International Journal of Trend in Scientific Research and Development (IJTSRD)

Volume 4 Issue 1, December 2019 Available Online: www.ijtsrd.com e-ISSN: 2456 – 6470

Illustrative Review on Radiopharmaceuticals

K. R. Satav, T. P. Shangrapawar, Dr. Ashok Bhosale
Department of Pharmaceutics, Shankarrao Ursal College of Pharmaceutical
Sciences & Research Center, Kharadi, Pune, Maharashtra, India

ABSTRACT How to cite this paper: K K. R. Satav | T. P.

Radiopharmaceutical is a key component involved in the field of nuclear Shangrapawar | Dr. Ashok Bhosale
medicine. It serves various purposes diagnostically and also serves with "Illustrative Review on
different diagnostic applications. Radioactive agents are employed in nuclear Radiopharmaceuticals" Published in
field for demonstration of high and exact localized radioactive effect in a International Journal
particular target tissue. In recent years various amount of radionuclides and of Trend in Scientific
radiopharmaceuticals are utilized for treating cancer and other complex Research and
disease like neuroendocrine disorder. This review focuses on the Development (ijtsrd),
manufacturing, quality control tests and diagnostic applications of ISSN: 2456-6470,
radiopharmaceuticals. Volume-4 | Issue-1,
December 2019, IJTSRD29762
KEYWORDS: Radioactivity, Radiopharmaceuticals, Radionuclide pp.905-911, URL:
www.ijtsrd.com/papers/ijtsrd29762.pdf

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INRODUCTION
Radioactivity: Radioactivity is termed as a spontaneous Abscess and, biliary tract blockage, Blood volume studies
emission of radiation which occurs in the form of particles or and diseases, Blood vessel diseases of the brain, Bone
high energy photons resulting from a nuclear reaction. diseases, etc.
Radioactivity is also known as nuclear decay, radioactive
decay, nuclear disintegration, or radioactive disintegration. Manufacturing of Radiopharmaceutical Dosage Form
There are many forms of electromagnetic radiation but they Radiopharmaceutical Dosage forms
are not always produced by radioactivity. Radioactive is a A radiopharmaceutical dosage form is termed as a solid,
substance that contains unstable atomic nuclei. Radioactive liquid or gaseous formulation comprising of radioisotopes,
decay is a random process which occurs at the level of present in a ready to use form, which are safe for
individual atoms. Based on decay constants or half-lives the administration in humans for diagnosis or for therapeutic
rate of decay of a group of atoms may be predicted, while it purpose. A radioactive component is present along with a
is impossible to predict exactly when a single unstable drug component. Inorganic compounds, organic compounds,
nucleus will decay. The time required for half of the sample proteins, peptides, monoclonal antibodies, fragments and
of matter to undergo radioactive decay is called as half-life. oligonucleotides labeled with radionuclide are included
under Radiopharmaceutical products. The half-life of a
Radiopharmaceuticals: A radiopharmaceutical is regarded radiopharmaceutical ranges from a few minutes to several
as a radioactive drug which is used for diagnosis or therapy days. The provision of static and dynamic images of internal
in a tracer quantity. It is comprises of two parts; a organs in a non-invasive manner along with therapeutic
radionuclide and pharmaceutical. Pharmaceutical drugs with efficacy is provided by Radiopharmaceutical dosage form.
radioactivity property can be used as Diagnostic and
therapeutic agents. Radiopharmaceuticals are drugs which Manufacturing of Radiopharmaceutical Dosage Forms
contain radioactive materials called radioisotopes. The manufacturing process for radiopharmaceutical
Radiopharmaceuticals can be administered by different preparations should meet the requirements of Good
route such as taken by mouth, inserted into a vein, or placed Manufacturing Practices.
in a body cavity. Radiopharmaceuticals materials travel to
different parts of the body for treating cancer or relieve its Radiopharmaceuticals are prepared in three steps.
symptoms. In small amounts radiopharmaceuticals are 1: Production of Radionuclide (radioactive isotope)
commonly used for imaging tests, but larger doses can be 2: Preparation of Radiopharmaceutical
used to deliver radiation. Radiopharmaceuticals are also 3: Preparation of Radiopharmaceutical kit
used in the diagnosis different diseases like infection,

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Step 1 Production of Radionuclide

Nuclear Neutron Cyclotron

Fission bombardment method

Formation of Radionuclide
(Can be used in either elemental or salt form as ready to use radiopharmaceutical

1. Production of Radionuclide (radioactive isotopes)
Fission is induced by bombardment of the parent

Artificial production of Radionuclides by the process of nucleus with a neutron.
nuclear activation in a nuclear reactor. 235 U + 1 n X+Y+2.5n
92 0

In such a reactor stable atoms are bombarded with X and Y are the radioactive isotopes formed.
excess neutrons. The resulting addition of neutron to

For each neutron consumed, an average of 2.5 new
stable atoms produces radionuclide.
neutrons are produced that may initiate the fission of

Methods of producing radionuclide are as follows:
other nuclei. Such a reaction is called chain reaction.
A. Nuclear fission 238 U + 1 n 131 Sn + 106 Mo + 1 n + 1 n
92 0 52 42 0 0
B. Neutron reactions
C. Cyclotron method
Sn (Tin) and Mo (Molybdenum) are radioactive and
decay further emitting beta particles.
131 Sn 131 sb 131 131 I
A. Nuclear fission 50 51 52 Te + 53

Nuclear Fission is termed as a radioactive process in I-131 (Iodine-131) is used for medical applications.
which a heavy nucleus split into two new nuclei of
almost equal size with simultaneous emission of two or
In this process, separation of the desired radioactive
three neutrons. element from the mixture is difficult and costly.

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B. Neutron Reactions (Neutron Bombardment) IV. Biosynthesis: A radionuclide is incorporated into a

The preparation of radionuclide is done by neutron molecule through some biosynthetic process.
activation or through transmutation reactions.

An acceptable target material is bombarded by neutrons 3. Preparation of Radiopharmaceutical Kit
in a nuclear reactor. A radiopharmaceutical kit permits the radio pharmacist for

Radioactive phosphorous can be made by transforming the radioactive isotope obtained from the
transmutation. generator into the desired radiopharmaceutical. It is a vial
32 S + 1 n 32 1
16 0 15 P + 1P containing freeze dried and sterile non-radioactive
The radioactive phosphorous can be separated by chemical components into which the appropriate radionuclide is
process. added or in which the appropriate radionuclide is diluted
before medical use. The nonradioactive ingredients of a
C. Cyclotron Method (Charged Particle Bombardment) normal formulation are ligands, reducing agents, stabilizers,

The cyclotron or particle accelerators can be used only buffers and antioxidants. The freeze dried kit is
with charged particles like electrons, protons and alpha reconstituted through aseptic transfer of the necessary close
particles, as operation of the machine is depend upon of the radioactive isotope using a sterile syringe or needle.
the interaction of magnetic or electrostatic fields with The amount of activity withdrawn for the reconstitution of
the charge of the particle which is undergoing the kit is depends on the number of patient doses to be
acceleration. manufactured. The reconstituted kit is aseptically divided to

Particles when accelerated to a very high velocity, they provide each patient a dose with sufficient activity.
are caused to strike a target comprising of the atoms to Radiopharmaceutical preparations obtain from kits are
be bombarded. normally intended for use within 12 hours of preparation.

2. Preparation of Radiopharmaceutical The radiopharmaceutical kit consist of

Radiopharmaceuticals are prepared by following two
Methylene diphosphonate: a ligand forming a complex
methods, with Technetium.
A. Radionuclide Generator
Stannous ions (Stannous chloride or fluoride): a
B. Radiolabel ling Method reducing agent which enhances the complication of
ligand with Technetium.
A. Radionuclide Generators
Other compounds such as stabilizers, buffers and
It is advantageous to use a nuclide with short half-life to antioxidants.
minimize the radiation dose received by the patient, when
Technetium complex obtained from the
radioactive isotopes are to be used clinically. Greater radiopharmaceutical kit after reconstitution should be
problems of supply are caused due to shorter half-life so, used within 8 hours after production.
radionuclide generator is used. It provides a mechanism for
separating a clinically useful, short half-life daughter from a Radiopharmaceutical Preparations
long-lived parent nuclide which is used later for the Following are some radiopharmaceutical preparations used
production of radiopharmaceutical dosage form. for diagnostic and therapeutic purpose.

e.g.: Molybdenum 99/Technetium 99m generator: It consists 1. Cobalt 57 (Co-57) and Cobalt 60 (Co-60)
of an alumina column on which Molybdenum 99 is adsorbed Cobalt in cyanocobalamine (Vitamin B12) is replaced either
as Ammonium molybdate. by radioactive cobalt 57 or cobalt 60. They are available as
capsules and injection.
B. Radiolabel ling method
Some radionuclide can be used in their elemental or salt Cobalt- 57 may be prepared by irradiating Nickel 58 (Ni-58)
form for medical or pharmaceutical purpose. However, most with gamma rays or by bombarding Iron 56 (Fe-56) with
radionuclide must be incorporated into some molecule or protons. Its half-life is 270 days.
compound to form a useful radiotracer or
radiopharmaceutical by a process known as radiolabel ling. Cobalt- 60 is prepared by bombarding stable Cobalt 59 by a
Carrier addition permits ready handling of the neutron. Its half-life is 5.27 years. It emits both beta and
radiopharmaceutical. In some conditions it will be important gamma particles.
to add carrier to enhance chemical, physical or biological
properties of the radiopharmaceutical preparation. The Cyanocobalamine Co-57 or Co-60 is used in diagnosis of
carrier may be in the form of inactive material, either pernicious anemia. Cobalt 60 is converted into needles, wires
isotopic with the radionuclide, or non-isotopic, but or seeds and implanted in the body cavity or directly into
chemically similar to the radionuclide. tumor. It is used in the treatment of the advanced stages of
cancer of cervix and vagina.
Radiolabel ling is done by the following methods
I. Introduction of a foreign label: A radioactive isotope 2. Iodine 125 (l-125) and iodine 131(l-131)
is chelated with other compounds to use it medically. They are available as capsules, solutions and injection.
II. Isotope exchange: Radioactive isotope is substituted Iodine 131 emits both beta and gamma radiations. Its half-
for a stable atom of the same element that is already a life is 8.08 days it is obtained as a by-product of Uranium
natural part of the molecule. fission. It can also be prepared by bombarding Tellurium 130
III. Labelling with bifunctional chelates: A bifunctional by neutrons is used in diagnosis of functioning of thyroid
chelate is a molecule used to link another molecule with gland. The size, position of the gland and possible tumor
a radionuclide. location can be assessed. Iodine 131 is used therapeutically

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to destroy thyroid tissue in cases of thyroid carcinoma, these tests become unique and ensure specificity for
hyperthyroidism, thyrotoxicosis and severe cardiac disease. radiopharmaceuticals.
In heart diseases like angina pectoris and congestive heart
disease, it is used to induce a hypothyroid state as a means of Physical Characteristics
reducing the work load on the heart. Iodinated Serum It contain of the colour and state of a radiopharmaceutical. A
Albumin (I-l25lI-131) is used to obtain circulating blood real solution mustn't be containing any particulate matter.
volume. It is also used for diagnosis of pulmonary blood flow, Any deflection from the original colour and clarity should be
lung and bronchial tumors. viewed with concern as it may replicate changes in the
radiopharmaceutical which would change its biological
3. Iron 59 (Fe-59) behaviour. Colloidal or aggregate preparations should have
It is prepared by neutron activation of Iron 58. It emits beta an accurate size range of particles for a given intended
and gamma radiations. Its half -life is 45 days. It is used in purpose.
diagnosis of problems related to iron metabolism and RBC
formation. It is administered orally as Sterile Ferrous citrate pH and Ionic Strength
solution to study absorption of iron from gastrointestinal All radiopharmaceuticals must comprise of a proper
tract. It is given intravenously to study plasma iron clearance hydrogen ion concentration or pH scale for maintaining their
and incorporation of iron into erythrocytes. stability and integrity. Ideal pH scale of a
radiopharmaceutical should be 7.4. Due to high buffer
4. Gold 198 (Au-198) capacity of the blood pH ranges between 2 and 9.
It is available in injection form which is a sterile, colloidal Radiopharmaceuticals should have correct Isotonicity, Ionic
suspension of metallic gold. It emits both beta and gamma strength, Osmolality so as to be appropriate for human
particles. Its short half-life is 2.7 days. It is prepared by administration. By adding a correct Acid, Alkali, or
bombarding stable Au-197 by neutrons. It is used for Electrolyte the right ionic strength can be achieved.
scintillation scanning of liver which helps in determining the
shape, position and size of the organ. It helps to assess Radio nuclidic Purity
functioning of Kupffer's cells in the liver. Therapeutically, it It can be defined as the fraction of the total radioactivity in
is used in the management of pleural effusion (accumulation the form of the desired radionuclide present in a
of serous fluid in the pleural cavity), ascites (accumulation of radiopharmaceutical. Many times extraneous impurities are
serous fluid in the peritoneal cavity) and rheumatoid known to arise during the production of the radionuclides.
arthritis Radionuclidic purity affects the absorbed radiation dose and
image quality. It can be measured by use of gamma
5. Barium sulphate spectrometry, half-life measurement and other methods to
Barium sulphate is used as a radiopaque contrast medium. detect extraneous nuclide
Radiopaque contrast media are compounds or elements of
high atomic number. They hinder the passage of X-rays and Radiochemical Purity
are used as diagnostic aid in radiology or roentgenology. It is defined as the fraction of the total radioactivity within
Barium sulphate is available as oral solution or as an enema. the desired chemical form in the radiopharmaceutical.
If taken by mouth, it makes the esophagus, the stomach, Radiochemical impurities arise from decomposition due to
and/or the small intestine opaque to the X-rays so that they the action of solvent, Presence of oxidizing or reducing
can be photographed. If it is given by enema, the colon agents, Change in pH scale or temperature, light and
and/or the small intestine can be seen and photographed by radiolysis. Absorption of radiations by tagged molecules
x-rays. leads to the formation of free radicals with unpaired
electrons .Which in turn leads to further decomposition of
6. Technetium-99m other molecules. A secondary method due to radiolysis
Technetium is an artificial element and all of its isotopes are produces H2O2 or HO2 from decomposition of water
radioactive. It is prepared by neutron bombardment of (solvent) that reacts with and ultimately decomposes tagged
Molybdenum 99.It emits gamma rays. Its half-life is 6 hours. molecules. Numerous analytical methods can be used to
It is available as sodium pertechnetate and a colloidal discover and confirm the radiochemical impurities in a given
preparation of Technetium sulphide. Technetium 99m radiopharmaceutical. These methods include Precipitation,
labelled human serum albumin is used to obtain lung scans. High-Performance Liquid Chromatography, Paper and
It is also used to measure cerebral blood flow and for Instant Thin-Layer Chromatography, Paper or
scintography of the salivary glands, stomach, heart and Polyacrylamide Gel Electrophoresis, Gel Chromatography,
joints. Technetium 99m glucoptate is used in assessment of etc.
kidney shape, size and position. It also identifies kidney
Chemical Purity
lesions.
The presence of chemical impurities before radiolabeling
may lead to undesirable tagged molecules which can or may
Quality Control of Radiopharmaceuticals
not interfere with the diagnostic test. The chemical
It includes numerous specific tests that ensure purity,
impurities may also cause a toxic effect. Purification of
potency, product identity, biological safety, and effectivity of
radiopharmaceuticals from Chemical impurities is usually
radiopharmaceuticals.
achieved by strategies of chemical separation methods such
as Precipitation, Distillation, Solvent extraction, etc.
Physicochemical Tests
These tests are essential for the determination of the purity Radio assay
and integrity of a radiopharmaceutical. The amount of radioactivity of a radiopharmaceutical before
Radiopharmaceuticals they contain radionuclides, therefore dispensing as well as before dose of administration to

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patients must be determined. These activity determinations test, three mature regular rabbits are taken whose weight
are accomplished by means of an isotope dose calibrator. not less than 1.5 kg, and their temperatures are controlled by
According to the Nuclear Regulatory Commission regulations maintaining them in a place of uniform temperature. The
the following quality control tests should be performed at volume of the test sample must be an equivalent human
the frequencies indicated: dosage, on a weight basis, and often three to ten instances
1. Constancy (daily) the human dosage by volume is used to achieve a greater
2. Accuracy (at installation, annually, and after repairs) protection factor. The ear vein of each of the three rabbits
3. Linearity (at installation, quarterly, and after repairs) the check sample is injected. The rectal temperatures of the
4. Geometry (at installation and after repairs) rabbits are measured after 1, 2, and 3 h injection ofthe test
material. If the temperature is push upward in man or
1. Constancy (daily): This test indicates the woman rabbits is less than 0.60C and if the sum of the
reproducibility of measurements by a dose calibrator. temperature rises in all three rabbits is not more than 1.40 C,
2. Accuracy (at installation, annually, and once then the check sample is considered apyrogenic. If any of the
repairs): The accuracy of a dose calibrator is decided by above conditions is not fulfilled, the test must be repeated
measuring the activities of minimum two long-lasting with five more rabbits. If not more than three of the total
reference sources and comparing the measured activity eight rabbits show a temperature rise of 0.60 C and if the sum
with the expressed activity. The measured activity of the man or woman temperature rises does not exceed 3.70
should consider the expressed activity within G10%. C, the material is taken into consideration pyrogen free.
3. Linearity (at installation, quarterly, and once
repairs): The linearity test specify the dose calibrator’s A rapid method for bacterial endotoxin test, also called the
capacity to measure the activity accurately over a wide LAL test, is used for the detection and quantitation of
range of value endotoxin-type pyrogens. This method uses the lysate of
4. Geometry (at installation and after repairs): Amebocyte from the blood of the horseshoe crab, Limulus
Variations in sample volumes or geometric Polyphemus. The principle of the test is based on the
configurations of the instrumentation. formation of an opaque gel by pyrogens in the presence of
Ca2+ upon incubating the sample with the LAL at 370C. An
Measurement of Radioactivity assay mixture usually includes of 0.1 mL LAL and a test
Radioactivity of a radiopharmaceutical is measured by sample at pH 6–8. The reaction takes place within 15–60 min
putting the sample within the dose calibrator with the after mixing and depends on the concentration of pyrogens.
acceptable isotope selector setting. The reading is displayed The formation of a gel shows the presence of pyrogens. The
in applicable units (curie or Becquerel) on the dial. LAL test is carried out on unknown samples as well as on E.
coli endotoxin and water samples. Usually 0.1 mL of every
Biological Tests sample and LAL are incubated at 370C for 60 min. If the E.
This test carried out essentially to examine the sterility, coli endotoxin sample shows gel formation (positive control)
Pyrogenicity and Toxicity of radiopharmaceuticals before and the water sample shows no gel formation (negative
human administration. control), then unknown samples are taken into
consideration positive or negative depending on whether
Sterility: they form gel or not. The US FDA has authorized the LAL test
Sterility indicates the absence of viable microorganisms such for endotoxin-kind of pyrogens.
as bacteria, fungi and yeast in a radiopharmaceutical
preparation. The methods of Sterilization are Autoclaving Diagnostic Applications of Radiopharmaceuticals:
and Membrane Filtration. Special difficulties arise, in For diagnostic purpose, a radiopharmaceutical dosage form
carrying out the test for sterility for radiopharmaceutical is administered to the patient by numerous routes such as
preparations because of the short half-life of most oral, inhalation, intravenous or alternative routes in a very
radionuclides, small size of batches and the radiation specific dose and acts as radioactive tracer. The radioactive
hazards. USP 32 indicates sterility tests are performed by isotope select for diagnostic purpose should have minimum
incubating the radiopharmaceutical sample in two different half-life, minimum retention within the body and may be
ways in order to detect bacterial and fungal contaminations: detectable in little amounts.
1: For bacterial contaminations the radiopharmaceutical
sample should be incubated in fluid thioglycollate 1. To find carcinoma growths:
medium at 30–350C for fourteen days I-131 is employed to find carcinoma tumour that is known
2: For fungal contaminations the radiopharmaceutical by a cold space within the liver.
sample should be incubated in soybean–casein digest
2. To assess liver functions: Au-198 injection is
medium for incubation at 20–250C for fourteen days
employed for scanning of liver to determine its shape,
position and size. The isotope gives information about
Pyrogenicity:
functioning of kupffer cells. Itdoesn’t enter the tumour
Radiopharmaceuticals for administration must be pyrogen
tissue, abscesses and cysts which then appear as cold
free. The pyrogens are both polysaccharides and proteins
space in the liver scan.
produced with the aid of microorganisms. They are 0.05 to 1
3. To detect bone tumours: Technetiurn - 99m is
mm in size, soluble and warmth stable. Administration of
employed to detect bone tumour which is known by a
pyrogens produces signs and symptoms of fever, malaise,
hot space in the bone.
chills, headache, pain in joints, leukopenia, flushing, dilation
4. To detect spleen and bone marrow cancer: Colloidal
of the pupils and sweating. In order to detect apyrogenicity
solution of Technetium sulphide when injected
of radiopharmaceuticals USP Rabbit test and Limulus
intravenously is taken up by endothelial cells of liver,
Amebocyte Lysate (LAL) test can be carried out. For rabbit
spleen and bone marrow.

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@ IJTSRD | Unique Paper ID – IJTSRD29762 | Volume – 4 | Issue – 1 | November-December 2019 Page 911