HAPPY NEW

ACADEMIC YEAR
(2009-2010)
 PHARMACEUTICS III
Topics in this course are related to special
considerations for the:
Sterile dosage Forms
*Parenteral products
*Vaccines
*Blood, fluids, electrolytes and
hematological drugs
*Ophthalmic pharmaceutical products
*Complexation and protein binding
*Radiopharmacuticals
Radiopharmaceuticals

Dr/ Samar Mansour

Associate Professor of Pharmaceutics
 Overall Aim

After the completion of this part of the

course the student should be able to:

Comprehend principles of radioactivity

and its pharmaceutical, diagnostic and
therapeutic applications
 Radiopharmaceuticals
Radiopharmaceuticals are medicinal
products that are radioactive.
They are used for

Diagnosis Radiotherapy
Principally in the branch of medicine known as:

Nuclear Medicine
 Radiopharmaceuticals are used for:
I- Radiotherapy
Treatment of disease by radiation
The radioactive material, when present in a tissue or organ in
sufficient quantity, will produce emanation (energy)
energy capable
of destroying existing cells and preventing the formation of
new tissue.
Applied to:
(1) Tumors
(2) Conditions in which an organ produces physiological harm
through overactivity.

II-Diagnosis
For diagnosis, The radioactive material are used as

Example: Radioactive Tracers

Organ and tumor visualization: Photoscan.
Dense regions in the scan are indicative of regions of high
activity
 Radiopharmaceuticals
*Radiopharmaceuticals vary from inorganic
salts to large organic molecules and
complexes
* They are prepared in a variety of dosage
forms which include
I.V. injections Oral
Solutions Aerosols Capsules
Gases
*Radiopharmaceuticals contain either:
long half- lives Short half- lives
radionuclides radionuclides
obtained from prepared in Hospital
Commercial Suppliers Radiopharmacies
 Constituents of the Atom
• The simplest model of the atom is shown in the diagram below:

The basic building of atoms :

Positively charged nucleus (composed of protons
and neutrons) with associated orbital electrons.
 The basic building of atoms

- Electrons, Protons, and Neutrons constitute the basic

building blocks of atoms, both stable and radioactive.
• The number of orbital electrons is equal to the number
of protons in the nucleus.
- The electron is the smallest of these three particles. Its
mass, me, is 9.1091 x10-28 g
- The mass of the electron, me, is used as a unit of mass
- The Electron is assigned a charge of – 1.
- The charge of the Proton is +1 (1836 mass e)
- The charge of the Neutron is zero(1838 mass e)
-
 Atomic Structure (Cont.)
• A Nuclide is an atom described by its atomic number (Z)
and its mass number (A). Nuclides may be stable or
unstable
• The atomic number (Z) is equal to the charge (number of
protons) in the nucleus, which is a characteristic of the
element
• The neutron number, N, is the number of neutrons in the
nucleus.
• The mass number, A, is equal to the sum of the protons
and neutrons in the nucleus .
• Thus, A = Z+N
P+N
• A 32
• Chemical symbol, e.g. P (Phosphorus)
• Z 15
P
•Radionuclides
unstable nuclides are radioactive
 Nuclides and Isotopes
• Isotopes are Nuclides with the same number of
protons but with different numbers of neutrons. i.e. The
same atomic number but differ in mass number.
• For example, deuterium (2,1H) and tritium (3,1H) are
isotopes of hydrogen with mass numbers two and
three, respectively. Only (tritium) is radioactive

• Radioactive nuclides or radioisotopes can generally be

described as those which have an excess or deficiency
of neutrons in the nucleus.

• There are 200 stable nuclides and over 1100 unstable

(radioactive) nuclides

• 1H, 2H, 12C, 23 Na are stable nuclides

• 3H, 14C, 22 Na are unstable Radionuclides
 Radioactive decay (Radioactivity)
• Radioactive decay or radioactivity is the process by which
an unstable atomic nucleus (radionuclides or radioisotopes)
can regain stability by nuclear transformation emitting
radiation in the form of particles or electromagnetic waves
to attain a more stable state and the nucleus may be
transformed into another.
• A-Natural radioactivity:
The stability of the atoms depends on the neutron to proton
(N/Z) ratio in the nucleus. Above atomic number 83, all
elements are radioactive. The nucleons are in a state of
continual motion (naturally occurring radionuclides).
Example: Uranium (238)- Radium (226).
B- Artificial radioactivity:
• Radioactivity could be through an artificial transmutation.
e.g. the bombardment of nitrogen of N=14 with a helium nucleus) to
produce radioactive oxygen
14 4 1 17
N + He H + O
7 2 1 8
 (Radioactivity)
• Radioactivity is a spontaneous process by
which the unstable atoms of an element emit
or radiate excess energy in the form of
particles or waves.
• These emissions are called ionizing
radiations.
• Depending on how the nucleus loses this
excess energy either:
A- a lower energy atom of the same form will
result,
B- or completely different atom can be
formed.
 Radiation from Radioactive
Nuclei
• The most frequently types of radiation
emitted from radioactive nuclei.

Beta Gamma
Alpha
Negatron and Positron Rays
Particles Electromagnetic
Particles Radiation
(photons)
 Radiation from Radioactive
Nuclei
1. Alpha Radiation
• They are compound particles consisting of
two protons and two neutrons.
neutrons
• Thus, the alpha particle is identical with
the helium nucleus.
• The range of alpha particles in air is about
5 cm, and less than 100µ in tissue.
 Radiation from Radioactive Nuclei
2. Beta Radiation
*They are electrons emitted from radioactive nuclei.
*When these electrons are emitted from radioactive
nuclei, they are called Beta particles.
*They are two types because there are two kinds of
electrons emitted,
A- The negative electron (negatron, β-)
b- The positive electron (positron, β+ )
*The positron is identical with the negatron in all
respects except for its charge of +1 instead of –1.
*The two particles are the same as e- and e+,
except for their origin.
*Beta particles may have a range of over 10ft in air
and up to about 1 mm in tissue.
 Radiation from Radioactive Nuclei
3. Gamma Radiation
• It is electromagnetic, whereas alpha and beta
radiations are particulate.
• Gamma rays are radiated as photons or
quanta of energy
• Gamma rays are the most penetrating of all
types of radiation emitted by radioisotopes
Can easily pass through more than a foot of
tissue or several inches of lead.
Radiation from Radioactive
Nuclei
 Common Particles of Nature
Particle Symbol Charge Mass

Negatron e– (β–) –1 1
(nucleus)
Positron e+(β+) +1 1
(nucleus)

Electron e– –1 1
(shells)
Proton p +1 1836 mass e
Neutron n 0 1838 mass e
Alpha α +2 7346(2N+2P)
Neutrino ν 0 0
Gamma Rays γ 0 0
 Modes of Nuclear Decay
1. Alpha - Decay (α - emission)
• This occurs with large nuclei, predominantly with
nuclides of atomic number greater than 83. It
involves the emission of an α - particle (helium
nucleus He), i.e.,
• A A-4 4
• X Y+ He + Q
energy
• Z Z -2 2
• For example :
• 226 Ra 222 Rn + 4 He
Radium Radon
 Alpha - Decay

Uranium Thorium

Alpha decay of the 238U "parent" nuclide produces

234Th as the "daughter" nuclide.
 2. Beta – Decay
a. Negatron (β –) emission
• Nuclei with excess neutrons gain stability by the
conversion of a neutron into a proton plus (β –) particle.
• (β –) particle has a very low mass there is no change in
the mass number, but the atomic number

• 1 1 0
Increases by one unit
• n P + β +ν
• 0 1 -1

A A o
• X Y + β +ν
• Z Z+1 -1

• 32 32 0
• P S + β + ν
• 15 16 -1
 2. Beta – Decay
b. Positron (β +) emission
• This process is occurs with neutron deficient nuclei. The
deficiency being rectified by the conversion of a proton into
a neutron plus a positron. Positrons are emitted with a
continuous energy spectrum.
• There is no change in mass number but the atomic number

Decreases by one unit

• P n + β+ +ν

• 58 58 0
• Co Fe + β+ν
27 26 +1
Iron
• Cobalt
 3. Electron capture (EC, K- capture)
• This is an alternative for β + emission decay with neutron
deficient nuclei.
• It involves the conversion of a proton into a neutron by
capture of an orbital electron from K-shell because
electrons in this orbital are the closest to the nucleus.
• 1 1
• P + e– n
• 1 0
• This capture causes a deficiency in the K shell, by the
migration of an electron of the outer shells. Since the
migrant electron loses energy in the process, the surplus
energy is emitted in the form of X-ray of an energy
characteristic of the product atom. X-rays are photons emitted
during energy level transitions of orbital electrons.
• 55 55
• Fe + e - Mn + Mn X - rays
26 25
• the mass number remains Decreases by one unit
• unchanged but the atomic number
 4. Nuclear Fission (Nuclear reactor)
• Large nuclei tend to be unstable and split into two
fragments. This process can occur spontaneously but it is
extremely slow.
• Natural uranium, the process has a half-life of about
0.9x106 years.
• However, if large nuclei are irradiated with neutrons of
sufficient energy the resultant neutron capture results in a
very high degree of instability and fission occurs
immediately accompanied by the ejection of one or more neutrons.
• This process is the basis of operation of the Nuclear
Reactor, in which a sufficient bulk of fissile material (235U
or 239Pu) is brought together so that the neutrons emitted
in the occasional spontaneous fission have a high
probability of capture by other nuclei.
• The latter disintegrate promptly to yield neutrons which
are captured in turn, resulting in a
• Neutron
. capture
then neutron Self - Sustaining Chain reaction
emission
 Gamma Rays emission (γ)
Isomeric Transition
• Some daughter nuclides produced by α-decay or
β-decay are often obtained in an excited state. The
excess energy associated with this excited state is
released when the nucleus emits a photon in the γ-
ray portion of the electromagnetic spectrum.
• There are certain well defined ways in which
neutrons and protons may be arranged within the
nucleus. In each configuration, a different amount
of energy is stored in the nucleus.
• The excited nucleus attains a more stable
configuration by gamma rays emission (γ) carries
neither charge nor mass.
 Gamma Rays emission (Cont.)
• The more excited (or upper isomeric state) is called
metastable state or level which indicated by “m” written
after the mass number (99mTc, 110mAg) and decay with
different short half- lives from the non - metastable
nuclides:
• Nuclide Half-life
• 99 Tc 2.1 x 105 years
• 99m Tc 6h
• Nuclear isomers: Nuclides with the same mass and atomic
numbers but different half- lives
• Isomeric transition: is the process by which a nuclide
decays to isomeric nuclide (one of the same Z and A) of
lower quantum energy.
 Production of radionuclides
Artificial Production of radionuclides

Nuclear Reactors Cyclotron- Produced Isotopes Generators

Artificial radionuclides are derived by either:

1- Bombardment of stable target nuclei with neutrons,
usually in a nuclear reactor .
2- Bombardment of stable target nuclei with charged
particles, usually in cyclotron.
3- Elution of the generator to produce short half life
radionuclides.
 1. Nuclear Reactors
(Nuclear piles)
• These are devices for producing high fluxes of neutrons.
• The neutrons in reactors are a mixture of:
Fast Neutrons
Thermal Neutrons
High Energy

•
• In the reactor the uranium fission reaction produces a
large supply of neutrons.
• One neutron for each uranium atom undergoing fission is
used to sustain the reaction.
• The remaining neutrons are used either to:
1- Produce plutonium by interaction with 238U nuclei,
2- Produce radioactive products by causing the neutrons to
interact with specific substances which have been
inserted into the pile. (process is known as neutron
activation).
 Nuclear Reactors
• Thus, there are two sources of useful radioactive
substances from the pile:
• (1) Those produced as fission products.
• (2) Those produced by neutron activation.
I- Production of radioactive Fission Products
• The following reactions illustrate one of many combinations of
fission reactions which are possible.
• 238 1 131 106 1 1
• U + n Sn + Mo + n + n
• 92 0 50 42 0 0
The Sn and the Mo are very radioactive and have very short half-
lives. They immediately decay by a series of beta decay
processes
• 131 131 131 131
• Sn Sb Te I
• 50 51 52 53
Antemony Telorium
 Nuclear Reactors (Cont.)

• 106 106 106 106

• Mo Tc Ru Rh
• 42 43 44 45 Rhodium
Technetium Ruthenium

*Both Iodine and Ru are available commercially as fission produced

isotopes. Before use, however, they must be separated chemically
from a large number of other fission -produced radioisotopes
(costly)
(costly . Hence, the majority of radioactive compounds are prepared
by neutron activation

II- Production of radioactive compounds by Neutron

Activation
A- The Neutron Capture (n,γ) reaction (Thermal Neutrons)
B- Transmutation process (n,p) reaction (Fast Neutrons)
II- Production of radioactive compounds by
Neutron Activation
A- The Neutron Capture (n,γ) reaction
This involves the capture of thermal neutrons by the
target nuclei to yield a radioactive compound
nucleus, which is in an excited state due to the
binding energy liberated by the capture of a neutron.
This surplus energy is emitted as gamma- radiation
• 23 1 24m 24
• Na + n Na Na + γ
• 11 0 11 11

The process usually does not yield material of high specific

activity in some cases since the product is chemically identical
to the target and so cannot be separated from it easily but high
specific activity nuclides may be obtained in some cases, such as 56Mn,
192Ir, 198 Au
II- Production of radioactive compounds by
Neutron Activation
B- Transmutation process (n,p) reaction
• These reactions involve the loss of heavy particles (P).
In these reactions protons or α- particles are emitted
from the compound nucleus following neutron
absorption.
• Fast neutrons may be required for these reactions to
occur, since considerable energy is needed to expel the
heavy particle.
• Examples of the use of these reactions in radionuclide
production:
• 32 1 32 1
• S + n P + P
• 16 0 15 1
• Advantage: In such cases the product is chemically
different from the target and can be separated in very
high specific activity.
activity
 2. Cyclotron- Produced Isotopes
(Accelerator)
• The cyclotron and similar particle accelerators can be used
only with charged particles such as electrons, protons,
deuterons, etc, because the operation of such machines
depends upon: the interaction of magnetic and/or
electrostatic fields with the charge (either + or -) of the
particle undergoing acceleration.
• When the particles have been accelerated to a high
velocity, they are caused to strike a target, containing the
atoms to be bombarded.
• in this way Sodium Na-22 can be produced by the
interaction of high - velocity deuterons with magnesium.
• 24Mg + 2 D 22Na + 4α

• Other medically important nuclides which have been

produced in a cyclotron by use of high-energy deuterons
include 11C, 13N, 15O. Those which have been produced
using high- energy alpha particles include 18F, 123I, 124I.
 Cyclotron Target

magnetic and/or
electrostatic
fields

Advantage: target material converted to different

elements producing carrier free radionuclide.
 3. Generators "cows“
Production of short- half life
radiopharmaceuticals
• Where clinical tests require that a radioisotope be
administered internally, it is advantageous to use an
isotope with a short half-life to minimize the radiation
dose received by the patient. One of the most
significant advances in radiopharmaceuticals is the use
of generators for the production of short half – life
radiopharmaceuticals.

• Generators are either:

ion exchange resins or alumina columns which contain
a parent radionuclide. With time, the parent
radionuclide decays to a daughter radionuclide that is
not specifically adsorbed on the column. The daughter
radionuclide is eluted or milked from the column by
eluent such as sterile saline on daily bases
 Generators
• Example:
• technetium Tech-99m, which is obtained from a
generator constructed of molybdenum-99 adsorbed to
an alumina column.
• Molybdenum-99 decays with 66 hour half- life to
technetium-99m, and the technetium-99m is eluted (or
milked) from the column with normal saline solution.
• The 66 hour half- life of molybdenum-99 provides
sufficient manufacturing time for once weekly
preparation. Elution of the generator on a daily basis,
by the nuclear pharmacist, provides technetium - 99 m
for the preparation of radiopharmaceuticals.

Molybdenum-99 Tec 99m eluted tech 99m

From nuclear reactor 66hr t1/2 Saline t1/2 6hr
 Radioisotope parent-daughter Generator
systems
Half-life Daughter Half-life Application
Parent isotope
isotope

90Sr 28 y 90Y(yttrium) 64 hours Cancer therapy

99Mo 66 h 99mTc 6 hours Imaging of

organs(diagnostic)
(molybdenum)

132Te(telorium)
3.2 day 132 I 2.3 h Thyroid scanning
Generator

ion exchange
resins or
alumina
columns which
contain a parent
radionuclide

The daughter
radionuclide is eluted
or milked from the
column by eluent
such as sterile saline
on daily bases
Generator
Best Wishes