ions in either a cyclotron or linear accelerator creating 18F. This is then synthesized into FDG and injected into a patient.

18O• 18O is a key isotope because it is the raw material for cyclotron

production of 18F used to produce 2-[18F] fluoro-2-deoxyglucose (18FDG) - a very important a tracer in PET. For this purpose, H2

18O is used as a precursor. To produce these scans 18FDG is needed. To do this, 18O enriched water, (95 % or 97 %), is proton bombarded in a cyclotron to produce fluorine 18F that is then used in the production of 18FDG in an automated radiochemical synthesis. The 18FDG is then injected into patients as an intravenous diagnostic radiopharmaceutical. 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.

18O

• 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. 18O is also used in the metabolic research community to measure energy expenditure and body water consumption

PET

• 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.

PET

• Detailed Product Description • With the growing demand for PET scans as a

diagnostic tool for physicians, 18O enriched water has become increasingly important.

•  To produce these scans 18FDG is needed. To do this, 18O enriched water at 95% or 97% is proton bombarded in a cyclotron to produce 18F that is then used in the production of 18F FDG in an automated radiochemical synthesis. The 18F FDG is then injected into patients as an intravenous diagnostic radiopharmaceutical. The PET scan is then performed on the patient.

18O

• 18O 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.

II. Oxygen Isotope Separation Methods

• 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.

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.

IBakhtadze (IAEA, Leipzig – 1977). IAEA –Modern Trends in Biological Applications of SI, Leipzig, 1977

A.B. Bakhtadze, TC – 90/1 – Separation of SI : A Review

• Research on the separation of SI and the investigation of their properties was started 70 years ago. Up to 1955, however, research on the separation of the SI 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 SI of oxygen. Starting in 1965, 18O has been produced in yearly amounts within the range of several hundred grammes

Data on enrichment plants for oxygen isotopes production, 1977 [1]

Isotope Separation method

Isotope conc. (at %)

Production

(kg/an)

Product form

Country Ref

18O H2O distillation 98 5.6 H218O Israel [1,55]

Distillation 95 Some kg H218O Germany [1]

O2 distillation at low temp.

25 18O2 UK [6]

NO distillation at low temp

0-99

95-99

90

1.5

2

1.85

H218O

H218O

H218O

USA

USA

SU

[1,43]

[1]

17O H2O distillation 20-

26

1.8 Israel [1.55]

D217O distillation 99.8 Germany [1]

NO distillation at low temp

0.3 USA [1.43]

16O NO distillation at low temp

99.99

99.9

2700-3500

40

USA

SU

[43]

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.

• 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)

ICON facility, Los Alamos National

Laboratories (LANL)

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.

CILXeniaOhioUSA

CIL has beenproducing 18Owater for the

PET community since 1996.

The expanded plant produces 250 Kg per year

of 18O used for the production of FDG in the PET industry and in other

medical research.

2001 ICON

• Lease agreements to be signed today between the Department of Energy, the Los Alamos Commerce and Development Corp. and Spectra Gases of New Jersey, 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.

• 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.

Icon

• Application of the stable isotopes of oxygen (17O and 18O) are useful in studies of cell and tissues by nuclear methods and mass spectrometry especially for the investigation of water molecule in normal and cancerous cells.

• 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.

CIL, Xenia, Ohio, USA

CIL, Xenia, Ohio, USA High Columns

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%) 18O water have come from the international PET community and for 10% 18O water from the metabolic research 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.

 

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 1

• GST is main producer of water 18O. 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 Positron Emission Tomography (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 Positron Emission Tomography (PET). Everywhere it obtained the highest appreciation for quality and the highest yield for FDG (Fluorodeoxyglucose). Our 18O - water has more 97.0 atom % Isotope Enriched 18O.

GST2

• 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.

• Oxygen is a mixture of 3 stable isotopes: 16O (99.759 atom%), 17O (0.037 atom%) and 18O (0.204 atom%). Natural water is a mixture of low boiling-point compound H2

16O with temperature of boiling point - 100ºC. And high boiling point compound H2

18O with temperature of boiling - 100.15ºC.• Separation of mixture H2

16O 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 H2

18O.

GST3

• Enriched water till 97% 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 МИ-1201В. Accuracy for 18O is ± 0.2 atom %, for enriched higher than 80 atom %.

GST Plant 1

GST Plant 2

Dostrovsky,• Dostrovsky, A. Raviv: Separation of the Heavy Isotopes of Oxygen

by Distillation • (Proc. of the Symposium on Isotope Separation, Amsterdam, 1957,

p. 336).• Following the discovery of 18O by Giauque and Johnston [1],

numerous attempts were made to obtain oxygen containing materials enriched in this isotope. This oxygen isotope excited particular interest among chemists as a possible tracer in the study of the very many reactions involving an oxygen bond. In the course of time all known processes which lead to isotope fractionation were tested for their suitability for oxygen isotopes enrichment. These included fractional distillation of water [2], of liquid oxygen [3-5] of carbon monoxide [6] or organic liquids [7-9], thermal diffusion of oxygen [10-15], electrolysis of water [17-22] and chemical exchange reactions [23-27].

Water distillation

• 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.)

Prof. Dostrovski

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 19982000 … 30 kg/y2002 … 60 kg/y

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.

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 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 water- 18O and gas by cryogenic distillation of nitric oxide since 1985 at concentrations up to > 99 atom %.

ISOTEC

has the world’s largest18O production capacity, andhas been enriching 18O by

cryogenic distillation of nitric oxidesince 1985.

ISOTEC

October 30, 1998 ISOTEC has started construction of

additional 18O capacity to greatly increase its total production of oxygen-

18 isotope. Isotec expects the expansion to increase output beginning in mid 1999

and again substantially in 2000 and 2001 to meet worldwide demand.

Isotec facility, Miami Township, Ohio

LANL developed isotope separation using

NO distillation technology. Isotec acquired

the technology for commercial use.

Sigma–Aldrich purchased the Isotecfacility in 2001 from Matheson Gas Products.

September 24, 2003

According to Isotec General Manager Diane Szydel, half to three quarters of the 180 water that the plant was producing came from a carbon monoxide process that was unaffected by the explosion of a nitric oxide tank. "The CO columns were

not affected at all," she said.

20-foot-diameter, 8-foot-deep crater and structural damage caused by NO process unit explosion

ISONICS Corporation (Nasdaq:ISON)

• Is the world’s second largest supplier of 18O.• 18O 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 18O 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.

ROTEM Industries (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 atom. % to 95 atom. % .

• 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 atom. % 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.

RotemIndustries

Ltd.,Israel

18O output will increase to120 kilograms in 2003

and250 kilograms in 2005.

Huayi Isotope Co. (HIC),

• 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% 18O enriched water for use in the production of radiotracer 18F (FDG), and 10% 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.

Huayi Isotope Co. Shanghai, China

SRICI

• 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 labelled compounds. From the 1960's, SRICI began the research on separating 2H, 15N, 13C, 22Ne ... etc. In 2000 SRICI built the world's largest 15N separation facility, which has met the 60% 15N needs of worldwide consumers. 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 (oxygen-18) water

• - 2002 - Success in the research on the water distillation of heavy ( oxygen-18 ) water and get the heavy (oxygen-18 ) water which abundance is 10.0%+(deuterium)  

• - 2003 - SRICI build up the China first manufacture of the heavy (oxygen-18) water     • - 2004 (April) - SRICI's manufacture get the certified heavy

( oxygen-18 ) water,which abundance is 99.0%+ ( oxygen-18) •  - 2004 (June) - SRICI's certified heavy ( oxygen-18 ) water,which abundance is

95.0%+ (oxygen-18) is successfully used in PET, and distributed to worldwide community 

•  - 2004 (August) - SRICI's capacity is up to 50Kg/y heavy (oxygen-18) water,which abundance is 95.0%+( oxygen-18)  

•  - 2005 (Jan) - SRICI's certified heavy ( oxygen-18 )water,which abundance is 97.0%+( oxygen-18) is distributed to worldwide community  

SRICI – Botles with18O - water

SRICI Shanghai, China

SRICI R & D Team

Medical Isotopes, Inc., Pelham, NH, US

• Supply 18O enriched water at 97%; 95% and 10% respectively to the medical community.

• 18O enriched water at 95% and the 97% is used for PET. • The 10% 18O - water is used in patients for metabolic

studies. • 18O 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.

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 combining two or more processes for a more economical isotope production.

• This paper reviews succinctly the various methods used for separation of heavy stable isotopes of oxygen. In Appendix, a selected bibliography are given, with 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.

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.

Leipzig 1977: Summary Report

• 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,H2O,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.

• Of all these processes only three have been found promising as methods of obtaining considerable amounts of highly enriched oxygen isotopes. There are: a. the fractional distillation of water, b. the fractional distillation of carbon monoxide and c. thermal diffusion of oxygen [10-11]. The latter process has yielded the highest concentration of 18O obtained to date – 99.5 %. As a consequence, however, of the low throughput of thermal diffusion columns this method is not particularly suitable for the production of 18O and 17O in quantities of gram per day. The low temperature distillation of carbon monoxide has been used at Harwell [6] 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 [29-35].

• 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 [36-37] 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. [38-39] and later by Baertschi and Kuhn [40]. 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.

• 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.

• 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 17,18O. For example:

• 18O - 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 yearly capacity of: 3 – 4 kg/y

18O (99%); Germany);• - by cryogenic distillation of oxygen ( Daniels, W.R. et al.,

England).

• 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]?

• 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).

• 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 1967, in the Karlsruhe nuclear research center (Germany) has been operated a water-deuterated plant for enrichment of 17,18O. The research activity has been performed in collaboration with norvegian scientists [1,56]. The enrichment attained was 99.8 at % H2

18O 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 + H2

16O• of which elementary separation factor was of only 1.02 [60]

Data on enrichment plants for oxygen isotopes production, 1977 [1]

[43]USA

SU

2700-3500

40

99.99

99.9

NO distillation at low temp

16O

[1.43]USA0.3NO distillation at low temp

[1]Germany99.8D217O distillation

[1.55]Israel1.820-

26

H2O distillation17O

[1,43]

[1]

USA

USA

SU

H218O

H218O

H218O

1.5

2

1.85

0-99

95-99

90

NO distillation at low temp

[6]UK18O225O2 distillation at low temp.

[1]GermanyH218OSome kg95Distillation

[1,55]IsraelH218O5.698H2O distillation 18O

RefCountryProduct form

Production

(kg/an)

Isotope conc. (at %)

Separation method

Isotope

• Industrial Pilot Plant for the production of 18O• 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 stepped cascade formed of terraced 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 of 17,18O 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 steam-heated columns, mostly 12 m high, and 100, 34 or 12 mm in diameter contained the well-known 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 electrolytical into H2

17O. Electrolysis cells are also used to produce chemical pure 18O2 gas from D2

18O for various syntheses.• The Karlsruhe separation process was a countercurrent distillation of heavy water at an

average temperature of 74 oC and a pressure of 200 torr at the top of each column. • 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 D2O 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 O-18 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)

• 18O 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 atom% and 17O at 96 at.% [55].

• At the Nuclear Research Centre at Karlsruhe (Germany) 18,17O 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], 18O was produced at 99.9 at.%. Intermediate product was converted into H2O and fed to a distillation unit in order to produce useful enrichments of 17O (approaching 30 at. %). Water-16O (depleted in both 17O and 18O) was produced at 99.99 at. % 16O.

• The separation of 16,17,18O by cryogenic distillation of nitric oxide was used at Los Alamos (USA).

• 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 16Oin the feedstock is present as 16,18O. 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 to undergo exchange reactions. Activation analysis seems to be a very promising method for the determination of this isotope.

• 18O 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.

J.G. Tracy et al. – SI Enrichment Techniques and ORNL …,1987

• Introduction• A broad spectrum of enriched SI is needed for basic and

applied needs. Isotopes of prime importance, isotopic-purity requirements, and quantities of material are continually changing, and the timely availability of highly-enriched materials are the subject of concern. Many of these isotopes are crucial to the continuation of research investigation and directly impact the nation’s health-care delivery programs.

• The purpose of this paper is to review the current isotope separation program and presents state-of-arts techniques utilized to achieve specific isotope requirements.

Producers, methods, capacityICON (Los Alamos National Laboratories, USA):

NO distillation -------------------------- 13 kg/y

CIL (Cambridge Isotope Laboratories, Xenia, Ohio, USA): Water distillation ---------------------- 250 kg/y

Rotem Industries (Israel): Water distillation ----------------------250 kg/yMarshall Isotopes (Israel): Water distillation ------------------ 100 kg/yIsotec (USA): NO distillation, CO distillation(?) --- ?Isonics (Russia ?) ------------------------------ ?ISI (Georgia, Tbilisi) NO distillation ----- 30 kg/y(Ukraina, Russia, Canada? …) ------------ ? Isoflex (Russia) Isotopes, incl. 18O)

F

W1

W2

P1

C3

C4

C5

C6

C1

A

B

Conceptual TD Cascadefor Enrichment Oxygen-17

See explanations in text !

P2

C2

Production of stable isotopes by membrane methodSeparation of Water Isotopomers by Porous Hydrophobic Membrane

(Institute of Nuclear Chemistry and Technology, Warsaw, Poland)

• 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.

Production of stable isotopes by membrane methodProduction of heavy oxygen (18O)

(Institute of Nuclear Chemistry and Technology, Warsaw, Poland) 1

18O is widely used in research of mechanisms of catalytic reactions. Double-labeledwater with 18O and D is employed in metabolism studies to measure energy expenditure andthe total body water composition in human subjects especially when subjected to extremeconditions, e.g. during surgical operations, persons under treat, etc. To increase precision ofmeasurements triple-labeling is sometimes employed (18O, 17O and D). In contrast to otheroxygen 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 forenriched oxygen isotopes, especially 18O, due to a large consumption of H2

18O by positronemission tomography (PET, a new medical diagnostic technique used principally for tumordetection). 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

Production of stable isotopes by membrane methodProduction 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.

Table 1. TARGET SYSTEM Nuclide Half-period [min] Reaction Target material 11C 20.4 14N (p, a) 11C Nitrogen gas (natural) 13N 9.97 16O (p, a) 13N Water (natural) 15O 2.07 15N (p n) 15O Nitrogen gas (15N - enriched) 18F 109.8 18O (p, n) 18F 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.

Fig.1. Laboratory stand for isotope separation experiments

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 (Fig.1).

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.

Fig.2. Double system of separation cascades for isotopes enrichment

• The application of double system of counter-current cascades connected in series (Fig.2) 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.

Table 2. Comparison of heavy oxygen enrichment methods

The methods of heavy oxygen enrichment are very expensive and very often difficultin their technological accomplishment. Effective processes as thermodiffusion or chemicalisotope exchange are characterised by low kinetics. NO distillation exhibits a large separationfactor (Table 2), however it is disadvantageous because of high price of feed material, itstoxicity, difficulty with handling and inconveniently low process temperatures.

Table 2. Comparison of heavy oxygen enrichment methods

Process Unit separation factor Energy consumption Apparatus Industrial hazard per 1 kg H2

18O [GJ]WaterDistillation 1,0032 4 - 8 Simple Safe Normal carbon steelWaterPermeation 1,005-1,04 1 - 12 Simple Safe Normal carbon steel, plasticsNODistillation 1,0406 - Complicated, NO – toxic special materials, substance corrosion hazard

Patents

• - A. G. Chmielewski, G. Zakrzewska-Trznadel, N. Miljević, W.A. Van Hook, Sposób wzbogacania wody w składniki wody cięŜkiej, PL161104 (31.05.1993).

• - A. G. Chmielewski, G. Zakrzewska-Trznadel, N. Miljević, W.A. Van Hook, Sposób wzbogacania wody naturalnej w tlen-18, PL 16 1105 (17.05.1994).

• - W. A. Van Hook, A. G. Chmielewski, G. Zakrzewska-Trznadel, N. Miljević, Enrichment of Water in Components of Heavy Water, U.S.Patent 5,084,181, (Jan. 28, 1992).

• - W. A. Van Hook, A. G. Chmielewski, G. Zakrzewska-Trznadel, N. Miljević, Method of Enrichment of Oxygen-18 in Natural Water, U.S. Patent No 5, 057, 225 (Oct. 15, 1991).

• - G. Chmielewski, G. Zakrzewska-Trznadel, N. Miljević, W.A. Van Hook, Sposób wzbogacania wody naturalnej w tlen-18, PL 168 152 (09.08.1995).

SILEX technology

• 18O 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.

• 18O is currently produced via old and ineffecient distillation techniques. The potential for highly effecient production with SILEX technology could result in significant economic value for the compant.

SILEX – Australia26 February 2004

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, photo-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 18O isotope used primarily in PET medical imaging.

• The world market for oxygen 18 is currently estimated to be worth approximately US$50M p.a (not including demand for milit. LIDAR appl.)

laser system

METHOD OF CONCENTRATING OXYGEN 18 WITH LASERJapanese 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 18O, and separating a product containing 18O from the products of said photolysis. The concentrated 18O can be used as a tracer or the like.

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.

Production of stable isotopes in RRC “Kurchatov Institute”Location of main producers of stable isotopes in Russia:

ECP, ZelenogorskSCP, Seversk

UCP, NovouralskEChPr, Lesnoi, EM

ECP, Nizhniy NovgorodSarov

Moscow, RRC “Kurchatov Institute”ECP, St.Petersburg

ELP, Angarsk

American Elements

• American Elements is a manufacturer and supplier specializing in the Stable (non-radioactive) Isoptopes of numerous elements and their oxide and fluoride compounds marketed under the trademark AE Isotopes™, including Oxygen (18O)

• Isotopes from American Elements are non-radioactive materials with numerous applications and properties.

• 18O 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.

Applications• H2O of 95 % 18O Positron Emission Tomography (PET) 18O 18F

Production:35 kg/an in 1997600 – 1000 kg/an in 2004

of 120 – 200 mil. USD/year

• D2O of 10 at-% 18O Organisms energetic consumption studies

• Others applications (labelled compounds, 17O in RMN imaging, etc. )

Research Projects - A.E. RugglesRESEARCH PERFORMED AT THE UNIVERSITY OF TENNESSEE

Title: Fluorine 18 Target Optimization 2001-2003, CTI, inc.

• Isotope production for Positron Emission Tomography (PET) is currently accomplished using cyclotrons producing 11 MeV protons. The protons bombard targets with 18O feedstock to produce 18F. Water enriched with 18O is a favorite target material. The short half-life of the 18F encourages rapid production and distribution cycles. The expense of the 18O motivates high conversion rates and small target inventories. The research focused on maximizing the beam power deposited per unit target mass while maintaining pressures and temperatures at levels acceptable to conventional beam window materials.

V.L.Avona et al. – Improvement of human condition by the use of SI, 1990

• SI find a myriad of applications which directly or indirectly improve the quality of human life or aid in the study of how to preserve our natural resources. Some of the most notable uses of SI are in the fields of agronomy, marine biology, environmental science, nutrition, biochemical research, medical diagnostics and medical therapy. The intent of this section of the paper is not to give detailed coverage of the many applications of SI. It does however present an overview of the recent research with stable isotopes of oxygen which will ultimately benefit humankind.

• Stable isotopic-labeled compounds offer several advantages over radioactive tracers. First, some biologically important element, e.g. oxygen, have no radioisotopes with sufficiently long half-lives to allow their practical use in biological systems. Secondly, several different isotopomers may be used simultaneously in a single study.

1. V.L.Avona et al. – Improvement of human condition by the use of SI, 1990

• Conclusion: SI of oxygen have a wide range of applications in almost every natural and physical science. The purpose of this brief review was to describe a few important applications to illustrate the possible uses for enriched stable isotopes of oxygen.

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):• 16O – Distillation NO, H2O at 99.98 – 99.99 at.% ; 1000s kg/yr• 17O - Distillation NO, H2O at 20 – 40 at.%; 2 -5 kg/yr• - Thermal Diffusion O2 at 96 at.%; 0.01 kg/yr• 18O - Distillation NO, H2O, D2O at 90 – 99.99 at.%; 0.2 – 0.4 kg/yr• At LANL large quantities of ICON’s are produced by low temperature distillation of carbon

monoxide and nitric oxide.

PET scanners have a cyclotron (particle accelerator) in which 18O is converted in Fluorine-18 (18F), which

is bonded to sugar molecules and injected into a patient's bloodstream.

18F is radioactive, with a two-hour half-life. It is absorbed by body tissues,

coloring diseased areas.

ISI, Tbilisi, GeorgiaJanuary 18, 2004

at NO distillation plant – two dead

Water distillation

NO cryogenic distillation

Thermal diffusion

explosion peril

no feasible

Separation methods of O-18 taken into consideration

Appendix

• H.G. Spicer – Methods for separating SI, Isotec, 1990.• General considerations• Enriched SI of many elements are widely used in agriculture, medicine, chemical processing,

scientific research and in a variety of specialized industrial processes.• This paper reviews the various industrial methods used to separate stable isotopes of oxygen.

The separation processes are considered from a commercial viewpoint. The separation technologies presented include distillation, thermal diffusion, chemical exchange, ion exchange ?, …The comparative advantages and disadvantages of these methods are discussed. Additionally, a table is given that summarizes most methods that have been investigated or used in oxygen isotopes separation.

• A stable isotope of an element is an isotope that is non radioactive or has a half-life exceeding 5x108 years. There are 63 elements having multiple stable isotopes. These elements gives us more than 260 total isotopes to separate.

• In the case of oxygen, current production methods are Distillation (DIST) and Gaseous Thermal Diffusion (GTD) and in R & D area, MLIS (Molecular Laser Isotope Separation), IEX (Ion Exchange) and CHEX (Chemical Exchange)

• Distillation (DIST) is an economical technique for separation of many light isotopes. Industrially distillation is used to separate the isotopes of oxygen.

• Gas-phase thermal diffusion (GTD) 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 (CHEX) 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.