Suspensions

Suspensions

1. ·Dispersion system consist of (1)- particulate matter (dispersed phase)
(2)- continuous medium (dispersion medium)
·Classification of dispersed systems (based on particle size)
1Molecular
dispersion
< 1 nm Oxygen molecules,
glucose solution
2Colloidal
dispersion
1nm- 0.5 mm Natural polymers
3
Coarse
dispersion
> 0.5 mm
Suspension and
emulsion
·Definition of suspension : Pharmaceutical suspensions are uniform
dispersions of solid drug particles in a vehicle in which the drug has
minimum solubility. Particle size of the drugs may vary from one
formulation to the other depending on the physicochemical
characteristics of the drug and the rheological properties of the
formulation.
·A suspension containing particles between 1 nm to 0.5 µm in size is
called colloidal suspension. When the particle size is between 1 to
100 µm, the suspension is called coarse suspension. Most of the
pharmaceutical suspensions are coarse suspension.
·Majority of the marketed suspensions are available as dry powders
that must be reconstituted before administration but occasionally
1

2. some products in the market are ready-to-use. The first products are
not very stable once reconstituted; must be used within 7 to 10 days.
Examples of Pharmaceutical Suspensions:
A.Antacid oral suspensions Antibacterial oral suspension
B.Dry powders for oral suspension (antibiotic)
C.Analgesic oral suspension
D.Anthelmentic oral suspension
E.Anticonvulsant oral suspension
F.Antifungal oral suspension
Pharmaceutical applications of suspensions:
1)Insoluble drug or poorly soluble drugs which required to be given
orally in liquid dosage forms ( in case of children, elderly, and
patients have difficulty in swallowing solids dosage forms)
2)To over come the instability of certain drug in aqueous solution:
a.Insoluble derivative formulated as suspension
AN EXAMPLE IS OXYTETRACYCLINE HCL Þ CALCIUM SALT
(instable) (stable)
b.Reduce the contact time between solid drug particles and
dispersion media Þ increase the stability of drug like Ampicillin
by making it as reconstituted powder.
2

3. c.A drug that degraded in the presence of water Þ suspended in
non-aqueous vehicles. Examples are phenoxymethypencillin/
coconut oil and tetracycline HCL/ oil
3) To mask the taste:
Examples are paracetamol suspension (more palatable) and
chloramphenicol palmitate.
4)Some materials are needed to be present as finely divided forms to
increase the surface area. Fore example, Mg carbonate and Mg
trisilcate are used to adsorb some toxins
5)Suspension can be used topical applications:
An example is calamine lotion Bp Þ after evaporation of dispersing
media; the active agent will be left as light deposit
6)Can be used for parentral administration Þ intramuscular (i.m.) to
control arte of absorption
7)In vaccines

3
Aluminum hydroxide
Absorbed antigen
Aluminum hydroxide
Absorbed antigen
e.g. Diphtheria and Tetanus vaccines

4. 8)X-ray contrast media: an example is oral and rectal administration of
propyliodone
9)In aerosol Þ suspension of active agents in mixture of propellants
Qualities of ideal suspension: A well-formulated suspension should have
the following properties:
1)The dispersed particles should not settle readily and the settle should
redispersed immediately on shacking. Ideally, the particles in a
suspension should not sediment at any time during the storage
period. Unfortunately, the present technology does not allow us to
prepare such a suspension. Since one cannot completely avoid the
sedimentation of particles, it is desirable that the particles should
settle slowly. The easy redispersion of sedimented particles in a
suspension is important for the uniformity of dose.
2)The particle should not form a cake on settling
3)The viscosity should be such that the preparation can be easily
poured. A highly viscous suspension would make pouring difficult.
4)It should be chemically and physically stable
5)It should be palatable (orally)
6)It should be free from gritting particles (external use)
FACTORS TO BE CONSIDERED
A-Wetting of the particles:
4
Suspending
media
Solid
particles
Hydrophilic can be
dispersed easily
Difficult to disperse and
float on the surface due to
hydrophobic surface or
entrapped air
Suspending
media
Solid
particles
Hydrophilic can be
dispersed easily
Difficult to disperse and
float on the surface due to
hydrophobic surface or
entrapped air

5. ·It is difficult to disperse solid particles in a liquid vehicle due to the
layer of adsorbed air on the surface. Thus, the particles, even high
density, float on the surface of the liquid until the layer of air is
displaced completely. The use of wetting agent allows removing
this air from the surface and to easy penetration of the vehicle into
the pores. Alcohol, glycerin, and propylene glycol are frequently
used to remove adsorbed air from the surface of particles when
aqueous vehicle is used to disperse the solids. When the particles
are dispersed in a non-aqueous vehicle, mineral oil is used as
wetting agent. Irrespective of the method of preparation, the solid
particles must be wetted using any of the suitable wetting agents
before the dispersion in the vehicle.
·Solid particles that are not easily wetted by aqueous vehicle after
the removable of the adsorbed air are referred to as hydrophobic
particles. It is necessary to reduce the interfacial tension between
the particles and the vehicle by using surface-active agents to
improve the wettibility. Sodium lauryl sulfate is one of the most
commonly used surface-active agents. Hydrophilic particles are
easy to disperse in the aqueous vehicle once the adsorbed air is
removed. Hydrophilic particles do not require the use of surface-
active agents.
5

6. ·The main function of wetting agents: (1)- to reduce the contact
angle between surface of solid particles and wetting liquid via
displace the air in the voids (2)- surfactant
·Examples of wetting agents are tragcanth mucilage, glycerin,
glycols, bentonite and polysorbates.
·Excessive amounts of wetting agents can cause foaming or
undesirable taste or odor.
·Contact angle can be used to measure wettibility, if the angle
approximately equal or more than 90
0
, particles are floating well
out of fluid.
B-Particle size:
·Particle size of any suspension is critical and must be reduced within
the range as determined during the preformulation study.
· Too large or too small particles should be avoided. Larger particles
will settle faster at the bottom of the container and too fine particles
will easily form hard cake at the bottom of the container.
·The particle size can be reduced by using mortar and pastel but in
large-scale preparation different milling and pulverization
equipments are used.
·Limitation in particle size reduction (after reaching a certain particle
size):
1.Expensive and time consuming
2.Movement of small particles due to brownian motion cause
particles to aggregate, settle, form hard cake that it is
difficult to redispersed
6

7. C-Sedimentation:
·Sedimentation of particles in a suspension is governed by several
factors: particle size, density of the particles, density of the vehicle,
and viscosity of the vehicle. The velocity of sedimentation of particles
in a suspension can be determined by using the Stoke's law:
Where:
v = velocity of sedimentation
d = diameter of the particle
g = acceleration of gravity
r1 = density of the particle
r2 = density of the vehicle
h = viscosity of the vehicle
·According to the Stoke's equation, the velocity of sedimentation of
particles in a suspension can be reduced by decreasing the particle
size and also by minimizing the difference between the densities of
the particles and the vehicle. Since the density of the particles is
constant for a particular substance and cannot be changed, the
changing of the density of the vehicle close to the density of the
particle would minimize the difference between the densities of the
particles and the vehicle. The density of the vehicle of a suspension
can be increased by adding the following substances either alone or
in combination: polyethylene glycol, polyvinyl pyrolidone, glycerin,
sorbitol, and sugar.
7
v=
d
2
(p
1
-p
2
) g
18 h
v=
d
2
(p
1
-p
2
) g
18 h

8. ·The viscosity of the vehicle also affects the velocity of sedimentation.
It decreases as the viscosity of the vehicle increases. The viscosity
and density of any vehicle are related to each other, so any attempt
to change one of these parameters will also change the other one.
D-Electrokinetic Properties
·Dispersed solid particles in a suspension may have charge in relation
to their surrounding vehicle. These solid particles may become
charged through one of two situations.
1.Selective adsorption of a particular ionic species present in the
vehicle. This may be due to the addition of some ionic species
in a polar solvent. Consider a solid particle in contact with an
electrolyte solution. The particle may become positively or
negatively charged by selective adsorption of either cations or
anions from the solution.
2.Ionization of functional group of the particle. In this situation,
the total charge is a function of the pH of the surrounding
vehicle.
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+ +
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a
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d
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d
Tightly
bound
layer
Diffusion
layer
Electro-neutral
region
Surface
CounterionShear plan
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++++
++ ++
--
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-- --
--
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++
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a
-
a
b
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b
c
-
c
d
-
d
Tightly
bound
layer
Diffusion
layer
Electro-neutral
region
Surface
CounterionShear plan

9. ·In the above figure, the particle is positively charged and the anions
present in the surrounding vehicle are attracted to the positively
charged particle by electric forces that also serve to repel the
approach of any cations. The ions that gave the particle its charge,
cations in this example, are called potential-determining ions.
Immediately adjacent to the surface of the particle is a layer of tightly
bound solvent molecules, together with some ions oppositely
charged to the potential-determining ions, anions in this example.
These ions, oppositely charged to the potential-determining ions, are
called counterions or gegenions. These two layers of ions at the
interface constitute a double layer of electric charge. The intensity of
the electric force decreases with distance from the surface of the
particle. Thus, the distribution of ions is uniform at this region and a
zone of electrolneutrality is achieved.
E-Nernst and zeta potential-
·The difference in electric potential between the actual surface of the
particle and the electroneutral region is referred to as Nernst
potential. Thus, Nernst potential is controlled by the electrical
potential at the surface of the particle due to the potential
determining ions. Nernst potential has little effect in the formulation
of stable suspension.
·The potential difference between the ions in the tightly bound layer
and the electroneutral region, referred to as zeta potential (see the
figure), has significant effect in the formulation of stable suspension.
Zeta potential governs the degree of repulsion between adjacent,
similar charged, solid dispersed particles.
9

10. · If the zeta potential is reduced below a critical value, the force of
attraction between particles succeed the force of repulsion, and the
particles come together. This phenomenon is referred to as
flocculation and the loosely packed particles are called floccule.
F-Deflocculation and flocculation:
·Deflocculation of particles is obtained when the zeta potential is
higher than the critical value and the repulsive forces supersede the
attractive forces.
·The addition of a small amount of electrolyte reduces the zeta
potential. When this zeta potential goes below the critical value, the
attractive forces supersede the repulsive forces and flocculation
occurs.
·The following table illustrates the relative properties of flocculated
and Non-flocculated suspension
10
FLOCCULATED NON-FLOCCULATED
1.Particles forms loose aggregates and
form a network like structure
2.Rate of sedimentation is high
3.Sediment is rapidly formed
4.Sediment is loosely packed and doesn’t
form a hard cake
5.Sediment is easy to redisperse
6.Suspension is not pleasing in appearance
7.The floccules stick to the sides of the
1.Particles exist as separate entities
2.Rate of sedimentation is slow
3.Sediment is slowly formed
4.Sediment is very closely packed and a hard cake
is formed
5.Sediment is difficult to redisperse
6.Suspension is pleasing in appearance
7.They don’t stick to the sides of the bottle

11. ·It should be noted that the deflocculated suspensions should be
avoided because of the formation of irreversible solid hard cake.
Although flocculated suspensions sediment faster and form a clear
supernatant, these are easy to redisperse.
·The following figure shows the effect of period of standing on
flocculated and deflocculated suspension:
G-Thixotropic suspension-A thixotropic suspension is the one that is
viscous during storage but loses consistency and become fluid upon
shaking. A well-formulated thixotropic suspension would remain fluid long
enough for the easy dispense of a dose but would slowly regain its original
viscosity within a short time.
Method of preparation
The preparation of suspension includes three methods: (1) use of
controlled flocculation and (2) use of structured vehicle (3)- combination of
both of the two pervious methods. The following is the general guidelines
to suspension formulation:
11

12. A-Structured vehicle
·Structured vehicles called also thickening or suspending agents. They
are aqueous solutions of natural and synthetic gums. These are used
to increase the viscosity of the suspension.
·Methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl
cellulose, acacia, gelatin and tragacanth are the most commonly
used structured vehicle in the pharmaceutical suspensions. These
are non-toxic, pharmacologically inert, and compatible with a wide
range of active and inactive ingredients.
12
Particles
Addition of wetting agent and dispersion medium
Uniform dispersion of deflocculated particles
A
Incorporation of
structured vehicle
Deflocculated suspension
in structured vehicle
as final product
B C
Addition of
flocculating agent
Flocculated suspension
as final product
Addition of
flocculating agent
Flocculated suspension
Incorporation of
structured vehicle
Flocculated suspension
in structured vehicle as
final product

13. ·These structured vehicles entrapped the particle and reduces the
sedimentation of particles. Although, these structured vehicles
reduces the sedimentation of particles, not necessarily completely
eliminate the particle settling. Thus, the use of deflocculated
particles in a structure vehicle may form solid hard cake upon long
storage.
·The risk of caking may be eliminated by forming flocculated particles
in a structured vehicle.
·Note that too high viscosity isn’t desirable and it causes difficulty in
pouring and administration. Also, it may affect drug absorption since
they adsorb on the surface of particle and suppress the dissolution
rate.
·Structured vehicles are pseudoplastic or plastic in their rheological
behaviors
·In the following table is summary of suspending agents
13

14. Table summary of suspending agent
14

15. B-Controlled flocculation
·Controlled flocculation of particles is obtained by adding flocculating
agents, which are (1)-electrolytes (2)- surfactants (3)- polymers
Typical Flocculation agents
·Most frequently used flocculating agents are electrolytes, which
reduce the zeta potential surrounding the solid particles. This leads
to decrease in repulsion potential and makes the particle come
together to from loosely arrange structure (floccules).
· The flocculating power increases with the valency of the ions. As for
example, calcium ions are more powerful than sodium ions because
the velency of calcium is two whereas sodium has valency of one.
·The following figure shows the flocculation of a bismuth subnitrate
suspension by means of monobasic potassium phosphate
(flocculating agents).
15
1-Addition of electrolyte to control flocculation

16. ·Both ionic and non-ionic surfactants could be used to control
flocculation
·Surfactant adsorbed on the surface of solid particle leading to
neutralization or reversing the surface charge
·Since most of surfactants act as wetting agents and flocculating
agents, the amount of surfactant to be added should be calculated
based on this fact.
16
The particles of bismuth subnitrate are positively charged originally. By addition of electrolyte
(phosphate, -ve) the zeta potential fell down near zero. At this neutralization value noted
absence of caking. Continuing adding of negatively charged electrolyte resulted in changing
the overall zeta potential of particles to negative and formation of cake.
2-Addition of surfactant to control flocculation

17. ·Polymers are long-chained, high molecular-weight compounds
containing active groups spaced along their length.
·These agents promote flocculation through adsorption of part of the
chain on the surface of particle and the remaining part project out
into the dispersion medium. Formation of bridge between the
projected parts leads to formation of floccules (see the following
figure)

17
3- Addition of polymers to control flocculation
Example of surfactant used as flocculating agents
Formation of bridge between particles
Projection out into
dispersion medium
Adsorption on the
surface of particles
Solid particle
Solid particle
Formation of bridge between particles
Projection out into
dispersion medium
Adsorption on the
surface of particles
Solid particle
Solid particle

18. ·Hydrophilic polymers also act as protective colloids resulting in
coated particles have fewer tendencies to form cake.
·Polymers exhibits pseudoplastic flow in solution that promotes the
physical stability of suspension
·Some polymers like gelatin stabilize the suspension based on the pH
and ionic strength of dispersion medium (carry charge)
·An example of polymer is xanthan gum
·Positively charged Liposomes (vesicles of phospholipids) adsorbed on
negatively charged particles to prevent caking formation.
B-Flocculation in structured vehicles
·Sometimes suspending agents can be added to flocculated
suspension to retard sedimentation
·Examples of these agents are Carboxymethylcellulose (CMC),
Carbopol 934, Veegum, and bentonite
·It should be noted that physical incompatibility can limit the addition
of suspending agent
18
Most of hydrophilic colloids are negatively charged
-
Compatible Incompatible
-
+
+
+
+
+
Addition of
electrolyte
_
_
_
_
_
_
-
+
+
+
+
+
+
-
-
--
-
+
-
-
-
--
-
+
-
Addition of
suspending
agent
_
_
_
_
_
Positively charged
particles
Negatively charged
particles
Particle settle rapidly
Most of hydrophilic colloids are negatively charged
--
Compatible Incompatible
-
+
+
+
+
+
--
+
+
+
+
+
Addition of
electrolyte
__
__
__
__
__
__
-
+
+
+
+
+
--
+
+
+
+
+
++
-
-
--
-
+
-
-
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--
-
+
-
--
-
+--
-
++
-
-
-
--
-
+
-
-
-
--
-
+
-
--
-
+--
-
++
-
Addition of
suspending
agent
__
__
__
__
__
Positively charged
particles
Negatively charged
particles
Particle settle rapidly

19. ·Under this circumstance, the formulator can protect particle by
changing sign of particle from negative to positive using protective
colloids. This is illustrated by the following figure:
19
Ready to use suspension and extemporaneous preparation

20. ·Ready to use suspension is manufactured as you learn in this class
·Extemporaneous suspension is unordinary preparation that
pharmacist wants to prepare to a water-insoluble drug that exists in
tablet or capsule for situations when liquid dosage from is needed.
The following steps could be done to prepare extemporaneous
suspension:
1.Put the tablet or capsule content in mortar and crush it
2.Add the suspending vehicle slowly with mixing
3.You could add any flavoring agent or coloring agent available
4. Example of ready available suspending agents are Roxanes diluent
and Cologel
Suspensions are evaluated by determining their physical stability. Two
useful parameters for the evaluation of suspensions are sedimentation
volume and degree of flocculation. The determination of sedimentation
volume provides a qualitative means of evaluation. A quantitative
knowledge is obtained by determining the degree of flocculation.
1.Sedimentation volume: (F), sedimentation volume of a suspension is
expressed by the ratio of the equilibrium volume of the sediment, Vu, to
the total volume, Vo of the suspension.
F = Vu/Vo
The value of F normally lies between 0 to 1 for any pharmaceutical
suspension. The value of F provides a qualitative knowledge about the
physical stability of the suspension.
20
Evaluation of suspensions

21. F= 1 No sedimentation, no clear
supernatant
F =0.5 50% of the total volume is occupied
by sediment
F > 1Sediment volume is greater than the
original volume due to formation of
floccules which are fluffy and loose
2.Degree of flocculation: (ß), degree of flocculation is the ratio of the
sedimentation volume of the flocculated suspension, F, to the
sedimentation volume of the deflocculated suspension, F¥
ß = F / F¥
21

22. (Vu/Vo) flocculated
ß = --------------------
(Vu/Vo) deflocculated
When the total volume of both the flocculated and the deflocculated
suspensions are same; the degree of flocculation, ß = (Vu)floc/(Vu)defloc .The
minimum value of ß is 1; this is the case when the sedimentation volume of
the flocculated suspension is equal to the sedimentation volume of
deflocculated suspension. ß is more fundamental parameter than F since it
relates the volume of flocculated sediment to that in a deflocculated
system
Rheological consideration: viscosity of suspension affects and controls the
settling of dispersed particle. It, also, affects pouring the product from
bottle and spreading qualities in case of lotion. Best viscosity for suspension
is to be high during storage to prevent sedimentation and to be low at high
shear to ease the administration. Thus, pseudoplastic/ thixotrpic and
plastic/ thixotropic suspending agents could be use for this purpose.
Combination of two suspending agents can enhance the stability of
suspension
Ingredients of suspension:

22
7.Active ingredient
8.Wetting agent
9.Suspending agent
10.Flocculated agent
1.Preservative
2.Buffer system
3.Color agent
4.Flavor agent

23. Typical buffering agents, flavors, colorants, and preservative used in
suspensions:
Packaging and Storage of Suspensions:
1) Should be packaged in wide mouth containers having adequate air space
above the liquid.
2) Should be stored in tight containers protected from: freezing, excessive
heat & light
3) Label: "Shake Before Use" to ensure uniform distribution of solid
particles and thereby uniform and proper dosage.
4) Stored in room temperature if it is dry powder (25
0
C). It should be
stored in the refrigerator after opening or reconstitute (freezing should be
avoided to prevent aggregation)
23
Buffer
Flavor
Ammonia solution
Citric acid
Fumaric acid
Sodium citrate
Cherry
Grape
Methyl salicylatte
Orange
Peppermint
Class Agent

24. A-Physical stability:
B-Chemical stability:

24
Stability of suspension
1.Appearance, color, odor and taste
2.pH
3.Specific gravity
4.Sedimentation arte
5.Sedimentation volume
6.Zeta potential measurement
7.Compatibility with container
1.Degradation of active ingredient
2.Viscosity change
3.antimicrobial activity:
a.Incompatibility with preservative