Pharmaceutical Inorganic chemistry UNIT-V Radiopharmaceutical.pptx

Pharmaceutical Inorganic chemistry UNIT-V Radiopharmaceutical.pptx
Isotopes Types of decay
Alpha rays, which could barely penetrate a piece of paper
Beta rays, which could penetrate 3 mm of aluminium
Gamma rays, which could penetrate several centimetres of lead
Units of Radioactivity:
Measurement of Radioactivity
The measurement of nuclear radiation and detection is an important aspect in the identification of type of radiations (, , ) and to assay the radionuclide emitting the radiation, suitable detectors are required. The radiations are identified on the basis of their properties.
e.g. Ionization effect is measured in Ionization Chamber, Proportional Counter and Geiger Muller Counter.
The scintillation effect of radiation is measured using scintillation detector and the photographic effect is measured by Autoradiography.
Gas Filled Detectors:
Ionization Chamber:
Proportional Counters:
Geiger-Muller Counter
Properties of α, β, γ radiations
Half –life of Radioelement
Sodium Iodide (I131)
Handling and Storage of Radioactive Material:
Storage of Radioactive Substances –
Precautions For Handling Radioactive Substances
Labelling of Radioactive Substances
Pharmaceutical Application Of Radioactive Substances

1. Pharmaceutical Inorganic chemistry UNIT-V Radiopharmaceuticals Presented By Ms. Pooja D. Bhandare (Assistant Professor) DADASAHEB BALPANDE COLLEGE OF PHARMACY BESA NAGPUR

2. Content: Radiopharmaceuticals Radio activity Measurement of radioactivity, Properties of α, β, γ radiations, Half life, radio isotopes and study of radio isotopes - Sodium iodide I131 , Storage conditions, precautions & pharmaceutical application of radioactive substances.

3. Radiopharmaceuticals. Radiopharmaceuticals, as the name suggests, are pharmaceutical formulations consisting of radioactive substances (radioisotopes and molecules labelled with radioisotopes), which are intended for use either in diagnosis or therapy or diagnosis. The use of radioactive material necessitates careful and safe handling of these products by trained and authorized personnel, in approved/authorized laboratory facility as per the guide lines of Atomic Energy Regulatory Board (AERB) of India.

4. Radiopharmaceuticals are essential components of nuclear medicine practice, where radiopharmaceuticals are administered to patients for diagnosing, managing and treating number of diseases. Nearly 95% of radiopharmaceuticals are used for diagnostic purposes, while the rest is used for therapy .

5. Definitions and Terminology A nuclide (or nucleide , from nucleus, also known as nuclear species) is an atomic species characterized by the specific constitution of its nucleus, i.e., by its number of protons, Z, its number of neutrons, N, and its nuclear energy state. A radionuclide (radioactive nuclide, radioisotope or radioactive isotope) is an atom that has excess nuclear energy, making it unstable. This excess energy can be used in one of three ways: emitted from the nucleus as gamma radiation; transferred to one of its electrons to release it as a conversion electron; or used to create and emit a new particle (alpha particle or beta particle) from the nucleus

6. Isotopes Isotopes are variants of a particular chemical element which differ in neutron number, and consequently in nucleon number. All isotopes of a given element have the same number of protons but different numbers of neutrons in each atom. Isotopes of an element are atoms of same element with the same atomic number ‘Z’ but different mass numbers ‘A’. They occupy the same place in the periodic table and have similar chemical properties.

7. Radioactive decay (also known as nuclear decay, radioactivity, radioactive disintegration or nuclear disintegration) is the process by which an unstable atomic nucleus loses energy by radiation. A material containing unstable nuclei is considered radioactive. Three of the most common types of decay are alpha decay, beta decay, and gamma decay, all of which involve emitting one or more particles.

8. Types of decay (Alpha, Beta and Gamma Radiations) Radioactive rays were observed to be of three types: 1 Alpha rays, which could barely penetrate a piece of paper Beta rays, which could penetrate 3 mm of aluminium Gamma rays, which could penetrate several centimetres of lead We now know that alpha rays are helium nuclei, beta rays are electrons, and gamma rays are electromagnetic radiation.

9. Units of Radioactivity: The old unit of radioactivity was Curie (Ci), named after the scientists Madame Marie Curie and Pierre Curie, the pioneers who studied the phenomenon of radioactivity. One Ci is the number of disintegrations emanating from 1 g of Radium-226, and is equal to 3.7 x 1010 Bq . In the International System (SI), the unit of radioactivity is one nuclear transmutation per second and is expressed in Becquerel ( Bq ), named after the scientist Henri Bequerel .

10. Measurement of Radioactivity The measurement of nuclear radiation and detection is an important aspect in the identification of type of radiations (  ,  ,  ) and to assay the radionuclide emitting the radiation, suitable detectors are required. The radiations are identified on the basis of their properties. e.g. Ionization effect is measured in Ionization Chamber, Proportional Counter and Geiger Muller Counter. The scintillation effect of radiation is measured using scintillation detector and the photographic effect is measured by Autoradiography.

11. Gas Filled Detectors: Ionization Chamber: Proportional Counters: Geiger-Muller Counter Ionization Chamber: It is the simplest gas filled detector which is based on the collection of all the charges created by direct ionization of the gas molecules through the application of electric field.

12. It consists of chamber filled with gas like Argon, Helium or Air etc. Ionization chamber is fitted with two electrodes kept at different electric potential (50-100V for each cm of distance between two electrodes) and a measuring device to indicate the flow of current. Radiations bring about ionization of gas molecules or ions which cause emission of electrons which in turn reveals the changes in electric current.

13. Advantages: Good Uniform response to a radiation over a wide range of energy. Disadvantages Relatively weak output pulse

14. 2. Proportional Counters: It is the modified form of ionization chamber. Operate at high voltage (1000-2000v). It is device used to detect charged particle having low ionization power (i.e.  , ). Filling gas 90% Ar and 10% methane Principal : When voltage between cathode anode is sufficiently increases, primary ion will produce by interaction of gas particles . They gain sufficient energy to further collide with gas molecule and produce secondary ions and give rice to detector pulse. Advantage: Detect low energy particle. High ionising power Disadvantages: Require high degree of stable voltage because slight change in voltage change the gas multiplication.

15. 3. Geiger-Muller Counter: GM counter was developed by Geiger and Muller in Germany in the year 1928. It is a devise used to detect and measuring ionizing radiation. It is used to all type radiations α, β, γ easily. It is the oldest radiation detector due to its low cost, simplicity and in case of operation; it is the best detector among all. Principle: A GM counter consists of a GM tube, sensing element which detects the radiation and processing electronics which displays the result. The GM tube is filled with an inert gas such as Helium, Neon or Argon at low pressure, to which a high voltage (450-500 V) is applied. The tube conducts electrical charge when a particle or photon of incident radiation makes the gas conductive by ionization. The ionization considerably amplified within the tube to produce easily measured detection pulse, which is fed to processing electronics and display the result.

16. Construction: It consists of a cylinder 1-2 cm in diameter of stainless steel or glass coated with silver on inner side which acts as cathode. Internally a tungsten wire is suspended which is mounted at one end with a glass bead, act as anode. Cylinder is filled mixture of gas (argon and helium generally used) at low pressure which also contain a small amount of quenching vapours.

17. Working: Radiations when enter the tube through a thin section also called as window causes the ionization of gas molecules. From these ionized atoms or molecules, an electron is knocked out of the atom and the remaining atom is positively charged. When the high voltage is applied across the electrode (300-1300), the electrons and positively charged ions are attracted towards anode and cathode respectively. Hence, each particle of radiation produces a brief flow or pulse of current which can be transmitted to radioactive sensor via an interface, which is finally recorded in computer. All pulses from a GM counter are of same amplitude for any incident radiations. Disadvantages: A GM counter cannot distinguish between types of different radiation and their energy. However, the multiplication factor is a big advantage in simple radioactive counting.

18. Types of GM Counter I. End window type : For alpha particle, low energy beta particle and low energy x-ray. They have window at one end covered with thin material through which low penetrate rays can easily pass. II. Window less type: These type of tube would not have any windows and thickness would be in the range of 1-2mm. This type of tube used in the detection of high penetrating radiation.

19. Quenching vapours are used: (a) To prevent the false pulse that may be produced due to positive ion reaching the cathode. (b) To absorb photons emitted by exciting atoms and molecules returning to their ground state. Note: Both Chlorine and Bromine are commonly used as quenching agents. Ethyl alcohol and Ethyl are commonly used as quenching agents. Depending on purpose, different counters are used, like: 1. For counting the radioactive solid source, the end window type GM counter has been used in which window has been made up of Aluminium alloy (7 mg /cm 2 ), Mica or may be thin glass bubble (15 mg/cm 2 ). 2. For counting beta and gamma particles, thin glass walled counters may be used. These have been normally of about 1 cm in diameter, having a glass wall of 20-40 mg/cm 2 thickness and tube is coated on inside with Graphite to form cathode. 3. In order to count radioactive liquids, the counter having the capacity of 10 cm 3 is used. In such a counter, 3% solution of Uranium salt gives nearly 10,000 counts per minute. 4. To count radioactive gases, radioactive gas is introduced together with counting gas. For more efficient gamma counting, counter having lead or copper cathode have been used.

20. Scintillation Detector: When high energy radiation or photons is incident on certain substance, a flash of light is emitted by the phenomenon called fluorescence or phosphorescence.  This output light can be used as a measure of adsorbed radiation on scintillation detector. This emitted light when enters into photo-multiplier tube; it multiplies and amplifies even a small signal. So it becomes possible to measure alpha, beta or gamma radiation by scintillation detector.

21. Important properties of good scintillation detector are: High scintillation efficiency. The light produced should be proportional to the light incident on detectors. Detector material should be transparent to the wavelength range and must not produce any interference in the resultant spectra. Short decay time of the induced fluorescence can be increased by dynodes which are made up of phosphor or fluor which multiplies the electrons when strike to them. Hence various inorganic and organic scintillation detectors can be used to measure the incident radiation. Inorganic scintillation detectors like alkyl halides are most common compounds. e.g. Sodium iodide, Cesium iodide, Lithium iodide. Organic Scintillators like plastic scintillators have good scintillation property but stilbene have low scintillation property.

22. Semiconductor Detector It is a diode of n (electron rich) and p (electron deficient) semiconductors. In a semiconductor the band gap is very small of the order of 2-3 eV and therefore large numbers of electron hole pairs are formed, thus, giving rise to very good resolution to these detectors. Application of a reverse bias across the diode causes transport of electrons towards the n-end and that of ‘holes’ towards p-end. The absorption of incident radiations results in the formation of electron and hole pairs which move under the influence of applied electric field. The collection of electrons at the electrode produces a voltage pulse, which is proportional to the intensity of the incident radiation.

23. Solid State Detectors: They have high resolution, compactness and easy interpretation of output signal. (a) Cerenkor Detector: These are based upon light which is emitted by fast charged particles through an optically transparent medium with refractive index of more than one. (b) Thermoluminescence dosimeters: These are made up of those inorganic crystals in which electron hole pairs have been formed due to radiations which can trap these pairs and on heating lead to emission of light. e.g. CaSO 4 :Mn, LiF , CaF 2 :Mn etc (c) Track-etch Detector: Ionizing radiations having higher linear energy transfer (LET), passing through a dielectric material create trail of damaged molecule along their path. In some material, the tract can be visible upon etching in a strong acid or alkali solution. The damaged molecular tracks are etched faster than the bulk and look like a pits on the surface. These tracks can be counted by viewing through a microscope. The commonly used track-etch materials are quartz, mica, silica glass, flint glass, polyethylene terephthalate, lexan , markrofol , cellulose triacetate, cellulose nitrate.

24. 4. Autoradiography It is a bioanalytical technique used to visualize the radiolabelled substance by using suitable radioisotopes. Principal: Radioisotopes will be emit and emitted radiation will ionize the photographic emulsion result is the formation dark spot. Example of photographic emulsion : Silver halide (Ag x)+ Gelatin Agx Ag + x ------------------ Ag Dark Spot - + radiation

25. Method. Cover the radioactive sample with photographic emulsion. Radioactive part of sample activate the Agx particle nearby The result is the product of Ag ion into Ag atom leaving dark colour band. The slide us washed with fixer to get insoluble silver atom and observe under autoradiogram. +

26. Certain precautions must be taken: ( i ) Radioactive material should never be touched with hands but handled by means of forceps. (ii) Food contaminated with radioactive material can cause serious damage to internal organs, so avoid any food intake, drinking and smoking within the lab. (iii) Sufficient protective clothing or shielding must be used while handling the material. (iv) Radioactive material should be kept in labeled containers and must be shielded. (v) Area of storage must be under proper supervision. (vi) Disposal of radioactive material is done with great care.

27. Properties of α, β, γ radiations Properties of α, β, γ radiations: - All substances are made of atoms. These have electrons (e) around the outside, and a nucleus in the middle. The nucleus consists of protons (p) and neutrons (n), and is extremely small. (Atoms are almost entirely made of empty space!). – In some types of atom, the nucleus is unstable, and will decay into a more stable atom. This radioactive decay is completely spontaneous. - When an unstable nucleus decays, there are three ways that it can do so. It may give out:- an alpha particle (α) a beta particle (β) a gamma ray (γ)

28. Alpha particles (α) Alpha particle radiation consists of two neutrons and two protons, as they are charged they are affected by both electric and magnetic fields. The speed of the α particle depends very much on the source, but typically are about 10% of the speed of light. The capacity of the α particle to penetrate materials is not very great, it usually penetrates no more than a few centi metres in air and is absorbed by a relatively small thickness of paper or human skin. However, because of their speed and size, they are capable of ionising a large number of atoms over a very short range of penetration. This makes them relatively harmless for most sources that are about a metre or more away, as the radiation is easily absorbed by the air. But if the radiation sources are close to sensitive organs α particle radiation is extremely dangerous.

29. Beta-particles (β) Beta-particle radiation consists of fast moving electrons. Every β -particle carries either one negative or one positive electronic charge (β 1.6 × 10-19 coulomb: -e, +e). They are affected by electric and magnetic fields. The speed depends on the source, but it can be up to 90% of the speed of light. β particles can penetrate up to 1 m of air. They are stopped by a few millimetres of aluminium or perspex . Their ionising capacity is much less than that of β radiation. They are very dangerous if ingested.

30. Gamma radiation (γ) Gamma radiation does not consist of charged particles, it is a form of very short wavelength electromagnetic energy. They travel at the speed of light (3 × 108 m/s). Gamma radiation is very difficult to stop, it takes up to 30mm of lead. Although the ionising capacity of γ radiation is considerably smaller than that of beta-radiation, their high penetration power means that they are dangerous even at a distance. They can penetrate our bodies and hit sensitive organs. They are particularly dangerous if ingested or inhaled.

31. Half –life of Radioelement The decay of individual atoms of radioactive substance has been found to be irregular. If a certain amount of radionuclide is taken and the number of disintegration per second is measured, it is found that, after certain time, half of the original atoms would have got disintegrate and only half of the original active atom would be left behind. The number of disintegrations per second will also now be half of the original value.

32. The decay time of radionuclide to its half has been constant irrespective of the quantity present. The time is termed as half-life of the radionuclide. Where is disintegration constant in unit of Half-lives for various radionuclides vary considerably; Polnium-212 half-life of 3x iodine 131has 8 days, Zn 65-150 days, Na 22-2.6 years while uranium 238 has 4.5 x years.  

33. Sodium Iodide (I 131 ) Synonym: Radioactive iodine Out of all radioactive isotopes of Iodine, I 131 is most commonly used. It is used as an aqueous solution of sodium iodide having sodium thiosulphate in addition as a reducing agent. Standards: It should not contain less than 90% and not more than 110% of labelled amount of Iodine-131 as iodide which is expressed in microcuries or millicuries at the time indicating in the labelling. Method of Preparation: The first production of Iodine-131 took place in France in the year 1949 at the Fort de Chatillon, the site of the first Zoe atomic reactor, before it was transferred to the nuclear research centre at Saclay . The isotope has been used since 1942, however, in the treatment of thyroid cancer. Most I-131 is prepared in nuclear reactor by neutron- irradiation of a natural Tellurium target. Irradiation of natural tellurium produces almost entirely I-131 as the only radionuclide with a half-life longer than hours. Ultimately in 8.02 days it gets converted into Xenon-131 (stable isotope). Te 130 Te 131 I 131 Xe 131 (n y) β β γ

34. Properties: It forms a colorless solution. I 131 have half-life of 8.4 days and emits beta and gamma radiations. Its solution is having pH range of 7 to 10. Assay: It is possible to determine its activity, using suitable counting equipment by comparison with a standardized I-131 solution or by measurement of an instrument calibrated with the aid of such solutions. Iodine-131 has been emitting both beta and gamma particles in its decay process. Radioactivity has to be recorded on a counting assembly which is having either a Geiger-Muller counter or a scintillation detector used as a sensing unit and an electronic sealing device. Hyperthyroidism Treatment by I 131 : Iodide inhibits the release of thyroid hormone and forms the basis for its use in hyperthyroidism. All the isotopes of iodine are rapidly taken up by thyroid follicles. Radioactive iodine i.e. I 131 is available as NaI 131 solution and is administered orally. The absorption of I 131 leads to highly localized destruction of thyroid follicles due to β-particles emission. This property of I 131 has promoted radioactive iodine as a therapeutic alternative in surgical removal of the gland. The radio iodine therapy is considered advantageous over surgery because of the simplicity of its procedure, its applicability to patients, avoidance of surgical risks and complications.

35. Sodium iodide-131 solution and capsule: Sodium iodide (I 131 ) are suitable both for oral or i.v. administration. The solution is clear and colourless, but as the time passes both the solution and glass may get darken due to the effect of radiation. The pH of solutions varies between 7.5-9.0. For injection, a suitable preservative such as benzyl alcohol is added. A reducing agent such as sodium thiosulphate is also added to the solution, to prevent the oxidation of sodium iodide in aqueous solutions. Potassium salt, iodide and iodate have been acting as a carrier for iodide ions and for iodate ions present in the sodium iodide I 131 solution. Sodium iodide (I 131 ) capsules are prepared by evaporating an alcoholic solution of sodium radio-iodide directly on the walls of the capsule or on inert capsule filling material. Radioactive Identification: The spectrum of I 131 has been complex but the most abundant type of photon is having energy of 0.364 MeV. It is possible to determine the energy in a spectrometer by detecting  -radiation with a scintillation counter which is having a thallium activated. The γ-ray scintillation spectrum of sodium iodide (I 131 ) solution has been found to be identical to that of specimen of I 131 of known purity, which exhibits major photoelectric peak, having energy of 0.365 MeV.

36. Handling and Storage of Radioactive Material: Great care must be taken in handling and storage of radioactive material so as to protect the people from its harmful effects. The radioactive materials are stored in remote areas such that it should be away from exposure to human beings.  and  -emitters are stored in thick glass such that shielding effect is provided, while  -emitters are stored in lead containers. The area of radioactive material should be tested for intensity of radioactivity. Exposure to radioactive radiation can cause blood cancer to persons. Lead shielding is required while handling with radioactive substances. Shielding effect can also be achieved by water layer and concrete blocks. Water layer blocks only radiation which allows visible light to pass while concrete blocks all the radiations.

37. Storage of Radioactive Substances – Radiopharmaceuticals should be kept in well-closed containers and stored in an area assigned for the purpose. The storage conditions should be such that the maximum radiation dose rate to which persons may be exposed is reduced to an acceptable level. Care should be taken to comply with national regulations for protection against ionizing radiation. Radiopharmaceutical preparations that are intended for parenteral use should be kept in a glass vial, ampoule or syringe that is sufficiently transparent to permit the visual inspection of the contents. Glass containers may darken under the effect of radiation.

38. Precautions For Handling Radioactive Substances The following guidelines provide information on the safe handling of radioactive substances. They are based on the relevant legislation and on the Code of Practice for Handling Radioactive Substances. The radioactive substances used should comply with the following characteristics: Radiotoxicity must be as low as possible. Short-living isotopes are preferred to long-living ones The amounts used must be kept to a minimum. Never work alone in a radioactive lab, especially not outside normal working hours. Always make sure to have someone nearby in case of emergency.

39. Take all precautions to prevent radioactive contamination: Always separate radioactive activities from non-radioactive activities. As far as possible, limit the area where radioactive substances are used and mark the area, e.g. by using containers with absorbent paper. Apply a radiation symbol to any containers and items that have come into contact with radioactive substances. Never bring documents such as notes into the radioactive zone. When handling radioactive materials, always wear the appropriate protective clothing: Wear a lab coat. If there is a risk of serious contamination, wear disposable clothing. Store your lab coat away from your regular clothes. Always wear gloves when handling radioactive substances. Regularly check the radiation level of these gloves. Never touch anything with potentially contaminated gloves; use paper tissues instead. Wear shoe covers in rooms where the floor may be contaminated. Keep personal items such as handbags, etc., outside the lab.

40. Use appropriate radiation shields. Return the stock solution to storage immediately after removing the amount needed. To avoid internal contamination, strict hygiene is essential when handling radioactive materials Eating, smoking, drinking, and applying cosmetics are prohibited in radioactive labs. Never pipette by mouth. Use pipetting devices instead. Wash your hands thoroughly when you leave the lab. Regularly check the radiation level of your working area and all objects used, or at least at the end of each working day. Replace contaminated absorption paper. Decontaminate contaminated objects. Dispose of all radioactive waste in the appropriate containers. Limit the amount of waste to a bare minimum. Separate short-living and long-living radioactive waste.

41. Labelling of Radioactive Substances Every radiopharmaceutical preparation must comply with the labelling requirements established under Good Manufacturing Practice. The label on the primary container should include: A statement that the product is radioactive or the international symbol for radioactivity The name of the radiopharmaceutical preparation; Where appropriate, that the preparation is for diagnostic or for therapeutic use; The route of administration; The total radioactivity present at a stated date and, where necessary, time; for solutions, a statement of the radioactivity in a suitable volume (for example, in MBq per ml of the solution) may be given instead; The expiry date and, where necessary, time; The batch (lot) number assigned by the manufacturer; For solutions, the total volume.

42. The label on the outer package should include: A statement that the product is radioactive or the international symbol for radioactivity o The name of the radiopharmaceutical preparation; Where appropriate, that the preparation is for diagnostic or for therapeutic use; The route of administration; The total radioactivity present at a stated date and, where necessary, time; for solutions, a statement of the radioactivity in a suitable volume (for example, in MBq per ml of the solution) may be given instead; The expiry date and, where necessary, time; The batch (lot) number assigned by the manufacturer; For solutions, the total volume; Any special storage requirements with respect to temperature and light; Where applicable, the name and concentration of any added microbial preservatives or, where necessary, that no antimicrobial preservative has been added .

43. Pharmaceutical Application Of Radioactive Substances Treatment of Cancers and Tumours Americium 241 used as antineoplastic. Californium 252 used as antineoplastic.“ Cobalt 60 used as antineoplastic. Gold 94 used as antineoplasatic . Holmium 66 (26 h) being developed for diagnosis and treatment of liver tumours. Iodine-125 (60 d) used in cancer brachytherapy (prostate and brain).

44. Treatment of Thyroid Disease with Iodine 131 Iodine-131 is therapeutically used for to treat thyroid cancer, hyperthyroidism (including Graves’ disease, toxic multinodular goiter , and toxic autonomously functioning thyroid nodules), and Nontoxic multinodular goiter . Palliative Treatment of Bone Metastasis Various radioisotopes and pharmaceuticals are used to deliver palliative treatment of bone metastases, including samarium-153 (Sm-153), strontium-89 (Sr-89) chloride, and phosphorus-32 (P-32) sodium phosphate. The two most common side effects occurring from radiopharmaceutical therapy for metastatic bone disease are initial increased bone pain (flare) and a decrease in WBC and platelet counts.

45. Treatment of Arthritis Erbium-169: Use for relieving arthritis pain in synovial joints - Diagnostic Radiopharmaceuticals Ammonia N 13 Injection used for diagnostic coronary artery disease. Chromium 51 used for diagnosis of pernicious anaemia. Holmium 166 used for diagnosis and treatment of liver tumours. Iodine 125 used diagnostically to evaluate the filtration rate of kidneys.

46. Thank You !