Emulsions

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EMULSIONSEMULSIONS

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EMULSIONSEMULSIONS

• Definition • Classification• Applications• Theory of emulsification• Additives for formulation of emulsion• Formulation of emulsions• Emulsification techniques• Stability of emulsions• Evaluation of emulsions

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What is an emulsion ??What is an emulsion ??An emulsion is a thermodynamically unstable

system consisting of at least two immiscible liquid phases one of which is dispersed as globules in the other liquid phase stabilized by a third substance called emulsifying agent.

The droplet phase is called the dispersed phase or internal phase and the liquid in which droplets are dispersed is called the external (continuous phase).

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EmulsionsEmulsions

A C B

A.: Two immiscible liquids not emulsified

B. An emulsion of phase B dispersed in Phase A

C. Unstable emulsion slowly separates.

Phase A

Phase B

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Types of emulsionsTypes of emulsions

Simple emulsions (Macro emulsions)

• Oil-in-water (O/W)

• Water-in-oil (W/O)Multiple emulsions

• Oil-in-water-in-oil (O/W/O)

• Water-in-oil-in-water (W/O/W)Micro emulsions

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• 1. Macroemulsions (Simple Emulsions) :

• i. Oil in water (o/w) : Oil droplets are dispersed in a continuous aqueous phase. a hydrophilic emulsifier is used. These are preferred for oral/ IV administration and cosmetics . These are useful as water washable drug bases.

• ii. Water in oil (w/o) : Aqueous droplets are dispersed in continuous oily phase. . a lipophillic emulsifier is used. These are used for cosmetics. The are employed for treatment of dry skin and emollient applications.

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• 2. Multiple emulsions : • They are developed with a view to delay the release of an

active ingredient. They have three phases. They may be oil-in-water-in-oil (o/w/o) or of water-in-oil-in-water (w/o/w). An emulsifier is present to stabilize the emulsions and various ionic and nonionic surfactants are available for this purpose. Lipophilic (oil-soluble, low HLB) surfactants are used to stabilize w/o emulsions, whereas hydrophilic (water-soluble, high HLB) surfactants are used to stabilize o/w systems In these emulsions within emulsions any drug present in innermost phase must now cross two phase boundaries to reach the external continuous phase.

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• Preparation of multiple emulsions :

• Aqueous phase is added to oily phase, containing a lipophilic surfactant. Upon mixing a w/o emulsion is formed.

• This w/o emulsion is then poured into a second aqueous solution , containing a hydrophilic surfactant. Upon mixing multiple emulsion w/o/w is formed.

• Types of multiple emulsions : w/o/w , o/w/o

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Types of emulsionsTypes of emulsions

w/o/w o/w/o

Multiple emulsions

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• 3. Microemulsions: ( diameter <0.1 um)

• They may be defined as dispersions of insoluble liquids in a second liquid that appears clear and homogenous to the naked eye.

• They are frequently called solubilized systems because on a macroscopic basis they seem to behave as true solutions.

• They are used for both internal and external formulations and show better bioavailability than conventional emulsions.

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MicroemulsionsMicroemulsions• Microemulsions are thermodynamically stable

optically transparent , mixtures of a biphasic oil –water system stabilized with surfactants.

Microemulsion Emulsion

Transparent Yes No

Size < 0.1 µ 0.1 – 100 µ

Formation Easily dispersed Require vigorous shaking

Stability Thermodynamically stable

Thermodynamically unstable

Viscosity Less viscous More viscous

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Factors affecting type of Factors affecting type of emulsionemulsion

Type of emulsifying agent usedPhase volume ratioViscosity of each phase

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Pharmaceutical Applications of Pharmaceutical Applications of emulsionsemulsions

• Oral products It covers the unpleasant taste Increases absorption rate

• Parenteral use emulsion i/v nutrients i/m – depot effect

• Topical use : Washable Acceptable viscosity Less greasy

Moisturizer/emollient

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Theory of emulsification Theory of emulsification

Droplets can be stabilized by three methods

i. Surface tension theory

ii. Oriented- wedge theory

iii. Plastic film theory

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Emulsifying agentsEmulsifying agents

• Added to an emulsion to prevent the coalescence of the globules of the dispersed phase.

• Help in emulsion formation by Reduction in interfacial tension – thermodynamic

stabilization Formation of a rigid interfacial film – mechanical

barrier to coalescence

http://www.pharmpedia.com/Emulsion

http://www.pharmpedia.com/Dispersed_phase

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Classification of emulsifying Classification of emulsifying agentsagents

• Synthetic

• Surface active agents ( Monomolecular films)

• Semi synthetic and natural

• Hydrophilic colloids ( Multimolecular films)

• Finely divided solid particles ( Particulate film)

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Synthetic surface active agentsSynthetic surface active agents

Description :

• Reduce interfacial tension and make the emulsion thermodynamically more stable.

• Form protective monomolecular film

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Synthetic surface active agents Synthetic surface active agents Monomolecular adsorptionMonomolecular adsorption

Oil

Rule of Bancroft : Type of emulsion is a function of relative solubility of surfactant . The phase in which it is soluble becomes the continuous

phase

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Combination of emulsifying agents

Oil

Sodium cetyl sulphate

Cholesterol

Combination of emulsifying agents at the interface of oil and water.

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Classification of Classification of SurfactantSurfactant emulsifying agents emulsifying agents

Synthetic (Surfactants) ( Monomolecular films)

Anionic Soaps -Mono valent -Polyvalent -Organic Sulphates Sulphonates (CH3(CH2)n CH2SO3 – Na+)

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Classification of Classification of SurfactantSurfactant emulsifying agentsemulsifying agents

Synthetic (Surfactants) ( Monomolecular films) Cationic Quaternary ammonium compounds Nonionic Glyceryl esters Sorbitan fatty acid esters Polyoxyethylene polyoxypopylene esters (Macrogels) Polyoxyethylene derivatives of sorbitan fatty acid esters

(polysorbate)

• Anionic surfactants• Soaps• 1) Monovalent• E.g. potassium, sodium, ammonium salts of oleic acid .

They are soluble in water and are good o/w emulsifying agents.

• Disadvantages :

• They are irritating to the GIT.. So they are useful only for external use emulsions.

• They have a high pH, so cannot be applied on broken skin.

• Anionic surfactants• Soaps• 2) Polyvalent • The calcium, magnesium and aluminum salts of fatty

acids ( metallic soaps) are water insoluble and give w/o emulsion.

• 3) Organic Soaps• Triethanol amine soaps of fatty acids give o/w emulsion.

• They are used for external use emulsions. They are less alkaline as compare to monovalent/polyvalent soaps so they can be used on broken skin.

• Anionic surfactants• Sulphates • They are neutralized esters of sulphuric acid and fatty

alcohols. Poor o/w E.A if used alone. They can be used as auxiliary emulsifying agents. E.g Sodium lauryl sulphate

• Sulfonates• Large group of surfactants used as detergents and

wetting agent• Very rarely used in pharmaceutical preparations.

• Cationic surfactants• They are mainly used in external preparations.

Quaternary ammonium compounds such as cetrimide, benzalkonium chloride and benzethonium chloride are examples of important cationic surfactants.

• These compounds besides having good antibacterial activity are used in combination with secondary emulsifying agents to produce o/w emulsions for external application.

• Cetrmide emulsifying wax ( 10% cetrimide + 90% cetosterylalcohol) produces a stable emulsion

– NON IONIC surfactants

• They are the class of surfactants widely used as emulsifying agents.

• They are extensively used to produce both o/w and w/o emulsions for internal as well as external use.

http://www.pharmpedia.com/Surfactant?action=edit

– NON IONIC surfactants

• Advantages : They are not effected by pH change and presence of electrolytes.

• They also show low irritancy as compared to other surfactants.

• Most commonly used nonionics are • glyceryl esters (auxillary E.A)• sorbitan fatty acid esters (spans) w/o• polyoxyethylene derivatives of sorbitan fatty acid esters

(Tweens or polysorbates) o/w• Polyoxyethylene / polyoxypropylene block polymers

(Macrogol) o/w emulsions used for IV

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Classification of Classification of HydrocolloidHydrocolloid emulsifying agentsemulsifying agents

SemisyntheticNatural

• Plant origin

• Animal origin

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Hydrocolloid Emulsifying agentsHydrocolloid Emulsifying agents

Description

- Provide a protective sheath (Multimolecular films )around the droplets

- Swell to increase the viscosity of the system ( so that droplets are less likely to change.)

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Semi synthetic ( Multi molecular films) Methyl cellulose Carboxy methyl cellulose

. They are used for formulating o/w type of emulsions. They primarily act by increasing the viscosity of the system.

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Natural (Multimolecular films)

From plant origin Polysaccharides ( Acacia, tragacanth, agar, pectin,

lecithin) o/w emulsions.

From animal origin Proteins ( Gelatin) o/w emulsions. Lecithin, o/w i/v emulsion Cholesterol. w/o Wool fat, w/o

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Accacia: (o/w)Best E.A for oral emulsions, they have low viscocity, so creaming occurs, addition of Tragacanth can improve the stability.

TragacanthHigh viscocity, used as emulsions stabilizer

AgarExtract from sea weed, used as emulsion stabilizerSoluble in boiling water, on cooling it forms gel.Low conc is used if the product is to be poured (oral)

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LecithinThey are used for formulating o/w emulsions. Purified lecithin from soy or egg yolk is used for i/v emulsions.

cholesterol : It forms w/o emulsion.

Wool fatIt is mainly used in w/o emulsions meant for external use. It is also used as eye ointment base

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Finely divided solidsFinely divided solids

• Description :

Finely divided solid particles that are wetted to some

degree by both oil and water act as emulsifying agents.

This results from their being concentrated at interface,

where they produce a particulate film around the dispersed

droplets to prevent coalescence.

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Classification of Finely divided Classification of Finely divided solid emulsifying agentssolid emulsifying agents

Finely divided solids ( Particulate film) Colloidal Clays

• Bentonite,( Al2O3.4SiO2.H2O),

• Veegum ( Magnesium Aluminium silicate) , • Magnesium trisilicate. Metallic hydroxides• Magnesium hydroxide, • Aluminium hydroxide,

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Classification of Finely divided Classification of Finely divided solid emulsifying agentssolid emulsifying agents

• Bentonite• Depend on the order of mixing, both o/w or

w/o emulsion can be formed with bentonite. For o/w emulsion, bentonite is first dispersed in water and allowed to hydrate to form magma. Then oil phase is gradually added with constant agitation. To prepare w/o emulsion, bentonite is first dispersed in oil and then water is added gradually.

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Auxiliary emulsifying agents Auxiliary emulsifying agents

• Auxiliary (Secondary) emulsifying agents include those compounds that are normally incapable themselves of forming stable emulsion. Their main value lies in their ability to function as thickening agents and thereby help stabilize the emulsion.

• E.g Stearic acid, Methyl cellulose

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Selection of emulsifying agent Selection of emulsifying agent

Properties of an ideal emulsifying agent

reduce the interfacial tension between the two immiscible liquids.

completely non irritant and non toxic in the concentrations used.

produce and maintain the required viscosity of the preparation.

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Preservation of emulsionsPreservation of emulsions

• Microbial contamination may occur due to:

• contamination during development or production of emulsion or during its

use.

• Usage of impure raw materials

• Poor sanitation conditions

• Contamination by the consumer during use of the product..

• Precautions to prevent microbial growth ;

• Use of uncontaminated raw materials

• Careful cleaning of equipment.

• Addition of anti microbial agent

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Antimicrobial agentsAntimicrobial agents

• The preservative must be :

• Less toxic

• Stable to heat and storage

• Chemically compatible

• Reasonable cost

• Acceptable taste, odor and color.

• Effective against fungus, yeast, bacteria.

• Preservative must no bind to other components of the emulsion

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Antimicrobial agentsAntimicrobial agents

• Acids and acid derivatives - Benzoic acid - Antifungal agent

• Aldehydes – Formaldehyde - Broad spectrum • Phenolics - Phenol - Broad spectrum Cresol Propyl p-hydroxy benzoate • Quaternaries -Chlorhexidine and salts - Broad spectrum Benzalkonium chloride Cetyl trimethyl ammonium bromide • Mercurials -Phenyl mercuric acetate - Broad spectrum

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Emulsification techniquesEmulsification techniques

• Laboratory scale preparation techniques

• Large scale preparation techniques

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Extemporaneous (Laboratory Extemporaneous (Laboratory scale ) method of preparationscale ) method of preparation

• Continental or dry gum method

• Wet gum method

• Bottle or Forbes bottle method

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Dry gum method ( Continental Dry gum method ( Continental method) method)

• used to prepare the initial or primary emulsion from oil , water and a hydrocolloid or “gum” type emulsifier ( usually acacia).

• Ratio of oil :gum : water in primary emulsion

Fixed oil = 4:1:2

Mineral oil = 3:1:2

Volatile oil = 2:1;2

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• In a mortar gum ( acacia) is levigated with oil until the powder is thoroughly wetted; Then water is added all at once and the mixture is vigorously and continuously triturated until the primary emulsion formed is creamy white.

• Additional water or aqueous solutions may be incorporated after the primary emulsion is formed.

• Excipients ( e.g. active ingredients, preservatives , color, flavors) are generally dissolved and added as a solution to the primary emulsion ,

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• oil soluble substances in small amounts may be incorporated directly into the primary emulsion.

• Any substance which might reduce the physical stability of the emulsion, such as alcohol ( which may precipitate the gum) should be added as near to the end of the process as possible to avoid breaking the emulsion.

• When all agents have been incorporated , the emulsion should be transferred to a calibrated vessel, brought to final volume with water, then homogenized or blended to ensure uniform distribution of ingredients.

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Wet gum method (English method)Wet gum method (English method)

• The proportion of oil and water and emulsifier ( gum) are the same as in dry gum method , but the order and technique of mixing are different.

• The gum is triturated with water to form a mucilage;

• Then oil is slowly added in portions , while triturating.

• After all the oil is added , the mixture is triturated for several minutes to form the primary emulsion.

• Then other ingredients are added as in continental method.

• Generally speaking, the English method is more difficult to perform successfully , especially with more viscous oils, but may result in a more stable emulsion.

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Bottle methodBottle method

• Used to prepare emulsions of volatile oils, or oligeneous substances of vary low viscosities.

• Acacia ( or other gum) is placed in a dry bottle and oil are added,

• The bottle is capped and thoroughly shaken.

• To this the required volume of water is added all at once and the mixture is shaken thoroughly until the primary emulsion is formed.

•

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Preparation of emulsionsPreparation of emulsions

Mechanical equipment for emulsification (Agitation)

• Mechanical stirrers• Propeller type mixers

-Turbine mixers • Colloid mills• Ultrasonifiers

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Mechanical stirrersMechanical stirrers

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Turbine stirrerTurbine stirrer

• For drawing the material to be mixed from above.

• Generates axial flow in the vessel.

•

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Propeller stirrersPropeller stirrers

• Standard stirring element. For drawing the material to be mixed from the top to the bottom.

• Local shearing forces. • Generates axial flow in

the vessel. • Used at medium to high

speeds..

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Colloidal millColloidal mill

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Colloidal mill rotor and statorColloidal mill rotor and stator

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Ultrasonifiers – Principle of Ultrasonifiers – Principle of Pohlman whistlePohlman whistle

Outlet

Viberating blade

Intlet

Nozzle

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Physical instability of emulsionsPhysical instability of emulsions

• Physical instability

• i. Flocculation

• Ii. Creaming or sedimentation

• iii. coalescence

• Iv. Phase inversion

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Emulsion

Coalescence

FlocculationCreaming

Breaking

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•Aggregation/flocculation : Dispersed particles come together but do not fuse. •Coalescence is the process by which emulsified particles merge with each to form large particles.•Breaking is the destroying of the film surrounding the particles.•Creaming & Sedimentation: upward or downward movement or particles

•.

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Flocculation :

• Redispersible association of particle within an emulsion to form large aggregates.

• Precursor to the irreversible coalescence. • differs from coalescence mainly in that

interfacial film and individual droplets remain intact.

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• Flocculation is influenced by the charges on the surface of the emulsified globules.

• The reversibility of flocculation depends upon strength of interaction between particles as determined by

• chemical nature of emulsifier, • phase volume ratio, • concentration of dissolved substances, specially

electrolytes and ionic emulsifiers.

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Physical instability of emulsionsPhysical instability of emulsionsCreaming & Sedimentation

• Creaming is the upward movement of dispersed droplets of emulsion relative to the continuous phase and Sedimentation is downward movement of doplets ( due to the density difference between two phases).

• Stoke’s law : dx / dt = d2 (ρi- ρe)g/18η• Dx/dt = rate of setting• D = diameter of particles• ρi and ρe density of internal nd external phase• g = gravitational constant• η =viscosity of medium

Methods to reduce Methods to reduce Creaming/SettlingCreaming/Settling

• Reduction in droplet size helps in reducing creaming or sedimentation.

• increase in viscosity of the continuous phase by adding thickening agents can reduce the rate of creaming, sedimentation, phase inversion

• Minimizing difference in densities of 2 phases (difficult to control) usually by temperature

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Coalescence and breaking

Coalescence is also called Cracking.Irreversible process.Sheath of EA around globules is lost.It can lead to Breaking (Separation of two

phases)

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Factors reducing the chance of Factors reducing the chance of Coalescence/breakingCoalescence/breaking

Uniformity in particle size (small size)Increase in viscosity of dispersed phaseMaintain phase volume ratio

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Physical instability of emulsionsPhysical instability of emulsionsPhase inversion• An emulsion is said to invert when it changes

from an o/w to w/o or vice versa.• Changing nature of emulsifying agent• Alteration in phase volume ratio • e.g o/w emulsifier is mixed with oil and little

quantity of water, it will form w/o emulsion by agitation. But when more water is added, it converts into o/w emulsion.

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Emulsions

Education

wo emulsions

dispersed phase

oil wo multiple emulsions

types of multiple emulsions

oil owo water

emulsion of phase b

water wow micro emulsions

innermost phase