Download SURFACE ACTIVE AGENTS

1
SURFACE ACTIVE AGENTS
Surfactants play an extremely important role in pharmaceutical formulation - we’ll examine
examples at the end of this section.
Revise structure of surfactants
The most important property of this compound is that there must be a balance between
the two groups to ensure that surface active properties are obtained. Both groups must
have some degree of solubility in both aqueous and organic phases in order to be attracted
to the interface.
Example: sodium stearate - C17H35COO-Na+ - this has a fairly strong polar head
stearic acid - C17H35COOH - this is completely insoluble in water and has a
very small polar head. It is therefore not surface active.
1. BEHAVIOUR OF SURFACTANTS IN SOLUTION
In dilute solutions, surfactants behave as normal compounds, forming ideal solutions,
but at reasonably well-defined concentrations, relatively sharp changes occur in the
physical properties of these solutions.
► At low concentrations a fraction of the surfactant will be adsorbed in monolayers at the
air-water interface and the remainder will be in the bulk in the form of monomers.
► As increasing amounts of surfactant are dissolved, the interfaces become more crowded
and eventually become saturated with surfactant.
►Usually simultaneously, the limiting solubility of the surfactant in the bulk is approached.
► At this concentration, instead of precipitating, the monomers in the bulk form colloidal
aggregates called micelles.
► This process begins at a characteristic concentration called the critical micelle
concentration (CMC).
► Ionic and non-ionic substances that display this behaviour are called association
colloids.
SLIDE : SHAPES OF MICELLES Physical Pharmacy p.397
2
In the case of amphiphiles in water, the HC chains face inward into the micelle to form their
own HC environment, and they are thus shielded from the aqueous solution. The polar
group is on the outside of the micelle, in contact with the water molecules.
Aggregation also occurs in nonpolar liquids. The orientation of the molecules is now
reversed; polar heads inwards and HC chains associated with nonpolar phase.
Spherical micelles exist at concs close to the CMC. At higher concs, laminar micelles tend
to form and exist in equilibrium with spherical micelles.
NB: do not regard micelles as solid particles. The individual molecules forming the
micelles are in dynamic equilibrium with the monomers in solution and at the interface i.e.
micelles are continuously breaking down and reforming.
A micellar solution consists, therefore, of many nonpolar droplets which can function as a
discrete phase and thereby "dissolve" drugs that would not normally be soluble in aqueous
systems. This process is called micellar solubilization.
2. STABILITY OF SPHERICAL MICELLES
► Water tends to squeeze out the HC chain of the monomer as the cohesive force
between water molecules is much stronger than the adhesive force between water and
the hydrocarbon chains.
► Micelle formation removes lipophilic groups from an aqueous environment.
► The incorporation of monomers into micelles substantially reduces the surface area
exposed to the water, thereby reducing the surface free energy of the system, so
orientation into micelles is preferable to adsorption at the surface.
► Micelles remain fairly stable in water as
→ the polar heads are attracted to the water molecules surrounding them
→ there is an attractive force (van der Waal's forces) between the hydrocarbon tails.
With ionic surfactants the electrical repulsion between adjacent similarly charged ions
tends to disrupt the micelle. However, the "squeezing out of solution" effect opposes this
so micelle formation depends on a balance between the two.
3
3. PHYSICAL PROPERTIES OF SAA’S AND MEASUREMENT OF THE CMC
To determine the CMC, we concentrate on various properties of surfactant solutions and
determine how they change with concentration e.g. osmotic pressure, surface tension, light
scattering, conductivity.
1. Determination of CMC by Titration
A solution of surfactant is titrated against various other solvents e.g. surfactant is titrated
against a suspension of oil-soluble dye in water. At the CMC the dye goes into solution
and a colour change is observed. At this concentration micelles start forming and
solubilise the dye. From the volume titrated, the concentration can be calculated.
2. Colligative Properties
Osmotic pressure depends on the number of units in solution, not on the size, chemical
structure or physical structure. As the concentration increases, each monomer acts as a
unit and exerts osmotic pressure. At the CMC, the monomers are now incorporated into
micelles, and one micelle will exert the same osmotic pressure as one monomer.
Therefore the osmotic pressure after the CMC will increase very gradually.
Determinations such as these are not common as the method is a tedious one.
3. Surface Properties
The adsorption of surfactant at the surface of water causes a decrease in surface
tension with an increase in concentration until the CMC is reached. Thereafter, and
additional surfactant monomers will form micelles in the bulk, and have no effect on
surface tension which will remain constant.
The minimum displayed by the dotted line is frequently caused by the presence of
adsorbed impurities in the system (recall that adsorption is usually a displacement
process). On initial addition of surfactant, both impurity and surfactant are adsorbed at
the surface, which results in the lowering of the surface tension to a greater degree than
that caused by the pure surfactant alone. However, at the CMC, the impurity is taken up
by micelles or solubilized. The surface tension then rises back up to the baseline surface
tension value caused by the pure surfactant beyond its CMC.
Comparing the CMC of ionic and non-ionic surfactants:
In non-ionic SAA’s charge is absent, so there are no
forces opposing micelle formation, and the formation
is aided by V D Waal’s attractive forces between the
tails. Micelles therefore form more easily than with
ionics, where repulsion will occur between the likecharged heads and tend to oppose formation.
4
4. Electrical/Molar Conductivity Cooper & Gunn p.64
The micellar surface has a high charge density so the conductivity power of micelles is
much greater than that of ions. One would therefore expect an increase in conductivity at
the CMC.
However, an atmosphere of counterions or gegions surrounds the micelle and causes a
partial neutralisation of charge, reducing charge density, thereby retarding conductivity.
This retarding effect is much greater for micelles than for single ions. At the CMC then
there is an overall decrease in conductivity as micelles start forming.
5. Solubility and the Krafft Temperature
At low temperatures, the solubility of surfactants
increases slightly with an increase in temperature. At a
particular temperature, sufficient surfactant is in solution
to allow the formation of micelles. This temperature is
known as the Krafft Temperature.
Beyond this temperature, there is a rapid increase in solubility as micelles are more
soluble than monomers. At temperatures below the Krafft point micelles will not be
formed, so it is often necessary to use heat to get a surfactant into solution.
6. Light Scattering
Micelles cause greater scattering of light than do monomers. At the CMC there will be an
abrupt increase in the amount of light scattered. This method enables calculation of the
aggregation number i.e. the number of monomers per micelle, and also provides
information on the shape of the micelle.
5
4. SOLUBILIZATION
An important property of association colloids or aqueous micellar solutions is the ability of
micelles to increase the solubility of materials that are normally insoluble in the dispersion
medium used. This property is called solubilization. is thus the property of SAA's to cause
an increase in the solubility of organic compounds in aqueous systems, and this only
occurs at and above the CMC. The site of solubilization within the micelle is closely related
to the chemical nature of the solubilisate.
SLIDE : SOLUBILIZATION IN MICELLES Aulton p.105
(i) Non-polar solubilization
The non-polar solubilisates such as the aliphatic hydrocarbons will be dissolved in the
hydrocarbon core of the micelle. The hydrocarbon chains of the SAA behave as a
hydrocarbon solvent. Solubility of this type of solubilisate should increase as the
concentration of SAA increases.
(ii) and (iii) Water-insoluble compounds containing polar groups
These compounds are orientated with the polar group at the surface of the ionic
micelle between the polar heads of the SAA as they are attracted to the water. The
hydrophobic group will be inside the hydrocarbon core of the micelle. The position of
the molecule depends on the strength of the polar group e.g. (ii) salicylic acid
(solubility 1 in 550) is more soluble than (iii) naphthalene (insoluble).
(iv) and (v) Solubilization in non-ionic surfactants
Solubilization in polyoxyethylated non-ionic SAA's can occur in the polyoxyethylene
shell which surrounds the core. p-hydroxy benzoic acid (iv) is solubilised entirely within
this region hydrogen bonded to the ethylene oxide groups, while esters such as the
parabens (v) are located at the shell-core junction, with the ester just within the core.
Solubilisate that are located within the micellar core increase the size of the micelle in
two ways; the core is enlarged by the solubilisate, so the number of surfactant
molecules per micelle increases in an attempt to cover the swollen core.
Solubilization and drug stability
The properties of micellar-bound drug can sometimes vary significantly from those of the
simple aqueous drug, as micellar-bound drug is located in an environment that is very
different from water (e.g. the dielectric constant is much lower).
► Solubilization has been shown to have a modifying effect on the rate of hydrolysis of
drugs e.g. alkaline hydrolysis of benzocaine is retarded ny non-ionic surfactants. The
extent of the change produced is likely to depend on the exact location of the solubilized
6
drug within the micelle. Non-polar compounds solubilised deep in the hydrocarbon core
of a micelle are likely to be better protected against attack by hydrolysing species than
more polar compounds located closer to the micellar surface.
► Protection from oxidative degradation has also been found with solubilized systems e.g.
Vit A
► Drugs themselves may be surface-active and such drugs form micelles. This selfassociation has been found to increase the drug's stability e.g. micellar solutions of
penicillin G have been reported to be 2.5 times as stable as monomeric solutions under
conditions of constant pH and ionic strength.