Suspension, interfacial properties of suspended particles, settling in suspensions, formulation of flocculated and deflocculated suspensions. Emulsions and theories of emulsification, microemulsion and multiple emulsions; Stability of emulsions, preservation of emulsions, rheological properties of emulsions.

1. PREPARED BY:
K. ARSHAD AHMED KHAN
M.Pharm, (Ph.D)
Dept. of Pharmaceutics
RIPER.

2. 4.Add Flocculating agent
& Structured vehicle
FORMULATION OF SUSPENSION:
Particles
1.Add Wetting Agent
Dispersion Medium
Uniform dispersion
of Deflocculated
Particles
2.Add Structured
vehicle
3.Add Flocculating
agent
Deflocculated Suspension
in Structured vehicle
Flocculated
Suspension
Flocculated
Suspension in
Structured
vehicle

3. Step-1: Dispersion of solids:
Water (solvent) + Insoluble solids (Hydrophobic)  Difficult
to disperse.
Small particles adsorb air and float on solvent surface.
Dispersion can be done by
1. Water miscible Co-solvents = Alcohol, Glycerin, PEG
Floating particles + Glycerin  removes air on surface,
forms a coat  ↑Dispersion.
2. Wetting agents:
Surfactants ↓IFT, ↓Contact angle(90-00) ↑Dispersion.
(HLB= 7-9)

4. Step-2: Deflocculated Suspension in Structured vehicle:
 Structured vehicles are the vehicles which exhibit
pseudo plastic/ plastic rheological behavior.
 These also posses thixotropic behavior i.e., gel-sol-gel
transformation to improve physical stability of
suspension.
 Structured vehicles are hydrocolloids, in low Conc.
absorb water, swell to give high viscosity.
 They act as protective colloid to stabilize charge.
Ex: Non-ionic = MC, HPMC
Anionic = Sodium CMC, Carbopol.
Clays = Bentonite

5. Concentration of suspending agent depends on:
1. Viscosity of vehicle:
Vehicle (low ɳ) + High Conc. suspending agent
Vehicle (high ɳ) + low Conc. suspending agent
2. Amount of solid:
Oral= high solid content + high Conc. S.A (non-ionic)
Parenteral= low solid content + low Conc. S.A (0.5% W/V)
If clays are used add preservatives (2-5% W/V)
3. Particle Size:
Small size + low Conc. suspending agent
Large size + High Conc. suspending agent
4. Density of solids:
Structured vehicles + PVP/PEG/Sugars  ↑ viscosity.
5. pH, Ionic strength.

6. Step-3: Flocculated Suspension:
Flocculating agent= electrolytes, surfactants, polymers.
1. Electrolytes:
All suspended particles same charge  Repulsive forces
Add electrolytes of opposite chargeAttractive forcesFlocs
Bismuth sub nitrate(+) + water + WA Deflocculated
suspension + Monobasic potassium phosphate(-)
electrolyte  Flocculated Suspension.
Flocculated Suspension + extra electrolyte all particles (-)
charged  repulsions Deflocculated suspension

7. Zeta potential & Sedimentation:
Suspension Charge Sedimentation(Vu/Vo)
Deflocculated [+] Low- hard cake
flocculated [+][-] = neutral High
Deflocculated [-][+][-] = [-] Low-hard cake
Other examples:
Sulfamerazine (-)
and flocculating
agent AlCl3 (+)

8. Controlled floccullation:
 Most dispersed particles posses charge depending on
pH of the system.
 The charge should be adjusted to zero and adjust pH to
make flocculated suspension in non-caking zone with
optimum zeta potential .

9. 2. Surfactants:
 Reduces IFT, act as wetting agent, deflocculating agent
& flocculating agent (Controlled Conc.)
 Particles + oppositely charges surfactant  Tails form
bridges between particles  Floccules
Anionic surfactants – SLS
Cationic surfactants – cetyl trimethyl ammonium bromide
Nonionic surfactants – tweens

10. 3. Polymers:
Polymers are long hydrocarbon chained molecules.
Half chain – adsorbed on particle
Other half chain – outside form brides with chains Flocs.
Ex: Sulfaguanidine + Xanthan gum Floccules

11. Protective colloidal action:
Hydrophilic polymers form sheath on floccules and
improve stability
Ex:
acidic solution of sulfthiazole  [-] particles 
Deflocculated suspension.
Sulfthiazole + Polymer (Gelatin)  Protective coat on
Floccule.

12. Step-4: Flocculated Suspension in Structured vehicle:
 Flocculated suspension have clear supernatant,
undesirable property.
 Add structured vehicle/ suspending agent  Good
Suspension.
 Flocculating agent – uniform sized floccules.
 Structured vehicle/ suspending agent – prevent settling
of floccules
Incompatability:
Charges of
1. Particle
2. Flocculating Agent
3. Suspending Agent

13. Physical stability of suspension:
 Physical stability is defined as a condition in which the
particles remain uniformly distributed throughout
dispersion with out any signs of sedimentation.
 Even if particles settle they should be easily
redispersed with moderate amount of shaking.
SUSPENSION EVALUATIONS:
1. Sedimentation volume (F)
2. Degree of flocculation (β)
3. Redispersibility.

14. 1. Sedimentation Volume (F):
F is dimension less quantity, value ranges from 1-0.
F value is proportional to stability
If F=1, Vu=Vo, ideal suspension
If F=0, Vu=0, total instability.
This evaluation is useful for
1. Selection of better suspension
2. Identifying suitable suspending agent
3. Obtaining optimum concentration of suspending agent.

16. 2. Degree of flocculation (β)
 β is dimension less quantity, value ranges from 1-infinity.
 β value is proportional to stability
 If β =1, F=Fα, minimum value indicating system is
defloccuated.
 The sedimentation volume of deflocculated system is less
than that of flocculated system.

17. 3. Redispersibility:
Mechanical shaker device simulating human motion.
Suspension in 100 ml measuring cylinder  stored to
sediment  placed in machine, rotated 3600 at 20 RPM
sediment redispersed time/no. of rotations NOTED.
Less time/ less rotations= disperse stable suspension
More time/ more rotations= disperse  unstable
suspension.

18. Rheological considerations:
 Important in manufacturing, storage, administration.
 Dispersion medium should have thixotropic behavior -
plastic/ pseudoplastic (gel-sol-gel)
Preformulation studies:
Performed to evaluate vehicle for optimum viscosity.
Method:
1. Vehicles mixed with various S.A/ various Conc. Of same
S.A
2. Shear stress noted form lower to higher rates of shear.
3. Obtained hysteresis loop is compared with standard
product graph.

19. Other Suspending agents:
Tragacanth,
Sodium alginate,
Sodium CMC.
Measurement of viscosity:
Cup-bob, Cone-plate viscometers not suitable because
they break floccules.

20. Brookfield viscometer:
 Best suitable for studying settling in
suspensions
 Contains helipathic stand with “T”
shaped spindle, moves in helix
manner up-down.
 As suspension exhibits thixotropic
behavior
Initial GEL show resistance  high dial
reading
Next SOL  less resistance  low dial
reading.
 A good suspension has less rate of
decrease in dial reading in Gel SOL
transformation.

21. 1. The results indicate how particles settle with respect to
time.
2. The technique provides information at which level the
floccule network is greater due to aggregation.
3. Effect of aging on storage can be evaluated.

22. Advanatges/Applications of Suspensions:
1. Stability
2. Choice of solvent
3. Taste masking
4. Prolonged drug action
5. Bioavailability

23. Advanatges/Applications of Suspensions:
1. Stability:
Drug in solution is unstable (hydrolysis)
Suspension = insoluble drug  STABLE.
Ex: Procaine Penicillin-G
2. Choice of solvent:
Drug is insoluble in water,
Solvent other than water is not acceptable  prepare
Suspension.
Ex: Corticosteroid Injection
3. Taste masking:
Suspension = (Unpleasant tasted Drug + Flavour/Sweetners)
Ex: Chloramphenicol Palmitate.

24. 4. Prolonged drug action:
Insoluble drug  Reservoir  drug released for long period
Ex: Procaine Penicillin –G
5. Bioavailability:
Suspensions have high bioavailability than Tab, Cap because
of large surface area, high dissolution rate.
Ex: Antacid Suspension acts faster than antacid tablets.

26. • DEF:
A thermodynamically unstable system consisting of at least
two immiscible liquid phases, one of which is dispersed
as globules in the other liquid phase.
• Emulsion is stabilized by an emulsifying agent.
• Globule diameter 0.1- 100µm
Ex: Milk, ice cream, paints, lotions of low viscosity to
ointments, creams which are semi-solids
Classification:
1. Basing on dispersed phase - 2 Types o/w and w/o
Medicinal emulsions are mostly o/w type.
2. Basing on globule size – 2 types
Microemulsions (0.01µm)
Fine emulsions (0.25-25 µm)

28. EMULSIFYING AGENT
Functions:
1. To prevent coalescence of dispersed globules.
2. To reduce IFT between polar and non-polar solvents.
Surfactants:
HLB (3-8)  W/O emulsifying agent- Spans
HLB (8-16)  O/W emulsifying agent- Tweens.
Brancrofts Rule: States that though emulsifying agent has
affinity towards polar and non-polar liquids, they have
preferential solubility in one of the liquid which becomes
continuous phase.
 Combination of E.A imparts better stability
 Ionic type of E.A not preferred for internal use as they
interact with biomembranes and effect cell functioning.
 Natural E.A show batch-batch variation & microbial
growth.

29. Classification of Emulsifying Agents
1. Natural Emulsifying Agents
Animal origin-wool fat. Egg yolk, gelatin, cholesterol, pectin,
chondrus.
Plant origin- Acacia, Tracaganth.
2. Synthetic Emulsifying Agents
Anionic-sodium stearate, sodium lauryl sulphate
Cationic- Benzalkonium chloride
Non-ionic- Sorbitan Fatty acid esters (Spans),
Polyoxyethylene sorbitan fatty acid esters (Tweens)
3. High molecular weight alcohols
Stearyl alcohol, cetyl alcohol & glyceryl monostearate.
4. Finely divided solids
Bentonite, magnesium hydroxide & aluminium hydroxide.

30. Mechanisms of emulsion formation
Emulsifying agent Forms film on dispersed globules.
1. Monomolecular adsorption film Surfactants-
Spans, Tweens.
2. Multimolecular adsorption film  Hydrophilic
colloids – Acacia, Gelatin.
3. Solid particle Adsorption  Finely divided solids-
Bentonite, Veegum.

31. 1. Monomolecular adsorption film:
 Surfactants form monomolecular film at oil-water
interface and cover the globule.
 The film should be strong, elastic, flexible to reform
when broken.
 Emulsion stability depends on physical, chemical,
mechanical properties of film.
 Oil soluble & water soluble surfactant combination
interactions forms complex & strong film.
 Ionic surfactants develop repulsive forces between
globules to prevent Coalescence.
 Nonionic surfactants forms thick film on globule to
prevent Coalescence.

32. 1. Sodium + Cholesterol  strong, strong  Good
cetyl sulphate interaction film emulsion
2. Sodium + Oleyl alcohol less  weak film  Poor
cetyl sulphate interactions emulsion
3. Sodium + Cetyl alcohol less complex  Poor emulsion
oleate film

33. 2. Multimolecular adsorption film
Acacia, Gelatin  multimolecular film  Prevent coalescence.

34. 3. Solid particle Adsorption:
 Finely divided solid particles adsorb at oil-water
interface to form rigid film.
 Film act as mechanical barrier to prevent coalescence.
 o/w  veegum, bentonite
 w/o  bentonite
 The stability of emulsion depends on the finer state of
sub-division of solid particles, irregular surface &
charge on surface.

35. Interfacial properties in emulsion:
Surfactants reduce IFT leading to globule formation and
increase in surface free energy.
ΔG = γ 0/w ΔA
γ 0/w = interfacial tension between oil & water
ΔA = increase in surface area.
With increase in surface free energy system becomes
unstable, to stabilize ΔG = 0.
1. Method-A:
ΔA =0 means regrouping of particles  phase seperation.
2. Method-B:
γ 0/w =0. This is not possible, but γ 0/w can be reduced by
adding surfactants.

36. THEORIES OF EMULSIFICATION:
Many theories have been advanced to account for the way
or means by which the emulsion is stabilized by the
emulsifier.
At the present time no theory has been postulated that
seems to apply universally to all emulsions.
1) Electric Double Layer Theory.
2) Phase Volume Theory.
3) Hydration Theory of Emulsions
4) Oriented wedge theory.
5) Adsorbed Film and Interfacial tension Theory
6) Surface tension theory.

37. 1) Electric Double Layer Theory:
The oil globules in a O/W emulsion carry a negative charge.
The water ionizes so that both hydrogen and hydroxyl
ions are present. The negative charge on the oil may
come from adsorption of the OH ions. These adsorbed
hydroxyl ions form a layer around the oil globules.
A second layer of oppositely charged ions forms a layer in
the liquid outside the layer of negative ions.
These two layers of oppositely charged ions are known as
the Helmholtz double layer.
They are not confined to emulsions but accompany all
boundary phenomena. The electric charge is a factor in
all emulsions, even those stabilized with emulsifying
agents

38. 2) Phase Volume Theory:
If spheres of the same diameter are packed as closely as
possible, one sphere will touch 12 others and the volume
the spheres occupy is about 74 per cent of the total
volume.
Thus if the spheres or drops of the dispersed phase remain
rigid it is possible to disperse 74 parts of the dispersed
phase in the continuous phase; but if the dispersed phase
is increased to more than 74 parts of the total volume, a
reversal of the emulsion will occur.
However, the dispersed phase does not remain rigid in shape
but the drops flatten out where they come in contact with
each other.

39. 3) Hydration Theory of Emulsions:
• Fischer and Hooker state that hydrated colloids make
the best emulsifiers.
• Fischer states the emulsifying agent, by which a
permanent emulsion is obtained, invariably "proves to
be a hydrophilic colloid when W/O emulsions are
concerned (a lyophilic colloid of some sort when other
than aqueous mixtures are under consideration). Put
another way, oil cannot permanently be beaten into
water, but only into a colloid hydrate."
• Fischer and Hooker have found albumin, casein, and
gelatin to be good emulsifying agents.

40. 4) Oriented wedge theory:
• This theory deals with formation of monomolecular
layers of emulsifying agent curved around a droplet of the
internal phase of the emulsion.
Example:
• In a system containing 2 immiscible liquids, emulsifying
agent would be preferentially soluble in one of the phases
and would be embedded in that phase.
• Hence an emulsifying agent having a greater hydrophilic
character will promote o/w emulsion and vice-versa.
• Sodium oleate is dispersed in water and not oil. It forms a
film which is wetted by water than by oil. This leads the
film to curve so that it encloses globules of oil in water.

41. 5) Adsorbed film and interfacial tension theory:
 Lowering interfacial tension is one way to decrease the
free surface energy associated with the formation of
droplets. Assuming the droplets are spherical,
 ΔF= 6 γ V
D
 V= volume of the dispersed phase in ml, d is the mean
diameter of the particles.
 γ = interfacial tension
It is desirable that:
 The surface tension be reduced below 10dynes/cm by the
emulsifier and Be absorbed quickly.

42. 6) Surface Tension Theory:
• A drop of liquid forms a spherical shape which gives it
the smallest surface area per unit volume
• When 2 drops come together to form a bigger drop-
gives lesser surface area. Also called surface tension at
air-liquid interface
• Surface Tension- Force that has to be applied parallel to
the surface of liquid to counterbalance exactly the
internal inward forces that tend to pull the molecule
together.
• When there are two immiscible liquids-it is called
interfacial tension.

43. Physical instability of Emulsions
Oil
Water

44. Instability Factors Prevention
1. FLOCCULATION:
Globules come
close to each other
to form
aggregates.
1. Ununiform
globule size
distribution
2. Opposite charge
on globule
surface
3. Low viscosity of
external
medium.
1. Unifrom sized
globules
2. Use same
charged ionic
E.A, electrolytes
3. Viscosity
improving
agents-
hydrocolloids.

45. Instability Factors Prevention
2. CREAMING:
Concentration of
globules at
top/bottom of
emulsion
1. Globule size
2. Viscosity of
external
medium
3. Differences in
density of oil-
water (aq>oil)
1. Homogenization
- Unifrom sized
globules
2. Thickening
agents to improve
viscosity
3. Reducing
density differences
(Bromoform + oil)
• Creaming is a reversible process/ temporary change and
shaking redisperses globules as E.A coating is present
• Creaming is detected by differences in colour shades.

46. Instability Factors Prevention
3. COALESCENCE:
Few globules fuse
to form bigger
globules.
Emulsifier film is
destroyed.
1. Insufficient amount of
E.A
2. Altered partitioning of
E.A
3. Incompatability
between E.A
4. Phase-volume ratio
greater than 74%
NO, this is
permanent
change.
4. BREAKING:
Complete
separation of oil &
aqueous phases.
1. Unnoticed Coalescence. NO, this is
permanent
change.

47. Instability Factors
5. PHASE
INVERSION:
Change in
emulsion
from o/w to
w/o or
viceversa
1. Change in chemical nature of E.A:
Sodium sterate (water soluble) o/w emul
Sodium sterate + CaCl2  Calcium sterate
Calcium sterate (oil soluble)  w/o emul
2. Altering phase-volume ratio:
o/w emul + oil  w/o emul + water  o/w
This method should be properly controlled
other wise leads to phase inversion.

48. Factors to improve physical stability:
Brownian motion theory, stokes law provides 9 factors.
1. Globule size
2. Globule size distribution
3. Viscosity
4. Phase-volume ratio
5. Charge on Electrical Double Layer
6. Physical properties of interface
7. Densities of phases
8. Temperature fluctuations
9. Experimental techniques.

49. 1. Globule size:
Globule diameter ↓1/2 then creaming ↓ 4 times.
Industrial size reduction = Colloidal mill
Maximum stability is by Optimum globule size
Globule size (5µ)  Brownian motion = NO Creaming.
Micro emulsion (0.01µ) = NO Creaming.
2. Globule size distribution:
Uniform, mono size = Stability
Ununifrom size = small globule settle in gaps of large
globules Coalescence.

50. 3. Viscosity:
High viscosity  NO sedimentation, NO Brownian motion &
administration problems.
Optimum viscosity  Good stability.
Viscosity improving agents
o/w= taragacnath CMC
w/o= long chain fatty acids, bees wax, alcohols, stearic acid.
4. Phase- volume ratio:
This is relative volume of water & oil in emulsion.
Medical emulsions (oil: water) = 50:50
In 50% oil globules  48% is porosity & 52% is globules
Critical point: is defined as concentration of internal phase
above which the E.A can not produce a stable emulsion of
desired type.
Critical point (74%)+ addition  Coalescence of globules.

51. 5. Charge of electrical double layer:
Ionic E.A form coat on globule  Repulsive forces  NO
Flocculation.
Charge on EDL depends on pH and important for Ionic E.A
6. Physical properties of interface:
Interface of Oil-Water  E.A Film STRONG (NO
Coalescence), ELASTIC (reform on breakage)
Film strength depends on pH. Optimum pH Stability.
7. Densities of phases: (Aq >Oil)
Aq = Oil  prevent Creaming.
Oil + Brominated oil  Oil density ↑ (But not practiced)

52. 8. Temperature fluctuations:
High temperature
1. Effect partitioning characteristics of E.A  instability
2. Chemical degradation of drug  instability
3. Water evaporate  instability
Low temperature
Aq. pahse = Ice Crystals  Rupture E.A film  Coalescence.
9. Experimental techniques:
Poor experimental techniques  incomplete emulsification
 instability
All preparation steps should be carefully followed.

53. Evaluation of physical stability of emulsions:
Stable emulsion should retain initial properties during
storage until usage.
Chemical instability:
Degradation of drug, E.A, preservative etc.,
Physical instability:
Flocculation, creaming, coalescence, phase separation,
phase inversion.
Evaluation of Emulsions:
1. Extent of phase separation
2. Globule size distribution
3. Centrifugation – Accelerated stability study
4. Microwave irradiation

54. 1. Extent of phase separation:
Suitable for poorly formed, rapidly breaking emulsions.
This is quick method, visible after manufacturing.
2. Globule size distribution:
Optical microscopy measures globule diameter.
Unstable emulsion  Small globules (1st day)  large
globules (after few days)
Globule size should not be measured immediately after
manufacturing, because of active coalescence stage
(stress removal).

55. 3.Centrifugation – Accelerated stability study:
Flocculation, creaming, phase separation is slow process.
For fast testing stress is induced by centrifugation (2000-3000
rpm)  Phase separation  Depth of oil phase is
measured.
Induction period-
Time required for stable emulsion for oil separation.

56. 4. Microwave irradiation:
Emulsion in beaker  Microwave irradiation (top-bottom)
measure temperature on Top & Bottom.
Stable emulsion  less difference b/o high transmittance.
Unstable emulsion  high difference b/o low transmittance.

57. PRESERVATION OF EMULSION:
Emulsion + Preservative  Oral (No microorganisms),
Parenteral (Sterile)
Microorganisms  destroy gums, proteins, instability.
(fungi, bacteria, yeast) carbohydrates,
Presevatives:- benzoic acid, sodium benzoate, methyl
paraben, propyl paraben etc.,
Factors for selection of preservative:
1. Aqueous phase:
Bacteria grow in water, interface Water soluble preservative
2. Volume fraction of aqueous phase:
o/w emul= high aq. Phase high Conc. Preservative.
w/o emul= low aq. Phase  low conc. Preservative.
3. pH of aqueous phase:
Adjust pH  Preservative undissociated form kill M.O easy

58. Preservative should be used in optimum concentration
for maximum effect.
[HA]w = concentration of undissociated acid in aq. phase
C = total concentration of acid
K = partition coefficient of acid
q = volume ratio of oil to aq. Phase
Ka = dissociation constant of acid
[H30+] = concentration of [H30+] ions in acid

59. Rheological properties of emulsion:
1. Removal of emulsion from bottle/tube
2. Flow of emulsion through hypodermic needle
3. Spreadability of an emulsion on skin
4. Stress induced flow changes during manufacturing.
 Optimum viscosity gives maximum stability.
Phase-volume
ratio
Type of flow Viscosity measurement
Dilute emul- 5% Newtonian Single point viscometer
Concentrated
emul- 50%
Pseudoplastic Multiple point viscometer-
Cone & plate,
Cup & bobConcentrated
emul- 74%
Plastic

60. Preparation of emulsion:
1. Selection of oil phase
Fixed, mineral, volatile oils oxidation  Add Anti-Oxidants
If oil is dispersed phase  phase volume ↓ 25%
2. Selection of aqueous phase:
Adjust pH, Add preservatives, organoleptic additives.
3. Selection of Emulsifying agent:
Selected basing on type of emulsion (o/w, w/o), HLB, Use
(internal, external). Optimum concentration is 2%.
4. Emulsion preparation:
Small scale:- Mortar & pestle
1. Wet gum method (English method)
2. Dry gum method (Continental method)
3. Bottle method.
Large scale:- Colloidal mill

61. Advantages of emulsions:
1. Mask the unpleasant taste
2. Economical
3. Improved bioavailability
4. Sustained release medication
5. Nutritional supplement
6. Diagnostic purpose
7. Topical use.

62. 1.Mask the unpleasant taste:
Unpleasant tasted drug  globules in emulsion
Ex: laxatives, vitamin-A
2. Economical:
Expensive solvents are used to dissolve lipids.
In emulsion lipids are dispersed in water (cheaper).
3. Improved bioavailability:
Absorption of drugs is faster & better in emulsion
Ex: griseofulvin corn oil-water emulsion > griseofulvin tablets
4. Sustained release medication:
Water soluble antigen dispersed in oil  o/w emul
Injected in body  Depots in muscle slow drug release
Multiple emulsions (o/w/o) (w/o/w) give sustained release

63. 5. Nutritional supplement:
Terminally ill patients are given nutrition parenterally.
Emulsion  oil phase (fats) ,Aq. phase (nutrients)
6. Diagnostic purpose:
radio-opaque emulsions are used in X-ray exam
7. Topical use:
Concentrated emulsion semi-solids.
Ex: cold cream, vanishing cream, benzyl benzoate etc.,