Short review about parenteral suspension, principle consideration during formulation, factors affecting formulation etc. are included in this presentation.
2. Learning outcomes
In this we will learn about parenteral suspensions.
Reason for developing the parenteral suspension.
Ideal properties of Parenteral suspension.
General characteristics of parenteral suspension to be accepted and fulfill the
PHARMACEUTICAL standards.
Advantages and Disadvantages of parenteral suspensions.
Principle formulation consideration of parenteral suspensions.
Some important factors which affects the formulation development.
Typical excipients used in parenteral suspension.
3. Definition
Parenteral suspension are dispersed,
heterogeneous systems containing
insoluble drug particles which when re-
suspended in either aqueous or oil
vehicles before administration to a patient.
They are administered via different parenteral
routes such as I.V, I.M, S.C etc.
Examples of such routes Insulin zinc
suspension (S.C), Paclitaxel suspension (I.V),
Procaine penicillin G suspension (I.M).
4. These are intended for administration only by
injections.
These suspensions have long time actions.
Active drug substance must be suspended
with water for injection.
These suspensions may show sediment which
is readily dispersible upon shaking.
5. Reason for development
The drugs which are insoluble and are difficult
to be formulated as SOLUTION.
The drugs which are more stable when
suspended than in solution form.
When there is a need to develop dosage forms
having retarded or controlled release of
drugs.
The larger surface area of dispersed drugs
may help ensure a high degree of availability
for absorption.
6. Ideal properties
It must be sterile during storage and use.
Syringeability and injectability are closely
related with viscosity and particle characteristics.
Particle size should be small and uniform.
Re-suspension of particle occurs easily.
Dispersed particles do not settle rapidly after
shaking.
Cake formation must not occur during its shelf
life.
It must be isotonic and non-irritating.
Its should contain 0.5-5.0% solids and particle
size less than 5 µm.
Maintain its stability and elegance during its shelf
7. Pharmaceutical Standards
They should be sterile, pyrogen free, stable, re-
suspendable, syringeable, injectable, isotonic,
non-irritable.
Because of above requirements, parenteral
suspensions are the most difficult dosage form
to be develop.
They may be formulated as a ready to use
injections or require a reconstitution step prior
to use.
Newer suspension delivery systems containing
drugs in microparticles or nanoparticles can be
used as I.V, I.M, S.C etc.
8. These suspensions must usually contain
between 0.5-5.0% solids and particle size
less than 5 µm for I.M or S.C administration.
9. Advantages
Better for drugs which are insoluble in convection
solvents.
Increased resistance to hydrolysis and
oxidation as is susceptible.
Provides chemical stability.
larger surface area is available as
microparticles or nanoparticles used to provide
better absorption.
Controlled release or sustained release of drug
is possible.(protamine zinc-insulin suspension)
Elimination of hepatic FPM.
10. Disadvantages
There may be chances of non-uniformity of
dose at the time of administration.
Maintenance of physical stability is very difficult
in this dosage form.
Stabilization of suspensions for period between
manufacture and use may face problems such as
sedimentation, cake formation, difficulty in
redispersion.
Difficulty in formulation such as selection of
ingredients.
Special facilities are required such as aseptic
area for process such as crystallization, size
reduction, sterilizations.
11. Formulation consideration
Interfacial properties:
Interfacial properties of dispersed particle such as the
increase in the specific surface area with reduction in
particle size and the presence of electrical charge on
the surface of particles play major role in stability.
∆𝐺 =
𝜒𝑠
𝑢 ∆𝐴
∆𝐺= change in surface free energy in ergs
𝜒𝑠/u = interfacial tension in dyne/cm2 dispersed particles
and medium
∆𝐴= change in surface area in cm2
12. As the particle sizes is reduced where there
is increased in surface area which causes
high surface free energy due to which
clumping of particles occur.
In order to make an stable system, high
surface free energy is reduced, which
minimizes the interfacial tension. This is done
by using surface active agents.
13. Flocculation and Deflocculation
The charges at the shear plane associated
with the particles surface is described as the
zeta potential.
When the zeta potential is high, results in
deflocculated particles.
This particles settles at slow rate and forms a
hard cake which cannot easily redispersed.
So this is overcome using flocculating agents
eg. Salts, organic polymers etc. causing the
formation of loose aggregates.
14. Flocculated suspensions are the more
common type of parenteral suspension
because most injectables suspensions
contains low concentration of solids, less
viscous and have less zeta potential to
produce stability problems.
Unless, this deflocculated phenomena is
applicable in the suspension contains high
solid concentrations such as procaine
penicillin G contain 30% solid particles.
15. Stock’s law
This law shows information based on
sedimentation rates of solid particles.
Thus increase in the viscosity of liquids or
decreasing particles size minimizes the
sedimentation rate which Is an important factor in
the stability of suspension.
𝑠 =
𝑑2 𝑃𝑠−𝑃𝑖 𝑔
18𝜂
Where,
𝑠 = sedimentation rate in cm/sec
d = diameter of particles in cm
16. 𝑃𝑠= density of dispersed phase
𝑃𝑖= density of dispersed medium
g= gravity constant
𝜂= viscosity in poise.
17. Crystal Growth
Crystal growth is a major stage of a
crystallization process which typically follow an
initial stage of either homogeneous or
heterogeneous nucleation.
The following factors affect the potential for
crystal growth in suspension.
Particle size distribution.
Dissolution and recrystallization.
Changes in pH and temperature.
18. Variable particles size distribution result from
various including:
Preparation of suspension by precipitation
methods where the degree of super saturation
and the rate of nucleations are greatest at the
beginning of the process results in large particles
formation initially and smaller particles formation.
Change in pH caused due to drug decomposition.
Temperature changes cause the nucleation
which will lead to crystal formation.
19. Thus, to minimizes the crystal growth,
particles size distribution, viscosity, use of
right polymorph, solvent, temperatures
cycles study, to evaluate the physical and
chemical stability of suspension.
20. Caking/ Cake formation.
The inability of re-suspended drug particles
upon caking result from particles settings as a
hardened sediment call a “cake”, occurs when
attractive between solid particles and vehicles
are greater.
21. Factors affecting formulation
Solubility of drugs in biological fluids at
injection site.
Lipid solubility and oil water partition
coefficient.
pKa, pH of drugs.
Particles size.
Compatibility.
Solvates and polymorphs.
pH stability.
Tonicity.
Dissolution rate.
22. Excipients used in parenteral
suspensions
Flocculating agents/ suspending agents-
e.g. hydro colloids, electrolytes, organic
polymers, surfactants, etc.
Wetting agents- e.g. non-ionic surfactant,
organic polymers, etc.
Solvents- aqueous or non aqueous solvents.
Preservatives- e.g. benzyl alcohol, parabens,
etc.
Anti-oxidants/chelating agents- e.g.
ascorbic acid, sodium bisulfite, tocopherols.
23. Tonicity agents- e.g. dextrose and other
electrolytes
Preservatives- e.g. benzyl alcohol, parabens,
etc.