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Surfactants and Emulsifying Agents

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20
Surfactants and
Emulsifying Agents
Melgardt de Villiers, PhD

Definitions
CHAPTER
OUTLINE Desirable Properties of Emulsifying Agents
Classification and Characteristics of Surfactants and Emulsifying Agents

I. DEFINITIONS
A. Surface-active agents, also called surfactants, are molecules or ions that are adsorbed at inter-
faces (1,2).
1. The molecular structure of these substances is composed of two parts: a hydrophilic (water-
loving) portion, which orients itself toward water or other relatively polar liquids or solids, and
a hydrophobic (water-hating) or lipophilic (oil-loving) part, which orients itself toward oil or
other nonpolar solids, liquids, or gas (e.g., air).
2. Surfactants orient themselves at interfaces so as to reduce the interfacial free energy produced
by the presence of the interface (2).They lower the surface tension between a liquid and a gas
(e.g., air) or the interfacial tension between two liquids.
3. Surfactants can function as wetting agents, detergents, foaming agents, dispersing agents, solu-
bilizers, and emulsifying agents.
Note: A detailed discussion of interfacial phenomena is beyond the scope of this text. For more
information on this subject refer to a book on physical pharmacy (1) or the chapters on inter-
facial phenomena, colloidal dispersions, and coarse dispersions in Remington’s The Science and
Practice of Pharmacy (2–4).
B. An emulsifying agent is a compound that concentrates at the interface of two immiscible
phases, usually an oil and water. It lowers the interfacial free energy, reduces the interfacial tension
between the phases, and forms a film or barrier around the droplets of the immiscible, discontin-
uous phase as they are formed, preventing the coalescence of the droplets.
A discussion of the emulsification process and of liquid emulsions can be found in Chapter 29,
Liquid Emulsions. Semisolid emulsions, also known as creams, are described in Chapters 23, Oint-
ment Bases, and Chapter 30, Semisolids: Ointments, Creams, Gels, Pastes, and Collodions.

II. DESIRABLE PROPERTIES OF EMULSIFYING AGENTS

A. Molecular structure

251
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252 Part 4 Pharmaceutical Excipients

1. Although emulsifying agents must contain both hydrophilic and lipophilic parts, neither por-
tion may be too strongly dominant (2,5). If the hydrophilic part of the molecule is completely
dominant, the substance does not concentrate at the water–oil interface; it remains dissolved in
the water phase. By the same token, if the lipophilic portion is too strong, the substance remains
dissolved in the oil.A good emulsifier should have a reasonable balance between its hydrophilic
and lipophilic groups.
2. As a general rule, emulsifying agents in which the hydrophilic groups are relatively dominant
produce oil-in-water (o/w) emulsions; those in which the lipophilic groups are strongest favor
the production of water-in-oil (w/o) emulsions; and those with nearly equal balance may give
either type, depending on the circumstances (5).The examples below illustrate.
a. In the soap sodium stearate, the hydrophilic group —COONa is somewhat dominant
over the lipophilic hydrocarbon chain C17H35—. As a result, sodium stearate is soluble in
water and insoluble in oil. It does possess sufficient balance between the groups so that it
concentrates at the oil–water interface and it produces o/w emulsions (6).
b. In contrast, calcium stearate contains two long hydrocarbon chains, rather than one, so that
the lipophilic groups dominate. Calcium stearate is insoluble in water and soluble in oil and
promotes the formation of w/o emulsions (5).
c. In both cases, the ionic portion is required. If a substance such as an acid is added to an
emulsion stabilized by one of these emulsifiers, the equilibrium for the reaction R-COO
Δ R-COOH shifts to the right. The un-ionized form now predominates; the required
hydrophilic-lipophilic balance is destroyed and the emulsifier leaves the water–oil interface
and dissolves in the oil.
B. The emulsifier must produce a stable film at the interface.
1. Some surface-active agents are capable of producing emulsions, but the emulsions separate on
standing or storage because the surfactant is incapable of producing stable, strong barriers to
prevent the coalescence of the dispersed droplets (5).
2. Agents such as these may be useful if combined with a second substance that acts as a stabilizer.The
surfactant is then referred to as the primary emulsifying agent and the stabilizer as the secondary or
auxiliary emulsifier (5).An example of such a system is the use of the primary emulsifier sodium lau-
ryl sulfate with the auxiliary emulsifier stearyl alcohol in Hydrophilic Ointment USP (6).
C. The emulsifying agent should be stable to chemical degradation.
D. The emulsifying agent should be reasonably inert and should not interact chemically with any of
the other ingredients in the formulation.
E. If the emulsifier is liable to microbiologic attack, adequate precautions must be taken.
1. In the emulsion section of USP Chapter 〈1151〉 Pharmaceutical Dosage Forms, it is stated that
all emulsions require the addition of a suitable preservative because the water phase is vulner-
able to the growth of microorganisms (7).
2. Other possible precautions when emulsifiers favor the growth of microorganisms include the
use of refrigeration and short beyond-use datings.
F. The substance should be nontoxic and nonirritating to skin or mucous membranes.
G. Depending on its use, it should be relatively odorless, tasteless, and colorless.
H. It should have a reasonable cost.

I III. CLASSIFICATION AND CHARACTERISTICS OF SURFACTANTS AND

EMULSIFYING AGENTS
A. Table 20.1 lists the USP 30/NF 25 articles categorized as surfactants and emulsifying agents (8).
B. Water-soluble polymers
The water-soluble or hydrophilic polymers may be grouped either by their origin or on the basis
of their electrical charge (4).
1. Based on their origin, there are three classes of water-soluble polymers: natural polymers, deriv-
atives of cellulose, and synthetic hydrophilic polymers.
a. The natural polymers include polysaccharides, such as acacia, agar, pectin, sodium alginate,
xanthan gum, and tragacanth, and polypeptides, such as casein and gelatin.
b. The cellulose derivatives are semisynthetic products, made by chemical modification of cel-
lulose to yield soluble polymers. Examples include methylcellulose, sodium carboxymethyl-
cellulose, hypromellose, and hydroxyethyl and hydroxypropyl cellulose.
c. The synthetic water-soluble polymers include vinyl polymers such as polyvinyl alcohol and
povidone (polyvinylpyrrolidone), carbomer (which is a copolymer of acrylic acid), and
polyethylene glycols.
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Chapter 20 Surfactants and Emulsifying Agents 253

Table 20.1 USP AND NF EXCIPIENTS CATEGORIZED AS EMULSIFYING

AND/OR SOLUBILIZING AGENTS

Acacia Carbomer Copolymer

Carbomer Interpolymer Cholesterol
Coconut Oil Diethylene Glycol Stearates
Ethylene Glycol Stearates Glyceryl Distearate
Glyceryl Monolinoleate Glyceryl Monooleate
Glyceryl Monostearate Lanolin Alcohols
Lecithin Mono- and Di-glycerides
Poloxamer Polyoxyethylene 50 Stearate
Polyoxyl 10 Oleyl Ether Polyoxyl 20 Cetostearyl Ether
Polyoxyl 35 Castor Oil Polyoxyl 40 Hydrogenated Castor Oil
Polyoxyl 40 Stearate Polyoxyl Lauryl Ether
Polyoxyl Stearyl Ether Polysorbate 20
Polysorbate 40 Polysorbate 60
Polysorbate 80 Propylene Glycol Monostearate
Sodium Cetostearyl Sulfate Sodium Lauryl Sulfate
Sodium Stearate Sorbitan Monolaurate
Sorbitan Monooleate Sorbitan Monopalmitate
Sorbitan Monostearate Sorbitan Sesquioleate
Sorbitan Trioleate Stearic Acid
Wax, Emulsifying
Source: The United States Pharmacopeial Convention, Inc. Front matter—NF: Excipients. 2007 USP 30/NF 25.
Rockville, MD: Author, 2006.

2. Based on electrical charge, the hydrophilic polymers are either uncharged or anionic; cationic
polymers are uncommon.
a. Examples of the nonionic or uncharged polymers include methylcellulose and ethylcellu-
lose, hypromellose, hydroxyethyl and hydroxypropyl cellulose, pyroxylin, polyethylene oxide,
polyvinyl alcohol, and povidone (polyvinylpyrrolidone),
b. Examples of anionic polymers include acacia, alginic acid, pectin, tragacanth, xanthan gum,
and carbomer at a pH favoring the ionic form of the acid group, and sodium alginate and
sodium carboxymethylcellulose.
3. Water-soluble polymers have the following characteristics in common:
a. They favor o/w emulsions.
b. They have the advantage of being viscosity-building agents in addition to having surface
activity.
c. With the exception of some of the natural gums, most of the water-soluble polymers are
used as auxiliary emulsifying agents.
4. Other properties of the water-soluble polymers depend on the particular chemical structure of
the polymer. These agents are discussed in detail in Chapter 19, Viscosity-Inducing Agents.
Information is given on their individual properties, solubilities, incompatibilities, formulation
methods, and uses.
C. Anionic soaps and detergents
1. Soft soaps
a. These are salts of fatty acids in which the positive ion is univalent, such as Na, K, and
NH4. The most common fatty acids are stearic (C-18), oleic (C-18, consisting mainly of
(Z)-9-octadecenoic acid), palmitic (C-16), and lauric (C-12).
b. Often the emulsifier is formed at the time of emulsification by adding an alkali base (e.g.,
NaOH, KOH, NH4OH, sodium borate) or an organic amine base (e.g., triethanolamine) to
a fixed oil that contains a sufficient amount of fatty acid. For this reason, these are often
called nascent (which means “having recently come into exisitence”) soap emulsifiers.
(1) Soaps with an organic amine as the cation are more balanced and less hydrophilic and
form more stable emulsions than the alkali soap emulsifiers (5).
(2) Emulsions made with alkali soap emulsifying agents sometimes require the addition of
auxiliary emulsifiers for stable emulsions.
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254 Part 4 Pharmaceutical Excipients

c. Soft soaps are water-soluble and/or water-dispersible.

d. They usually form o/w emulsions.
(1) The classic vanishing creams and other water-washable creams of this type are o/w
emulsions that use soft-soap emulsifiers.
(2) Two exceptions are Rose Water Ointment and Cold Cream. These are w/o emulsions
formed when a solution of sodium borate (borax) is added to melted white and cetyl
ester waxes, which contain sufficient fatty acids for the formation of a soap emulsifier.
e. Soft soaps give emulsions with a pH in the basic range.
(1) The alkali soap emulsions have a pH in the range of 8 to 10 (9) and are most stable above
pH 10 (5).
(2) The organic bases give soaps that have a lower neutrality point (about pH 8), with the
pH of the emulsions nearer to neutrality and more stable to changes in pH (5).
f. Soap emulsifiers are weak electrolytes (salts of a carboxylic acid [R-COO–], a weak acid)
and require this ionic center for their surface activity. This means that any drug or other
ingredient that neutralizes that ionic center will destroy an emulsion stabilized by these
emulsifiers. Problematic ingredients include drugs or additives that are acids or that produce
an acid pH (e.g., phenol, salicylic acid), because lowering the pH shifts the equilibrium in
favor of the weakly dissociated, oil-soluble R-COOH form.
g. Soft soaps are incompatible with multivalent cations (Mg, Ca) because these replace
the univalent ion, forming the multiple hydrocarbon chain soap of the multivalent ion.This
shifts the hydrophilic-lipophilic balance of the molecule in favor of the lipophilic type.This
new emulsifier favors the opposite type of emulsion (w/o) and may cause the emulsion to
“crack” or coalesce.
h. Soaps are also incompatible with high concentrations of electrolytes and with high-molecular-
weight cations such as the preservatives benzalkonium chloride and benzethonium chloride (9).
The anionic portion of the soap binds these preservatives and renders them inactive.
i. Soft soaps are unsuitable emulsifiers for internal-use emulsions because of their soapy taste
and laxative action (5).
2. Hard soaps
a. These are salts of fatty acids in which the positive ion is divalent or trivalent (Ca2, Mg2,
Zn2, Al3).The most common hard soap is calcium oleate.This is formed by reacting cal-
cium hydroxide in Calcium Hydroxide Topical Solution (also known as lime water) with
oleic acid found in olive oil and certain other fixed oils.
b. Hard soaps are oil-soluble and water-insoluble.
c. They form w/o emulsions.
d. Like soft soaps, these are salts of a carboxylic acid (R-COO), a weak acid, which gives the
weakly dissociated R-COOH form on addition of drugs or other ingredients that are acids
or that produce an acid pH. Hard soaps are particularly sensitive to acid ingredients (5).
e. The R-COO– groups of hard soaps may interact with and bind high-molecular-weight
cations like benzalkonium chloride.
f. Hard soaps are unsuitable for internal-use emulsions.
3. Detergents
a. These are salts of alkyl sulfates, sulfonates, phosphates, and sulfosuccinates.Two examples of
detergents from this group that are commonly used in pharmaceuticals are sodium lauryl
sulfate and dioctyl sodium sulfosuccinate (docusate sodium).
b. Detergents are very hydrophilic and are soluble in water.
c. They always form o/w emulsions.
d. As strong electrolytes, they are more stable to acids, such as phenolic compounds and sali-
cylic acid, and are not sensitive to high concentrations of electrolytes.
e. Because their ionic centers strongly repel each other, detergents do not form firm, intact
barriers. These surfactants are most often used in conjunction with secondary non-ionic
emulsifiers such as cetyl or stearyl alcohol.
f. Like soaps, detergents are unsuitable for internal-use emulsions because of their soapy taste
and laxative action.
D. Cationic surfactants
1. The cationic surfactants are quaternary ammonium compounds such as benzalkonium chlo-
ride, benzethonium chloride, and cetylpyridinium chloride.
2. They are very hydrophilic and are very soluble in water.
3. Cationic surfactants do not make good emulsifiers but are useful as antimicrobial agents. Their
properties and uses as antimicrobial agents are discussed in Chapter 16 Antimicrobial Preservatives.
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Chapter 20 Surfactants and Emulsifying Agents 255

E. Finely divided solids

1. These are usually finely divided hydrophilic inorganic solids. When these solids are in a very
fine state of subdivision, they tend not to be easily wetted by liquids, and they orient at inter-
faces, forming a barrier to coalescence. The most common examples of this type include the
colloidal clays bentonite and Veegum and metallic hydroxides, such as magnesium oxide and
zinc oxide.
2. Large quantities of finely divided solids, which are in a product formulation for therapeutic
purposes, may function as emulsifiers if an appropriate order of mixing is used. An example is
the emulsification of 25% mineral oil with 75% magnesia magma (Haley’s M-O).
3. The finely divided solids are not usually used by themselves but are useful as auxiliary emulsi-
fiers. An exception is the magnesia magma–mineral oil emulsion mentioned previously. Here,
the finely divided magnesium oxide of magnesia magma serves as the sole emulsifier agent for
the mineral oil (9).
4. Hydrophilic solids favor o/w emulsions and are used most often as auxiliary emulsifier for this
emulsion type.There are, however, examples of hydrophilic solids present in w/o formulations.
An example is the presence of the hydrophilic solids calamine and zinc oxide in Calamine Lin-
iment NF IX, a w/o emulsion that has calcium oleate as the primary emulsifying agent.
5. Finely divided hydrophobic solids favor the formation of w/o emulsions. If a large quantity of
a hydrophobic solid is added to a system with the primary emulsifier favoring an o/w emul-
sion, the final emulsion type is difficult to predict. An example is the formulation of an oral
o/w emulsion of the water-insoluble hydrophobic drug sulfadiazine, with a non-ionic emulsi-
fying system that favors an o/w emulsion. Depending on the exact conditions, the result may
be either a w/o or an o/w emulsion. Because o/w emulsions are preferred for oral products,
the formation of a w/o emulsion in this case may create a compounding problem.
F. Natural non-ionic surfactants
1. These include fatty acid alcohols, such as stearyl alcohol and cetyl alcohol, wool fat or wool
wax and its derivatives, wool alcohols and cholesterol, and derivatives of other natural waxes,
such as spermaceti and cetyl esters wax (synthetic spermaceti). These are available as fractions
of the natural products or their synthetic versions.
2. Some of the natural waxes, such as wool wax, Lanolin USP (wool fat, the waxlike substance
from the wool of sheep, that has been cleaned, decolorized, and deodorized), Modified Lano-
lin USP (wool fat that has been processed to reduce the contents of free lanolin alcohols and
detergent and pesticide residues), and hydrous lanolin (hydrous wool fat) and its synthetic ver-
sion Hydrophilic Petrolatum USP are complex mixtures of oils, waxes, and emulsifiers (6).The
purified emulsifying agents in Hydrophilic Petrolatum are the non-ionic emulsifiers stearyl
alcohol and cholesterol. Lanolin and hydrous lanolin contain mixtures of similar natural emul-
sifiers. All are capable of absorbing water to form w/o emulsions.These are discussed in more
detail in Chapter 23, Ointment Bases.
3. Although the purified fractions and their synthetic counterparts may be used to produce w/o
emulsions, they are also commonly used as auxiliary emulsifiers to stabilize o/w emulsions
when a powerful o/w emulsifying agent, such as a detergent, is present as the primary emulsi-
fier. An example of such a system is the o/w cream Hydrophilic Ointment USP (6). In this
product, sodium lauryl sulfate is the primary emulsifier, with stearyl alcohol as the auxiliary
emulsifying agent.
G. Synthetic non-ionic surfactants
1. These are complex esters and ester-ethers, derived from polyols, alkylene oxides, fatty acids, and
fatty alcohols.The hydrophilic portion of these molecules consists of free hydroxyl and oxyeth-
ylene groups.The lipophilic part has long-chain hydrocarbons of fatty acids and fatty alcohols.
Although they are given a chemical designation based on the primary component, these are
actually complex mixtures of closely related derivatives. For example, sorbitan monooleate, also
known as Span 80, is a mixture, but the primary component is sorbitan monooleate. Polysor-
bate 80 (Tween 80) is polyoxyethylene 20 sorbitan monooleate; the 20 indicates that there are
approximately 20 moles of ethylene oxide for each mole of sorbitol and sorbitol anhydride.
Commonly used non-ionic surfactants include various Spans,Tweens, Arlacels, and Myrjs.
2. Non-ionic surfactants have the following characteristics in common:
a. They are neutral compounds that are stable over a wide pH range.
b. They are relatively insensitive to the presence of high concentrations of electrolytes.
c. They are heat stable.
d. Because these compounds do not possess significant innate ability as viscosity-inducing
agents, depending on the water–oil phase ratio and the melting point of the oil phase,
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256 Part 4 Pharmaceutical Excipients

emulsions made with these agents may require auxiliary viscosity-inducing agents or a vis-
cous vehicle for the external phase.
e. Non-ionic surfactants are mixed in various proportions to give either w/o or o/w emul-
sions.The appropriate amounts of individual emulsifiers needed to form a specific emulsion
type can be determined using a mathematic system called the HLB system. This system
assigns numeric values to fats and oils and to emulsifiers based on the relative amounts of
hydrophilic and lipophilic portions present in these molecules. Examples of the calculation
and use of the HLB system can be found in Chapter 29, Liquid Emulsions.
H. Amphoteric or zwitterionic surfactants
1. These surfactants can be anionic, cationic, or non-ionic in solution, depending on the acidity
or pH of the water.They are usually mild, making some of them particularly suited for use in
pharmaceutical products and preparations.
2. An amphoteric surfactant frequently used in pharmaceutical dosage forms is Lecithin NF, a
complex mixture of phosphatides, mainly phosphatidyl choline (8). Two major sources of the
phosphatides are egg yolks and soya beans. Lecithins are mainly used as dispersing, elmulsify-
ing, and stabilizing agents (10). Lecithin is often included in injectable products, especially par-
enteral nutrition solutions. Therapeutically, lecithin and derivatives have been used as pul-
monary surfactants. Lecithin also forms a component of the bilayers of liposomes (3).
3. Lecithin is a major component of Pluronic (poloxamer) lecithin organogel (PLO gel). This
transdermal vehicle is used by compounding pharmacists to administer medications through
the skin when the medication is to be absorbed through the skin for almost immediate effect.
This use is illustrated with Sample Prescription 30.7 in Chapter 30.

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