EMULSIONS

Emulsions:

Definition: It is thermodynamically unstable system consisting of at least two immiscible liquid phases one of which is dispersed as globules (the dispersed phase) in the other liquid phase (the continuous phase) stabilized by presence of emulsifying agent.

To stabilize these droplets, emulsifying agent should be added -Particle diameter of dispersed phase (Internal phase) ranged from 0.1 to 10 um.

Pharmaceutical applications of emulsions:

1. They can mask the bitter taste and odor of drugs, e.g. castor oil, cod-liver oil etc. 2. They can be used to prolong the release of the drug thereby providing sustained release action. 3. Essential nutrients like carbohydrates, fats and vitamins can all be emulsified and can be administered to bed ridden patients as sterile intravenous emulsions. 4. Emulsions provide protection to drugs which are susceptible to oxidation or hydrolysis. 5. Intravenous emulsions of contrast media have been developed to assist in diagnosis. 6. Emulsions are used widely to formulate externally used products like lotions, creams, liniments etc.

Emulsions:
Types Of Emulsions: 1- Oil in water emulsions 2- Water in oil emulsions 3- Multiple emulsions (O/W/O) or (W/O/W) 4- Microemulsions

DIFFERENCE

BETWEEN O/W EMULSIONS:

AND

W/O

(o/w)
Water is the dispersion medium and oil is the dispersed phase

(w/o)
Oil is the dispersion medium and water is the dispersed phase

non greasy and easily removable from the skin used externally to provide cooling effect e.g. vanishing cream

greasy and not water washable

used externally to prevent evaporation of moisture from the surface of skin e.g. Cold cream

preferred for internal use as bitter taste of oils can be masked.

preferred for external use like creams.

( O/W )

( W/O )

Microemulsions:

clear, stable, liquid mixtures of oil, water and surfactant, frequently in combination with a cosurfactant. In contrast to ordinary emulsion, microemulsions form upon simple mixing of the components and do not require the high shear conditions generally used in the formation of ordinary emulsions. The two basic types of microemulsions are (o/w) and (w/o). Unlike the common macroemulsion 1- Appear as clear transparent solution. 2- Diameter of internal phase droplets ranged 10-200nm 3-Thermodynamically stable in that:

between

Microemulsions:

Tests Used To Identify Emulsion Type:

Dilution test: based on the solubility of external phase of emulsion. - o/w emulsion can be diluted with water. - w/o emulsion can be diluted with oil.

Tests Used To Identify Emulsion Type:

Conductivity Test: water is good conductor of electricity whereas oil is non-conductor. Therefore, continuous phase of water runs electricity more than continuous phase of oil.

Tests Used To Identify Emulsion Type:

Dye-Solubility Test: when an emulsion is mixed with a water soluble dye such as amaranth and observed under the microscope. if the continuous phase appears red, then it means that the emulsion is o/w type as water is the external phase if the scattered globules appear red and continuous phase colorless, then it is w/o type.

Tests Used To Identify Emulsion Type:

Fluorescence test: oils give fluorescence under UV light, while water doesnt. Therefore, O/W emulsion shows spotty pattern while W/O emulsion fluoresces.

Emulsifying agents:

Emulsifier or surface active agent (SAA) is molecule which has two parts, one is hydrophilic and the other is hydrophobic. Upon the addition of SAA, it tends to form monolayer film at the oil/water interface.

Mechanism of action of emulsifying agents:

When two immiscible liquids are agitated together so that one of the liquids is dispersed as small droplets in the other. To prevent coalescence between globules, it is necessary to use emulsifying agent.

Type of film Monomolecular

Example SAA (K laurate, tween) Synthetic SAA Hydrophilic colloid ( acacia, gelatin)

Proposed mechanism - Coherent monomolecular film - flexible film formed by SAA, - depend on lower the o/w , - can prepare o/w and w/o emulsion - Strong rigid film formed, mostly by the hydrocolloid, - which produce o/w emulsion, - is not reduced to any extent , - the stability due to strength of the formed interfacial film -Film formed by solid particles that are small in size compared to the droplet of the dispersed phase. - Particles must be wetted by both phases in order to remain at the interface and form stable film, - can form o/w and w/o

Multimolecular

Solid particles

Colloid clays (bentonite, Mg(oH)2)

Mechanism of action of emulsifying agents:

Monomolecular adsorption:

Rule of Bancroft: The type of the emulsion is a function of the relative solubility of the surfactant, the phase in which it is more soluble being the continuous phase.

Classification of emulsifying agents:

Emulsifying agent may be classifying into three groups: 1-Natural emulsifying agents: - form monomolecular and multimolecular film A-Those from vegetable source as acacia - tragacanth- pectin- derivative of cellulose B-Those from animal source as gelatincholesterol Advantages: Non toxic and

wool

fat

relatively

inexpensive

Disadvantages: -They show considerable batch to batch variation - readily support M.O. growth - susceptible to alcohol, electrolytes

Classification of emulsifying agents:

2- Finely divided solid: - as bentonite - Mg(OH)2 forming a coherent film which physical prevents coalescence of the dispersed globules. - if the particles are: preferntially wetted by the aqueous phase o/w emulsion :preferntially wetted by the oil phase w/o emulsion

Classification of emulsifying agents:

3Synthetic emulsifying agents as: - form monomolecular film A- Anionic emulsifying agents Alkali soap: - e.g. sodium, potassium and ammonium salts of fatty acids - Form o/w emulsions - in acidic condition precipitated Fatty acid - For external use - incompatible with polyvalent cations

Classification of emulsifying agents:

Soap of di/trivalent metal - e.g. Cal oleate - Promote w/o emulsions Amine soaps: N(CH2CH2OH)3 - neutral pH - incompatible with acids and high concentration of electrolytes - Produce o/w emulsion Sulfated and sulfonated compound - E.g.Sodium lauryl sulphate - stable over high pH range - o/w emulsions

Classification of emulsifying agents:

B- Cationic surfactants Quaternary ammonium compounds: E.g. Cetyl trimethylammonium bromide (Cetrimide) and benzalkonium chloride Disadvantages: Toxicity and irritancy Incompatible with anionic surfactants, polyvalent anions unstable at high pH It has marked antibacterial and anti infective properties

Classification of emulsifying agents:

C- Nonionic surfactants

Low toxicity and irritancy so suitable for oral and Parenteral administeration High degree of compatibility Less sensitive to change pH or to addition of electrolytes E.g. Tweens (polyethylene fatty acid ester) O/W E.g. Span ( sorpitan fatty acid ester) W/O

D- Amphoteric surfactants charge depending on the pH of the system low pH high pH cationic anionic

i.e. lecithin: used to stabilize i.v., fat emulsion

Hydrophile-Lipophile Balance (HLB):

HLB: the ratio between the hydrophilic portion of the molecule to the lipophilic portion of the molecule. The higher the HLB of an agent the more hydrophilic it is. Spans are lipophilic have low HLB. Tweens are hydrophilic have high HLB.

Hydrophile-Lipophile Balance (HLB):

Hydrophile-Lipophile Balance (HLB):

Calculation of HLB: Griffin equation: HLB = 20 (1 S / A) S: saponification number of the ester A: the acid number of the fatty acid

Davis equation:
HLB = hydrophilic group number lipophilic group number + 7

Methods of emulsion preparation:

On small scale: Porcelain mortar and pestle On large scale: Mechanical stirrer

Colloid mill

Homogenizer

Proportions of Oil, Water and Gum required for formation of primary emulsion:
Proportions of: Type of oil Fixed oil Mineral oil Volatile oil oil 4 3 2 water 2 2 2 gum 1 1 1

Methods of emulsion preparation:

Continental or dry gum method:

Emulsifier is triturated with the oil in perfectly dry porcelain mortar

water is added at once

triturate immediately, rapidly and continuously (until get a clicking sound and thick white cream is formed, this is primary emulsion)

the remaining quantity of water is slowly added to form the final emulsion

Methods of emulsion preparation:

English or Wet Gum Method

triturate gum with water in a mortar to form a mucilage oil is added slowly in portions the mixture is triturated after adding all of the oil, thoroughly mixed for several minute to form the primary emulsion

Once the primary emulsion has been formed remaining quantity of water is added to make the final emulsion.

Methods of emulsion preparation:

Bottle or Forbes Bottle Method

It is extemporaneous preparation for volatile oils or oil with low viscosity. gum + oil (dry bottle)

Shake

water (volume equal to oil) is added in portions with vigorous shaking to form primary emulsion

remaining quantity of water is added to make the final emulsion

Emulsion Stability:

The instability of pharmaceutical emulsions may be classified as the following:

a) b) c) d)

Flocculation and creaming coalescence and breaking Phase inversion Miscellaneous physical and chemical change

Emulsion Stability

Emulsion Stability:

Flocculation and creaming: Flocculation - The small spheres of oil join together to form clumps or flocs which rise or settle in the emulsion more rapidly than individual particles. Creaming - it is a concentration of the floccules of the internal phase formed upward or downward layer according to the density of internal phase.

Creaming

Creaming:

Stokes equation included the factors that affect the creaming process:

dx/dt = d2 (i-e)g/18
dx/dt = rate of setting D = diameter of particles = density of internal phase and external phase g = gravitational constant = viscosity of medium

Creaming:
Factors affect creaming: 1- Globule size:

globule size creaming

2- The density of the internal and external phases: pi-pe = 0 dx/dt = 0 pi-pe = -ve [i.e.-ve velocity upward creaming ] pi-pe =+ve [ downward creaming] 3- Gravity: const, However centrifugation is applied. 4- Viscosity: creaming

Strategies to reduce creaming:

Principle
Reduce droplet size (r) Reduce density difference ( p)

Method
Homogenizer Add weighting agent are oils that, have a density greater than the density of water Add thickening or gelling agent e.g. methylcellulose

Increase continuous phase viscosity ()

Coalescence and Breaking:

Coalescence is the process by which emulsified particles merge with each to form large particles. Breaking - Due to Coalescence and creaming combined, the oil separates completely from the water so that it floats at the top in a single, continuous layer.

Major differences between creaming and breaking:

Items Definition Creaming
Formation of upward or downward layer Reversible Reconstitute intact

Breaking
Separation of emulsion to upward oily layer and downward aq layer irreversible not reconstituting destroyed

Reverersability Agitation Emulsifying film around particles Internal phase globules Effect of phase volume ratio

Partial or no coalescence No or little

Complete fusion in o/w if oil >74%

Phase inversion:
In phase inversion o/w type emulsion changes into w/o type and vice versa. It is a physical instability. It may be brought about by: 1- the addition of an electrolyte e.g. addition of CaCl2 into o/w emulsion formed by sodium stearate can be inverted to w/o. 2- by changing the phase volume ratio 3- by temperature changes. - Phase inversion can be minimized by: 1- using the proper emulsifying agent in adequate concentration 2- keeping the concentration of dispersed phase between 30 to 60 % 3- storing the emulsion in a cool place.

Cracking

When an emulsion cracks during preparation, i.e., the primary emulsion does not become white but acquires an oily translucent appearance. In such a case, it is impossible to dilute the emulsion nucleus with water and the oil separates out. Cracking of emulsion can be due to:

1- addition of an incompatible emulsifying agent e.g. monovalent soap + divalent soap e.g. anionic + cationic emulsifying agent 2- chemical or microbial decomposition of emulsifying agent

Cracking
e.g. alkali soaps decomposed by acids e.g. monovalent soaps salted out by electrolytes such as NaCl e.g. nonionic emulsifying agents are incompatible with phenols e.g. alcohol precipitates gums and gelatin 3- exposure to increased or reduced temperature 4- Addition of common solvent e.g. addition of a solvent in which the two phases are soluble (alcohol)

Preservation Of Emulsions
Preservation from microorganisms: Contamination due to microorganisms can result in problems such as: 1- color and odor change 2- gas production 3- hydrolysis 4- pH change 5- breaking of emulsion e.g. methyl, propyl and butyl parabens e.g. organic acids such as ascorbic acid and benzoic

Preservation Of Emulsions

Preservation from oxidation: Antioxidants can be used to prevent the changes occurring due to atmospheric oxygen such as rancidity. e.g.butylated hydroxyanisole (BHA) e.g.butylated hydroxytoluene (BHT)

Quality control tests for Emulsions

1. Determination of particle size and particle count: - It is performed by optical microscopy and Coulter counter apparatus. 2. Determination of viscosity: - Determination of viscosity is done to assess the changes that might take place during aging. The viscometers used: cone and plate viscometers.

Quality control tests for Emulsions

-

In case of o/w emulsions, flocculation of globules causes an immediate increase in viscosity. After this change, the consistency of the emulsion changes with time. In case of w/o emulsions, the dispersed phase particles flocculate quite rapidly resulting in a decrease in viscosity, which stabilizes after 5 to 15 days. As a rule, a decrease in viscosity with age reflects an increase of particle size due to coalescence.

Quality control tests for Emulsions

3. Determination of phase separation: - Phase separation may be observed visually or by measuring the volume of the separated phases. 4. Determination of electrophoretic properties: - Determination of electrophoretic properties like zeta potential is useful for assessing flocculation since electrical charges on particles influence the rate of flocculation. - O/W emulsion having a fine particle size will exhibit low resistance but if the particle size increase, then it indicates a sign of oil droplet aggregation and instability.

Assessment of emulsion shelf life:

Stress conditions employed for evaluating the stability of emulsions: 1- Aging and temperature - Cycling between two temperatures (4 and 45C) - At elevated temperature: accelerates the rate of coalescence and creaming and this is coupled with change in viscosity temperature thin emulsion Room temperature thick emulsion - Freezing damage emulsion more than heating ? Since, the solubility of emulsifiers is more sensitive to freezing than heating.

Assessment of emulsion shelf life:

2- Centrifugation: Centrifugation at 3750 rpm for 5 hours = effect of gravity for one year. 3- Agitation: The following physical parameters are evaluated to assess the effect of any of the above stress conditions: a Phase separation b Viscosity c Electrophoretic properties d Particle size and particle count

Overview of the possible effects during emulsion centrifugation for O/W and W/O emulsions (a); flocculation (b), coalescence (c), fractionation according to particle size distribution (d), detection of the presence of a surfactant aggregate (e) (promoting emulsion creaming by the depletion effect)

Assessment of emulsion shelf life:

a centrifuged emulsion with: surfactant sediment (a), aqueous layer (b), emulsion layer (c), close-packed oil droplets (d).