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Particle Sciences - Technical Brief: 2010: Volume 1
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The word surfactant is a contraction of the term surface active agent (SAA). To be surface active a molecule needs to have two mutually insoluble portions. Surfactants are amphiphilic – they have hydrophilic polar head group combined with a hydrophobic tail 1,2 (Figure 1). SAA’s also referred to as tensides, are broadly classified according to their polar head group nature: nonionic (neutral), cationic (positively charged), anionic (negatively charged) or amphoteric. An SAA is classified as being amphoteric only if its charge changes as a function of H+/OH- concentration, i.e., a positive charge in acidic media, a negative charge in basic media, and a zwitterionic (or isoelectric) species at intermediate pH Values. Living systems, including cells, make use of naturally occurring amphoteric surfactants such as lecithin and phospholipids. A separate category now exists for SAA’s where the hydrophobe is not hydrocarbon, but silicone-based2 (i.e., dimethicone copolyol).

Thousands of SAA’s are commercially available4, with many in each class. The structure of the SAA determines its functionality. The range of SAA functions is very broad – about thirteen in all. Some of the more common are: detergents, emulsifiers, wetting agents, dispersants and solubilizers; with the first two being the most important applications. From a physicochemical perspective, each function is discrete and a particular SAA class can serve multiple functions but usually has only one or two at which excels.

To choose which SAA is best requires a thorough understanding of the particular application. One example is the process of laundering and dishwashing, which ideally necessitates several discrete functions from the same molecule including wetting, emulsification, dispersion, and solubilzation. However, the best wetting agents are not the best overall detergents and vice versa. Wetting agents lower the surface tension of a fluid and also lower the interfacial tension with another fluid or solid. Detergents are cleaning agents that remove dirt and grease from porous and non-porous surfaces. For a homologous series of SAA such as the alkyl sulfonates, optimum detergent action is achieved with the C14 tensides and optimal wetting by the C8 tensides. Cationic SAA’s do not function well as detergents, but are exceptionally substantive hence their use as fabric, hair and skin conditioning agents. Most non-ionic SAA are much less effective in dirt removal than anionics; an exception are the poly(ethylene oxide)-based nonionics. Detergent action is dependent only on the concentration of monomeric SAA molecules but solubilazation of dirt requires associated tenside structures called micelles. There is no correlation between the detergent action and dispersing power of an SAA; some tensides that are excellent dispersants are bad detergents. It is for all these reasons that commercial laundry detergents are formulated to contain mixtures of different SAA. The same reasoning needs to be applied to any application where SAA use is considered.

Amphiphilic molecules can increase transport of active pharmaceutical ingredients (API’s) across the skin (a hydrophobe of C18 chain length is most favorable by modulating the organization of stratum corneum (SC) lipids and by the formation of separate domans within the intercellular lipid regions. However, SAA’s that function as detergents must be avoided since they are powerfully membrane-disruptive. With respect to biologic systems, another important property of an SAA is they increase the osmotic pressure of liquids.

Properties and Characteristics

SAA structure endows them with unusual physicochemical properties such that they tend to absorb at any interface with the hydrophilic group located in one phase and the hydrophobic group in the other. The first important distinguishing property of an SAA is its ability to lower the ST at a liquid/air interface or the IT between two immiscible liquids (Figure 1). It is this latter property that allows an SAA to function as an emulsifier. The amphiphilic nature of many SAA emulsifiers (particularly nonionics) can be expressed in terms of an empirical scale of the HLB5 (hydrophilelipophile balance) numbers, which range from 1 to 20. SAA functionality tends to fall into rough ranges of HLB values (Table 1). An SAA does not have to be completely soluble and may lower the ST or IT by spreading over the interface. They also lower the contact angle of a liquid in contact with a solid substrate thus allowing it to act as a wetting agent.

Micellization and Liquid Crystal Structures

A second important property of SAA’s is that, above some specific narrow concentration range (depending on MW and shape of the hydrophobe) they will spontaneously self-associate through an aggregation process known as micellization6. The concentration at which these micelles form is termed the critical micelle concentration (CMC) (Figure 1). Micelles contain from tens to hundreds of molecules referred to as the aggregation number. In water, the hydrophobic chains are oriented inward away from the aqueous phase. This is relevant for drug deliver of poorly water-soluble as very hydrophobic API’s can be readily solubilized within micellar systems. “Inverse” micelles are formed when the liquid is non-aqueous; in this case water-soluble API’s can be solubilized in oils – such micelles can also sequester very high electrolyte levels (2M NaCl).

At higher concentrations, surfactants may also associate to form mesomorphic phases, i.e., a state intermediate between the liquid and drystalline, termed lyotropic liquid crystals (LC’s). Lyotropic strucures range from cubic to hexagonal cylindrical array to lamellae (Figure 2). The rheological (viscoelastic) properties of these LC structures vary considerably (from shear thinning to thixotrpic) and have been used to greate effect in food emulsions. A notable feature of many LC phases is their ability to incorporate large amount of very hydrophilic to very hydrophobic molecules and to form very small to very large particles. The protective properties of the LC systems are useful for oral administration where the API is sensitive to hydrolysis or degradation.


Vesicles are hollow colloidal-size spheres constructed from apmphiphilic SAA’s. A wide variety of natural lipids, in particular phosphatidylcholine (PC) or synthetic non-ionic surfactants can be used in their preparation. These are referred to as liposomes an niosomes, respectively. These amphiphilic SAA’s can form – in the presence of excess water – one (unilamellar vesicles) or more (multilamellar vesicles) concentric bilayers that surround an equal number of aqueous compartments. Both water-soluble and hydrophilic compounds can be trapped in the internal aqueous compartments while water-insoluble and lipophilic compounds can be trapped within the vesicle bilayer, or can partition between the bilayer and the aqueous phase (Figure 2). Liposomal systems have attracted attention because they can provide skin transport enhancement and pH-responsive controlled-release characteristics7. The lipid composition and thermodynamic state of the bilayers plays a crucial role in the effect of vesicle interaction with the SC and also on drug transport rate across skin.

Surface Activity of API’s

API’s themselves are frequently amphiphilic and can be surface active. One potential deleterious side effect is foaming especially in high shear mixing. Both an API’s pharmacokinetics and pharmacodynamics is somewhat affected by its surface activity. Note that the presence of a surface active API in a formulation could affect the type of structure formed by a primary surfactant plus excipient polymer system as well as the structure’s stability.

Surfactants as Dispersing Aids

The act of dispersing an API into a liquid entails overcoming the various binding forces between particles by use of both physicochemical and mechanical means (see PSI Technical Brief 2009 Vol 1); a comprehensive review has been given elsewhere8. The first step is to completely wet the powder using a suitable SAA4. Only a very low concentration of a wetting agent is needed (ca 0.01%). In the second stage – that of comminution and distribution of particles in the liquid – a distinction must be made between massive (crystalline) particles and agglomerated/aggregated materials. The former materials are usually harder and need high shear pulverizing to break them down into smaller particles. The latter process one of separation of the agglomerated material using deflocculants. Here charged tensides are useful because they can promote internal wetting; the charge must be the same sign as the charge on the particles being dispersed. SAA’s that are good deflocculants must be capable of significantly reducing the contact angel between solid and liquid but only slightly lower the liquid surface tension (to ca 60 mNm-1). This distinction is critical. Typical tensides are isopropylnaphthalenesuphonate (anionic) and cetyltrimethylammonium bromide (cationic).

All dispersants adsorb at the solid-liquid interface and can prevent primary particles or fragments formed after communition from re-agglomerating but higher MW Polyelectrolytes are far superior to tensides. Importantly, the two species are not interchangeable; each must be chosen with care because, depending on the fineness of the dispersion, the concentration of dispersing aid needed is 10% -- 20% of the particles by mass, whereas, the concentration of wetting agent needed to initially wet the unmilled solid is on the order of only 0.01% or less.


The Choice of a surfactant system is based upon the desired performance of the end-product. SAA are most often used in combination to achieve the optimal combination of API state, stability and appropriate deliver characteristics. Although there are frequently-used SAA systems, the best results are obtained by tailoring each system through careful consideration of the physicochemicalproperties of the API and the delivery goal.


  1. M.J. Rosen, Surfactants and interfacial Phenomena, Wiley, New York (1978)
  2. D. Meyers, Surfactant Science and Technology, VCH Publishers, New York (1988)
  3. R.M. Hill (ed.), Silicone Surfactants, Marcel Dekker, New York (1999)
  4. McCutcheon’s Emulsifiers and Detergentsand McCutcheon’s Functional Materials, MC Publishers, Glen Rock, NJ, published annually.
  5. P. Becher, Encyclopedia of Emulsion Technology, Volume 2, Applications, Marcel Dekker, New York (1985)
  6. Th. Tadros, Surfactants, Kirk-Othmer Encyclopedia of Chemical Technology Series, Wiley, London (2006)
  7. G.P. Martin and A.W. Lloyd, Basic Principles of Liposomes for Drug Use in Liposomal Dermatics, Springer-Verlag, Berlin (1992)
  8. D. Fairhurst and M.A. Mitchnick in Sunscreens, eds. N.J. Lowe, N.A. Shaath and M.A. Pathak, 2nd Edition, Marcel Dekker, New York (1997)

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