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Radiopharmaceutical Production

Radiopharmaceutical Production. Radionuclide Production Practical Targets Design and Construction. STOP. Need to produce radionuclides reliably to meet our research needs Need to produce large quantities to meet current and future demands

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Radiopharmaceutical Production

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  1. Radiopharmaceutical Production Radionuclide Production Practical Targets Design and Construction STOP

  2. Need to produce radionuclides reliably to meet our research needs Need to produce large quantities to meet current and future demands May need high specific activity for diagnostic or research applications Simple targets which do not degrade in performance Recycle enriched isotopes Minimize the amount of non-radioactive isotope in the final product (high specific activity) Targets which will withstand high power deposition and use favorable nuclear reactions Contents Basic Principles Carbon-11 Example Fluorine-18 example Iodine-124 example Summary Requirements in Targetry STOP

  3. Basic Principles There are several decisions which must be made when starting to design a cyclotron target. These include: • Choice of Nuclear Reaction • Choice of the physical state • Gas target • Water target • Solid target • Choice of processing • Gas target - chemical separation • Solid target - distillation or sublimation • Choice of the chemical form • Element or Compound • Target Geometry • What is the best shape for the target • Target Body Material • Chemical Interactions • Thermal Conductivity • Activation • Front Foil Material • Strength • Chemical Interactions

  4. Carbon-11 Example As an example, let us assume we want to produce carbon-11. There are several potential nuclear reactions which may be used to produce C-11. Isotope half-life Carbon-11 20.4 min Fluorine-18 110 min Nitrogen-13 10 min Oxygen-152 min The possibilities are given in the following slides

  5. Potential Reactions We can explore the potential nuclear reaction pathways by looking at a chart of the nuclides. We want all the reactions to end on carbon-11, but they can start from different stable elements (black squares)

  6. Types of Nuclear Reactions The radionuclides that can potentially be made from different nuclear reactions are shown in the following diagram. The first letter is the particle in and the letter after the comma is the particle(s) emitted by the excited nucleus. This template can be overlaid on a chart of the nuclides to get the products Nuclear Charge Nuclear Mass

  7. Potential Reactions 11B(p,n)11C Proton in Neutron out

  8. Potential Reactions 14N(p,α)11C Proton in Alpha particle out

  9. Potential Reactions 12C(p,pn)11C Proton in Proton and Neutron out

  10. Three potential nuclear reactions 14N(p,α)11C 11B(p,n)11C 12C(p,pn)11C Carbon-11 Production The cross sections for these three reactions are given in the table below In terms of the yield of the nuclear reactions, it is clear that the best choice is the 11B(p,n)11C reaction

  11. PET Radioisotope Production The difficulty with these type of solid targets is removing the carbon-11 carbon dioxide efficiently from the boron oxide matrix One must choose the chemical form for the target. The best choice is a Solid Phase Target The target is boron oxide which is a solid The 11B(p,n)11C reaction in a boron oxide matrix will produce carbon dioxide An example of a target designed for this reaction is shown on the next slide

  12. Helium in protons 11B + 11B216O3 11COx in Helium out to flow-through chemistry 11COx flow-through target John Clark - circa1975 Target design features Use of B2O3 to provide oxygen for COx production Enriched 11B to increase yield Slanted target material to increase 11COx diffusion High temperature to increase 11COx diffusion Helium carrier gas to remove 11COx from target The actual yields are quite low due to the difficulty of getting the 11CO2 out

  13. Gas inlet Gas outlet Water cooling channels Gas target body is made from polished aluminum Carbon-11 Production The next option to be considered is the Nitrogen Gas Target for 14N(p,α)11C reaction. This target has the advantage of using a gas as the target material which makes the extraction of the carbon-11 carbon dioxide much easier.

  14. Carbon-11 Production This is a cutaway drawing of a typical target for the production of carbon-11 from nitrogen-14 in the chemical form of nitrogen gas. Nitrogen Gas Target for 14N(p,α)11C reaction

  15. Range of protons in N2 Gas at 1 atm The first decision is how long to make the target and what pressure to use. If we want to stop the beam we can calculate the range of the protons in the gas. At 1 atmosphere, the target would need to be 2.6 meters long to stop the beam. Energy Range (MeV) 4.50277.00 mm 5.00 332.37 mm 5.50 392.20 mm 6.00 456.41 mm 6.50 524.95 mm 7.00 597.76 mm 8.00 755.83 mm 9.00 930.42 mm 10.00 1.12 m 11.00 1.33 m 12.00 1.55 m 13.00 1.79 m 14.00 2.04 m 15.00 2.31 m 16.00 2.59 m

  16. Range of protons in N2 Gas at 10 atm At a pressure of 10 atmospheres, the beam will stop in about 26 cm. Which is a much more reasonable target length although most nitrogen targets are shorter than this and operate at higher pressures. Energy Range (MeV) 4.00 22.62 mm 4.50 27.70 mm 5.00 33.24 mm 5.50 39.22 mm 6.00 45.64 mm 6.50 52.50 mm 7.00 59.78 mm 8.00 75.58 mm 9.00 93.04 mm 10.00 112.12 mm 11.00 132.79 mm 12.00 155.03 mm 13.00 178.81 mm 14.00 204.12 mm 15.00 230.92 mm 16.00 259.21 mm

  17. Shape of the Target We need to decide the shape of the target. We know that the beam will spread out due to small angle multiple scattering. This straggling can be calculated most easily using a program such as SRIM Energy Straggling (MeV) 4.00 730.98 um 4.50 885.82 um 5.00 1.05 mm 5.50 1.23 mm 6.00 1.42 mm 6.50 1.63 mm 7.00 1.84 mm 8.00 2.31 mm 9.00 2.82 mm 10.00 3.37 mm 11.00 3.97 mm 12.00 4.61 mm 13.00 5.29 mm 14.00 6.01 mm 15.00 6.78 mm 16.00 7.58 mm 8.0 mm

  18. Entrance Foil Material The table below gives the physical characteristics of some common foil materials. The ideal has high strength, low density, good thermal conductivity, a reasonable dE/dx and high melting point. None is perfect but Al, Ti and Havar are common.

  19. Getting High Specific Activity In order to get high specific activity carbon-11, it is necessary to take precautions when fabricating the target. These include: • Use Electrical Discharge machining to cut the metal • Use only alumina (Al2O3) abrasives in polishing the inside surface. • Never use oils in the target • If organic solvents must be used, follow the use with repeated rinses of ethanol and water Cleaning the target • Should never need to be cleaned • If it is necessary, then Acetone and Ethanol should be used as they are soluble in water • If abrasives are used, they should be alumina • The target should be irradiated and the gas discarded after any cleaning procedure and before a production irradiation

  20. Fluorine-18 Example Isotope half-life Carbon-11 20.4 min Fluorine-18 110 min Nitrogen-13 10 min Oxygen-152 min

  21. Fluorine-18 Example There is really only one reasonable nuclear reaction with protons as the bombarding particle. This is the 18O(p,n)18F reaction. Proton in Neutron out

  22. 18O(p,n)18F Reaction The most convenient chemical form of the target material is in the form of oxygen-18 enriched water. This is the reaction that is used by nearly all facilities for the production of FDG The nuclear reaction cross section is shown on the right and it should be noted that the peak of the reaction is about 6 MeV and it tails off rapidly above 11 MeV.

  23. Front flange Target water Beam Cooling water Fluorine-18 Fluoride Production The target is usually a depression cut into a metal block which contains the oxygen-18 enriched water There is a inlet and outlet for the water and the target is deep enough to allow some boiling in the target without loosing yield. The rear of the target is cooled with a high pressure water flow The front foil is made of a material that is strong enough to hold the pressure generated by the boiling water and chemically resistant to the fluoride and the oxygenated species like peroxide generated in the water.

  24. Fluorine-18 Fluoride Production Typical water target. This particular target is made from solid silver to help in the heat transfer. A more modern water target is typically made from niobium. • 18O(p,n)18F Nuclear Reaction in 95% enriched water • Volume of the target from 0.3 mL up to 3.0 mL

  25. Water Target Operation Filling and Irradiation Cycle Vent Helium push gas Beam [18O]Water To the Chemistry Lab

  26. Water Target Operation After Irradiation, pushing the water from the target to the Chemistry Lab Vent Helium push gas Beam [18O]Water To the Chemistry Lab

  27. F-18 transfer line - 60 meters Transfer of the F-18 from the Cyclotron to the Chemistry Laboratory

  28. Initial Fabrication and Cleaning of F-18 targets Fabrication of Fluorine targets • Should never use soldering fluxes as they contain fluorine which will reduce specific activity • The back wall should be thin to allow good heat transfer • A “reflux” volume helps with keeping the target material in the liquid state Cleaning of Fluorine targets • Silver targets need to be cleaned fairly frequently • Niobium and Titanium can be cleaned much less frequently • No cleaning may be necessary if these last two are used • Mild abrasive and repeated water rinses are best

  29. Iodine-124 Example As the next example, suppose you wanted to make I-124 on the cyclotron and wanted to design a target for the production

  30. Chart of the Nuclides Here we can use the 124Te(p,n)124I nuclear reaction n p

  31. Cross-section 124Te(p,n)124I This excitation function for the nuclear reaction shows that the best energy interval is from 15 down to about 5 MeV

  32. Tellurium Solid Targets Here we have the option of two different chemical forms of the tellurium to use for the target. We can use tellurium metal as shown on the left or tellurium dioxide as shown on the right Both of these target materials are used for production and the choice depends on ease of chemical processing and target material recovery. Since the target material is isotopically enriched, it is relatively expensive and so must be recovered

  33. Preparation of solid targets by electrodeposition The tellurium metal target may be prepared by electrodeposition. There are several constraints on the targets prepared this way. Some of these are given below. • Requirements • The layer must be homogeneous over the entire surface area to ±5%. • The layer must adhere strongly to the carrier up to the irradiation temperatures. • The layer must be smooth (not spongy), dense (no occlusions nor vacuoles), and stress free. • The layer must be free of any organic plating additives (complexing agents or surfactants).

  34. A diagram of an electrodeposition apparatus is shown on the right This particular apparatus will prepare four targets simultaneously. The composition of the solutions used to prepare these targets are beyond the scope of this presentation, but may be found in the IAEA publication TRS 432 A picture of the actual apparatus is shown on the next slide. Electrodeposition Apparatus

  35. Electrodeposition Apparatus

  36. Radioiodine Production The target can be an internal target which can have a very low angle of incidence and high power dissipation The target is mounted inside the vacuum tank of the cyclotron and is irradiated under high vacuum Loss of the I-124 during irradiation is a concern Courtesy of John Clark

  37. Radioiodine Production The idea of an inclined plane can be used as well with the target attached directly to the cyclotron This target attaches to the beam port of the cyclotron Courtesy of Advanced Cyclotron Systems, Inc.

  38. Range of Protons in TeO2 The target can also be formed from a tellurium dioxide powder target. This target has the advantage of being able to be reused without extensive processing by distilling the iodine out of the TeO2.. The target needs to be about 1.5 mm thick Energy Range (MeV) 4.50 204.55 um 5.00 242.96 um 5.50 284.11 um 6.00 327.95 um 6.50 374.42 um 7.00 423.48 um 8.00 529.12 um 9.00 644.68 um 10.00 769.91 um 11.00 904.59 um 12.00 1.05 mm 13.00 1.20 mm 14.00 1.36 mm 15.00 1.53 mm 16.00 1.71 mm 17.00 1.90 mm 18.00 2.10 mm 20.00 2.52 mm

  39. Depth distribution of 124I yield The yield will vary as a function of depth into the target. In this plot we see the yield as a function of depth into the target. You can see that the yield is very low when the beam has penetrated 0.6 mm into the target. This can be compared to the excitation function as shown on the previous slide. The target is 124TeO2, with a incident proton energy of 14.9 MeV)

  40. Initial target preparation To prepare the target, the enriched tellurium dioxide powder is placed in a platinum dish which has a depression of about 1.5 mm deep.

  41. Inserting the target into furnace The platinum dish is placed in the furnace to melt the TeO2 powder into a glass for irradiation

  42. Supercooled liquid TeO2 on the Pt disk After melting, the powder has formed a glass and is ready for irradiation

  43. TeO2before and after irradiation After irradiation Before irradiation After irradiation with IBA Cyclone 18/9 (20 min, 6 μA, 13,5 MeV protons): yield ~1,5 mCi (56 MBq) 124I

  44. Heater Thermocouple °C Air in TeO2 target melted on a platinum disk Air out Al2O3 trap for TeO2 vapours Solution for trapping radioiodine Thermochromatographic release of radioiodines The I-124 is distilled out of the TeO2 target and then the target can be reused

  45. Final Summary Here are the steps we must take to design and build useful targets • Simple targets can be designed, but the material and method of construction is critical • The physical form of the target material often determine the recycling • Non-radioactive isotopes have many sources High power targets are being developed There are several characteristics of targets which make them more useful and robust • Simple targets which do not degrade in performance • Recycle enriched isotopes • Minimize the amount of non-radioactive isotope in the final product • Targets which will withstand high power deposition and use favorable nuclear reactions

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