1. RADIONUCLIDE GENERATORS
SMRITI SHARMA
DEPARTMENT OF NUCLEAR MEDICINE, AIIMS

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

4. 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

5. To ´milk´ the´cow´?

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

7. 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

8. Generator Principles

9. 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

10. 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 ( 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

11. 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

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

14. Yield from column generator
A99mTc = (A99Mo)t
(A99Mo)t = (A99Mo)0* e t

15. 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

17. Production of Parent Radionuclide Primary Source:
* Reactor
* Cyclotron

18. 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

19. 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

20. 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

21. 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)

22. Solvent extraction generator
Parent 99Mo
Parent radiochemical 99MoO4-
Daughter 99mTcO4-
Organic solvent MEK
Aqueous solvent KOH

23. 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.

24. Advantage
Ability to utilize relatively inexpensive low specific activity 99Mo.
High extraction efficiency.
High radionuclide purity.

25. 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

26. 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.

27. Setup

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

30. 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.

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

32. 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.

33. 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

34. 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.

36. Sublimation generator
Parent 99Mo
Parent radiochemical 99MoO3
Daughter 99mTc2O7
Boiling point 99mTc C
Melting point 99Mo 7950C
Boiling point 99Mo C

38. Brief introduction about other radionuclide generators

39. 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

40. 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

41. 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%

42. 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

43. 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.

44. REGULATIONS AND STANDARDS FOR GENERATOR USE

45. pH
Sterility and Apyrogenicity

48. 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

49. 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

50. 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

51. THANKS