Topics Covered
Background
What is Zeta
Potential?
How is Zeta
Potential Measured?
Zeta
Potential and Electrolytes
Potential Determining Ions
Zeta
Potential and Flocculation
Studying
Zeta Potential
Intravenous Fat Emulsions
Formulation
Protocol
Problems Correlating The stability of
Emulsions with Zeta Potential
Drug
Targeting and Delivery Systems
Non-Aqueous
Systems
Background
Although particle size and its measurement
are intuitively familiar to particle technologists, the concept of zeta
potential is less widely understood and applied. This is unfortunate since it is
at least as fundamentally important as particle size in determining the
behaviour of particulate materials, especially those with sizes in the colloidal
range below a micrometer. Zeta potential is related to the charge on the surface
of the particle, and so influences a wide range of properties of colloidal
materials, such as their stability, interaction with electrolytes, and
suspension rheology.
What is Zeta
Potential?
When a particle is immersed in a fluid, a
range of processes causes the interface to become electrically charged. Some of
the most commonly found charging mechanisms include adsorption of charged
surfactants to the particle surface (for example in an emulsion stabilised by an
ionic surfactant), loss of ions from the solid crystal lattice (silver halide
particles used in photographic emulsions) and ionization of surface groups
(carboxylate in polymer microspheres). These processes lead to the production of
a surface charge density, expressed in coulombs per square metre, which is the
fundamental measure of charge at the interface. The charge cannot be measured
directly, but only via the electrical field it creates around the particle. Thus
the surface charge is normally characterised in terms of a voltage at the
particle surface, the surface potential, rather than a charge density, although
one can usually be calculated from the other. The zeta potential occurs at a
distance from the surface and this will be different to the surface potential.
In the simplest approximation, the potential decays exponentially with distance
from the surface of the particle (Fig. 1). As we will see, the rate of decay is
dependent on the electrolyte content of the fluid.
Figure 1. Approximation of zeta potential
as a function of distance from the particles’ surface.
How is Zeta Potential
Measured?
So far, we have not defined zeta potential,
and in order to do this we need to understand the basic method for its
measurement, which is electrophoresis. To many, this method is familiar because
of its use for the separation of macromolecules, and particle electrophoresis is
a similar phenomenon. The particles in their suspending medium are placed in an
electric field; if charged, they will drift in the field, positive particles
drifting towards the negative electrode, and negative particles drifting towards
the positive electrode. However, the particles do not drift on their own; they
carry a thin layer of ions and solvent around them. The surface separating the
stationary medium from the moving particle and its bound ions and solvent is
called the surface of hydrodynamic shear, and the zeta potential is the
potential at this surface. Consequently zeta potential can be determined by
measuring the drift velocity of the particle in an electrical field of known
strength. Early instruments for this purpose (the Rank micro electrophoresis
apparatus) used manual observation of the particles, a procedure that was
fraught with error and also extremely slow. Fortunately, we now have a range of
instruments that measure the velocity using the doppler shift of light scattered
from the moving particles – the Malvern Zetasizer series. Advance signal recovery techniques reliably
measure the tiny doppler shift due to the particle movement (only a few tens of
Hz in 1015 Hz) and automatically calculate the distribution of zeta potentials
in the sample. Normally this value lies within the range +/- 100mV for most
systems immersed in aqueous media.
Figure 2. The Malvern Zetasizer for
measurement of zeta potential.
Zeta Potential and
Electrolytes
One of the major uses of zeta potential is
to study colloid-electrolyte interactions. Since most colloids, particularly
those stabilised by ionic surfactants, are charged, it is not surprising that
they interact with electrolytes in a complex manner. Ions of charge opposite to
that of the surface (counterions) are attracted to it, while ions of like charge
(co-ions) are repelled from it. Consequently the concentrations of ions near the
surface are not the same as those in the bulk of the solution (i.e. at a long
distance from the surface) as shown in Figure 3. The accumulation of counterions
near the surface causes the particle charges to be screened, thus reducing the
zeta potential. Ions can conveniently be divided into three classes depending on
how they interact with the surface:
Figure 3. Concentration of ions near to
the surface of a particle in solution.
Indifferent ions are those which are only
attracted to the surface by virtue of their charge in a purely electrostatic
manner, a process known as non-specific adsorption. If we measure the zeta
potential of a colloid as a function of concentration of such an ion, we find
that the screening effect of the ions gradually reduces the zeta potential (not
the surface potential), and this asymptotes to zero at high electrolyte
concentrations (Figure 4a).
Figure 4. Zeta potential as a function of
electrolyte concentration for an indifferent electrolyte (a) and for a
specifically adsorbed electrolyte (b).
Specifically adsorbed ions interact
chemically with the surface, for example by complexation with groups on the
surface. Consequently as their concentration is increased, they also screen the
zeta potential, but the additional chemical (as distinct from electrostatic)
binding on the surface causes sufficient adsorption of ions for the original
particle charge to be neutralised and then reversed as the electrolyte
concentration increases (Figure 4b). In such a system we see a point of zero
charge or PZC at a welldefined electrolyte concentration, prior to charge
reversal.
Potential
Determining Ions
Potential-determining ions (PDI) are a
special case of specifically adsorbed ions; this term is usually reserved for
those involved in whatever process is responsible for the particle charge. For
example, most polymer microspheres are charged because they have carboxylate
groups on the surface; ionisation of these groups leads to the charge, so H+ is
a PDI on this surface. Similarly Ag+ and I- are PDI’s on silver iodide
particles. The distinction between specifically adsorbed and potential
determining ions is often vague, particularly in those systems in which the
surface chemistry is not fully understood.
Zeta Potential and
Flocculation
The major area of application of
colloid-electrolyte phenomena is to understand stability and flocculation
effects. The simplest model of these phenomena arises directly from Figure 4,
and is known as the DLVO (Deryaguin- Landau-Verwey-Overbeek) theory. This simply
states that the stability of the colloid is a balance between the attractive Van
der Waals’ forces and the electrical repulsion due to the surface charge. If the
zeta potential falls below a certain level, the colloid will aggregate due to
the attractive forces. Conversely, a high zeta potential maintains a stable
system. The point at which electrical and Van der Waals’ forces exactly balance
can be identified with a specific electrolyte concentration, known as the
critical flocculation concentration or CFC (Figure 5). Indifferent ions cause
the zeta potential to continuously decline at high concentration, so we see a
single CFC, and the colloid aggregates at all higher electrolyte concentrations.
In contrast, specifically adsorbed ions cause charge reversal that may be
sufficient to re-stabilise the colloid. In this case we will see an upper and
lower CFC, with a region of instability between them.
Figure 5. The effect of electrolyte
concentration on flocculation.
Studying Zeta
Potential
The foregoing discussion shows us that the
zeta potential measured in a particular system is dependent on the chemistry of
the surface, and also how it interacts with its surrounding environment. This is
a most important point; zeta potential must always be studied in well-defined
environments (specifically pH and ionic strength) or the data is valueless. It
is quite meaningless to talk about "the zeta potential of a surface" unless the
conditions are specified. In order to illustrate the planning of a zeta
potential study, it is useful to take a case study on a particular system. We
have studied triglyceride fat emulsions for some years, and these studies
provide a useful illustration of the power of zeta potential measurement in
understanding colloid stability in complex systems.
Intravenous Fat
Emulsions
Triglyceride emulsions are medical products;
they are sub micron emulsions of vegetable oils in water, emulsified by
phospholipids, which provide a high zeta potential, and a correspondingly long
shelf life (2-3 years). The emulsions are used to feed patients intravenously
who cannot be fed orally (e.g. due to gastrointestinal surgery). Such patients
also need other nutrients, including amino acids, glucose and electrolytes. For
some time it has been the common practice to mix all of these materials, in
varying proportions, in a single liquid mixture (a total parenteral nutrition or
TPN mixture) and infuse it into a patient, at a rate of about 3 litres a day.
Naturally, in such a mixture, there is a wide scope for interaction between the
components, and in many mixtures the fat emulsion becomes unstable, and
coalesces or flocculates in a few days. In this condition it is unsuitable for
infusion, and so the mixtures are normally made up just before administration,
using sterile techniques. An understanding of the stability of the emulsion in
these systems would be helpful in predicting which mixtures would be unstable,
and even possible in producing stable mixtures with long shelf life.
Formulation
Protocol
Early studies demonstrated that the emulsion
itself, at a pH of 7 and low electrolyte concentration, had a zeta potential of
–40 to –50mV, which is sufficient to provide good stability and a shelf life of
at least 2 years. This potential was markedly reduced by electrolytes, with
monovalent cations being indifferent, while divalent cations adsorbed
specifically with a PZC of 3 mM and a significant degree of charge reversal.
These ions are all present in TPN mixtures, and this accounts for the
instability of the emulsion in these systems.
Problems Correlating
The stability of Emulsions with Zeta Potential
It should be possible to use the DLVO theory
to correlate the stability of the emulsions in a particular mixture with its
zeta potential; unfortunately there are a number of problems involved in making
such a measurement. The mixtures contain a large phase fraction (1-5%) of the
emulsion, and so are very turbid, and must be diluted before light scattering
measurements can be performed. Early workers who did not understand the nature
of zeta potential simply diluted the mixtures with distilled water. The
resultant zeta potentials bore no resemblance to those of the emulsion in the
original mixture since the dominant ions were reduced in concentration by some
orders of magnitude! In order to obtain a relevant zeta potential it is
necessary to maintain the continuous phase composition on dilution. There are
two approaches to this problem; if the composition of the continuous phase is
known, it can be prepared without any emulsion component and used as a diluent.
A more common situation is that the continuous phase composition is uncertain;
even if you knew what went into it, adsorption to the disperse phase may have
depleted some components. In this case, the usual trick is to centrifuge the
dispersion to get a clean sample of the continuous phase for
dilution.
The second problem with this measurement is
the extremely high ionic strength (0.2-0.4M) which leads to high conductivity
and consequently rapid sample heating and large cell voltage drops. The early Zetasizer 2 could not cope particularly well with this
problem, but the current Zetasizer range has cell voltage pulsing that keeps the mean
current down; and the reengineering of the electrophoresis cell has resulted in
major improvements in electrical stability. It is now possible to use this
instrument to routinely measure zeta potentials in these high conductivity
mixtures, and the resulting values (± 1-5mV) correlate well with the stability
of the emulsion in the mixtures. Studies of this type are now allowing us to
understand the behaviour of emulsions in complex colloidal systems and provide
real predictive power for formulation purposes.
Drug Targeting and Delivery
Systems
Emulsions have also been used as drug
delivery systems, and in many cases an understanding of the electrophoretic
properties is crucial in formulation design. Although most drugs are
water-soluble, an increasing number are surfaceactive or even hydrophobic, and
such materials can provide significant problems for conventional formulation
techniques. Consequently hydrophobic drug candidates are usually sent back to
the chemistry department with a note to prepare a water-soluble analogue! In
some cases this is not possible, for example some natural products or
biotechnology materials, or where the mode of action is related to the
lipophilicity, e.g. anaesthetics, hypnotics, and tranquillisers. In these cases
emulsion delivery is increasingly used. Examples are ICI’s Diprivan, an
intravenous anaesthetic, and Kabi’s Diazemuls, a sedative.
An example of the problems that can be
encountered in this approach is shown in Figure 6, which is the zeta potential –
pH curve for a drug-containing emulsion that is flocculated at pH 7. Data of
this type allows a rational selection of formulation pH and emulsifier to
maximise zeta potential and hence emulsion stability.
Figure 6. pH versus zeta potential data
allowing optimisation of emulsion stability.
Non-Aqueous
Systems
A further example of the use of zeta
potential in understanding suspension stability occurs in the suspensions of
drugs in aerosol propellants used for delivery of drugs by inhalation, for
example bronchodilators. The micronised drug is suspended in the aerosol
propellant, so that when the aerosol is fired, particles of drug are sprayed out
and can be inhaled. It is important to control the particle size by controlling
the zeta potential, to guarantee a repeatable dose to the patient. The problem
in this case is that it is extremely difficult to measure zeta potentials of
particles suspended in nonaqueous media like CFC propellants, since the particle
mobilities are very small. However, it can be done with appropriate design of
the electrophoresis cell, and Malvern Instruments make such a cell for their Zetasizer. Figure 7 shows the zeta potential of lactose (a
model solid dispersion) in chloroform (a model non-aqueous medium) as a function
of the concentration of lecithin, an ionic surfactant. The lecithin clearly
causes major changes to the potential even at small concentrations; the
suspension is flocculated in the absence of lecithin, but becomes dispersed at
lecithin concentrations above about 10%. Although our understanding of
electrophoresis in non-aqueous systems is still primitive, such studies allow at
least an empirical understanding of stability and surfactant adsorption in these
systems.
Figure 7. Demonstration of how an ionic
surfactant can affect zeta potential.
Source: "Zeta Potential in Pharmaceutical Formulation”,
Application Note by Malvern Instruments.
For more information on this source please
visit Malvern
Instruments Ltd (UK) or Malvern Instruments
(USA).