Characteristics of Surfactants and Emulsions
A surface active agent (surfactant) possesses approximately an equal ratio between the polar and nonpolar portions of each molecule. When placed in an oil-water system, the polar groups are attracted to or orient toward the water, and the nonpolar groups are oriented toward the oil. The surfactant molecule lowers the interfacial tension between the oil and water phases.
Realizing that the surfactant is adsorbed at the interface and by assuming that it is adsorbed in a monomolecular layer, the amount of emulsifing agent required to emulsify a given volume of a liquid to a certain globular size can be calculated. The molecular weight and the cross-sectional area occupied by a molecule of the surfactant must be known.
Surfactants are classified as cationic, anionic and nonionic based on the type of polar group on the surfactant. Cationic surfactants are often used as antibacterial agents because of their ability to disrupt the cell membrane of the microorganism. The ionized surfactants have a relatively high water solubility and thus generally make oil in water emulsions. The nonionic surfactants, however, can be used to make either type of emulsion.
EMULSIONS: PREPARATION AND STABILIZATION
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.
The consistency of emulsions varies from easily pourable liquids to semisolid creams. Their consistency will depend upon:
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.
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 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:
Hydrocolloid emulsifiers may be classified as:
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 Emulsifying Agents
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.
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 crushed 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?
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.
Schematic structure of amphiphiles and of their self-assembled supramolecular aggregates.
To assist formulators in the selection of an appropriate surfactant, the HLB score was developed.
HLB stands for hydrophile-lipophile balance. Surfactants with a low HLB are more lipid loving and thus tend to make a water in oil emulsion while those with a high HLB are more hydrophilic and tend to make an oil in water emulsion. The HLB value of each surfactant is determined by an analysis of the characteristics of the surfactant. A list of HLB values for various surfactants is available in many references such as the Handbook of Pharmaceutical Excipients, 3rd Edition.
Calculation of HLB
For the surfactant CH3(CH2)17-(OCH2CH2)3OH
First find the formula weight of the molecule = 403
FW of head group = 44X3 + 17 = 149
HLB = (FW of head group/FW of molecule) * 20 = 7.4
HLB = (149/403) * 20 = 7.4
For the molecule:
For the surfactant CH3(CH2)17-(OCH2CH2)20OH
FW of molecule = 1150
FW of head group = 44X20 + 17 = 897
HLB = (FW of head group/FW of molecule) * 20
HLB = (897/1150) * 20 = 15.6
You should observe the increase in HLB as the head group becomes more polar.
Here is the generalized equation you must solve in order to determine the ratios of emulsifying agents to be used in your specific formula:
HLB requirement = (HLB A x Fraction A) + (HLB B x Fraction B) + …
This equation is easy to solve for simple systems but becomes more complex as the number of emulsifiers increases. For a two emulsifier system, use this equation:
(HLB req – HLB B) / (HLB A – HLB B) = amount (fraction) of material A required
The amount of material B required equals 1 – A (amount of material A required, as calculated above).
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)?
The HLB values of the surfactants are additive and the HLB value of the blend can be determined . For example, the HLB value of a 60% Tween 80(HLB of 15) and 40 % Aracel 80 (HLB of 4.3) is
4.3 X 0.4 = 1.7
Tween 80 15.0 X 0.6 = 9.0
Some oils require different HLB surfactants to form the most stable emulsion. The required HLB value for some of the most common oils used in pharmaceutical emulsions have been determined experimentally. Mixtures of these material will need a surfactant that matches the average HLB requirement of the oil components of the emulsion.
Several factors can influence the stability of your emulsions. Think of your emulsion as a lava lamp. You have colorful oil droplets drifting around inside the water. Similarly, depending upon whether you are making an oil in water (O/W) emulsion or a water in oil (W/O) emulsion, your lotion’s emulsion consists of small droplets of one material (either oil or water) dispersed amongst the larger body of the other material (either oil or water).
In order to keep your emulsion stable, you must use the correct amount and type of emulsifier. This keeps the small droplets dispersed properly. One rule of thumb to keep in mind:
For O/W emulsions: one part oil to 2 parts water
For W/O emulsions: one part water to 2 parts oil
These are maximum measurements. Tighter emulsions are formed when using less than these amounts. Try to stay to a ratio of 1:3 or 1:4 or more.
Each oily material requires a To ensure that you are using the correct emulsifier/s given the outcome of the above calculation, you must figure which combination of emulsifiers is appropriate. Do not be fooled into thinking that just because you use only one or two vegetable oils that one emulsifier will do. Even emulsifying wax (e-wax) is a combination of more than one emulsifier.
As we mentioned previously, the more emulsifiers used, the more complex the equation becomes. Fortunately, there are ways to Oh, But There’s More!
The HLB match is not your only consideration. Several other factors may influence the stability of an emulsion.
Thermal Inversion Phenomena
This issue can come into play in both processing and stability in use.
Under normal circumstances, the emulsifier molecule will stay oriented in the correct direction. That is to say, the water-loving end (polar) stays in the water while the oil-loving end (non-polar) stays in the oil. Each end of the emulsifier molecule may have minor solubility in the opposite phase. Usually, they stay put, preferring to be with their own.
Generally, solubility (the ability to leave its own and break out of the emulsion) increases as temperature increases. Once this inversion begins, the emulsion becomes unstable and breaks apart. The specific temperature at which this destabilization takes place is known as the “phase inversion temperature.”
Low phase inversion temperatures can limit processing as an emulsion will not form. This is why we recommend processing at no more than 140F. We have all seen the result of summer’s heat on a lotion – especially those left to simmer in a closed car.