6.1 Formation of Emulsions

6
Emulsions
Despite their nite stability, emulsions have several advantages as drug delivery
systems. For example, they offer opportunities for solubilizing relatively large
amounts of hydrophobic substances, with advantages relating to, e.g., the effective drug solubility, the drug release rate, and the drug chemical stability. Furthermore, the amount surfactant required for generating and stabilizing emulsions is
generally quite low, and relatively nontoxic surfactants, such as phospholipids
and other polar lipids, as well as block copolymers, can be used as emulsiers/
stabilizers.
6.1
FORMATION OF EMULSIONS
Since oil and water do not mix, oil-water mixtures eventually separate into two
macroscopic phases. Thus, contrary to microemulsions, emulsions are thermodynamically unstable systems. In order to form emulsions which are useful for drug
delivery, their kinetic destabilization must generally be slowed down by the use
of different surface active agents. These may also help forming the emulsion,
and to reach a sufciently small droplet size.
The formation of emulsion systems is a complex process which involves
generation and stabilization of new oil-water interface. In drug delivery, highpressure homogenization is frequently used for generating new surface, and for
Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.
162
Chapter 6
producing emulsion droplets. Within high-pressure homogenization, the liquid

mixture is passed through a chamber where turbulent motions are generated. This,
in turn, generates shear forces, which tear appart any larger entities in the
system, and result in droplet formation. With increasing pressure used in the
homogenization process the shear forces increase, which results in the formation
of smaller droplets (Figures 6.1 and 6.2). Of course, the effect of pressure depends
also on the geometry of the homogenization chamber.
Furthermore, since the high-pressure homogenization is usually performed
in a ow system, where the system passes through the high pressure chamber,
the latter is only exposed to the shear forces for a limited time. Therefore,
exposing the system to the shear forces for a prolonged time results in a more
efcient homogenization. Practically, this is achieved by passing the system
through the homogenization chamber a number of times. Consequently, with an
FIGURE 6.1 Dependence of the drop radius r on the shear strain amplitude s (a)
and steady shear rate (b). The o/w emulsion consisted of nonylphenol
heptaethoxylate/water/PDMS at an oil volume fraction of 0.7. (Redrawn from Mason et al., Phys. Rev. Lett. 1996, 77, 3481 and Langmuir 1997, 13, 4600.)
Emulsions
163
FIGURE 6.2 Effect of (a) homogenization pressure p H on the emulsion droplet size
d 43 and (b) the number of passages on the width of the droplet size distribution c 2
of the emulsion formed. Results obtained with two high-pressure homogenizers are
shown, one very small (low Re) and one large (high Re). (Redrawn from Walstra
et al., in Binks, ed., Modern Aspects of Emulsion Science, The Royal Society of
Chemistry, 1998.)
increasing number of passages, the droplet size generally decreases and becomes
more uniform.
If the droplets generated in the homogenization process are not stabilized,
they will almost momentarily coalesce to two macroscopic phases, since this
reduces the free energy associated with the surface area. In order to stabilize
emulsion droplets, surface active components such as surfactants, polymers or
proteins are added. While the long-term stabilization puts certain requirements
on these stabilizers, as discussed below and also in Chapter 9, the emulsication
164
Chapter 6
process as such requires relatively fast transport of the surface active component
to newly generated surface. This, in turn, makes particularly low molecular
weight surfactants useful as emulsiers. The role of the surfactant in the emulsication process is therefore:
1. To reduce the interfacial tension and thereby promote droplet formation (the free energy increase of forming new surface is directly proportional to the interfacial tension)
2. To stabilize emulsion droplets from occulation and coalescence
Surfactants generally display an adsorption at oil-water interfaces which is
low at low concentrations, increases monotonously with increasing surfactant
concentration, and levels off at the cmc. In parallel, the interfacial tension decreases monotonously with increasing surfactant concentration until it reaches
the cmc, where it levels off. This concentration-dependent surfactant adsorption
and interfacial tension reduction facilitates emulsication, as seen by a decreasing
emulsion droplet size (or increasing the specic surface area A). In fact, there is
a direct relation between the size of the emulsion droplets formed during emulsication, on one hand, and the oil-water interfacial tension in the presence of the
emulsier, on the other (Figure 6.3).
Note, however, that interfacial tension measurements generally relate to
equilibrium conditions. In the emulsication process, on the other hand, the situation is highly dynamic. Therefore, not only the equilibrium adsorption and interfacial tension but also the adsorption kinetics and the dynamic surface tension behav-
FIGURE 6.3 Specic droplet surface area A and average droplet size d 32 as a function of emulsier concentration at an oil volume fraction of 0.2. Plateau values of
the interfacial tension are also given. (Redrawn from Walstra et al., in Dickinson
et al., eds., Food Colloids: Proteins, Lipids and Polysaccharides, The Royal Society
of Chemistry, 1997.)
Emulsions
165
ior are of importance for emulsication processes. In particular, sufciently fast

mass transport to newly formed oil-water interface and following surface tension
reduction is required for reaching an efcient emulsication. This is the reason
why proteins and high molecular weight polymers, which are frequently very good
stabilizers of preformed emulsions, are generally not very efcient emulsiers.
As an illustration of the latter, Figure 6.4 shows the effective adsorption
isotherms for a protein stabilizer (-casein) in emulsions and at a macroscopic
oil-water interface. As can be seen, much higher concentrations are needed to
reach a high adsorption for the emulsion system than for the corresponding macroscopic surface in the case of -casein. The reason for this is the insufcient
adsorption time for the protein in the emulsication process. For a low molecular
weight emulsier (SDS), on the other hand, identical adsorption isotherms are
obtained for the emulsion and the macroscopic interface, showing that in this
case the adsorption is sufciently fast in order to reach surface saturation also
in the emulsication process.
Due to the deformability of emulsion droplets in a shear eld, and a nite
mass transport even of low molecular weight surfactants, there is ample opportunity during the emulsication process for creation of surfactant concentration
gradients at the oil-water interface. This, in turn, allows for a number of different
processes to occur, essentially instantaneously (Figure 6.5).
Both in drug delivery and in other contexts, the term spontaneous emulsication is used for some systems. True spontaneous emulsication leads to the
FIGURE 6.4 Adsorption of -casein and SDS at a macroscopic interface and in an

emulsion. (Redrawn from Walstra et al., in Binks, ed., Modern Aspects of Emulsion
Science, The Royal Society of Chemistry, 1998.)
166
Chapter 6
FIGURE 6.5 Schematic illustration of processes occuring during emulsication related to surfactant interfacial gradients. Processes illustrated are a: droplet breakage, b: gradient relaxation, c: coalescence, and d: droplet stabilization. (Redrawn
from Walstra et al., in Dickinson et al., eds., Food Colloids: Proteins, Lipids and
Polysaccharides, The Royal Society of Chemistry, 1997.)
formation of microemulsions, but this is generally not what is intended. Instead,

such spontaneous emulsication generally results in droplets with a size typical for emulsion systems. The origin of sponatenous emulsication is the following: If two liquids (phase 1 and 2) are both good solvents for a surfactant, but
the solubility in phase 2 is better than that in phase 1, but the surfactant initially
is present only in phase 1, the difference in chemical potential of the surfactant
in the two phases results in an unstable system. If the interfacial tension between
the two phases is sufciently low, the occurrence of minor turbulence may cause
surfactant gradients, which in turn may lead to small droplets of phase 1 breaking
off into phase 2 (Figure 6.6).
FIGURE 6.6 Schematic illustration of the mechanism of spontaneous emulsication. Phase 1 originally contains the surfactant, which, however, is more soluble in
phase 2. (Redrawn from Walstra et al., in Binks, ed., Modern Aspects of Emulsion
Science, The Royal Society of Chemistry, 1998.)
Emulsions
6.2
167
STRUCTURE OF EMULSIONS
The type of emulsion formed (e.g., w/o or o/w) depends on a number of factors,
including the surfactant, the oil and water volume fraction, temperature, salt concentration, and the presence of cosurfactants and other cosolutes. In particular,
the hydrophobicity of the surfactant plays a major role in determining the
type of emulsion formed. This is summarized in the so called Bancrofts rule,
which says that the phase in which the emulsier is most soluble will be the
continuous phase after emulsication. From a practical perspective this means
that extensively water-soluble surfactants (high HLB; see Chapter 3) favor formation of o/w emulsions, whereas hydrophobic surfactants which are readily soluble
in the oil phase but not so in the aqueous phase (i.e., with a low HLB number)
form w/o emulsions (Figure 6.7).
There are many ways to discriminate o/w and w/o emulsions. Particularly
straightforward and not experimentally demanding is simply to measure the electrical conductivity in the system. Thus, while the conductivity in water-continuous emulsions is high even at quite high oil volume fractions, w/o emulsions
display orders of magnitude lower conductivity even at high water content (Figure 6.8).
6.3
PHASE INVERSION OF EMULSIONS
An important feature of emulsions is the so called phase inversion displayed by

such systems. By this we mean the transition from a water-continuous o/w emul-
FIGURE 6.7 Effect of the HLB of the surfactant mixture (nonylphenol ethoxylates)
on the emulsion structure as probed by droplet size measurements. (Redrawn from
Brooks et al., Chem. Eng. Sci. 1994, 49, 1053.)
168
Chapter 6
FIGURE 6.8 Conductivity of o/w and w/o emulsions as a function of volume fraction
of the discontinuous phase. (Redrawn from Smith et al., Langmuir 1994, 10, 2516.)
sion to an oil-continuous w/o emulsion, or vice versa, on changing some parameter, such as the surfactant mixture composition, temperature, or the salt concentration. The dramatic effects this may have on transport-related properties (such as
conductivity or drug release rate) is illustrated in Figure 6.9 for an emulsion
FIGURE 6.9 Effect of temperature on the conductivity for a heptane-water emulsion

stabilized by C 12 E 5 . Note, that the system undergoes a transition from water continuous to oil continuous at 30C. (Redrawn from Binks, Langmuir 1993, 9, 25.)
Emulsions
169
stabilized by C 12 E 5 undergoing phase inversion from o/w to w/o at a critical

temperature (the so called phase inversion temperature, PIT).
The phase inversion in emulsion systems is related to the packing of the
surfactants at the interface. In analogy to micellar, liquid crystalline, and microemulsion systems, nonionic EO-containing surfactants favor cruvature toward the
oil at low temperature, and toward water at elevated temperature. This, in turn,
results in o/w emulsions at low temperature and w/o emulsions at elevated temperature. At a given intermediate temperature, planar interfaces are favored, resulting in a structural transition for emulsion systems. Naturally, this is completely analogous to the temperature-dependent surfactant packing in other types
of surfactant structures (cf. Chapters 2, 3, and 5). Not entirely unexpected, the
phase inversion temperature, with its high surfactant packing density, is also characterized by a very low oil-water interfacial tension (Figure 6.10).
The phase inversion conditions also depend on the composition of both the
aqueous phase, the surfactant mixture used for emulsication, and the oil phase.
For example, addition of moderate to high salt concentrations affects the solvency
conditions for EO-containing nonionic surfactants (cf. Chapters 2 and 3). In a
similar manner, addition of salt affects the phase inversion temperature. As is
the case also for other nonionic surfactant systems, such salt effects are mainly
lyotropic in nature and occur rst at rather high salt concentrations (Figure 6.11).
Also, the nature of the oil affects the PIT in nonionic surfactant systems
(Figure 6.12). The main origin of this is the relative solubility of the surfactant
FIGURE 6.10 Temperature-dependent water-octane interfacial tension ab at c

cmc for a few C 12 E n surfactants. (Redrawn from Sottmann et al., J. Chem. Phys.
1997, 106, 8606.)
170
Chapter 6
FIGURE 6.11 Effect of salt on the phase inversion temperature of a water-heptane

emulsion stabilized by a nonylphenol surfactant. (Redrawn from Shinoda et al., J.
Colloid Interface Sci. 1970, 32, 642.)
FIGURE 6.12 Effect of the hydrocarbon structure on the PIT shown by 1:1 oil :
water emulsions stabilized by a nonylphenol ethoxylate surfactant. (Redrawn from
Shinoda et al., J. Phys. Chem. 1964, 68, 3485.)
Emulsions
171
in the water and the oil phases. According to Bancrofts rule, for w/o emulsions
to be favored (i.e, for the PIT to be low), the surfactant should be readily soluble
in the oil phase, and in fact more soluble in the oil phase than in the water phase.
This is illustrated in Figure 6.12, showing that in the case of aromatics, benzene,
for example, in which the nonylphenol ethoxylate surfactant is readily soluble,
displays a low PIT, whereas long-chain alkanes, such as hexadecane, in which
the surfactant has a limited solubility, are characterized by a high PIT.
In a similar way that the structure of nonionic surfactants affects their selfassembly to form micelles, liquid crystalline phases, and microemulsions, it affects the PIT of emulsions. Specically, with increasing length of the polar head
group and/or decreasing size of the hydrophobic part, aggregates curved toward
the oil become relatively more favored. An analogous behavior is observed in
emulsion systems, in that o/w emulsions are relatively more favored over a larger
temperature range for surfactants with a large polar head group and a small hydrophobic part (i.e., more hydrophilic surfactants), whereas w/o emulsions are
favored by more hydrophobic surfactants. Expressed in the vocabulary generally
used for emulsions, the higher the HLB, the higher the PIT, and vice versa (Figure 6.13).
Another type of temperature-dependent emulsions of interest in relation
to drug delivery are those stabilized by phospholipids. The latter are efcient
emulsiers and stabilizers since their molecular structure generally favors close
to planar packing (as in larger emulsion droplets), and since they exert hydration
force stabilization of emulsion droplets. They are also of natural origin and well
FIGURE 6.13 Correlation between HLB and PIT for water-cyclohexane emulsions
stabilized with nonionic surfactants. (Redrawn from Shinoda et al., Emulsions and
Solubilization, Wiley, 1986.)
172
Chapter 6
tolerated in various drug delivery applications. Often, pharmaceutical emulsions

are prepared from technical lecithins, the composition of which depends on the
origin, but which generally is dominated by PC (Figure 1.9) followed by PE, PI,
PA, and PS and lysophosphatides, the latter two in minor quantities. Also pure
PC and fractions thereof are used sometimes for emulsication and emulsion
stabilization.
An important aspect to consider for phospholipid emulsiers is the chain
melting temperature. As discussed also in Chapter 4, the hydrophobic chains are
in a liquidlike state above the chain melting temperature, but frozen below
this temperature. Since an efcient emulsication requires fast transport to the
newly created interface and packing there, temperatures below the chain melting
temperature are detrimental for emulsication. Therefore, emulsication should
preferably be performed above the chain transition temperature. This means that
the longer and more saturated the phospholipid, the higher the emulsication
temperature required (Figure 6.14).
At high temperature, on the other hand, there may also be detrimental effects, e.g., relating to Ostwald ripening (see below), chemical degradation of
compounds incorporated in the emulsion, etc. Partly for this reason, but also due
to cost issues, phospholipids used for drug delivery are often technical lecithin
mixtures. Since these contain a distribution of chain lengths and saturation, and
also minor fractions of charged phospholipids, the chain melting temperature is
generally considerably lower for such lecithins than for the pure phospholipid
components.
FIGURE 6.14 Effect of chain length on the main transition temperature for phosphatidylcholine. (Redrawn from Small, Handbook of Lipid Research, Plenum
Press, 1986.)
Emulsions
6.4
173
RHEOLOGY OF EMULSIONS
The rheology of emulsion systems is of some general interest in drug delivery.

In some applications, a high viscosity and shear resistance is desired (e.g., ointments and creams), whereas in others, e.g., injectable emulsions, a low viscosity
is required for practical administration reasons and for reduction of pain for the
patient. As with other types of disperse systems, the rheological properties of
emulsion systems depend critically on the volume fraction of the disperse phase.
However, the most abundant phase is not necessarily the continuous one. Instead,
the emulsion structure is given largely by the relative solubility of the surfactant
in the two phases. It is therefore possible to have, e.g., a water-continuous emulsion containing 90% oil and less than 10% water (Figure 6.15).
The viscosity of emulsions is relatively insensitive to the volume fraction
of the disperse phase up to rather high volume fractions. Only at volume fractions
of the order 0.30.5 does the viscosity increase more dramatically (Figure 6.16).
The onset of the viscosity increase is a result of an increasing degree of close
packing of the droplets, and hence depends on both the droplet size distribution
FIGURE 6.15 Schematic illustration of an emulsion where the volume fraction of

the disperse phase is high.
174
Chapter 6
FIGURE 6.16 Viscosity of a w/o emulsion containing PEG7-hydrogenated castor

oil/dicaprylyl ether/decyl oleate/MgSO 4 as a function of water content (i.e., water
droplet volume fraction). (Redrawn from Forster et al., Cosmet. Toiletries. 1997,
112, 73.)
and on the interaction between the emulsion droplets. For example, for very polydisperse droplets, increasing the droplet concentration without causing a major
viscosity increase is facilitated. For droplets stabilized by thick polymer layers
or through long-range electrostatic interactions, on the other hand, the viscosity
increase with increasing droplet concentration is more pronounced.
Such self-thickened emulsion systems (e.g., w/o systems containing
6580% water) are commonly used in cosmetic and topical drug delivery applications. Even more concentrated emulsions may be prepared, and for certain systems the volume fraction of the disperse phase may be as large as 0.99! Due to the
gel-like consistency of such systems, they are frequently referred to as emulsion
gels. An attractive feature with such systems is that they are frequently transparent, which may offer opportunities in, e.g., periodontal anesthesia, and in dermal
or occular drug delivery. Also, such systems are interesting for drug delivery due
to their capacity to incorporate both water-soluble and oil-soluble drugs. With
increasing volume fraction of the discontinuous phase, the release of substances
incorporated in this increases. The diffusion and release of a compound from
emulsion gels will also depend on its partitioning between the oil and the water
phase. As an illustration of this, Figure 6.17 shows the effect of addition of salt
on the partitioning of mandelic acid toward the oil phase, and on its diffusion
rate. As can be seen, the ratio between the observed diffusion coefcient and the
partition coefcient remains essentially constant over the salt concentration
range, indicating that for this particular system, the diffusion is entirely determined by the partitioning between the phases.
Emulsions
175
FIGURE 6.17 Effect of electrolyte concentration on the diffusion coefcient D of

mandelic acid from gel emulsions consisting of water-decane-C 10 E 3. Shown also
is the diffusion coefcient normalized with the partition coefcient as a function
of salt concentration (circles). Triangles and squares refer to NaCl and Na 2 SO 4 ,
respectively. (Redrawn from Caldero et al., Langmuir 1997, 13, 385.)
A promising feature is that emulsion gels may be used as in situ forming

gel systems. Thus, as can be seen in Figure 6.18, the system water-decane-C 16 E 4
with a water volume fraction of 99% and an oil/surfactant ratio of 1.5 displays
a pronounced increase in elastic modulus on increasing the temperature from
room temperature to body temperature. Quantitatively, however, the temperature-
FIGURE 6.18 Elastic modulus G 0 as a function of temperature for the system

water-decane-C 16 E 4 with a water volume fraction of 99% and an oil/surfactant
ratio of 1.5. (Redrawn from Pons et al., J. Phys. Chem. 1993, 97, 12320.)
176
Chapter 6
induced thickening is much smaller than that displayed, e.g., by block copolymer
(Chapter 3) and polysaccharide (Chapter 8) systems.
6.5
DESTABILIZATION OF EMULSIONS
In analogy to other disperse systems, emulsions are not thermodynamically stable, but instead undergo continuous destabilization until one macroscopic water
phase and one macroscopic oil phase have been formed. The timescale for destabilization of emulsions depends critically on a number of factors, and several
different destabilization mechanisms exist. In general, the kinetics of destabilization of emulsions is therefore more complex than that of destabilization of a
polymer latex dispersion (Chapter 9). At least four different emulsion destabilization mechanisms may be identied, i.e., creaming, occulation, coalescence, and
Ostwald ripening (Figure 6.19). The relative importance of the rst three of these
depends primarily on the emulsion droplet size and the droplet concentration,
with creaming favored for large droplets at low droplet concentrations, coalescence at high droplet concentration, and occulation for small emulsion droplets
at low droplet concentration.
Since creaming is a gravity effect similar to sedimentation, it depends on
the density difference between the continuous phase and the droplets. Thus, if
the droplets are heavier than the continuous phase, sedimentation will occur,
whereas creaming will occur for droplets less dense than the continuous phase.
Apart from the density difference, the creaming rate depends on the droplet size.
FIGURE 6.19 Schematic illustration of emulsion destabilization mechanisms.
Emulsions
177
With increasing droplet size, the buoyancy increases, thereby promoting creaming. Also, since the driving force for creaming is generally rather weak, it can
be kinetically hindered by increasing the viscosity of the system, e.g., through a
high droplet concentration or through addition of a thickening agent to the continuous phase (Figure 6.20).
Flocculation in emulsion systems is largely analogous to occulation in
other disperse systems, such as polymer latices. As discussed in some detail in
Chapter 9, the main parameter of interest in this context is the interparticle (interdroplet) interactions. As with polymer particles, electrostatic stabilization of
emulsions is efcient at low droplet concentration and at low salt content. Addition of salt, on the other hand, screens the electrostatic repulsion between the
droplets, and promotes occulation. This behavior is illustrated in Figure 6.21.
Thus, as Ca 2 is added to Intralipid, a phospholipid-stabilized o/w emulsion used
for parenteral nutrition, the droplet surface charge is reduced. At a certain Ca 2
concentration, the droplet electrostatic potential is zero, which results in fast
occulation of the emulsion. Increasing the Ca 2 concentration further results in
charge reversal, i.e., at high Ca 2 concentration, the droplets are positively
charged. They are then charge-stabilized again, and the occulation rate therefore
decreases.
Similar to polymer dispersions, emulsions are often further stabilized by
adsorbed or otherwise surface-bound polymers, which generate a steric stabiliza-
FIGURE 6.20 Creaming proles at different times of 20 vol% heptane-hexadecane

(9 :1)-in-water emulsions stabilized by Brij 35 in the presence of hydroxyethyl cellulose in the aqueous phase. (Redrawn from Hibberd et al., Colloids Surf. 1988, 31,
347.)
178
Chapter 6
FIGURE 6.21 Effects of Ca 2 concentration on the droplet electrostatic potential

(a) and the emulsion occulation rate (b) for Intralipid emulsion. (Redrawn from
Washington et al., in Sitges-Serra et al., eds., Clinical Progress in Nutrition Research, Karger, 1988.)
tion of the emulsions which is largely salt independent (Chapter 9). At moderate
salt concentrations, however, electrostatic and/or hydration force interactions
may be sufcient for reaching a sufcient emulsion stability.
For oil continuous systems such as w/o emulsions, the interdroplet interactions are different from those in o/w systems. Although electrostatic interactions
are very long range due to the low dielectric constant of the oil phase, charges
are energetically disfavored, and tend to be minimized, e.g., through extensive
counterion binding or protonation/deprotonation. Therefore, w/o emulsions are
generally not electrostatically stabilized. Instead, steric stabilization is frequently
employed for such systems.
Emulsions
179
It is important to note, however, that just as for polymer lattices and other
dispersions, the stability of emulsions against occulation does not exclusively
depend on the interdroplet interactions, but also on external elds, such as
sedimentation/creaming, and shaking/shearing. Thus, in the presence of such external elds, which force the droplets to approach each other, the stability toward
occulation and coalescence is generally reduced. In fact, a commonly employed
acceleration method for emulsion destabilization is to apply either random or
regular shaking (Table 6.1). The stability of the emulsion is then determined by
the interplay between interdroplet interactions and external elds.
When two droplets approach each other, as in occulation, the water lm
between them becomes thinner due to drainage of the continuous phase. If the
lm ruptures, the two droplets can merge and become one, i.e., coalescence occurs. The probability for coalescence in emulsions therefore depends on the activation barrier for forming a hole in the lm between droplets. The lower the
activation energy, the more probable the coalescence. The activation energy for
hole formation, in turn, depends on a number of factors. In particular, the spontaneous curvature of the surfactant molecules stabilizing the emulsions, as well as
the surfactant lm bending energy is of critical importance. For example, deemulsication may be caused by (1) reducing the absolute value of the monolayer
spontaneous curvature (Figure 6.22), e.g., by addition of surfactant with the opposite spontaneous curvature, or by (2) reducing the monolayer bending elasticity,
e.g., by addition of short chain alcohols.
Yet another destabilization mechanism for emulsion systems is so called
Ostwald ripening. The origin of this effect is that the pressure inside droplets is
higher the higher the surface curvature, i.e., the smaller the droplets. This, in
turn, means that the solubility of an oil outside a small oil droplet is larger than
that outside a larger droplet (and analogously for w/o emulsions). As a consequence of this, material contained within the small droplets will dissolve prefer-
TABLE 6.1 Mean Droplet Size (m) of a Lecithin-Stabilized O/W Emulsion

with 0.01 M Phosphate Buffer in the Aqueous Phase after Different Times of
Shaking. The Emulsion Droplet Charge Decreases with Decreasing pH
Buffer
0h
3h
6h
24 h
48 h
pH
pH
pH
pH
pH
0.37
0.37
0.37
0.37
0.37
0.37
0.37
0.38
0.41
0.86
0.37
0.37
0.43
0.44
2.02
0.37
0.37
0.54
0.61
phase sep.
0.37
0.37
phase sep.
phase sep.
phase sep.
9.3
7.5
5.7
4.0
2.5
Source: Data from Lindstrom et al., J. Disp. Sci. Technol. 1999, 20, 247.
180
Chapter 6
FIGURE 6.22 Hole activation barrier W vs the monolayer spontaneous curvature

H 0 for a phospholipid-stabilized emulsion. Note that in the vicinity of zero curvature,
multiple emulsions are favored. (Redrawn from Kabalnov et al., Langmuir 1996,
12, 276.)
entially, diffuse through the continuous phase, and recondensate onto the larger
droplets. Thus, the large droplets will grow larger while the small droplets will
shrink until they eventually disappear. The kinetics by which this process occurs depends strongly on the solubility of the compounds contained in the droplets within the continuous phase. More precisely, the higher their solubility in
the continuous phase, the faster the mass transport, and the faster the emulsion
destabilization. As can be seen in Figure 6.23, the destabilization kinetics increases with decreasing oil chain length, and is also higher for alkenes than for
alkanes. Both these effects follow the solubility of the oils in the aqueous
phase.
Since the emulsion destablization through Ostwald ripening has nothing
to do with droplet occulation or coalescence, surfactant addition may have
little or no effect on the emulsion destabilization kinetics (Figure 6.24). Note,
however, that the role of the surfactant in Ostwald ripening may also be somewhat more complex than this at c cmc, since the solubilization in the aqueous phase and the oil transport from small droplets to large ones can occur
through micelles. The destabilization kinetics in that case depends on the solubilization capacity of the micelles, the micelle concentration, and the size of the
micelles, all determining the total oil mass transfer between small and large droplets.
Apart from working at surfactant concentrations just below the cmc and
using sparingly soluble oils (o/w emulsions), another possibility to slow down
Emulsions
181
FIGURE 6.23 (a) Time dependence of the drop concentration for o/w emulsions
containing 0.02 wt% hydrocarbon in a 2 wt% Tween 20 aqueous phase. (b) Time
dependence of the median drop diameter for the same emulsions as in (a). Circles:
C 14 ; squares: C 16 ; triangles: C 18 ; lled symbols: alkanes; open symbols: alkenes.
(Redrawn from Weiss et al., Colloid Surf. A 1997, 121, 53, and Coupland et al.,
J. Food Sci. 1996, 61, 1114.)
FIGURE 6.24 Variation of the average droplet diameter d av with time for SDS-containing undecane-in-water emulsions undergoing Ostwald ripening for different
SDS concentrations. Note that the droplet growth is essentially independent of
SDS concentration. (Redrawn from Kabalnov, Langmuir 1994, 10, 680.)
182
Chapter 6
FIGURE 6.25 Droplet size r increase as a function of time in the absence (a) and
presence (b) of a ripening inhibitor (Migliol 812) in o/w diamino ether emulsions
stabilized by galactolipids. (Redrawn from Welin-Berger et al., Int. J. Pharm. 2000,
200, 249.)
Ostwald ripening is to add a second component to the oil phase, with a lower
solubility in the water phase than that of the oil. Due to the solubility difference
between the two oil components, the Ostwald ripeningrelated transport between
small and large droplets will occur at different rates for the two oil components,
which means that the smaller droplets will be successively enriched in the least
water-soluble component, whereas the opposite applies for the larger droplets.
This gradual concentration increase results in an increased chemical potential of
the least soluble component in the smaller droplets, and of the more soluble
component in the larger droplets, both of which counteract the curvature-driven
transport from smaller to larger droplets. At a certain point, the back transport
equals the Ostwald ripening, and no further overall destabilization of the emulsion
through Ostwald ripening occurs (Figure 6.25).
6.6
MULTIPLE EMULSIONS
Multiple emulsions refer to emulsions where the dispersed phase contains inner
droplets of the continuous phase. Such emulsions can either be of the water-inoil-in-water (w/o/w) or oil-in-water-in-oil (o/w/o) type (Figure 6.26). Generally,
both types of multiple emulsions are prepared through a double homogenization
process, e.g., rst preparing a w/o emulsion, and then dispersing this in an aqueous phase to reach a w/o/w emulsion, or the opposite procedure for preparing
an o/w/o emulsion. However, multiple emulsions may also be prepared in a onestep procedure, and utilizing the PIT. As shown, e.g., in Figure 6.22, multiple
Emulsions
183
FIGURE 6.26 Schematic illustration of w/o/w and o/w/o multiple emulsions. (Redrawn from Nielloud et al., eds., Pharmaceutical Emulsions and Suspensions, Marcel Dekker, 2000.)
emulsions are favored close to zero curvature of the surfactant monolayer, i.e.,
close to the PIT. Frequently, however, multiple emulsions are quite unstable, and
rapidly separate into o/w or w/o emulsions.
6.7
EMULSIONS IN DRUG DELIVERY
Emulsions, and particularly o/w emulsions, offer several advantages as drug delivery systems. In particular, due to their relatively large droplet size, the hydrophobic volume is relatively large in comparison to the o/w surface area. This
means that relatively large amounts of hydrophobic active ingredients may be
incorporated in o/w emulsions, with advantages relating to, e.g., the effective
drug solubility, and the drug release rate and chemical stability. Furthermore,
since the specic surface area is not very large, the amount of surfactants required
for generating and stabilizing emulsions is comparatively low, and relatively nontoxic surfactants, such as phospholipids and other polar lipids, can be used as
stabilizers.
The oils used for pharmaceutical emulsions are generally of natural origin.
In some cases, i.e., when the drug is a liquid oil, the drug itself may constitute
the oil phase of the emulsion with no other added oil components. More frequently, however, the drug is solubilized in the oil phase (for o/w emulsion for-
184
Chapter 6
TABLE 6.2 Oils Commonly Used in

Pharmaceutical Emulsions
Natural oils
Cottonseed
Soybean
Safower seed
Sesame
Cod liver
Linseed
Coconut
Corn
Olive
Synthetic/semisynthetic
materials
Triolein
Ethyl oleate
Dibutyl sebacate
Iso-amyl salicylate
Source: From Boyett et al., in Lieberman et al., eds.,

Pharmaceutical Dosage Forms, Vol. 2, Marcel Dekker, 1989.
mulations of hydrophobic drugs). Oils commonly used for this include, e.g., soybean and safower oil. Irrespective of the origin of the oil, however, these are
generally multicomponent mixtures (Tables 6.2 and 6.3.).
The quality of an oil processed from a potentially variable source must
be closely controlled in order to minimize oxidation, remove unsaponiable
materials (such as waxes and steroidal components), and check for possible presence of aatoxins, herbicides, pesticides, which may be inadvertent contaminations. In general, high-quality food grade oils are likely sources for the preparation of injectable emulsions or emulsions for oral administration. For dermal use,
the quality requirements are generally less rigorous.
TABLE 6.3 Distribution of Fatty Acids in Cottonseed,

Soybean and Safower Oils
Fatty acid
Palmitic (C16 :0)
Stearic (C18:0)
Oleic (C18:1)
Linoleic (C18:2)
-Linolenic (C18 :3)
Cottonseed
Soybean
Safower
21
2
29
45
2
12
4
24
51
9
7
3
13
77
Source: From Boyett et al., in Lieberman et al., eds., Pharmaceutical

Dosage Forms, Vol. 2, Marcel Dekker, 1989.
Emulsions
185
Commonly used emulsiers in drug delivery are either pure phospholipid

fractions or lecithin mixtures, obtained from animal (egg yolk) and vegetable
(soybean) sources. Apart from being relatively efcient emulsiers and providing
quite good physicochemical stability to the emulsion, these are rather stable toward hydrolysis and oxidation. Furthermore, they are metabolized in the same
way as fats, rather than excreted via the kidneys as are many synthetic surfactants.
Due to their natural origin, lecithins are multicomponent mixtures, which
may also contain compounds unsuitable, e.g., for intravenous injection. They
must therefore be puried (e.g., chromatographically) before use in injectable
emulsions. However, some puried lecithins are insufcient emulsiers, and additives are therefore commonly used for such systems to improve emulsion stability. Examples of such additives include PEO-containing surfactants and block
copolymers. Improved stability may also be obtained by a slight hydrolysis of
lecithin, achieved, e.g., by addition of a small amount of NaOH.
Since emulsied oil exerts a limited osmotic effect, additives to the aqueous
phase are sometimes necessary in order to achieve isotonic conditions. Examples
of such additives include electrolytes (e.g., NaCl), reducing sugars (e.g., glucose),
glycerin, and others (sorbitol, xylitol, etc.).
6.7.1
Emulsions in Parenteral Drug Delivery
Given the numerous destabilization mechanisms of emulsions, their frequently

broad droplet size distribution, and the need for small emulsion droplets and
absence of large ones, the use of emulsions in intravenous applications is rather
challenging. These and other aspects result in a number of requirements for the
safe and efcient use of injectable emulsions (Table 6.4).
First, the emulsions should be prepared with a sufciently small droplet
size and with a sufciently narrow droplet size distribution. If the droplets are
larger than a certain size, typically a few micrometers in diameter, they can get
stuck in narrow blood vessels, e.g., in the lung, thereby causing emboli (Figure
6.27).
Once prepared, the emulsions should typically be stable for at least 2 years
of storage at room temperature without considerable droplet size growth or formation of large droplets. Emulsions for intravenous use should also be sufciently
stable against shear-induced occulation or coalescence. Apart from coalescence,
these requirements on colloidal stability are not different from those on other
injectable colloidal dispersions. However, due to the possibility of both coalescence and Oswald ripening in emulsion systems, the latter are generally more
difcult to stabilize than, e.g., polymer latex dispersions.
Another practical issue of some complexity in injectable emulsion formulations is that of sterility. In particular, heat sterilization is frequently not possible
due to a combination of limited chemical stability of the emulsion components
186
Chapter 6
TABLE 6.4 Requirements for Injectable Emulsions

Physicochemical
1.
2.
3.
4.
Physically stable (should not occulate at high electrolyte concentrations)

Particle size less than 2 m (in order to avoid thrombosis)
Sterilizable
Chemically stable (decomposition affects both drug effectivity and toxicity)
Biological
1.
2.
3.
Low incidence of side effects (toxicity)

Nonantigenic (immunologically acceptable)
All components metabolized or excreted (no substances may accumulate in
the body)
Practical
1.
2.
Stable to temperature extremes

Reasonable cost
Source: From Boyett et al., in Lieberman et al., eds., Pharmaceutical Dosage Forms, Vol.
2, Marcel Dekker, 1989.
FIGURE 6.27 Relationship between droplet size, physiological processes, and biodistribution of intravenously administered emulsion droplets. (Redrawn from Buszello et al., in Nielloud et al., eds., Pharmaceutical Emulsions and Suspensions,
Marcel Dekker, 2000.)
Emulsions
187
and increased emulsion destabilization through Oswald ripening at elevated temperature. Also, similar to other dispersed formulations, emulsions cannot be sterile ltered when the droplet size is of the order of a couple of hundred nanometers
or larger. Ethylene oxide or radiation sterilization are both possible alternatives,
however, as is sterilization of the emulsion components followed by aseptic manufacturing.
Despite the numerous problems with emulsion formulation stability, and
the high requirements on any formulation to be used in intravenous drug delivery,
o/w emulsions have indeed found use within this area (Table 6.5).
Even without active drug ingredients, o/w emulsions have found use in a
couple of important biomedical applications. For example, parenteral administration of o/w emulsions has been used for nutrition of patients who cannot retain
uid or who are in acute need of such treatment. In these nutritional formulations, soybean, cottonseed, or safower oil is typically emulsied with a phospholipid (mixture) in an aqueous solution containing also, e.g., carbohydrates.
Furthermore, o/w emulsions have been used as blood substitute formulations.
These are peruorochemical emulsions with a typical droplet size of about 100
200 nm, which provide oxygen-carrying capacity through dissolution of oxygen
in the oil droplets. Also, in the development of vaccines it is frequently found
that puried immunogens do not provoke a strong immune response by themselves, but rather require the simultaneous presence of immune response promoters, or so called adjuvants. It is well known that adjuvants inuence both the
TABLE 6.5 Examples of Uses of Emulsions as Injectable Formulation

1.
2.
3.
4.
5.
Nutrition
Emulsions are concentrated sources of calories (higher than, e.g., proteins and hydrocarbons), exerting only a small negative osmotic effect.
Emulsions are able to provide essential fatty acids, which other nutrition
sources are not.
Drug delivery
Emulsions allow incorporation of hydrophobic drugs in large quantities in
the droplet interior.
The drug is not in direct contact with body uids and tissues.
A controlled and sustained release/uptake of the drug may be achieved.
By surface modication of the droplets, some targeting to different tissues may be achieved.
Emulsions may provide chemical stabilization, e.g., for drugs which rapidly hydrolyze in aqueous solution.
Diagnostics
Vaccines (Emulsions may provide adjuvant effects.)
Blood substitute (uorocarbon emulsions)
188
Chapter 6
duration and the intensity of the immune response, as well as the actual type of
immune response. In analogy to some other colloidal systems, o/w emulsions
have been found to display adjuvant activity, and are therefore used in immunization applications.
Due to their capacity to solubilize large quantities of hydrophobic drugs,
and the rather low surfactant concentration required, o/w emulsions are interesting in relation to intravenous drug delivery. As with other types of colloidal drug
carriers, such as liposomes or polymer particles, the fate of emulsion droplets
following intravenous administration is largely determined by the interaction between the emulsion droplets and RES. Similar to liposomes, o/w emulsion droplets to be administered intravenously are frequently surface modied in order to
display low serum protein adsorption, and hence result in a prolonged bloodstream circulation and a more even tissue distribution (Chapter 4). In particular,
adsorption of EO-containing surfactants or block copolymers has been found to
be efcient in this context, although care must be taken in selecting the surfactant/
block copolymer system so that extensive desorption does not occur due to the
dilution of the formulation following intravenous administration. With these precautions, however, a prolonged bloodstream circulation after intravenous administration can be obtained also for emulsion systems (Figure 6.28).
Another advantage with these surface modications is that they result in
an additional emulsion stabilization mechanism, steric stabilization, which prevents the emulsion from occulating at the high electrolyte concentration present
under physiological conditions.
FIGURE 6.28 Blood clearance of 123 I-labeled emulsions stabilized by egg lecithin
(squares) and Poloxamine 908 (circles) intravenously administered to rabbit. (Redrawn from Illum et al., Int. J. Pharm. 1989, 54, 41.)
Emulsions
189
Due to the nite physicochemical stability of emulsions, another possibility

in relation to parenteral administration is to use microemulsions as precursors,
generating o/w emulsions on dilution with aqueous solution following intravenous administration. As discussed in Chapter 5, microemulsions may be prepared
such that on dilution with water, they form o/w emulsions, with a sufciently
small droplet size to avoid emboli formation. In fact, it has been found to be
possible to administer up to at least 0.5 ml/kg of microemulsion with an oil
weight fraction of 50% without signicant detrimental effects on the acid-base
balance, blood gases, plasma electrolytes, mean arterial blood pressure, heart rate,
and time lag between depolarization of atrium and chamber.
6.7.2
Emulsions in Oral Drug Delivery
Emulsion formulations are relevant also for the oral administration route.
Overall, the requirements on emulsion chemical and physical stability, as well
as concerns regarding the purity of the raw materials used, are qualitatively similar to those in intravenous administration. Generally, however, both stability requirements and toxicity issues are somewhat less critical for this administration
route.
As with intravenous administration, the use of emulsions in oral administration mainly originates from various drug delivery advantages, such as an effectively increased solubility of sparingly water-soluble drugs and decreased hydrolysis due to the low pH in the stomach. Emulsions are also commonly used in
oral administration for taste masking. This is the case particularly for hydrophobic
substances encapsulated in the droplets of o/w emulsions. Yet another specialized
use of emulsions in oral drug delivery is in laxatives.
The absorption from o/w emulsion formulations in the gastrointestinal tract
depends on a number of factors, including, e.g.,
1.
2.
3.
4.
Drug dissolution rate

The o/w partition coefcient of the drug
Flow of bile juice
Membrane permeability
As discussed also in Chapter 5, sparingly soluble hydrophobic drugs frequently display a poor bioavailability following oral administration. There are
several reasons for this, including, e.g.,
1. Slow diffusion-controlled uptake due to low water solubility
2. Degradation of the drug in the gastrointestinal tract
3. Physical absorption barriers due to the charge and size of the drug
Furthermore, oral administration of hydrophobic drugs frequently results
in a strong intra- and intersubject uptake variability, which precludes efcient
190
Chapter 6
FIGURE 6.29 Fraction of cyclosporine remaining vs. time after intestinal perfusion
in rats. Results are shown for both homogenized (droplet size 2.0 m; squares)
and stirred (droplet size 4.0 m; circles) emulsions. In both cases, the cyclosporine
concentration was 0.08 mg/ml. (Redrawn from Tarr et al., Pharm. Res. 1989, 6,
40.)
administration of the required dose in a safe and reproducible manner. Through

the use of o/w emulsions as drug carrier systems, this variability following oral
administration of hydrophobic drugs may be reduced. The improved uptake of
hydrophobic drugs following oral administration by the use of o/w emulsions
is illustrated in Figure 6.29 for cyclosporine, an oligopeptide drug used as an
immunosuppressive agent in order to prolong allograft survival in organ transplantation and in the treatment of patients with certain autoimmune diseases.
Interestingly, the intestinal absorption for this drug can be increased by reducing
the droplet size, suggesting that the oil droplets, analogously to, e.g., biodegradable polymer particles used in oral vaccination (Chapter 9), are taken up in a
size-dependent manner.
Not surprisingly, o/w microemulsions, with their very small oil droplets,
have been found to be even more efcient than emulsions for the oral administration of cyclosporine (Chapter 5).
Also of interest in oral drug delivery are the so-called self-emulsifying
emulsion. As discussed above, truly self-emulsifying emulsion systems would
be microemulsions, but this is generally not what is referred to when using the
term in pharmaceutical literature. Instead, self-emulsication is a result of
differential surfactant solubility in the two phases, coupled to surfactant concentration gradients at the oil-water interface, and minor turbulence. Such selfemulsifying drug delivery systems have received particular attention as a means
to increase the oral bioavailability of poorly absorbed drugs. The main reason
Emulsions
191
FIGURE 6.30 Average whole-blood concentration vs. time following intraduodenal

administration of a penclomedicine in o/w mineral oil emulsion (open symbols) or
mineral oil (lled symbols). (Redrawn from Myers et al., Int. J. Pharm. 1992, 78,
217.)
for this is that such systems combine the advantages of oil-based formulations,
which are easier to formulate and stabilize than emulsions, with the better physiological effect of o/w emulsions compared to an oil phase formulation (Figure
6.30).
6.7.3
Emulsions in Dermal Drug Delivery
Like liposomes (Chapter 4) and microemulsions (Chapter 5), both o/w and w/o
emulsions are of interest in dermal drug delivery. The emulsion formulations
used in dermal drug delivery are frequently quite similar to those used in cosmetic
products, but with a different active compound. O/W emulsions are characterized by an aqueous feel and, more importantly, by ease of removal by simple
washing with water. Since the continuous water phase is in contact with air after
administration, there is a continuous evaporation of water, as well as of other
volatile components. As a result of this, there is a drift in the composition of the
applied formulation, which must be taken into consideration in its design. W/O
emulsions, on the other hand, often have a softening effect, and may result in an
enhanced drug uptake. As with microemulsions and liposomes, the uptake from
dermally administered emulsions is a complicated issue, which depends not only
on the partition of the drug between the oil and water phases, the concentration
of the drug, and the droplet size and concentration, but also on the interaction
between the surfactants used for stabilizing the emulsion and the stratum corneum
lipids.
192
Chapter 6
TABLE 6.6 Examples of Emulsiers Used in

Dermal Drug Delivery and Cosmetic Applications
Nonionic ethoxylates
Orthophosphoric acid esters
Protein condensates
Amine oxides
Phytosteroids
Sucrose esters
Glycerine esters
Block copolymers
Silicones
Beeswax
A number of different surfactants are used in both dermal drug delivery

systems and cosmetic applications (Table 6.6). Ethoxylated surfactants play a
particular role as emulsier for emulsions for dermal drug delivery and cosmetic
applications. Due to their uncharged nature, these are compatible with both cationic and anionic surfactants, and are also largely insensitive to pH and salt. An
additional advantage is that this type nonionic surfactant have low skin sensitation, e.g., due to weak interactions with skin proteins. A disadvantage of these
surfactants, however, is the presence of low amounts of dioxane originating from
a side reaction in the ethoxylation process, as well as the formation of aldehydes
as a result of partial oxidative degradation of the PEO chain after exposure to
oxygen and light. During the last few years in particular, alternatives to EO-based
nonionic surfactants have been developed. In particular, sugar-based surfactants
have been found to be promising here.
Somewhat related to emulsions are ointments and creams. These semisolid
formulation types undergo a transition from solidlike to liquidlike behavior under pressure, which allows easy administration to the skin, and an efcient
localization after administration. In general, ointments refer to formulations which remain on the surface of the skin and display skin protection and
occlusion, whereas creams refer to formulations which are able to penetrate
the skin to at least some extent. Ointments are generally water-poor, or even
water-free systems, whereas creams often are o/w or w/o emulsions (Figure
6.31).
6.8
EMULSIONS AS PRECURSORS FOR SLN
An interesting use of o/w emulsions in drug delivery is to use them as precursors

for preparing solid lipid nanoparticles (SLN). There are several ways of preparing
SLN, e.g.,
1. Preparation of an o/w emulsion containing the lipid and the drug dissolved in a volatile solvent, followed by evaporation of the solvent,
and solidication of the lipid matrix (Figure 6.32)
Emulsions
193
FIGURE 6.31 Schematic illustration of the structure of a w/o cream, consisting of

both crystalline and amorphous domains, emulsion droplets, liquid crystalline
phases, and free emulsiers. (Redrawn from Junginger, in Kreuter, ed., Colloidal
Drug Delivery Systems, Marcel Dekker, 1994.)
FIGURE 6.32 Schematic illustration of preparation of SLN through emulsication

of the lipid mixture in an organic solvent, followed by the evaporation of the latter,
and solidication of the lipid mixture. (Redrawn from Sjostrom et al., J. Pharm. Sci.
1993, 82, 584.)
194
Chapter 6
2. Preparation of an o/w emulsion by high-pressure homogenization at

elevated temperature, followed by cooling and solidication of the lipids droplets
3. Spray cooling of a molten lipid/emulsier mixture
4. Sonication of molten lipid
Spray cooling of a molten lipid/emulsier mixture, although seemingly
simple, is generally limited to larger particle sizes (of the order of several micrometers), and hence SLN prepared through this process generally less suitable for
intravenous administration. Dissolution of the lipid/drug mixture in a volatile
organic solvent, on the other hand, may result in quite small SLN, but a concern
with this approach is residual solvent which may preclude use of SLN prepared
in this manner in intravenous administration. It is therefore of major importance
that the solvent is thoroughly evaporated and monitored (Figure 6.33).
Since SLN are prepared from emulsions, one would expect their size to
FIGURE 6.33 Concentration of toluene in a SLN dispersion as a function of evaporation time. The SLN consisted of cholesteryl acetate stabilized by PEO-(20)-sorbitan monooleate (5 or 10%; open and lled symbols, respectively), and were prepared through emulsication of cholesteryl acetate in toluene. (Redrawn from
Sjostrom et al., J. Disp. Sci. Technol. 1994, 15, 89.)
Emulsions
195
FIGURE 6.34 Correlation between the size of SLN and the corresponding precursor
emulsion. The SLN were prepared by dissolving cholesteryl acetate in cyclohexane
followed by emulsication of this oil phase in water in the presence of surfactant.
Each point corresponds to one surfactant (mixture) composition. (Redrawn from
Sjostrom et al., J. Pharm. Sci. 1993, 82, 584.)
depend on the size of the precursor emulsion. In fact, at least in some cases, the
particle size after solidication has been found to be essentially identical to that
of the emulsion droplets (Figure 6.34).
SLN with a particle size essentially identical to that of the precursor emulsion is expected for SLN prepared through homogenization of the lipid mixture
in the absence of solvent at elevated temperature, due to the small volume change
on decreasing the temperature over a limited temperature range (in the absence
of crystallization-induced large-scale morphological changes of the particles).
For SLN prepared through use of a solvent, the nding of the SLN having a
comparable particle size is, on the other hand, unexpected, and indicates that the
particles prepared by this approach are hollow.
From Figure 6.34 it can further be noted that the emulsier has a dramatic
inuence of the size of the resulting SLN. Thus, for identical conditions, and for
otherwise identical composition, the nature of the surfactant largely determines
both the emulsion droplet and the SLN particle size.
The degree of crystallinity is another parameter of interest for SLN systems.
For a crystallizing lipid (mixture), one would expect crystallization to occur as
SLN form, irrespective of whether the SLN formation occurs through cooling of
a dispersed lipid mixture or evaporation of a solvent containing the lipid(s). However, the formation of SLN is a kinetic process, and at high lipid concentrations
(e.g., in the melt or at low solvent concentrations), crystallization may be kinet-
196
Chapter 6
TABLE 6.7 Thermoanalytical Data for Bulk Glycerides and

Their Colloidal Dispersions
Disp.
(fresh)
Disp.
(stored)
3839
3233
2022
2829
1213
3133
6567
5658
4445
4142
5456
Bulk
Hard fat
Melting point
Melting point
Melting point
T recryst (C)
Tripalmitate
Melting point
Melting point
Melting point
T recryst (C)
( i ; C)
(; C)
(; C)
( i ; C)
(; C)
(; C)
810
5659
3940
2021
, i, and refer to different polymorphs.

Source: From Siekmann et al., Colloids Surf. B 1994, 3, 159.
ically hindered. As a result of this, it is generally found that the degree of crystallinity in SLN is lower than that for a corresponding macroscopic lipid sample.
With increasing storage temperature, however, the dispersed material becomes
more similar to the macroscopic sample, indicating that crystallization occurs
slowly during storage (Table 6.7).
Furthermore, the crystallization in SLN may be more complex than that of
the bulk glyceride systems. For example, the crystallization behavior of SLN
may depend on, e.g., the SLN particle size, the nature of the emulsier used, and
the presence of a drug (Figure 6.35). With increasing temperature SLN typically
become less stable, in analogy to the frequently poorer physicochemical stability
displayed by emulsions (Figure 6.36).
From a practical drug delivery perspective, SLN systems are attractive for
several reasons:
1. They allow a high load of hydrophobic drugs (in analogy to o/w emulsions).
2. Hydrolytic degradation is limited (in analogy to o/w emulsions).
3. The drug release rate can be controlled by the particle size and composition.
4. They combine the advantages of polymeric nanoparticles (in that they
provide a solid matrix for controlled release) and o/w emulsions (in
that they consist of physiological compounds and that they can straightforwardly be produced industrially on a large scale), but simultaneously avoid the disadvantages of these systems, such as the use of
Emulsions
197
FIGURE 6.35 Effect of the concentration of ubidecarenone on the heat of fusion

of the i-polymorph (H i ; circles) and the concentration of fat present in the i form
(C i ; squares) for SLN prepared from hard fat, lecithin and sodium glycocholate.
(Redrawn from Siekmann et al., Colloids Surf. B 1994, 3, 159.)
FIGURE 6.36 Typical result of the inuence of storage temperature on the stability
of SLN. Results are shown for 8C (circles), 20C (squares), and 50C (diamonds).
(Redrawn from Freitas et al., Int. J. Pharm. 1998, 168, 221.)
198
Chapter 6
FIGURE 6.37 Schematic illustration of the burst release frequently observed with
o/w emulsions, and the more gradual drug release from SLN.
solvents for the preparation of polymer particles and the burst release
frequently observed for emulsion systems (Figure 6.37).
SLN formulations have been found to be of interest, e.g., in anticancer
therapy. Due to the adverse side effects of several anticancer drugs, burst release
is preferably avoided. Due to this, and the hydrophobic nature of several anticancer drugs, and particularly interchalating ones, SLN provide a formulation possibility. It has been found that the cytotoxicity of SLN in the absence of incorporated drugs is very low, which is benecial for their use in vivo. Contrary to this,
the cytotoxicity of SLN containing incorporated anticancer agents has been found
to be substantial. In fact, for several drugs, SLN formulations have been found
to be signicantly more efcient than the free drug in solution, which indicates
that particle-mediated uptake (e.g., phagocytosis) is of major importance here
(Table 6.8).
TABLE 6.8 Inhibitory Concentration of Doxorubicin and
Paclitaxel Producing 50% of Cell Inhibition or Death
Doxorubicin (solution)
Doxorubicin (SLN)
Paclitaxel (solution)
Paclitaxel (SLN)
IC 50 (HL60 cells;
ng/ml)
IC 50 (MCF-7 cells;
ng/ml)
45.5
0.9
11.1
16.7
10.9
1.0
102.0
1.16
Source: From Miglietta et al., Int. J. Pharm. 2000, 210, 61.
Emulsions
199
Apart from displaying a higher efciency, SLN also result in a decreased

exposure of irrelevant tissue to the active substance, which should reduce side
effects and allow a higher dosage.
BIBLIOGRAPHY
Becher, P., Encyclopedia of Emulsion Technology, vol. 1, Marcel Dekker, New York,
1983.
Becher, P., Encyclopedia of Emulsion Technology, vol. 2, Marcel Dekker, New York,
1985.
Binks, B. P., ed., Modern Aspects of Emulsion Science, The Royal Society of Chemistry,
1998.
Boyett, J. B., C. W. Davis, Injectable emulsions and suspensions, in H. A. Lieberman,
M. M. Rieger, and G. S. Banker, eds., Pharmaceutical Dosage Forms: Disperse
Systems, vol. 2, Marcel Dekker, New York, 1989.
Evans, D. F., H. Wennerstrom, The Colloidal Domain, Wiley, New York, 1999.
Johnston, I.D.A., ed., Current Perspectives in the Use of Lipid Emulsions, Marcel Dekker,
New York, 1983.
Jonsson, B., B. Lindman, K. Holmberg, B. Kronberg, Surfactants and Polymers in Aqueous Solution, Wiley, New York, 1998.
Junginger, H. E., in J. Kreuter, ed., Colloidal Drug Delivery Systems, Drugs and the Pharmaceutical Sciences, vol. 66, Marcel Dekker, New York, 1994.
Kreuter, J., in J. Kreuter, ed., Colloidal Drug Delivery Systems, Drugs and the Pharmaceutical Sciences, vol. 66, Marcel Dekker, New York, 1994.
Nielloud, F., G. Marti-Mestres, eds., Pharmaceutical Emulsions and Suspensions, Drugs
and the Pharmaceutical Sciences, Marcel Dekker, 2000.
Shinoda, K., S. Friberg, Emulsions and Solubilization, Wiley, New York, 1986.
Sjoblom, J., ed., Emulsions and Emulsion Stability, Surfactant Science Series, vol. 61,
Marcel Dekker, New York, 1996.

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6

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producing emulsion droplets. Within high-pressure homogenization, the liquid

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ior are of importance for emulsication processes. In particular, sufciently fast

FIGURE 6.4 Adsorption of -casein and SDS at a macroscopic interface and in an

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formation of microemulsions, but this is generally not what is intended. Instead,

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PHASE INVERSION OF EMULSIONS

An important feature of emulsions is the so called phase inversion displayed by

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FIGURE 6.9 Effect of temperature on the conductivity for a heptane-water emulsion

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stabilized by C 12 E 5 undergoing phase inversion from o/w to w/o at a critical

FIGURE 6.10 Temperature-dependent water-octane interfacial tension ab at c

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FIGURE 6.11 Effect of salt on the phase inversion temperature of a water-heptane

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Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

tolerated in various drug delivery applications. Often, pharmaceutical emulsions

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The rheology of emulsion systems is of some general interest in drug delivery.

FIGURE 6.15 Schematic illustration of an emulsion where the volume fraction of

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

FIGURE 6.16 Viscosity of a w/o emulsion containing PEG7-hydrogenated castor

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

FIGURE 6.17 Effect of electrolyte concentration on the diffusion coefcient D of

A promising feature is that emulsion gels may be used as in situ forming

FIGURE 6.18 Elastic modulus G 0 as a function of temperature for the system

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

FIGURE 6.19 Schematic illustration of emulsion destabilization mechanisms.

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

FIGURE 6.20 Creaming proles at different times of 20 vol% heptane-hexadecane

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

FIGURE 6.21 Effects of Ca 2 concentration on the droplet electrostatic potential

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

TABLE 6.1 Mean Droplet Size (m) of a Lecithin-Stabilized O/W Emulsion

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

FIGURE 6.22 Hole activation barrier W vs the monolayer spontaneous curvature

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

EMULSIONS IN DRUG DELIVERY

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

TABLE 6.2 Oils Commonly Used in

Source: From Boyett et al., in Lieberman et al., eds.,

TABLE 6.3 Distribution of Fatty Acids in Cottonseed,

Source: From Boyett et al., in Lieberman et al., eds., Pharmaceutical

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

Commonly used emulsiers in drug delivery are either pure phospholipid

Emulsions in Parenteral Drug Delivery

Given the numerous destabilization mechanisms of emulsions, their frequently

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

TABLE 6.4 Requirements for Injectable Emulsions

Physically stable (should not occulate at high electrolyte concentrations)

Low incidence of side effects (toxicity)