Current Opinion in Colloid & Interface Science 13 (2008) 245 251

www.elsevier.com/locate/cocis

Nano-emulsions: New applications and optimization of their preparation

J.M. Gutirrez a,, C. Gonzlez a , A. Maestro a , I. Sol a , C.M. Pey a , J. Nolla b
a

Chemical Engineering Department, University of Barcelona, c/ Mart i Franqus 1, 08020 Barcelona, Spain
b
CSIC/IIQAB, CIBER-bbn, c/Jordi Girona 18-26, 08034-Barcelona, Spain
Received 10 September 2007; received in revised form 29 January 2008; accepted 30 January 2008
Available online 15 February 2008

Abstract
Nano-emulsions, as non-equilibrium systems, present characteristics and properties which depend not only on composition but also on the
preparation method. Although interest in nano-emulsions was developed since about 20 years ago, mainly for nanoparticle preparation, it is in the
last years that direct applications of nano-emulsions in consumer products are being developed, mainly in pharmacy and cosmetics. These recent
applications have made that studies on optimization methods for nano-emulsion preparation be a requirement. This review is focused on the most
recent literature on developments of nano-emulsions as final application products and on the optimization of their preparation.
2008 Elsevier Ltd. All rights reserved.
Keywords: Nano-emulsions; Preparation; Applications; Optimization; Emulsification

1. Introduction
There are two major misunderstandings in the literature
regarding nano-emulsions. One arises from their similarities to
microemulsions. Nano-emulsions are emulsions with an extremely small droplet size [1] which can overlap those of microemulsions. The definition of emulsions by the International
Union of Pure and Applied Chemistry (IUPAC) states: In an
emulsion, liquid droplets and/or liquid crystals are dispersed in
a liquid [2]. Obviously, microemulsions are excluded from this
definition if the word dispersed is interpreted as non-equilibrium and opposite to solubilized, a term that can be applied to microemulsions and micellar systems. Therefore, there
is a fundamental difference between microemulsions and nanoemulsions: microemulsions are equilibrium systems (i.e. thermodynamically stable), while nano-emulsions are non-equilibrium systems with a spontaneous tendency to separate into the
constituent phases. Nevertheless, nano-emulsions may possess a
relatively high kinetic stability, even for several years [1]. The
other source of misunderstandings about nano-emulsions is

Corresponding author. Tel.: +34 934021292; fax: +34 934021291.

E-mail address: josemaria.gutierrez@ub.edu (J.M. Gutirrez).
1359-0294/$ - see front matter 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.cocis.2008.01.005

related to the method of preparation. For instance, in Ref. [3], a

review on nano-emulsions, only emulsions with droplet size in
the nanometer range obtained by shear methods are considered
as nano-emulsions. According to these authors, emulsions with
extremely small droplet size (i.e. nano-emulsions) obtained by
the so-called condensation methods (e.g. phase inversion temperature (PIT) or composition (PIC) methods, self-emulsifying
methods, etc.) should not be considered as nano-emulsions.
Evidently, the preparation method influences emulsion properties (e.g. droplet size, stability, etc.), but the nature of the final
dispersion (the constituent phases) is the same whether the
method of preparation uses high shear (external energy, dispersion methods) or the chemical energy stored in the system
(condensation methods). The view expressed in Ref. [3] is based
in a misinterpretation of the mechanisms by which nanoemulsions form by low-energy methods, described, for instance,
in Ref. [5]. Phase transitions involving equilibrium phases,
such as lyotropic liquid crystalline, microemulsion and/or micellar phases, take place during emulsification by condensation
or low-energy methods. However, this does not mean that at
the end of the emulsification process the system is in thermodynamic equilibrium.
As a summary of this point, nano-emulsions are emulsions
(non-equilibrium systems, defined according to [1]) with a
remarkable small droplet size (in the nanometer range, e.g. 20

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200 nm), regardless of the preparation method. A photography

of an oil-in-water (O/W) nano-emulsion with a schematic example of the structure is presented in Fig. 1.
Evidently the size range may vary depending on the authors.
Some authors consider 500 nm as the upper limit [1,6]. In any
case, the size limit is not a key issue because no qualitative
differences are established by droplet size. The formation,
properties and stability of nano-emulsions are well established in
numerous papers which are reviewed [1,5]. Regarding applications, nano-emulsions were firstly developed, and used for
a long time, to obtain nanoparticles by polymerization [7], the
so-called miniemulsion polymerization method, and more
recently to obtain solid lipid nanoparticles [810], and ceramic
particles [11]. At present, new applications are being developed
to use nano-emulsions as consumer products.
In this review, recent literature on the new applications of
nano-emulsions as consumer products is reviewed and classified
according to the field of application. This direct application of
nano-emulsions requires the optimization with respect to formulation and preparation variables in order to obtain the desired
characteristics. Recent literature on optimization of nano-emulsion preparation is also reviewed and classified according to three
approaches: considerations on phase behavior, selective variation
of parameters and experimental designs.
2. Direct application of nano-emulsions in final products
Practically all original and review papers on nano-emulsions
stress their great potential for applications. However, after more
than 10 years since a growing interest in nano-emulsions was
developed, reports on direct applications of nano-emulsions
are not as numerous as expected. The main limitation for developing applications for nano-emulsions is their stability.
Although practically all papers on nano-emulsions indicate
that nano-emulsions can be stable even by years, the small

Fig. 1. Visual aspect of an O/W nano-emulsion and structural conformation of

the droplets.

droplet size makes nano-emulsions break by the Ostwaldripening mechanism [1214] in time periods which pose a great
limitation for developing applications different than nanoparticle preparation. In fact, only an extremely low solubility of the
dispersed phase, as presented by silicone oils, would give the
stability needed for most of the applications. In this context,
Mason research group has published several papers studying
nano-emulsions with silicone oils as dispersed phase, [1517].
These nano-emulsions show great stability even for such a high
concentration that droplets are deformed to a foam-like structure
[3], but no applications have been yet developed for these nanoemulsions.
Due to the limitations in the stability of nano-emulsions, a
revision of the most recent literature results in few papers proposing new applications, and in most of them, nano-emulsions
must be prepared shortly before their use.
With respect to agrochemical applications, in a recent
reference [18] nano-emulsions are proposed for solubilizing
water-insoluble pesticides, the classical potential application.
Nano-emulsions are formed before the application by dilution
of a concentrate containing oil, surfactant, the active and 50% of
water. It is claimed that the nano-emulsions obtained show good
stability, but the diameter increases about five times in 14 h,
from 40 to 200 nm. Therefore, application should be carried out
a few hours after preparation for obtaining the advantages
of small droplet size. In this paper, the preparation of nanoemulsions is presented as a novelty when comparing with
commercial microemulsion formulations which also result by
dilution in nano-emulsions. This fact demonstrates that application of nano-emulsions for solubilizing pesticides is not a
potential application but a commercial one.
Concerning the applications in food technology, two recent
reviews about possibilities of nanotechnology [19,20] indicate
that there are potential applications of nano-emulsions, but no
specific applications are given. In Ref. [19], potential applications for nanostructured materials in general are analyzed,
but regarding nano-emulsions, only a mention about their
potential application is made. In Ref. [20], a detailed review on
emulsification techniques is presented but the possible applications that are indicated are not likely to have an important impact
in the future food technology. Finally, nano-emulsification of
carotene containing hexane is described in Ref. [21] although the
final application proposed after evaporation of hexane is a
dispersion of carotene, not a nano-emulsion.
In cosmetics, a generic paper [22] presents the possibilities
for improving stability through using different oils and oil
mixtures. Adequate stability is only achieved by using more
than 50% of such heavy oil as isocetyl isostearate. Cosmetic
properties of nano-emulsions are analyzed and favorable
conclusions are obtained. Other papers presenting studies for
nano-emulsion application on skin were also published [2326].
Pharmacy is the field where more direct applications of
nano-emulsions are proposed. Many of them consist in selfemulsifying systems, so the stability problem is solved by
using the nano-emulsions short after their preparation. Selfemulsifying nano-emulsions for parenteral application [27] or
oral application [2830] have been described. Nano-emulsion

J.M. Gutirrez et al. / Current Opinion in Colloid & Interface Science 13 (2008) 245251

formulations are studied for their application as nanocarriers

which allow the treatment of a variety of diseases. The following
are examples of the most recent proposals of drugs solubilized
in nano-emulsions for disease treatments: anticonvulsant
[27], antihypertensive [28] antibiotic [30]; antinflammatory
applied through skin [26]. There are reports on: drugs solubilized
in nano-emulsions for HIV/AIDS therapy [31]; mechanisms of
atherogenesis studied with cholesterol nano-emulsions [32];
cancer therapy investigated by solubilizing the drug in a
cholesterol rich nano-emulsion [33]; intestinal absorption of
three model drugs solubilized in nano-emulsions [34]; efficacy of
a schistosomicidal compound solubilized in nano-emulsions;
[35]; and application of anthrax vaccine through W/O nanoemulsions [36]. Special magnetic nano-emulsions are also
being studied for medicine applications [3739]. A recent
review [40] shows extensively potential multifunctional
applications of nanocarriers including nano-emulsions in
pharmacy. As stated in the paper, multifunctional nanocarriers
could provide almost unlimited opportunities in producing
highly efficient and specialized systems for drugs, genes and
diagnostic agents. Antimicrobial generic activity of nanoemulsions is also being investigated [41] with W/O nanoemulsions that are diluted in water just before application
reverse to O/W emulsions. More specifically, inactivation of
Ebola virus by nano-emulsion was studied [42] with promising
results. It was concluded that nano-emulsions could be used as
disinfectants.
3. Optimization of nano-emulsion preparation
The properties of nano-emulsions, as non-equilibrium systems, depend not only on composition variables but preparation
variables such as emulsifying path, agitation or emulsification
time. These variables can have a significant influence on the
nano-emulsion final properties. Direct application of nanoemulsions requires optimization studies for achieving the best
properties for specific applications. The most frequent aim for
optimization is to exploit the advantages of nano-emulsions with
respect to conventional emulsions (i.e. macroemulsion): small
size and low polydispersity. Therefore, in general, optimization
is directed to obtain minimum droplet size and/or minimum
polydispersity. Another aim in nano-emulsion optimization is
to improve the stability because, as stated above, stability is
the main problem to overcome to find practical applications
for nano-emulsions. Optimization is also directed to obtain an
optimum in the function for which the nano-emulsions are used
(e.g. drug delivery).
The properties to be optimized, for example droplet size and
polydispersity, will depend, of course, on composition variables,
and could depend on preparation variables, so optimization can be
carried out with respect to these two types of variables. Concerning optimization methods, sometimes the characteristics of
emulsification path allow predicting optimum properties of nanoemulsions, so optimizations are carried out by studying the phase
behavior of the systems. In other occasions, optimization is
experimentally carried out by selective variation of one variable.
Finally, given the high number of variables that can influence the

247

final properties of nano-emulsions, optimization is carried out

by experimental designs which allow reducing the number
of experiments needed. Review of papers about optimization is
presently classified according to these three types of methods.
3.1. Phase behavior studies for optimization
Studies on phase behavior for optimization of nano-emulsion
properties can be important when the so-called condensation or
low-energy emulsification methods are used, because the phases
involved during emulsification are determinant in order to obtain
nano-emulsions of small droplet size and low polydispersity. In
contrast, if shear methods are used, there is not a composition
emulsification path and only phases at the final composition are
important.
The importance of the phase behavior, namely crossing
microemulsion (bicontinuous, D) or lamellar liquid crystalline
phase regions during emulsification is described in detail
in recent reviews [1 ,4,5 ]s. Some recent original works in
which this conclusion is experimentally proved are [4346]
for nano-emulsions obtained by the phase inversion temperature method (PIT); [4749] for nano-emulsions obtained by
phase inversion composition method (PIC), or [18,28,30]
for nano-emulsions prepared by a self-emulsifying method.
Only bicontinuous (D) or O/W microemulsions are considered
appropriate for self-emulsifying while lamellar liquid crystal
compositions do not self-emulsify by dilution, probably due
to viscosity of the lamellar phase [18]. Comparing results
from Refs. [47] and [48] with results from Ref. [18], it can
be concluded that by slow addition of water to a lamellar
liquid crystalline phase nano-emulsions can be obtained,
while emulsions with higher droplet size are obtained by rapid
dilution (as in self-emulsifying methods).
In Ref. [50], nano-emulsions with a very small droplet size are
obtained in an ionic surfactant system by adding aqueous phase
through an emulsification path crossing a micellar cubic liquid
crystalline phase. Other recent not published experimental results
demonstrate that the initial droplet sizes of the nano-emulsions
coincide with the micelle size of the cubic liquid crystalline phase
from which the nano-emulsion is obtained by dilution [Fig. 2].
Actually, conditions for obtaining O/W nano-emulsions with
a minimum in droplet size and consequently low polydispersity
can be summarized as follows: in emulsification by phase
inversion temperature or composition methods an aqueous
continuous phase, O/W or bicontinuous, with all the oil
solubilized must be crossed immediately before reaching the
final two phase region where the nano-emulsions form. These
are composition conditions necessary but not sufficient, because
the kinetics of incorporation of oil to this water continuous phase
or the coalescence can make that nano-emulsion droplet size also
depends on preparation variables such as aqueous phase addition
rate for PIC method or cooling rate for PIT method.
3.2. Optimization by selective variation of parameters
Parameters whose influence on nano-emulsion characteristics
can be studied may be classified as composition or preparation

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J.M. Gutirrez et al. / Current Opinion in Colloid & Interface Science 13 (2008) 245251

Fig. 2. Nano-emulsion obtention by dilution of a cubic liquid crystal.

variables. For emulsification by low-energy methods composition

variables will have a much higher influence than preparation
variables, however for shear emulsification, the influence of
preparation variables will be determinant.
Examples of recent literature about optimization of nanoemulsions obtained by shear include the study of the influence of
different variables and the correlation of droplet size with them
[51]. In this paper two different industrial scale emulsifier
equipments were studied, and the Sauter diameter was correlated
with viscosities, stabilizers, volume fractions and pressure for a
jet mill, number of disc mixers for a static mixer, and passage
number for the two equipments. For both, an equilibrium size is
reach for high number of passages resulting in constant droplet
size.
For other systems, optimum pressure or passage number can
exist if coalescence is facilitated by high pressures or passage
number. In Ref. [52] a food system is studied with a high pressure
microfluidizer to emulsify and using a surfactant and different
polymers for stabilizing the emulsions. The competing phenomena of breaking and coalescence are discussed taking into account
the effect of stabilizers.
In Ref. [53], optimization of nano-emulsion preparation by
submitting a coarse emulsion to subcritical water conditions is
presented. The optimization was studied by selective variation
of composition parameters (surfactant and oil concentration),
and preparation parameter (temperature). For this system small
sizes, 40 nm, are obtained.
For other condensation methods, variables whose effect is
commonly studied are the surfactant oil ratio and the ratio between surfactants when a surfactant mixture is used.
For nano-emulsions prepared by the phase inversion temperature method, optimization by selective variation parameters is
presented in several cited references of recent bibliography. In
[43,46] variation of droplet size is studied with respect to oil
surfactant ratio with the obvious result that the higher the oil

surfactant ratio the greater the droplet size, and in [45] variation
of droplet size with surfactant mixing ratio is studied with the
remarkable result that droplet size does not depend on surfactant
mixing ratio if nano-emulsions are prepared by cooling from the
HLB temperature.
For nano-emulsions prepared by the phase inversion composition method, there are also several studies in recent bibliography. In [54] optimization with respect to preparation
method and variation of droplet size with oil surfactant ratio are
presented. In [49] different routes for emulsification are studied
and droplet size variation with HLB, water fraction and surfactant concentration is also reported. In Ref. [55], effect of
variables HLB and oil surfactant ratio are separately studied with
the expected result that there is an optimum HLB and that the
higher the oil surfactant ratio the greater the droplet size. In Ref.
[56] optimization of W/O nano-emulsion preparation is presented. For different combinations of Span-Tween surfactants,
an optimum surfactant composition presenting a water solubility
maximum is chosen, and droplet size variation is studied with
respect to water concentration. Also with W/O nano-emulsions,
the result is, as expected and coinciding with Ref. [47], that the
higher the water concentration the greater the droplet size.
For nano-emulsions prepared by self-emulsification, there is
a detailed work on optimization [57]. Droplet size variation
with oil, surfactant HLB, and solvents, was studied. The results
indicated that there are optimum values for HLB and proportions
of solvents.
As an example of optimization of nano-emulsion function, in
Ref. [26] the influence of sucrose surfactants on percutaneous
penetration is studied, and in Ref. [35] the efficacy of a
schistosomicidal agent is improved by incorporating the agent
in nano-emulsions.
3.3. Experimental designs for optimization
Experimental designs allow to experimentally study the
influence of several variables with a limited number of
experiments. Statistical analysis of results will allow to know
which variables have a significant influence, and to correlate
desired response with variables by polynomial equations. In
Fig. 3 an example of experimental design is shown, and in Fig. 4
there is an example of response surface.
Not many papers present optimization of nano-emulsion
preparation by experimental designs, and most of them deal about
pharmaceutical formulations for self-emulsification [27,5861].
In Ref. [27] experimental design was used to determine the
influence of two qualitative independent variables: type of oil and
type of lipophilic emulsifier. The other four references correspond
to the same research group. In Refs. [58,59] the incorporation of
retinol to a self nanoemulsifying formulation is studied, being
oil, surfactant and cosurfactant amounts in the formulation the
three independent variables, and mean droplet size, turbidity, and
dissolution rate at 10 and 30 min, the four response variables
studied. Response equations are presented, and system is optimized for dissolution rate at 30 min using the other three
responses as restrictions. In Ref. [60] the surface response
technology explained in a more detailed way and six response

J.M. Gutirrez et al. / Current Opinion in Colloid & Interface Science 13 (2008) 245251

249

Fig. 3. Example of experimental design for the preparation variables agitation and addition rate.

variables are analyzed. In Ref. [61], authors apply the same

methodology to evaluate ultrasonic technique in characterization
of nano-emulsions.
In Ref. [48] a complete explanation of experimental design
application to study the preparation of nano-emulsions is
presented. Methodology is applied to low-energy emulsification
by phase inversion composition method, and effects of composition variables and preparation variables were all together
evaluated. Droplet size as response surface was minimized
separately, first with respect to composition variables, and afterwards with respect to preparation variables. The results confirm
that the higher the oil surfactant ratio the greater the droplet size,
and that there is an optimum surfactant mixing ratio or, what is
the same, an optimum HLB. Concerning the preparation variables, addition and agitation rate have little but significant
influence and an optimum agitation rate is found.
In Ref. [62], optimization methodology by experimental
design is applied to nano-emulsions in an ionic surfactant system
obtained by the phase inversion composition method. Again, the
higher the oil surfactant ratio the greater the droplet size, and
there is an optimum ratio of surfactants in the mixture used.
Concerning the preparation variables, they present again no or
low influence on droplet size. Other not published results of the
authors on nano-emulsions prepared by the phase inversion
temperature confirm that preparation variables such as cooling
rate or agitation do not have a significant influence on droplet
size.
A general conclusion of papers using experimental designs is
that this methodology constitutes a very good tool for studying
preparation of nano-emulsions.

Fig. 4. Example of surface response from the preparation variables agitation and
addition rate.

4. Conclusions
Possible applications of nano-emulsions are strongly
limited by the stability of nano-emulsions, except for nanoparticle preparation when the process of physical or chemical
solidification takes place within the period of stability of nanoemulsions.
Nano-emulsions are proposed for numerous applications
in pharmacy as drug delivery systems because of their capacity of solubilizing non polar active compounds. Due to the
stability problems, most of proposed formulations are selfemulsifying systems and the nano-emulsions are produced
just before their application. Although there have not been
reported too many applications in other fields, there is a great
potential for nano-emulsion applications if Oswald-ripening
destabilization mechanism is limited by using very insoluble
oils.
Concerning optimization in preparation of nano-emulsions
by shear, an optimum shear or time shearing can exist if breaking
and coalescence are competing phenomena during the process.
Concerning optimization in the preparation of nano-emulsions by low-energy methods, recent literature confirms that
crossing bicontinuous or aqueous continuous phases during
emulsification allows obtaining O/W nano-emulsions of small
droplet size and low polydispersity.
Optimizations by selective variation of parameters or experimental designs allow to conclude that, with respect to
composition variables, generally there is an optimum surfactant mixture composition, or HLB, and that the higher the oil
surfactant ratio the greater the droplet size. The preparation
variables, as addition, agitation or cooling rate, generally do
not have a significant influence if the system is optimized with
respect to composition.
This last conclusion has a very important derivation: if
preparation variables do not have influence, the system can be
scaled-up, from lab to industrial, and similar results can be
expected.
As a final comment, judging from the most recent literature,
the interest in nano-emulsion preparation and application is
growing, but few of the numerous ideas reported become commercial final applications.

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Acknowledgment
Financial support from the Spanish Ministry of Science
and Education, MEC (grants CTQ 2005-09063-C03-01/PPQ
and CTQ 2005-09063-C03-02/PPQ) is acknowledged.
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