COARSE DISPERSION

Suspensions

Dr R.N. Kaali

May. 2022
 TOPIC OUTLINES
• Introduction, definition and classification

• Desirable features of suspensions.

• Advantages & Disadvantages of their use

• Formulation Challenges.

• Formulation methods
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 TOPIC OUTLINES
• Stability of suspensions

• Manifestations of instability

• Assessment of quality of suspensions.

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 Expected Learning Outcomes.
• Be able to define suspensions.

• Be able to classify suspensions on the

basis of route of administration;
proportion of solid particles in the
suspension; response of the dispersed
phase to agitation and on the basis of
strength of particle aggregation.

• Understand and be able to rationalize the

desirable attributes of suspensions. 4
 Expected Learning Outcomes
• Understand the clinical implications of
instability of suspensions.

• Understand and be able to discuss the

challenges of high surface free energy and
sedimentation velocity of drug particles and
their relevance to formulation of suspensions.

• Understand and be able to discuss the various

manifestations of instability in suspensions
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 Introduction
Size based classification of dispersed phase:

•Solutions- single phase molecular dispersions the

size of which is <1 nm

•Colloids (1nm-100 nm) Examples: Milk, blood, iron

dextran injection.

•Coarse dispersions:- Include suspensions and

emulsions with average particle diameter of size
> 100 nm.
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 Suspensions
• Definition: Pharmaceutical liquid systems
containing finely divided insoluble solids (as
dispersed phase) in a liquid medium (water) as
the dispersion or continuous phase.

• All suspensions must contain a “Shake Well

Before use” label on the container to enable
taking a correct dose.

• Reason: With time all suspension lose their

uniformity due to sedimentation of solid
particles. 7
 Classification
• Based on route of administration (e.g. oral,
parenteral, otic and ophthalmic suspensions)

• Based on concentration of dispersed phase

(e.g. dilute – 2 to 10 w/v%, concentrated- (10
to 50 w/v%) and pastes >50% w/v)

• Based on response to agitation (1) diffusible

suspensions- contains light solids and (2)
indiffusible suspensions contains heavy solids.8
Desirable Features of Suspensions
• Upon shaking, the uniformity of the
suspended particles should last long enough
to allow taking a correct dose.

• The product should have suitable flow

properties including: be easy to pour out but
not too watery.

• Should have pleasant odour, colour and

taste. (any potential disadvantages?)
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 Particles in injectable formulation must
not block needle.

 Must be physically (ref. precipitation),

chemically (ref. example of hydrolysis)
and microbiologically stable (ref.
solutions).

 Should be sterilizable (injections & eye

drops)

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 Advantages of Suspensions
• Convenient for use by children and elderly who
have difficulties in swallowing solid dosage
forms

• They offer a way of fast rate of drug

absorption. Usual order of decreasing rate of
absorption is solution > Suspension > Solid
formulations (eg tablets)

• Multiple routes of drug administration e.g.

parenteral, topical routes and intradermal
(vaccines)
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 Possible to Control effectiveness by controlling the
effective surface area.

Example 1:The anti-acid effect of magnesium

carbonate and trisilicate.

Example 2: The adsorbent effect of activated

charcoal (used to treat poisoning) is directly
proportional to its effective surface area.

 Mask unpleasant/ bitter taste of drug. E.g.

unpleasant taste of chloramphenicol and
Paracetamol is lessened by adding
sweetener/flovours (enhances compliance)
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 Control of sedimentation velocity by use of
suspending agents makes it possible to
administer correct dose.

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 Disadvantages of Suspensions

• By comparison to solutions, the physical

instability of suspensions calls for specialized
formulation expertise.

• Due to bulkiness, greater care is needed during

handling and transport.

• Not every one can measure dose by volume

accurately.
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Challenges in the Formulation of
Suspensions

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 Introduction
• Most drugs are rich in hydrocarbons;
and usually resist wetting and
characteristically float on water.

• Reason: (1) high surface free energy

and (2) hydrophobic nature of organic
material.

• The Gibbs free energy equation (next)

provides more information in this case.16
 1. Gibbs Free Energy
• The Gibbs free energy equation summarizes
the factors which affect the free energy of a
system.

• G= YSL. Sa
(G is surface free energy; Y is the
interfacial tension at the solid-liquid (SL)
interface. and Sa is the effective surface
area)

• The equation shows that the surface free

energy G, is directly proportional to surface
area, Sa and interfacial tension, Y 17
 2. Sedimentation Velocity
• Particles in suspensions do sediment according to
Stokes’s law and equation (below)

• The equation indicates that the sedimentation

velocity, V of particles is influenced by the
diameter, d; difference in the density of particle
and vehicle, Δρ and viscosity, ƞ of the system.

• The particle sedimentation velocity determines the

time needed for phase separation to be completed.
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Outcome of Phase Separation

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 3. Aggravating Factors and
Implication.
• Rapid phase separation makes it far more
difficult to take a correct dose from
suspension formulations.

• Particle growth can occur (how: see next

slide)

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 Mechanism of Particle Growth
• A wide particle size distribution provide
ground for particle growth.

• (1) Smaller particles usually dissolve to form

an unstable supersaturated solution due to
factors which influence solubility e.g.
change in temperature or pH.

• Precipitation then follows; with the

precipitate being deposited on the large
particles which have not dissolved.
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 (2) Polymorphic forms.: Particle growth can also
occur due to presence of multiple polymorphic
forms in the system.

 More soluble forms dissolve to form a

supersaturated solution which is
thermodynamically unstable. This can be
accelerated by change in temperature or pH.

 Enlargement of the stable particles occurs due

to deposition of excess solute in the
supersaturated solution on the surface of the
undissolved less soluble polymorphs
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Formulation Strategy

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 1. Dealing with Resistance to Wetting

• The free energy equation suggest factors

which can be altered in order to minimize
difficulties of wetting of powder particles.

• Steps taken must aim to lower G, the free

energy.

• The inclusion of Surface Active Agents will

lower the interfacial tension (Y) as well as
the surface free energy (G).
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 Caution: Based on Gibbs equation the free
energy, it can be assumed that G can be
lowered by reduction of surface area (Sa). This
implies enlarging particle size.

 However particle enlargement is NOT a logical

option because it will increase the
sedimentation velocity of particles and
aggravate phase separation.

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2. Minimizing Sedimentation Velocity

• Based on Stokes equation the sedimentation

velocity can be controlled by:

(1) Minimizing particle diameter is likely to

crate difficulties (ref. Gibbs free energy
equation.

(2) Raising the viscosity of the vehicle. Stokes’

equation predicts that the sedimentation
velocity of powder particles will be lowered by
raising the viscosity of the system.
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 3. Particle growth
 Prevent particle growth by:
a) proper choice of polymorphic form
b) Add buffer to control pH
c) Store product in temperature
controlled storage facility.

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 Aids for formulation of
Pharmaceutical Suspensions

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 1. Use of Structured Vehicle.
• Suspension are usually prepared with the
aid of the so called structured vehicles;
defined as solvents with added substances
to serve a particular purpose.

• Example:
a) solvents with viscosity enhancers.
b) solvents with surface active agents.
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 Caution related to Viscosity

• Too high viscosity isn’t desirable:

(a) if it causes difficulty in pouring and

administration of doses.

(b) if it negatively affects drug

dissolution and absorption by inhibiting
diffusion.
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 Examples of Viscosity Enhancers.

(a) Natural gums (eg acacia, tragacanth)

(b) polymers/copolymers eg polysorbates.

(C) Cellulose derivatives like Methylcellulose

(d) Clays (eg bentonite)

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 2. Surface active Agents
• These promote wetting of hydrophobic
particles.

• They do so by accumulatin at interfaces

and typically lower the interfacial tension
(Y) at the solid liquid interface

• In so doing they eliminate floating of the

hydrophobic material.
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 3. Polymers
• Polymers (e.g. alginate and cellulose
derivatives) possess long chain in their
structures.

• The long chain is adsorbed on the surface of

the particles while the remaining part
projects out into the dispersion medium.

• Formation of bridge between the polymer

tails prevents compact particle aggregation.
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Polymer Inter-particle Bridge

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 Summary
Stability of suspensions depends on control
of:
1.Viscosity of the vehicle by:
a) control storage temperature
because high temperature reduces viscosity.

b) Including viscosity enhancers/Use of

polymers

2. Promote wetting by inclusion of SAA.

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 Dispensing Suspension
• Finely powder the material in the mortar.

• Add a suspending agent and mix/triturate

thoroughly in the mortar.

• Gradually add the vehicle to make a pourable

smooth paste.

• Rinse and adjust up to volume in a calibrated

bottle.
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 Suspension from Solid Dosage form
• Crush tablets or empty capsule contents
into a mortar and add a suspending agent.

• Form a paste by trituration with the vehicle

and add any other desired ingredients such
as preservatives or flavours.

• Transfer to a calibrated amber coloured

bottle, adjust to final volume and attach a
label with a 7 day expiry date.
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Assessment of Quality

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 Stability Parameters
• Suspensions are evaluated by determining stability
parameters which are (1) sedimentation volume and
(2) degree of flocculation.

• Sedimentation volume (F) is defined as the ratio of

the final volume of the sediment (Vf) to the
original volume (Vo) of the product i.e F = Vf/Vo

• It is commonly determined without comparing the

product with a reference product

• Commonly the sedimentation vvolume is less than

one (F < 1) 39
 When F =1, then Vf = Vo. Here the
system is in flocculation equilibrium and
shows no phase separation. (Good quality)

 When F > 1, then Vf > Vo. Here the

sedimentation volume is greater than the
original volume due to high porosity of the
sediment. This is uncommon

 The next slides diagrammatically

illustrates the three possible quality of
suspensions based on sedimentation.
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41
Sedimentation Volume F,> 1

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 Degree of Flocculation (ß)
• It is defined as the ratio, ß of the final
sedimentation volume (Ft) of a test
suspension to that of a reference suspension
(fr) meaning that ß=Ft/ Fr)

• The best reference suspension is that which

is recommended by regulatory authority.

• The degree of flocculation (ß) is normally

regarded to be of greater importance than
the sedimentation volume, F. 43
 References
• Aulton, M E. (2007), Aulton’s
Pharmaceutics: The design and
manufacture of Medicines, 4th edition,
Churchill Livingstone.

• Sinko, P J (2006), Martin’s Physical

Pharmacy and Pharmaceutical Sciences, 5th
Edit, Lippincott Williams & Wilkins.

• https://www.youtube.com/watch?
v=E9rHSLUr3PU
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