PHARMACEUTICAL

SUSPENSIONS
Day-2 Day-1:
Pharmaceutical Suspensions (4 hrs) ▪ Formulation approaches (structure vehicle, controlled
flocculation and combination)
§ Introduction
§ Rheology of suspension
§ Desirable properties
Day-2:
Day-1: § Preparation of suspensions (diffusible, indiffusable, poorly
§ Sedimentation in suspensions wettable solids)

§ Interfacial properties of suspended particles § Label and storage

Day-2:
§ Electrical properties of suspended particles (EDL and DLVO
theory)
§ Flocculated/deflocculated suspensions (properties and
evaluations)
SUSPENSIONS – COARSE
DISPERSION
A suspension is a heterogeneous (biphasic) system consisting of a solid phase in a liquid
phase.
The solid phase is subdivided into small particles (particle size > 0.1µ) and dispersed in
the liquid medium in which the solid is insoluble or sparingly (or slightly) soluble.
Defined as a coarse dispersion of finely subdivided insoluble solid drug suspended in a
suitable liquid (usually aqueous) medium.
A suspension may be for internal, external or parenteral use.
Oral suspensions avoid swallowing problems of tablets and capsules.
As suspensions contain subdivided solid particles, surface area is large – which
is an advantage with adsorptives or antacids. Eg kaolin, magnesium stearate
Drugs which are bitter tasting in their soluble form are administered in their
insoluble form as suspensions to mask taste. Eg insoluble chloramphenicol
palmitate instead of chloramphenicol base with bitter taste.
Suspensions for external use are mainly lotions. External suspensions are not
messy as ointments. Eg calamine lotion.
Parenteral suspensions are for depot therapy. Eg insulin zinc suspension
DESIRABLE PROPERTIES
❖ there should NOT be rapid settling of suspended particles
❖ if particles settle, they should NOT form a hard cake at bottom, but redisperse
into uniform mixture when shaken.
❖ suspension should be easily pourable
❖ parenteral suspensions should flow through the syringe needle without
blocking
❖Suspensions for external use should spread easily on skin but not run off
INTERFACIAL PROPERTIES
❖Increase in surface free energy due to increase in surface area of suspended
particles and
❖presence of electrical charges on the surface of the dispersed solid particles are
to be considered.
INTERFACIAL PROPERTIES –
SURFACE FREE ENERGY
ΔG = ΥΔA
ΔG = increase in surface free energy
Υ = interfacial tension
ΔA = increase in surface area

When ΔG > 0 , ie excess free energy, due to increase in surface area, the system
tends to approach a stable state by reducing the surface free energy
spontaneously.
When ΔG = 0 , the system is thermodynamically stable.
Smaller the ΔG, the more thermodynamically stable is the suspension.
A reduction in interfacial tension can be brought by adding a wetting agent
(surfactant).
Molecules of surfactant get adsorbed between the particle and the medium and
cause a reduction in interfacial tension, which produces a reduction in ΔG
making the suspension stable.
However the interfacial tension cannot be made equal to 0, and therefore the
suspended particles in contact with liquid medium possess a finite positive
interfacial tension, leading the particles to flocculate or aggregate.
If particles remain deflocculated, they settle relatively slowly. Thus settled
particles tend to form eventually a hard cake which is extremely difficult to
redisperse uniformly.
When reduced greatly in size, particles (solids) or globules (liquids) tend to
agglomerate or stick together, be the medium liquid or air.
This tendency is due to excess free energy and the system becomes
thermodynamically unstable.
In order to become thermodynamically stable, regrouping of particles or
agglomeration (particles are held together by weak forces of attraction like
vander waals) tales place.
INTERFACIAL PROPERTIES –
ELECTRICAL PROPERTIES AT SURFACE
OF DISPERSED
Both attraction and repulsion forces exist between dispersed particles.
Particle-particle interaction may be:
1. various electrostatic contributions – may be ion-ion, ion-dipole, dipole-dipole.
They have both attractive (between dissimilar charges) and repulsive (between
similar charges) forces
2. London dispersion forces – it is induced dipole- induced dipole interaction
(attraction) . Between atoms of one particle with those of other.
3. covalent bonds (attractive)
4. born repulsion forces (repulsive) – due to overlapping of electron clouds of
the atoms present in a molecule or ion
Covalent bonds and born repulsion forces effect only when particles touch each
other.
In general, particles in suspension have forces of attraction which are of the
London vander waals type and forces of repulsion due to the interaction of
electric double layer surrounding each particle.
The region in which the influence of the surface charge (ie potential) of the
particle is appreciable is termed the electric double layer region.
The electric double layer shall comprise of :
1. stern layer of counterions – potential drop across stern layer from the surface
of particle is sharp
2. diffuse double layer – potential drop is somewhat gradual and drops to zero
at the end of its surface
Charged particles migrate towards oppositely charged electrode.
Potential energy of two particles (as they approach each other) may be plotted
as a function of distance of separation.
 VR

VN
Net energy

VA
❖When the repulsion energy is high, the potential barrier is also high, and
collision of the particles is opposed. The system remains deflocculated.
❖When sedimentation is complete, the particles form a close-packed
arrangement with the smaller particles filling the voids between the larger
ones.
❖Those particles lowest in the sediment are gradually pressed together by
the weight of the ones above; the energy barrier is thus overcome, allowing
the particles to come into close contact with each other.
❖To resuspend and redisperse these particles, it is again necessary to
overcome the high-energy barrier
❖Because this is not easily achieved by agitation, the particles tend to remain
strongly attracted to each other and form a hard cake.
❖When the particles are flocculated, the energy barrier is still too large to be
surmounted, and so the approaching particle resides in the second energy
minimum, which is at a distance of separation of perhaps 1000 to 2000 Å.
❖To summarize, flocculated particles are weakly bonded, settle rapidly, do
not form a cake, and are easily resuspended.
❖Deflocculated particles settle slowly and eventually form a sediment in
which aggregation occurs with the resultant formation of a hard cake that is
difficult to resuspend.
FLOCCULATED / DEFLOCCULATED
Zeta potential – the overall (or resultant) charge on the suspended particle is
zeta potential, it is a measurable indication of charge.
Therefore, flocculation and deflocculation may be considered in terms of zeta
potential.
When the zeta potential is high, the particles remain dispersed and are said to
be deflocculated. These particles resist collision due to high zeta potential even
when brought close.
When zeta potential is low, particles when they approach each other, form loose
aggregates, commonly called flocs. Such a system is said to be flocculated. Zeta
potential can be lowered by addition of an electrolyte (whose ion is oppositely
charged to that of suspended particle) till the forces of attraction dominate
forces of repulsion.
SETTLING AND ITS CONTROL
Sedimentation velocity of particles in a suspension is related to
 Size of particle
 Density of particle
 Viscosity of dispersion medium

The velocity of sedimentation is expressed by Stokes's law:

where v = average velocity of sedimentation of particles in cm/sec, d = diameter of the particle in cm, ρs
and ρf = the densities of the dispersed phase and dispersion medium, respectively, g = acceleration due
to gravity, η = viscosity of the dispersion medium in poise.
According to stoke’s law, settling rate for the particles can be reduced by
decreasing the particle size, provided the particles are deflocculated.
Rate of sedimentation may be delayed by increasing the viscosity of the
medium. However, above a limit pourability is affected and redistribution of
particles difficult.
Stokes law is applicable in following condition
1. The particle should be spherical, but in suspensions particle are largely
irregular.
2. The particles do not interfere with one another during sedimentation, and
free settling occurs in a streamline, which is possible only for dilute
suspensions
In most pharmaceutical suspensions that contain dispersed particles in
higher percentages, the particles exhibit hindered settling. The particles
interfere with one another as they fall, and Stokes's law no longer applies.
However, these factors influence the rate of settling.
BROWNIAN MOVEMENT
For particles having a diameter of about 2 μm (depending on the density of
the particles and the density and viscosity of the suspending medium),
Brownian movement counteracts sedimentation to a measurable extent at
room temperature by keeping the dispersed material in random motion.
However, considering the size of particles in pharmaceutical suspensions, it
is unlikely that the particles will undergo Brownian movement.
SEDIMENTATION PARAMETERS
Two useful parameters that can be derived from sedimentation studies are
sedimentation volume, V, and degree of flocculation.
The sedimentation volume, F, is defined as the ratio of the final, or ultimate,
volume of the sediment, Vu, to the original volume of the suspension, Vo,
before settling. Thus,
F = Vu/ Vo
❖ The sedimentation volume can have values ranging from less than 1 to greater
than 1.
❖ F is normally less than 1, and in this case, the ultimate volume of sediment is
smaller than the original volume of suspension.
❖ If the volume of sediment in a flocculated suspension equals the original volume of
suspension, then F = 1
❖ Such a product is said to be in flocculation equilibrium and shows no clear
supernatant on standing. It is therefore pharmaceutically acceptable.
❖ It is possible for F to have values greater than 1, meaning that the final volume of
sediment is greater than the original suspension volume.
❖ This comes about because the network of flocs formed in the suspension is so
loose and fluffy that the volume they are able to encompass is greater than the
original volume of suspension
Degree of flocculation is a better parameter to compare different formulations
in terms of flocculation.
It is the ratio of the sedimentation volume of the flocculated suspension (F) to
the sedimentation volume of the suspension when deflocculated (F∞)
β = F/ F∞
The degree of flocculation refers to increased sediment volume because of
flocculation. For example, if β = 4, the sediment volume in the flocculated
suspension is increased by 4 times that of deflocculated state.
A suspension with a higher degree of flocculation is preferred.
FORMULATION APPROACHES
A physically stable suspension may be produced by
❖ use of structured vehicle to keep the deflocculated particles in suspension
- the deflocculated particles are entrapped which reduces the settling
time
- due to shear thinning property, redispersion is somewhat easier
- but, when particles settle , they form a cake at the bottom of the container
making it difficult to redisperse

or
❖ use of principles of flocculation in order to assure an easy uniform
redispersion of particles with minimum of agitation
- in this the particles settle rapidly and the redispersion is easy
- but particles may settle down and lead to subtherapeutic dose, if there is time
gap between shaking and transferring the contents

Hence, optimum physical stability may be obtained by producing suspensions with

controlled flocculation in a structured vehicle.
DISPERSION OF PARTICLES
Before dispersion of particles can be effected, the
particles should be properly wetted.
Wetting is a problem with hydrophobic particles, which
can be overcome with wetting agents.
Wetting agents act by lowering the contact angle between
the surface of the particle and the dispersion medium.
Wetting agents are surfactant with HLB 7-9.
Glycerin flow into void space between particles, coat and
separate bringing dispersion.
CONTROLLED FLOCCULATION
Flocculation in a suspension may be brought by adding
 Electrolytes – most widely used
 Surfactants
 Polymers
ELECTROLYTES
When added to a well wetted and dispersed particles suspension, electrolytes
cause a reduction in electrical forces of repulsion bringing about flocculation.
Electrolytes reduce the electrical barrier thereby reduce zeta potential.
If added more, the zeta potential crosses zero and enters opposite zone where
the net charge reverses. In such a case, the particles again get deflocculated
since zeta potential starts to increase now.
Eg. Monobasic potassium phosphate – negatively charged phosphate ions
adsorb on surface of positively charged bismuth subnitrate suspension particles
Aluminium chloride – positively charged aluminium ions adsorb on negatively
charged sulfamerazine suspension particles
SURFACTANTS
Ionic and nonionic surfactants are used.
Concentrations are critical because they act as wetting agents also to bring
dispersion of powder particles in suspension medium.
POLYMERS
Polymers act as flocculating agents by forming a bridge between particles.
Sedimentation volume is higher in a suspension in which polymers have been
used for flocculation.
Eg xanthan gum
FLOCCULATION IN STRUCTURED
VEHICLE
Although the controlled flocculation approach is capable of fulfilling the
desired physical chemical requisites of a pharmaceutical suspension, the
product can look unsightly if F, the sedimentation volume, is not close or
equal to 1.ie sediment volume less than total volume.
Consequently, in practice, a suspending agent is frequently added to retard
sedimentation of the flocs.
Such agents as carboxymethylcellulose, Carbopol 934, Veegum, tragacanth,
and bentonite have been employed, either alone or in combination.
This can lead to incompatibilities, depending on the initial particle charge and
the charge carried by the flocculating agent and the suspending agent.
For example, suppose we prepare a dispersion of positively charged
particles that is then flocculated by the addition of the correct concentration
of an anionic electrolyte such as monobasic potassium phosphate.
We can improve the physical stability of this system by adding a minimal
amount of one of the hydrocolloids .
No physical incompatibility will be observed because the majority of
hydrophilic colloids are themselves negatively charged and are thus
compatible with anionic flocculating agents.
 If, however, we flocculate a suspension of negatively charged particles with
a cationic electrolyte (aluminum chloride), the subsequent addition of a
hydrocolloid may result in an incompatible product, as evidenced by the
formation of an unsightly stringy mass that has little or no suspending action
and itself settles rapidly.
Under these circumstances, it becomes necessary to use a protective colloid
to change the sign on the particle from negative to positive.
This is achieved by the adsorption onto the particle surface of a fatty acid
amine (which has been checked to ensure its nontoxicity) or a material such
as gelatin, which is positively charged below its isoelectric point.
We are then able to use an anionic electrolyte to produce flocs that are
compatible with the negatively charged suspending agent.
PHYSICALLY STABLE SUSPENSION
May be produced by
❖ reducing the particle size
❖ adding a suitable suspending agent to increase viscosity
❖ using suitable electrolyte to cause flocculation
❖ selecting proper surfactants or polymers to avoid crystals of drugs getting
dissolved as temperature increases, which could otherwise cause
supersaturated solution and crystal growth. Eg PVP used in sulphathiazole and
acetaminophen suspension
RHEOLOGIC PROPERTIES
Rheologic consideration is of great importance because the viscosity of a
suspension can modify the sedimentation rate.
The viscosity of a liquid is a measure of its resistance to flow.
Greater viscosity of dispersion medium offers the advantage of slower
sedimentation; but on the other hand, it may compromise other desirable
properties such as ease of redispersibility, syringability for parenteral
suspensions, spreadability for topical suspensions, and ease of
administration for oral suspensions.
From the manufacturer’s point of view, low viscous products are more
productive. Rheology can affect the manufacturing process of suspensions
since highly viscous mixture produces excessive frictional drag on the mixing
vessel and other machinery accessories, thereby resulting in wasted energy.
Such a combination of property may be obtained by a mixture of bentonite (which exhibits
thixotropy) and cmc (which exhibits pseudoplastic behavior)

Viscosity of pseudoplastic flow decreased with the increased in shear rate it showed the shear thinning behaviour.
Thixotropy is the property of some non-newtonian pseudoplastic fluids to show a time-dependent change in viscosity .Viscosity
decreases as the material is stirred until some minimum value is reached. It increases again when the substance is no longer agitated.
Newtonian – eg water. Shear rate doesn’t change viscosity . Shear rate is proportional to shear stress.
OTHER FORMULATION ASPECTS
 Introduction

 A perfect suspension is one, which provides content uniformity. The

formulator shall encounter important problems regarding particle size
distribution, specific surface area, inhibition of crystal growth and changes in
the polymorphic form. The formulator must ensure that these and other
properties should not change after long term storage and do not adversely
affect the performance of suspension.
 Choice of pH, particle size, viscosity, flocculation, taste, color and odor are
some of the most important factors that must be controlled at the time of
formulation.
FORMULATION COMPONENTS
The various components, which are used in suspension formulation, are as follows.

 API ………….Active drug substances

 Wetting agents ………They are added to disperse solids in continuous liquid phase.
 Flocculating agents ………They are added to floc the drug particles
 Thickeners …………They are added to increase the viscosity of suspension.
 Buffers and pH adjusting agents ………They are added to stabilize the suspension to a
desired pH range.
 Osmotic agents ………They are added to adjust osmotic pressure comparable to biological
fluid.
 Coloring agents ………..They are added to impart desired color to suspension and improve
elegance.
 Preservatives ……….They are added to prevent microbial growth.
 External liquid vehicle ………They are added to construct structure of the final suspension.
WETTING AGENTS
Hydrophilic materials are easily wetted by water while hydrophobic materials are
not. However hydrophobic materials are easily wetted by non-polar liquids. The
extent of wetting by water is dependent on the hydrophillicity of the materials. If the
material is more hydrophilic it finds less difficulty in wetting by water.
Inability of wetting reflects the higher interfacial tension between material and liquid.
The interfacial tension must be reduced so that air is displaced from the solid surface
by liquid.
 Non-ionic surfactants are most commonly used as wetting agents in pharmaceutical
suspension. Non-ionic surfactants having HLB value between 7-10 are best as wetting
agents. High HLB surfactants act as foaming agents. The concentration used is less
than 0.5 %. A high amount of surfactant causes solubilization of drug particles and
causes stability problem.
 Ionic surfactants are not generally used because they are not compatible with many
adjuvant and causes change in pH.
SURFACTANTS
 Surfactants decrease the interfacial tension between drug particles and liquid and
thus liquid is penetrated in the pores of drug particle displacing air from them and
thus ensures wetting.
 Surfactants in optimum concentration facilitate dispersion of particles. Generally
we use non-ionic surfactants but ionic surfactants can also be used depending
upon certain conditions.
 Disadvantages of surfactants are that they have foaming tendencies.
 Further they are bitter in taste. Some surfactants such as polysorbate 80 interact
with preservatives such as methyl paraben and reduce antimicrobial activity.
SURFACTANTS
 Polysorbate 80 is most widely used surfactant both for parenteral and oral
suspension formulation.
 Polysorbate 80 is also adsorbed on drug particle and decreases its zeta
potential. This effect of polysorbate80 stabilizes the suspension.
SURFACTANTS
 In absence of polysorbate 80, difficulty was observed in re-dispersion of
sedimented particles.
 Polysorbate 80 is most widely used due to its following advantages
 It is non-ionic so no change in pH of medium
 No toxicity.
 Safe for internal use.
 Less foaming tendencies however it should be used at concentration less than
0.5%.
 Compatible with most of the adjuvant.
HYDROPHILIC COLLOIDS

 Hydrophilic colloids coat hydrophobic drug particles in one or more than one
layer. This will provide hydrophillicity to drug particles and facilitate wetting.
 They cause deflocculation of suspension because force of attraction is
declined. e.g. acacia, tragacanth, alginates, guar gum, pectin, gelatin, wool fat,
egg yolk, bentonite, Veegum, Methylcellulose etc.
SOLVENTS

 The most commonly used solvents used are alcohol,

glycerin, polyethylene glycol and polypropylene glycol. The mechanism by
which they provide wetting is that they are miscible with water and reduce
liquid air interfacial tension. Liquid penetrates in individual particle and
facilitates wetting.
Co-solvents Used in suspensions
 Some solvents which themselves have high viscosity are used as co-solvents
to enhance the viscosity of dispersion medium:
 Glycerol, propylene glycol, sorbitol.
MIXING PROCEDURES
THE DISPENSING OF SUSPENSIONS
 The method of dispensing suspensions is the same for most, with some
differences for specific ingredients.
1. Crystalline and granular solids should be finely powdered in the mortar. The
suspending agent should then be added and mixed thoroughly in the mortar.
Do not apply too much pressure, otherwise gumming or caking of the
suspending agent will occur and heat of friction will make it sticky.
2. Add a little liquid vehicle to make a paste and mix well until smooth and free
of lumps. Continue with gradual additions until the mixture can be poured
into a bottle. Further liquid is used to rinse all the powder into the bottle
where it is made up to volume.
3. When water is prescribed as a vehicle, use freshly boiled and cooled water
or potable water where permissible
VARIATIONS
 If the wetting agents are included in the formulation, add them before
forming the paste
 If syrup and/or glycerol are in the formulation, use this rather than water to
form the initial paste
 If soluble solids are being used, dissolve them in the vehicle before or after
making the paste
 Leave addition of volatile components, colouring or concentrated flavouring
tinctures such as chloroform spirit, liquid liquorice extract and compound
tartrazine solution until near the end
STABILITY OF SUSPENSIONS
Factors that contribute to appreciable stability of a suspension include:
a) Small particle size- reducing the size of the dispersed particle
increases the total surface area of the solid. The greater the
degree of subdivision of a given solid the larger the surface
area. The increase in surface area means also an increase in
interface between the solids and liquids leading to an
increase in viscosity of a system.
STABILITY OF SUSPENSIONS
b). Increasing the viscosity – increasing the viscosity of the continuous
phase can lead to the stability of suspensions. This is so because the
rate of sedimentation can be reduced by increase in viscosity.
Viscosity increase is brought about by addition of thickening agents
to the external phase. In water these must be either soluble or swell.
It is important to note that the rate of release of a drug from a
suspension is also dependent on viscosity. Of a product. The more
viscous the preparation, the slower is likely to be the release of a
drug. Sometimes this property may be desirable for depot
preparations.
STABILITY OF SUSPENSIONS
C). TEMPERATURE.
Another factor which negatively affects the stability and usefulness of
pharmaceutical suspensions is fluctuation of temperature. Temperature
fluctuations can lead to caking.
IDEAL REQUIREMENTS OF
PACKAGING MATERIAL
It should be inert.
It should effectively preserve the product from light, air, and other
contamination through shelf life.
It should be cheap.
It should effectively deliver the product without any difficulty
CONTAINERS FOR SUSPENSIONS
 Choices of packaging of all pharmaceutical products are extremely important
aspect of ensuring stability of the product.
 Suspensions should be packed in amber coloured bottles- plain for internal
use and ribbed for external use. There should be adequate air space above the
liquid to allow shaking and easy pouring.
 A 5ml medicine spoon or oral syringe should be given when the suspension is
for oral use.
SPECIAL LABELS AND ADVICE FOR
SUSPENSIONS
 All pharmaceutical suspensions should be properly labelled.
 The most important additional information in addition to the product name
and directions for use is the inclusion of the direction “shake the bottle well
before use” as some sedimentation of medicament would normally be
expected. Shaking the bottle will redisperse the medicament and ensure that
the patient can measure the accurate dose.
 Other labelling information include directions to store in a cool place, expiry
date.