microemulsion vs. nanoemulsion

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Micro-emulsionvs.

Nano-emulsion

Micro/Nano-emulsion

By- Devesh Kumar JainM.S. (Pharm)PharmaceuticsNIPER, Mohali2014

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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

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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

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• 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

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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

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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. StabilityThermodynamically 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

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l-Microemulsion ll-emulsion

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Some Basics related to Micro-emulsion

Micelle

Reverse micelle

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• In generalo/w- Microemulsionw/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.


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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


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Components of Micro-emulsion Formulation

Micro emulsion

Surfactant +

cosurfactant

Aqueous phase

Oil phase

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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

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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•AlcoholsIt is better to choose non-inoic surfactant due to

its better cutaneous tolerance

2. Surfactant


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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


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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



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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 waterS = increase in entropy due to dispersion of oil as droplets

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Why are microemulsions thermodynamically stable?*

A

B

DC

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)

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Theories of Microemulsion formation

Mixed film theory

• Complex film formation at interface

• Due to co-surf.

Thermodynamic theory

• G = -ve• G = g A

Solubilization theory

• Packing ratio & CPP • V/a*l

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Phase diagram for microemulsions

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

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Phase diagram for microemulsionsTernary 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

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Water Oil Surfactant20 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?

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Phase Titration Method

Spontaneous emulsification methoddepicted 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

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Aqueous Phase Titration Method

Oil + Surfactant + Cosurfactant

Clear dispersion

Microemulsion

Vortex mixing / Stirring

Titration with water

Vortex mixing / Stirring

Method of Preparation

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Types of Micro-emulsion

Micro-emulsion O/W

Bi-continou

s

W/O

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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


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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


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• 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


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Microemulsion characterization

• Electron microscopya) SEMb) TEM

• Scattering techniquesa) DLSb) SAXSc) SANS

• Nuclear magnetic resonance (NMR)• Spectroscopic techniques

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Electron microscopyTEM

• 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

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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

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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

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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

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• Environmentally responsive drug delivery • phase changes occur after administration, by changes in

a)temperatureb)pHc)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


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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

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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

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What are nano-emulsions??

Is both are same or different?

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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

Similarities

sub micron range

Higher amount of surfactant

more stable then

simple emulsion

low viscosity

transparent

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formed by self-assembly

thermodynamically stable

form spontaneously

Micro

mechanical shear

kinetically stable

Formed intentionally

Nano

Differences b/w Micro & Nano-emulsion

Kataria et al. International Journal of Pharmacy, 3 (2012) 5-10

THANK YOU ! 41

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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


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• 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


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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


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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

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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


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Method of preparation Mechanical (Need energy input)

High-shear stirring

High-pressure homogenizers

Ultrasonication

microemulsion vs. nanoemulsion

Health & Medicine