This will help in find out the difference between micro and nano emulsions. Contain good explanations of their thermdynamic and kinetic stability also ternary phase diagram.

1. 1

2. Micro/Nano-
emulsion
By-
Devesh Kumar Jain
M.S. (Pharm)
Pharmaceutics
NIPER, Mohali
2014

3. 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

4. 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

5. • 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.
History
5

6. 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

7. Difference b/w Emulsion and
Micro-emulsion
S.
No
Property Emulsion Microemulsion
1. Appearance Cloudy Transparent (or translucent)
2. Optical Isotropy Anisotropic Isotropic
3. Interfacial tension High Ultra low
4. Microstructure Static
Dynamic (interface is continuously
and spontaneously fluctuating)
5. Droplet size > 500 nm 20-200 nm
6. Stability
Thermodynamically
unstable (kinetically
stable)
Thermodynamically stable, long
shelf-life
7. Phases Biphasic Mono-phasic
8. Preparation
Require a large input of
energy, higher cost
relatively lower cost for commercial
production
9. Viscosity Higher viscosity
Low viscosity with Newtonian
behavior 7

8. l-Microemulsion ll-emulsion
8

9. Some Basics related to
Micro-emulsion
Micelle
Reverse
micelle
9

10. • 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.
Some Basics related to
Micro-emulsion
10

11. 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
Some Basics related to
Micro-emulsion
11

12. Components of Micro-emulsion
Formulation
Micro emulsion
Surfactant
+
cosurfactant
Aqueous
phase
Oil phase
12

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

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

15. 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
Components of Micro-emulsion
Formulations
15

16. 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
Components of Micro-emulsion
Formulations
Talegaonkar S. et al, Recent Patents on Drug Delivery & Formulation 2008, 2, 238-257 16

17. Formation of Microemulsions
2Oil
1 2 3mG G G G T S        
Gm = free energy change for microemulsion formation
G1 = free energy change due to increase in total surface area
G2 = free energy change due to interaction between droplets
G3 = free energy change due to adsorption of surfactant at the
oil/water interface from bulk oil or water
S = increase in entropy due to dispersion of oil as droplets
17

18. Why are microemulsions
thermodynamically stable?*
A
B
D
C
R*
ΔGm
*
ΔGm
R
ΔGm
* < 0 for A & B in certain R range
↓
microemulsion formation in that R range
ΔGm > 0 for C & D  emulsion formation
Microemulsions form spontaneously only when IFT is small. (order of 10-3
mN/m)
18

19. Theories of Microemulsion
formation
19
• Complex film formation at
interface
• Due to co-surf.
Mixed film
theory
• G = -ve
• G = g A
Thermodyna
mic theory
• Packing ratio & CPP
• V/a*l
Solubilization
theory

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

21. Phase diagram for microemulsions
Ternary Plot
X Data0 10 20 30 40 50 60 70 80 90 100
Y Data
0
10
20
30
40
50
60
70
80
90
100
Z Data
0
10
20
30
40
50
60
70
80
90
100
Col 1 vs Col 2 vs Col 3
21

22. 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
How to make Phase diagram?
22

23. 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
Method of Preparation
23

24. Aqueous Phase Titration Method
Oil + Surfactant + Cosurfactant
Clear dispersion
Microemulsion
Vortex mixing / Stirring
Titration with water
Vortex mixing / Stirring
Method of Preparation
24

25. Types of Micro-emulsion
Micro-
emulsion
O/W
Bi-
continousW/O
25

26. 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

27. 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

28. • 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
Bi-continous micro-emulsions
Malik M.A. et al, Arabian Journal of Chemistry (2012) 5, 397–417 28

29. Microemulsion characterization
• Electron microscopy
a) SEM
b) TEM
• Scattering techniques
a) DLS
b) SAXS
c) SANS
• Nuclear magnetic resonance (NMR)
• Spectroscopic techniques
29

30. 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

31. 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
Electron microscopy
Fig 1 Fig 2 31

32. 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
32Acharya D. P. et al, Current Opinion in Colloid & Interface Science 17 (2012) 274–280

33. 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

34. • 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
Recent Advancements
34Talegaonkar S. et al, Recent Patents on Drug Delivery & Formulation 2008, 2, 238-257

35. 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
35Kai Lun LEE, Applications and Use of Microemulsions, Imperial College London, November 2010

36. 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
/ year
300 20
Stability Less More
36

37. 37
What are nano-emulsions??
Is both are same or different?

38. 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
38

39. Similarities b/w Micro & Nano-
emulsion
39
Similarities
sub
micron
range
Higher
amount of
surfactant
more stable
then simple
emulsion
low
viscosity
transparent

40. formed by
self-assembly
thermodynami
cally stable
form
spontaneously
Micro mechanical
shear
kinetically
stable
Formed
intentionally
Nano
40
Differences b/w Micro & Nano-
emulsion

41. Kataria et al. International Journal of Pharmacy, 3 (2012) 5- 41

42. 42

43. 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
43Acharya D. P. et al, Current Opinion in Colloid & Interface Science 17 (2012) 274–280

44. • 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)
Scattering techniques
44Acharya D. P. et al, Current Opinion in Colloid & Interface Science 17 (2012) 274–280

45. 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
45Acharya D. P. et al, Current Opinion in Colloid & Interface Science 17 (2012) 274–280

46. 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

47. 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
47Acharya D. P. et al, Current Opinion in Colloid & Interface Science 17 (2012) 274–280

48. Method of preparation
 Mechanical (Need energy input)
 High-shear stirring
 High-pressure homogenizers
 Ultrasonication
48