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Microemulsion vs. nanoemulsion
This document provides an overview of microemulsions, including their definition, history, and significance in drug delivery systems. It discusses the properties distinguishing microemulsions from traditional emulsions, their components, formation methods, and characterization techniques. Additionally, the document highlights recent advancements and applications, such as enhanced drug solubilization and stability in pharmaceutical formulations.
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Microemulsion vs. nanoemulsion
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- 2. Micro/Nano- emulsion By- Devesh Kumar Jain M.S.(Pharm) Pharmaceutics NIPER, Mohali 2014
- 3. Introduction • What isMicro-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 microemulsion 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 prepareda 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? • Highdrug-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 Emulsionand 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
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- 9. Some Basics relatedto 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 swollenmicelles ? • 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 Microemulsion 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 Microemulsion 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-chainsurfactants 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 12 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 thermodynamicallystable?* 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 formicroemulsions 20Malik M.A. et al, Arabian Journal of Chemistry (2012) 5, 397–417
- 21. Phase diagram formicroemulsions 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 2080 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 Spontaneousemulsification 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 TitrationMethod Oil + Surfactant + Cosurfactant Clear dispersion Microemulsion Vortex mixing / Stirring Titration with water Vortex mixing / Stirring Method of Preparation 24
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- 26. W/O micro-emulsions • Duringpreparatoin 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 • Thecharged 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 andoil 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 • Electronmicroscopy a) SEM b) TEM • Scattering techniques a) DLS b) SAXS c) SANS • Nuclear magnetic resonance (NMR) • Spectroscopic techniques 29
- 30. Electron microscopy TEM • Cryo-TEMcommonly 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 emissionSEM (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 responsivedrug 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 OilRecovery • 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 termsof 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?? Isboth 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 Micromechanical 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.
- 43. Scattering techniques • Scatteringtechniques 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- Applicationof 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 • Chemiluminescencetechniques 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 • UltrafastIR 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
Editor's Notes
- #10 In short, reverse micelles can be defined as ‘‘Water in oil microemulsion in which polar head groups of surfactant molecules are attracted by aqueous core and directed towards inside and hydrocarbon chain i.e. a polar part is attracted by non aqueous phase and directed towards outside’’. The reverse-micelles obtained at a particular ratio of the aqueous phase to the surfactant leads to uniformsize nanoreactors and have an aqueous core of 5–10 nm
- #29 The sponge structure is a good example: the sponge has a continuous structure, but it is possible to ‘‘fill’’ the sponge with a liquid. Most of the microemulsions that are bicontinous contain comparable amounts of water and oil hexagonal liquid crystal structure- where one of the liquid lies inside interconnected tubules or conduits.
- #31 Image 1 TEM image for silica-coated Pt metal nanoparticles which we prepared using w/o microemulsion Image 2 Silica-based nanocomposites via reverse microemulsions
- #32 provides narrower probing beams at low as well as high electron energy, resulting in both improved spatial resolution Although the sample preparation in this technique is less invasive than in FF-TEM, since it only involves the freezing and fracturing of the sample with a knife on the stage of the microscope, formation of ice crystals during transfer of the samples often cannot be completely avoided which can make it difficult to distinguish frozen water from microemulsion droplets. Image 1 SEM image of PMMA prepared from a bicontinous microemulsion system consisting of 35 wt% H2O Image 2 Nanocasting nanoporous inorganic and organic materials from polymeric bicontinuous microemulsion templates.
- #34 IPM isopropyl myristate
- #36 The use of microemulsions is of high interest in many aspects of crude oil exploitation, but none more so that in enhanced oil recovery. In cases where the pressure exerted by gushing sea water on the oil phase is not able to overcome capillary forces sufficiently, microemulsions are the key to extracting more than just a minor portion of crude oil. This is also known as chemical flooding. The S(M)EDDS formulation of Norvir® (soft capsules) for HIV ritonavir
- #39 Both micro emulsions and nano emulsions can be in the sub 100nm size range. Quote: "The two systems are very different since nanoemulsions are formed by mechanical shear and microemulsion phases are formed by self-assembly. “ basically, microemulsions form spontaneously and are thermodynamically stable. This is not true for nanoemulsions, which are somewhat more stable than common emulsions, but only kinetically stable. Due to the large surface to volume ratio of droplet interfaces in nanoemulsions, the concentration of surfactant required to stabilize them is larger than for microscale emulsions, yet it is generally smaller than for lyotropic microemulsion phases.
- #46 In bicontinuous microemulsions, free diffusion of solvent phases is restricted in two directions due to the presence of the surfactant stabilised interface, resulting in reduced diffusion coefficients. Hence, simultaneously high diffusion coefficients of both component solvents provide evidence of bicontinuous structures, and a sharp change in the diffusion properties of one of the solvents corresponds to the transition from bicontinuous to discontinuous microemulsions.