Disperse Systems Disperse Systems

ntroduction, ntroduction,
1heory 1heory of of suspensions suspensions and and emulsions, emulsions,
1ypes 1ypes of of addities addities used used in in formulations, formulations,
\ehicles, \ehicles,
Stabili-ers, Stabili-ers,
Preseraties, Preseraties,
Vetting Vetting agents, agents,
Suspending Suspending agents, agents,
Emulsifying Emulsifying agents, agents,
HLB HLB alue alue and and its its determination, determination,
Colors, Colors, flaours flaours and and others, others,
Manufacturing Manufacturing packaging packaging and and ealuation ealuation
Suspensions Suspensions and and emulsions emulsions official official in in pharmacopoeia pharmacopoeia
1
0lSPFRSl0t SYSTFHS
FHulSl0t
SuSPFtSl0t
Types
dentification Test
Emulsifying agents
Method of Preparation
nstabilities
Packaging, Labeling & Storage
Properties of emulsion
Quality control tests
Stability testing
Procriics of Suscnsion Procriics of Suscnsion
TIcorics involvcd in discrsc Iasc TIcorics involvcd in discrsc Iasc
Tycs of Suscnsions Tycs of Suscnsions
Various aroacIcs for dcvcloing Various aroacIcs for dcvcloing
suscnsions suscnsions
Formulaiion of Suscnsion Formulaiion of Suscnsion
Sialiliiy of suscnsion Sialiliiy of suscnsion
Qualiiy conirol Tcsis of Suscnsions Qualiiy conirol Tcsis of Suscnsions
Susiaincd Fclcasc Suscnsions Susiaincd Fclcasc Suscnsions
Formulaiion addiiivcs Formulaiion addiiivcs
Suscnding & iIiclcning agcnis Suscnding & iIiclcning agcnis
Wciiing agcnis Wciiing agcnis
Discrsing agcni Discrsing agcni
Flocculaiing agcnis Flocculaiing agcnis
2
Ii.c.cv ,.cn. .in iqviv
(oninvov. Tnv.c.
Dispersed phase TechnicaI term ExampIe
gas foam meringue, whipped cream
liquid emulsion milk, mayonnaise, butter
solid sol, suspension latex, paint, blood
ulspergere (LaLln) Lo remove Lo redlsLrlbuLe
Lmulgere (LaLln) Lo mllk ouL
Suspendere (LaLln) Lo keep ln Lo keep ln floaLlng
3
SuSPFtSl0t
Pharmaceutical suspensions are uniform
dispersions of solid drug particles in a
vehicle in which the drug has minimum
solubility.
Colloidal suspension 1 nm to 0.5 m
Coarse suspension 1 to 100 m
4
SuSPFtSl0tS SuSPFtSl0tS
Examples of Pharmaceutical Suspensions:
1. Antacid oral suspensions
2. Antibacterial oral suspension
3. Dry powders for oral suspension (antibiotic)
4. Analgesic oral suspension
5. Anthelmentic oral suspension
6. Anticonvulsant oral suspension
7. Antifungal oral suspension
5
THF0RlFS 0F SuSPFtSl0t
nterfaciaI phenomenon
EIectricaI DoubIe Iayer and Zeta potentiaI
Sedimentation Concept
DLVO Theory
6
Forces Acting on Particles
'8-8
o
)g
2-5 3m
Gravity
Brownian Movement
Sedimentation
equilibrium: Gravity is
neutralized by Brownian
movement
7
nc{v.iv ncnoncnon nc{v.iv ncnoncnon
Smaller solid particles are used to disperse in a continuous medium.
Smaller particle size Smaller particle size and large surface area large surface area is associated with a surface surface
free energy free energy making it thermodynamically unstable thermodynamically unstable.
Thus the particles possess high energy high energy which leads to grouping together grouping together
to reduce surface free energy reduce surface free energy thus leading to formation of floccules leading to formation of floccules.
These floccules are held together among themselves and within by weak
van van der der waals waals forces forces.
However in cases where particles are adhered by stronger forces adhered by stronger forces to form
aggregates forming hard cake forming hard cake.
These phenomena occur in order to make system more
thermodynamically stable.
n order to achieve a state of stability the system tend to reduce the to reduce the
surface free energy surface free energy, which may be accomplished by reduction of by reduction of
interfacial tension interfacial tension that is achieved by use of surfactants achieved by use of surfactants.
8
c.i.v Iovc v,c vnv Zcv ocniv c.i.v Iovc v,c vnv Zcv ocniv
Most surfaces acquire a surface electric charge surface electric charge when they come in
contact with aqueous surface.
A solid charged surface when in contact with an aqueous medium
possesses positive and negative ions positive and negative ions. The counter ions counter ions are attracted
towards the surface co-ions that ions of like charge are repelled away
from the surface.
This results in the formation of an electrical double layer electrical double layer, made up of the
charged particles charged particles. The charges influence the distribution of ions resulting
in the formation of an electrical double layer, made up of the charged
surface and a neutralizing excess of counter-ions over co-ions distributed
in a diffuse manner in the aqueous medium resulting into electric
potentials.
The zeta potential zeta potential refers to the electrostatic charge on the particles electrostatic charge on the particles, which
causes them to move in electric field towards a pole of opposite charge them to move in electric field towards a pole of opposite charge.
ts magnitude may be measured using microelectrophoresis or any other
of the electrokinetic phenomena.
9
c.i. Iovc v,c c.i. Iovc v,c
-
-
-
-
-
-
+
+
+
+
+
+
+
-
+
+
-
+
-
-
+
+
-
+
-
-
+
+ -
+
+
gegenion
Nernst potential
zeta potential
tightly
bound
diffuse
electroneutral
bulk
10
The two parts of the double layer are separated by a plane, the stern plane.
The stern plane, which occur at a hydrated ion radius from the particle surface.
The ions or molecules to be strongly adsorbed at the surface-termed specific
adsorption rather than by electrostatic attraction.
The specifically adsorbed ion or molecule
may be uncharged e.g., with non-ionic
surfactant.
Surfactants specifically adsorb by the
hydrophobic effect and impart effect on the
stern potential.
Thus the zeta potential is reduced by
additives to the aqueous system in either (or
both) of two different ways.
c.i.v Iovc v,c vnv Zcv ocniv c.i.v Iovc v,c vnv Zcv ocniv
11
cvincnvion (on.c cvincnvion (on.c
n dispersions the dispersed particles encounters between themselves as
a result of Brownian movement Brownian movement.
Depending upon the forces of interactions-electrical forces of repulsion,
forces of attraction and forces arising due to solvation, the particles particles
aggregate aggregate to form collection of particles.
The collisions result in permanent contact of particles known as
coagulation coagulation leading to the formation of larger aggregates formation of larger aggregates, which
sediment out sediment out known to exhibit flocculation exhibit flocculation or if the particles rebound they
remain freely suspended and form stable system.
These particles sediment according to stokes' law.
v = 2a2g (o v = 2a2g (o- -p)/9q p)/9q
Where v is velocity of sedimentation,
a is the radius of particles,
o density of solid particles,
g is acceleration due to gravity and
p is the density and
q is the viscosity of the dispersion phase.
The equation of stokes' law reflects that larger particles larger particles exhibit greater greater
velocity of sedimentation velocity of sedimentation.
The velocity of sedimentation velocity of sedimentation is inversely proportional to the viscosity inversely proportional to the viscosity of
dispersion medium.
12
I(O Inco, I(O Inco,
((Der|agnIn Der|agnIn, Iandan, , Iandan, Vervey Vervey, , UverIeeI UverIeeI))
13
I(O Inco, I(O Inco,
According to DLVO (Derjaguin Landau Verwey and
overbeek) theory, in a dispersed system the
interactions involved between particles are electrical
repulsion and van der Walls attraction.
The total potential energy of interaction is addition of
these parameters. Fig.1. the curve between total
energy of interactions versus distance between
particles.
n the curve the attraction predominates at small
distances hence a very deep primary minimum.
The attraction at large interparticle distance that
produces the secondary minimum as the fall-off in
repulsive energy with distance is more rapid than that
of attractive energy.
At intermediate distances double-layer repulsion is
larger giving a primary maximum in the curve. f this
maximum is large as compared to thermal energy of
the particles the system would be stable.
Otherwise the interacting particles will reach the
energy depth of the primary minimum and irreversible
aggregation.
14
' 5timal istance
istance
Energy
Attraction
Repulsion
Attraction
Optimal istance
15
DLVO Theory DLVO Theory
0
+
-
distance
between
particles
repulsion
attraction
t
o
t
a
l

p
o
t
e
n
t
i
a
l

e
n
e
r
g
y

o
f

i
n
t
e
r
a
c
t
i
o
n
16
DLVO Theory DLVO Theory
0
+
-
distance
between
particles
repulsion
attraction
t
o
t
a
l

p
o
t
e
n
t
i
a
l

e
n
e
r
g
y

o
f

i
n
t
e
r
a
c
t
i
o
n
[electrolyte]
17
f the secondary minimum is smaller than thermal energy the particles will
not aggregate but will always repel one another leading a de-flocculated
system, but if it is significantly larger than thermal energy. A loose
aggregate will form with the ease of redispersibility by shaking i.e.,
flocculation occurs.
The depth of secondary minimum depends on particle size and particles
should be of radius greater than 1 m. The particles possessing particle
size less than 1 m exhibit great attractive forces for flocculation to occur.
The height of the primary maximum energy barrier to coagulation
depends on the zeta potential.
The addition of electrolyte compresses the double layer and reduces the
zeta potential, this has the effect of lowering the primary maximum and
deepening the secondary minimum and is the principle of the controlled
flocculation approach to pharmaceutical suspension.
The primary maximum can also be lowered (and the secondary minimum
deepened) by adding substances, such as ionic surfactants, which are
adsorbed within the Stern Layer.
I(O Inco, I(O Inco,
18
Classification Classification
ased On GeneraI CIasses ased On GeneraI CIasses
Oral suspension
Externally applied suspension
Parenteral suspension
ased On Proportion Of SoIid ParticIes ased On Proportion Of SoIid ParticIes
Dilute suspension (2 to10 percnt; w/v solid)
Concentrated suspension (50 percnt; w/v solid)
ased On ased On EIectrokinetic EIectrokinetic Nature Of SoIid ParticIes Nature Of SoIid ParticIes
Flocculated suspension
Deflocculated suspension
ased On Size Of SoIid ParticIes ased On Size Of SoIid ParticIes
Colloidal suspension (< 1 micron)
Coarse suspension (>1 micron)
Nano suspension (10 ng) 19
IoccuIation & defIoccuIation
IoccuIated Non-fIoccuIated
ParticIes forms Ioose aggregates and form
a network Iike structure
ParticIes exist as separate entities
weakIy bonded to form fIuffy congIomerates RepuIsion energy is high
Rate of sedimentation is high Rate of sedimentation is sIow
Sediment is rapidIy formed Sediment is sIowIy formed
Sediment is IooseIy packed and doesn't
form a hard cake
Sediment is very cIoseIy packed and a hard
cake is formed
Sediment is easy to redisperse Sediment is difficuIt to redisperse
Suspension is not pIeasing in appearance Suspension is pIeasing in appearance
The fIoccuIes stick to the sides of the bottIe They don't stick to the sides of the bottIe
CIear supernatant CIoudy supernatant
20
0atur0s D0sir0/ In Pharmac0utical 0atur0s D0sir0/ In Pharmac0utical
Susp0nsions Susp0nsions
The suspended particles should not settle rapidly and sediment
produced, must be easily re-suspended by the use of moderate
amount of shaking.
t should be easy to pour yet not watery and no grittiness.
t should have pleasing odour, colour and palatability.
Good syringeability.
t should be physically, chemically and microbiologically stable.
Parenteral/Ophthalmic suspension should be sterilizable.
21
onvvion o{ v.cn.ion. onvvion o{ v.cn.ion.
Suspensions containing diffusible solids
Suspensions containing indiffusible solids
Suspensions containing poorly wettable solids
Suspensions of precipitate forming liquids
Suspensions produced by chemical reactions
22
Susp0nsions containing /iffusibl0 soli/s consist of solids
insoluble in water but easily wettable.
On shaking with water solid particles diffuse readily through out the
liquid and remain suspended for a long time.
The suspensions containing diffusible solids are prepared by
triturating the solids in a mortar with sufficient quantity of vehicle to
form a smooth cream.
Any soluble nonvolatile substance is then added by separately
dissolving them in a small quantity of vehicle.
More vehicles are then added and any foreign particle is strained
through a muslin cloth.
Any volatile component is added at this stage and adding the
required quantity of vehicle makes up the final volume.
Example: agnesium Trisilicate ixture
23
Susp0nsions containing Susp0nsions containing in/iffusibl0 in/iffusibl0 soli/s soli/s consist of
substances, which do not remain distributed in the
dispersion medium when shaken for long time to ensure
uniformity of dose.
They are prepared by adding a suitable thickening agent thickening agent
to the vehicle, which increases the viscosity increases the viscosity of the
vehicle and delays the separation or sedimentation of
indiffusible particles.
Example: alamine Lotion
24
Susp0nsions containing poorly Susp0nsions containing poorly w0ttabl0 w0ttabl0 soli/s soli/s
consist of substances, which are poorly soluble, and at
the same time poorly wetted by the dispersion medium,
and clump together with the difficulty to disperse.
They are prepared by including suitable wetting agent in
the formulation. These agents get adsorbed at the
solid/liquid interface and promote wetting of the solid
particles by the liquid of the dispersion medium.
Example: $ulphur $ulphur Lotion Lotion
25
Susp0nsions of pr0cipitat0 forming liqui/s Susp0nsions of pr0cipitat0 forming liqui/s consist of
liquid tinctures which are alcoholic or hydroalcoholic
extract of vegetable drugs which contain resinous
material.
When tinctures are added to water they precipitate.
Precipitates are indiffusible and stick to the walls of the
container.
They are prepared by adding a suitable thickening agent
prior to the addition of the precipitate forming liquid.
Example: Lobelia and $tramonium ixture
26
Susp0nsions pro/uc0/ by ch0mical r0actions Susp0nsions pro/uc0/ by ch0mical r0actions
are prepared by mixing two dilute solutions of
reactants to form a fine precipitate.
Generally precipitates so formed are diffusible and
no suspending agent is required.
f precipitate is indiffusible a suitable thickening or
suspending agent may be added.
They are prepared by dissolving the reactants
separately in approximately half volumes of the
vehicle and the two portions are then mixed
together.
Example: inc $ulphide Lotion
27
ormulation A//itiv0s ormulation A//itiv0s
n addition to vehicle, stabilizer, sweetening and flavouring agents, which are
common in liquid dosage forms, the following additives are required to prepare
suspensions which include:
Suspending and Thickening agents
2 etting Agents
3 Dispersing agent
4 IoccuIating Agent
Suspending and Thickening agents: They are added with the objective to
increase apparent viscosity increase apparent viscosity of the continuous, phase thus preventing rapid preventing rapid
sedimentation sedimentation of the dispersed particles.
a) NaturaI PoIysaccharides :Gum acacia, Tragacanth, sod. Alginate, Xanthan
Gum
b) Semi-Synthetic PoIysaccharides: Sodium Carboxymethyl cellulose, Methyl
cellulose, Hydroxypropyl methyl cellulose, microcrystalline cellulose
c) CIays: Aluminium Magnesium Silicate, Bentonite, Hectorite
d) Synthetic Agents: Carbomer, Colloidal Silicon dioxide
28
ormulation A//itiv0s ormulation A//itiv0s
2. etting Agents: Wetting agents are additives which are usually added to
decrease this hydrophobicity. These agents generally get adsorbed at the
solid-liquid interface and promote wetting of the solid particles by the liquid of
the dispersion medium.
a) Surfactants: polysorbates, sorbitan, esters, sodium lauryl sulfate, sodium
dioctyl sulfosuccinate
b) HydrophiIic PoIymers: acacia, bentonite, colloidal silicon dioxide and
cellulose derivatives
c) HydrophiIic Liquids: alcohol, glycerol, propylene glycol
3 Dispersing agent: These additives are generally added as an aid to uniform
distribution and dispersion of solid particles of the dispersed phase. Wetting
agents such as surfactants are often employed as dispersing agents.
4 IoccuIating Agent: These are substances added to cause controlled
aggregation of the particles of the dispersed phase in a suspension. Examples
of such agents include surfactants, electrolytes and hydrophilic polymers.
29
0tho/ of pr0paration 0tho/ of pr0paration
ncorporation of
structured vehicIe
A A C C
Addition of
fIoccuIating agent
Addition of
fIoccuIating agent
DefIoccuIated suspension
in structured vehicIe as
finaI product
IoccuIated suspension
as finaI product
IoccuIated
suspension
ncorporation of
structured vehicIe
IoccuIated suspension
in structured vehicIe as
finaI product
ParticIes
Uniform dispersion of defIoccuIated particIes
Addition of wetting agent & dispersion medium
S.H. HAJuH0AR S.H. HAJuH0AR
30
Pr0paration of Susp0nsions Pr0paration of Susp0nsions
Reduce drug powder to desired size
Add drug and wetting agent to solution
Prepare solution of suspending agent
Add other ingredients
electrolytes, color, flavor
Homogenize medium
Package
31
Structur0/ V0hicl0 Structur0/ V0hicl0
Structured vehicles called also thickening or suspending agents. They are
aqueous solutions of natural and synthetic gums. These are used to increase the
viscosity of the suspension.
Methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose,
acacia, gelatin and tragacanth are the most commonly used structured vehicle in
the pharmaceutical suspensions. These are non-toxic, pharmacologically inert,
and compatible with a wide range of active and inactive ingredients.
These structured vehicles entrapped the particle and reduces the sedimentation
of particles. Although, these structured vehicles reduces the sedimentation of
particles, not necessarily completely eliminate the particle settling. Thus, the use
of deflocculated particles in a structure vehicle may form solid hard cake upon
long storage.
The risk of caking may be eliminated by forming flocculated particles in a
structured vehicle.
Note that too high viscosity isn't desirable and it causes difficulty in pouring and
administration. Also, it may affect drug absorption since they adsorb on the
surface of particle and suppress the dissolution rate.
Structured vehicles are pseudoplastic or plastic in their rheological behaviors
32
Pr0paration Of Structur0/ Pr0paration Of Structur0/
V0hicl0 V0hicl0
Structured vehicles are prepared with the help of
Hydrocolloids.
n a particular medium, they first hydrolyzed and swell to
great degree and increase viscosity at the lower
concentration. n addition, it can act as a 'Protective
colloid' and stabilize charge.
Density of structured vehicle also can be increased by:
Polyvinylpyrrolidone
Sugars
Polyethylene glycols
Glycerin
33
ontrolled Flocculation
eta-potential
F'
u
/'
o
Caking Caking
Non-caking
Flocculating Agent
+
+
-
Flocculating agent
changes zeta-potential
oI the particles it can
be electrolyte, charged
surIactant or charged
polymer adsorbing on
a surIace).
II the absolute value
oI the zeta-potential is
too high the system
deIlocculates because
oI increased repulsion
and the dispersion
cakes.
34
Packaging an/ Storag0 of Susp0nsions Packaging an/ Storag0 of Susp0nsions
1. Should be packaged in wide mouth containers having
adequate air space above the liquid.
2. Should be stored in tight containers protected from:
freezing, excessive heat & light
3. Label: "Shake Before Use" to ensure uniform distribution
of solid particles and thereby uniform and proper
dosage.
4. Stored in room temperature if it is dry powder (25
0
C). t
should be stored in the refrigerator after opening or
reconstitute (freezing should be avoided to prevent
aggregation)
35
TQ( Ic.. o{ v.cn.ion. TQ( Ic.. o{ v.cn.ion.
Appearance Of Phases
Viscosity Of Phases
Particle Size Of Dispersed Phase
pH Test
Pourability
Final Product Assay
Zeta Potential Measurement
Centrifugation Test
36
inv Qvvi, (ono O{ v.cn.ion. inv Qvvi, (ono O{ v.cn.ion.
The following tests are carried out in the final quality control of
suspension:
Appearance
Color, odor and taste
Physical characteristics such as particle size determination and
microscopic photography for crystal growth
Sedimentation rate and Zeta Potential measurement
Sedimentation volume
Redispersibility and Centrifugation tests
Rheological measurement
Stress test
pH
Freeze-Thaw temperature cycling
Compatibility with container and cap liner
Torque test
37
vii, O{ v.cn.ion. vii, O{ v.cn.ion.
Stability of suspension can be considered in two ways:
Physical Physical
Particle-Particle nteraction & ts Behaviour
nterfacial Properties of Solids
Ostwald Ripening
This phenomenon could result in the pharmaceutically unstable suspensions
(caking) & alter the bio-availability of the product, through an alteration in the
dissolution rate.
This problem can be surmounted by the addition of polymer (Hydrophilic
Colloid) such as cellulose derivatives, which provides the complete surface
coverage of the particles, so that their solubilization is minimized to some
extent.
Another way is to have uniformity in particle size of the dispersed material,
which is to be considered prior to the manufacturing of suspensions.
Chemical Chemical
38
(ncni.v vii, (ncni.v vii,
Most of the drug materials although insoluble, when suspended in a liquid
medium has some intrinsic solubility intrinsic solubility, which triggers the chemical reactions such
as hydrolysis, to occur leading to degradation.
So, the particles that are completely insoluble in a liquid vehicle are unlikely to
undergo chemical degradation.
The ChemicaI stabiIity of the suspensions is governed by the foIIowing facts:
t is assumed that the decomposition of the suspension is solely due to the
amount of the drug dissolved amount of the drug dissolved in aqueous phase.
This solution will be responsible for drug decomposition and more drug will be drug will be
released from insoluble suspended particles released from insoluble suspended particles within the range of solubility. t
behaves like a reservoir depot. So, the amount of the drug in the solution remains
constant inspite of the decomposition with time,
Thus, primarily suspensions behave as a zero order zero order. But once all the suspended
particles have been converted into the drug in the solution, the entire system
changes from zero order to first order changes from zero order to first order, as now the degradation depends upon the
concentration in the solution. Thus, it can be said that suspension follows
apparent zero apparent zero- -order kinetics order kinetics.
39
;vvvion o{ v.cn.ion ;vvvion o{ v.cn.ion
Sedimentation volume Sedimentation volume- -
F = V
sed
/V
tot
The value of F normally lies between 0 to 1 for any
pharmaceutical suspension.
The value of F provides a qualitative knowledge about
the physical stability of the suspension.
40
;vvvion o{ v.cn.ion ;vvvion o{ v.cn.ion
Degree of flocculation Degree of flocculation- -
= F
floc
/F
defloc
(V
sed
/V
tot
)
floc
=-------------------
(V
sed
/V
tot
)
defloc
41
nv.ionIc{iniion
An emuIsion is a mixture of two immiscible (unblendable)
substances. One substance (the dispersed phase) is
dispersed in the other (the continuous phase).
Examples of emulsions include butter and margarine, milk
and cream.
A stable emulsion consisting of two pure liquids cannot be
prepared; to achieve stability, a third component, an
emulsifying agent, must be present. t lowers the interfacial
tension of the two phases
Emulsions may be prepared readily by shaking together the
two liquids or by adding one phase drop by drop to the other
phase with some form of agitation, such as irradiation by
ultrasonic waves of high intensity. n industry, emulsification
is accomplished by means of emulsifying machines.
A Two immiscibIe Iiquids, not
yet emuIsified;
An emuIsion of Phase
dispersed in Phase ;
C The unstabIe emuIsion
progressiveIy separates;
D The surfactant (purpIe
outIine) positions itseIf on
the interfaces between
Phase and Phase ,
stabiIizing the emuIsion
42
v;vnvc.
1. They can mask the bitter taste and odor of drugs, thereby making
them more palatable. e.g. castor oil, cod-liver oil etc.
2. They can be used to prolong the release of the drug thereby
providing sustained release action.
3. Essential nutrients like carbohydrates, fats and vitamins can all be
emulsified and can be administered to bed ridden patients as
sterile intravenous emulsions.
4. Emulsions provide protection to drugs which are susceptible to
oxidation or hydrolysis.
5. ntravenous emulsions of contrast media have been developed to
assist in diagnosis.
6. Emulsions are used widely to formulate externally used products
like lotions, creams, liniments etc.
43
Ii.vv;vnvc. Ii.vv;vnvc.
Preparation needs to be shaken well before use
Measuring device needed for administration
Needs a degree of technical accuracy to measure a
dose
Storage condition may affect stability
Bulky, difficult to transport & prone to container
breakages
Liable to microbial contamination which can lead to
cracking
44
I,c. o{ nv.ion. I,c. o{ nv.ion.
OiI in water emuIsions
ater in oiI emuIsions
MuItipIe emuIsions
MicroemuIsions
45
(v..i{i.vion (v..i{i.vion
An emulsion is denoted by the
symbol O/W if the continuous
phase: is an aqueous solution and
By W/O if the continuous phase is
an organic liquid (an `oil').
More complicated emulsions such
as O/W/O (i.e. oil droplets
contained within aqueous droplets
dispersed in a continuous oil
phase) are also possible.
46
DERENCE ETEEN O/ AND /O EMULSONS DERENCE ETEEN O/ AND /O EMULSONS
Sr
No
OiI in water emuIsion (o/w) ater in oiI emuIsion (w/o)
1 Water is the dispersion medium and oil is
the dispersed phase
Oil is the dispersion medium and water is the
dispersed phase
2 They are non greasy and easily
removable from the skin surface
They are greasy and not water washable
3 They are used externally to provide cooling
effect e.g. vanishing cream
They are used externally to prevent evaporation
of moisture from the surface of skin e.g. CoId
cream
4 Water soluble drugs are more quickly
released from o/w emulsions
Oil soluble drugs are more quickly released from
w/o emulsions
5 They are preferred for formulations meant
for internaI use as bitter taste of oils can
be masked
They are preferred for formulations meant for
externaI use like creams.
6 O/W emulsions give a positive
conductivity test as water is the external
phase which is a good conductor of
electricity.
W/O emulsions go not give a positive
conductivity test as oil is the external phase
which is a poor conductor of electricity
47
dentification tests dentification tests
DiIution test DiIution test: emulsion can be diluted only with external phase
Dye test Dye test: : water or oil soluble dyes
COCI COCI
2 2
/fiIter paper test /fiIter paper test: : filter paper impregnated with COCl
2
and
dried (blue) changes to pink when o/w emulsion is added
Iuorescence Iuorescence: some oils fluoresce under UV light
Conductivity Conductivity: for ionic o/w emulsions (o/w emulsions conduct
electric current)
48
DiIution test DiIution test
n this test the emulsion is diluted either with oil or water.
f the emulsion is o/w type and it is diluted with water, it will remain
stable as water is the dispersion medium but if it is diluted with oil,
the emulsion will break as oil and water are not miscible with each
other.
Oil in water emulsion can easily be diluted with an aqueous solvent
whereas water in oil emulsion can be diluted with a oily liquid
49
CobaIt ChIoride Test CobaIt ChIoride Test
When a filter paper soaked in cobalt
chloride solution is added to an emulsion
and dried, it turns from blue to pink,
indicating that the emulsion is o/w type.
50
Iuorescence Test Iuorescence Test
f an emulsion on exposure to ultra ultra- -violet violet
radiations radiations shows continuous florescence
under microscope, then it is w/o type and if
it shows only spotty fluorescence, then it is
Oil in o/w type.
51
Conductivity Test Conductivity Test
This test is based on the basic principle that water is a good
conductor of electricity.
Therefore in case of o/w emulsion , this test will be positive as water
is the external phase.
n this test. An assembly consisting of a pair of electrodes connected
to a lamp is dipped into an emulsion.
f the emulsion is o/w type, the lamp glows
52
#ovc. o{ vvnini.vion o{ cnv.ion. #ovc. o{ vvnini.vion o{ cnv.ion.
OraI EmuIsions: Generally o/w emulsions are used for internal use as the oil
is more readily absorbed in a fine state of subdivision through the gastro
intestinal tract and secondly the preparation becomes more palatable when
water forms the continuous phase, as the medicinal oil is enveloped in a thin
film of emulgent which masks the bitter and oily taste of the drug like liquid
paraffin. Orally emulsions are also used to facilitate the absorption of the oil
soluble drugs like vitamins A,D, E and K.
Example: Liquid Paraffin Oral Emulsion
RectaI EmuIsions: Enemas are formulated as o/w emulsions.
TopicaI EmuIsions: For external use, emulsions may be either o/w or w/o
type. Emulsions finds the maximum use in topical preparations , both for
therapeutic and cosmetic use. Therapeutically they are used as carrier for a
drug. n cosmetic industry o/w emulsions have been used for formulation of
moisturing lotions, hand lotions and make up foundation lotions. When oily
layers are desired to prevent moisture loss from the surface of skin, for barrier
action and for cleansing action, then w/o emulsions are formulated like cold
creams.
Example: Antiseptic cream
53
EmuIsifying agents EmuIsifying agents
These are the substances added to an emulsion to prevent the
coalescence of the globules of the dispersed phase.
They are also known as emulgents or emulsifiers.
These agents have both a hydrophilic and a lipophilic part in their
chemical structure.
All emulsifying agents concentrate at and are adsorbed onto the
oil/water interface to provide a protective barrier around the
dispersed droplets.
n addition to this protective barrier, emulsifiers stabilize the
emulsion by reducing the interfacial tension of the system.
Some agents enhance stability by imparting a charge on the droplet
surface thus reducing the physical contact between the droplets and
decreasing the potential for coalescence.
Thus these act in three ways:
1) Formation of a protective barrier
2) Reduction of interfacial tension
3) Decreasing the potential for coalescence by forming an electrical double layer
54
Action of EmuIsifiers Action of EmuIsifiers
Main Main
Actions Actions
reducing the interfaciaI tension reducing the interfaciaI tension
between the phases between the phases
forming a barrier between forming a barrier between
the phases the phases
55
Action of EmuIsifiers Action of EmuIsifiers
-promoting the formation of an emulsion,
-making it easier to prepare,
-producing finer droplet size,
- aiding stability to the dispersed state
controlling the type of emulsion that is
to be formed: oil in water (O/W) or
water in oil (W/O)
56
o[in in.ic o{ cnv.i{ic o[in in.ic o{ cnv.i{ic
oil
water
oil
W/ /W
Hydro5il ead
i5o5il cain
water
57
Inco, o{ nv.i{i.vion Inco, o{ nv.i{i.vion
Many theories have been advanced in an attempt to explain
how emulsifying agents promote emulsification & main the
stability of emulsion.
Certain of these theories apply rather specifically to certain
types of emulsifying agents & to certain conditions.
n general, these theories describe the manner in which
emulsions may be produced & stabilized.
Among the most prevalent theories are
-- v{v.c cn.ion nco, v{v.c cn.ion nco,
-- Inc oicncv Inc oicncv.cvc nco, .cvc nco,
-- Tv.i. o inc{v.iv {in nco, Tv.i. o inc{v.iv {in nco,
58
v{v.c cn.ion nco, v{v.c cn.ion nco,
All liquids have a tendency to assume a shape having minimal surface
area exposed.
A drop of liquid has internal forces that tend to promote association of
the molecules to resist distortion of sphere.
oalesce. oalesce.
$urface tension $urface tension
Interfacial tension Interfacial tension
According to this theory, the use of the substances as emulsifiers &
stabilizers lowers the interfacial tension of the two immiscible liquids &
diminishing each liquid's attraction for its own molecules.
Thus surface-active agents facilitate the breaking up of large globules
into smaller ones, which then have a lesser tendency to reunite or
coalesce.
59
Inc oicncv Inc oicncv.cvc nco, .cvc nco,
Monomolecular layer of emulsifying agent curved around a droplet of
the internal phase of the emulsion.
Certain emulsifying agents orient themselves about & within a liquid in
a manner reflective of their solubility in that particular liquid.
Molecule have a hydrophilic & a hydrophobic portion.
Molecule position or orient themselves into each phase.
Depending on the shape & size of the molecules, their solubility
characteristics, a wedge shape orientation occurs to the surrounding of
the globule.
60
Tv.i. o inc{v.iv {in nco, Tv.i. o inc{v.iv {in nco,
The emulsifying agent is placed at the interface between the oil &
water, surrounding the droplets of the internal phase as a thin
layer of film adsorbed on the surface of the drops.
The film prevents contact & coalescing of the dispersed phase.
The tougher & more pliable the film, the greater the stability of
emulsion
61
Criteria for seIecting EmuIsifying Agent Criteria for seIecting EmuIsifying Agent
An ideal emulsifying agent should posses the following characteristics:
t should be able to reduce the interfacial tension between the two
immiscible liquids.
t should be physically and chemically stable, inert and compatible
with the other ingredients of the formulation.
t should be completely non irritant and non toxic in the
concentrations used.
t should be organoleptically inert i.e. should not impart any colour,
odour or taste to the preparation.
t should be able to form a coherent film around the globules of the
dispersed phase and should prevent the coalescence of the droplets
of the dispersed phase.
t should be able to produce and maintain the required viscosity of
the preparation.
62
SeIection of EmuIsifying Agents using
HL method
A system was developed in 1949 by iIIiam C Griffin to assist making systemic decisions about
the amounts and types of surfactants needed in stable products.
The system is called the HLB (hydrophiIe-IipophiIe baIance) system and has an arbitrary scale
of 1 - 18. HLB numbers are experimentally determined for the different emulsifiers.
HL RANGE USE
0-3 Antifoaming agents
4-6 W/O emulsifying agent
7-9 Wetting agents
8-18 O/W emulsifying agent
13-15 Detergents
10-18 Solubilizing agents
An emulsifier having a low HLB number low HLB number indicates that the number of hydrophilic groups present in
the molecule is less and it has a IipophiIIic character. For example, spans generally have low
HLB number and they are also oil soluble. Because of their oil soluble character, spans cause the
oil phase to predominate and form a w/o emulsion.
A higher HLB number indicate that the emulsifier has a large number of hydrophilic groups on the
molecule and therefore is more hydrophiIic in character. Tweens have higher HLB numbers and
they are also water soluble. Because of their water soluble character, tweens will cause the water
phase to predominate and form an o/w emulsion.
63
-- o. vnv .on. o. vnv .on.
Positives
Excellent starting point
Generally produces a fairly good emulsion
Negatives
gnores the importance of:
Electrical double layer
Temperature effects of ethoxylates
Fatty alcohols
Placement of emulsifier
% of emulsifier to be used
Phase volume ratios
Component interactions
Liquid crystals
64
CIassification of EmuIsifying Agents CIassification of EmuIsifying Agents
NaturaI EmuIsifying agents
NaturaI emuIsifying agents from vegetabIe sources
eg Gum Acasia, Tragacanth, Starch, agar, pectin
2 NaturaI emuIsifying agents from animaI source
eg GeIatin, egg yoIk
2 Semi-synthetic poIysaccharides
eg MethyI ceIIuIose, Sodium carboxymethyI ceIIuIose
3 Synthetic emuIsifying agents
Anionic Surfactant: e.g. Alkali soaps, amine soaps, alkyl sulphonates,
2 Cationic Surfactant: e.g Quaternary ammonium compounds such as cetrimide,
benzalkonium chloride and benzethonium chloride
3 Non-ionic surfactant: e.g. glyceryl esters such as glyceryl monostearate, propylene
glycol monostearate, macrogol esters such as polyoxyl stearates and polyoxyl-castor oil
derivatives, sorbitan fatty acid esters such as spans and their polyoxyethylene derivatives
such as tweens (polysorbates).
4 AmphoIytic surfactant: e.g. lecithin.
4 ineIy Divided SoIids
e.g. bentonite, aluminium magnesium stearate, attapulgite, colloidal anhydrous silica, hectorite
5 AuxiIIary EmuIsifying Agents
e.g. fatty acids (e.g., stearic acid), fatty alcohols (e.g., stearyl or cetyl alcohol), and fatty esters
(e.g., glyceryl monostearate)
65
Methods for preparing emuIsions Methods for preparing emuIsions
Preparation Of EmuIsions
Preparation of emulsions depends on the scale at which it
is produced.
On small scale mortar & pestIe can be used but its
efficiency is limited. To overcome these drawback small
electric mixers can be used although care must be
exercised to avoid excessive entrapment of air.
For large scale production mechanicaI stirrers are used
to provide controlled agitation and shearing stress to
produce stable emulsions.
The methods commonly used to prepare emulsions can be
divided into two categories: Method for nternaI &
ExternaI Emulsion 66
Methods for preparing EmuIsions for nternaI use Methods for preparing EmuIsions for nternaI use
Trituration Method: This method consists of dry gum
method and wet gum method.
Continental or Dry Gum Method Continental or Dry Gum Method : n this method the oil is
first triturated with gum with a little amount of water to
form the primary emulsion. The trituration is continued till
a characteristic 'clicking' sound is heard and a thick white
cream is formed. Once the primary emulsion is formed,
the remaining quantity of water is slowly added to form
the final emulsion.
English or wet Gum Method English or wet Gum Method : As the name implies, in this
method first gum and water are triturated together to form
a mucilage. The required quantity of oil is then added
gradually in small proportions with thorough trituration to
form the primary emulsion. Once the primary emulsion
has been formed remaining quantity of water is added to
make the final emulsion.
67
Methods for preparing EmuIsions for nternaI use Methods for preparing EmuIsions for nternaI use
Bottle or Forbes Bottle Method Bottle or Forbes Bottle Method : This method is employed for
preparing emulsions containing volatile and other non-viscous
oils. Both dry gum and wet gum methods can be employed for
the preparation. As volatile oils have a low viscosity as
compared to fixed oils, they require comparatively large
quantity of gum for emulsification. n this method, oil or water
is first shaken thoroughly and vigorously with the calculated
amount if gum. Once this has emulsified completely, the
second liquid (either oil or water) is then added all at once and
the bottle is again shaken vigorously to form the primary
emulsion. More of water is added in small portions with
constant agitation after each addition to produce the final
volume.
68
Proportions of Oil, Wat0r an/ Gum r0quir0/ for Proportions of Oil, Wat0r an/ Gum r0quir0/ for
formation of primary 0mulsion formation of primary 0mulsion
69
Methods for preparing EmuIsions for Methods for preparing EmuIsions for
ExternaI use ExternaI use
Emulsions meant for external application such as
creams, lotions and liniments contain in their formula
waxy solids which require melting before mixing.
Such emulsions may be prepared by melting the oily
components separately at 60
0
C. Similarly in another
vessel, the aqueous components are mixed and are
warmed gently to 60
0
C. the aqueous phase is then
added to the oily phase at the same temperature and
stirred until cold.
70
c.nvni.v qvincn {o nv.i{i.vion c.nvni.v qvincn {o nv.i{i.vion
Mechanical Stirrer
Homogenizers
Ultrasonifiers
Colloid mills
71
Icvvvion o{ nv.ion. Icvvvion o{ nv.ion.
72
cvion o.c..c. cvion o.c..c.
73
nstabiIities n EmuIsions nstabiIities n EmuIsions
An emulsion is a thermodynamically unstable preparation so care
has to be taken that the chemical as well as the physical stability of
the preparation remains intact throughout the shelf life.
There should be no appreciable change in the mean particle size or
the size distribution of the droplets of the dispersed phase and
secondly droplets of the dispersed phase should remain uniformly
distributed throughout the system.
nstabilities seen in emulsion can be grouped as
Creaming
Cracking
Phase nversion
74
Phase Separation Phase Separation
75
Creaming Creaming
An emulsion is said to cream when the oil or fat rises to the
surface, but remains in the form of globules, which may be
redistributed throughout the dispersion medium by shaking.
An oil of low viscosity tends to cream more readily than one of
high viscosity. ncreasing the viscosity of the medium
decreases the tendency to cream.
Creaming is a reversible phenomenon which can be corrected
by mild shaking.
The factors affecting creaming are best described by stroke's
law
V= 2r
2
(d
1
-d
2
) g/9
Where V= rate of creaming
r=radius of globules
d
1
= density of dispersed phase
d
2
= density of dispersion medium
g= gravitational constant
= viscosity of the dispersion medium
76
Creaming Creaming
ontd.
The following approaches can be used for decreasing Creaming
Reduction of gIobuIe size: According to stroke's law, rate of
creaming is directly proportional to the size of globules. Bigger
is the size of the globules, more will be the creaming.
Therefore in order to minimize creaming, globule size should
be reduced by homogenization.
ncreasing the viscosity of the continuous phase: Rate of
creaming is inversely proportional to the viscosity of the
continuous phase i.e. more the viscosity of the continuous
phase, less will the problem of creaming. Therefore to avoid
creaming in emulsions, the viscosity of the continuous phase
should be increased by adding suitable viscosity enhancers
like gum acacia, tragacanth etc.
77
Cracking Cracking
Occasionally, it happens that an emulsion cracks during
preparation, i.e., the primary emulsion does not become
white but acquires an oily translucent appearance.
n such a case, it is impossible to dilute the emulsion
nucleus with water and the oil separates out.
Cracking of emulsion can be due to
addition of an incompatible emulsifying agent,
chemical or microbial decomposition of emulsifying agent,
addition of electrolytes,
exposure to increased or reduced temperature
change in pH.
78
Phase nversion Phase nversion
n phase inversion o/w type emulsion changes into w/o
type and vice versa.
t is a physical instability.
t may be brought about by the addition of an electrolyte
or by changing the phase volume ratio or by temperature
changes.
Phase inversion can be minimized by using the proper
emulsifying agent in adequate concentration, keeping
the concentration of dispersed phase between 30 to 60
% and by storing the emulsion in a cool place.
79
Phase nversion Phase nversion
80
Points to be considered during formuIations of emuIsions Points to be considered during formuIations of emuIsions
Stability of the active ingredient
Stability of the excipients
Visual appearance
Color
Odor (development of pungent odor/loss of fragrance)
Viscosity, extrudability
Loss of water and other volatile vehicle components
Concentration of emulsifier
Order of addition of ingredients
Particle size distribution of dispersed phases
pH
Temperature of emulsification
Type of equipment
Method and rate of cooling
Texture, feel upon application (stiffness, grittiness, greasiness, tackiness,
spreadibility)
Microbial contamination/sterility (in the unopened container and under conditions of
use)
Release/bioavailability (percutaneous absorption)
Phase distribution, Phase nversion (homogeneity/phase separation, bleeding 81
Packaging, LabeIing And Storage Of Packaging, LabeIing And Storage Of
EmuIsions EmuIsions
Depending on the use, emulsions should be packed in suitable
containers.
Emulsions meant for oral use are usually packed in well filled bottles
having an air tight closure.
Light sensitive products are packed in amber coloured bottles.
For viscous emulsions, wide mouth bottles should be used.
The label on the emulsion should mention that these products have
to be shaken thoroughly before use.
External use products should clearly mention on their label that they
are meant for external use only.
Emulsions should be stored in a cool place but refrigeration should
be avoided as this low temperature can adversely effect the stability
of preparation.
82
;vvvion o{ cnv.ion ;vvvion o{ cnv.ion
Phase Separation
Globule Size
Flow properties
Effect of thermal stresses
Electrical Property measurement
83
Phase Separation Phase Separation
Coalescence is a definite sign of instability & it is
generally becomes apparent within a month in instable
formulations.
The phase separation can be accelerated by
centrifugation at low/moderate speeds.
High speed centrifugation (2,00,000) can be used to test
the strength of interfacial films. At such speeds emulsions
would crack up completely while only those with tough
interfacial films may survive.
The rate & degree of phase separation in an emulsion
can be determined by
Keeping a certain amount in a graduated cylinder &
measuring the volume of separated phase after definite time
intervals. The phase separation may result from creaming or
coalescence of globules.
Another method to get an idea of the coalescence rate is to
layer the hydrophobic phase containing water soluble
substances. Then a drop of the hydrophobic phase is
introduced into the water layer by means of a syringe & the
time required for this drop to merge with the main oily phase
noted. Time taken for the merger of the drop can be directly
related to stability of the emulsion

;
v

v
v

i
o
n

o
{

c
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v

.
i
o
n

;
v

v
v

i
o
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o
{

c
n
v

.
i
o
n
84
Globule Size Globule Size
Growth in globule size after the preparation of an
emulsion is an indication of its physical instability.
The globule size is measured by
optical microscopy,
laser light scattering, diffraction & transmission
by electronic devices such as coulter counter.

;
v

v
v

i
o
n

o
{

c
n
v

.
i
o
n

;
v

v
v

i
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n

o
{

c
n
v

.
i
o
n
85
Flow properties Flow properties
The rheological characteristics of an emulsion system
depends upon globule size, emulsifier & its
concentration, phase volume ratio etc. & hence
determination of its flow characteristics serve an index of
its stability.
Use of heliapath attachment with Brookfield viscometer
helps in detection of creaming tendency.
Follow up of rheological properties over extended
periods of time can help in prediction of their long-term
behaviours.

;
v

v
v

i
o
n

o
{

c
n
v

.
i
o
n

;
v

v
v

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o
{

c
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v

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i
o
n
86
Effect of thermal stresses Effect of thermal stresses
t is usual to evaluate the stability of an emulsion by
subjecting to high & low temperatures in alternating
cycles.
The samples are first exposed to 60
o
C for few hours &
then to 0 to 4
o
C.
Such exposures are repeated a number of times &
emulsion stability assessed after each cycle.
These thermal stresses cannot be directly correlated
to actual shelf life situations.
The effect of thermal stresses on different emulsions
do not follow any pattern & vary from formulation to
formulation

;
v

v
v

i
o
n

o
{

c
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v

.
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v
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c
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v

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i
o
n
87
EIectricaI Property measurement EIectricaI Property measurement
The surface charge & zeta potential of emulsified
droplets is often an important indicator for the stability
of the system because electrostatic repulsion can
significantly contribute to the avoidance of flocculation
& coalescence.
Recently a new method is used in which, the
conductivity of the emulsion at different heights of the
storage cell & at different times is measured, the values
are converted into volume fraction of the disperse
phase.
The creaming profile of O/W was described based on a
kinetic model to extrapolate for the long-term stability
prediction.

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88
References
"The Theory and Practice of Industrial Pharmacy The Theory and Practice of Industrial Pharmacy, Leon
Lachman, H.A. Liberman, J.L. Kanig, 3
rd
Ed.,
"odern Pharmaceutics odern Pharmaceutics, by Banker & Rhodes, Chapter
9 (Disperse System).
Remington's $cience and Practice of Pharmacy Remington's $cience and Practice of Pharmacy
Physical Pharmacy ,artin, Alfred N Physical Pharmacy ,artin, Alfred N
www.mpikg.mpg.de/kc/scripts/icelles_and_ www.mpikg.mpg.de/kc/scripts/icelles_and_mulsions mulsions
_Tauer_W$_2005_06/ _Tauer_W$_2005_06/mulsions mulsions. .
89