Pharmaceutical Dosage Form and

Calculations
Suspension Chapter

Howard C. Ansel
Nicholas G. Popovich
Loyd V. Allen, Jr.
Lecturer: Dr. Majed R. Feddah

Pharmaceutical Suspension
Chapter Objectives:
At the end student should be able to:

Describe what pharmaceutical suspensions are and what roles they play in the
pharmaceutical science.
Discuss the factors that affect the stability of suspensions, and explain flocculation.
Describe settling and sedimentation theory, and calculate sedimentation rates.
Define and calculate the two useful sedimentation parameters, sedimentation
volume and degree of flocculation.
Describe the approaches commonly used in the preparation of physically stable
suspensions.

Introduction:

Pharmaceutical suspension is a coarse dispersion in which insoluble solids particles are

dispersed in a liquid medium.
The particle diameter of the particles is greater than 0.1 m.
Some of the small particles exhibit Brownian movement in low viscosity vehicles.
Most pharmaceutical suspension as Oral antibiotics, Anti-Acids, contains high concentration
of solid materials 20 to 30%.
Parenterals suspension intended to be taken as injections contains from 0.5 to 30% of solid
particles with small particles.

Classification:

1. Oral suspension.
Antibiotics, oral drops, anti-acids
2. Topical suspension
Calamine Lotion USP
3. Parenterals suspension

Pharmaceutical Applications:

Suspension may be used pharmaceutically for a number of reasons:

Drug that have very low solubility.
Drug that have unpleasant taste.
Insoluble for of drugs may prolong the action of a drug by preventing rapid
degradation of the drug in the presence of water.

Criteria for good suspension:

The dispersed particles should not settle rapidly.

The settling particles should not form hard cake, but should be readily re-dispersed,
when the container is shaken.
Not too viscous to poor freely from the orifice of the container, or to flow through a
syringe needles.
The product must be fluid enough to spread easily over the affected area.
Must not be so mobile that it runs off the surface to which is applied.
Should have an acceptable odor and color.
The dispersed phase must be chosen with care so as to produce a suspension having
optimum physical, chemical and pharmacologic properties.

Factors affecting the formulation of suspension:

Particle size and particle size distribution.

Specific surface area.
Inhibition of crystal growth.
Changes in polymorphic form.

These properties should do not change during storage.

Physical Stability of Suspension:

Physical stability of suspension:

The condition in which the particles do not aggregate and remain uniformly
distributed throughout the dispersion.
This is an ideal situation and in reality not happened, so:

Shake well before use should be written on the bottle and the should easily resuspended by a moderate amount of agitation.

Interfacial Properties of Suspended Particles:

The combinations of the of the particles results in the increase of the surface area of
the particles, hence increase of the free surface energy which makes the system
thermodynamically unstable..
In this case the particles is high energetic and tends to group to reduce the surface
area.
The particles in the liquid suspension therefore tend to flocculate, and form tight
fluffy conglomerates that held together by weak van der-waals forces.
In some cases these particles may adhere by stronger forces to form what are
termed aggregates (cake).
The formation of any types of agglomerate, either floccules or aggregates, is taken
as a measure of the system tendency to reach more thermodynamically stability
stable state.
To reach the stable state the system tends to reduce the surface free energy.
Equilibrium is reached when G = 0, this can be achieved by reduction of the
interfacial tension, by decreasing the interfacial area
The interfacial tension between particles can be reduced by the addition of
Surfactant.
But not reduced to the zero

The forces at the surface of the particles affect the degree of flocculation and
agglomeration in a suspension.
Electrical barrier on surface:

Charged particles repel or attract each other

When the repulsion energy is high, the potential barrier is also high, & collision is
stopped.
The system remains de-flocculated, and when sedimentation occurs, the particles
form a close packed arrangement with the smaller particles filling the voids between
the larger ones. Those particles are gradually pressed together by the weight of the
ones above.
In order to re-suspend and re-disperse these particles, it is again necessary to
overcome the high energy barrier, this is not easy to achieve by agitation.
The particles tend to remain strongly attracted to each other and form a hard cake.

Summary:
1. Flocculated particles: Are weakly bonded, settle rapidly, do not form cake,
and are easily re-suspended.
2. Deflocculated suspension: Particles settle slowly, and eventually form
sediment in which aggregation occurs with resultant formation of a hard cake
that is difficult to re-suspend.
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Settling in Suspension:

One aspect of physical stability in pharmaceutical suspension is concerned

with keeping the particles uniformly distributed through the dispersion.

It is not possible to prevent settling completely over the prolonged period of

time.

So it is necessary to consider the factors that influence the velocity of the

sedimentation.

Factors influence the velocity of the sedimentation:

Particle size, Density of the particles, Density of the medium, Gravity,

viscosity of the medium.

Problems encountered when formulating insoluble solids into

suspensions:
Factors need to be considered when formulating insoluble solids into a suspension.
Sedimentation:

The factors affecting sedimentation rate of particles are described in Stokess equation.
= 2r2( -)g
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= Velocity of spherical particle of radius r and density, in a liquid of density, and

viscosity

Theory of Sedimentation:

In diluted suspensions 2% or less the particles will not interfere one another
during sedimentation.

In most pharmaceutical preparation this is in not the case and the

concentration is much higher 20 or 30%.

In this case some estimation may be obtained by diluting the suspension and
this may affect the degree of flocculation and the de-flocculation of the
suspension.

Effect of Brownian movement

For particles having diameter between 2 to 5 m, (depending on the density

of the particles and the density and viscosity of the suspending medium),

Brownian movement counteracts (prevent) sedimentation to measurable

extent at room temperature by keeping the dispersed material in random
motion.

In pharmaceutical suspension, no Brownian movement are observed, as

most of them are viscous preparation with suspending agents.

Sedimentation of Flocculated Particles:

Whether the supernatant liquid is clear or turbid during the initial stages of settling is a
good indication of whether the system is flocculated or deflocculated.

Sedimentation parameter:
1. Sedimentation volume ( V), or the height H.
2. Degree of flocculation.

Flocculated:
In flocculated suspensions, Flocs tend to fall together, producing distinct boundary
between the sediment and the supernatant liquid.
Hence the liquid above the sediment is clear because even the small particles present in
the system are associated with the flocs.

Deflocculated:
It is not the case in the deflocculated suspension having a range of particle size, and
accordance with Stokes law the larger particles settle more rapidly than the smaller
ones, hence no clear boundary is formed, and supernatant remain not clear for longer
time.
Whether or not the supernatant liquid is clear or turbid during the initial stages of
settling is a good indication of whether the system is flocculated or deflocculated

Sedimentation Volume
Sedimentation volume (F) = the ratio of the final or ultimate volume of the sediment, Vu
to the original volume of the suspension Vo, before settling:

Degree of Flocculation
It is more useful parameter is than the sedimentation volume:
If we consider a suspension that is completely de-flocculated, the ultimate volume of
the sediment will be small.
Writing this volume as V, based on equation (F = Vu/Vo), we have
F = V/Vo is the sedimentation volume of deflocculated.
The degree of flocculation () = the ratio of F to V or

Crystal Growth.
Crystal growth is attributed to one of the followings mechanisms:
1. The growth of large particles at the expense of small ones, owing to a difference
in solubility rates of different size particles.

2. Temperature fluctuations on storage temperature cycling of a difference of 20C

or more.
3. Change from one polymorphic form to another more stable crystalline form.
4. The crystal growth may also arise when the more energetic amorphous or glassy
forms of a drug exhibit significantly greater initial solubility in water than their
corresponding crystalline forms.
5. The size reduction by crushing and grinding can produce particles whose
different surfaces exhibit high or low solubility rates, and this effect can be
correlated to differences in the free surface energy introduced during
comminuting.

Crystal Growth Control:

Crystal growth and changes in particle size distribution can be controlled by:

1. Selection of particle with narrower range of particle sizes.

2. Selection of more stable crystalline form of the drug, which usually exhibits
decreased solubility in water (which have the highest melting point.
3. Avoidance of the use of high energy milling during particle size reduction.
4. Use of wetting agent (water-dispersible surfactant) in formulating to scatter free
surface energy of particles by reducing the interfacial tension between the solid
and suspending vehicle.
5. Use protective colloid, such as gelatin, gums, or cellulosic derivatives, to form a
film barrier around the particle, thus inhibiting dissolution and subsequent
crystal growth.
6. Increase the vescosity of the vehicle to retard particle dissolution and
subsequent crystal growth.
7. Avoidance of temperature extremes during product storage, such as the
exposure to freeze-thaw conditioning.
Most drugs vary in particle size and in particle shape. This influence the physical
stability, appearance, bioavailability and potency of pharmaceutical suspension

The Use of Wetting Agent:

The initial dispersion of an insoluble powder in a vehicle is an important step in manufacturing
process.
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Some insoluble drug particles are easy wetted by the water by minimal mixing, and
most of the drugs however, will exhibit varying degrees of hydrophobicity and will not
easy wetted.
Some particles form large porous clumps with the liquid, others remain on the surface
and become attached to the upper part of the container.

Hydrophilic solids can be suspended easily in water without the aid of a water
dispersible surfactant or wetting agent.
Hydrophobic solids can be suspended in oil and non polar vehicles with the use of lipidsoluble surfactants.

Hydrophobic and Hydrophilic:

Powders that are not easily wetted by water and show large contact angle with water
are called Hydrophobic. (Sulfur, charcoal, Magnesium stearate)
Powders that are readily wetted by water are called Hydrophilic. (Zinc oxide, Talk,
Magnesium carbonate)
To ensure adequate wetting, the interfacial tension between the solid and the liquid
must be reduced so that the adsorbed air is displaced from the solid surfaces by the
liquid.
Wetting agent is used to decrease the interfacial tension between the drug particles and
the liquid and in lesser extent, between liquid and air.
Polysorbates (Tweens) and sorbitan esters sulphate, sodium dioctylsulphosuccinate.

The role of surfactant in the preparation of suspension:

By reducing the interfacial tension between solid particles and liquid so:
1. The contact area is lowered.
2. The air is escape from the surface of the particles.
3. Wetting and dispersion are promoted.

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Glycerin and similar hygroscopic substances are also valuable in levigating

the insoluble materials.

Glycerin flows into the voids between the particles, to displace the air and
during mixing operation.

Control Flocculation:
Once the powder is properly wetted and dispersed, attention should be given to keep
these powders flocculated and to prevent them from forming compact sediment that is
difficult to re-disperse.
Controlled flocculation is usually achieved by a combination of particle size control, the
use of Electrolytes to control the Zeta potential, and the addition of Polymers to enable
cross linking to occur between particles and Surfactants

Electrolytes
Electrolytes acts as flocculating agent by reducing the electric barrier between the
particles by a decrease the zeta potential and the formation of bridge between adjacent
particles so as the link them together in a loosely arranged structured.
Example: Bismuth subnitrate in water.

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Surfactants:
Ionic and nonionic surfactants have been used as flocculating agent of suspended
particles.
The concentration of surfactant is critical since these compounds may also act as
wetting and deflocculating agents to achieve dispersion.
Examples:
Anionic /Docusate sodium, sodium lauryl sulfate.
Nonionic/ Polysorbate 65, Polysorbate 80, octoxynol-9,

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Polymers:
Polymers are long chain, high molecular weight compounds containing active groups
spaced along their length.
These agents act as flocculating agents because part of the chain is adsorbed on the
particle surface, the other parts projecting toward the dispersion medium and hydrated.
Bridging between these particles lead to the formation of flocs.

Examples:

Xanthan gum (anionic heteropholysaccharide).

Addition of xanthan gum result in the increase of the sedimentation volume.
Hydrophilic polymers (Negatively charged) is used as protective colloids, particles
coated in this manner are less prone to cake than are uncoated particles.
The hydrophilic polymers posses a pseudo plastic flow in suspension so it will enhance
the physical stability of the suspension.
Gelatin (polyelectrolytic polymer, exhibit its flocculation that depends on the pH and
ionic strength of the dispersion medium.

Formulation of Suspension
1. The use of structured vehicle.
2. Flocculation principle. To produce flocs that, although they settle rapidly,
however, easily re-suspended with a minimum of agitation.
3. Flocculation in structured vehicle.

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Formulation of suspension summary

Structured Vehicles
Structured vehicles are pseudo plastic and plastic in nature.

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Thixotropy associated with these two types of flow.

It acts by entrapping the particles so that, ideally, no settling occurs.
The shear thinning property of these vehicles does, however, facilitate the reformation
of a uniform dispersion when shear is applied.
Disadvantages:
Formation of hard cake when eventually settled.

Optimum physical stability and appearance will be obtained when the suspension is
formulated with flocculated particles in a structured vehicle of the hydrophilic colloidal
type.
1. Flow readily from the container.
2. Possess a uniform distribution of particles in each dose.

Flocculation in Structured Vehicles:

Although the controlled flocculation approach is good in regards of physical and
chemical stability of the system.
A suspending agent is added to the system to retard sedimentation of the flocs.
Examples:

Carboxymethycellulose (CMC), Carbopol 934, Veegum, Tragacanth, or bentonite.

Alone or in combination

1. Reologic Considaration:
The principles of rheology may be applied to a study of the following factors:

2. The viscosity of a suspension, which affect the settling of particles.

3. The change in flow properties of the suspension when the container is shaken.
4. The spreading qualities of the lotion when it is applied to an affected area.

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Structured Vehicle preparation:

Ideal suspending Agent:

High viscosity at negligible shear (during the shelf life of the product)
Low viscosity at high shearing rates (during pouring from the bottle or spreading in case
of lotion.
Pseudo plastic substances such as Tragacanth, sodium alginate, and sodium
Carboxymethylcellulose show these desirable qualities.
Newtonian liquid:

Glycerin, is suitable for suspending particles but is too high to pour easily and to spread
on the skin.
Glycerin shows the undesirable property of stickiness and it too hygroscopic to use in
undiluted form.

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Suspending Agent:
A suspending agent that is Thixotropic as well as pseudoplastic should prove to be useful
since it forms a gel on standing and becomes fluid when disturbed.
Example:
Bentonite and CMC 50:50 form thixotroy and pseudoplastic properties.

They produce excellent suspension.

Stability of Suspension:

Rising the temperature: Leads to flocculation of sterically stabilized suspension.

Freezing: During freezing process, cause the particles to aggregate, and it remain
aggregated even when the ice is melted.

In temperature fluctuation: Particle growth were observed (change the particle

size and particle size distribution and the polymorphic form of the particles.

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