By Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development; Courtaney Davis, BBA, PCCA Senior Formulation Specialist; Stacey Lemus, BS, PCCA Senior Formulation Specialist; and Suki Pramar, PhD, PCCA Compounding Consultant
Surfactants are important ingredients used in pharmacy compounding and perform a variety of functions. They can be used to formulate emulsions and suspensions, and they can improve the solubility of poorly soluble drugs in water. To help you understand these versatile excipients, we will explain what surfactants are and some of their important characteristics, cover important things to consider when using them, and list many of the surfactants you can use in compounding.
The term &#;surfactant&#; (from &#;surface-active agent&#;) refers to any substance that orients at the interface between two phases. Surfactants can therefore function as wetting agents, detergents, foaming agents, dispersing agents, solubilizers and emulsifying agents. Surfactants contain an oil-loving (lipophilic) portion and a water-loving (hydrophilic) portion in their molecules. This unique property allows them to migrate to the surface of immiscible liquids and lower the surface tension, helping them to mix without immediately separating again.
Immiscible liquids like oil and water repel each other and form two separate layers when combined. Upon vigorous shaking, one of the liquids may temporarily break up into droplets (dispersed phase) that are dispersed throughout the second liquid (dispersion medium). A surfactant lowers the surface tension between the two by spontaneously orienting itself on the surface of the droplets, preventing them from coalescing into separate layers again, even after the shaking is stopped.
Surfactants similarly reduce the natural repulsion between a very lipophilic drug like progesterone and a hydrophilic vehicle like water. In general, surfactants facilitate the wetting of lipophilic drugs in aqueous vehicles to form suspensions. Surfactants can therefore also behave as suspending agents.
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Surfactants can also improve the water solubility of insoluble drugs. They do this by orienting at the drug particle surface in such a manner that the lipophilic portion faces the drug particle while the hydrophilic portion faces outward, making the particle more water loving. In this manner, a surfactant can function as a solubilizing agent. For example, coal tar solution contains polysorbate 80 as a solubilizing agent to prevent precipitation of coal tar if the solution is diluted with water. Coal tar needs alcohol to dissolve and would precipitate in water in the absence of a hydrophilic surfactant such as polysorbate 80.
Water-soluble polymers can also align at interfaces to facilitate dispersion of insoluble drugs in water. Viscosity-enhancing materials increase the viscosity of the dispersion medium (or the external phase) and aid in minimizing separation of immiscible liquids or settling of insoluble particles.
The proportion of hydrophilic to lipophilic parts of a surfactant molecule can be quantified by its HLB value (hydrophilic-lipophilic balance). If the HLB value is low, it means that there is a small number of hydrophilic groups in the surfactant molecule, which means it is more lipophilic (oil soluble) than hydrophilic (water soluble). As an example, sorbitan monooleate 80 (Span® 80) has an HLB value of 4.3 and is oil soluble. If the HLB value is high, it means that there are large number of hydrophilic groups in the surfactant molecule, which makes it more water soluble than oil soluble. For example, polysorbate 20 (Tween® 20) has an HLB value of 16.7 and is water soluble.
Knowledge of the two broad categories of HLB values is important for the compounding pharmacist. Surfactants with higher HLB values ranging from 8-18 are more hydrophilic and favor the formation of oil-in-water (O/W) emulsions, such as vanishing cream and PCCA&#;s VersaBase®. Surfactants with lower HLB values from 3-6 are more lipophilic in nature and favor the formation of water-in-oil (W/O) emulsions, such as Eucerin ®, cold cream and PCCA&#;s Emollient Cream&#;.
SURFACTANT NAME
HLB VALUE
Sorbitan monooleate (Span) 80
4.3
Sorbitan monooleate (Span) 20
8.6
Methylcellulose
10.5
Acacia
8-12*
Polysorbate (Tween) 60
14.9
Polysorbate (Tween) 80
15.0
Polysorbate (Tween) 20
16.7
Poloxamer
17.0
*Some references list an HLB value of 8 for acacia, and some list a revised value of 12. Both indicate that it is hydrophilic.
For more information, PCCA members can also access PCCA Document #, which has an extensive list of surfactants with their HLB values as well as information on which surfactants are best for different situations (e.g., antifoaming agent, emulsifying agent, wetting agent, etc.). This can also provide guidance if substitutions need to be made.
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One important consideration when creating an emulsion is if it will be administered internally or externally. For example, emulsifying agents like polysorbate 20 are more palatable than polysorbate 80 and are therefore preferred for internal use.
Another consideration is the stability of the API. If the drug is unstable in the presence of water, it should not be compounded in an emulsion.
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Finally, it&#;s important to consider preservatives, antioxidants and buffers. If the external phase of the emulsion is water, preservatives need to be included to discourage microbial growth. This may also be necessary if the external phase is an oil, depending on the situation. Antioxidants and buffers may be needed if the drug is sensitive to oxidation and if it requires a certain pH for maximum stability.
TYPE OF SURFACTANT
EXAMPLES
COMMON CHARACTERISTICS
Water-soluble polymers
Acacia
Sodium alginate
Xanthan gum
Methylcellulose
Carboxy methylcellulose
Hydroxyethyl cellulose
Hydroxypropyl cellulose
Polyvinyl alcohol
Povidone
Carbomer
Anionic soaps and detergents
Sodium lauryl sulfate
Cationic surfactants
Benzalkonium chloride
· Do not make good emulsifiers but are useful as antimicrobial agents
Benzethonium chloride
Cetylpyridinium chloride
Natural nonionic surfactants
Stearyl alcohol
· Can be mixed in various proportions to give either water-in-oil or oil-in-water emulsions
Cetyl alcohol
Lanolin
Synthetic nonionic surfactants
Polysorbate (Tweens)
Sorbitan monooleate (Spans)
Proprietary PCCA Emulsifying Agents
Krisgel 100&#;
Emulsifix®-205
· Compatible with polar solvents, but needs more mixing
If PCCA members with Clinical Services support have questions about working with surfactants, they can contact our clinical compounding pharmacists to discuss options.
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Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development, received her pharmacy degree from Mercer University in Atlanta, Georgia, in . She currently is involved with and oversees the development and implementation of new formulas at PCCA. She had more than six years of compounding experience with pharmacies in Georgia and Florida prior to joining the PCCA staff in . Her areas of interest include women&#;s health, veterinary and pain management compounding.
Courtaney Davis, BBA, is a senior formulation specialist and technical consultant with more than 18 years&#; combined experience in the compounding industry. She joined PCCA&#;s Formulation Development department in , where she assists in the creation of new formulas and the updating and revising of existing formulas. Courtaney also works closely with our Research and Development team to bring innovative products to our membership. Prior to joining PCCA&#;s staff, she worked for a member pharmacy as a certified technician.
Stacey Lemus, BS, became a compounding technician in . She worked with a PCCA member pharmacy for more than 10 years before joining the PCCA Formulation Development team in . Her work at PCCA focuses on new formula development as well as updating and testing existing formulations. Her experience with equipment, compounding techniques and calculations makes her a valuable resource for member technical calls. She received her BS in biology and chemistry from Texas A&M University &#; Kingsville.
Suki Pramar, PhD, is a compounding consultant at PCCA. She earned her PhD in pharmaceutics from the University of Houston in , and she joined PCCA&#;s staff in . Suki was appointed to the American Pharmacists Association&#;s Compounding Pharmacy Task Force in .
Allen, L. V., Jr. (). The art, science, and technology of pharmaceutical compounding (2nd ed.). American Pharmacists Association.
Thompson, J. E., & Davidow, L. W. (). A practical guide to contemporary pharmacy practice (2nd ed.). Lippincott Williams & Wilkins.
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