Dear G. Sailesh, Your questions reflects the curiosity and interest about microemulsions. Answer to your queries along with the references are enlisted below; 1) Is the technique of preparation of microemulsions expalained by you (by construction of terinary phase diagram) followed in industries? or are there any other techniques for preparation of microemulsions in large scale. Answer: Yes. Since microemulsions are thermodynamically stable, they can be prepared simply by blending oil, water, surfactant and co-surfactant with mild agitation. The orders of mixing the components are generally considered not to be critical, since microemulsions form spontaneously. However, Rosano and co-worker (1, 2) demonstrated that although micro emulsification is a spontaneous process, the driving forces are small and the time taken for these systems to reach the equilibrium interfacial tension can be long. Large transitory fluctuation in interfacial tension can occur during the microemulsion mixing process, as the components arrange themselves in such a way that the resulting interfacial and bulk microstructures lead to an overall minimum free energy. The time to establish equilibrium is influenced by the order of mixing. This is established more slowly if the co-surfactant is injected into the oil phase, as its greater solubility (3, 4), in this phase hinders its diffusion into the aqueous phase. References: * Rosano H.L., Cavello J.L., Lyson G.B., "Mechanism of formation of six Microemulsion Systems- In Microemulsion system." Marcel Dekker. Inc.NY., (1987), 259-275. * Rosano H.L., Cavello J.L, Chang D.L., Whitman J.H., J.soc. Cosmetic Chem.,39,(1988), 202-209. * Khanna Surabhi, Katare OP, Nasa Atul, Garg Arun, " Microemulsions: Developmental aspects", Research Journal of Pharmaceutical, Biological and Chemical Sciences, http://rjpbcs.com/pdf/2010_1(4)/[73].pdf 2) How to identify the Micro emulsion region from the terinary phase diagram? Answer: The microemulsion region can be identified by observing end point during titration i.e., clear system either by visual observation or instrumental analysis like carbon-13 nuclear magnetic resonance spectroscopy, conductivity testing etc. Reference: G. Lund and S. L. Holt, "Detergentless water/oil microemulsions: IV. the ternary pseudo-phase diagram for and properties of the system toluene/2-propanol/water", JOURNAL OF THE AMERICAN OIL CHEMISTS' SOCIETY, Volume 57, Number 8, 264-267, DOI: 10.1007/BF02668258, http://www.springerlink.com/content/b766681jun7633h6/ 3) What is the purpose of co-surfactant? Can I prepare micro emulsion by varying the concentration of single surfactant? * Answer: The co-surfactant partitions between the oil phase and interphase. Normally surfactant is in the interphase in microemulsion system, a smaller fraction of co-surfactant finds in interphase with the balance remaining in the oil phase. It changes the composition of oil and so the change in original oil/water tension. Most preferably medium chain alcohols are used as co-surfactant in microemulsions. Yes varying concentration can be used respective to pseudoternary phase diagram. Reference: K. L. Mithal, "Handbook of microemulsion", Marcell dekker, 13-45 4) How can we expect reduce patient variability? Answer: Because of their unique solubilization properties, uniform distribution within the system. Reference: * JM Kovarik, "Reduced Inter- and Intraindividual Variability in Cyclosporine. Pharmacoklnetics from a Microemulsion Formulation"Journal of Pharmaceutical SciencesVolume 83, Issue 3,. * Olivier Midler, "Microemulsion as delivery system",www.vetcontact.com/presentations/midler1/abstracts/midler.pdf 5) What is thermodynamic stability and why microemulsions are thermodynamically stable whereas macroemulsions are not stable. Answer: The understanding of basis for the thermodynamic stability of microemulsions was advanced considerably with development of several thermodynamic theories. Ruckonstein and chi, considered the free energy formation of microemulsion to be contributions of three components. 1. Interfacial energy 2. Energy Interaction between droplets. 3. Entropy of dispersion. The free energy of microemulsion formation can be considered to depend on the extent to which surfactant lowers the surface tension of oil water interface and change in entropy of the system such that. Where, = Free energy formation = Change in interfacial area on microemulsion. = Surface tension between oil water interface. T = Temperature = Change in entropy of the system. In macroemulsions, the interfacial energy of the system is much larger than the entropy hence the process of emulsification is nonspontaneous. In other words, energy is needed to produce the emulsion by use of high-speed mixtures. Since free energy of formation of the system is positive, the emulsion tends to break down by flocculation and coalescence, which reduce the interfacial energy. To reduce flocculation and coalescence, one creates an energy barrier between the droplets, thus preventing the close approach. This is achieved by the emulsifiers, which could be ionic, nonionic, or polymeric in nature. The electrostatic or stearic repulsion between the droplets prevents their close approach, thus preventing flocculation or coalescence, at least within a set period. This explains the limited shelf life of most emulsion systems, which by definition are thermodynamically unstable. But in case of microemulsions, the interfacial tension is made sufficiently low so that the interfacial energy becomes comparable to or even lower than the entropy of dispersion. In this case, the free energy of formation of this system becomes zero or negative. This explains the thermodynamic stability of microemulsions. Thus the main driving force for microemulsion formation is the ultra low interfacial tension, which is usually achieved by the use of two or more emulsifiers. This can be understood from the effect of surfactant concentration C and nature of interfacial tension between oil and water. Addition of surfactant to the aqueous or the oil phase causes a gradual lowering of interfacial tension reaching a limiting value at the critical micelle concentration (CMC). Any further increase in concentration above the CMC causes little or no further decrease in interfacial tension. References: *Mrunali R. Patel, "Microemulsions : As Novel Drug Delivery Vehicle", * Latest Reviews, Vol. 5 Issue 6, 2007, http://www.pharmainfo.net/reviews/microemulsions-novel-drug-delivery-veh... *Applied surfactants: principles and applications By Tharwat F. Tadros, Th. F. Tadros

Dear G. Sailesh, Thanks for showing interest in my presentation & the query. The answer is for the evaluation of microemulsions, following parameters are tested along with physicochemical properties; 1.Phase Behavior Studie 2.Scattering Techniques for Microemulsions Characterization 3.Nuclear Magnetic Resonance Studies 4.Interfacial Tension 5.Viscosity Measurements 6.Predicting Microemulsion Type References: 1) M. Jayne Lawrence, Gareth D. Rees, "Microemulsion-based media as novel drug delivery systems", Advanced Drug Delivery Reviews 45 (2000) 89-121 (http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T3R-41V29N8-8...) 2) Mrunali R. Patel, "Microemulsions : As Novel Drug Delivery Vehicle", Latest Reviews, Vol. 5 Issue 6, 2007 (http://www.pharmainfo.net/reviews/microemulsions-novel-drug-delivery-veh...) Kindly refer the references (hyperlinks are given in bracket). I hope your query was answered satisfactorily, please send your comment & in case any other doubt please let me know that. Thanks & regards

Dear Sirisha, Answer of your query; Microemulsion polymerization is a complex heterogeneous process where transport of monomers, free radicals and other species (such as chain transfer agent, co-surfactant and inhibitors) between the aqueous and organic phases, takes place. Reference: "A Microemulsion Process for Producing Acrylamide-Alkyl Acrylamide Copolymers", S. R. Turner, D. B. Siano and J. Bock, U. S. Patent No. 4,521,580, June 1985

Dear Sandeep, Answer to your queries; 1) Almost all drugs can be formulated in Microemulsion based on requirement of enhancement of solubility or other property. 2) About ADR, possible reaction would be co-related with % of surfactant + co-surfactant & about newer excipients that are yet to prove their clinical safety. Regards

Dear Shafi, Thanks for the question, Explain Autoemulsification? Ans: It is also called Self-Emulsification Process. It is of two types, 1.SMEDDs: Self Micro-Emulsifying Drug Delivery Systems. 2.SEDDs: Self Emulsifying Drug Delivery Systems. Commonly,Self Emulsifying Drug Delivery Systems and Self Micro-Emulsifying Drug Delivery Systems are isotropic solutions of oil and surfactant and/or Co-Surfactant,which forms o/w emulsion/Microemulsion as the case may be,on mild agitation in the presence of water. Reference: M. Jayne Lawrencea ,*, Gareth D. Reesb ,*Microemulsion-based media as novel drug delivery systems,Advanced Drug Delivery Reviews 45 (2000) 89-121. (http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T3R-41V29N8-8...)

Thanks for the question, Answer: For the treatment of eye diseases,drugs are essentially delivered topically. O/W microemulsions have been investigated for ocular administration to dissolve poorly soluble drugs to increase absorption and to attain prolong release profile. The microemulsions containing pilocarpine were formulated using lecithin, propylene glycol and PEG 200 as co-surfactant and IPM as the oil phase.The formulations were of low viscosity with a refractive index lending to ophthalmologic applications. Microemulsions can be sterilized by filtration and their production is relatively simple and inexpensive. Because of these properties, they have attracted a great interest as drug delivery vehicles (1,2). Microemulsions can be applied as liquid membrane carriers to transport lipophilic substances through an aqueous medium or to carry hydrophilic substances across lipoidal medium. Reference: 1.ANNA RADOMSKA-SOUKHAREV* and JOANNA WOJCIECHOWSKA,MICROEMULSIONS AS POTENTIAL OCULAR DRUG DELIVERY SYSTEMS: PHASE DIAGRAMS AND PHYSICAL PROPERTIES DEPENDING ON INGREDIENTS,Acta Poloniae Pharmaceutica n Drug Research, Vol. 62 No. 6 pp. 465n471, 2005 (http://www.ptfarm.pl/pub/File/wydawnictwa/acta_pol_2005/acta6_2005/pdf-y...) 2.Mrunali R. Patel,Microemulsions : As Novel Drug Delivery Vehicle (http://www.pharmainfo.net/reviews/microemulsions-novel-drug-delivery-veh...)

Thanks for the question, As in case of conventional emulsion,creaming and coalescence occurs,which are reversible and can be corrected by shaking or agitation. But in case of Microemulsion,it is not the case because better stabilization of the dispersed phase occurs due to addition of mixture of Surfactant & Co-Surfactant,so the chances of creaming and coalescence are negligible,so the need of providing direction "shake well before use" is not needed But it may be done depending on the other ingredients added. Thanks.

Thanks for the question. Following are the Emulsifying agents used. Surfactant: Polysorbate 80,soybean lecithin,polyoxyethylene surfactants such as Brij 35 (C E ) or a sugar esters such as sorbitan monooleate (Span 80),didodcecylammonium bromide,sodium bis-2-ethylhexylsulphosuccinate,Quaternary ammonium alkyl salts. Co-Surfactant: n-butanol,pentanol,hexanol,and other short chain alcohols.

Dear Harsh, As we know that in case of suspensions there is a high concentration of solids,so there always persists the problem of settling of particles and cake formation. But in case of Microemulsion and Emulsion there is no Settling of particles and Cake formation as there are no dispersed solid present and the surfactants and the drug(if present) are present in dissolved state in either water or oil phase.So there's surely no problem of caking. Thanks

1.Microemulsions are single optically isotropic because they are transparent in appearance.Optical isotropy means having the same optical properties in all directions. 2.Multiple emulsions are the type of emulsions where the emulsion formed is dispersed into large amount of the dispersed phase present in it. They are : W/O/W emulsions, O/W/O emulsions. In case of microemulsions,this type of systems are called as Bicontinuous Microemulsion. It also has the same type i.e. W/O/W microemulsions, O/W/O microemulsions. Hence,it can be said that multiple emulsions are modified type of emulsions & microemulsions.

1.Selection of Surfactant & Co-Surfactant. The selection of emulsifying agents is done on the basis of oils used and suitablity according to oil and drug used.The optimum concentration can be calculated using the ternary graph method or by using the CHEMIX software. 2.Reduction of Patient variability. As we know that microemulsions has high solubilizing capacity for drugs,hence it increases the bioavailability of drug and produces better tissue distribution and therefore reduces patient variablity. 3.Mechanism of Drug Release. A better drug release can be obtained in case of microemulsion as compared to simple emulsion due to inceased solubility of drugs. In case of lipophillic drugs,if the drug is present in dispersion medium (W/O Microemulsion) then fast release is obtained and if the drug is solubilised in dispersed phase (O/W Microemulsion) then sustained release can be obtained because the dispersed phase globule is surrounded by thick layer of emulsifying agents. In case of hydrophillic drugs,if the drug is present in dispersion medium (O/W Microemulsion) then fast release is obtained and if the drug is solubilised in dispersed phase (W/O Microemulsion) then sustained release can be obtained because the dispersed phase globule is surrounded by thick layer of emulsifying agents.

Thanks for the Question, As such there is no specific criteria for selection of aqueous phase. Only the proper proportion of oil and aqueous phase should be maintained. The proportion should be accurate. Thanks

Thanks for the question, Microemulsion is very easy to manufacture and there is no such specific equipments for the manufacture. A simple agitator or colloid mill can be used to manufacture the microemulsion. Thanks and Regards.

Thanks for the question, Generally cosolvents are not used in microemulsions because the co-surfactant used,itself is always short chain alcohol which itself can act as cosolvents. Thanks

Dear Pooja, In case of microemulsions,co-solvents are generally not used.The microemulsion system itself has high solubilising capacity.Although the co-surfactant added is a organic solvent(generally short chain alcohols are preferred) but it is added to act only as co-surfactant. Thanks

Dear Pooja, Its already described in the presentation. 1.Liquid dispersions of water and oil with Surfactant & Co-Surfactant 2.Thermodynamically Stable 3.Homogenous, transparent (or translucent) 4.Diameter of droplets :- 100-1000 A0 (10-100 nm) 5.High surface area & high solubilizing capabilities Reference: Mrunali R. Patel,Microemulsions : As Novel Drug Delivery Vehicle (http://www.pharmainfo.net/reviews/microemulsions-novel-drug-delivery-veh...)

Factors To Be Considered During Preparation Of Microemulsion Three important conditions: 1.Surfactants must be carefully chosen so that an ultra low interfacial tension (http://www.pharmainfo.net/reviews/microemulsions-novel-drug-delivery-veh...

Applications Of Microemulsions uParenteral delivery uOral drug delivery uTopical drug delivery uOcular and pulmonary delivery uMicroemulsions in biotechnology Thanks Reference: 1.M. Jayne Lawrencea ,*, Gareth D. Reesb ,*Microemulsion-based media as novel drug delivery systems,Advanced Drug Delivery Reviews 45 (2000) 89-121. (http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T3R-41V29N8-8...) 2.Mrunali R. Patel,Microemulsions : As Novel Drug Delivery Vehicle (http://www.pharmainfo.net/reviews/microemulsions-novel-drug-delivery-veh...)

Thanks for the question, As you said that according to size range microemulsion should be called as nanoemulsion,it is true because the size itself suggest that it is nano. The term can be used instead of microemulsion.But conventionally it is been called as microemulsion.So,it is a matter of thinking. Thanks and Regards. Abhishek Rathi