Radiopharmaceuticals

A brief intoducation on Radiopharmaceutical including types of radiation, isotopes, manufacturing, Quality control , and equipments for measurement of radioactivity and Application of radiopharmaceuticals.

1. Radiopharmaceuticals PRESENTED BY GUIDANCE BY DANISH SAYYAD Dr. A.P. PINGLE Quality Assurance Techniques Dept. Pharmaceutical Chemistry FIRST YEAR M.PHARM Roll no - 09 NDMVP SAMAJ’S COLLEGE OF PHARMACY, NASHIK. 1

2. We will Cover the Following Points: What Are Radioisotopes? Radioactive Decay Radiation Units Radiopharmaceuticals Properties of an Ideal Diagnostic Radioisotope Radiopharmaceutical Categories & Production Radiopharmaceutical Quality Control Radiation Measurement Application of Radiopharmaceuticals Journey of a Radiopharmaceutical

3. Radioactive Decay. An unstable atomic nucleus spontaneously loses energy by emitting ionizing particles and radiation. Radioactive isotope Parent Nuclide Daughter Nuclide When an unstable nucleus decays, it may give: 1) Alpha or helium Radiation. 2) Beta or Electron Radiation. 3) Gamma Radiation.

4. 1) ALPHA PARTICLE DECAY Alpha particles are made up of 2 protons and 2 neutrons . Are same as helium nucleus. W hen a nucleus emits alpha particle, its atomic number decreases by 2 and its atomic mass decreases by 4. These particles are relatively slow and heavy . Low penetrating power. As they have large charge , alpha particles ionize other atoms strongly. Alpha decay occurs in very heavy elements like Uranium and Radium.

5. 2) Beta Particle Decay These particles are as same as electrons as they have charge of minus 1 . When a nucleus emits β particle the Atomic number increases by 1 and Atomic mass is unchanged. They are fast and light . Have Medium Penetrating Power. Example of radioisotope emitting β, phosphorus-32. These particles ionize atoms that they pass, but not as strongly as alpha particles do.

6. 3) GAMMA RAYS Gamma rays are Waves not Particles. They have no mass and no charge. Atomic mass and number unchanged. High Penetrating Power. Do not directly ionize other atoms. We don’t find pure gamma source, they are emitted along alpha or beta particles. Useful gamma source technetium-99, used as tracer in medicine.

7. HALF-LIFE The half life of radioisotope is the time for the radiation level to decrease (decay) to one half of the original value. Naturally occurring tend to have longer half lives . Used in nuclear medicine have short half lives . Radioisotope Half Life 14 C 5730 year 40 K 1.3 x 10 9 year 226 Ra 1600 year 238U 4.5 x 10 9 year 59 Fe 46 days 57 Cr 28 days 131 I 8 days 99m Tc 6 hrs

8. Radiation Units Curie ( Ci ) -measures activity as the number of atoms that decay in one second. rad (radiations absorbed dose)- Measures the radiation absorbed by the tissues of the body. rem (radiation equivalent mass)- Measures the biological damage caused by different types of radiation. Becquerel ( Bq ) - 1Bq = 1 Disintegration per sec ( dps ) Sievert ( Sv ) = 100 rem Gray ( Gy ) = 1 J/Kg Tissue

9. Radiopharmaceuticals These are medical formulation containing radioisotopes. Composed of two parts: Radionuclide + Pharmaceutical. Nuclide - Any species of atom characterized by a specific number of neutrons and protons within the atoms.

10. Properties of an Ideal Diagnostic Radioisotope: Type of Emission: -Pure Gamma Emitter: (Alpha & Beta particles are unimaginable & deliver High Radiation Dose) Energy of Gamma Rays: -Ideal: 100-250 keV Photon Abundance: -Should be high to minimize imaging time Easy available: -Readily available, easily produced and inexpensive Target to Non Target Ratio -Should be high which max efficiency and min the radiation

11. Effective Half Life -It should be short enough to minimize the radiation dose to patients and long enough to perform the procedure. Patients Safety Should not exhibit toxicity to the patients. Preparation Quality C ontrol No complicated equipment No time consuming steps

12. Radiopharmaceuticals can be divided into Four Categories: Radiopharmaceutical Preparation Radionuclide Generator Radiopharmaceutical precursor Kit for Radiopharmaceutical Preparation. Manufacture - Radionuclide Production Nuclear Fission Charged particle bombardment Neutron Bombardment Radionuclide Generator System

13. Example of Production of Technetium 99 Uranium 235 is bombarded with neutrons which splits into Molybdenum 99 and other particles. Molybdenum 99 undergoes β decay to produce Technetium 99m

14. Production of Radiopharmaceutical Preparation. Sterilization For heat stable products- Autoclave. For heat labile products- Using membrane filtration of the radiopharmaceutical using 0.22 μ m Millipore filters. 2) Addition of anti microbial preservative. The nature of the antimicrobial preservative, if present, is stated on the label or, where applicable, that no antimicrobial preservative is present.

15. Radiopharmaceutical Quality Control Identity Test The radionuclide is generally identified by its half-life or by the nature and energy of its radiation or by both as stated in the monograph. ii. Radionuclides Purity The gamma-ray spectrum, should not be significantly different from that of a standardized solution of the radionuclide. iii. Radiochemical Purity Assessed by a variety of analytical techniques such as liquid chromatography, paper chromatography, thin-layer chromatography and electrophoresis.

16. iv. Chemical Purity Refers to the proportion of the preparation that is in the specified chemical form regardless of the presence of radioactivity; it may be determined by accepted methods of analysis . v. pH For radioactive solutions the pH may be measured using paper pH indicator strips (Ideally should be in between 6.8 – 7.5 ) vi. Sterility Radiorespirometry The sample of radiopharmaceutical is incubated in a culture medium containing 14C glucose or 14C acetate at 37°C for 3-24 h. If bacteria are present in the sample, they metabolize the 14C-glucose or 14C-acetate, which is measured in a liquid scintillation counter. Radiorespirometry is a faster technique for sterility testing of radiopharmaceuticals.

17. b. Colony culture The sample of radiopharmaceutical is incubated in thioglycolate medium (30-35°C) for aerobic and anaerobic bacteria or in soybean casein medium (20-25°C) for fungi, molds. The test medium is observed for 7-14 days. The presence or absence of micro-organism in the sample is determined by bacterial growth or lack of it in the culture. vii. Bacterial Endotoxin/ Pyrogen Testing - For Bacterial Endotoxin Test- LAL Test - For Pyrogen Test – Rabbit Pyrogen Test

18. viii. Labeling

19. Storage - Should be kept in well closed container -Storage condition should be such that maximum radiation dose rate to which persons maybe be exposed is reduced to an accepted level. -Radiopharmaceutical preparation intended for parenteral use should be kept in glass vials, ampule or syringe that is sufficiently transparent to permit the visual inspection of the contents.

20. Radiation Measurement 1. Geiger Muller Counter Detects beta and gamma radiation. Uses ions produced by radiation to create an electrical current. It is a gaseous ionization detector and uses the Townsend avalanche  phenomenon to produce an easily detectable electronic pulse from as little as a single ionizing event due to a radiation particle . a gas  ionization  process where free electrons are accelerated by an electric field, collide with gas molecules, and consequently free additional electrons.

21. 2. Scintillation Counter - An instrument for detecting and measuring ionizing radiation  by using the excitation effect of incident radiation on a scintillating material, and detecting the resultant light pulses.

22. Applications of Radiopharmaceuticals. Treatment of diseases (Therapeutic Radio Pharmaceuticals): They are radio labeled molecules designed to therapeutic doses of ionizing radiation to specific diseased sites. Examples: Chromic phosphate P32 for lung, ovarian, uterine, and prostate cancers Sodium iodide I 131 for thyroid cancer Samarium Sm 153 for cancerous bone tissue Sodium Phosphate P32 for cancerous bone tissue and other types of cancers Strontium chloride Sr 89 for cancerous bone tissue Erbium 169 for relieving arthritis pain in synovial joints

23. 2. As an aid in the diagnosis of disease (Diagnostic Radiopharmaceuticals) The Radiopharmaceutical accumulated in an organ of interest emit gamma radiation which are used for imaging of the organs with the help of an external imaging device called gamma camera. Radiopharmaceutical used in tracer techniques for measuring physiological parameters ( eg . 51 Cr EDTA for measuring Glomerular filtration rate). Radiopharmaceuticals for diagnostic imaging ( eg . 99m TC-methylene diphosphonate (MDP)used in bone scanning ).

24. PET (Positron Emission Tomography) and  SPECT (Single Photon Emission Tomography) are imaging technologies that enable physicians to diagnose different types of cancer, cardiovascular diseases, neurological disorders and other diseases in their early stages. PET SPECT Involves Positron Involves Gamma Rays More Sensitive Optimum Sensitivity Higher Resolution Lower Resolution Detection by PET Scanner Detection by Gamma Camera Expensive Scanner Cheaper than PET Limited Half life of Radiopharmaceuticals Longer Half life of Radiopharmaceuticals

25. Journey of A Radiopharmceutical

26. Reference: World Health Organization, “Radiopharmaceuticals-Final Text to the addition of International Pharmacopeia”, 4 th ed. Nov 2008 . ( Link - http :// www.who.int/medicines/publications/pharmacopoeia/Radgenmono.pdf ) Attila Keresztes , Attila Borics , Csaba Tomboly , “ Therapeutic and D iagnostic R adiopharmaceuticals”, Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary, Oct 31, 2015.