SUSPENSION

INTRODUCTION

PHYSICAL PROPERTIES OF WELL FORMULATED SUSPENSIONS

PHARMACEUTICAL APPLICATIONS OF SUSPENSIONS

FORMULATION OF SUSPENSIONS [CONSIDERATIONS]

PHYSICAL STABILITY OF SUSPENSIONS

 TYPES OF SOLUTION: 3
INTRODUCTION Clear solution, Colloids,
Coarse dispersion
• A pharmaceutical suspension is a coarse dispersion in which insoluble
particles, generally greater than 1 µm in diameter, are dispersed in a liquid
medium, usually aqueous.

• An aqueous suspension is a useful formulation system for administering an

MOST API’S ARE
insoluble or poorly soluble drug. UN-IONISED
[6METHODS TO
DISSOLVE IN WATER]
• The large surface area of dispersed drug ensures a high availability for
dissolution and hence absorption.
Colloids are micro-heterogeneous dispersed systems, in which the size of the dispersed phase particles is within the range 1 - 1000 nm. The
colloids phases can not be separated under gravity, centrifugal or other forces.
Coarse dispersions are heterogeneous dispersed systems, in which the dispersed phase particles are larger than 1000 nm. Coarse dispersions
are characterized by relatively fast sedimentation of the dispersed phase caused by gravity or other forces.
 PHYSICAL PROPERTIES OF WELL FORMULATED SUSPENSIONS
• The product must remain sufficiently homogenous for at least the period between shaking
the container and removing the required amount/dosing.

• The sediment produced on storage, must be easily re-suspended by moderate agitation of

the container.

• The product may be required to be thickened in order to reduce the rate of settling of the
particles. The resulting viscosity must not be so high that removal of the product from the
container and transfer to the site of application are difficult.

• Any suspended particles should be small and uniformly sized in order to give a smooth,
elegant product, free from a gritty texture.
 PHARMACEUTICAL APPLICATIONS OF SUSPENSIONS

• Suspensions as oral drug delivery systems:

• Many people have difficulty in swallowing solid dosage forms and therefore require
the drug to be dispersed in a liquid.

• Some materials are required to be present in the gastrointestinal tract in a finely

divided form, and their formulation as suspensions will provide the desired high
surface area.

Example: Solids such as kaolin, magnesium carbonate and magnesium trisilicate, for
example, are used for the adsorption of toxins, or to neutralize excess acidity.
 PHARMACEUTICAL APPLICATIONS OF SUSPENSIONS

• The taste of most drugs is more noticeable if it is in solution rather than in an

insoluble form.

Example: Paracetamol is available both in solution as Pediatric Paracetamol oral

solution (elixir) and also as a suspension. The latter is more palatable, and therefore
particularly suitable for children.

Suspensions for topical administration:

• They can be fluid preparations, such as Calamine lotion, which are designed to leave
a light deposit of the active agent on the skin after quick evaporation of the
dispersion medium. [SUNSCREEN LOTION, protective].
 PHARMACEUTICAL APPLICATIONS OF SUSPENSIONS
• Suspensions for parenteral use : Suspensions can also be formulated for
parenteral administration, Vaccines for the induction of immunity are often
formulated as dispersions of killed microorganisms, as in Cholera vaccine, or
of the constituent toxoids adsorbed on to a substrate of aluminium hydroxide
or phosphate, as in Adsorbed Diphtheria and Tetanus vaccine.
 PHARMACEUTICAL APPLICATIONS OF SUSPENSIONS

• Some X-ray contrast media are also formulated in this way. Barium sulphate,
for the examination of the alimentary tract, is available as a suspension for
either oral or rectal administration [barium meal]. Menthol and Eucalyptus Inhalation BP 1980
MENTHOL 2%, EUCALYPTUS OIL 10%
For relief of the symptoms of coughs, colds and
• Suspensions for inhalation therapy: blocked noses
Add one 5ml spoonful to a pint of hot, but not
boiling water.
• The volatile components of menthol and eucalyptus oil would be lost from
solution very rapidly during use, whereas a more prolonged release is
obtained if the two active agents are adsorbed on to light magnesium
carbonate prior to the preparation of a suspension.
 FORMULATION OF SUSPENSIONS CONSIDERATION
• 1. Particle size control:
• It is first necessary to ensure that the drug to be suspended is of a fine particle size
prior to formulation [1-5 µM]. This is to ensure a slow rate of sedimentation of the
suspended particles. Large particles, if greater than about 5 µm diameter, sediment
quickly, will also impart a gritty texture to the product, and may cause pain/irritation
Particles are arranged in an
if injected or instilled into the eyes. orderly repeating pattern
ISSUES???? extending in all three spatial
dimensions
• In suspension, there is always a degree of crystal growth that occurs on storage,
particularly if temperature fluctuations occur. This is because the solubility of the
drug may increase as the temperature rises, but on cooling, the drug will crystallize
out. This is a particular problem with slightly soluble drugs such as paracetamol.
How to avoid???
 FORMULATION OF SUSPENSIONS
• The inclusion of surface-active agents or polymeric colloids, which adsorb on
to the surface of each particle, may also help to prevent crystal growth.
Cellulose derivatives (sodium CMC,
INSOLUBLE PARTICLES IN WATER methyl cellulose), clays(bentonite),
• 2A. The use of wetting agents/surfactants: HOW TO DISPERSE UINFORMLY? carbomers, and colloidal silicon dioxide
WITHOUT HARD CAKE are used to enhance the viscosity of the
dispersion medium.

• Some insoluble solids may be easily wetted by water and will disperse readily
wetting

throughout the aqueous phase with only minimal agitation.

• To ensure adequate wetting, the interfacial/surface tension between the solid

and the liquid must be reduced so that the adsorbed air is displaced from the
solid surfaces by the liquid. The particles will then disperse readily throughout
the liquid, particularly if an intense shearing action is used during mixing.
 Wetting agent
• Wetting is the first step in the dispersion process. The air that surrounds the solid
particles in an agglomerate must be substituted by liquid. Wetting will take place
when the surface tension of the liquid is low compared to the surface energy of
the solid particles. Wetting will not occur when the surface tension of the liquid
is too high. In that case, the surface tension of the liquid can be lowered by
adding a wetting agent/surfactants. WETTING AGENT/ The hydrocarbon
SURFACTANT chains would be
adsorbed by the
hydrophobic
particle surfaces,
whereas the polar
groups project into
the aqueous
medium and
Deflocculated suspension become hydrated.
 Surfactants

• Surfactants are compounds that lower the surface tension (or interfacial
tension) between two liquids or between a liquid and a solid.

• Surfactants are usually organic compounds that contain

both hydrophobic groups (their tails) and hydrophilic groups (their heads).
Therefore, a surfactant contains both a water-insoluble (or oil-soluble)
component and a water-soluble component.
 Surfactants
• In the aqueous phase, surfactants form aggregates, such as micelles,
where the hydrophobic tails form the core of the aggregate and the
hydrophilic heads are in contact with the surrounding liquid.

• Other types of aggregates can also be formed, such as spherical or

cylindrical micelles or lipid bilayers.

Surfactant classification according to the composition of their

head: nonionic, anionic, cationic, amphoteric.
 Surfactants
• Anionic surfactants contain anionic functional groups at their head, such
as sulfate, sulfonate, phosphate, and carboxylates.

• Examples: Sodium lauryl sulfate, Perfluoro octane sulfonate, Ceteth

phosphates, Docusate (dioctyl sodium sulfosuccinate), sodium stearate.

• Cationic surfactants : quaternary amines

• Examples: Cetylpyridinium chloride, Benzalkonium chloride, Benzethonium

chloride [preservatives/antiseptics only] [TOXIC FOR INTERNAL USAGE]

• Amphoteric surfactants: have both cationic and anionic centers attached to

Cocamido
the same molecule. propyl betaine
very mild and are used in
shampoos and other cosmetics
 Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate)
Sorbitan monolaurate (Span 20)
Sorbitan monopalmitate (Span 40)
Sorbitan monostearate (Span 60)
Surfactants Polysorbate 40 (polyoxyethylene (20) sorbitan
monopalmitate)
Polysorbate 60 (polyoxyethylene (20) sorbitan monostearate)
Sorbitan monooleate Span 80 Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate)

• Nonionic surfactant: Many long chain alcohols exhibit some surfactant properties.

• Poly ethylene glycol sorbitan alkyl esters: Polysorbate [Tween]

• Sorbitan alkyl esters: Span

• Block copolymers of polyethylene glycol and polypropylene glycol: Poloxamers

a:2-130 b: 15-67
triblock copolymer consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol (PEG). Poloxamer 407??
• Polyethylene glycol alkyl ethers (Brij): CH3–(CH2)10–16–(O-C2H4)1–25–OH: 40x100=4000 MW of POP
7x10=70% POE core
188, 124 ………
Oleth 20
• Polyethylene glycol octylphenyl ethers: C8H17–(C6H4)–(O-C2H4)1–25–OH: Triton X-100

• Polyethylene glycol nonylphenyl ethers: C9H19–(C6H4)–(O-C2H4)1–25–OH: Nonoxynol-9

Nonoxynol-9 interacts with the lipids in the membranes of
the acrosome and the midpiece of the sperm. The sperm
membranes are lysed; the acrosome, neck and midpiece of
the spermatozoa are loosened and then detached which
results in their immobilization and death.
Detergent
 a. Surface-active agents [Non-ionic]
The hydrophilic-lipophilic balance [HLB]

HLB scale showing classification of surfactant function It is the relative efficiency of the hydrophilic portion
of the surfactant molecule to its lipophilic portion of
the same molecule.
It is an arbitrary scale between 0 and 18-20 which
expresses numerically the size and strength of the
polar portion relative to the non-polar portion of
the molecule.
determined by calculating values for the different regions
of the molecule, as described by Griffin.

where Mh is the molecular mass of the hydrophilic portion

of the molecule, and M is the molecular mass of the whole
molecule, giving a result on a scale of 0 to 20.
 What is the chemistry of a nonionic surfactant ?
• Each surfactant has a hydrophilic group and a lipophilic group

• the hydrophilic group is usually a polyhydric alcohol or ethylene oxide

• the lipophilic group is usually a fatty acid or a fatty alcohol

• The relationship ( or balance ) between the hydrophilic portion of the nonionic

surfactant to the lipophilic portion is what we call HLB

• All nonionic surfactants have an HLB Value [In general it applies to nonionic
surfactants only]
 Here is an example of an HLB value calculation
• BRIJ ® 98 INCI name : oleth-20 is a 20 mole ethoxylate of oleyl alcohol

• we calculate the molecular weight of the 20 moles of ethylene oxide ( one mole ETO =44 ) -CH2CH2O
• 20 x 44 = 880 -C2H40
2X12, 4X1,1X16=44
• we add this number to the molecular weight of the oleyl alcohol [C18H36O or CH3(CH2)7-CH=CH-(CH2)8OH,
269]
Polyethylene glycol alkyl ethers (Brij): CH3–(CH2)10–16–(O-C2H4)1–25–OH
• 880+ 270 = 1150 ( the mol. wt of BRIJ 98 )
Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate)
• What percentage of 1150 is 880 ? Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate)
Polysorbate 60 (polyoxyethylene (20) sorbitan monostearate)
• 880/1150 = 76.5% Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate)
1227.54
Sorbitan monolaurate (Span 20)
• 76.5% divided by 5 = 15.3 (Span 40) Sorbitan monopalmitate
Sorbitan monostearate(Span 60)
Sorbitan tristearate (Span 65)
• 15.3 is the HLB value of BRIJ 98 (Span 80) Sorbitan monooleate
346.46
 HLB
• HLB value between about 7 and 9 would be suitable for use as wetting agents. The hydrocarbon
chains would be adsorbed by the hydrophobic particle surfaces, whereas the polar groups project
into the aqueous medium and become hydrated.

• Most surfactants are used at concentrations of up to about 0.1% as wetting agents and include,
for oral use, sorbitan esters (Spans).

• For external application, sodium lauryl sulphate, sodium dioctylsulphosuccinate can be used.

• The choice of surfactant for parenteral administration is polysorbates, some of the poloxamers
(polyoxyethylene/polyoxypropylene block copolymers).
ADVANTAGE OVER ANIONIC/CATIONIC?
• Disadvantages in the use of this type of wetting agent include excessive foaming and the possible
formation of a deflocculated system
 Flocculated & deflocculated suspension
Deflocculated System Flocculated System
1. Pleasant appearance, because Somewhat unsightly sediment.
of uniform dispersion of particles.
2. Supernatant remains cloudy. Supernatant is clear
3. Particles exist as separate Particles form loose aggregates.
entities
4. Rate of sedimentation is slow, as Rate is high, as flocs are the
the size of particles are small. collection of smaller particles
having a larger size.
5. Particles settle independently Particles settle as flocs.
and separately
6. The sedimentation is closely Sediment is a loosely packed
packed and form a hard cake. network and hard cake cannot
form.
7. The hard cake cannot be The sediment is easy to
re-dispersed. re-disperse.
8. Bioavailability is higher due to Bioavailability is comparatively less Agglomeration of destabilized particle into
large specific surface area. due to small specific surface area. larger size particles known as flocs
 Flocculated & deflocculated suspension
• In summary, deflocculated systems have the advantage of a slow
sedimentation rate, thereby enabling a uniform dose to be taken from
the container, but when settling does occur the sediment is
compacted and difficult to re-disperse.

• Flocculated systems form loose sediments which are easily

re-dispersible, but the sedimentation rate is fast and there is a danger
of an inaccurate dose being administered; also, the product will look
inelegant.
 Controlled flocculation
• Usually a compromise is reached in which the suspension is partially
flocculated to enable adequate re-dispersion if necessary, and viscosity is
controlled so that the sedimentation rate is at a minimum.

• Controlled flocculation is usually achieved by a combination of the use of

electrolytes to control zeta potential, and the addition of polymers to enable
crosslinking to occur between particles.

The zeta potential (ζ-potential) is the potential difference across phase boundaries
between solids and liquids. It's a measure of the electrical charge of particles that are suspended in liquid.
 Zeta potential
• For molecules and particles that are small enough, with a high zeta potential
will confer stability, i.e., the solution or dispersion will resist aggregation.
When the potential is small, attractive forces may exceed this repulsion and
the dispersion may break and flocculate. So, suspension with high zeta
potential (negative or positive) are electrically stabilized while suspension with
low zeta potentials tend to coagulate or flocculate.
Colloid?
Zeta potential
Stability behavior of the colloid
[mV]
from 0 to ±5, Rapid coagulation or flocculation
from ±10 to ±30 Incipient instability
from ±30 to ±40 Moderate stability
from ±40 to ±60 Good stability
 Flocculating agents
• It is necessary for the suspension to be converted from a deflocculated to a partially flocculated
state, this may be achieved by the addition of electrolytes, and hydrophilic polymers.

• Electrolytes: The addition of an inorganic electrolyte to an aqueous suspension will alter the
zeta potential of the dispersed particles and, if this value is lowered sufficiently, flocculation
may occur. Eg: sodium salts of acetates, phosphates and citrates.

• Polymeric flocculating agents: Starch, alginates, cellulose derivatives, tragacanth, carbomers

and silicates are examples of polymers that can be used for controlled flocculation. Their linear
branched-chain molecules form a gel-like network within the system and become adsorbed on
to the surfaces of the dispersed particles, thus holding them in a flocculated state.
 b. Hydrophilic colloids
• These materials include acacia, bentonite, tragacanth, alginates,
xanthan gum and cellulose derivatives, and will behave as protective
colloids by coating the solid hydrophobic particles with a
multi-molecular layer. This will impart a hydrophilic character to the
solid and so promote wetting.
INCREASES
VISCOSITY
 Rheology is the science of
measurement of deformationRheology of suspensions
• An ideal pharmaceutical suspension would exhibit a high apparent
viscosity at low rates of shear so that, on storage, the suspended
particles would either settle very slowly or, preferably, remain
permanently suspended. At higher rates of shear, such as those caused
by moderate shaking of the product, the apparent viscosity should
lower sufficiently for the product to be poured easily from its container.
Thixotroy

Xanthomonas campestris.
comprising glucose, mannose,
and glucuronic acid in the molar
XANTHAN GUM ratio 2:2:1.
GUAR GUM
TRACAGANTH GUM
CLAYS

galactomannan polysaccharide
extracted from guar beans
 Components of Suspension
Ingredient Use
API Active Pharmaceutical Ingredient
Wetting Agents They are added to disperse solids in continuous liquid phase
Flocculating Agents They covert individual particles to ‘flocs’ (aggregates)
Thickeners They increase the viscosity of the formulation
Buffers and pH They stabilize the suspension to desired pH range
adjusting agents
Coloring Agents, They impart desired color (oral suspensions) and protect from
Preservatives microbial degradation respectively
Structured Vehicles Added to construct final ‘structure’ of the suspension
Flow Chart for Manufacture of Suspensions
Finely Divided
Solid Particles
1-5 micron

Particles are added to dispersion medium

containing wetting agents

Uniform Dispersion
(Deflocculated)

Addition of
Addition of other ingredients structured
like color, preservatives, vehicle
buffers etc
De-flocculated
suspension in structured
vehicle
formed,/Flocculating
agents are added to the
structured vehicle

Controled
Flocculated
Suspension
Formed
 PHYSICAL STABILITY OF SUSPENSIONS
• The physical stability of a suspension is normally assessed by the measurement of its rate of
sedimentation, the final volume or height of the sediment, and the ease of re-dispersion
of the product.

• The first two parameters can be assessed easily by a measurement of the total initial
volume or height of the suspension (Vo) and the volume or height of the sediment (Vt).

• By plotting the value of Vt / Vo against time for a series of trial formulations (all initial values
will equal unity), it can be seen, by an assessment of the slope of each line, which
suspension shows the slowest rate of sedimentation. When the value of Vt / Vo becomes
constant this indicates that sedimentation has ceased.
 PHYSICAL STABILITY OF SUSPENSIONS

• The ease of re-dispersion of the product can be assessed qualitatively

by simply agitating the product in its container.