This document provides an overview of microemulsions and multiple emulsions. It defines microemulsions as thermodynamically stable, optically isotropic and clear dispersions of oil and water stabilized by an amphiphile. Three types of microemulsions are described: oil-in-water, water-in-oil, and bi-continuous. Preparation methods and characterization of microemulsions are also outlined. Multiple emulsions involve a second level of emulsification, forming either oil-in-water-in-oil or water-in-oil-in-water dispersions. Common preparation techniques for multiple emulsions include two-step emulsification and phase inversion methods.

1. PESENTED BY,
K.SAILAKSHMI,
M.PHARMACY,
(Pharmaceutics),
256213886016.
UNDER THE GUIDENCE
OF
Dr . YASMIN BEGUM
M.pharm , Ph.d
1

2. 2
CONTENTS
• INTRODUCTION
• MICRO EMULSIONS
TYPES OF MICRO EMULSIONS
DIFFERENCE BETWEEN MICRO AND MACRO
PREPARATION AND CHARACTERISATION
ADVANTAGES
STABILITY STUDIES
USES
• EQUIPMENTS
• MUTIPLE EMULSIONS
TYPES
PREFORMULATION OF DOUBLE EMULSIONS
PREPARATION OF MULTIPLE EMULSIONS
MECHANISMS AND EVALUATION
STABILITY
USES
• CONCLUSION

3. EMULSION
An emulsion is a thermodynamically unstable system consisting
of atleast two immisible liquid phases one of which is dispersed
as a globules in the other liquid phase stabilised by a third
substance called emulsifying agent
An emulsion is a mixture of two or more
immiscible(unblendable) liquids
Emulsions are a part more general classes of two phase systems
of matter called Colloids
In an emulsion one liquid(the dispersed phase) is dispersed in
the other (the continuos phase)
3

4. 4
MICRO EMULSIONS
DEFINITION: (Danielsson and Lindman)
“ A micro emulsion is a system, of water ,oil and an
amphiphile which is a single optically isotropic and
thermodynamically stable liquid solution.”
 In some aspects, micro emulsions can be considered as
small scale versions of emulsions ,i.e , droplet type dispersions
either of oil-in-water (o/w) or of water in oil (w/o) with a size
range in the order of 5-50nm in drop radius.

5. TYPES OF MICROEMULSIONS
 Three types of micro emulsions are most likely to be formed
depending on the composition:
• Oil in water micro emulsions wherein oil droplets are
dispersed in the continuos aqueous phase
• Water in oil micro emulsions wherein water droplets are
dispersed in the continuous oil phase
• Bi-continuous micro emulsions where in micro domains of oil
and water are inter dispersed within the system.
 In all three types of microemulsions, the interface is
stabilized by an appropriate combination of surfactants and/or
co-surfactants.
5

6.  The term micro emulsion introduced by Schulman and co-works.
 The term "micro emulsion" refers to a thermodynamically stable
isotropically clear dispersion of two immiscible liquids, such as oil
and water, stabilized by an interfacial film of surfactant molecules.
 A micro emulsion is considered to be a thermodynamically or
kinetically stable liquid dispersion of an oil phase and a water
phase, in combination with a surfactant.
6

7. The key difference between emulsions and
micro emulsions are that the former, whilst they may
exhibit excellent kinetic stability, are fundamentally
thermodynamically unstable and will eventually phase
separate.
Another important difference concerns their appearance;
emulsions are cloudy while micro emulsions are clear or
translucent.
In addition, there are distinct differences in their method
of preparation, since emulsions require a large input of
energy while micro emulsions do not.
 Micro emulsion formation and stability can be
explained on the basis of a simplified thermodynamic
rationalization.
7

8. Microemulsions and (Macro) emulsions are
Different
Microemulsion
• Thermodynamically Stable
• Droplet size 10 - 100 nm
(transparent)
• High surface area: 200 m2/g
• Ultra Low O/W IFT (10-2 –
10-3 mN/m)
• W/O , O/W and
Bicontinuous types
• Forms at CPP = 1
Macroemulsion
• Kinetically Stable
• 1-10 m (opaque)
• Low surface area: 15 m2/g
• O/W IFT 1-10 mN/m
• W/O or O/W types
• Forms at CPP > or < 1
8

9. PREPARATION OF MICROEMULSION:
Microemulsions were prepared at 27°C by a titration
method.
The drug is be dissolved in the lipophilic part of the microemulsion
i.e. Oil and the water phases can be combined with surfactant and
a cosurfactant is then added at slow rate with gradual stirring until
the system is transparent.
The amount of surfactant and cosurfactant to be added and the
percent of oil phase that can be incorporated shall be determined
with the help of pseudo-ternary phase diagram.
Ultrasonicator can finally be used so to achieve the desired size
range for dispersed globules. It is then be allowed to equilibrate.
9

10. Oil-in-water microemulsions were prepared by the titration
method.
A mixture of fatty acid and oil was added to a caustic solution
to produce a microemulsion, which was then titrated with a
cosurfactant, an alcohol, until the system turned clear.
It was found that as the chain length of the surfactant
increased, microemulsions with significant transmittances by
visible spectrum could be formed with oils of longer chain
lengths.
It was also found that different alcohols affected the formation
of microemulsions in different ways.
The best results, in terms of the greatest percent
transmittance coupled with the widest range of oil (dispersed
in water) concentration, were obtained from short or
branched alcohols.
10

11. The free energy of microemulsion formation can be
considered to depend on the extent to which surfactant
lowers the surface tension of the oil–water interface and
the change in entropy of the system such that,
DG f = γDA - T DS
where
DG f is the free energy of formation,
γ is the surface tension of the oil–waterinterface,
DA is the change in interfacial area on
microemulsification,
DS is the change in entropy of the system which is
effectively the dispersion entropy,
and T is the temperature.
It should be noted that when a microemulsion is formed the
change in DA is very large due to the large number of very
small droplets formed.
11

12. Though it has been know that several factors determine
whether a w/o or o/w system will be formed but in general
it could be summarised that the most likely microemulsion
would be that in which the phase with the smaller volume
fraction forms the droplets i.e. internal phase.
The surfactants used to stabilise such systems may be:
(i) Non-ionic
(ii) Zwitterionic
(iii) Cationic
(iv) Anionic surfactants
12

13. Various pharmaceutically acceptable available
that can be used in microemulsion formulation exicipents are:
 Long chain or high molecular weight (>1000) surfactants
include
Gelatin, casein, lecithin (phosphatides), gum acacia,
cholesterol, tragacanth, polyoxyethylene alkyl ethers,
e.g., macrogol ethers such as cetomacrogol 1000,
polyoxyethylene castor oil derivatives,
polyoxyethylene sorbitan fatty acid esters,
e.g., the commercially available Tweens, polyethylene
glycols, polyoxyethylene stearates.
The low molecular weight (<1000) surfactants include:
Stearic acid, benzalkonium chloride, calcium stearate,
glycerol monostearate, cetostearyl alcohol,
cetomacrogol emulsifying wax, and sorbitan esters.
13

14. Characterization Of Microemulsion
The droplet size, viscosity, density, turbidity, refractive
index, phase separation and pH measurements shall be
performed to characterize the microemulsion.
The droplet size distribution of microemulsion vesicles can
be determined by either light scattering technique or
electron microscopy. This technique has been advocated
as the best method for predicting microemulsion stability.
14

15. Advantages Of Microemulsion Over Other Dosage Forms
· Increase the rate of absorption
· Eliminates variability in absorption
· Helps solublize lipophilic drug
· Provides a aqueous dosage form for water insoluble drugs
· Increases bioavailability
· Rapid and efficient penetration of the drug moiety
· Helpful in taste masking
· Liquid dosage form increases patient compliance.
· Less amount of energy requirement.
15

16. Stability Studies
The physical stability of the microemulsion must be
determined under different storage conditions
(4, 25 and 40 °C) during 12 months.
Fresh preparations as well as those that have been kept
under various stress conditions for extended period of
time is subjected to droplet size distribution analysis.
 Effect of surfactant and their concentration on size of droplet
is also be studied.
16

17. Uses
Microemulsions have many commercially important uses:
Water-in-oil microemulsions for some dry cleaning
processes
Floor polishers and cleaners.
Personal care products
Pesticide formulations
Cutting oils.
Pharmaceutical applications of microemulsions
Increase bioavailability of drugs poorly soluble in water.
Topical drug delivery systems
17

18. Applications of microemulsions
 Microemulsions in enhanced oil recovery
 Microemulsions as fuels
 Microemulsions as coatings and textile finishing
 Microemulsions as lubricants, cutting oils and corrosion
inhibitors
 Microemulsions in detergency
 Microemulsions in cosmetics
 Microemulsions in agrochemicals
 Microemulsion in pharmaceuticals
18

19. EQUIPMENT USED IN PREPARATION OF
EMULSIONS
COLLOIDAL MILL
APPLICATION:
Product is feed to the operating area of a rotor,
having a speed of 2800 R.P.M by specially
designed feed device. The product is processed
by high sheer, pressure and friction between the
stator and rotor, the angular gap becomes
narrower towards the discharges section. This
processed product continuously leaves the mill
through the drain pipe, if required, it can be re-circulated.
SALIENT FEATURES
All contact parts can be easily and quickly
dismantled and cleaned.
Machine is designed for continuous operation.
Cylindrical screen for higher output.
Flame proof electrical can be provided at extra
cost. 19

20. HOMOGENISER
High Speed Homogenizer
Vats & Vessels Homogenizer is used to
homogenize, emulsify, and disperse
material in pharmaceutical, cosmetics,
food, chemical, petrochemical industry, etc.
Working Principle -
High speed mechanical and hydraulic shear
forces are the real key to the success of this
machine. Rotor & stator generates a
shearing action which insures that materials
being processed are subjected to thousands
of shearing actions each minute.
20

21. ROTORSTATOR
High speed rotor operating at close clearance
to stator draws material in from the bottom of
the mixing vessel and subjects it to intense
mixing and shearing action.
 The rotor accelerates the product towards the
blades periphery. There it is expelled through
the stator openings into the body of the mix
while undergoing an intensive mechanical and
hydraulic shearing action.
 Simultaneously new material is drawn in.
 The expelled mixture is deflected by the tank
wall completing the circulation pattern.
21

22. 22

23. DEFINITION
Multiple emulsions are the emulsion system in which the
dispersed phase contain smaller droplets that have the
same composition as the external phase.
 This is made possible by double emulsification hence the
systems are also called as “double emulsion”.
 Like simple emulsions, the multiple emulsions are also
considered to be of two
types:
•Oil-in-Water-in-Oil (O/W/O) emulsion system
•Water-in-Oil-in-Water (W/O/W) emulsion system
23

24. O/W/O EMULSION
 In O/W/O systems an aqueous phase (hydrophilic)
separates internal and external oil phase.
 In other words, O/W/O is a system in which water droplets
may be surrounded in oil phase, which in true encloses one
or more oil droplets.
24

25. W/O/W EMULSION
 In W/O/W systems, an organic phase (hydrophobic)
separates internal and external aqueous phases.
 In other words, W/O/W is a system in which oil droplets may
be surrounded by an aqueous phase, which in turn encloses
one or several waterdroplets.
25

26. These systems are the most studied among the multiple
emulsions.
The immiscible oil phase, which separates two
miscible aqueous phases is known as “liquid membrane”
and acts as a different barrier and semi-permeable
membrane for the drugs or moieties entrapped in the
internal aqueous phase.
26

27. Schematic Diagram of W/O/W & O/W/O
27

28. Pre-Formulation of Double Emulsion
The formulate a double emulsion, it is necessary to
choose, at least, an oil and two surfactants, one low in HLB
and one high in HLB.
In the example mentioned here, we have been working
with span surfactants (HLB<5) and
Tween surfactants (HLB>10) and
with a vegetable oil (caprylic/ capric triglyceride).
28

29. Methods of Preparation
Multiple emulsions are best prepared by
re- emulsification of primary emulsion.
The following are the method of multiple emulsions:
Two Steps Emulsification (Double Emulsification)
Phase Inversion Technique (One Step Technique)
29

30. Two Steps Emulsification
(Double emulsification)
 Two steps emulsification methods involve
re-emulsification of primary W/O or O/W emulsion
using a suitable emulsifier agent.
 The first step involves, obtaining an ordinary W/O or
O/W primary emulsion wherein an appropriate
emulsifier system is utilized.
 In the second step, the freshly prepared W/O or
O/W primary emulsion is re-emulsified with an excess
of aqueous phase or oil phase.
 The finally prepared emulsion could be W/O /W or
O/W/O respectively. 30

31. Two Steps Emulsification
31

32. Modified Two Steps Emulsification
32

33. Phase Inversion Technique
(One Step Technique)
An increase in volume concentration of dispersed phase
may cause an increase in the phase volume ratio, which
subsequently leads the formation of multiple emulsions.
 The method typically involves the addition of an aqueous phase
contains the hydrophilic emulsifier
[ Tween 80/sodiumdodecylsulphate (SDS) or Cetyl trimethyl
ammonium salt CTAB)] to an oil phase consisted of liquid
paraffin and containg lipophilic emulsifier (Span80).
33

34.  A well-defined volume of oil phase is placed in a vessel of
pin mixer.
 An aqueous solution of emulsifier is then introduced
successively to the oilphase in the vessel at a rate of 5 ml/min,
while the pin mixer rotates steadily at 88 rpm at room
temperature. When volume fraction of the aqueous solution
of hydrophilic emulsifier exceeds 0.7, the continuous oil
phase is substituted by the aqueous phase containing a
number of the vesicular globules among the simple oil
droplets, leading to phase inversion and formation of
W/O/W multiple emulsion.
34

35. Phase Inversion Technique
35

36. 36
POSSIBLE MECHANISMS OF DRUG RELEASE
FROM MULTIPLE EMULSIONS
 Diffusion mechanism.
 Micellar transport.
 Thinning of oil membrane.
 Rupture of oil phase.
 Faciliated diffusion (carrier mediated transport).
 Photo -osmotic transport.
 Solubilization of internal phase in the oil membrane.

37. 37
EVALUATION OF MULTIPLE EMULSIONS
 Characterization
 Average globule size and size distribution
 No.of globules
 Percentage drug entrapment
 Rheological evaluation
 Zeta potential
 In-vitro stability studies
 In-vitro drug release

38. 38
Characterization :
Emulsions are mostly characterized by the size distribution
of the droplet and other physical properities such as dielectric
properities thermal behaviour, rheological properities and other
microscopic and macroscopic observation.
Macroscopic examination:
Primary observations like color, consistency, and
homegeneity are frequently used to ensure type of multiple
emulsions formed (w/o/w or o/w/o) can be validated by dilution
with the external phase.

39. • Various other techniques used to characterize emulsions like
coulter counter, freeze-fracture electron microscopy and scanning
electron microscopy and are also used to determine average
globule size and size distribution of multiple emulsions droplets.
39
Number of globules
• Number of globules per cubic millimeter can be measured using
a haemocytometer cell after approriate dilution of the multiple
emulsions.
• The globules in five groups of 16 small squares (total 80 small
squares) can be counted and the total number of globules in per
cubic mm is calculated using the formula
No . of Globules/mm3 =No . of globules x Dilution x 4000
No . of small squares counted

40. 40
 Percentage Drug Entrapment:
• Percent entrapment of drug or active moiety in the multiple
emulsion is generally determined using dialysis , centrifugation,
filtration and conductivity measurements.
• However , recently an internal tracer /marker was used to
evaluate the entrapment of an impermeable marker molecule
contained in the inner aqueous phase of w/o/w emulsion.

41. 41
The % Entrapment can be calculated using the following
equation :

42. 42
Rheology :
(Jim et al, 2003)
 By increasing the shear rate and shear time the apparent
viscosity increased.
 Further shearing caused increase in shear stress of
emulsion and induced phase inversion
 Reasons of phase inversion:
 Increase in volume fraction of oil droplets by
entrapment of water molecules
 Coalescence of oil droplets upon shearing

43. 43
Zeta- potential
• The zeta-potential and surface charge can be calculated using
smoluchowski’s equation from the mobility and electrophoretic
velocity of dispersed globules using the zeta-potentiometer.
• The apparatus consists of cylindrically bored micro-electrophoresis
cell equipped with platinum-iridium electrodes
to measure the electrophoretic mobility of the diluted w/o/w
emulsion.

44. 44
Zeta-potential was calculated using following formula:

45. 45
In vitro stability studies
• Phase separation is a phenomenon by which one phase of
emulsion gets separated due to colescence.
• Percentage phase separation is the volume of phase in
percentage separated from the total volume of emulsion after
storage .
• 20ml of freshly prepared w/o/w emulsion is kept in 25ml of
graduated cylinder and allowed to stand for defined period at
40˚c.
• The volume of separated aqueous phase (V sep) is observed
periodically at regular intervals.

46. Percent phase separation is calculated using following
formula:
46

47. 47
In Vitro Drug Release
• The drug released from the aqueous inner phase of a w/o/w
emulsion can be estimated using the conventional dialysis
method using a cellophane tubing.
• Typically, 5ml of (w/o/w) multiple emulsion is placed in the
dialysis tube which is then tied at both ends by thread and
placed in basket (usually 100rpm) and dialyzed against
specified dissolution media (usually 200ml) at 37±1˚C.
• Aliquots were withdrawn at different time intervals and
replaced with fresh dissolution media and estimated using
standard procedure and the data were used to calculate
cumulative drug release profile.

48. 48
Fig: Assembly use for invitro drug release.

49. Stability of Multiple Emulsions
 Emulsion stability is a phenomenon, which depends upon the
equilibrium between water, oil and surfactant.
Unfortunately multiple emulsions are thermodynamically
unstable.
The possible indications of instability includes:
Leakage of the contents from the inner aqueous phase.
Expulsion of internal droplets in external phase.
Constriction or distension of the internal droplets due to
osmotic gradient across the oil membrane.
Flocculation of internal aqueous phase and multiple
emulsion droplets.
Disruption of oil layer on the surface of internal droplets.
Phase separation.
49

50. Methods to Stabilize Multiple
Emulsions
 The followings are some of the attempt or studies made
to restore or strengthen the stability of multiple emulsions :
Liquid crystal stabilized multiple emulsion.
Stabilization in presence of electrolytes.
Stabilization by forming polymeric gel.
Stabilization by interfacial complexation between
non- ionic surfactant and macromolecules.
Steric stabilization
Phase-inversion stabilization of W/O/W emulsion
50

51. 51
Fig; Various approaches to stabilize w/o/w multiple emulsion.
A-stabilizing through liquid crystal formation
B-stabilization by interfacial polymerization
C-stabilization by adsorption of electrolyte or adsorption or covalent
anchoring of polymer
D-gelation of either internal or external phase or oil core

52. Applications in Therapeutics & Cosmetics:
Multiple emulsion systems are finding unlimited
uses because of their vesicular structure with
innermost phase closely similar to that of
liposomal vesicles and the selective permeability
characteristic of liquid membrane.
 In cancer therapy.
 In herbal drugs.
 In taste masking.
 In food industry.
 In drug over dosage treatment.
 In inverse targeting.
52
APPLICATIONS

53. 53
CONCLUSION
• Micro emulsion properties are extremely varied. The
extreme diversity of their practical applications is one
consequence.
 One of their disadvantages is the large amount of
surfactant required to stabilize them because of the small
dispersion size.
 Although micro emulsion properties are beginning to
be satisfactorily understood, especially the droplet
structure, large research domains remain to be clarified.
 With evaluation of newer techniques of preparation,
stabilization, rheological properties can serves as potential
carrier for drugs ,cosmetics ,pharmaceutical agents

54. 54
 Multiple emulsions are complex polydispersed systems
where both oil in water and water in oil emulsion exists
simultaneously which are stabilized by lipophillic and
hydrophilic surfactants respectively.
 The ratio of these surfactants is important in achieving
stable multiple emulsions. Among water-in-oil-in-water
(w/o/w) and oil-in-water-in-oil (o/w/o) type multiple
emulsions; the former has wider areas of applications.

55. Multiple emulsions have also been employed as intermediate
step in the microencapsulation process and are the systems of
increasing interest for the oral delivery of hydrophilic drugs,
which are unstable in gastrointestinal tract like proteins and
peptides.
55
With the advancement in techniques for preparation,
stabilization and rheological characterization of multiple
emulsions, it will be able to provide a novel carrier system for
drugs, cosmetics and pharmaceutical

56. 56
 S.P. Vyas , R.K. Khar. Targeted & Controlled drug
delivery: novel carrier systems , 1st ed. New Delhi: CBS
publishers ; 2004,page no 303-303
 Micro emulsions as drug delivery system,A.N
Lalwani,T.J shah&N.S Parmar-309
 Targeted &Controlled Drug delivery vyas/khar-303
 Progress in controlled and novel drug delivery system-nk
jain
 Advance in controlled &drug delivery A.j khapae&N.K
jain-381
Remington the science and practice of pharmacy 21st ed.
page no-745
Martin’s physical pharmacy and pharmaceutical sciences
6th ed. Page no- 410
 Journals.
REFERENCES

57. 57