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Paper Coordinator
Content Reviewer
Dr. Vijaya Khader Dr. MC Varadaraj
Principal Investigator
Dr. Vijaya Khader
Former Dean, Acharya N G Ranga Agricultural University
Content Writer
Prof. Farhan J Ahmad
Jamia Hamdard, New Delhi Paper No: 05 Product Development 1
Module No: 33 Emulsions Part 1
Development Team
Dr. Gaurav Kumar Jain Jamia Hamdard, New Delhi
Prof Roop K. Khar
BSAIP, Faridabad
Prof. Dharmendra.C.Saxena SLIET, Longowal Dr. Gaurav Kumar Jain Jamia Hamdard, New Delhi
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Introduction
A precise definition of the term emulsion depends on the observer’s point of view. The physical chemist defines an emulsion as a thermodynamically unstable mixture of two essentially immiscible liquids. For the product development technologist, it is more useful to regard an emulsion as an intimate mixture of two immiscible liquids that exhibits an acceptable shelf life near room temperature.
When two immiscible liquids are mechanically agitated, both phases initially tend to form droplets.
When the agitation is stopped, the droplets quickly coalesce, and the two liquids separate. The lifetime of the droplets is materially increased if an emulsifier is added to the two immiscible liquids. Usually, only one phase persists in droplet form for a prolonged period of time. This phase is called the internal (disperse or discontinuous) phase, and it is surrounded by an external (continuous) phase. An assembly of close-packed monodisperse spherical droplets as the internal phase can occupy no more than approximately 74% of the total volume of an emulsion. It is evident, however, that the internal phase can exceed 74% if the spherical particles are not mono-disperse (as in most emulsions). A further increase in the ratio of internal external phase can result if the internal, phase is assumed to consist of polyhedra rather than spheres.
An emulsifier functions and is operationally defined as a stabilizer of the droplet form (globules) of the internal phase. On die basis of their’ structure, emulsifiers (wetting agents or surfactants) may be described as molecules comprising both hydrophilic (oleophobic) and hydrophobic (oleophilic) portions.
For this reason, misgroup of compounds is frequently called amphiphilic (i.e., water- and oil-loving).
It is almost universally accepted that the term emulsion should be limited to liquid-in-liquid systems.
Emulsions are normally formed by “mixing” two immiscible liquids. If necessary, the two phases are heated to ensure that they are liquids during emulsification. The most; common types of pharmaceutical or cosmetic emulsions include water as one of die phases and an oil or lipid as the other. If the oil droplet are dispersed in a continuous aqueous phase, the emulsion is termed oil-in-water (o/w); if the oil is the continuous phase, the emulsion is of 1 the water-in-oil type (w/o). It has been observed that o/w emulsions occasionally change into w/o, emulsions and vice versa. This change of emulsion type is called inversion.
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Since approximately 1978, two additional types of emulsions, classified as multiple emulsions, received the attention of surface chemists. It is entirely feasible to prepare a multiple emul-sion with die characteristics of oil-in-water-in-oil (o/w/o) or of water-in-oil-in-water (w/o/w) emulsions. Such emulsions also can invert; however, during inversion they usually form “simple” emulsions. Thus, a w/o/w emulsion normally yields an o/w emulsion.
The particle size of the disperse phase determines the appearance of an emulsion. The radius of the emulsified droplets in an opaque, usually white, emulsion ranges from 0.25 to 10 microns. It is fairly well established that dispersed particles having a diameter of less than V4 the wave length of visible light, i.e., less than approximately 120 nm, do not refract light and therefore appear transparent to the eye. Dispersions of a liquid to such small particle sizes yield microemulsions or micellar emulsions.
Often, these terms are erroneously used interchangeably because such emulsions appear transparent to the human eye in daylight. In a microemulsion, disperse globules having a radius below the range of 10 to 75 nm are present.
The production of a transparent dispersion of an oil by micellization does not result in the formation of droplets, but in the inclusion of the lipid into micelles, which may, but need not, possess spherical shapes.
In terms of size, mi-celles have dimensions ranging from about 5 to 20 nm. To the practicing technologist, transparent emulsions, solubilized oils, micellar emulsions, and microemulsions are one and the same because they appear clear. However, solubilization in any form represents an entirely different phenomenon, from that of emulsification.
APPLICATION AND UTILITY
Emulsions are sometimes difficult to prepare and require special processing techniques. To warrant this type of effort and to exist as useful dosage forms, emulsions must possess desirable attributes and cause a minimum of associated problems. The “mixing” of immiscible liquids for various purposes has been met by the emulsification process for centuries. Today, emulsions continue to have a variety of cosmetic and pharmaceutical applications. The latter may be further classified by route of administration, i.e., topical, oral, or parenteral. In principle, cosmetic applications and topical pharmaceutical applications are similar and together form one of the most important groups of emulsions.
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(i) Patient acceptance undoubtedly is the most important reason why emulsions are popular oral and topical dosage forms. Many medicinal agents have an objectionable taste or texture, and can be made more palatable for oral administration when formulated into emulsions. As a result, mineral oil-based laxatives, oil-soluble vitamins, and high-fat nutritive preparations are commonly administered as o/w emulsions.
(ii) The utility of orally administered emulsions resides in their efficacy, i.e., absorption or bioavailability of the drug. It has been demonstrated that some drugs are more readily absorbed when they are administered orally in the form of emulsions. It has even been reported that normally unabsorbable macromolecules, such as insulin and heparin, are absorbed when they are incorporated into emulsions.
(iii) Patient acceptance is also important in topically applied emulsions. Emulsions possess a certain degree of elegance and are easily washed off whenever desired. In addition, the formulator can control the viscosity, appearance, and degree of greasiness of cosmetic or dermatologic emulsions.
(iv) With regard to emulsion type, o/w emulsions are most useful as water-washable drug bases and for general cosmetic purposes. W/o emulsions are employed more widely for the treatment of dry skin and emollient applications. The utility of topical emulsions depends on their ability to “penetrate.” This much abused term has entirely different meanings to the layman and to the technologist. To the former, rapid
“penetration” is desirable and refers to the disappearance of the product or of oiliness from the skin during injunction. It is generally believed that this process of penetration into the skin is facilitated if the emulsion is thixotropic, i.e., if it becomes less viscous during shearing. To the technologist, penetration of the vehicle is of secondary importance; instead, rapid and efficient penetration of the drug moiety to the site that needs to be treated is desired.
(v) Emulsions have been used for the intravenous administration of lipid nutrients, which is facilitated by emulsification and probably would be impossible unless the lipid were in the form of an emulsion.
Such emulsions of the o/w type require most rigorous control of the emulsifying agent and/or particle size.
Some other pharmaceutical and clinical applications of emulsions include the following: (vi) radiopaque emulsions have been used as diagnostic agents in X-ray examinations. (vii) w/o emulsions have been employed to disperse water-soluble antigenic materials in mineral oil for intramuscular depot injection.
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The presence of emulsifiers in injectable drugs that are relatively insoluble in water (or serum) may help lower the tendency of the drug to crystallize and cause thrombophlebitis. (viii) Emulsification of perfluorinated hydrocarbons is required to make them useful as oxygen carriers in blood replacements.
(ix) Emulsions also possess an important cost advantage over single-phase preparations. Most lipids and solvents for lipids that are intended for application to or into the human body are relatively costly. As a result, dilution with a safe and inexpensive diluent, such as water, is highly desirable from an economic point of view as long as efficacy or performance is not impaired.
THEORY OF EMULSIFICATION DROPLET STABILIZATION
Two conceptual alternatives exist for creating opaque, i.e., milky-appearing, emulsions. Such dispersions can be formed and stabilized by lowering the interfacial tension and/or by preventing die coalescing of droplets. According to classic emulsion theory, emulsifying agents are capable of performing both objectives. The materials commonly used as emulsifying agents can be divided into three categories:
surface-active, hydrophilic colloids, and finely divided solids. They reduce interfacial tension, and they act as barriers to droplet coalescence since they are adsorbed at the interface, or more precisely, on the surface of die suspended droplets. Emulsifying agents assist in the formation of emulsions by three mechanisms:
1. Reduction of interfacial tension—thermodynamic stabilization.
2. Interfacial film formation — mechanical barrier to coalescence.
3. Electrical repulsion— electrical barrier to approach of particles.
Reduction of Interfacial Tension
The adsorption of a surfactant lowers the interfacial tension between two liquids. A reduction in attractive forces of dispersed liquid for its own molecules lowers the interfacial free energy of the system and prevents the coalescence or phase separation. Even though reduction of interfacial tension lowers the interfacial free energy produced on dispersion, it is the role of emulsifying agents as interfacial barriers that is most important. This can be seen clearly when one considers that many polymers and finely
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divided solids, not efficient in reducing interfacial tension, form excellent interfacial barriers, act to prevent coalescence, and are useful as emulsifying agents.
Interfacial Film formation
It could be considered as an extended interfacial tension theory, in which the adsorbed emulsifier at the interface surrounds the dispersed droplets forming a coherent monomolecular or multimolecular film, which prevents the coalescence, as the droplets approach each other. The stability of the emulsions depends on the characteristics of the film formed at the interface which in turn depends upon type of emulsifier.
Surface active agents – Monomolecular film formation
The formation of films by an surfactant on the surface of water or oil droplets has been studied in great detail. It is reasonable to expect an amphiphilic molecule to align itself at a water-oil interface in the most energetically favorable position-oleophilic portion in the oil phase and hydrophilic portion in the aqueous phase. It is also well established that the surface-active agents tend to concentrate at interfaces and that emulsifiers are adsorbed at oil-water interfaces as monomolecular films. These monomolecular films formed at the interface depend upon the nature, characteristics and concentration and combination of surfactant.
Gaseous films. In gaseous films, the adsorbed surfactant molecules separate, do not adhere to each other laterally, and move freely around the interface. One example of a gaseous film is that formed by anionic surfactant, sodium dodecyl sulfate. The charged sulfate head groups repel one another in the aqueous solution as the droplet covered with the film moves closer to another. When the film is strongly anchored to the dispersed phase droplet, the emulsion is stable. If the monolayer film is loosely fixed, the adsorbed molecules move away from the interface and coalescence occurs.
Condensed films. If the concentration of the emulsifier is high enough, it forms a rigid film between the immiscible phases, which acts as a mechanical bar to both adhesion and coalescence of the emulsion droplets. The molecules of the long straight-chain fatty acids, such as palmitic and stearic acids, are more tightly packed and the film steeply rises from the compression. The hydrocarbon chains are adjacent to and in cohesive contact with one another. As the chains interlock, the molecules do not freely move in the interface leading to a stable emulsion.
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Expanded films. The films formed by oleic acid are more expanded film than palmitic and stearic acids do. The hydrocarbon chains in oleic acid are less cohesive and less orderly packed in the liquid than those in stearic acid. The unsaturated double bond is polar and has a greater affinity for water. The presence of branched and bent-shaped hydrocarbon chains, bulky head groups and multiple polar groups causes lateral cohesion to be reduced and expanded films to form. Nonionic surfactants produce the same interfacial films in a similar fashion as that mentioned above. As expected, there is no charge repulsion contribution, however, the polar polyoxyethylene groups of the surfactants are hydrated and bulky, causing steric hindrance among droplets and preventing coalescence.
Interfacial complex condensed films. Measurements of the area occupied by a single molecule of surface-active agent at the interface of emulsion droplets have shown that in stable emulsions, the molecules of surface-active agents are in fact closely packed and form a tough interfacial film. To improve stability, the combinations of surfactants are often used rather than a single surfactant.
Combination of a water-soluble surfactant that produces a gaseous film, and an oil-soluble auxiliary surfactant produce a stable interfacial complex condensed film. This film is flexible, highly viscous, coherent, elastic, and resistant to rupture since the molecules are efficiently packed between each other.
Lamellar liquid crystalline films. Recent studies have helped to clarify further the nature of these interfacial films. Stable emulsions are now believed to comprise liquid crystalline layers on the interface of emulsified droplets with the continuous phase.7-9 In their pioneering studies, Friberg and co-workers were able to show by optical (polarized light) and electron microscopy and low-angle x-ray diffractometry that mixed emulsifiers can interact with water to form three-dimensional association structures. The classic concept of emulsions as two-phase systems with a monomolecular layer of emulsifier at the interface must be revised. Emulsions should instead be viewed as three-component systems comprising oil, “water, and lamellar liquid crystals, the latter consisting of consecutive layers of water-emulsifier-oil-water (Figure 1).
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FIG. 1. A lamellar liquid crystal consists of consecutive layers of water - emulsifier - oil - emulsifier - water.
Interlamellar layers representing the internal and external phases of an emulsion have recently been identified by freeze fracture micrography of o/w creams. In addition, it has recently been learned that emulsion droplets can be surrounded by liquid crystals of a closed lamellar type in appropriately prepared emulsions.
Hydrophilic colloids – Multimolecular film formation
Hydrophilic colloids such as polysaccharides and proteins do not lower appreciably the interfacial tension but form a multimolecular film at the oil–water interface (Figure 2). The multimolecular films are strong and elastic and give mechanical protection to coalescence. An additional effect of these hydrophilic colloids is the electrostatic charge repulsion due to carboxylic acid groups of polysaccharides and the amino acid groups of the proteins. Hydrophilic colloids, are used to stabilize emulsions and form O/W-type emulsions.
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FIG.2. Multimolecular film formed by hydrophilic colloids.
Finely Divided Solids – Solid particle film formation
Finely divided solid particles are lodged at the interface, adhere strongly to each other, forming a stable film at the surface. They formed stable emulsions by preferentially wetting one of the phases (Fig 3).
When wetted by water, the contact angle is less than 90°, and O/W-type emulsions are formed, while when wetted by oil, W/O-type emulsions are formed.
FIG. 3. Adsorption of finely divided solid particles on liquid droplets.
Electrical Repulsion
It has just been described how interfacial films or lamellar liquid crystals significantly alter the rates of coalescence of droplets by acting as barriers. In addition, the same or similar film can produce repulsive electrical forces between approaching droplets. Such repulsion is due to an electrical double layer, which may arise from electrically charged groups oriented on the surface of emulsified globules. To simplify, let us consider the case of an o/w emulsion stabilized by a sodium soap. Not only are the molecules of this surfactant concentrated in the interface, but because of their polar nature, they are oriented as well (Fig. 4). The hydrocarbon tail is dissolved in the oil droplet, while the ionic heads are facing the continuous aqueous phase. As a result, the surface of the droplet is studded with charged groups, in this case negatively charged carboxylate groups. This produces a surface charge on the droplet, while cations of opposite sign are oriented near the surface, producing what is known as the (diffuse) double layer of charge.
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FIG. 4. Idealized representation of the electrical double layer at an oil-water interface.
The potential produced by the double layer creates a repulsive effect between the oil droplets and thus hinders coalescence. Although the repulsive electrical potential at the emulsion interface can be calculated, it cannot be measured directly for comparison with theory. The related quantity, however, zeta potential, can be determined. The zeta potential for a surfactant-stabilized emulsion compares favorably with the calculated double-layer potential. In addition, the change in zeta potential parallels rather satisfactorily the change in double-layer potential as electrolyte is added. These and related data on the magnitude of the potential at the interface can be used to calculated the total repulsion between oil droplets as a function of the distance between them.
EMULSION TYPE
Only o/w and w/o emulsions have achieved commercial and practical importance. To understand the various factors that determine whether an o/w or a w/o emulsion will be produced, one must again think in terms of two critical features: (1) droplet formation and (2) formation of an interfacial barrier. The phase volume ratio, i.e., the relative amount of oil and water, determines the relative number of droplets formed initially and hence the probability of collision; the greater the number of droplets, the greater is the chance for collision. Thus, normally, the phase present in greater amount becomes the external phase.
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To predict the type of emulsion formed under a given set of conditions, the interaction of various parameters must be estimated. This estimation is nearly impossible, and only a few generalized and somewhat empiric rules can be given.
Despite these complications, one can expect a predominantly water-soluble emulsifier to form o/w emulsions, whereas the reverse is true of primarily oil-soluble surfactants - Bancroft’s Rule.
Occasionally, it is desirable to determine the type of emulsion formed. Methods for. this purpose are shown in Table 1.
TABLE 1. Methods for the Determination of Emulsion Type
Test Observation Comments
Dilution test Emulsion can be diluted only with external
phase. Useful for liquid emulsions only.
Dye test Water-soluble solid dye tints only o/w emulsions and reverse. Microscopic observation usually helpful.
May fail if ionic emulsifiers are present.
CoCl2/fllter paper Filter paper impregnated with CoCl2 and dried (blue) changes to pink when o/w emulsion is added.
May fail if emulsion is unstable or breaks in presence of electrolyte.
Fluorescence Since oils fluoresce under UV light, o/w emulsions exhibit dot pattern, w/o emulsions fluoresce throughout.
Not always applicable.
Conductivity Electric current is conducted by o/w emulsions,
owing to presence of ionic species in water. Fails in nonionic o/w emulsions.
Microemulsions. Operationally, micro-emulsions may be defined as dispersions of insoluble liquids in a second liquid that appear clear and homogeneous to the naked eye. Microemulsions are frequently called solubilized systems because on a macroscopic basis they seem to behave as true solutions. Careful examination of these complex systems has shown that clear emulsions can exist in several differentiable forms. Microemulsions should not be confused, however, with solutions formed by cosolvency, e.g., the clear system consisting of water, benzene, and ethanol.
Blending of a small amount of oil with water results in a two-phase system because “water and oil do not mix.” If the same small amount of oil is added to an aqueous solution of a suitable surfactant in the
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micellar state, the oil may preferentially dissolve in the interior of the micelle because of its hydrophobic character. This type of micellar microemulsion, has also been called an o/w micellar solution. Similarly, w/o solubilization-especially that by a nonionic surfactant-has recently been attributed to the existence of swollen micelles. In these systems, sometimes called reverse micellar solutions, water molecules are found in the polar central portion of a surfactant micelle, the nonpolar portion of which is in contact with the continuous lipid phase. A third type of microemulsion (usually of the w/o type) is formed by ionic surfactants (e.g., sodium stearate) in the presence of cosurfactants (e.g., pentanol or dioxyethylene dodecyl ether) with hydrocarbons (e.g., hexadecane) and water. The pseudo-ternary phase representing the existence of various emulsions and micellar system is shown in Figure 5.
In general, microemulsions or solubilized systems are believed to be thermodynamically stable.
Transparent or clear emulsion in which a water-insoluble oil or drug is “dissolved” in an aqueous surfactant system play an important role in drug administration.
FIG. 5. Pseudo-ternary phase diagram illustrating the existence of emulsion and micellar system.
FORMULATION COMPONENTS
It is difficult to designate a general approach or a set of rules for selecting the components and their amounts to yield a desired emulsion. The ingredients of any pharmaceutical or cosmetic emulsion must conform to various requirements. There are situations in which certain oils, emulsifiers, and other
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ingredients must be avoided or used exclusively. Usually, however, ingredient selection is made on the basis of the experience and personal tastes of the formulator and by trial and error. Formulators are cautioned to establish the safety and regulatory acceptance of emulsion ingredients for a particular application.
Lipid Phase
The materials making up the oil portion of an emulsion and their relative amounts are determined primarily by the ultimate use of the product. For pharmaceutical and cosmetic products, the oil phase, unless it is the active ingredient, may include a wide variety of lipids of natural or synthetic origin. The consistency of these lipids may range from mobile liquids to fairly hard solids.
A drug in an emulsion type of dosage form distributes itself between the oil phase and the aqueous phase in accordance with its oil/water partition coefficient. The drug’s absorption by the gastrointestinal tract or the skin can be expected to depend on its solubility in the oil phase. In principle, the less soluble an active ingredient is in the nonvolatile portion of the vehicle, the more readily it penetrates into and through a barrier. On the other hand, a finite solubility of the active ingredient in the vehicle is necessary to ensure its presence in a fine state of subdivision. It is generally accepted that the release of a medicinal agent from a dosage form is a function of the solubilities of the agent in the base and in the body membrane. The key point is that the drug must not be so soluble preferentially in the base that it prevents penetration or transfer.
A final consideration in the selection of a lipid component for a topical preparation is its “feel.”
Emulsions normally leave a residue of the oily components on the skin after the water has evaporated.
Therefore, the tactile characteristics of the combined oil phase are of great importance in determining consumer acceptance of an emulsion.
Phase Ratio. The ratio of the internal phase to the external phase is frequently determined by the solubility of the active ingredient, which must be present at a pharmacologically effective level. If this is not the primary consideration, the phase ratio is normally determined by the desired consistency. As a rule of thumb, it can be assumed that fluid emulsions result from low levels of the internal phase, whereas heavier emulsions are the result of higher percentages of the internal phase. Also, a high internal phase
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ratio normally requires a high level of emulsifying agent; this point affects the decision concerning the phase ratio.
Emulsifying Agents
It is customary to differentiate three broad classes of emulsifying agents: the surfactants, the hydrophilic colloids, and the finely divided solids. Although hydrophilic colloids and finely divided solids can be used as the only emulsifier, their greatest utility is in the form of auxiliary emulsifiers; accordingly, they are discussed under this heading. A particular class of emulsifier is selected primarily on the basis of required “shelf-life” stability, the type of emulsion desired, and emulsifier cost.
Surface active agents or surfactants
Substances having both hydrophilic and hydrophobic regions in their molecular structures are called surface active agents or surfactants (Figure 6). These materials are soluble in both water and oil. Upon addition of the surfactants into the dispersed system, the hydrophilic (polar) and hydrophobic (nonpolar) groups orient themselves in a monomolecular layer facing the polar (i.e., water) and nonpolar (i.e., oils) solvents, respectively. Surfactants diffuse from the solution onto the interface where adsorption and accumulation take place. The interfacial tension must be lowered for the interface to expand and if the interfacial tension is decreased sufficiently, the dispersed system will readily be emulsified.
FIG. 6. Representative structure of surface active agent
As the concentration of surfactant in an aqueous solution is increased, the interfacial tension is appreciably lowered. Further addition leads to a saturated level at the surface where the surfactant molecules are closely packed. Beyond saturation the excess surfactant moves into the bulk and form micelles within the aqueous solution and there is no longer a change in the surface tension.
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The number of surfactants available for the formation of emulsions is so huge that even a cursory description is impossible. Surfactants are classified into four main categories depending on the nature of the charge carried by the hydrophilic part of the surfactant: anionic, cationic, nonionic, and ampholytic surfactants. (Table 2).
Anionic surfactants are negatively charged in an aqueous solution (i.e., COO,), and widely used because of their cost and performance. Sodium lauryl sulfate, the main component of which is sodium dodecyl sulfate, is highly soluble in water and commonly used to form oil-in-water (O/W) emulsions.
Reacting an alkali hydroxide with a fatty acid (e.g., oleic acid) can produce alkali metal soaps (e.g., sodium oleate). Careful attention must be paid to the pH of the dispersion medium and the presence of multivalent metals. Alkali earth metal soaps (e.g., calcium oleate) produce stable water-in-oil (W/O) emulsions because of their low water solubility and are produced by reacting oleic acid with calcium hydroxide. Triethanolamine stearate produces stable O/W emulsions in situ by reacting triethanolamine in aqueous solution with melted stearic acid at approximately 65C (e.g., vanishing cream).
Cationic surfactants are positively charged in an aqueous solution (e.g., quaternary ammonium and pyridinium), and expensive. Because of their bactericidal action, they are widely used for other applications such as preservatives, sterilizing contaminated surfaces, and emulsions.
Nonionic surfactants consist of a (CH2CH2O)nOH or OH as the hydrophilic group and exhibit a variety of hydrophile–lipophile balances (HLB) which stabilize O/W or W/O emulsions. Unlike anionic and cationic surfactants, nonionic surfactants are useful for oral and parenteral formulations because of their low irritation and toxicity. Based on their neutral nature, they are much less sensitive to changes in the pH of the medium and the presence of electrolytes. The best use of nonionic surfactants is to produce an equally balanced HLB of two nonionic surfactants: one hydrophilic and one hydrophobic. Sorbitan esters (Spans) are the products of the esterification of a sorbitan with a fatty acid. Their hydrophilicity comes from the hydroxyl groups of the saturated cyclic ring. They are not soluble in water and used for W/O-type emulsions. Polysorbates (Tweens), on the other hand, are soluble in water since a number of ethylene oxides are adducted by the hydroxyl groups of the sorbitan esters. They are hence used as emulsifying agents for O/W emulsions. In general, both sorbitan esters and polysorbates are used in conjunction to produce a wide range of emulsions. Fatty alcohol polyoxyethylene ethers are condensation
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products of fatty alcohols with polyethylene glycol, while fatty acid polyoxyethylene esters are esterification products of fatty acids with polyethylene glycol. They are soluble in water and used in conjunction with auxiliary emulsifying agents (e.g., cetyl and stearyl alcohols) to give O/W emulsions.
Ampholytic surfactants possess both cationic and anionic groups in the same molecule and are dependent on the pH of the medium. Lecithin is used for parenteral emulsions.
TABLE 2. Classification of Surfactants for Pharmaceutical Emulsions Surfactant Typical
representative
Utility Chemical Structure
Anionic surfactants
Soaps Sodium oleate T
Sodium palmitate T
Sulphates Sodium lauryl sulfate TO
Ether sulphates
Sodium laureth sulphate
Benzene sulphonate
4-benzyl dodecane sulphonate sodium
T
Hemiesters Sodium dioctyl sulfosuccinate
TO
Sarcosides Lauryl sarcosinate TO Cationic surfactants
Amines Tetradecyl methyl amine
T
Quaternary ammoniums
Bezalkonium chloride TO
Hexadecyltrimethyl ammonium chloride
TO
Cetrimide TO
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Miscellaneous Cetylpyridinium chloride
T Nonionic surfactants
Ethoxylated alcohols
Tridecanol TO
Ethoxylated amides
Di-acyl ethoxy urea
Fatty acid esters
Sorbitan monostearate (Span 60)
TO
Polyoxyethylene sorbitan monolaurate (Polysorbate 20 or Tween 20)
TO
Glycerol trimer TO
Ampholytic surfactants
Ammonium phosphates
Lecithin TOP
Amino
propionic acids
TO
Quaternary compounds
Betain TO
sulfobetain TO
T = some representatives useful in topicals.
O = some representatives useful in oral preparations or ingested drugs.
P = some representatives useful in parenterals.
Hydrophilic-Lipophilic Balance (HLB) concept
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Emulsion technologists have for many years selected emulsifiers from an intuitive knowledge of their hydrophilic, lipophilic behavior and of the type of emulsion produced with a given lipid or aqueous phase. This approach is most readily illustrated with nonionic surfactants, but the principles involved can be extrapolated to any type of emulsifier or combination of emulsifiers. It is apparent that the choice of specific emulsifiers by this method, although practical, is empiric and tedious. To systematize the hydrophilic/lipophilic approach to emulsifier selection, Griffin in 1947 developed the (still somewhat empiric) system of the HLB of surfactants. The HLB value of an emulsifier can be determined experimentally or can be computed as long as the structural formula of the surfactant is known.
The HLB values of the surfactants based on polyhydric alcohol fatty acid esters may be estimated by:
HLB=20(1 −𝑆
𝐴) (8)
where S is the saponification number of the ester and A is the acid number of the fatty acid. If one cannot obtain the saponification numbers (e.g., beeswax and lanolin derivatives), their HLB values may be calculated by:
(9)
Where E is the weight percent of oxyethylene chains in the surfactant and P is the weight percent of the polyhydric alcohol groups (e.g., glycerol or sorbitol) in the material. If the hydrophilic region is polyoxyethylene, the HLB value is calculated by:
(10)
Another useful means of finding the HLB of an unknown emulsifier is that proposed by Davies, which permits calculation of the HLB value by algebraically adding the values assigned to a particular atomic grouping within the molecule of the emulsifier.
HLB of surfactant = ∑ (hydrophilic groups) - ∑ (hydrophobic groups) +7 (11)
Occasionally, it will be found that a single emulsifier can yield the desired type of emulsion at the desired viscosity. More often, however, especially in the case of o/w emulsions, stable emulsions can be prepared readily by utilizing a combination of a lipophilic and a hydrophilic surfactant. Such combinations appear
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to produce mixed interfacial phases of high surface coverage as well as of sufficient viscosity to prevent creaming and promote stability.
It is not easy to match the required HLB value of the oil or the oil mixture with that of a single surfactant to form the most stable emulsion. The appropriate combination of surfactants should be chosen. The HLB value of the mixture of surfactants A (HLBA) and B (HLBB) is calculated by:
𝐻𝐿𝐵𝑚𝑖𝑥𝑡𝑢𝑟𝑒= 𝑓𝐴×𝐻𝐿𝐵𝐴 + (1 − 𝑓𝐴) × 𝐻𝐿𝐵𝐵 (12)
where, fA is the weight fraction of surfactant A in the mixture.
In general, molecules that are oil-soluble or oil-dispersible have low HLB values; those that are water- soluble have high HLB values.
The HLB required for emulsifying particular oil in water can be determined by trial and error, i.e., by preparing appropriate emulsions with emulsifiers having a range of HLB values and then determining that HLB value that yields the “best emulsion.” Although the numbers have been derived empirically, they are useful starting points for the preparation of a variety of emulsions. The knowledge of the required HLB permits selection of an emulsifier or a combination of emulsifiers that will produce the required HLB.
Phase inversion temperature. The practical importance of emulsification temperature on emulsion stability has been known to formulators for many years. As a rule, maximum particle size reduction occurs at or near the PIT. At that temperature, surfactants that are normally water-soluble may actually become soluble in the oil phase. As the emulsion cools, emulsifiers migrate, e.g., by changing their location from the internal to the external phase of the emulsions. How this alters emulsion formation, particle size, and stability has not been rigorously studied; however, some of Lin’s data in Table 3 illustrate these points. In this simple system of one single emulsifier at HLB 9.9, complete placement of the surfactant into the oil phase seems most advantageous regardless of the temperature. However, the emulsification will be successful regardless of the location of the emulsifier as long as the temperature exceeds the PIT during emulsification.
TABLE 3. Effect of Surfactant Lotion and Emulsification Temperature on Droplet Size
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Average Droplet Size (m) at Emulsification Temp.
Percentage of Emulsifier in Oil Phase*
30°C 40°C 50°C 60°C
0 15.0 13.0 11.0 0.2
40 13.0 10.0 9.0 0.2
80 2.0 2.0 1.5 0.2
100 1.5 1.5 0.9 0.2
*The emulsion consists of 30% mineral oil, 5% polyoxyethylene (5) oleyl ether, and 65% water. The emulsifier was added to one or both phases before emulsification at the indicated temperatures.
Determination of surfactant amount. This discussion of the selection of emulsifiers would be incomplete without a brief examination of how one can determine that surfactant mixture of which the least amount is required for optimal stability of an emulsion. Often, this goal can be achieved by determining the amount of water that can be solubilized in a given oil-plus-surfactant(s) mixture under carefully controlled temperature and stirring conditions. For this purpose, 10 g of the lipid/surfactant mixture is weighed into a 68-ml capacity square glass vial. After equilibration at a temperature at which this (not always homogeneous) system is fluid, water is added in 0.10-ml increments. The mixture is shaken and allowed to stand at the equilibration temperature until all air bubbles have escaped. The addition of water (in 0.10-ml increments) is continued until the system remains permanently turbid. If the initial lipid/ surfactant mixture is not clear, it will usually become clear upon addition of water and then become cloudy again upon continued addition of water. This second cloudpoint is the end of the titration. As a rule, the most stable o/w emulsion with the finest particle size results at that surfactant/oil ratio that can tolerate the largest quantity of water and still remain clear.
HLB system shortcomings. Emulsion specialists generally agree that the HLB system is useful and that it may be used judiciously and with caution. It is a dictum of the HLB concept that the HLB value is critical, but this is not always the case. There is no assurance that a stable emulsion prepared from one chemical class of emulsifiers at a particular HLB can be duplicated by another class of emulsifiers exhibiting the same HLB. Thus, marked differences in emulsion type, viscosity, and time for phase separation were noted when polyoxyethylene ether derivatives were compared to polyoxyethylene ester-
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type surfactants having the same HLB and concentration. Additional complications arise from the observations that the HLB required for a particular emulsion to some extent depends on the phase ratio and the salt content.
Several improvements on the classical HLB system for the selection of emulsifiers have been proposed. The phenol index, developed by Marszall, makes it possible to determine the “effective”
HLB of nonionics as a function of their concentration and in the presence of additives such as alcohols and glycols.
Griffin originally proposed that emulsifiers with HLB values ranging from 3.5 to 6.0 should be used for w/o emulsions, but Ford and Furmidge showed that correlation between emulsion type and HLB is far from perfect. Stable mineral oil-in-water emulsions have been obtained with a combination of nonionic ethers having an HLB value as low as 1.9. HLB may be one consideration in the preparation of a stable emulsion; another is the solubility of the emulsifier’s lipid chain in the oil phase.
Most of our current knowledge of the selection of emulsifiers is based on the HLB concept and is applied to the commonly used nonionic surfactants. Recently, the optimization of the stability of a parenteral, ultrasonically emulsified nutrient oil preparation stabilized with various phospholipids and a nonionic has also been explained on the basis of HLB. A somewhat different interpretation of the emulsifying efficacy of phospholipids, which does not involve HLB, was offered by Rydhag. She reported that the best soya bean oil in water emulsions can be obtained with mixed (commercial) phospholipids containing the largest amounts of negatively charged phospholipids (i.e., phosphatidyl inositol, phosphatidic acid, and phosphatidyl serine). Pure phosphatidyl choline (or its combination with phosphatidyl ethanolamine) yields the least stable emulsion. These findings are best explained by the phase-forming ability of these emulsifiers as postulated by Friberg.
Auxiliary Emulsifiers Hydrophilic Colloids
Polymers that are water-sensitive (swellable or soluble) have some utility as primary emulsifiers;
however, their major use is as auxiliary emulsifiers and as thickening agents. Natural and synthetic clays of the smectite or amphibole groups are com-monly used for building the viscosity of emulsions or for
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suspending solids, such as pigments, in makeup preparations. A large variety of natural and synthetic clays is available, and the selection of useful clay is occasionally difficult. The most commonly used clays, bentonites, are derived from montmorillonite, a typical smectite clay. These swell in the presence of water but raise the viscosity of aqueous media only at pH 6 or higher. Clays derived from the amphibole group, such as attapulgite, thicken not by swelling but primarily because of particle anisotropy, which interferes with formation of a compact sediment.
The naturally occurring gums and synthetic hydrophilic polymers listed in Table 17-7 are useful as emulsifiers and as emulsion stabilizers. Most natural hydrocolloids are polysaccharides, and their chemistry is extremely complex. These gums exhibit some type of incompatibility or instability depending on the presence of various cations, on pH, or on a second hydrophilic polymer. Some of the most useful synthetic hydrocolloids are ethers derived from cellulose. Among the completely synthetic group of polymers, the carboxyl vinyl polymers deserve special mention: Their outstanding characteristic is their ability to impart a yield value to aqueous systems. These materials are also included in Table 4.
TABLE 4. Organic Hydrocolloids Useful in Emulsion Technology
Source Name Comment
Tree exudates Gum Arabic (Acacia) Essentially neutral polysaccharide
Gum Ghatti Essentially neutral polysaccharide
Karaya Essentially neutral polysaccharide
Tragacanth Essentially neutral polysaccharide
Sea weeds Agar, Carrageenan Sulfated polysaccharide
Alginates Acidic polysaccharide
Seed extracts Locust bean Essentially neutral polysaccharide
Guar Essentially neutral polysaccharide
Quince seed Essentially neutral polysaccharide
Synthetic Xanthan gum Essentially neutral polysaccharide
(fermentation)
Cellulose Methyl-, hydroxyethyl-hydroxypropyl-ether Neutral polysaccharide
Carboxymethyl-ether Anionic polysaccharide
Collagen Gelatin Amphoteric protein
Synthetic Polyoxethylene polymer Neutral
Carboxyvinyl polymer (cross-linked) Anionic
The water-sensitive hydrocolloids generally favor o/w emulsions because they form excellent hydrophilic barriers. Their use is warranted whenever it is desired to increase the viscosity of an emulsion
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without a corresponding increase in the lipid portion of the emulsion. Proteins, as a group, are effective not only as primary emulsifiers but also as auxiliary emulsifiers. They are particularly useful in oral dosage forms.
Finely divided solids
Finely divided solids have been shown to be good emulsifiers, especially in combination with surfactants and/or macromolecules that increase viscosity. Included are polar inorganic solids, such as heavy metal hydroxides, certain non-swelling clays, and pigments. Even nonpolar solids, e.g., carbon or glyceryltristearate, can be used. Polar solids tend to be wetted by water to a greater extent than by the oil phase, whereas the reverse is true for nonpolar solids. In the absence of surfactants, w/o emulsions are favored by the presence of nonpolar solids, presumably because the wetting by oil facilitates the coales-cence of oil droplets during the initial steps of emulsification. An analogous interpretation may be given for the tendency of polar solids to favor water as the external phase.
In the presence of wetting agents, i.e., when such solids are used as auxiliary emulsifiers, their behavior is controlled by the so-called Young equation. For example, barium sulfate in the presence of sodium laurate (at pH 12) favors o/w emulsions, whereas barium sulfate coated with sodium dodecyl sulfate favors w/o emulsions. In view of the limited utility of such solids as primary emulsifiers, or even as auxiliary emulsifiers, they are not of major interest to the formulator.
