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Emulsions:
¡ Definition: It is thermodynamically unstablesystem consisting of at least two immiscibleliquid phases one of which is dispersed asglobules (the dispersed phase) in the otherliquid phase (the continuous phase) stabilizedby 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 andvitamins can all be emulsified and can be administeredto bed ridden patients as sterile intravenousemulsions.
¡ 4. Emulsions provide protection to drugs which aresusceptible to oxidation or hydrolysis.
¡ 5. Intravenous emulsions of contrast media have beendeveloped to assist in diagnosis.
¡ 6. Emulsions are used widely to formulate externallyused 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 AND W/OEMULSIONS:
(o/w) (w/o)
Water is the dispersion medium and oil is the dispersed phase
Oil is the dispersion medium and water is the dispersed phase
non greasy and easily removable from the skin
greasy and not water washable
used externally to provide cooling effect e.g. vanishing cream
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.
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 notrequire the high shear conditions generally used in theformation of ordinary emulsions.
¡ The two basic types of microemulsions are (o/w) and(w/o).
¡ Unlike the common macroemulsion in that:1- Appear as clear transparent solution.
2- Diameter of internal phase droplets ranged between10-200nm
3-Thermodynamically stable
Tests Used To Identify Emulsion Type:
¡ Dilution test: based on the solubility of external phaseof 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, continuousphase of water runs electricity more thancontinuous 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 themicroscope.
¡ if the continuous phase appears red, then itmeans that the emulsion is o/w type as water isthe external phase
¡ if the scattered globules appear red andcontinuous phase colorless, then it is w/o type.
Tests Used To Identify Emulsion Type:
¡ Fluorescence test: oils give fluorescenceunder UV light, while water doesn’t. Therefore,O/W emulsion shows spotty pattern while W/Oemulsion fluoresces.
Emulsifying agents:¡ Emulsifier or surface active agent (SAA) is
molecule which has two parts, one ishydrophilic and the other is hydrophobic.Upon the addition of SAA, it tends to formmonolayer film at the oil/water interface.
Mechanism of action of emulsifying agents:
¡ When two immiscible liquids are agitatedtogether so that one of the liquids is dispersedas small droplets in the other.To prevent coalescence between globules, it isnecessary to use emulsifying agent.
Proposed mechanismExampleType of film- Coherent monomolecular film- flexible film formed by SAA, - depend on lower the γo/w , - can prepare o/w and w/o emulsion
SAA(K laurate,
tween)Synthetic SAA
Monomolecular
- Strong rigid film formed, mostly by the hydrocolloid,- which produce o/w emulsion, - γ is not reduced to any extent ,- the stability due to strength of the formed interfacial film
Hydrophilic colloid
( acacia,gelatin)
Multimolecular
-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
Colloid clays (bentonite,Mg(oH)2)
Solid particles
Mechanism of action of emulsifying agents:
¡ Monomolecular adsorption:
Rule of Bancroft: The type of the emulsion is afunction of the relative solubility of thesurfactant, the phase in which it is more solublebeing 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 sourceas acacia - tragacanth- pectin- derivative of cellulose
B-Those from animal sourceas gelatin- cholesterol –wool fat
Advantages: Non toxic and 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:3- Synthetic emulsifying agents as:
- form monomolecular filmA- Anionic emulsifying agentsAlkali soap:
- e.g. sodium, potassiumand 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 cationichigh pH anionic
¡ i.e. lecithin: used to stabilize i.v., fat emulsion
Hydrophile-Lipophile Balance (HLB):
¡ HLB: the ratio between the hydrophilic portionof the molecule to the lipophilic portion of themolecule.
¡ The higher the HLB of an agent themore hydrophilic it is.
¡ Spans are lipophilic have low HLB.¡ Tweens are hydrophilic have high HLB.
Hydrophile-Lipophile Balance (HLB):
¡ Calculation of HLB:Griffin equation:
HLB = 20 (1 – S / A)S: saponification number of the esterA: 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 oil water gum
Fixed oil 4 2 1
Mineral oil 3 2 1
Volatile oil 2 2 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 Methodtriturate gum with water in a mortar
to form a mucilage
oil is added slowly in portionsthe mixture is triturated
after adding all of the oil, thoroughlymixed 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) Flocculation and creamingb) coalescence and breakingc) Phase inversiond) Miscellaneous physical and chemical change
Emulsion Stability:¡ Flocculation and creaming:¡ Flocculation - The small spheres of oil join
together to form clumps or flocs which rise orsettle in the emulsion more rapidly thanindividual particles.
¡ Creaming - it is a concentration of the flocculesof the internal phase formed upward ordownward layer according to the density ofinternal phase.
Creaming:¡ Stoke‘s equation included the factors that
affect the creaming process:
dx/dt = d2 (ρi-ρe)g/18η
dx/dt = rate of settingD = diameter of particlesρ = density of internal phase and external phaseg = gravitational constantη = viscosity of medium
Creaming:¡ Factors affect creaming:1- Globule size:
2- The density of the internal and external phases:
* ↑globule size → ↑creaming
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 Method
Reduce droplet size (r) Homogenizer
Reduce density difference (Δ p) Add weighting agent are oils that, have a density greater than the density
of water
Increase continuous phase viscosity (η)
Add thickening or gelling agent e.g.
methylcellulose
Coalescence and Breaking:
¡ Coalescence is the process by whichemulsified particles merge with each to formlarge particles.
¡ Breaking - Due to Coalescence and creamingcombined, the oil separates completely fromthe water so that it floats at the top in a single,continuous layer.
Major differences between creaming and breaking:
BreakingCreamingItems
Separation of emulsion to upward
oily layer and downward aq layer
Formation of upward or
downward layer
Definition
irreversibleReversibleReverersability
not reconstituting ReconstituteAgitation
destroyedintactEmulsifying film around
particles
Complete fusionPartial or no coalescence
Internal phase globules
in o/w if oil >74% No or littleEffect of phase volume ratio
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 tow/o.
2- by changing the phase volume ratio3- by temperature changes.- Phase inversion can be minimized by:1- using the proper emulsifying agent in adequate
concentration2- 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 acquiresan oily translucent appearance.
¡ In such a case, it is impossible to dilute the emulsionnucleus with water and the oil separates out.
¡ Cracking of emulsion can be due to:
1- addition of an incompatible emulsifying agente.g. monovalent soap + divalent soape.g. anionic + cationic emulsifying agent
2- chemical or microbial decomposition of emulsifyingagent
Cracking
e.g. alkali soaps decomposed by acidse.g. monovalent soaps salted out by electrolytes such as
NaCle.g. nonionic emulsifying agents are incompatible with
phenolse.g. alcohol precipitates gums and gelatin
3- exposure to increased or reduced temperature
4- Addition of common solvente.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 change2- gas production3- hydrolysis4- pH change5- breaking of emulsion
e.g. methyl, propyl and butyl parabense.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 oxygensuch as rancidity.
¡ e.g.butylated hydroxyanisole (BHA)e.g.butylated hydroxytoluene (BHT)
Quality control tests for Emulsions
1. Determination of particle size and particlecount:
- It is performed by optical microscopy andCoulter 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 ofglobules causes an immediate increase inviscosity. After this change, the consistency ofthe emulsion changes with time.
- In case of w/o emulsions, the dispersedphase particles flocculate quite rapidlyresulting in a decrease in viscosity, whichstabilizes after 5 to 15 days.
- As a rule, a decrease in viscosity with agereflects an increase of particle size due tocoalescence.
Quality control tests for Emulsions3. 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 sinceelectrical charges on particles influence the rate offlocculation.
- O/W emulsion having a fine particle size will exhibit lowresistance but if the particle size increase, then itindicates a sign of oil droplet aggregation and instability.
Assessment of emulsion shelf life:
¡ Stress conditions employed for evaluating thestability of emulsions:
1- Aging and temperature- Cycling between two temperatures (4 and 45°C)- At elevated temperature: accelerates the rate of
coalescence and creaming and this is coupledwith change in viscositytemperature 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 theabove stress conditions:
a· Phase separationb· Viscosityc· Electrophoretic propertiesd· 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)