Micro-emulsion

vs.
Nano-emulsion

1
 Micro/Nano-
emulsion

By-
Devesh Kumar Jain
M.S. (Pharm)
Pharmaceutics
NIPER, Mohali
2014
 Introduction
• What is Micro-emulsion ?

• “a system of water, oil and amphiphile which is a

single optically isotropic and thermodynamically
stable liquid solution’’

• They are thermodynamically stable and therefore

do not require high inputs of energy or shear
conditions for their formation.

Lawrence M. J. et al, Advanced Drug Delivery Reviews 45 (2000) 89–121 3

 History
• The micro emulsion concept was introduced around 1940s
by Hoar and Schulman

• They prepared a quaternary solution of water, benzene,

hexanol, and K-oleate which was stable, homogenous and
slightly opalescent

• These systems became clear as soon as a short chain

alcohol was added

• Spherical micro-droplets have the diameter between 600

and 8000 nm

Lawrence M. J. et al, Advanced Drug Delivery Reviews 45 (2000) 89–121 4

 History
• They prepared a coarse emulsion and then titrated to
clarify by adding a co-surfactant (second surface active
substance)
• When the combination of the four components was right,
the system cleared spontaneously
• 4 component was:
a) Hydrocarbons (aliphatic or aromatic),
b) ionic surfactants,
c) Co-surfactants(generally 4–8 carbon chain aliphatic
alcohol)
d) an aqueous phase.

5
 Why Microemulsion?
• High drug-loading capacity
• Stable at temperatures up to 110° C and from pH 2-8
• Excellent thermodynamic stability
• Longer shelf life and Ease of manufacturing
• Converts fat soluble chemicals to stable water
dispersions
• Act as a super solvent
• Improves the bioavailability
• Suitable for most routes of administration

6
 Difference b/w Emulsion and
Micro-emulsion
S.
Property Emulsion Microemulsion
No
1. Appearance Cloudy Transparent (or translucent)
2. Optical Isotropy Anisotropic Isotropic
3. Interfacial tension High Ultra low

Dynamic (interface is continuously

4. Microstructure Static
and spontaneously fluctuating)

5. Droplet size > 500 nm 20-200 nm

Thermodynamically
Thermodynamically stable, long
6. Stability unstable (kinetically
shelf-life
stable)
7. Phases Biphasic Mono-phasic
Require a large input of relatively lower cost for commercial
8. Preparation
energy, higher cost production
Low viscosity with Newtonian
9. Viscosity Higher viscosity
behavior 7
l-Microemulsion ll-emulsion
8
Some Basics related to
Micro-emulsion

Reverse
micelle

Micelle

9
 Some Basics related to
Micro-emulsion
• In general
o/w- Microemulsion
w/o Reverse microemulsion

• If the medium is free of oil then aggregates are very small,

while the presence of oil makes large surfactant
aggregates

• In general, all microemulsions are made of swollen

micelles with oil/water inside them.

10
 Some Basics related to
Micro-emulsion
What are swollen micelles ?

• In a O/W micro emulsion Oil/surfactant ratio defines the

size of a micelle
• When water and surfactant are present without any oil
added (oil/surfactant ratio=0.0), there will be empty
micelles
• With the addition of oil, size of a micelle keeps on
increasing ( for a given micelle shape)
• Means with increase in ratio of oil to surfactant, the
micelles swell

11
Components of Micro-emulsion
Formulation

Oil phase
Aqueous
phase

Surfactant
+
cosurfactant

Micro emulsion
12
 Components of Micro-emulsion
Formulations
1. Oil Phase
• The oil component influences curvature by its ability to
penetrate
• swell the tail group region of the surfactant monolayer
• Saturated fatty acids e.g. lauric, myristic and capric acid
• Unsaturated fatty acids e.g. oleic acid, linoleic acid and
linolenic acid
• Fatty acid esters such as ethyl or methyl esters of
lauric,myristic and oleic acid

Talegaonkar S. et al, Recent Patents on Drug Delivery & Formulation 2008, 2, 238-257 13
 Components of Micro emulsion
Formulations
2. Surfactant

Low HLB High HLB

surfactants (>12) HLB> 20
•w/o micro • •Oftern
o/w micro
required co-
emulsion emulsion surfactant
•ItSpan
is better to choose •Tween
non-inoic •Alcohols
surfactant due to
its better cutaneous tolerance
Talegaonkar S. et al, Recent Patents on Drug Delivery & Formulation 2008, 2, 238-257 14
Components of Micro-emulsion
Formulations
Choice of surfactant

• It should lower the surface tension to a very small value to

aid in dispersion

• It must provide flexible film that can readily form around the
small droplets

• It should have appropriate curvature to form a correct

curvature on interfacial region

15
 Components of Micro-emulsion
Formulations
3. Cosurfactant
• single-chain surfactants alone are unable to reduce the o/w
interfacial tension sufficiently

• Cosurfactants allows the interfacial film sufficient flexibility

• Helps to take up different curvatures required to form

microemulsion

• Short to medium chain length alcohols (C3-C8) are

commonly added to reduce it further
Talegaonkar S. et al, Recent Patents on Drug Delivery & Formulation 2008, 2, 238-257 16
 Formation of Microemulsions
Gm  G1  G2  G3  T S

2
Oil

DGm = free energy change for microemulsion formation

DG1 = free energy change due to increase in total surface area
DG2 = free energy change due to interaction between droplets
DG3 = free energy change due to adsorption of surfactant at the
oil/water interface from bulk oil or water
DS = increase in entropy due to dispersion of oil as droplets
17
 Why are microemulsions
thermodynamically stable?*
ΔGm
ΔGm > 0 for C & D  emulsion formation
D
C
R*
R
B
ΔGm*
A

ΔGm* < 0 for A & B in certain R range

↓
microemulsion formation in that R
range
Microemulsions form spontaneously only when IFT is small. (order of 10-3
mN/m)
18
 Theories of Microemulsion
formation
• Complex film formation at
Mixed film interface
theory • Due to co-surf.

Thermodynamic • DG = -ve
theory • DG = g DA

Solubilizat • Packing ratio & CPP

ion theory • V/a*l
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 Phase diagram for microemulsions

Malik M.A. et al, Arabian Journal of Chemistry (2012) 5, 397–417 20

 Phase diagram for microemulsions
Ternary Plot
Y Data

0
100

10
90

20
80

30
70

40
60

50
50

60
40

70
30

80
20

90
10

100
0
Z Data 0 10 20 30 40 50 60 70 80 90 100 X Data

Col 1 vs Col 2 vs Col 3

21
How to make Phase diagram?
Water Oil Surfactant
20 80 0
20 70 10
20 65 15
20 60 20
20 55 25
20 50 30
30 70 0
30 65 5
30 60 10
30 55 15
30 50 20

22
 Method of Preparation
Phase Titration Method

Spontaneous emulsification method

depicted with the help of phase diagrams

Phase Inversion Method

• occurs upon addition of excess of the dispersed phase

or in response to temperature
• These methods make use of changing the spontaneous
curvature of the surfactant.
• changing the temperature of the system, forcing a
transition from an o/w microemulsion at low temperatures to
a w/o microemulsion at higher temperatures
23
 Method of Preparation
Aqueous Phase Titration Method

Oil + Surfactant + Cosurfactant

Vortex mixing / Stirring

Titration with water

Vortex mixing / Stirring

Clear dispersion

Microemulsion
24
Types of Micro-emulsion

Micro-
W/O emulsion O/W

Bi-
continou
s

25
 W/O micro-emulsions
• During preparatoin firstly Reverse micelles forms, to
minimise S. free energy

• They are dynamic i.e. micelles frequently collide via

random Brownian motion

Malik M.A. et al, Arabian Journal of Chemistry (2012) 5, 397–417 26

 O/W micro-emulsions
• The charged head group of the microemulsion droplets is
the driving force for producing O/W micro-emulsion
• This also increases Temperature stability
• can be used as carriers for a wide number of organic
compounds

Malik M.A. et al, Arabian Journal of Chemistry (2012) 5, 397–417 27

 Bi-continous micro-emulsions
• Water and oil both are continuous phases
• Amount also comparable
• It is like sponge
• Encountered in microemulsions, in mesophases, and even
in relatively dilute surfactant solutions
• Indicated by the average mean curvature zero
• May also exist as hexagonal liquid crystal structure

Malik M.A. et al, Arabian Journal of Chemistry (2012) 5, 397–417 28

Microemulsion characterization
• Electron microscopy
a) SEM
b) TEM
• Scattering techniques
a) DLS
b) SAXS
c) SANS
• Nuclear magnetic resonance (NMR)
• Spectroscopic techniques

29
 Electron microscopy
TEM
• Cryo-TEM commonly used
• It also detecs spongy phase of bi-continuous micro-
emulsion
• Bicontinuous microemulsion phases are seen to have
characteristic zig-zag channel like complex structures
• In Water-in-oil/microemulsion systems, small droplets are
seen on a continuous background

Fig 1 Fig 2 30
 Electron microscopy
SEM
• Field emission SEM (FESEM) is used specifically
• Resulting in improved spatial resolution
• Minimized sample charging and damage
• Cryo-FESEM also used for better surface morphology
• Technique can be used differentiate bicontinuous from
droplet type micro-emulsions

Fig 1 Fig 2 31
 Other Methods

• Rheology- Bicontinuous microemulsions exhibit a

Newtonian behavior (constant viscosity) at low to medium
shear rates
• But shear thinning is observed at high shear rates,
probably due to fragmentation of the bicontinuous structure

• Conductivity- simple and inexpensive technique

• used to determine the type of microemulsion

Acharya D. P. et al, Current Opinion in Colloid & Interface Science 17 (2012) 274–280 32
 Recent Advancements
• Geraniol- a non-toxic, perfume, cosurfactant / cosolvent
• SMEDDs- Self-emulsifying drug delivery systems, a
solution of oil and surfactant, which form o/w
(micro)emulsion on mild agitation in the presence of water
• Ocular Micelles- microemulsions containing pilocarpine
were formulated using lecithin, pylene glycol and PEG 200
as cosurfactants, and IPM as the oil phase. non-irritant in
rabbit eyes
• Topical microemulsions were based on oleic acid as the
oil phase, enhanced delivery rates for Prostaglandin E1
• Fluorinated surfactants- for the stabilisation of
microemulsion, more surface-active than their
hydrocarbon, less haemolytic, low toxicity
33
 Recent Advancements
• Environmentally responsive drug delivery
• phase changes occur after administration, by changes in
a)temperature
b)pH
c)ionic strength can be particularly
• e.g. reverse micellar solution of lecithin in IPM:
Converted to a lamellar liquid crystal resulting in the
controlled release of the anti-inflammatory fenoprofen

Talegaonkar S. et al, Recent Patents on Drug Delivery & Formulation 2008, 2, 238-257 34
 Applications
• Enhanced Oil Recovery
• increasing attention as potential drug delivery
systems Because of their unique solubilization
properties
• The dog shampoo "Allermyl" marketed by Virbac is
the first application of microemulsions to a
therapeutic cleansing product
• Solvium is a topical Ibuprofen gel marketed by
Chefaro (Akzo). In this case, microemulsion has been
used to formulate a poorly soluble active at a dose of
5% into a perfectly transparent gel

Kai Lun LEE, Applications and Use of Microemulsions, Imperial College London, November 2010 35
 Conclusion
• In terms of drug solubilisation capacities, microemulsions
should better than micelles because of the extra locus for
solubilisation provided by the oil phase

Liposomes Microemulsion

Developed in 1972 1974

Research paper 300 20

/ year

Stability Less More

36
What are nano-emulsions??

Is both are same or different?

37
What are nano-emulsions?
• Nano emulsions are in the sub 100nm size range

• formed by mechanical shear

• microemulsions form spontaneously and are

thermodynamically stable but this is not true for
nanoemulsions

• are somewhat more stable than common emulsions, but

only kinetically stable

• Due to the large surface higher concentration of surfactant

required to stabilize them
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Similarities b/w Micro & Nano-
emulsion

sub
transpare
micron
nt
range

Similaritie
s

Higher
low
amount of
viscosity
surfactant
more
stable
then
simple
emulsion 39
Differences b/w Micro & Nano-
formed by self-
emulsion
mechanical shear

assembly

thermodynami kinetically stable

cally stable

Micro Nano
form Formed intentionally

spontaneously

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THANK YOU !
Kataria et al. International Journal of Pharmacy, 3 (2012) 5- 41
42
 Scattering techniques
• Scattering techniques involving X-rays, neutrons and light
• used to obtain quantitative information on size, shape and
morphology of microemulsions
• The basic principle of these techniques involves applying
an incident beam of radiation to the sample, and recording
the intensity and angle of the scattered beam

• DLS- Dynamic light scattering (DLS), also known as

photon correlation spectroscopy, can be used to analyse
microemulsion droplet size via determination of
hydrodynamic radius

Acharya D. P. et al, Current Opinion in Colloid & Interface Science 17 (2012) 274–280 43
 Scattering techniques
• SAXS- Application of SAXS in determining shape and
size of microemulsion droplets relies on the difference in
the ability of oil and water phases to scatter x-rays
• This property has been commonly used to estimate the
radius of a confined phase in O/W or W/O microemulsions
• SANS- In small-angle neutron scattering (SANS),
neutrons from a reactor source are scattered by the atomic
nuclei of the sample. Different nuclei or even different
isotopes of the same element have different abilities to
scatter neutrons, expressed as their characteristic
scattering length density (SLD)

Acharya D. P. et al, Current Opinion in Colloid & Interface Science 17 (2012) 274–280 44
 Nuclear magnetic resonance
(NMR)
• NMR relaxation technique for characterizing
microemulsions involves measuring the molecular
relaxations of component molecules
• Using models, it can provide information about aggregate
shape and size, and it is sensitive in picking up subtle
changes in droplet shape and size without any interference
from droplet interactions
• The technique permits one to differentiate between
discontinuous and bicontinuous microemulsions and also
to determine whether a discontinuous microemulsion is
W/O type or O/W type

Acharya D. P. et al, Current Opinion in Colloid & Interface Science 17 (2012) 274–280 45
 Spectroscopic techniques
• Chemiluminescence techniques have also been
employed to study transitions between polar and non-polar
environments inmicroemulsion systems

• Fluorescence correlation spectroscopy (FCS) is

an excellent tool for measuring molecular diffusion and size
under extremely dilute conditions

• Fourier transform Infrared (FTIR) spectroscopy

has been used to distinguish between the local
environments of water molecules confined in the core of
reverse microemulsions because of its high sensitivity to
interactions between water molecules
46
 Spectroscopic techniques
• Ultrafast IR spectroscopy techniques have also
been employed to study the hydrogen bonding network
and dynamics of water molecules in reverse
micelles/microemulsions

• Dielectric spectroscopy is another spectroscopic

technique which can provide information about the
morphology of microemulsions and dynamics of different
polar groups and aggregates by measuring the variation of
conductivity and dielectric constant

Acharya D. P. et al, Current Opinion in Colloid & Interface Science 17 (2012) 274–280 47
 Method of preparation
 Mechanical (Need energy input)

 High-shear stirring

 High-pressure homogenizers

 Ultrasonication

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