RADIONUCLIDE RADIONUCLIDE GENERATORSGENERATORS

SMRITI SHARMA

DEPARTMENT OF NUCLEAR MEDICINE, AIIMS

HistoryHistory

1951 - 132Te/132I – BNL1960 – 113Sn/113mIn – 393Kev-not suitable for

imaging1993 – 99Mo/99mTc, 81Rb/81mKr and 82Sr/82Rb

column generators became commercially available

DefinitionDefinition

A generator is a device containing a long-lived parent and a short-lived daughter in a state of radioactive equilibrium.

It is constructed on the principle of decay growth relationship between the long lived parent radionuclide so that the daughter can be easily separated

To ´milk´ the´cow´?

Cont...Cont...

Generators thus overcome the problem of supplying short-lived radio-nuclides to distant places

GENERATORS

• Principle :Types of Equilibrium

•Characteristics of Ideal Generators System

• Principles of Operation of a 99Mo/99mTc Generator

•Other generators

• Quality Control of 99Mo/99mTc Generator

• Regulations and Standards for generator use

Generator PrinciplesGenerator Principles

Mathematical RelationshipsMathematical Relationships

Bateman described mathematically the relationship between parent and daughter activity

The characteristics of any generator system are based on the decay constants of the two isotopes involved

The relationship of these decay constants determines the type of equilibrium that can be attained for a given parent-daughter pair

Successive Decay and Parent/Daughter Equilibrium

Parent--p----> daughter ---d----> daughter decays

Ap(t) = Ap (0) e-pt

• Ad(t)=Ap (0)[d/ d- p ] (e-pt - e-dt) + Ad(0) e-dt

•If p << d (100-1000 times)

Ad(t)=Ap (0) (1 - e-dt) Secular equilibrium

•If p < d (10 to 50 times)

Ad(t)=Ap (0)[d/ d- p ] e-pt Transient equilibrium

Parent activity remains nearly constant

Activity of daughter increases until it becomes equal to that of the parent

Activity and decay rate of daughter and parent are same

Activity of Daughter becomes higher than that of the parent and decay with the same rate.

Yield from column generatorYield from column generator

A99mTc = 0.956 (A99Mo)t

(A99Mo)t = (A99Mo)0* e-0.0103t

Desirable CharacteristicsDesirable Characteristics High separation efficiency of daughter radionuclide High selectivity in separation (high radio-nuclide purity) High radiochemical and chemical purity High yield during each elution Simple and rapid operation at user end Radiological safety to operate Continuous availability of parent radionuclide Easily Transportable Daughter with Ideal Half life and Gamma Energy Chemistry of the Daughter Allows Hospital preparation

Production of Parent Radionuclide

Primary Source:– * Reactor – * Cyclotron

Nuclear Fission Reactor Fission products are generated from rods of 235U inserted into reactor

core. Chemical separation of 99Mo, 131I, 133Xe is readily possible from rod

material 235U(n,f)99Mo, fission yield 6.1%

Nuclear Reactors

• AX (n, ) A+1X

• 98Mo (n, ) 99Mo------> 99mTc

• Starting Material and Products have the Same Chemical Identity.

• Low Specific Activity Radionuclides

Cyclotrons

• Example : 68Zn (p,2n) 67Ga

• Starting Material & Product Have Different Chemical Identity

• Radionuclides with High Specific Activity

• Expensive

• Radionuclides Decay by + or EC

N. ReactorN. Reactor CyclotronCyclotronn bombardment charged particle(n,g), (n,f) (p,n), (d,n)n excess p excessB- decay B+, ECLong T1/2 daughter short T1/2(n,g) low specific activity high (n,f) high specific activityeconomical Expensive

Radionuclide Separation techniquesRadionuclide Separation techniques

Differences in physical stateDifferences in chemical properties

Solvent extraction (based on different solubilities)

– Chromatography(based on differing affinities for an ion-exchange resin) Gel generator Sublimation (based on differing volatilities)

Solvent extraction generatorSolvent extraction generator

Parent 99MoParent radiochemical 99MoO4-

Daughter 99mTcO4-

Organic solvent MEKAqueous solvent KOH

The separation is based on selective extraction of Tco4 into methyethyl ketone from aqueous alkaline solution of sodium molybdate.

Mixing of aqueous and organic phase. Purification of organic medium by passing through

alumina column. Evaporation of organic phase. Residue is reconstituted with physiological saline

and sterilized to obtain Tc in the form of Tco4- suitable for I.V use.

Advantage Advantage

Ability to utilize relatively inexpensive low specific activity 99Mo.

High extraction efficiency.

High radionuclide purity.

Drawback Drawback

It is a time consuming separation procedure.

It introduce operator dependent error in the form of reduced radiochemical purity.

Hazard of handling inflammable solvent

Column generatorColumn generator

99Mo/99mTc Generator • Parent: 99Mo as molybdate (99MoO4-2) • Daughter:99mTc as pertechnetate(99mTcO4-1) • Adsorbent Material: Alumina (aluminum oxide,

Al2O3) • Eluent: saline (0.9% NaCl) • Eluate: 99mTcO4-1 99Mo Half-life: 67 hr. • Decays by b decay 1.2 Mev(82%) and g - emission,

gamma: 740, 780 keV. • High affinity to alumina compared to 99mTc.

SetupSetup

AdvantageAdvantage

Ease of operation.High elution efficiency.High purity.High radioactive concentration.

DisadvantageDisadvantage

Cost of these generator are relatively high mainly due to the need for fission produced 99Mo.

Difficult to manage the toxic fission product waste generated.

Column Gel GeneratorColumn Gel Generator

Parent 99MoParent radiochemical ZrMo gelDaughter 99mTcAdsorbent material Gel + Alumina

Eluate 99mTcO4-

Technical challenges

Gel formationGel formation

Moly trioxide is irradiated and then dissolved in basic ammonia.

The resultant solution is then added to an aqueous zirconium to obtain zirconium moly precipitate in the form of gel like matrix.the matrix is then separated from the solution by filtration ,evaporation ,air dried and sized for use in the generator.

It provides more 99Mo medium then prior alumina adsorption.

DisadvantageDisadvantage

This systems require significant handling and processing of irradiated materials, including dissolution, precipitation, filtration, drying, gel fragmentation and column packing steps, all occurring after irradiation of the molybdenum trioxide.

These processing steps necessitate the use of cumbersome shielded processing equipment, result in relatively high manufacturing costs and pose significant potential safety risks

In order to overcome some of the problems in connection with the production of 99m Tc, all the steps are avoided by directly irradiating zirconium molybdate instead of molybdenum trioxide

The direct irradiation of zirconium molybdate resulted in the production of radioactive contaminants unacceptable for clinical therapeutic or diagnostic applications, including 97 Zr, 95 Zr, 175 Hf, 181 Hf, and 24 Na.

Sublimation generatorSublimation generator

Parent 99MoParent radiochemical 99MoO3

Daughter 99mTc2O7

Boiling point 99mTc 310.60CMelting point 99Mo 7950CBoiling point 99Mo 11500C

Brief introduction about other radionuclide generators

8181Rb/Rb/8181Kr GeneratorKr Generator

113 sn half life=117d,EC 113In half life=100 min,IT,393KEV Adsorbed on zirconium oxide column Eluted with 0.05N HCl. Elution efficiency 80%.

81 Rb half life=4.6hr,Ec 81 kr half life=13s,IT,190KEV Adsorbed on AG 50 resin. Eluted with air.• Used for lung ventilation. • Elution efficiency 70-80%

113113Sn/Sn/113113In GeneratorIn Generator

6868Ge/Ge/6868Ga GeneratorGa Generator 68 Ge half life=271 days 68 Ga half life=68min, Adsorbed on tin dioxide/alumina Eluent 1N HCl Nowadays we use Tio2,eluted with 0.1N

Hcl Yield of gallium-75-80% Shelf life 1 year

82Sr/82Rb Generator

82Srhalf life=25dys,Ec 82 Rb half life=75s,B+ Adsorbed in sno2 column. Eluted with 0.9%Nacl solution. Positron generator Used for cardiac studies. Sodium nonatitanate.Eluted with 1M

Nacl. Life span 3-4 months.alumina column

requires periodical checking of sterility , apyrogenicity and breakthrough levels.

Elution efficiency 85-95%

188W half life=69.4 days,B-,349kev

188Re half life=16.9 hr,B-,155 kev gamma photon(15%)

Adsorbed on alumina or zirconium oxide.

eluted with NaCl solution.

Used to label several tumor-specific antibodies.

The parent radionuclide 188W, formed by the double neutron capture on 186W, by β-decay produces 188Re:

186W(n,)187W(n,) → 188Re

188Tungsten/188Rhenium generator

Potential problem and trouble shootingPotential problem and trouble shooting

problem Possible cause Trouble shooting

Absent or reduced elute volume

Vial lost partial or complete vacuum

Fluid line blocked.

Eluting needle don’t pierce septum.

Elution needle blocked.

Use fresh evacuated vial.

Try larger evacuated vial.

Try another needle if feasible.

Replace needle if possible.

Lower than expected activity

May occur in 1st day of elution. long time gaps in between elution.

Elute repeatedly

99Mobreak through close to specified limit

Faulty generator/column damaged

Elute column for 5-6 times, record 99Mo activity for ach elution if it drops to within acceptable limit ,column is ok if not contact manufacturer.

REGULATIONS AND REGULATIONS AND STANDARDS FOR STANDARDS FOR GENERATOR USEGENERATOR USE

pH 4.5-7.5

Sterility and Apyrogenicity

Radiation Safety concernsRadiation Safety concerns

– Possession and use of radionuclide generators are restricted to licensed persons from AERB

– A number of regulations dealing with receipt, storage and disposal of generators have been developed by AERB

Radiation Safety concernsRadiation Safety concerns– Receipt

Use gloves to prevent hand contamination Inspect package for any damage Monitor external exposures rates at 1m distance Check for surface contamination

– Operation Wear TLD badges and gloves Use syringe shields while handling high activities Perform wipe testing regularly Work behind L-bench

Radiation Safety concernsRadiation Safety concerns– Storage

HVL for 99Mo (7 mm) Below 200mCi generator self shielding is adequate Keep behind lead bricks/shielded

– Disposal Decay in storage

– Dismantle the oldest generator first

– Log the generator date and disposal date

– Remove or deface the radiation labels on generator shield

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