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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...
History
• The micro emulsion concept was introduced around 1940s
by Hoar and Schulman
• They prepared a quaternary solutio...
• They prepared a coarse emulsion and then titrated to
clarify by adding a co-surfactant (second surface active
substance)...
Why Microemulsion?
• High drug-loading capacity
• Stable at temperatures up to 110° C and from pH 2-8
• Excellent thermody...
Difference b/w Emulsion and
Micro-emulsion
S.
No
Property Emulsion Microemulsion
1. Appearance Cloudy Transparent (or tran...
l-Microemulsion ll-emulsion
8
Some Basics related to
Micro-emulsion
Micelle
Reverse
micelle
9
• In general
o/w- Microemulsion
w/o Reverse microemulsion
• If the medium is free of oil then aggregates are very small,
w...
What are swollen micelles ?
• In a O/W micro emulsion Oil/surfactant ratio defines the
size of a micelle
• When water and ...
Components of Micro-emulsion
Formulation
Micro emulsion
Surfactant
+
cosurfactant
Aqueous
phase
Oil phase
12
1. Oil Phase
• The oil component influences curvature by its ability to
penetrate
• swell the tail group region of the sur...
Components of Micro emulsion
Formulations
Low HLB
surfactants
• w/o micro
emulsion
• Span
High HLB
(>12)
• o/w micro
emuls...
Choice of surfactant
• It should lower the surface tension to a very small value to
aid in dispersion
• It must provide fl...
3. Cosurfactant
• single-chain surfactants alone are unable to reduce the o/w
interfacial tension sufficiently
• Cosurfact...
Formation of Microemulsions
2Oil
1 2 3mG G G G T S        
Gm = free energy change for microemulsion formation
...
Why are microemulsions
thermodynamically stable?*
A
B
D
C
R*
ΔGm
*
ΔGm
R
ΔGm
* < 0 for A & B in certain R range
↓
microemu...
Theories of Microemulsion
formation
19
• Complex film formation at
interface
• Due to co-surf.
Mixed film
theory
• G = -v...
Phase diagram for microemulsions
20Malik M.A. et al, Arabian Journal of Chemistry (2012) 5, 397–417
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
1...
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 t...
Phase Titration Method
Spontaneous emulsification method
depicted with the help of phase diagrams
Phase Inversion Method
•...
Aqueous Phase Titration Method
Oil + Surfactant + Cosurfactant
Clear dispersion
Microemulsion
Vortex mixing / Stirring
Tit...
Types of Micro-emulsion
Micro-
emulsion
O/W
Bi-
continousW/O
25
W/O micro-emulsions
• During preparatoin firstly Reverse micelles forms, to
minimise S. free energy
• They are dynamic i.e...
O/W micro-emulsions
• The charged head group of the microemulsion droplets is
the driving force for producing O/W micro-em...
• Water and oil both are continuous phases
• Amount also comparable
• It is like sponge
• Encountered in microemulsions, i...
Microemulsion characterization
• Electron microscopy
a) SEM
b) TEM
• Scattering techniques
a) DLS
b) SAXS
c) SANS
• Nuclea...
Electron microscopy
TEM
• Cryo-TEM commonly used
• It also detecs spongy phase of bi-continuous micro-
emulsion
• Bicontin...
SEM
• Field emission SEM (FESEM) is used specifically
• Resulting in improved spatial resolution
• Minimized sample chargi...
Other Methods
• Rheology- Bicontinuous microemulsions exhibit a
Newtonian behavior (constant viscosity) at low to medium
s...
Recent Advancements
• Geraniol- a non-toxic, perfume, cosurfactant / cosolvent
• SMEDDs- Self-emulsifying drug delivery sy...
• Environmentally responsive drug delivery
• phase changes occur after administration, by changes in
a)temperature
b)pH
c)...
Applications
• Enhanced Oil Recovery
• increasing attention as potential drug delivery
systems Because of their unique sol...
Conclusion
• In terms of drug solubilisation capacities, microemulsions
should better than micelles because of the extra l...
37
What are nano-emulsions??
Is both are same or different?
What are nano-emulsions?
• Nano emulsions are in the sub 100nm size range
• formed by mechanical shear
• microemulsions fo...
Similarities b/w Micro & Nano-
emulsion
39
Similarities
sub
micron
range
Higher
amount of
surfactant
more stable
then simp...
formed by
self-assembly
thermodynami
cally stable
form
spontaneously
Micro mechanical
shear
kinetically
stable
Formed
inte...
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 informati...
• SAXS- Application of SAXS in determining shape and
size of microemulsion droplets relies on the difference in
the abilit...
Nuclear magnetic resonance
(NMR)
• NMR relaxation technique for characterizing
microemulsions involves measuring the molec...
Spectroscopic techniques
• Chemiluminescence techniques have also been
employed to study transitions between polar and non...
Spectroscopic techniques
• Ultrafast IR spectroscopy techniques have also
been employed to study the hydrogen bonding netw...
Method of preparation
 Mechanical (Need energy input)
 High-shear stirring
 High-pressure homogenizers
 Ultrasonicatio...
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Microemulsion vs. nanoemulsion

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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.

Published in: Health & Medicine

Microemulsion vs. nanoemulsion

  1. 1. 1
  2. 2. Micro/Nano- emulsion By- Devesh Kumar Jain M.S. (Pharm) Pharmaceutics NIPER, Mohali 2014
  3. 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. 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. 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. 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. 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. 8. l-Microemulsion ll-emulsion 8
  9. 9. Some Basics related to Micro-emulsion Micelle Reverse micelle 9
  10. 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. 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. 12. Components of Micro-emulsion Formulation Micro emulsion Surfactant + cosurfactant Aqueous phase Oil phase 12
  13. 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. 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. 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. 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. 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. 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. 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. 20. Phase diagram for microemulsions 20Malik M.A. et al, Arabian Journal of Chemistry (2012) 5, 397–417
  21. 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. 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. 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. 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. 25. Types of Micro-emulsion Micro- emulsion O/W Bi- continousW/O 25
  26. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 37 What are nano-emulsions?? Is both are same or different?
  38. 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. 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. 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. 41. Kataria et al. International Journal of Pharmacy, 3 (2012) 5- 41
  42. 42. 42
  43. 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. 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. 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. 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. 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. 48. Method of preparation  Mechanical (Need energy input)  High-shear stirring  High-pressure homogenizers  Ultrasonication 48

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