MODULE 1. GENERAL CONCEPTS OF DRUG TECHNOLOGY. POWDERS. LIQUID DOSAGE FORMS.
CONTENT MODULE 2. LIQUID MEDICAL FORMS.
LESSON 11. EMULSIONS.
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An emulsion is liquid preparation containing two immiscible liquids, one of which is dispersed as globules (dispersed phase = internal phase) in the other liquid (continuous phase = external phase).
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To stabilize these droplets, emulsifying agent should be added |
· Microemulsion: Droplets size range 0.01 to 0.1 m m
· Macroemulsion: Droplets size range approximately 5 m m.
General Types of Pharmaceutical Emulsions:
1) Lotions
2) Liniments
3) Creams
4) Ointments
5) Vitamin drops
Primary and secondary emulsion:
· Primary emulsion containing one internal phase, for example, oil-in-water emulsion (o/w) and water-in-oil emulsion (w/o).
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Secondary emulsion= multiple-emulsion: it contains two internal phase, for instance, o/w/o or w/o/w. It can be used to delay release or to increase the stability of the active compounds.
Emulsion Type and Means of Detection: using of naked eye, it is very difficult to differentiate between o/w or w/o emulsions. Thus, the four following methods have been used to identify the type if emulsions.
1) 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.
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2) 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.
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= Bulb glows with O/W = Bulb doesn’t glow with W/O |
3) Dye-Solubility Test:
– Water-soluble dye will dissolve in the aqueous phase.
– Oil-soluble dye will dissolve in the oil phase.
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What is look like under the microscope after mixing with suitable dye |
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Pharmaceutical applications of emulsions:
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1. To mask the taste
2. O/W is convenient means of orally administration of water-insoluble liquids
3. O/W emulsion facilitates the absorption of water-insoluble compounds comparing to their oily solution preparations (e.g. vitamins)
4. Oil-soluble drugs can be given parentrally in form of oil-in water emulsion. (e.g Taxol)
5. Emulsion can be used for external application in cosmetic and therapeutic uses.
Theories of Emulsification:
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Incase of two immiscible liquids
· An explanation of this phenomenon is because of cohesive force between the molecules of each separate liquid exceeds adhesive force between two liquids. This is manifested as interfacial energy or tension at boundary between the liquids.
· Therefore, to prevent the coalescence and separation, emulsifying agents have been used.
· Types of emulsifying agents:
1. Surface active agent: adsorbed at oil/water interface to form monomolecular film to reduce the interfacial tension
2. Hydrophilic colloids: forming a multimolecular film around the dispersed droplet
3. Finely divided solid particles: they are adsorbed at the interface between two immiscible liquid phases to form particulate film
A-Monomolecular adsorption
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· In emulsion, the surface area is high to maintain the dispersion of the droplets. Thus, based on the above equation surface free energy becomes high consequently. The only way to keep it low is to reduce the interfacial tension.
· Surface active agent (SAA) is molecule which have two parts, one is hydrophilic and the other is hydrophobic. Upon the addition of SAA, they tend to form monolayer film at the oil/water interface.
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Form monomolecular film |
· The functions of surface active agents to provide stability to dispersed droplets are as following:
i. Reduction of the interfacial tension
ii. Form coherent monolayer to prevent the coalescence of two droplet when they approach each other
iii. Provide surface charge which cause repulsion between adjust particles
· Combination of surface-active agents is used most frequently. The combination should form film that closely packed and condensed
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This figures shows schematic of oil droplets in an oil-water emulsion. You can see the orientation of a Tween and a Span molecule at the interface |
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· Figure (a) shows good combination, which forms excellent emulsion. · Figure (b) and (c) show poor emulsion due to lack of closely packed or lack of complexation, respectively. |
Classification of surface-active agents:
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Note that: · Anionic SAA are mainly used for external used. · Cationic SAA are used for external used. They have, also, good antimicrobial activity (e.g. Benzalkonium chloride) · Nonionic SAA are stable over wide range of pH. They are not affected by change in pH or addition of electrolytes. They are less toxic and main function to provide steric repulsion |
B-Multimolecular adsorption
· Hydrophilic colloids form multimolecular adsorption at the oil/ water interface. They have low effect on the surface tension.
· Their main function as emulsion stabilizers is by making coherent multi-molecular film. This film is strong and resists the coalescence. They have, also, an auxiliary effect by increasing the viscosity of dispersion medium.
· Most of the hydrophilic colloids form oil-in-water emulsions.
· Some of them can provide electrostatic repulsion like acacia, which contains Arabic acid and proteins (COOH and NH3)
C-Solid particle adsorption
· Finely divided solid particles are adsorbed at the surface of emulsion droplet to stabilize them. Those particles are wetted by both oil and water (but not dissolved) and the concentration of these particles form a particulate film that prevent the coalescence.
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· Particles that are wetted preferentially by water from o/w emulsion, whereas those wetted more by oil form w/o emulsion
· Note that they are very rare to use and can affect rheology of the final product
· Size of the particle is very important, larger particles can lead to coalescence
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Other emulsifying agents
Natural emulsifying agents:
1.Egg yolk: it contains phospholipids and cholesterol. The main withdraw back is that spoils quickly; therefore, it can’t be used in industry. It is used for extemporaneous preparation.
2.Wool fat: anhydrous lanolin, it is used to prepare w/o emulsion for external uses.
3.Starch: it forms starch mucilage and it is restricted for enemas preparation.
4.Cholesterol: it has stabilizing action; therefore, another emulsifier should be included.
How to control emulsion type during formulation?
a. Volume of internal and external phases controls the type of emulsion. The smaller volume will be for the internal phase and the larger volume will be for external phase. In some cases, internal phases can be more than 50% of the total volume (see the following section)
b. Dominance of polar and non-polar characteristic of emulsifying agents (relative solubility of emulsifying agent in water and oil). Dominance of polar part results in formation of o/w emulsion and dominance of non-polar part results in formation of w/o emulsion. Note that polar groups are better barriers than non-polar; therefore, o/w emulsion can be prepared with more than 50 % of oil phase “ internal phase”.
What the factors that affect the choice of emulsion type?
The choice of emulsion depends on (1)-properties and uses of final products (2)- the other material required to be present.
· Oil-soluble drug is prepared in o/w emulsion due its solubility and its taste can be masked by adding flavoring agents
· For intravenous injection “ i.v.” o/w emulsion is the only type could be used.
· For intramuscular injection “i.m.” both o/w and w/o types of emulsion could be used. Water-soluble drug can be prepared in w/o emulsion to get prolonged action (depot therapy)
· Topical application:
o Semisolid emulsions are called creams and lotions
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Methods for preparation of emulsion:
· In small scales such as in pharmacy-hospital labs, mortar and pestle are the needed equipments.
· In large scale such as in pharmaceutical industry, different machines are used:
1. Mixer or mechanical stirring: the emulsion is prepared by agitation of emulsion ingredient
2. Colloid mills
Emulsifying Agents:
1) Carbohydrate Materials:
Acacia, Tragacanth, Agar, Pectin. o/w emulsion.
2) Protein Substances:
Gelatin, Egg yolk, Caesin o/w emulsion.
3) High Molecular Weight Alcohols:
Stearyl Alcohol, Cetyl Alcohol, Glyceryl Mono stearate———–o/w emulsion.
cholesterol——————————————————- w/o emulsion
4) Wetting Agents:
Anionic, Cationic, Nonionic
o/w emulsion
w/o emulsion
5) Finely divided solids:
Bentonite, Magnesium Hydroxide, Aluminum Hydroxide o/w emulsion.
Phase Inversion:
The relative volume of internal and external phases of an emulsion is important.
(increase) internal concentration (increase) viscosity up to a certain point.
Viscosity will decrease after that point.
At this point the emulsion has undergone inversion i.e. it has changed from an o/w to a w/o, or vice versa. In practice, emulsions may be prepared without inversion with as much as about 75% of the vol. of the product being internal phase.
Methods of Preparation of Emulsions:
1) Continental or Dry Gum Method:
“4:2:1” Method
4 parts (volumes) of oil [Ansel. 7th ed. page 369]
2 parts of water
1 part of gum
Acacia or other o/w emulsifier is triturated with oil in a perfectly dry Wedgwood or porcelain mortar until thoroughly mixed. Glass mortar has too smooth a surface to produce the proper size reduction of the internal phase (Do not use glass mortar). After the oil and gum have been mixed, the two parts of water are then added all at once and the mixture is triturated immediately.
2) English or wet Gum Method:
Same proportion of oil, water and gum are used as in the continental or dry gum method but the order of mixing is different. Mucilage of the gum is prepared by triturating acacia (or other emulsifier) with water. The oil is then added slowly in portions, and the mixture is triturated to emulsify the oil. Should the mixture become too thick during the process, additional water may be blended into the mixture before another successive portion of oil is added.
3) Bottle or Forbes Bottle Method:
Useful for-
Extemporaneous preparation of emulsion from volatile oils or oleaginous substance of low viscosity.
put powdered acacia in a dry bottle
Add 2 parts of oil
Thoroughly shake the mixture in the capped bottle. A volume of water approximately equal to the oil is then added in portions, the mixture being thoroughly shaken after each addition.
This method is not suitable for viscous oils (i.e. high viscosity oil).
Stability of Emulsion:
An emulsion is considered to be physically unstable if :
a) The internal phase tends to form aggregates of globules.
b) Large globules or aggregates of globules rise to the top or fall to the bottom of the emulsion to form a concentrated layer of the internal phase.
c) If all or part of the liquid of the internal phase becomes “unemulsified on the top or bottom of the emulsion.
Separation of the internal phase from the external phase is called BREAKING of the emulsion. This is irreversible.
-Protect emulsions against the extremes of cold and heat.
-Emulsions may be adversely affected by microbial contamination.
Gels and Magmas:
Gels are defined as semisolid systems consisting of dispersions made up of either small inorganic particles or large organic molecules enclosing or interpenetrated by a liquid. Magmas or Milks are gels consisted of floccules of small distinct particles. Gels and Magmas are considered colloids because they contain particles within the range of colloidal dispersions.
Examples of Magmas & Gels:
Bentonite Magma, NF:
Preparation of 5% bentonite, a native, colloidal hydrated aluminum silicate, in purified water.
Aluminum Hydroxide Gel, USP:
This is an aqueous suspension of a gelatinous precipitate composed of insoluble aluminum hydroxide and hydrated aluminum oxide, equivalent to about 4% of aluminum oxide.
Milk of Magnesia, USP:
This is a preparation containing between 7 and 8.5% of Magnesium hydroxide.
• An emulsion is a type of disperse system in which one liquid is dispersed throughout another liquid in the form of fine droplets.
• The two liquids, generally an oil and water, are immiscible and constitute two phases that tend to separate into layers.
• A third agent, an emulsifier or emulsifying agent (EA), is added to facilitate the emulsification process and to provide stability to the system.
• The disperse phase is referred to as the internal phase,
• The dispersing phase is termed the external phase.
• When the oil is the internal phase, the emulsion is called an oil-in-water or “o/w” emulsion.
• If water is the internal phase, the emulsion is called a water-in-oil or “w/o” emulsion.
• The type of emulsion produced is largely determined by the hydrophilicity or lipophilicity of the EA.
• EA may have both hydrophilic and lipophilic characteristics.
• The term hydrophilelipophile balance (HlB number):
1. ………………………;
2. ………………………:
• EA that are more hydrophilic generally produce O/W emulsions,
• EA that are more lipophilic generally produce W/O emulsions.
• Calculations are used to determine the quantities of oil, water, and EA to use in preparing a stable emulsion.
• Oral Emulsions are prepared & administered orally for the medicinal benefit of the oil (e.g., mineral oil, oleaginous vitamins A and D).
• The taste and oleaginous feel of the oil is masked:
1. ………………………;
2. ………………………,.
3. ………………………:
lotions, foams, and creams.
4. Intravenous Emulsions are prepared for the nutritional benefit of the oil (usually ………………………).
An emulsion is a dispersion in which the dispersed phase is composed of small globules of a liquid distributed throughout a vehicle in which it is immiscible.
Classification of emulsions :
n Based on dispersed phase
Oil in Water (O/W): Oil droplets dispersed in water
Water in Oil (W/O): Water droplets dispersed in oil
n Based on size of liquid droplets
0.2 – 50 mm Macroemulsions (Kinetically Stable)
0.01 – 0.2 mm Microemulsions (Thermodynamically Stable)
Theories of Emulsification:
1) Surface Tension Theory:
lowering of interfacial tension.
2) Oriented-Wedge Theory:
mono molecular layers of emulsifying agents are curved around a droplet of the internal phase of the emulsion.
3) Interfacial film theory:
A film of emulsifying agent prevents the contact and coslescing of the dispersed phase.
Emulsifying Agents:
It is a substance which stabilizes an emulsion .
Pharmaceutically acceptable emulsifiers must also :
§ be stable .
§ be compatible with other ingredients .
§ be non – toxic .
§ possess little odor , taste , or color .
§ not interfere with the stability of efficacy of the active agent .
Emulsifying Agents:
1) Carbohydrate Materials:
Acacia, Tragacanth, Agar, Pectin. o/w emulsion.
2) Protein Substances:
-Gelatin, Egg yolk, Caesin o/w emulsion.
3) High Molecular Weight Alcohols:
Stearyl Alcohol, Cetyl Alcohol, Glyceryl Mono stearate o/w emulsion, cholesterol w/o emulsion.
4) Wetting Agents:
Anionic, Cationic, Nonionic
o/w emulsion
w/o emulsion
5) Finely divided solids:
Bentonite, Magnesium Hydroxide, Aluminum Hydroxide o/w emulsion.
Methods of Preparation of Emulsions:
1) Continental or Dry Gum Method:
“4:2:1” Method
4 parts (volumes) of oil
2 parts of water
1 part of gum
2) English or wet Gum Method:
4 parts (volumes) of oil
2 parts of water
1 part of gum
3) Bottle or Forbes Bottle Method:
useful for extemporaneous preparation of emulsion from volatile oils or oleaginous substance of low viscosity.
powdered acacia
+ Dry bottle
2 parts of oil
This method is not suitable for viscous oils (i.e. high viscosity oil).
Emulsion Type and Means of Detection:
Tests for Emulsion Type (W/O or O/W emulsions)
1) Dilution Test:
– o/w emulsion can be diluted with water.
– w/o emulsion can be diluted with oil.
2) Conductivity Test:
Continuous phase water > Continuous phase oil.
3) Dye-Solubility Test:
– water soluble dye will dissolve in the aqueous phase.
– oil soluble dye will dissolve in the oil phase.
4) Refractive index measurement
5) Filter paper test
Emulsions are Kinetically Stable!
Rate of coalescence – measure of emulsion stability.
It depends on:
(a) Physical nature of the interfacial surfactant film
For Mechanical stability, surfactant films are characterized
by strong lateral intermolecular forces and high elasticity
(Analogous to stable foam bubbles)
(b) Electrical or steric barrier
Significant only in O/W emulsions.
In case of non-ionic emulsifying agents, charge may arise due to
(i) adsorption of ions from the aqueous phase or
(ii) contact charging (phase with higher dielectric constant is charged positively)
No correlation between droplet charge and emulsion stability in W/O emulsions
Steric barrier – dehydration and change in hydrocarbon chain conformation.
(c) Viscosity of the continuous phase
(many emulsion are more stable in concentrated form than when diluted.)
Viscosity may be increased by adding natural or synthetic thickening agents.
(d) Size distribution of droplets
Emulsion with a fairly uniform size distribution is more stable
(e) Phase volume ratio
As volume of dispersed phase stability of emulsion ¯
(eventually phase inversion can occur)
(f) Temperature
Temperature , usually emulsion stability ¯
Temp affects – Interfacial tension, D, solubility of surfactant, viscosity of liquid, phases of interfacial film.
(d) Size distribution of droplets
Emulsion with a fairly uniform size distribution is more stable
(e) Phase volume ratio
As volume of dispersed phase stability of emulsion ¯
(eventually phase inversion can occur)
(f) Temperature
Temperature , usually emulsion stability ¯
Temp affects – Interfacial tension, D, solubility of surfactant, viscosity of liquid, phases of interfacial film.
Inversion of Emulsions (Phase inversion)
O/W® W/O
1. The order of addition of the phases
W ®O + emulsifier ® W/O
O ®W + emulsifier ® O/W
2. Nature of emulsifier
Making the emulsifier more oil soluble tends to produce a W/O emulsion and vice versa.
3. Phase volume ratio
Oil/Water ratio ®W/O emulsion and vice versa
4. Temperature of the system
Temperature of O/W makes the emulsifier more hydrophobic and the emulsion may invert to W/O.
5. Addition of electrolytes and other additives.
Strong electrolytes to O/W (stabilized by ionic surfactants) may invert to W/O
Example. Inversion of O/W emulsion (stabilized by sodium cetyl sulfate and cholesterol) to a W/O type upon addition of polyvalent Ca.
Emulsion Breaking
Separation of the internal phase from the external phase is called BREAKING of the emulsion. This is irreversible.
n Protect emulsions against the extremes of cold and heat.
n Emulsions may be adversely affected by microbial contamination.
General Guidelines:
1. Type of emulsion determined by the phase in which emulsifier is placed.
2. Emulsifying agents that are preferentially oil soluble form W/O emulsions and vice versa.
3. More polar the oil phase, the more hydrophilic the emulsifier should be. More non-polar the oil phase more lipophilic the emulsifier should be.
In pharmacy it is generally accepted that the term ‘emulsion’ as a dosage form refers only to products for oral adminstration.
Emulsion for oral use are almost invariably o/w and are a convenient means of administering oils and fats or oily solution of unstable drug of low aqueous solulibilty
1- Emulsion For Internal use :
4Acacia Emulsion
Unless otherwise specific, extemporaneously prepared emulsion for Internal use are made with acacia gum. To prepare acacia emulsions using a pestle and mortar, thin (primary) emulsion must be made first. The quantities for primary emulsions have been determined by experience and are given in Table-1
Table-1 Quantities for primary emulsions
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Example |
Quantities for primary emulsions (parts) Oil Water Gum |
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Almond oilA rachis oil Castor oil Cod-liver |
2 |
1 |
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Mineral |
3 |
2 |
1 |
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Volatile |
Turpentine oil Cinnamon oil Peppermint oil |
2 |
2 |
1 |
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Oleo-resin |
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1 |
2 |
1 |
Rx
Almond oil 50ml
Double strength chloroform water 100ml
Water 200ml
Sent 100ml
Procedure:
1) Almond oil is a fixed oil, therefore, the qualities for primary emulsion are (oil: water: gum =4:2:1)
Almond oil 25ml
Water 12.5ml
Acacia 6.25g
2) use the dry gum technique for Acacia Emulsion as follow
·weigh the Acacia powder and place it in dry mortar
·dispense the Acacia powder lightly in the water
·add 25ml oil at once and triturate until the primary emulsion is well established
·the primary emulsion is then diluted with the remaining ingredients and transfer to measuring cylinder to adjusted volume with water.
3) Use amber dispensing bottle with a wide mouth
4) Write label & add “shake the bottle before use” label.
Use: Demulcent and mildly laxative
2-Emulsions for External use :
4White Liniment B.P
Rx after cal.
Ammonium chloride 12.5g 0.625g
Dilute Ammonia solution 42ml 2.25ml
Oleic acid 85ml 4.25ml
Turpentine oil 225ml 12.25ml
purified Water 625ml 31.25ml
Sent 50ml
Calculation : factor = 50/1000 = 0.05
1. Make emulsifier (Ammonium Oleate) the reaction between dilute Ammonia and oleic acid as follow
a- Take 4.25 of Oleic acid & 12.5 of Turpentine oil and 2.2ml of Dilute Ammonia solution (2.5%) and 10ml of water.
b- Shake vigorously to form TurpentineH2O emulsion
2. Dissolve 0.625g Ammonium chloride in the remaining water and mix it with to produce the preparation after adjusting the volume with H2O to 50ml
3. Write label as follow :
Use : counter – irritant and rubefacient.
4Calamine Lotion B.P.
Rx
Calamine 15g
Zinc Oxide 5g
Bentonite 3g
Sod. Citrate 0.5g
Liquid phenol 0.5g
Glycerin 5ml
Purified Water 100ml
Procedure:
1) Dissolve Sod. Citrate in 35ml Purified Water
2) Weigh Calamine, Zinc Oxide and Bentonite & triturate it with Sod. Citrate solution.
3) Add Liquid phenol, the Glycerin and sufficient quantity of water to make up the required volume.
4) Write Label
Use: Astringent & protective.
Learning Objectives
Upon completion of this exercise, you should be able to:
Define and/or identify emulsions and emulsifying agents.
Identify two factors that determine emulsion type (o/w vs. w/o).
Describe the levels of instability to which emulsions are subject.
Describe 3 mechanisms by which emulsions are stabilized.
Classify emulsifying agents by type and describe their uses, advantages, limitations.
Define and calculate HLB for any nonionic surfactant system.
Describe and/or demonstrate 3 methods of emulsion preparation.
Identify pharmaceutical uses of emulsions.
Introduction
An emulsion is a thermodynamically unstable two-phase system consisting of at least two immiscible liquids, one of which is dispersed in the form of small droplets throughout the other, and an emulsifying agent. The dispersed liquid is known as the internal or discontinuous phase, whereas the dispersion medium is known as the external or continuous phase. Where oils, petroleum hydrocarbons, and/or waxes are the dispersed phase, and water or an aqueous solution is the continuous phase, the system is called an oil-in-water (o/w) emulsion. An o/w emulsion is generally formed if the aqueous phase constitutes > 45% of the total weight, and a hydrophilic emulsifier is used. Conversely, where water or aqueous solutions are dispersed in an oleaginous medium, the system is known as a water-in-oil (w/o) emulsion. W/O emulsions are generally formed if the aqueous phase constitutes < 45% of the total weight and an lipophilic emulsifier is used.
Emulsions are used in many routes of administration. Oral administration can be used, but patients generally object to the oily feel of emulsions in the mouth. But some times, emulsions are the formulation of choice to mask the taste of a very bitter drug or when the oral solubility or bioavailability of a drug is to be dramatically increased.
More typically, emulsions are used for topical administration. Topical emulsions are creams which have emollient properties. They can be either o/w or w/o and are generally opaque, thick liquids or soft solids. Emulsions are also the bases used in lotions, as are suspensions. The term “lotion” is not an official term, but is most often used to describe fluid liquids intended for topical use. Lotions have a lubricating effect. They are intended to be used in areas where the skin rubs against itself such as between the fingers, thighs, and under the arms.
Emulsions are also used a ointment bases and intravenously administered as part of parenteral nutrition therapy. Their formulation and uses in these roles will be covered in the appropriate chapters.
The consistency of emulsions varies from easily pourable liquids to semisolid creams. Their consistency will depend upon:
the internal phase volume to external phase volume ratio
in which phase ingredients solidify
what ingredients are solidifying
Stearic acid creams (sometimes called vanishing creams) are o/w emulsions and have a semisolid consistency but are only 15% internal phase volume. Many emulsions have internal phases that account for 40% – 50% of the total volume of the formulation. Any semisolid character with w/o emulsions generally is attributable to a semisolid external phase.
W/O emulsions tend to be immiscible in water, not water washable, will not absorb water, are occlusive, and may be “greasy.” This is primarily because oil is the external phase, and oil will repel any of the actions of water. The occlusiveness is because the oil will not allow water to evaporate from the surface of the skin. Conversely, o/w emulsions are miscible with water, are water washable, will absorb water, are nonocclusive, and are nongreasy. Here water is the external phase and will readily associate with any of the actions of water.
Emulsions are, by nature, physically unstable; that is, they tend to separate into two distinct phases or layers over time. Several levels of instability are described in the literature. Creaming occurs when dispersed oil droplets merge and rise to the top of an o/w emulsion or settle to the bottom in w/o emulsions. In both cases, the emulsion can be easily redispersed by shaking. Coalescence (breaking or cracking) is the complete and irreversible separation and fusion of the dispersed phase. Finally, a phenomenon known as phase inversion or a change from w/o to o/w (or vice versa) may occur. This is considered a type of instability by some.
Emulsifying Agents
Emulsions are stabilized by adding an emulsifier or emulsifying agents. These agents have both a hydrophilic and a lipophilic part in their chemical structure. All emulsifying agents concentrate at and are adsorbed onto the oil:water interface to provide a protective barrier around the dispersed droplets. In addition to this protective barrier, emulsifiers stabilize the emulsion by reducing the interfacial tension of the system. Some agents enhance stability by imparting a charge on the droplet surface thus reducing the physical contact between the droplets and decreasing the potential for coalescence. Some commonly used emulsifying agents include tragacanth, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and polymers known as the Spans® and Tweens®.
Emulsifying agents can be classified according to: 1) chemical structure; or 2) mechanism of action. Classes according to chemical structure are synthetic, natural, finely dispersed solids, and auxiliary agents. Classes according to mechanism of action are monomolecular, multimolecular, and solid particle films. Regardless of their classification, all emulsifying agents must be chemically stable in the system, inert and chemically non-reactive with other emulsion components, and nontoxic and nonirritant. They should also be reasonably odorless and not cost prohibitive.
Synthetic Emulsifying Agents
Cationic, e.g., benzalkonium chloride, benzethonium chloride
Anionic, e.g., alkali soaps (sodium or potassium oleate); amine soaps (triethanolamine stearate); detergents (sodium lauryl sulfate, sodium dioctyl sulfosuccinate, sodium docusate).
Nonionic, e.g., sorbitan esters (Spans®), polyoxyethylene derivatives of sorbitan esters (Tweens®), or glyceryl esters
Cationic and anionic surfactants are generally limited to use in topical, o/w emulsions. Cationic agents (quarternary ammonium salts) are incompatible with organic anions and are infrequently used as emulsifiers. Soaps are subject to hydrolysis and may be less desirable than the more stable detergents.
Natural Emulsifying Agents
A variety of emulsifiers are natural products derived from plant or animal tissue. Most of the emulsifiers form hydrated lyophilic colloids (called hydrocolloids) that form multimolecular layers around emulsion droplets. Hydrocolloid type emulsifiers have little or no effect on interfacial tension, but exert a protective colloid effect, reducing the potential for coalescence, by:
providing a protective sheath around the droplets
imparting a charge to the dispersed droplets (so that they repel each other)
swelling to increase the viscosity of the system (so that droplets are less likely to merge)
Hydrocolloid emulsifiers may be classified as:
vegetable derivatives, e.g., acacia, tragacanth, agar, pectin, carrageenan, lecithin
animal derivatives, e.g., gelatin, lanolin, cholesterol
Semi-synthetic agents, e.g., methylcellulose, carboxymethylcellulose
Synthetic agents, e.g., Carbopols®
Naturally occurring plant hydrocolloids have the advantages of being inexpensive, easy to handle, and nontoxic. Their disadvantages are that they require relatively large quantities to be effective as emulsifiers, and they are subject to microbial growth and thus their formulations require a preservative. Vegetable derivatives are generally limited to use as o/w emulsifiers.
The animal derivatives general form w/o emulsions. Lecithin and cholesterol form a monomolecular layer around the emulsion droplet instead of the typically multimolecular layers. Cholesterol is a major constituent of wool alcohols and it gives lanolin the capacity to absorb water and form a w/o emulsion. Lecithin (a phospholipid derived from egg yolk) produces o/w emulsions because of its strong hydrophilic character. Animal derivatives are more likely to cause allergic reactions and are subject to microbial growth and rancidity. Their advantage is in their ability to support formation of w/o emulsions.
Semi-synthetic agents are stronger emulsifiers, are nontoxic, and are less subject to microbial growth. Synthetic hydrocolloids are the strongest emulsifiers, are nontoxic, and do not support microbial growth. However, their cost may be prohibitive. These synthetic agents are generally limited to use as o/w emulsifiers.
Finely Divided or Finely Dispersed Solid Particle Emulsifiers
These agents form a particulate layer around dispersed particles. Most will swell in the dispersion medium to increase viscosity and reduce the interaction between dispersed droplets. Most commonly they support the formation of o/w emulsions, but some may support w/o emulsions. These agents include bentonite, veegum, hectorite, magnesium hydroxide, aluminum hydroxide and magnesium trisilicate.
Auxiliary
A variety of fatty acids (e.g., stearic acid), fatty alcohols (e.g., stearyl or cetyl alcohol), and fatty esters (e.g., glyceryl monostearate) serve to stabilize emulsions through their ability to thicken the emulsion. Because these agents have only weak emulsifying properties, they are always use in combination with other emulsifiers.
A system was developed to assist in making systemic decisions about the amounts and types of surfactants needed in stable products. The system is called the HLB (hydrophile-lipophile balance) system and has an arbitrary scale of 1 – 18. HLB numbers are experimentally determined for the different emulsifiers. If an emulsifier has a low HLB number, there is a low number of hydrophilic groups on the molecule and it will have more of a lipophilic character. For example, the Spans® generally have low HLB numbers and they are also oil soluble. Because of their oil soluble character, Spans® will cause the oil phase to predominate and form an w/o emulsion.
The higher HLB number would indicate that the emulsifier has a large number of hydrophilic groups on the molecule and therefore should be more hydrophilic in character. The Tweens® have higher HLB numbers and they are also water soluble. Because of their water soluble character, Tweens® will cause the water phase to predominate and form an o/w emulsion.
Combinations of emulsifiers can produce more stable emulsions than using a single emulsifier with the same HLB number. The HLB value of a combination of emulsifiers can be calculated as follows:
e.g. What is the HLB value of a surfactant system composed of 20 g Span 20 (HLB = 8.6) and 5 g Tween 21 (HLB = 13.3)?
Commonly Used Emulsifiers And Their HLB Values
|
Commercial Name |
Chemical Name |
HLB Value |
|
Glyceryl monostearate |
Glyceryl monostearate |
3.8 |
|
PEG 400 Monoleate |
Polyoxyethylene monooleate |
11.4 |
|
PEG 400 Monostearate |
Polyoxyethylene monostearate |
11.6 |
|
PEG 400 Monolaurate |
Polyoxyethylene monolaurate |
13.1 |
|
Potassium oleate |
Potassium oleate |
20.0 |
|
Sodium lauryl sulfate |
Sodium lauryl sulfate |
40 |
|
Sodium oleate |
Sodium oleate |
18 |
|
Span® 20 |
Sorbitan monolaurate |
8.6 |
|
Span® 40 |
Sorbitan monopalmitate |
6.7 |
|
Span® 60 |
Sorbitan monostearate |
4.7 |
|
Span® 65 |
Sorbitan tristearate |
2.1 |
|
Span® 80 |
Sorbitan monooleate |
4.3 |
|
Span® 85 |
Sorbitan trioleate |
13.2 |
|
Triethanolamine oleate |
Triethanolamine oleate |
12 |
|
Tween® 20 |
Polyoxyethylene sorbitan monolaurate |
16.7 |
|
Tween® 21 |
Polyoxyethylene sorbitan monolaurate |
13.3 |
|
Tween® 40 |
Polyoxyethylene sorbitan monopalmitate |
15.6 |
|
Tween® 60 |
Polyoxyethylene sorbitan monostearate |
14.9 |
|
Tween® 61 |
Polyoxyethylene sorbitan monostearate |
9.6 |
|
Tween® 65 |
Polyoxyethylene sorbitan tristearate |
10.5 |
|
Tween® 80 |
Polyoxyethylene sorbitan monooleate |
15.0 |
|
Tween® 81 |
Polyoxyethylene sorbitan monooleate |
10.0 |
|
Tween® 85 |
Polyoxyethylene sorbitan trioleate |
11.0 |
Methods of Emulsion Preparation
Commercially, emulsions are prepared in large volume mixing tanks and refined and stabilized by passage through a colloid mill or homogenizer. Extemporaneous production is more concerned with small scale methods. Several methods are generally available to the pharmacist. Each method requires that energy be put into the system in some form. The energy is supplied in a variety of ways: trituration, homogenization, agitation, and heat.
Continental (Dry Gum, or 4:2:1) Method
The continental method is used to prepare the initial or primary emulsion from oil, water, and a hydrocolloid or “gum” type emulsifier (usually acacia). The primary emulsion, or emulsion nucleus, is formed from 4 parts oil, 2 parts water, and 1 part emulsifier. The 4 parts oil and 1 part emulsifier represent their total amounts for the final emulsion.
In a mortar, the 1 part gum is levigated with the 4 parts oil until the powder is thoroughly wetted; then the 2 parts water are added all at once, and the mixture is vigorously and continually triturated until the primary emulsion formed is creamy white and produces a “crackling” sound as it is triturated (usually 3-4 minutes).
Additional water or aqueous solutions may be incorporated after the primary emulsion is formed. Solid substances (e.g., active ingredients, preservatives, color, flavors) are generally dissolved and added as a solution to the primary emulsion. Oil soluble substance, 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.
English (Wet Gum) Method
In this method, the proportions of oil, water, and emulsifier are the same (4:2:1), but the order and techniques of mixing are different. The 1 part gum is triturated with 2 parts water to form a mucilage; then the 4 parts oil is added slowly, 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 may be added as in the 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.
Bottle (Forbes) Method
This method may be used to prepare emulsions of volatile oils, or oleaginous substances of very low viscosities. It is not suitable for very viscous oils since they cannot be sufficiently agitated in a bottle. This method is a variation of the dry gum method. One part powdered acacia (or other gum) is placed in a dry bottle and four parts 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 forms. It is important to minimize the initial amount of time the gum and oil are mixed. The gum will tend to imbibe the oil, and will become more waterproof.
It is also effective in preparing an olive oil and lime water emulsion, which is self-emulsifying. In the case of lime water and olive oil, equal parts of lime water and olive oil are added to the bottle and shaken. No emulsifying agent is used, but one is formed “in situ” following a chemical interaction between the components. What emulsifying agent is formed?
Beaker Method
When synthetic or non-gum emulsifiers are used, the proportions given in the previous methods become meaningless. The most appropriate method for preparing emulsions from surfactants or other non-gum emulsifiers is to begin by dividing components into water soluble and oil soluble components. All oil soluble components are dissolved in the oily phase in one beaker and all water soluble components are dissolved in the water in a separate beaker. Oleaginous components are melted and both phases are heated to approximately 70°C over a water bath. The internal phase is then added to the external phase with stirring until the product reaches room temperature. The mixing of such emulsions can be carried out in a beaker, mortar, or blender; or, in the case of creams and ointments, in the jar in which they will be dispensed.
Auxiliary Methods
Instead of, or in addition to, any of the preceding methods, the pharmacist can usually prepare an excellent emulsion using an electric mixer or blender. An emulsion prepared by other methods can also usually be improved by passing it through a hand homogenizer, which forces the emulsion through a very small orifice, reducing the dispersed droplet size to about 5 microns or less.
From Pharmpedia
Emulsions are biphasic systems consisting of two immiscible liquids, one of which (the dispersed phase) is finely subdivided and uniformly dispersed as droplets throughout the other phase (the dispersion medium).
The dispersed phase is also called as the internal phase and the dispersion medium as external phase. These immiscible liquids are made miscible by adding a third substance known as emulsifying agent. They stabilize the system by forming a thin film around the globules of the dispersed phase.
Advantages
1. They can mask the bitter taste and odor of drugs, thereby making them more palatable. 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.
Types Of Emulsions
DIFFERENCE BETWEEN O/W AND W/O EMULSIONS
|
S.No |
Oil in water emulsion (o/w) |
Water in oil emulsion (w/o) |
|
1 |
Water is the dispersion medium and oil is the dispersed phase |
Oil is the dispersion medium and water is the dispersed phase |
|
2 |
They are non greasy and easily removable from the skin surface |
They are greasy and not water washable |
|
3 |
They are used externally to provide cooling effect e.g. vanishing cream |
They are used externally to prevent evaporation of moisture from the surface of skin e.g. Cold cream |
|
4 |
Water soluble drugs are more quickly released from o/w emulsions |
Oil soluble drugs are more quickly released from w/o emulsions |
|
5 |
They are preferred for formulations meant for internal use as bitter taste of oils can be masked. |
They are preferred for formulations meant for external use like creams. |
Routes of administration of emulsions
Oral Emulsions: Generally o/w emulsions are used for internal use as the oil is more readily absorbed in a fine state of subdivision through the gastro intestinal tract and secondly the preparation becomes more palatable when water forms the continuous phase, as the medicinal oil is enveloped in a thin film of emulgent which masks the bitter and oily taste of the drug like liquid paraffin. Orally emulsions are also used to facilitate the absorption of the oil soluble drugs like vitamins A,D, E and K.
Example: Liquid Paraffin Oral Emulsion
Liquid Paraffin 500 ml
Methyl cellulose 20 20 g
Vanillin 0.5 g
Chloroform 2.5 ml
Benzoic acid solution 20 ml
Saccharin sodium 0.05 g
Purified Water q.s 1000ml
Uses: Laxative. It acts as an emollient purgative in chronic constipation especially during pregnancy and old age.
Example: Castor oil Emulsion
Castor oil 16 ml
Gum acacia q.s
Water 80 ml
Uses: Purgative
Example: Cod-Liver oil Emulsion
Cod-liver oil 30 ml
Syrup 12 ml
Ferric ammonium citrate 4 g
Cinnamon water q.s. 90 ml
Uses: Source of vitamin A and D. It is used as dietary supplement in infants and children to prevent the occurance of rickets and to improve nutrition in undernourished children and patients with rickets.
Rectal Emulsions: Enemas are formulated as o/w emulsions.
Topical Emulsions: For external use, emulsions may be either o/w or w/o type. Emulsions finds the maximum use in topical preparations , both for therapeutic and cosmetic use. Therapeutically they are used as carrier for a drug. In cosmetic industry o/w emulsions have been used for formulation of moisturing lotions, hand lotions and make up foundation lotions. When oily layers are desired to prevent moisture loss from the surface of skin, for barrier action and for cleansing action, then w/o emulsions are formulated like cold creams.
Example: Antiseptic cream
Cetrimide 1g
Cetostearyl alcohol 10 g
White soft paraffin 10 g
Liquid paraffin 29 g
Purified water 50 g
Uses: Antiseptic cream for the treatment of cuts, wounds and burns.
Example: Cold Cream
Liquid paraffin 20 g
Hard paraffin 4.5 g
Lanette wax 3.5 g
Glycerine 4.5 g
Water 17.5 g
Propyl paraben 0.1 g
Uses: Skin protective and skin smoothner.
EMULSIFYING AGENTS
Tests Used To Identify Emulsion Type
Since emulsion (o/w or w/o) looks the same in appearance with naked eyes, therefore certain tests have been developed to differentiate between them. At least two tests should be done to reach a conclusive decision about the identity of the emulsion.
Dilution test
In this test the emulsion is diluted either with oil or water. If the emulsion is o/w type and it is diluted with water, it will remain stable as water is the dispersion medium but if it is diluted with oil, the emulsion will break as oil and water are not miscible with each other. Oil in water emulsion can easily be diluted with an aqueous solvent whereas water in oil emulsion can be diluted with a oily liquid.
Fig: Dilution Testfor oil in water emulsion
Fig: Dilution test for water in oil emulsion
Conductivity Test
This test is based on the basic principle that water is a good conductor of electricity. Therefore in case of o/w emulsion , this test will be positive as water is the external phase. In this test. An assembly consisting of a pair of electrodes connected to a lamp is dipped into an emulsion. If the emulsion is o/w type, the lamp glows.
Fig: Conductivity test for oil in water emulsion
Fig: Conductivity test for water in oil emulsion
Dye Solubility Test
In this 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 and the dye will dissolve in it to give color but if the scattered globules appear red and continuous phase colorless, then it is w/o type. Similarly if an oil soluble dye such as Scarlet red C or Sudan III is added to an emulsion and the continuous phase appears red, then it w/o emulsion.
Fig: Dye solubility test
Cobalt Chloride Test
When a filter paper soaked in cobalt chloride solution is added to an emulsion and dried, it turns from blue to pink, indicating that the emulsion is o/w type.
Fluorescence Test
If an emulsion on exposure to ultra-violet radiations shows continuous florescence under microscope, then it is w/o type and if it shows only spotty fluorescence, then it is Oil in o/w type.
Instabilities In Emulsions
An emulsion is a thermodynamically unstable preparation so care has to be taken that the chemical as well as the physical stability of the preparation remains intact throughout the shelf life. There should be no appreciable change in the mean particle size or the size distribution of the droplets of the dispersed phase and secondly droplets of the dispersed phase should remain uniformly distributed throughout the system. Instabilities seen in emulsion can be grouped as
Creaming
An emulsion is said to cream when the oil or fat rises to the surface, but remains in the form of globules, which may be redistributed throughout the dispersion medium by shaking. An oil of low viscosity tends to cream more readily than one of high viscosity. Increasing the viscosity of the medium decreases the tendency to cream. Creaming is a reversible phenomenon which can be corrected by mild shaking. The factors affecting creaming are best described by stroke’s law
V= 2r2 (d1-d2) g/9η
Where V= rate of creaming
r=radius of globules
d1= density of dispersed phase
d2= density of dispersion medium
g= gravitational constant
η = viscosity of the dispersion medium
The following approaches can be used for decreasing Creaming
Reduction of globule size: According to stroke’s law, rate of creaming is directly proportional to the size of globules. Bigger is the size of the globules, more will be the creaming. Therefore in order to minimize creaming, globule size should be reduced by homogenization.
Increasing the viscosity of the continuous phase: Rate of creaming is inversely proportional to the viscosity of the continuous phase i.e. more the viscosity of the continuous phase, less will the problem of creaming. Therefore to avoid creaming in emulsions, the viscosity of the continuous phase should be increased by adding suitable viscosity enhancers like gum acacia, tragacanth etc.
Cracking
Occasionally, it happens that 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 emulsioucleus with water and the oil separates out. Cracking of emulsion can be due to addition of an incompatible emulsifying agent, chemical or microbial decomposition of emulsifying agent, addition of electrolytes, exposure to increased or reduced temperature or change in pH.
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 the addition of an electrolyte or by changing the phase volume ratio or by temperature changes. Phase inversion can be minimized by using the proper emulsifying agent in adequate concentration, keeping the concentration of dispersed phase between 30 to 60 % and by storing the emulsion in a cool place.
Points to be considered during formulations of emulsions
Stability of the active ingredient
Stability of the excipients
Visual appearance
Color
Odor (development of pungent odor/loss of fragrance)
Viscosity, extrudability
Loss of water and other volatile vehicle components
Concentration of emulsifier
Order of addition of ingredients
Particle size distribution of dispersed phases
pH
Temperature of emulsification
Type of equipment
Method and rate of cooling
Texture, feel upon application (stiffness, grittiness, greasiness, tackiness, spreadibility)
Microbial contamination/sterility (in the unopened container and under conditions of use)
Release/bioavailability (percutaneous absorption)
Phase distribution, Phase Inversion (homogeneity/phase separation, bleeding
Packaging, Labelling And Storage Of Emulsions
Depending on the use, emulsions should be packed in suitable containers. Emulsions meant for oral use are usually packed in well filled bottles having an air tight closure. Light sensitive products are packed in amber coloured bottles. For viscous emulsions, wide mouth bottles should be used. The label on the emulsion should mention that these products have to be shaken thoroughly before use. External use products should clearly mention on their label that they are meant for external use only. Emulsions should be stored in a cool place but refrigeration should be avoided as this low temperature can adversely effect the stability of preparation.
Preservation Of Emulsions
Preservation from microorganisms:
It is necessary to preserve the emulsions from microorganisms as these can proliferate easily in emulsified systems with high water content, particularly if carbohydrates, proteins or steroidal materials are also present.
Contamination due to microorganisms can result in problems such as color and odor change, gas production, hydrolysis, pH change and eventually breaking of emulsion. Therefore is necessary that emulsified systems be adequately preserved. An ideal preservative should be nonirritant, nonsensitizing and nontoxic in the concentration used. It should be physically as well as chemically compatible with other ingredients of the emulsions and with the proposed container of the product. It should not impart any taste, color or odor to the product. It should be stable and effective over a wide range of pH and temperature. It should have have a wide spectrum of activity against a range of bacteria, yeasts and moulds. The selective preservative should have high water solubility and a low oil/water partition coefficient. It should have bactericidal rather than bacteriostatic activity.
Examples of antimicrobial preservatives used to preserve emulsified systems include parahydroxybenzoate esters such as methyl, propyl and butyl parabens, organic acids such as ascorbic acid and benzoic acid, organic mercurials such as phenylmercuric acetate and phenylmercuric nitrate, quarternary ammonium compounds such as cetrimide, cresol derivatives such as chlorocresol and miscellaneous agents such as sodium benzoate, chloroform and phenoxyethanol.
Preservation from oxidation:
Oxidative changes such as rancidity and spoilage due to atmospheric oxygen and effects of enzymes produced by micro-organisms is seen in many emulsions containing vegetables and mineral oils and animal fats. Antioxidants can be used to prevent the changes occurring due to atmospheric oxygen.
Antioxidants are agents having a high affinity for oxygen and compete for it with labile substances in the formulation. The ideal antioxidant should be nontoxic, nonirritant, effective at low concentration under the expected conditions of storage and use, soluble in the medium and stable. Antioxidants for use in oral preparation should also be odorless and tasteless.
Some of the commonly used antixidants for emulsified systems include alkyl gallate such as ethyl, propyl or dodecyl gallate, butylated sshydroxyanisole (BHT), butylated hydroxytoluene (BHT)
Preparation Of Emulsions
See Main article Methods for preparing emulsions
Properties of emulsion
See Main article Properties of emulsion
PROPERTIES OF EMULSIONS The basic properties which should be present in an emulsion include appearance, feel, odour, desirable viscosity, consistency, effectiveness and stability. These properties depends on the ingredients, type of emulsion, ratio of the two phases, type and quantity of emulsifying agents and method of emulsification . O/w emulsions will generally have a sheen or matte surface as compared to w/o emulsions which have a shiny or oily surface due to the presence of oil as external phase. W/o emulsions are oily and greasy iature, not easily removable from the surface of the skin whereas o/w emulsions are non greasy and easily removable from the skin surface. The viscosity of the emulsions depends generally on the viscosity of the continuous phase. As the ratio of dispersed phase increases, the viscosity also increases to a point where emulsion starts loosing its fluidity.
Quality control tests for Emulsions
The following are the quality control tests done for emulsions:
1. Determination of particle size and particle count: Determination of changes in the average particle size or the size distribution of droplets is an important parameter used for the evaluation of emulsions. It is performed by optical microscopy, sedimentation by using Andreasen apparatus and Coulter counter apparatus.
2. Determination of viscosity: Determination of viscosity is done to assess the changes that might take place during aging. Emulsions exhibit non-newtonian type of flow characterstics. The viscometers which should be used include cone and plate viscometers. Capillary and falling sphere type of viscometrs should be avoided. For viscous emulsions, the use of penetrometer is recommended as it helps in the determination of viscosity with age. 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.
3. Determination of phase separation: This is another parameter used for assessing the stability of the formulation. 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.
Stability testing
Stability of emulsions is an important parameter for the formulator. Stability testing of emulsions involves determining stability at long term storage conditions, accelerated storage conditions, freezing and thawing conditions. Stress conditions are applied in order to speed up the stability testing. The stress conditions used for speeding up instability of emulsions include:
Centrifugal force Agitational force Aging and temperature The following physical parameters are evaluated to assess the effect of any of the above stress conditions:
· Phase separation
· Viscosity
· Electrophoretic properties
· Particle size and particle count
Particle size and size distribution The freeze-thaw cycling technique used to assess emulsions for stress testing for stability testing result in increase of particle growth and may indicate future state after long storage. It is of importance to study the changes for absolute particle size and particle size distribution. It is performed by optical microscopy, sedimentation by using Andreasen apparatus and Coulter counter apparatus. None of these methods are direct methods. However microscopic method allows the observer to view the actual particles.
Rheological studies Cone and Plate viscometer with variable shear stress control can be used for evaluating viscosity of emulsions.
An emulsion is a mixture of two or more liquids that are normally immiscible (nonmixable or unblendable). Emulsions are part of a more general class of two-phase systems of matter called colloids. Although the terms colloid and emulsion are sometimes used interchangeably, emulsion should be used when both the dispersed and the continuous phase are liquids. In an emulsion, one liquid (the dispersed phase) is dispersed in the other (the continuous phase). Examples of emulsions include vinaigrettes, milk, mayonnaise, and some cutting fluids for metal working. The photo-sensitive side of photographic film is an example of a colloid.
The word “emulsion” comes from the Latin word for “to milk”, as milk is (among other things) an emulsion of milk fat and water.
Two liquids can form different types of emulsions. As an example, oil and water can form, firstly, an oil-in-water emulsion, where the oil is the dispersed phase, and water is the dispersion medium. Secondly, they can form a water-in-oil emulsion, where water is the dispersed phase and oil is the external phase. Multiple emulsions are also possible, including a “water-in-oil-in-water” emulsion and an “oil-in-water-in-oil” emulsion.
Emulsions, being liquids, do not exhibit a static internal structure. The droplets dispersed in the liquid matrix (called the “dispersion medium”) are usually assumed to be statistically distributed.
Emulsions contain both a dispersed and a continuous phase, with the boundary between the phases called the “interface”. Emulsions tend to have a cloudy appearance because the many phase interfaces scatter light as it passes through the emulsion. Emulsions appear white when all light is scattered equally. If the emulsion is dilute enough, higher – frequency and low-wavelength light will be scattered more, and the emulsion will appear bluer – this is called the “Tyndall effect”. If the emulsion is concentrated enough, the color will be distorted toward comparatively longer wavelengths, and will appear more yellow. This phenomenon is easily observable when comparing skimmed milk, which contains little fat, to cream, which contains a much higher concentration of milk fat.
Two special classes of emulsions – microemulsions and nanoemulsions, with droplet sizes below 100 nm – appear translucent.[1] This property is due to the fact that light waves are scattered by the droplets only if their sizes exceed about one-quarter of the wavelength of the incident light. Since the visible spectrum of light is composed of wavelengths between 390 and 750 nanometers (nm), if the droplet sizes in the emulsion are below about 100 nm, the light can penetrate through the emulsion without being scattered.[2] Due to their similarity in appearance, translucent nanoemulsions and microemulsions are frequently confused. Unlike translucent nanoemulsions, which require specialized equipment to be produced,[3] microemulsions are spontaneously formed by “solubilizing” oil molecules with a mixture of surfactants, co-surfactants, and co-solvents.[1] The required surfactant concentration in a microemulsion is, however, several times higher than that in a translucent nanoemulsion, and significantly exceeds the concentration of the dispersed phase. Because of many undesirable side effects caused by surfactants, their presence is disadvantageous or prohibitive in many applications. In addition, the stability of a microemulsion is often easily compromised by dilution, by heating, or by changing pH levels.
Common emulsions are inherently unstable and, thus, do not tend to form spontaneously. Energy input – through shaking, stirring, homogenizing, or exposure to power ultrasound[4] – is needed to form an emulsion. Over time, emulsions tend to revert to the stable state of the phases comprising the emulsion. An example of this is seen in the separation of the oil and vinegar components of vinaigrette, an unstable emulsion that will quickly separate unless shaken almost continuously. There are important exceptions to this rule – microemulsions are thermodynamically stable, while translucent nanoemulsions are kinetically stable.[1]
Whether an emulsion of oil and water turns into a “water-in-oil” emulsion or an “oil-in-water” emulsion depends on the volume fraction of both phases and the type of emulsifier (surfactant) (see Emulsifier, below) present. In general, the Bancroft rule applies. Emulsifiers and emulsifying particles tend to promote dispersion of the phase in which they do not dissolve very well. For example, proteins dissolve better in water than in oil, and so tend to form oil-in-water emulsions (that is, they promote the dispersion of oil droplets throughout a continuous phase of water).
Instability
Emulsion stability refers to the ability of an emulsion to resist change in its properties over time.[5] There are four types of instability in emulsions: flocculation, creaming, coalescence and Ostwald ripening. Flocculation occurs when there is an attractive force between the droplets, so they form flocs, like bunches of grapes. Coalescence occurs when droplets bump into each other and combine to form a larger droplet, so the average droplet size increases over time. Emulsions can also undergo creaming, where the droplets rise to the top of the emulsion under the influence of buoyancy, or under the influence of the centripetal force induced when a centrifuge is used.
An appropriate “surface active agent” (or “surfactant”) can increase the kinetic stability of an emulsion so that the size of the droplets does not change significantly with time. It is then said to be stable.
Monitoring physical stability
The stability of emulsions can be characterized using techniques such as light scattering, centrifugation and rheology. Each method has advantages and disadvantages.
Accelerating methods for shelf life prediction
The kinetic process of destabilization can be rather long – up to several months, or even years for some products. Often the formulator must accelerate this process in order to test products in a reasonable time during product design. Thermal methods are the most commonly used – these consist of increasing the emulsion temperature to accelerate destabilization (if below critical temperatures for phase inversion or chemical degradation). Temperature affects not only the viscosity, but also the interfacial tension in the case of non-ionic surfactants, or on a broader scope, interactions of forces inside the system. Storing an emulsion at high temperatures enables the simulation of realistic conditions for a product (e.g. a tube of sunscreen emulsion in a car in the summer heat), but also to accelerate destabilization processes up to 200 times.
Mechanical methods of acceleration, including vibration, centrifugation, and agitation, can also be used.
These methods are almost always empirical, without a sound scientific basis.
Emulsifiers
An emulsifier (also known as an “emulgent”) is a substance that stabilizes an emulsion by increasing its kinetic stability. One class of emulsifiers is known as “surface active substances”, or surfactants.
Examples of food emulsifiers are:
Egg yolk – in which the main emulsifying agent is lecithin. In fact, lecithos is the Greek word for egg yolk.
Mustard – where a variety of chemicals in the mucilage surrounding the seed hull act as emulsifiers
Proteins[which?]
Low molecular weight emulsifiers[which?]
Soy lecithin is another emulsifier and thickener
Pickering stabilization – uses particles under certain circumstances
sodium stearoyl lactylate
DATEM (Diacetyl Tartaric (Acid) Ester of Monoglyceride) – an emulsifier primarily used in baking
Detergents are another class of surfactants, and will physically interact with both oil and water, thus stabilizing the interface between the oil and water droplets in suspension. This principle is exploited in soap, to remove grease for the purpose of cleaning. Many different emulsifiers are used in pharmacy to prepare emulsions such as creams and lotions. Common examples include emulsifying wax, cetearyl alcohol, polysorbate 20, and ceteareth 20.[6] Sometimes the inner phase itself can act as an emulsifier, and the result is a nanoemulsion, where the inner state disperses into “nano-size” droplets within the outer phase. A well-known example of this phenomenon, the “Ouzo effect”, happens when water is poured into a strong alcoholic anise-based beverage, such as ouzo, pastis, arak, or raki. The anisolic compounds, which are soluble in ethanol, then form nano-size droplets and emulsify within the water. The resulting color of the drink is opaque and milky white.
Mechanisms of emulsification
A number of different chemical and physical processes and mechanisms can be involved in the process of emulsification:
Surface tension theory – according to this theory, emulsification takes place by reduction of interfacial tension between two phases
Repulsion theory – the emulsifying agent creates a film over one phase that forms globules, which repel each other. This repulsive force causes them to remain suspended in the dispersion medium
Viscosity modification – emulgents like acacia and tragacanth, which are hydrocolloids, as well as PEG (or polyethylene glycol), glycerine, and other polymers like CMC (carboxymethylcellulose), all increase the viscosity of the medium, which helps create and maintain the suspension of globules of dispersed phase
A. Two immiscible liquids, not yet emulsified
B. An emulsion of Phase II dispersed in Phase I
C. The unstable emulsion progressively separates
D. The surfactant (purple outline around particles) positions itself on the interfaces between Phase II and Phase I, stabilizing the emulsion
Macroemulsions – At least one immiscible liquid dispersed in another as drops whose diameters generally exceed 100 nm. The stability is improved by the addition of surfactants and/of finely divided solids. Considered only kinetically stable.
Miniemulsions – An emulsion with droplets between 100 and 1000 nm, reportedly thermodynamically stable.
Microemulsions – A thermodynamically stable, transparent solution of micelles swollen with solubilizate. Microemulsions usually require the presence of both a surfactant and a cosurfactant (e.g. short chain alcohol).
Emulsion stability
ΔF =σΔA < 0
Drops coalesce spontaneously.
+
ΔF =σΔA+ work of desorption
If the work of desorption is high, the coalescence is prevented.
Surface activity in emulsions
Emulsions are dispersions of droplets of one liquid in another.
Emulsifiers are soluble, to different degrees, in both phases.
Electrostatic stabilization – at lower volume fractions
Steric stabilization – at all volume fractions
Additional factors –
1. Steric stabilization is enhanced by solubility in both phases:
2. Mixed emulsifiers (cosurfactants) are common. They can come from
either phase.
3. Temperature is important – solubility changes quickly.
“The emulsifier stabilizes the emulsion type where the continuous phase is the medium in which it is most soluble.”
The long tail on the surfactant is to represent the longer range interaction of a “hydrophobic” molecule through oil.
Intermittent milling
