PHARMACEUTICAL SUSPENSIONS

This note has been prepared mainly from the above two books. There may be phrases
that have been reproduced from these books. A large number of pictures used in this
note are from various websites and books, some of which I did not cite to avoid
clutters.
LEARNING OBJECTIVES
• Define suspensions
• Understand the concepts related to suspensions
• Know the application of suspensions in pharmacy
• Know about desired properties of suspensions
• Know the concepts of flocculation, deflocculation, controlled
flocculation, aggregation and sedimentation
• Learn compounding of suspensions
• Recognize the formulation additives used in suspensions
• Be familiar with the stability problems of suspension
• Be able to calculate the sedimentation volume and degree of
flocculation
• Know about packaging and storage of suspensions
• Be familiar with different types of commercial suspensions
• Know how to dispense dry powder for suspensions
WHAT IS A SUSPENSION?
• Suspension is a liquid dosage form that is defined as
preparation containing finely divided drug particles
(also called suspensoid) dispersed in a vehicle with
which the drug has a minimum degree of solubility
or interactions.

• Suspensions may be available in two forms:

• Ready-to-use form: In this type of suspension,
the drug is already dispersed in the vehicle with
or without any preservatives or any other
additives.
• Dry powders for suspensions: In dry powder for
suspension, drug is mixed with suitable
suspending and dispersing agents that can be
dissolved in a vehicle, generally water, by simple
agitation.
APPLICATION OF SUSPENSIONS
• There are some situations when some drugs are required to be formulated as
suspensions:

• Many people have difficulty in swallowing solid dosage forms and require the
drug to be dispensed as suspension

• Some drugs are insoluble in water or any other solvent. Those drugs are then
formulated as suspension.
• For example, hydrocortisone or neomycin are available as suspension because of their
poor solubility in water

• Certain drugs are unstable in aqueous solution but stable when they are
suspended in a non-aqueous solvent
• Oxytetracycline is unstable in aqueous solution, but a stable liquid dosage form of this
drug can be prepared by suspending the insoluble calcium salt of this drug in a suitable
vehicle.
APPLICATIONS OF SUSPENSIONS
• Suspensions can be used to mask the taste of many
poor-tasting drugs.
• For example, acetaminophen is available as suspension for
pediatric patients, because suspension is more palatable than
solution
• Chloramphenicol palmitate, the water insoluble form of
cholramphenicol, is available as a better tasting suspension

• Some drug substances may be required to be present in

the GIT in a finely divided form, so that these
formulations can offer a high surface area
• For example, kaolin, magnesium trisilicate and magnesium
carbonate are used for adsorption of toxins or to neutralize
excess acidity.
SUSPENSION AS A DOSAGE FORM
• Suspension type formulations are available for oral,
ocular, topical and parenteral administration.
• Suspensions for topical use could be mobile liquid or of
semisolid consistency.
• For example, calamine lotion, a freely mobile liquid, is used in
some skin conditions
• Some pastes may contain a high percentage of
dispersed particles.
• Rate of absorption of parenterally administered drugs
can be controlled, when administered as suspension.
• In order to increase the duration of action, particles of varying
sizes can be dispersed to form suspension.
SUSPENSION AS A DOSAGE FORM

• Certain drugs can also be suspended in oil that can be

administered as globules to produce a depot action.

• Vaccines are often formulated as suspension. Most

vaccines are dispersions of killed microorganisms or of
toxoids adsorbed onto a substrate of alum.

• Suspensions are also used as diagnostic agents.

• Barium sulfate suspension is administered orally or rectally to
examine GIT.
DESIRED PROPERTIES OF A GOOD SUSPENSION
• In addition to therapeutic efficacy, chemical stability and aesthetic
appeal, a pharmaceutical suspension should have the following
properties:
• The suspension must remain sufficiently homogeneous during
the period between shaking the container and removing the
required dose.
• The suspended particles should settle slowly
• The sediment produced must be easily re-suspended by the
use of moderate agitation.
• The viscosity of the preparation should not be so high that
will make the removal of the product from the container and
its transfer to the site of application difficult. In other words,
suspension should pour readily and evenly from its container.
• The particle size of suspensions should remain fairly constant
throughout the periods of undisturbed standing.
• Parenteral/Opthalmic suspension must be setilizable
• Gets easily into a syringe or flows through a
needle(parenteral)
FORMULATION INGREDIENTS USED IN
SUSPENSIONS

• The followings are the main formulation components of suspensions:

• Wetting agents
• As we know wetting agents are surfactants, which when added to
water increase its ability to wet hydrophobic powders
• Surfactants that are used as wetting agents include polysorbates
(Tweens), sorbitan esters (Spans) and sodium dodecyl sulfate
• Some polymers (acacia, tragacanth and bentonites) and solvents
(alcohol, glycerol and glycols) can also be used as wetting agents
• Viscosity modifiers:
• Hydrophilic polymers that are used as wetting or deflocculating
agents can also be used as viscosity modifiers in suspension.
• Examples include acacia, starch, carboxymethylcellulose,
magnesium aluminium silicate.
 Components Function

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 They are added to stabilize the suspension to a
and pH adjusting agents 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.
FORMULATION INGREDIENTS USED IN
SUSPENSIONS
• Buffers
• Density modifiers
• Glycerin or propylene glycols
• Colors, flavors and perfumes
• Humectants
• Glycerin or propylene glycols
• Preservatives
• Sweetening agents
FACTORS THAT MAY AFFECT FORMULATION OF A
SUSPENSION
• Particle size
• Drug to be suspended should be pulverized or subdivided prior to mixing
with the dispersion medium
• Particles larger than 5 m will impart a gritty texture to the product and
may produce irritation if injected or instilled into the eyes.
• The ease of administration of a parenteral suspension may also be
affected by the particle size and shape. Particle larger than 25 m may
block the needle
• Too fine particles will easily form a hard cake at the bottom of
suspension
• Flocculation and deflocculation
• Sedimentation and degree of flocculation
FLOCCULATION, AGGREGATION AND CAKING OF
SUSPENDED PARTICLES
• Suspended particles are highly energetic and
therefore they are thermodynamically unstable.
• Highly energetic particles tend to reduce surface
free energy and surface area by regrouping with
each other.
• The suspended particles therefore form light and
fluffy conglomerates or floccules (flocs).
• The resulting flocs or conglomerates are held
together by van der Waals forces.
• The process of formation of flocs or conglomerates
is called flocculation
• In certain conditions, the particles may adhere to
each other by stronger forces to form aggregates
or agglomerates
• Caking occurs by the growth and fusion of crystals
in the precipitates to produce a solid aggregate
FLOCCULATION, AGGREGATION AND CAKING OF
SUSPENDED PARTICLES
Particles
Boundary layer

flocculation
1-10µ range
A Wetting and Deflocculation
B
dispersion
Crystal
growth
Agglomerate
or Coagulates
Stable floc
C

Agglomerate
1-10µ range or Coagulates
D E
 FACTORS AFFECTING FLOCCULATION
• As we have learned in the
colloidal dispersion lecture, the
forces that act on colloidal
particles are London-van-der
Waals type forces of attraction
and repulsive forces that arise Repulsion curve
from electrical double layer. Energy of
interaction
• The potential energy of two
particles is shown in the figure particle
as a function of the distance of particle
separation (DLVO theory)
• Based on the relative strength
of attractive and repulsive Attractive curve
forces, a suspension could be
Distance between
• Deflocculated or particles
• Flocculated
FLOCCULATED SUSPENSION

• A flocculated suspension is formed when the repulsive forces are

moderately high.
• In flocculated suspensions, distance of particle separation is
between 1000 to 2000Å.
• Flocculated particles are weakly bonded and settle rapidly.
• Flocculated particles do not form a cake, rather they form a
porous sediment.
• The sediment can easily be resuspended.
• In a flocculated suspension, the supernatant quickly becomes
clear as flocs settle rapidly
• A distinct boundary between the supernatant liquid and
sediment is observed in flocculated suspension.
DEFLOCCULATED SUSPENSION
• A deflocculated suspension is formed when the repulsive energy is too
high and collision of the particles is opposed.
• When sedimentation occurs in a deflocculated suspension, particles
form a closed pack arrangement with the smaller particles filling the
voids between larger ones.
• In deflocculated suspensions, particles settle slowly and form aggregates
that lead to the formation of a hard cake (hardening of sediment is
called caking).
• The hard cake formed due to sedimentation and subsequent aggregation
of particles is difficult to resuspend.
• Simple agitation may not be enough to overcome the energy required to
resuspend the cake formed after sedimentation.
• The supernatant of a deflocculated suspension will remain cloudy for an
appreciable time after shaking due to very slow settling rate.
• No distinct boundary between supernatant liquid and sediment is
observed.
FLOCCULATED AND DEFLOCCULATED SUSPENSION

Deflocculated Flocculated

Colloidally Pharmaceutically
“Stable” “Stable”

Colloidally
“Unstable”

Sediments slowly to small Sediments rapidly to small

sediment volume sediment volume
Difficult to redisperse Easily redispersed
FLOCCULATED OR DEFLOCCULATED SUSPENSION?
• In a deflocculated suspension, sedimentation occurs at a slow rate, a
uniform dosing can be achieved.
• In a flocculated system, as the sedimentation rate is fast, there is a risk
of inaccurate dosing.
• A deflocculated suspension with a sufficiently high viscosity to prevent
sedimentation would be an ideal situation.
• However, a deflocculated system that would remain homogeneous
during the shelf-life is difficult to achieve
• For this reason, deflocculated suspensions are called colloidally stable
but pharmaceutically unstable and flocculated suspensions are called
pharmaceutically stable but colloidally unstable
• Because of these conflicting situations, it is desirable that a suspension
is partially flocculated and viscosity is controlled to minimize the rate of
sedimentation.
• Therefore, a good suspension should have a controlled flocculation
CONTROLLED FLOCCULATION

• As discussed earlier, it is important that the suspension exhibits

the correct degree of flocculation
• Under-flocculation will give undesirable properties that are
associated with deflocculated suspension
• Over-flocculation may be irreversible and the product may not
look good or may have difficulty in re-dispersion.
• An optimal flocculation or controlled flocculation may be
achieved by one or more of the following processes:
• Particle size control
• Use of electrolytes to control zeta potential
• Addition of polymers that enables cross-linking to occur between particles
• Excipients that are used to achieve controlled flocculation are
often termed as flocculating agents
 FLOCCULATING AGENTS
• Electrolytes:
• Addition of inorganic electrolytes to an aqueous suspension can change the
zeta potential to an optimal value so that flocculation may occur.
• The Schultz-Hardy rule indicates that the flocculating power of a chemical
rises rapidly with its valance. For example, Al3+ and SO42- ions are almost
1000 times more effective than Na+ and Cl- ions.
• Most widely used electrolytes include sodium salt of acetates, phosphates
and citrates.
• Surfactants:
• Ionic surface active agents may cause flocculation by neutralization of the
charge
• Although nonionic surfactants have little effect on charge density, they may
adsorb on to more than one particle and thus form a loose flocculated
structure.
• Polymeric flocculating agents:
• Hydrophilic polymers such as tragacanth, carbomers and starch are used as
protective hydrophilic colloids.
• These polymers form gel like structures and become adsorbed on the
surfaces of particles, thus holding them in a flocculated state
INFLUENCE OF ZETA POTENTIAL ON FLOCCULATION
• There is a correlation between zeta potential, sedimentation volume,
caking and flocculation.
• This correlation has been shown for bismuth subnitrate (BN)
suspension containing increasing concentrations of an electrolyte,
monobasic potassium phosphate (MPP).
• The addition of MPP to the suspension of BN causes positive zeta
potential to decrease because of the adsorption of negatively charge
phosphate ions.
• With the addition of more electrolyte, zeta potential falls to zero and
become increasingly negative.
• The figure shows that at certain zeta potential value maximum
sedimentation occur and the flocculation will continue to exist until
zeta potential has become sufficiently negative for deflocculation to
occur.
• Sedimentation volume (F) was maximum at the onset flocculation and
it remains constant up to a certain zeta potential.
• F (discussed in next few slides) starts to fall when zeta potential
becomes sufficiently negative
INFLUENCE OF ZETA POTENTIAL ON FLOCCULATION

100
Vu / V0
ratio

0.06
Vu / V0
curve

Zeta potential 0.03

curve

caked Not caked caked

50
Concentration KH2PO4
PARTICLE CHARGE AND STABILITY OF SUSPENSION
• Suspending agents that are often added to increase viscosity or wetting of drug
particles may interact with the colloidal particles or flocculating agents.
• However, as most of the suspending agents are negatively charged
(carboxymethylcellulose, carbopol 934, Veegum, tragacanth, also known as
hydrocolloid), they may lead to incompatibility depending on the initial charge
of the particle, flocculating agent or any other agents.
• For example, we have a positively charged suspended particle that is
flocculated with an anionic electrolyte.
• If we use one of the negatively charged hydrocolloids to stabilize the
suspension, an incompatibility is unlikely to occur because the flocculating
agents are also anionic.
• If the suspended particles were negatively charged and flocculating agents
were positively charged, use of a negatively charged hydrocolloid may lead to
an incompatibility.
• In the later case, one will need to change the sign of the suspended particles by
using protective colloid.
• For example, fatty acid amine or gelatin which are positively charged can be
used to change the sign from negative to positive.
PARTICLE CHARGE AND STABILITY OF SUSPENSION
• Once the sign has been changed, we can use anionic electrolytes as a
flocculating agent and anionic suspending agent to reduce sedimentation

Cationic Anionic (-)

Adsorbent Flocculant
(-RNH2+)

Uncoated Particles Coated Flocculated

(Positively charged, Particles
Particles
Negatively charged or
Neutral particles)
Suspension of
flocculated particles Suspending Finished
before adding Agent (-)
Suspension
suspending agent
SEDIMENTATION OF SUSPENDED PARTICLES
• Particles suspended in a suspension undergo sedimentation and the velocity of
sedimentation is expressed by Stokes’s law

d 2 (  s  o ) g (cm) 2  (g/cm3 )  (cm/sec 2 )

v v
18 o (g/cm  sec)

• v = rate of settling (cm/sec) ; d = diameter of the particles (cm)

• s = density of the dispersed phase (g/cm3), ; o = density of dispersion
medium (g/cm3),
• g = acceleration due to gravity (981 cm/sec2); o = viscosity of the medium
(poise; gm-1sec-1)
• Based on this equation, the following parameters can be modified to minimize
sedimentation (g and density of the solid remain constant).
• r: the particle size should be as small as possible
• o: Increase the density of the liquid, if the density of the dispersion
medium becomes equal to the density of the solid, sedimentation rate
becomes zero, although this can rarely be achieved
• o: increase the viscosity of the dispersion medium
MODIFICATION OF STOKES’S LAW
• Stokes’s law was derived for a dilute suspension in
which particles are uniform and spherical, that settle
without producing turbulance
• Stokes’s law also assumes that the particles have no
physical or chemical interaction with the dispersion
medium.
• As a result, Stokes’s equation does not apply to
nonspherical particles of varying diameter.
• To account for nonuniformity in particle shape and size
that we encounter in real systems, Stokes’s law is
written as follows
•  = n
George Gabriel Stokes
•  = rate of fall at the interface in cm/sec,  = velocity of
sedimentation according to Stokes’s law;  = porosity
(initial volume fraction of uniformly mixed suspension
that varies from zero to unity; n is a constant for each
system that measure the hindering of the system
CALCULATE THE RATE OF SEDIMENTATION
• The average particle diameter of calcium carbonate in aqueous suspension is 54
µm. The densities of CaCO3 and water, respectively, are 2.7 and 0.997 g/cm3. the
viscosity of water is 0.009 poise at 250C. Compute the rate of fall v’ for CaCO3
samples at two different porosities, 1 =0.95 and 2 = 0.5. the n value is 19.73.
• Solution: From Stokes’s law,

d 2 (  s  o ) g (54  10 4 ) 2 (2.7  0.997)981

v v  0.30 cm / sec
18 o 18  0.009

• Taking logarithms on both sides of equation v’ = vn,

ln v’ = lnv + n ln 
• For 1 = 0.95,
ln v’ = -1.204 + [19.73(-0.051)] = -2.210
 v’ = 0.11 cm/sec
Similarly, for 2 = 0.5,
v’ = 3.5 x 10-7 cm/sec
SEDIMENTATION PARAMETERS
• The following parameters, known as sedimentation parameters, can be used
to define sedimentation:
• Sedimentation volume or height
• Degree of flocculation

150 150 150 Sedimentation volume

exceeds volume of
sediment, therefore extra
vehicle is added
100 100 100

50 50 50

F=0.5 F=1.0 F=1.5

(a) (b) (c)
SEDIMENTATION VOLUME OR HEIGHT
• Sedimentation volume, F, is defined as the ratio of the final volume of
sediment, Vu, to the original volume of suspension Vo, before settling.

Vu
F
Vo

• The value for sedimentation volume may vary from less than 1 to greater
than 1
• F < 1, when the final volume of sediment is smaller than the original
volume of suspension,
• F = 1, when the final volume of sediment is equal to the original volume of
suspension.
• F > 1, when the final volume of sediment is greater than the original
volume of suspension. This situation occurs when very loose and fluffy
flocs are formed that encompass a volume greater than the original volume
of suspensions
DEGREE OF FLOCCULATION
• When a suspension is completely deflocculated, the final volume
of the sediment becomes very small.
• The degree of flocculation, , is then defined as the ratio of
sedimentation volume for flocculated suspension, F, to the
sedimentation volume of deflocculated suspension, F or as the
ratio of Vu to V (sediment volume of deflocculated suspensions)

F Vu Ultimate sediment volume of flocculated suspension

  
F V Ultimate sediment volume of deflocculated suspension
CALCULATE SEDIMENTATION VOLUME AND DEGREE
OF FLOCCULATION

• (a) Compute the sedimentation volume of a 5% (w/v) suspension

of magnesium carbonate in water. The initial volume is V0 = 100
ml and the final volume of the sediment is Vu = 30 ml.
• (b) If the degree of flocculation is  = F/F = 1.3, what is the
deflocculated sedimentation volume, F.
• Solution:

30
F  0.30
100
F 0.30
F    0.23
 1.3
Viscosity of Suspensions
• Viscosity of suspensions is of great importance for stability and pourability
of suspensions. As we know suspensions have least physical stability
amongst all dosage forms due to sedimentation and cake formation.

• So as the viscosity of the dispersion medium increases, the terminal settling

velocity decreases thus the dispersed phase settle at a slower rate and they
remain dispersed for longer time yielding higher stability to the suspension.

• On the other hand as the viscosity of the suspension increases, it’s

pourability decreases and inconvenience to the patients for dosing increases.

• Thus, the viscosity of suspension should be maintained within optimum

range to yield stable and easily pourable suspensions.
Different Approaches To Increase The Viscosity of
Suspensions
• Various approaches have been suggested to enhance the
viscosity of suspensions. Few of them are as follows:
1. Viscosity Enhancers

Some natural gums (acacia, tragacanth), cellulose derivatives

(sodium CMC, methyl cellulose), clays(bentonite, veegum),
carbomers, colloidal silicon dioxide (Aerosil), and sugars (glucose,
fructose) are used to enhance the viscosity of the dispersion
medium. They are known as suspending agents.
• 2. Co-solvents

• Some solvents which themselves have high viscosity are used as

co-solvents to enhance the viscosity of dispersion medium:
Glycerol, propylene glycol, sorbitol.
Most suspending agents perform two functions i.e.
besides acting as a suspending agent they also imparts
viscosity to the solution. Suspending agents form film
around particle and decrease interparticle attraction.

At rest the solution is sufficient viscous to prevent

sedimentation and thus aggregation or caking of the
particles. When agitation is applied the viscosity is
reduced and provide good flow characteristic from the
mouth of bottle.
EFFECT OF BROWNIAN MOVEMENT ON SUSPENDED
PARTICLES

• Brownian movement can counteract sedimentation

of particles to a certain extent by keeping the
dispersed material in random motion.
• There is a critical radius, below which particles will
be kept in suspension.
• Particles having a diameter of 2 to 5 m are
prevented from sedimentation because of
Brownian movement.
RHEOLOGIC PROPERTIES OF SUSPENSIONS

• Rheology describes flow properties of liquid and

deformation of solid (we will learn more about
rheology in a separate session)
• A suspension should easily be poured from the
bottle
• The force requires to redisperse should be
negligible.
• A good suspension should have well developed
thixotropy.
PREPARATION OF SUSPENSIONS
• In order to prepare a well-formulated suspension, the
pharmacist must be familiar with nature of both
dispersed phase and dispersion medium.
• A dispersed phase may have a varying degree of
affinity for the dispersion medium
• The first step of the preparation of suspension is to mix
the wetting agents and drug particles in a small
amount of vehicle.
• For large scale preparation, a colloid mill may be used
to perform this step and for small scale preparation, a
mortar and pestle is used.
• Once the powder is wet, the dispersion medium, in
which other formulation additives (colors, flavors,
preservatives) have already been mixed, is added in
portions and the resulting mixture is thoroughly mixed.
• A portion of the dispersion medium is used to bring
the suspension to final volume.
EVALUATION OF SUSPENSION FORMULATIONS

• The following parameters should be tested for a

suspension
• Viscosity

• Spreadability

• Sedimentation volume

• Zeta potential

• Pourability

• Redispersibility
PHYSICAL STABILITY OF SUSPENSIONS

• Stability of a suspension may be affected by

temperature, particle aggregation and interaction with
excipients
• Temperature:
• Increase in temperature of a suspension may lead to under or
over flocculation of the suspension.
• When a suspension is heated, energy of repulsion tends to
decrease
• Similarly, during freezing and thawing, the force of repulsion
is minimized due to ice formation that may lead the particles
to experience strong attraction and form aggregates.
• The size of aggregates is inversely related to the freezing rate.
• Fluctuation in temperature can also alter particle size and
polymorphic form of a drug
 PHYSICAL STABILITY OF SUSPENSIONS

• Excipients
• Some excipients may also adversely affect the stability of a
suspension.

• Cetylpyridium chloride, a positively charged preservative,

adsorbs strongly to the negatively charged surface of
suspended zinc oxide particles and this may lead to charge
reversal of the suspension
DRY POWDERS FOR SUSPENSIONS

• Antibiotics are generally available as dry powder for suspension.

• All dry powders for suspensions contain all excipients required to
prepare a suspension except the vehicle
• Pharmacists may often be asked to reconstitute the dry powder
for suspension.
• You should first loosen the powder at the bottom of the container
by lightly tapping it against a hard surface
• Then add exactly the right amount of water to the dry mixture
• Purified water rather than tap water is used
• A pharmacist should not “eyeball” the amount of water to be
added.
COMMERCIAL SUSPENSIONS
• Antacid oral suspensions
• One of the OTC preparations used for the treatment of gastric acidity
• These preparations contain water insoluble salts of aluminum, calcium
and magnesium
• Antibacterial oral suspensions
• As many antibiotics are unstable when in contact with water for a longer
period of time, the insoluble form of the drug is formulated in aqueous
suspension or as dry powders for suspension
• Rectal suspensions
• Barium sulfate suspension is used for diagnostic visualization of the GIT
• Mesalamine suspension is used for Crohn’s disease, distal ulcerative
colitis.
STORAGE AND DISPENSING OF SUSPENSIONS

• Suspensions are packaged in wide mouthed containers with

adequate airspace to provide ease of pouring and thorough
mixing.
• Suspensions should be protected from freezing, excessive
heat and light.
• Patients should be instructed to shake the container before
each dosing
• Patients should be advised not to mix suspension with
another liquid dosage forms especially electrolytes
• Patients should be asked not to use reconstituted dry
powder for suspension after 7-14 days or as indicated in the
label