RADIONUCLIDE GENERATORS SMRITI SHARMA DEPARTMENT OF NUCLEAR MEDICINE, AIIMS

History 1951 - 132Te/132I – BNL 1960 – 113Sn/113mIn – 393Kev-not suitable for imaging 1993 – 99Mo/99mTc, 81Rb/81mKr and 82Sr/82Rb column generators became commercially available

Definition 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... 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 Principles

Mathematical 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--lp----> daughter ---ld----> daughter decays Ap(t) = Ap (0) e-lpt • Ad(t)=Ap (0)[ld/ ld- lp ] (e-lpt - e-ldt) + Ad(0) e-ldt If lp << ld (100-1000 times) Ad(t)=Ap (0) (1 - e-ldt) Secular equilibrium If lp < ld (10 to 50 times) Ad(t)=Ap (0)[ld/ ld- lp ] e-lpt 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 generator A99mTc = 0.956 (A99Mo)t (A99Mo)t = (A99Mo)0* e-0.0103t

Desirable 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, g) A+1X • 98Mo (n, g ) 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 b + or EC

N. Reactor Cyclotron n bombardment charged particle (n,g), (n,f) (p,n), (d,n) n excess p excess B- decay B+, EC Long T1/2 daughter short T1/2 (n,g) low specific activity high (n,f) high specific activity economical Expensive

Radionuclide Separation techniques Differences in physical state Differences 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 generator Parent 99Mo Parent radiochemical 99MoO4- Daughter 99mTcO4- Organic solvent MEK Aqueous 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 Ability to utilize relatively inexpensive low specific activity 99Mo. High extraction efficiency. High radionuclide purity.

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 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.

Setup

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

Disadvantage 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 Generator Parent 99Mo Parent radiochemical ZrMo gel Daughter 99mTc Adsorbent material Gel + Alumina Eluate 99mTcO4- Technical challenges

Gel 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.

Disadvantage 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 generator Parent 99Mo Parent radiochemical 99MoO3 Daughter 99mTc2O7 Boiling point 99mTc 310.60C Melting point 99Mo 7950C Boiling point 99Mo 11500C

Brief introduction about other radionuclide generators

113Sn/113In Generator 81Rb/81Kr 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% 81Rb/81Kr Generator

68Ge/68Ga 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%

188Tungsten/188Rhenium generator 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,g)187W(n,g) → 188Re

Potential problem and trouble shooting 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 STANDARDS FOR GENERATOR USE

pH 4.5-7.5 Sterility and Apyrogenicity

Radiation 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 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 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 Return to manufacturer

THANKS