Radiopharmaciutics......................................

Debre Berhan University
Health Science College
Pharmacy Department
Pharmaceutics Unit
Aychew M. (B.Pharm, MSc Candidate)
2014E.C
Radiopharmaceuticals
Integrated Physical Pharmacy and
Pharmaceutics II (Phar 3121)

Chapter objective
➢After completion of this chapter, you will be
able to:
✓Compare and contrast the three principal types of
radioactive decay
✓Discuss the use of radiopharmaceuticals in
diagnostics and therapeutics.
✓Discuss preparation of radiopharmaceuticals
By: Aychew M. IPP II(Phar3121) 2014EC 2

Chapter objective…
✓Enumerate the ideal properties of
radiopharmaceuticals
✓Describe storage and disposal of
radiopharmaceuticals

Introduction
➢Radiopharmaceutical is a radioactive
pharmaceutical agent that is used for diagnostic or
therapeutic procedures
✓ The diagnostic side is well established, while the
therapeutic side of nuclear medicine is evolving
➢Radiation is an inherent characteristic of all
radiopharmaceuticals, and patients always receive
an unavoidable radiation dose

Introduction…
➢A radiopharmaceutical can be
✓As simple as a radioactive element such as
133Xe,
✓A simple salt such as 131I-NaI, or
✓A labeled compound such as 131I-iodinated
proteins and 99mTc-labeled compounds.
(Technetium-99m)

Introduction…
➢A radiopharmaceutical has two components
✓ Radionuclide
❖ Provides the desired radiation characteristics
✓ Pharmaceutical
❖ A chemical compound with structural or
chemical properties that determine the in vivo
distribution and physiological behavior of the
radiopharmaceutical
✓ Other additives

Introduction…
➢A suitable radionuclide is tagged onto the chosen
pharmaceutical such that after administration of
the radiopharmaceutical, radiations emitted from
it are detected by a radiation detector
✓Thus, the morphologic structure or the
physiologic function of the organ can be
assessed

Introduction…
➢The usefulness of a radiopharmaceutical is
dictated by the characteristics of these two
components which are radionuclide and
pharmaceutical

Radionuclide
➢ Radionuclides are unstable nuclei that are
stabilized upon radioactive decay.
➢Approximately 3000 nuclides have been
discovered so far; most of these are unstable, but
only about 30 of these are routinely used in
nuclear medicine.

Radionuclide…
➢The nucleus of an atom is composed of protons
and neutrons, collectively called nucleons.
✓The number of protons in a nucleus is called the
atomic number of the atom, denoted by Z.
✓The number of neutrons is denoted by N.
➢The total number of nucleons in a nucleus is
referred to as the mass number, denoted by A.
Thus, A is equal to Z + N.

Radionuclide…
➢The ratio N/Z is an approximate index of the
stability of a nuclide.
✓This ratio equals 1 in the stable nuclei with a
low atomic number, such as 12
6C, 16
8O, and 14
7N
✓The ratio increases with the increasing atomic
number of the nucleus.
✓For example, it is 1.40 for 127
53I and 1.54 for
208
82Pb.

Radionuclide…
➢Nuclei with N/Z different from the stable nuclei
are unstable and decay by emitting different types
of ionizing radiation:
✓Alpha (α)
✓Beta minus (β-)
✓Positron (β+) and
✓Gamma (γ) radiation.

Decay of Radionuclide
➢If the daughter nucleus is stable, this
spontaneous transformation ends
✓If the daughter is unstable, the process
continues until a stable nuclide is reached
➢Diagnostic radiopharmaceuticals should decay
by gamma emission or positron emission

Decay of Radionuclide…
➢Therapeutic radiopharmaceuticals should decay
by particulate decay (alpha or beta minus) since
the intended effect is radiation damage to specific
cells

Alpha () decay
➢Alpha () decay is characterized by the emission
of an alpha particle from the nucleus.
➢ particle is a helium ion containing two
protons and two neutrons bound together in the
nucleus. 2
4
2
4
A
2
Z
A
Z He
Y
X +
−
− +
→

➢The  particles are mono-energetic, and their
range in matter is very short (on the order of 10-6
cm) due to their mass, thus leaving much of its
energy on a very small area (only a few cell
diameters)
➢Used only for therapeutic purposes
➢Their clinical use is very limited, and they are
mainly used for research purposes

Beta-Minus (Negatron) Decay
➢Beta-minus (-) decay characteristically occurs
with radionuclides that have an excess number of
neutrons (‘‘neutron rich’’) compared with the
number of protons
i.e., has a higher N/Z ratio compared to the
stable nucleus
In - decay, a neutron (n) decays into a proton
(p) and a - particle

Beta-Minus (Negatron) Decay…
➢After - decay, the atomic number of the daughter
nuclide is one more than that of the parent nuclide;
however, the mass number remains the same for
both nuclides
✓ An antineutrino ( ) is an entity almost without
mass and charge and is primarily needed to
conserve energy in the decay

β
Y
X -
A
1
Z
A
Z +
+
→ +


➢The - particle is emitted with variable energy
from zero up to the decay energy.
✓The decay or transition energy is the difference
in energy between the parent and daughter
nuclides.
✓An antineutrino carries away the difference
between the - particle energy and the decay
energy.

➢Beta emitters represent different energy levels,
and have different range in matter (40-100μm)
depending on their energy.
➢Beta particles are not as destructive as alpha
particles
✓However, Beta emitting radionuclides are used
in radiopharmaceuticals mainly for therapeutic
purposes

Positron or β+ Decay
➢Nuclei that are ‘‘neutron deficient’’ or ‘‘proton
rich’’ (i.e., have an N/Z ratio less than that of the
stable nuclei) can decay by β+-particle emission
accompanied by the emission of a neutrino (V),
which is an opposite entity of the antineutrino.

Positron or β+ Decay…
➢In β+ decay, a proton transforms into a neutron by
emitting a β+ -particle
✓The daughter nuclide has an atomic number that
is 1 less than that of the parent
➢Since a β+ particle can be emitted with energy
between zero and decay energy, the neutrino
carries away the difference between decay energy
and β+ energy. 23

Positron or β+ Decay…

β
Y
X A
1
-
Z
A
Z +
+
→ +

Decay of Radionuclide….
Gamma radiation
➢A nucleus can remain in several excited energy
states above the ground state
✓All these excited states are referred to as
isomeric states and decay to the ground state
✓The decay of an upper excited state to a lower
excited state is called the isomeric transition

Gamma radiation…
➢In isomeric transition, the energy difference
between the energy states may appear as gamma
(γ) rays.
✓Gamma radiation is characterized as
electromagnetic radiation
✓When used in diagnostic radiopharmaceuticals,
gamma rays are powerful enough to be detected
outside the body of the patient

Activity of Radionuclide
➢The activity of radioactive material may be
calculated by a decay equation that allows the
clinician to predict the activity at any time
➢The specific decay equation:
Where: Ao is the initial activity,
✓ Ae is the specific activity at time t,
✓ λ is the decay constant calculated as
ln2/half life, and t is time

Activity of radioactive…
➢The fundamental unit of radioactivity is the curie
(Ci)
✓Defined as 3.700 × 1010 nuclear
transformations per second or disintegrations
per second (dps)
➢ Another unit of activity is the becquerel (Bq).
✓The becquerel is equivalent to 2.703 × 10−11 Ci

Example
➢If a doctor is prescribed a 15 mCi dose of
99mTc to the patient how much is it in Bq

➢The amount of radiation absorbed by body tissue
in which a radioactive substance resides is called
the radiation dose.
✓The Gray (Gy) is the international unit of
absorbed dose, equal to 1 joule of energy
absorbed by 1 kg of tissue
➢Radiopharmaceutical doses are dispensed to
patients in units of activity, typically mCi or μCi.

Production of Radionuclide
➢All radionuclides commonly administered to
patients in nuclear medicine are artificially
produced
➢Most are produced by:
✓Cyclotrons
✓Nuclear reactors
✓Radionuclide generators

Production of Radionuclide…
Cyclotron-Produced Radionuclides
➢Cyclotrons produce radionuclides by bombarding
stable nuclei (target elements) with high-energy
charged particles such as protons, deutérons,
and α particules
➢When targets of stable elements are irradiated
nuclear reactions take place.

Cyclotron-Produced Radionuclides…
➢In a nuclear reaction, the incident particle may
leave the nucleus after the interaction, leaving
some of its energy in it, or it may be completely
absorbed by the nucleus, depending on the
energy of the incident particle.

➢Depending on the energy deposited by the
incident particle, a number of nucleons are
emitted randomly from the irradiated target
nucleus, leading to the formation of different
nuclides.

➢Cyclotron-produced radionuclides are usually
neutron deficient and therefore decay by β+
emission
Example
➢ Iodine-123 can be produced by several nuclear
reactions in cyclotron such as
✓ 121Sb(α, 2n) 123I 123Te (p, n) 123I
✓ 122Te (d, n)123I 124Te(p, 2n) 123I.

➢Gallium-67 can also be produced by several
nuclear reactions
✓66Zn(d, n)67Ga,
✓68Zn(p, 2n) 67Ga, and
✓64Zn(α, Þ) 67Ga.

Reactor-Produced Radionuclides
➢A nuclear reactor is constructed with fuel rods
made of fissile materials such as enriched 235U &
239Pu
➢When a target element is inserted in the reactor
core, a thermal neutron will interact with the
target nucleus to produce various radionuclides.

Reactor-Produced Radionuclides…
➢In the reactor, two types of interaction with
neutrons are of considerable importance in the
production of various useful radionuclides:
✓Fission of heavy elements
✓Neutron capture reaction

Fission Reaction
➢ Fission is defined as the breakup of a heavy
nucleus into two fragments of approximately
equal mass, accompanied by the emission of
two to three neutrons with mean energies of
about 1.5 MeV.

➢When a target of heavy elements is inserted in the
reactor core, heavy nuclei absorb thermal
neutrons and undergo fission.
➢Fissionable heavy elements are 235U, 239Pu, 237Np,
232Th.

➢Many clinically useful radionuclides such as 131I,
99Mo, 133Xe, and 137Cs are produced by fission of
235U.

➢Nuclides produced by fission may range in
atomic number from about 28 to nearly 65
➢These isotopes of different elements are separated
by appropriate chemical procedures that involve:
✓ Precipitation
✓ Solvent extraction
✓ Ion exchange chromatography
➢The fission products are usually neutron-rich and
decay by - particle emission

Neutron Capture Reaction
➢The target nucleus captures one thermal neutron
and emits gamma (γ) rays to produce an isotope
of the same element
✓The target and the product nuclei belong to the
same element

Neutron Capture Reaction…
➢Some examples of neutron capture reactions are
✓98Mo(n, γ ) 99Mo
✓196Hg(n, γ) 197Hg
✓50Cr (n, γ) 51Cr

Radionuclide Generators
➢Since cyclotrons and reactors are expensive,
these facilities are limited and supply
radionuclide to remote facilities that do not
possess such equipment.

Radionuclide Generators…
➢Very short-lived radionuclides are available only
in the institutions that have the cyclotron or
reactor facilities; they cannot be supplied to
remote institutions or hospitals because they
decay rapidly.

➢For remote facilities, however, there is a
secondary source of radionuclides, particularly
short-lived ones, which is called a radionuclide
generator

Principles of a Generator
➢A generator is constructed on the principle of the
decay-growth relationship between a long-lived
parent radionuclide and its short-lived daughter
radionuclide.
➢In a generator, basically a long-lived parent nuclide
is allowed to decay to its short-lived daughter
nuclide, and the latter is then chemically separated.

➢The importance of radionuclide generators lies in
the fact that they are easily transportable and
serve as sources of short-lived radionuclides in
institutions far from the site of a cyclotron or
reactor facility.

➢An ideal radionuclide generator should be
✓ Simple
✓ Convenient
✓ Rapid to use
✓ Give a high yield of the daughter nuclide
repeatedly and reproducibly
✓ Properly shielded to minimize radiation
exposure
✓ Strong and compact for shipping

➢Generator systems important in nuclear medicine:
✓99Mo – 99mTc
✓113Sn – 113mIn
✓82Sr – 82Rb
✓68Ge – 68Ga

99Mo–99mTc Generator system
➢The parent radionuclide 99Mo has a half-life of 66
hr and decays to the metastable state 99mTc
➢The daughter radionuclide 99mTc has a half-life of
6 hr and decays to 99Tc (stable one) by the
isomeric transition of 140 keV (emit gamma-ray)
✓Nearly ideal for the current generation of
imaging devices in nuclear medicine.

Ideal properties of radiopharmaceutical
1. Easy Availability
➢ Should be inexpensive, and readily available in
any nuclear medicine facility.
2. Short Effective Half-Life
➢ A radionuclide decays with a definite half-life,
which is called the physical half-life (the time
during which an initial activity of a
radionuclide is reduced to one half- Tp) and

Ideal properties of radiopharmaceutical…
➢ It disappears from the body with a certain
biologic half-life (the time needed for half of the
radiopharmaceutical to disappear from the
biologic system - Tb).
➢ In any biologic system, the loss of a
radiopharmaceutical is due to both the physical
decay of the radionuclide and the biologic
elimination of the radiopharmaceutical

Ideal properties…
✓ Therefore the effective half-life can be given as:
✓ Radiopharmaceuticals should have a relatively
short effective half-life, which should not be
longer than the time necessary to complete the
study in question.

Ideal properties…
Example
➢The physical half-life of 111In is 67 hr and the
biologic half-life of 111In-DTPA used for
measurement of the glomerular filtration rate is
1.5 hr. What is the effective half-life of 111In-
DTPA?

3. Appropriate radiation
oParticle Emission
➢Radionuclides decaying by α- and β-particle
emission should not be used as the label in
diagnostic radiopharmaceuticals.
➢These particles cause more radiation damage to
the tissue than do γ rays
➢α and β emitters are useful for therapy, because
of the effective radiation damage to abnormal
cells.

Ideal properties…
oGamma (γ)emitter
For diagnostic studies the radionuclide must
emit a γ radiation with an energy preferably
between 30 and 300 keV.
Below 30 keV, γ rays are absorbed by tissue
and are not detected by the detector

Gamma (γ)emitter …
Above 300 keV, the gamma ray penetrate the
detector of the imaging device without being
stopped and hence recorded.

Ideal properties…
4. High Target-to-Non-target Activity Ratio
For diagnostic study, it is desirable that the
radiopharmaceutical be localized preferentially
in the organ under study since the activity from
non-target areas can obscure the structural
details of the picture of the target organ.

High Target-to-Non-target Activity Ratio…
➢A low target-to-non-target ratio may result in
inadequate treatment of the primary disease and
delivery of a potentially lethal radiation dose to
bone marrow or other radiosensitive tissues

Ideal properties…
5. Low dose rate to both patient and personnel
6. Non-toxicity of radiopharmaceuticals
They must be non-toxic in nature, sterile and
pyrogenic-free.
7. Chemical Reactivity
Should react with variety of substrates for
radiolabeling reactions

Ideal properties…
8. Chemical stability during use
Must be stable both pre- and post-reconstitution
9. Ease of preparation and appropriate quality
control
Several steps and a complex variety of
equipment should not be required.

Ideal properties…
Quality control procedures should be available
to check each batch of the radiopharmaceutical
reconstituted in the working laboratory.

Storage of radiopharmaceuticals
Should be properly stored so that they are not
degraded by light or temperature.
For example
99mTc-labeled macro aggregated albumin
should be stored at 2 to 4oC to prevent any
bacterial growth and denaturation of proteins,
99mTc-sulfur colloid can be stored at room
temperature without any adverse effect.

Storage…
Since radiation exposure is a serious problem in
the nuclear pharmacy, the vials or syringes
containing radiopharmaceuticals must be stored
in a shielded area.
Various high atomic number materials that absorb
radiation can be used to provide radiation
protection.

Storage…
Since the ranges of α and β particles are short in
the matter, the containers themselves act as
shields for these radiations.
γ radiations are highly penetrating, and therefore
highly absorbing material must be used for
shielding of γ -emitting sources.
➢For economic reasons, lead is most commonly
used for this purpose.

Lead barrier shield, behind which all formulations
and manipulations of radioactive materials are
carried out.

Storage…
Lead-shield syringe holder for transporting the
syringes containing radioactive material.

Radioactive Waste Disposal
Radioactive waste generated in nuclear medicine
or pharmacy (e.g., syringes, needles, vials
containing residual activities, liquid waste, gas,
and contaminated papers, tissues, and liners) is
disposed of by the following methods:
Decay-in-storage
Release into a sewerage system

Radioactive Waste Disposal…
Transfer to an authorized recipient
Other disposal methods (e.g., incineration and
atmospheric release of radioactive gases).

Decay-in-storage
Radionuclides with half-lives less than 120 days
usually are disposed of by this method.

Decay-in-storage…
The waste is allowed to decay for a period of
time and then surveyed. If the radioactivity of
the waste cannot be distinguished from the
background, it can be disposed of in the normal
trash after the removal of all radiation labels.

Decay-in-storage…
Most appropriate for short-lived radionuclides
such as 99mTc, 123I, 201Tl, 111In, and 67Ga,

Release into a Sewerage System
Radioactive waste disposal into a sewerage
system is permitted provided the radioactive
material is soluble (or dispersible biological
material) in water.
Disposal depends on the flow rate of water but is
limited to 1 Ci (37 GBq) of 14C, 5 Ci (185 GBq)
of 3H, and 1 Ci (37 GBq) for all other
radionuclides annually. By: Aychew M. IPP II(Phar3121) 2014EC 76

Transfer to an Authorized Recipient
➢A transfer to an authorized recipient method is
adopted for long-lived radionuclides
➢Usually involves the transfer of radioactive waste
to authorized commercial firms that bury or
incinerate it at approved sites or facilities.

Radiopharmaciutics......................................

Radiopharmaciutics......................................

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