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18-12-20151Surfactant & polyphasic systemDepartment of Pharmacy (Pharmaceutics) | Sagar savaleMr. Sagar Kishor Savale[Department of Pharmacy (Pharmaceutics)]2015-016avengersagar16@gmail.com

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Contents1. Surfactant1.1 Function1.2 Classification1.3 Physicochemical Background1.4 HLB System2. Co-surfactant3. Oil 4. Phase Behavior4.1 Ternary phase diagram 4.2 Pseudo Ternary Phase Diagram 5. Micelle5.1 Micelle Formation5.2 Kraft Point And Cloud Point5.3 Types of Micelles5.4 Effect of Micellization on Physical Properties5.5 Factors Affecting CMC and Micellar Size5.6 Stability of Micelle5.7 Micellar Solubilization and Factors of Micelle Solubilization5.8 Pharmaceutical Application of Micellar Solubilization

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6. Self-emulsifying drug delivery systems (SEDDS)7. Self Micro-emulsifying Drug Delivery System (SMEDDS)8. Multiple emulsion9. Zeta potential10. References

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Surfactant & polyphasic system1. SurfactantThe molecules and ion are adsorbed at Interface kwon as Surfactant.1.1 Function To reduced interfacial tension , and surface tension.Surfactant is a surface active agent which are used to prevent surface tension and interfacial tension. It is important prevent interfacial fluidity, it is amphiphilic molecule having Hydrophilic head and Lipophilic tail. It is important for poorly water soluble drug and it is important to influencing water solubility of poorly water soluble drug. It is important to prevent the inter and intra subject variability.It act as solubilizing agent, suspending and emulsifying agent, stabilizing agent, wetting agent, detergent, Foaming agent.It is important for preparation of Nanoemulsion, Nanosuspension, Microemulsion.It is important to show antibacterial as well as antimicrobial activity.It is important for Novel drug delivery system, oral drug delivery system, Targeted drug delivery system.It is important to influencing oral bioavailability of poorly water soluble drug.

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1.2 Classification

Surfactant molecules may be classified based on the nature of the hydrophilic group within the molecule. The four main groups of surfactants aredefined as follows,Anionic surfactantsCationic surfactantsAmpholytic surfactantsNon ionic surfactants

1. Anionic Surfactants, where the hydrophilic group carries a negative charge such as carboxyl (RCOO-),sulphonate (RSO3-) or sulphate (ROSO3-).Examples: Potassium laurate, sodium lauryl sulphate.2: Cationic surfactants, where the hydrophilic group carries a positive charge.Example: quaternary ammonium halide.3: Ampholytic surfactants (also called zwitterionic surfactants) contain both a negative and a positive charge.Example: sulfobetaines.4. Non ionic surfactants, where the hydrophilic group carries no charge but derives its water solubility from highly polar groups such as hydroxyl or polyoxyethylene (OCH2CH2O).Examples: Sorbitan esters (Spans), polysorbates (Tweens).

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1.3 Physicochemical Background

cohesive forces between molecules down into liquidthe intermolecular attractive forces is called surface tension cohesive forces between molecules down into liquidthe intermolecular attractive forces is called surface tension18-12-20156

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1.4 HLB System

1.HLB value If high > more polar > more hydrophilic.E.g. polyoxyethylene derivatives

2.HLB value- If low > less polar > more lipophilic. E.g. sorbitan estersTypes of emulsion formation whether o/w or w/o depends on the emulsifying agents used.

O/W- HLB 9-12 surfactant Soluble in water

W/O HLB 3-6 surfactant Insoluble in water The hydrophilic-lipophilic balance of a surfactant is a measure of the degree to which it is hydrophilic or lipophilic, determined by calculating values for the different regions of the molecule, as described by Griffin in 1949[and 1954.[Other methods have been suggested, notably in 1957 by Davies.18-12-20157

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1. Griffins methodGriffins method for non-ionic surfactants as described in1954 works as follows:HLB = 20 Mh/Mwhere Mh is the molecular mass of the hydrophilic portionof the molecule, and M is the molecular mass ofthe whole molecule, giving a result on a scale of 0 to An HLB value of 0 corresponds to a completelylipophilic/hydrophobic molecule, and a value of 20 corresponds to a completely hydrophilic/lipophobic molecule.The HLB value can be used to predict the surfactant properties of a molecule: < 10 : Lipid-soluble (water-insoluble) > 10 : Water-soluble (lipid-insoluble) 1.5 to 3: anti-foaming agent. 3 to 6: W/O (water in oil) emulsifier. 7 to 9: wetting and spreading agent.13 to 15: detergent.12 to 16: O/W (oil in water) emulsifier.15 to 18: solubilizers or hydrotropic.

2. Davies methodIn 1957, Davies suggested a method based on calculatinga value based on the chemical groups of the molecule.The advantage of this method is that it takes into accountthe effect of stronger and weaker hydrophilic groups. Themethod works as follows:HLB = 7 +mi=1 Hi n 0:475where:m - Number of hydrophilic groups in the moleculeHi - Value of the i the hydrophilic groups (see tables)n - Number of lipophilic groups in the molecule

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Aim of HLB Griffins Scale

Although the HLB approach is empirical, it does allow comparison between different chemical types of surfactants. Besides that, it provides a systematic method of selecting mixtures of emulsifying agents to produce physically stable emulsions. The higher surfactant HLB value, the more hydrophilic it is. The lower surfactant HLB value, the more lipophilic it is .

Determination of the Required HLB values and Blending of Surfactants

Oils used in the formulation of emulsions require a certain HLB value to be formulated as w/o emulsion or o/w emulsion.

For the same oil, the required HLB value for O/W emulsion is higher than the required HLB value for W/O emulsion.

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Calculation of the required HLB for a mixture of oils, fats or waxes 1. Multiply the required HLB of each ingredient by its fraction from the total oily phase. 2.Add the obtained values to get the total required HLB for the whole oily phase.

ExampleLiquid paraffin 35% Wool fat 1 % Cetyl alcohol 1% Emulsifier system 7% Water to 100% Solution The total percentage of the oily phase is 37 and the proportion of each is: Liquid paraffin 35/37 x 100 = 94.6% Wool fat 1/37 x 100 = 2.7% Cetyl alcohol 1/37 x 100 = 2.7% The total required HLB number is obtained as follows: Liquid paraffin (HLB 10.5) 94.6/100 X 10.5 = 9.93 Wool fat (HLB 10) 2.7/100 x 10 = 0.3 Cetyl alcohol (HLB 15) 2.7/100 X 15 = 0.4 Total required HLB = 10.63 18-12-201511

Calculation of ratio of emulsifier to produce a particular required HLB value

One of the most important aspects of the HLB system is that HLB values are additive if the amount of each in a blend is taken into account. Thus, blends of high and low HLB surfactants can be used to obtain the required HLB of an oil. The HLB of the mixture of surfactants, consisting of fraction x of A and (1-x) of B is assumed to be the algebraic mean of the two HLB numbers, i.e.:

HLB mixture = x HLBA + (1-x) HLBB

Rearrangement the above equation in percent (%) form will be

A = 100 (X-HLBB) / (HLBA HLBB) B = 100 A Where X is the required HLB of the surfactant (oil) mixture 18-12-201512

Worked example A formulator is required to formulate an o/w emulsion of the basic formula: Liquid paraffin 50 g Emulsifying agents (required HLB 10.5) 5 g Water to 100 g Calculate the fraction of Tween 80 (HLB of 15) and Span 80 (HLB of 4.3) used to produce a physically stable liquid paraffin emulsion. Solution Assume that Tween 80 is A and Span 80 is B. So, A = 100 (x-HLBB) / (HLBA-HLBB) = 100 (10.5-4.3) / (15-4.3) = 57.9% B = 100 A = 100- 57.9 = 42.1 % A = 57.9 5100 = 2.89 g B = 5 2.89 = 2.11 g 18-12-201513

2. Co-surfactantFor the production of an optimum SMEDDS, high concentration of surfactant is required in order to reduce interfacial tension sufficiently, which can be harmful, so co-surfactants are used to reduce the concentration of surfactants. Co-surfactants together with the surfactants provide the sufficient flexibility to interfacial film to take up different curvatures required to form micro-emulsion over a wide range of composition. Selection of proper surfactant and co-surfactant is necessary for the efficient design of SMEDDS and for the solubilization of drug in the SMEDDS. generally co-surfactant of HLB value is used. such as hexanol, pentanol and octanol which are known to reduce the oil water interface 3. Oil The oil represents the most important excipient in the SMEDDS formulation. it can solubilize the amount of the poorly water soluble drug. Both long-chain triglyceride (LCT) and medium chain triglyceride (MCT) oils with different degrees of saturation have been used in the design of SMEDDS.

It can not only solubilize large amount of lipophilic drugs or facilitate self-emulsification but also enhance the fraction of lipophilic drug transported via intestinal lymphatic system, there by increase its absorption from GIT. E.g. - Corn oil, olive oil, soybean oil, hydrolysed corn oil. 18-12-201514

Examples18-12-201515

4. Phase Behavior4.1 Ternary phase diagram

WINSOR PHASE :- WI , WII , WIII , WIV

O :- Oil W:- Water

L1:- A single phase region of normal micelles or oil in water micro emulsion.

L2:- A reverse micelles or water in oil micro emulsion.

D :- Anisotropic lamellar liquid crystalline phase

E:- Microemulsion. 18-12-201516

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In this diagram a corner will represent the binary mixture of two components such as surfactant/co-surfactant, water/drug or oil/drug.At low concentration of surfactant there are certain phases exists in equilibrium. These phases are referred to as WINSOR PHASES .

WINSOR-1 :- With two phases, the lower (o/w) microemulsion phase in equilibrium with excess oil.

WINSOR-2 :- With two phases, upper (w/o) microemulsion phase in equilibrium with excess water.

WINSOR-3 :- With three phases, middle microemulsion phase (o/w plus w/o, called bio-continuous) in equilibrium with upper excess oil and lower excess water.

WINSOR-4 :- In single phase, with oil, water, and surfactant homogenously mixed.

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4.2 Pseudo Ternary Phase Diagram

These diagrams were constructed with oil, surfactant/co-surfactant and water using Phase Titration method. The procedure consisted of preparing solutions Containing oil and the different ratio of surfactant to co-surfactant by weight such as: 1:1, 2;1, 3:1 etc, these solutions then vortexed for 5 min and isotropic mixture was obtained. observed for their appearance (turbid or clear). Turbidity of the samples would indicate formation of a coarse emulsion, whereas a clear isotropic solution would indicate the formation of a microemulsion. Percentage of oil, smix and water. the values were used to prepare Pseudo ternary phase diagram. 18-12-201518

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5. MicelleDefinitionThe aggregation of monomers i.e. SAA in given solvent at particular temp. is known as MICELLE. Each micelle may contains around 50 or more monomers in its structure and size may be about 50 A. This 50 A size is falls into colloidal range and hence micelle called alternatively as Association colloids.Critical Micelle ConcentrationThe concentration of monomer at which the micelles are start to form in solvent at particular temperature. Micelles form only when the concentration of surfactant is greater than the critical micelle concentration (CMC). The no. of monomers that aggregate to form micelle is known as Aggregation No. of micelle.The Lowest concentration of surfactant at which micelle is from is known as CMC.5.1 Micelle FormationThe process of formation of micelle is known as micellization. Below CMC, the conc. of SAA adsorbed at interface of air and liquid and the exist individually. As the conc of SAA is incresed the monomers gets saturated at surface, further addition leads saturation of bulk of solution. After saturation of surface and bulk of solution, the monomers start to aggregate at this level the conc of SAA is reached to CMC. Further addition enhance the process of micelle formation. 18-12-201522

Fig-Process of Formation of Micelles Micelle are not stable aggregate but dissociate ,regroup and reassocaiate. For e.g.-half life of Ionic surfactants is only a small fraction of second.18-12-201523

5.2 Kraft Point And Cloud PointKraft PointThe solubility of SAA depends on the temp. of system and adequate conc. of SAA is required to form micelle, this relationship is stated by Kraft Pt. Kt is defined as the temp at which the solubility of surfactants is equal to CMC.At Kt, conc. of surfactants is sufficient to form micelle. It is seen that micelles are more soluble in water than monomers.Cloud PointAt a particular temp and pressure the solubilized micelles gets separated out as a distinct phase which leads to appearance of cloudy solution, this is known as cloud pt.Procedure for determination of Cloud Point and Kraft pointPrepare 100 ml of 1 to 10 % aqueous solution containing nonionic surfactant (Triton X-45). Take 10 ml above solution in a test tube and either heat or cool with a temperature range of 0.5 to 1 C in every time. Stabilize the solution for 2 minutes to achieve thermal equilibrium. Continue the process of either heating or cooling till you observe cloudiness or turbidity.18-12-201524

Cloud point (Cp) is determined visually by noting the temperature at which turbidity is observed or disappeared. The average of the temperatures of appearance and disappearance of turbidity is taken as the cloud point.While for an aqueous solution containing dispersible nonionic surfactant, such as dispersible Triton X-45 in water under room temperature, only the temperature of cloudy disappearance is taken as Kraft point.Applications/Significance/Importance of Cloud point (Cp):Knowing the cloud point helps us to determine the storage stability since storing formulations at temperatures significantly higher than the cloud point may result in phase separation and instability.The cloud point of petroleum products and biodiesel fuels is an index of the lowest temperature of their utility for certain applications. Wax crystals of sufficient quantity can plug filters used in some fuel systems.For low-foam applications, the cloud point of the product should be just below the use temperature.Cloud point extraction is used for determination of pyrene in natural water.For determining of the Nickel and Zinc through the cloud point preconcentration.For finding out the lead from the water samples by using cloud point extraction flow injection-atomic absorption.

Applications/Significance/Importance of Kraft point (Kt):Below Kraft point, mere increase in the concentration of the surfactant, micelle formation does not occur. Below the Kraft point, an increase in the concentration of the surfactant leads to precipitation rather than micelle formation in the form of insoluble mass. 18-12-201525

The solubility of the surfactant goes on increasing with increase in temperature, however, above the Kraft point; there is the sudden increase in the solubility of the surfactant. This gives break in the plot of the solubility of the surfactant Vs temperature. The temperature corresponding to the break is the Kraft temperature or point. It may be mentioned here that the Kraft point varies with the pH of the solution as well as the ionic strength of the solution.5.3 TYPES OF MICELLES1. Spherical Micelle- In this type the Hydrophobic Tails oriented towards inner core and Hydrophilic heads towards polar solvents. Ex. - Micelle in water

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2. Reverse Micelle - In this case Hydrophobic tails oriented towards non-polar solvent phase and head portion towards the inner core Ex. - micelle formation in oil and water.

3. Laminar Micelle - Spherical and laminar micelle are inter convertible. In this type of micelle arrangement of monomer is in a laminar manner. Laminar micelle form at higher conc., initially micelles are of spherical type, but as conc. increases towards higher side leads to formation of Laminar micelle.18-12-201527

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Polymeric Micelle

Chemicals which have an amphiphilic nature (hydrophilic and hydrophobic portions) inherently have the capacity to form micelles in aqueous solution. Micelles are generated when the hydrophobic portions are driven to an interior structure while hydrophilic portions are turned outward facing toward the water.Most PolyVivo block copolymer products are inherently amphiphilic as they contain both hydrophobic polyester blocks (PL) and hydrophilic poly(ethylene glycol) blocks (PEG).5.4 Effect of Micellization on Physical Properties

Surface Tension - Below CMC the S.T decreases by Surfactant, however above CMC the further addition of surfactants doesnt affect S.T reduction.Interfacial Tension - Similarly interfacial tension markly reduce below CMC but no affecting the I.T above CMC.Equivalent Conductivity - is slightly decreased unto CMC and above it rapidly reduced to 0 value.Solubility enhancement of poorly Water soluble drugs-below CMC there is little increased in solubility, but above CMC there is rapidly increased in solubility of poorly water soluble drugs.

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1. At very low concentrations of surfactant only slight change in surface tension is detected.2. Additional surfactant decreases surface tension3.Surface becomes fully loaded, no further change in surface tension.18-12-201532

18-12-2015335.5 Factors Affecting CMC and Micellar SizeStructure of hydrophobic group: Increase in hydrocarbon chain length causes decrease in CMC and increase in micellar size.Nature of hydrophilic group: Increase in chain length increases hydrophilicity and CMC.Nature of counter ions: The counter ions associated with charged group of ionic surfactants has a significant effect on micellar properties. Cationic surfactants - counter ion like Cl-, Br- leads to increase in micellar size. Anionic surfactants Na+, k+ leads to increase in micellar size. Addition of electrolyte: Addition of electrolytes to ionic surfactants decreases CMC and increases the micellar size. This is due to reduction in repulsion between charged head group of micelle.Addition of non-electrolyte: Addition of compounds like water soluble raises the CMC and decreases micelle formation.Effect of temperature: Mainly micelles of nonionic surfactants are get affected. As an increase in temperature up to cloud point, an increase in micellar size and a decrease in CMC.5.6 Stability of MicelleWhen dilute solution to below the CMC, some ionic micelles shown to have half-life of a centisecond or less.Micelle stability is slightly increased by an increase in alkyl chain length and affected small extent by the nature of the counter-ion. Traces of hydrocarbon dissolved in the micelle interior appear to reduce the rate of micelle breakdown.Micelle stability increases with increasing concentration of amphipath above the CMC but decreases with increasing temperature.

18-12-2015345.7 Micellar Solubilization and Factors of Micelle SolubilizationMicelles can be used to increase the solubility of materials that are insoluble or poorly soluble in the dispersion medium used. This phenomenon is known as Solubilization.The solubilized substance is referred to the solubilizate.Nature of Surfactant: If solubilizate is located within the core or deep within micelle solubilization capacity increases with increase in alkyl chain length. E.g. Barbiturates: Polysorbate 20 (C12) to Polysorbate 80 (C18) Nature of Solubilizate: Non polar solubilizate are dissolved in micellar core and polar solubilizate orient themselves towards the surface of micelles. Hydrophobic drugs solubilized in micelle core, as an increase in Lipophilic chain length of surfactant and as the length increases, there is increase in micellar size and increases entry of drug into micelle. Effect of temperature: In general, the amount of solubilized increase with a rise in temperature. E.g. Increase in solubilization of Griseofulvin by surfactant like sodium cholate, sodium deoxycholate.Effect of pH: Main effect of pH on solubilizing power of nonionic surfactants is to alter the equilibrium between ionized and un-ionized drugs. E.g. for simple molecule, the unionized form is more solubilized.5.8 Pharmaceutical Application of Micellar SolubilizationPhenolic compounds, such as chloroxylenol, cresol are solubilized with soap to form clear solutions for use as disinfectants.Solubility of steroids is increased using the polysorbates for ophthalmic formulations.Aqueous injections of water-insoluble vitamins like A, D, E and K are prepared using nonionic surfactants like polysorbates.Nonionic surfactants are also efficient solubilizers of iodine.Polymeric micelle is used to target the cancerous tumor site.

18-12-2015356. Self-emulsifying drug delivery systems (SEDDS) Self-emulsifying drug delivery systems (SEDDS) are defined as isotropic mixtures of oils and surfactant. SEDDS are solid dosage form with a unique properties that is they are able to self emulsifying rapidly into fine of o/w emulsion result in small droplet of oil dispersed in GI fluid that provide a large interfacial area enhancing the activity and minimizing the irritation .6.1 AdvantageEnhanced oral bioavailabilitySelective targeting of drug(s) toward specific absorption in GIT.Protection of drug(s) from the hostile environment .Reduced variability including food effects.Protective of sensitive drug substances.

18-12-2015366.2 Drawback SEDDSLack of good predicative in vitro models for assessment of the formulations. The large quantity of surfactant use in self-emulsifying formulations (30-60%) irritatesVolatile co-solvents can migrate on capsule shell.

6.3 Components of SEDDSsDrug (API)SurfactantOil [Reference of data slide no. 4 to 15]6.4 Mechanism of self emulsificationThe free energy of the conventional emulsion is a direct function of the energy required to create a new surface between the oil and water phasesIn emulsification process the free energy (G) associated is given by the equation:

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18-12-2015376.5 General formulation ApproachPreliminary solubility profiling studies are performed for selection of oil.Drug excipient compatibility studies.Preparation of a series of SEDDS system containing drug in various oil and surfactant with different combinations.Optimization of formulation on the basis of in vitro self-emulsification properties, droplet size analysis, stability studies, robustness to dilution upon addition to water under mild agitation conditions.6.7 Evaluation of SEDDSDispersibility testTurbidimetric EvaluationViscosity DeterminationDroplet Size Analysis and Particlesize measurement Electro Conductivity StudyDrug Content

18-12-2015386.8 ApplicationSelfemulsifying drug delivery systems are a promising approach for the formulation of drug compounds with poor aqueous solubility. The oral delivery of hydrophobic drugs can be made possible by SEDDSs, which have been shown to substantially improve oral bioavailability. With future development of this technology, SEDDSs will continue to enable novel applications in drug delivery and solve problems associated with the delivery of poorly soluble drugs.7. Self Micro-emulsifying Drug Delivery System (SMEDDS)SMEDDS is an isotropic mixture of oil, surfactant, Cosurfactant and drug.

Upon mild agitation followed by dilution in aqueous media, such as gastrointestinal (GI) fluids, the systems can form fine oil in water (O/W) Microemulsions which usually have a droplet size less than 100 nm.

Self-microemulsifying drug delivery systems (SMEDDS) have been successfully used to improve the solubility, chemical stability, and oral bioavailability of many poorly water soluble drugs.

They have characteristic properties such as a low interfacial tension, large interfacial area and capacity to solubilize both aqueous and oil-soluble compounds.

18-12-2015397.1 HistoryThe Microemulsion concept was introduced as early as 1940s by Hoar and Schulman who generated a clear single-phase solution by titrating a milky emulsion with hexanol. Schulman and co-worker (1959) subsequently coined the term microemulsion The Microemulsion definition provided by Danielson and Lindman in 1981 will be used as the point of reference. 7.2 Difference between SEDDS And SMEDDSSr.no. SEDDS SMEDDS1It is a mixture of Oil, Surfactant and DrugIt is a mixture of Oil, Surfactant, Co-surfactant and Drug2Droplet size is 100 300 nmDroplet size is less than 100 nm3It is a Turbid in natureIt is Transparent in nature4It is Thermodynamically not StableIt is Thermodynamically Stable5Ternary Phase Diagrams are used to optimizedPseudo Ternary Phase Diagrams are used to optimized

18-12-2015407.3 Advantages Enhanced oral bioavailability and stability of drugs which show low bioavailability.Reduction of inter-subject and intra subject variation.Ease of manufacturing and scale up. Less amount of energy requirement.Ability to deliver peptides that are prone to Enzymatic hydrolysis in GIT.SMEDDS are used for both liquid and solid dosage forms.Useful in topical application.7.4 DisadvantagesOne of the obstacles for the development of SMEDDS is the lack of good predicative in vitro models for assessment of the formulations and Traditional dissolution methods do not work.The drawbacks of this system include chemical instabilities of drugs and high surfactant concentrations in formulations.7.5 Components of SMEDDSDrug (API)SurfactantOil Co-surfactantCo-solvent[Reference of data slide no. 4 to 15]

18-12-2015417.6 Preparation of SMEDDSDrug has to dissolve in to oil phase (lipophilic part) of microemulsion.Water phase is combined with the surfactant and then Cosurfactant is added slowly with constant stirring until the system is become transparent.The amount of surfactant and co-surfactant to be added and the parent oil phase that can be incorporated is determined with the help of pseudo ternary phase diagram. 7.8 Mechanism of SMEDDS Self-Microemulsification occurs when the entropy change that favours dispersion is greater than the energy required to increase the surface area of the dispersion. So, The free energy of the conventional emulsion is a direct function of the energy required to create a new surface between the oil and water phases.In emulsification process the free energy (G) associated is given by the equation:

where, G = free energy associated with the process N = number of dropletsr = Radius of droplets = interfacial energyThe two phases of emulsion tend to separate with time to reduce the interfacial area, and subsequently, the emulsion is stabilized by emulsifying agents.

18-12-2015427.9 Evaluations of SMEDDS Scattering TechniqueFourier transform-infrared spectroscopy (FT-IR)Transmittance (U.V.)Viscosity DeterminationElectro Conductivity Study Macroscopic evaluationDifferential scanning Colariometry (DSC)Droplet Size Analysis and Particle Size MeasurementsStability Testing Evaluation 7.10 Applications of SMEDDSOral bioavailability enhancement poorly water soluble drugs Protection against Biodegradation Solid SMEDDSSupersaturable (S-SMEDDS)Ocular Drug delivery SystemParenteral Drug Delivery SystemTopical Drug Delivery

18-12-2015438. Multiple emulsion8.1 IntroductionEmulsion - it is a biphasic liquid dosage from of medicament in which two immiscible phases of liquid one can dispersed in finite globules in another liquid phase is known as Emulsion.Multiple Emulsion it is biphasic liquid dosage from of medicament in which two or more and more than two immiscible phases of liquid one can dispersed in finite globules in another liquid phase is known as Multi emulsion. It is a Emulsion of emulsion, double or triple emulsion Dispersed phase contain smaller droplets that have the same composition as the external phase. Liquid film which separate the liquid phases acts as a thin semi permeable film through which solute must diffuse in order to travel from one phase to another Liquid Membrane System. 8.2 Types There are divided in two typesOil-in-water-in-oil (O/W/O) emulsion system.Water-in-oil-in-water (W/O/W) emulsion system.

18-12-2015448.3 Methods of preparationEither by the re-emulsification of a primary emulsion or they can be produced when an emulsion inverts from one type to another.Two Step Emulsification (Double Emulsification)Phase Inversion Technique (One Step Technique)Membrane Emulsification TechniqueTwo Step Emulsification: - (Double Emulsification)

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18-12-201546Membrane Emulsification Technique

18-12-2015478.4 characterizationAverage globule size & size distribution

Area of interfaces

Rheological evaluation

Percent drug entrapment8.5 Stability of Multiple EmulsionDepending upon equilibrium between water, oil and surfactant.Unfortunately multiple emulsion are thermodynamically unstable.Possible indication of instability include:Leakage of the contents from the inner aqueous phasesRupture of oil layer on the surface of the internal droplet i. e. expulsion of internal droplet in external phase.Shrinkage and swelling of the internal drops due to osmotic gradient across the oil membranePhase separation

18-12-2015488.6 Methods to stabilize multiple emulsionLiquid crystal stabilized multiple emulsionStabilization in the presence of electrolytesStabilization by forming polymeric gel

A B C

18-12-2015498.7 ApplicationControlled and Sustained Drug Delivery

Drug Targeting

Vaccine Adjuvant

Cosmetics preparation

Taste masking of the drug

18-12-2015509. Zeta potentialZeta potential is a scientific term for electro kinetic potential in colloidal dispersions.

It is usually denoted using the Greek letter zeta (), hence - potential.

The electric potential at the boundary of the double layer is known as the Zeta potential of the this particles and has values that typically range from +100 mV to -100 mV. Zeta potential: It is the potential observed at the shear plane.Zeta potential or electro-kinetic potential is defined as the difference in the potential between shear plane and electro-neutral region of lotion the solution.Zeta potential is more important than Nernst potential because the electrical double layer also moves, when the particle is under motion.

18-12-201551Nernst potential: It is the potential of the solid surface itself owing to the presence of potential determining ions.Nernst potential or electro thermodynamic potential is defined as the difference in potential between the actual surface and the electro neutral region of the solution.

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18-12-2015539.1 Factors affecting zeta potentialpH : In aqueous media, the pH of the sample is one of the most important factors that affects its zeta potential. zeta potential versus pH curve will be positive at low pH and negative at high pH. There may be a point where the plot passes through zero zeta potential. This point is called isoelectric point and is very important from a practical consideration.Thickness of double layer: The thickness of the double layer depends upon the concentration of ions in solution and can be calculated from the ionic strength of the medium The higher the ionic strength, the more compressed the double layer becomes. The valiancy of the ions will also influence double layer thickness.

18-12-2015549.2 Zeta Potential MeasurementZeta potential is not directly measurable, it can be calculated using theoretical models like electro kinetic phenomena and electroacoustic phenomena.Electro kinetic Phenomena:Electrophoresis: The movement of charged particle relative to the liquid it is suspended in under the influence of an electric field.

Zeta potential of dispersion is measured by applying an electric field across the dispersion. Particles within the dispersion with a zeta potential will migrate towards the electrode of opposite charge with a velocity proportional to the magnitude of the zeta potential.The velocity of a particle in a unit electric field is referred to as its electrophoretic mobility. Zeta potential is related to the electrophoretic mobility by the Henry equation

18-12-2015559.3 Henry equationUE = 2 z f(a)/3

Where: UE = electrophoretic mobility, z = zeta potential, = dielectric constant, = viscosity f(a) = Henrys function.

18-12-201556Electroacoustic phenomena: The electroacoustic technique characterizes the dynamic mobility of particles in colloidal systems.In this method, a high frequency electric field is applied to the samples, causing charged particles to oscillate and to produce a sound wave of the same frequency.The oscillation (dynamic mobility) of the particles is described by its magnitude and phase angle. The sound wave is detected and analyzed to determine the motion of the particles.9.4 DLVO TheoryThe scientists Derjaguin, Landau, Verwey and Overbeek developed a theory in the 1940s which dealt with the stability of colloidal systems.DVLO theory suggests that, the stability of a colloidal system is determined by the sum of the vander Waals attractive (VA) and electrical double layer repulsive (VR) forces that exist between particles as they approach each other due to the Brownian motion they are undergoing.The vander waal forces depend on chemical nature and size of particle. The electrostatic repulsive forces depend on density, surface charge and thickness of double layer.

18-12-2015579.5 Methods for stabilizing colloidsStability can be obtained by surrounding colloidal particle with:An electrical double layer (electrostatic or charge stabilization).Adsorbed or chemically attached polymeric molecules (steric stabilization).9.6 ApplicationFlocculate SuspensionEmulsionCeramicsWaste water

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18-12-201559Patel PA, Chaulang GM, Akolkotkar A, Mutha SS, Handicap SR and Bhosale AV. Self Emulsifying Drug Delivery System: A Review Research J. Pharm. And Tech. 2008; 1(4): 313-323. T. Gershanik and S. Benita, "Positively-charged self-emulsifying oil formulation for improving oral bioavailability of progesterone," Pharm. Dev. Technol. 1, 147157 (1996). Vyas S.P. and Khar R.K., Targeted and controlled Drug Delivery, Novel Carrier System, CBS Publishers and Distributers PVT. Ltd., New Delhi,First Edition, 2002, P.P.280-303.Weiner M,B ernstin IL Advance Reaction to drug formulation Agents. New York; Marcel Dekker, Inc, 1989Kawakami, K. and Yoshikawa, T. Microemulsion formulation for enhanced absorption of poorly soluble drug I Prescription design. Journal of Controlled Release; 2002; 81; 65-74. Lawrence, M. J. and Rees, G. D. Microemulsion-based media as novel drug delivery systems. Adv. Drug Delivery Rev.; 2000; 45; 89-121.Nishad Deshmukh, Vesicular and Particulate Drug Delivery Systems, CAREER Publications, First Edition March 2010, P.P.105-140. Kumar, P. and Mital, K. L. Handbook of microemulsion:Science and Technology. Marcel Dekker, New York, Basel; 1999. Ozawa, K.; Olsson, U. and Cawes, A. Oil-induced structural change in nonionic microemulsions. Journal of Dispersion Science and Technology; 1986; 22(1); 119-124. Kanchan Kohali, Sunny Chopra ,Deepika Dhar , Saurabh Arora ; Self-Emulsifying Drug Delivery Systems: An Approach To Enhance Oral Bioavailability. J Drug Discovery Today : 2010; 15;960.L.chia li,Y.tian,(2012) Encyclopedia of Pharmacetical Technology. 2nd edition.Volume-3.Marcel Dekk Series,page.no.3020-3031.Malvern (2010) User Manual of Zetasizer Nano. MANO317-5.0, United Kingdom,Page.No.15.1-15.12

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