International Journal of Pharmaceutics 526 (2017) 425–442

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Review

Microemulsion utility in pharmaceuticals: Implications for multi-drug

delivery
Shannon P. Callendera , Jessica A. Mathewsa , Katherine Kobernyka , Shawn D. Wettiga,b,*
a
School of Pharmacy, University of Waterloo, 200 University Ave. W., Waterloo, Ontario N2L3G1, Canada
b
Waterloo Institute for Nanotechnology, University of Waterloo, 200 University Ave. W., Waterloo, Ontario N2L3G1, Canada

A R T I C L E I N F O A B S T R A C T

Article history:
Received 2 March 2017 Emulsion technology has been utilized extensively in the pharmaceutical industry. This article presents a
Received in revised form 2 May 2017 comprehensive review of the literature on an important subcategory of emulsions, microemulsions.
Accepted 3 May 2017 Microemulsions are optically transparent, thermodynamically stable colloidal systems, 10–100 nm
Available online 7 May 2017 diameter, that form spontaneously upon mixing of oil, water and emulsifier. This review is the first to
address advantages and disadvantages, as well as considerations and challenges in multi-drug delivery.
Keywords: For the period 1 January 2011–30 April 2016, 431 publications related to microemulsion drug delivery
Microemulsions were identified and screened according to microemulsion, drug classification, and surfactant types.
Drug delivery
Results indicate the use of microemulsions predominantly in lipophilic drug delivery (79.4%) via oil-in-
Emulsions
water microemulsions and non-ionic surfactants (90%) for oral or topical administration. Cancer is the
Multi-drug delivery
disease state most targeted followed by inflammatory diseases, microbial infections and cardiovascular
disease. Key generalizations from this analysis include: 1) microemulsion formulation is largely based on
trial-and-error despite over 1200 publications related to microemulsion drug delivery since their
discovery in 1943; 2) characterization using methods including interfacial tension, droplet size, electrical
conductivity, turbidity and viscosity may provide additional information for greater predictability; 3)
microemulsion drug delivery publications arise primarily from China (27%) and India (21%) suggesting
additional research opportunities elsewhere.
© 2017 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
1.1. Emulsion systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
1.1.1. Emulsion types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
1.1.2. Macroemulsions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
1.1.3. Nanoemulsions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428
1.1.4. Microemulsions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
1.1.5. Self-emulsifying drug delivery systems (SEDDS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
1.2. Advantages and disadvantages of microemulsion sub-class in drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
1.2.1. Advantages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
1.2.2. Disadvantages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
2. Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
3. Results and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
3.1. Relevance of microemulsions in multi-drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
3.1.1. Concurrent disease in Canada and the resulting pill burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
3.1.2. Clinical effectiveness and economic impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
3.2. Considerations in multi-drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438

* Corresponding author at: School of Pharmacy, University of Waterloo, 200

University Ave. W., Waterloo, Ontario N2L3G1, Canada.
E-mail address: wettig@uwaterloo.ca (S.D. Wettig).

http://dx.doi.org/10.1016/j.ijpharm.2017.05.005
0378-5173/© 2017 Elsevier B.V. All rights reserved.
426 S.P. Callender et al. / International Journal of Pharmaceutics 526 (2017) 425–442

3.2.1. Components of the microemulsion system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438

3.2.2. Drug-drug and other interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
3.3. Challenges in multi-drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
3.3.1. Lack of understanding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
3.3.2. Characterization6¼ The full picture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
3.4. Funding/dedication to research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441

1. Introduction an oil continuous phase. In O/W emulsions, the water phase is

referred to as the outer, continuous phase while oil is referred to as
1.1. Emulsion systems the inner, discontinuous phase (and vice versa). The two types of
macroemulsions are shown in Fig. 3.
Emulsion technology is utilized in a wide variety of industries Macroemulsions may also be prepared as multiple emulsions.
including the cosmetic, agricultural, food and pharmaceutical In particular, there are oil-in-water-in-oil (O/W/O) and water-in-
industries (Bibette et al., 1999; Prince, 1977). Emulsions are oil-in-water (W/O/W) emulsions where the continuous phases are
metastable colloidal systems comprised of droplets of one liquid oil and water, respectively. Multiple emulsions are often used in
dispersed within another immiscible liquid (Rosen and Kunjappu, delayed or controlled release formulations.
2012). These two immiscible liquids themselves cannot mix and
require the presence of emulsifying agents (emulsifiers) or surface- 1.1.2.2. Size. In general, macroemulsions consist of droplets larger
active agents (surfactants) (Rosen and Kunjappu, 2012; Leal- than 400 nm in diameter. These are significantly larger than the
Calderon et al., 2007). Surfactants are amphiphilic in nature with a droplet sizes of micro- and nanoemulsions, often resulting in
polar head and non-polar tail that orient at the interface of the highly turbid solutions (Rosen and Kunjappu, 2012).
water and oil phases, respectively, to reduce overall tension and
promote miscibility. Fig. 1 depicts the orientation of surfactant 1.1.2.3. Formation. At a simple organic-aqueous interface, there is
molecules at an organic and aqueous interface. a difference in the potential energies between molecules in the
In general, there are three main types of emulsion systems: (i) bulk and molecules lying at the interface. Molecules lying at the
macroemulsions, (ii) nanoemulsions and (iii) microemulsions. The interface possess higher potential energies as a result of their
latter will be the primary focus of this article. interactions not only with molecules of their respective phases, but
also with molecules of the opposing liquid across the interface
1.1.1. Emulsion types (Rosen and Kunjappu, 2012). This increase in potential energies
The three main emulsion systems may be characterized based represents the minimum work required to form the interface, or
on their type, size, method of formation, and stability character- the interfacial tension.
istics. These differences are summarized in Table 1 and depicted in Upon addition of an amphiphilic emulsifying agent or surfac-
Fig. 2. tant, the hydrophilic portions of the molecule orient themselves
with the molecules of the aqueous phase (and vice versa for the
1.1.2. Macroemulsions hydrophobic portions with the organic phase). This results in
Macroemulsions are often referred to as ‘coarse’ or opaque stronger interaction energies between the amphiphile and
emulsions due to their relatively large droplet sizes which results respective phase in comparison to the system without an
in a turbid solution (Rosen and Kunjappu, 2012). emulsifier. As a result, the overall interfacial tension is reduced.
Without a surfactant, it is nearly impossible to sufficiently stabilize
such a system. Where very low interfacial tensions are desired, co-
1.1.2.1. Type. In general, there are two main types of surfactants may be added. Co-surfactants act in consort with
macroemulsions: oil-in-water (O/W) and water-in-oil (W/O). O/ surfactants to further reduce interfacial tension and introduce an
W emulsions consist of oil droplets dispersed in a water continuous element of flexibility into the interfacial film. This allows the
phase while W/O emulsions consist of water droplets dispersed in system to adapt a wider variety of curvature values across an
extended range of conditions for droplet formation (Talegaonkar
and Negi, 2015). Medium chain alcohols or oils such as ethyl esters
of fatty acids are usually used as co-surfactants as they reduce
interfacial tension as well as introduce flexibility into the
interfacial film (Talegaonkar and Negi, 2015). In addition, they
may adjust the HLB value of the system by changing surfactant
portioning characteristics, curb the formation of gel-like and
crystalline phases which inhibit emulsion formation and decrease
the sensitivity to fluctuations in structure (Talegaonkar and Negi,
2015).
The type of macroemulsion formed also depends heavily on the
type of emulsifier used (Rosen and Kunjappu, 2012). O/W
emulsions are produced by emulsifiers that are more soluble in
water than oil, and vice versa (Bancroft, 1913). In other words, the
continuous phase of any emulsion is dependent on the phase in
Fig. 1. Orientation of surfactant molecules at an oil-water interface. The polar head
groups of the surfactant orient to face the polar, water phase while the non-polar
which the emulsifier is most soluble. Several theories have been
tails groups of the surfactant orient to face the non-polar, organic phase. This type of suggested for macroemulsion formation. Qualitative theories
orientation reduces the tension between the two interfaces promoting miscibility. generally involve consideration of the interactions, i.e. interfacial
 S.P. Callender et al. / International Journal of Pharmaceutics 526 (2017) 425–442 427

Table 1
Summary of emulsion types and their characteristics.

Emulsion Types Droplet Size (diameter) Energy Required Stability

Macroemulsion O/W and W/O >400 nm Yes Kinetic
Nanoemulsion O/W and W/O 100–400 nm Yes Kinetic
Microemulsion Type I: biphasic O/W; 10–100 nm No Thermodynamic
Type II: biphasic W/O;
Type III: triphasic bicontinuous
Type IV: monophasic

Fig. 2. Types and typical droplet diameter sizes of macro, nano and microemulsions. Upon surfactant addition, the non-polar surfactant tails orient to face the oil phase while
the polar surfactant head groups orient to face the outer water phase.

tension and contact angles, between each immiscible phase and

the emulsifier. Kinetic theories like those proposed by Davies
(1957), as described by Rosen and Kunjappu (2012), rely on the rate
of coalescence of each immiscible phase; the phase with a faster
coalescence rate becomes the continuous phase of the macro-
emulsion.

1.1.2.4. Stability. Given the relatively larger sizes of

Fig. 3. Schematic representation of W/O (left) and O/W (right) macroemulsion
systems. In a water-in-oil macroemulsion system, water is the inner, discontinuous
phase dispersed in the outer, continuous oil phase. The reverse is true for an oil-in-
water macroemulsion system. Surfactant molecules concentrate at the interface of
each emulsion droplet and orient themselves so that their polar heads face water
while their non-polar tails face oil. When the interface is saturated with surfactant,
micelle formation occurs with W/O systems forming reverse micelles and O/W
systems forming normal micelles.
macroemulsion droplets, stability in this context usually refers
to susceptibility to coalescence. Coalescence is the merging of two
droplets into one, which eventually leads to phase separation and
emulsion ‘breaking’. Coalescence depends on the interfacial film
surrounding individual droplets and the elasticity or rigidity of this
film (Rosen and Kunjappu, 2012). Given that this interfacial film is
comprised of surfactant molecules, it is the surfactant properties
that dictate the system’s propensity for coalescence. In general,
surfactant molecules at the interface of each droplet provide an
elastic mechanical barrier to droplet–droplet collision, reducing
the overall probability of coalescence. If the head groups are
charged, as in the case of ionic surfactants, an additional barrier is
introduced as these charged droplets would repel each other. In the
absence of an ionic surfactant, salt may also be added (Rosen and
Kunjappu, 2012). Temperature and the size range of droplets
within the macroemulsion system also affect coalescence (Rosen
and Kunjappu, 2012). In general, any factor that disturbs the
emulsifier (essentially the heart of the emulsion system) and its
resulting interfacial film, disrupts stability. It is important to note
428 S.P. Callender et al. / International Journal of Pharmaceutics 526 (2017) 425–442
that due to their larger droplet sizes and high interfacial energy,
macroemulsions are kinetically, and not thermodynamically,
stable. This means that energy is required to combine the
components, i.e., oil, water and surfactant, to form a
macroemulsion. Thus, over time, a macroemulsion will
inevitably revert to its phase separated components.
Emulsifying agents and the use of strong agitation to introduce
energy into the system for macroemulsion formation, simply
delays this reversion process for a fixed amount of time.
1.1.3. Nanoemulsions
Nanoemulsions are commonly referred to as mini-emulsions or
ultrafine emulsions. In comparison to macroemulsions and
microemulsions, nanoemulsions are most similar to macroemul-
sions with the exception of their smaller droplet sizes. Nano-
emulsions are usually blue-white to semi-opaque in nature (Rosen
and Kunjappu, 2012). They are classified according to the same
types as macroemulsions; either as oil-in-water and water-in-oil.
1.1.3.1. Size. Size is the main differentiating factor between
nanoemulsions and macroemulsions. There is much confusion
in the scientific community regarding the exact droplet size range
of nanoemulsions. Articles that do specify sizes often fail to
mention whether they are referring to diameter or radii
measurements. Contrary to their nomenclature and popular
belief, however, nanoemulsions do not necessarily contain
droplets that are smaller than those found in microemulsions.
In fact, droplet sizes in nanoemulsions are usually in the mid-size
range between that of macroemulsions and microemulsions, i.e.,
Fig. 4. Schematic of the effect of temperature (T) or salinity (S) and surfactant concentration on microemulsion type. Spherical structures represent the microemulsion phase
containing micelles, yellow regions represent oil and blue regions represent water.. (For interpretation of the references to colour in this figure legend, the reader is referred to
the web version of this article.)
approximately 100–400 nm in diameter (Rosen and Kunjappu,
2012).
1.1.3.2. Formation. Much like macroemulsions, nanoemulsions
often require the input of energy and agitation for formation as an
energy barrier must be overcome. For this reason, many
nanoemulsions are formed by high-pressure processes such as
homogenization. Nanoemulsions are also found to generally
require less emulsifier than macro or microemulsions, typically
on the order of 1–3% of the volume of the oil phase (Rosen and
Kunjappu, 2012). The length of the co-surfactant required is also
found to be higher than that of microemulsions (at least 12 carbons
as compared to the much shorter length chains required for
microemulsions) (Rosen and Kunjappu, 2012).
1.1.3.3. Stability. Like macroemulsions, nanoemulsions are not
thermodynamically stable. These emulsions are kinetically stable,
meaning that the components must be mixed in such a way as to
overcome an energy barrier in order for the nanoemulsion to be
formed. The free energy of the separate oil and water phases of a
nanoemulsion is lower than free energy of the colloidal dispersion
system, creating a thermodynamically unstable system. This
instability may be overcome by ensuring there is a large energy
barrier between the two phases. The greater the height of the
energy barrier between the nanoemulsion and the separated
phases, the greater the stability of the nanoemulsion (McClements,
2012). As a result, nanoemulsions like macroemulsions also revert
to their original phases over time. Their smaller droplet sizes and
hence resistance to coalescence, however, significantly delays this
 S.P. Callender et al. / International Journal of Pharmaceutics 526 (2017) 425–442
reversion process. Some nanoemulsion formulations can therefore
remain stable for months and even years.
1.1.4. Microemulsions
Microemulsion solutions gained recognition in 1943 after Hoar
and Schulman mixed a milky solution with hexanol to produce a
uniform single-phase, non-conducting solution (Gibaud and Attivi,
2012). The first commercial application of microemulsions was in
the formulation of liquid waxes, discovered by Rodawald in 1928
(Prince, 1977). By 1970, microemulsion research peaked, in part
due to its application in enhanced oil recovery (Langevin, 1988)
where the use of microemulsions increased oil recovery through
their ability to achieve ultralow interfacial tensions (Rosen and
Kunjappu, 2012). Microemulsions are transparent, thermodynam-
ically stable mixtures of oil and water stabilized by emulsifiers.
They have significantly different properties (type, size, formation
and stability) relative to nano and macroemulsions, which will be
discussed in detail, below.
1.1.4.1. Type. According to Winsor (1948) there are four types of
microemulsions: (i) Type I- biphasic with an upper excess oil phase
and lower O/W emulsion, (ii) Type II- biphasic with an upper W/O
emulsion and lower excess water phase, (iii) Type III- triphasic
with upper excess oil phase, middle bicontinuous microemulsion
and lower excess water phase, (iv) Type IV- monophasic, single
microemulsion phase. Depending on the emulsifier used,
microemulsions can transition between each type quite easily.
In general, microemulsions follow trends displayed in Fig. 4,
typically referred to as a fish diagram. A simple change in
Fig. 5. Schematic of the various micellar structures possible depending on the ratio of water, surfactant and oil utilized. Adapted from Brinker et al. (1999).
429
temperature, T, in the case of a non-ionic surfactant or salinity, S, in
the case of an ionic surfactant can result in transition from a Type
I ! III ! II microemulsion. An increase in surfactant concentration
can also induce a transition from any of these microemulsion types
to a Type IV microemulsion, within temperature or salinity
constraints.
1.1.4.2. Size. Contrary to their terminology, microemulsions
consist of the smallest droplet sizes found in emulsion systems,
in comparison to macro and nanoemulsions. Specifically,
microemulsion droplet sizes range from 10 to 100 nm in
diameter (Rosen and Kunjappu, 2012; McClements, 2012).
According to Eriksson et al. (2001), one of the most important
factors influencing droplet size includes the packing density of
surfactant molecules in the interfacial film (Eriksson et al., 2001).
This curvature and compressibility of the interfacial film then
dictates the interfacial tension (Eriksson et al., 2001) and
contribution to overall free energy (1984). In particular, the
more rigid the film, the higher the packing density and the smaller
the droplet size. Lang et al. (1992) also stress the importance of
surfactant and oil alkyl chain, and temperature, in determining
droplet size (Lang et al., 1992); a shorter surfactant or co-surfactant
alkyl chain results in larger water-in-oil droplets and an increase in
droplet–droplet interaction at constant oil alkyl chain length,
which may affect microemulsion stability (Lang et al., 1992). In
contrast, an increase in the oil alkyl chain length or in temperature
results in larger droplets and increased droplet–droplet
interactions (Lang et al., 1992).
430 S.P. Callender et al. / International Journal of Pharmaceutics 526 (2017) 425–442

1.1.4.3. Formation. The energy profile of microemulsions is
opposite to that of macro and nanoemulsions. In a
microemulsion system, the components are at a higher
energetic state than that of the final microemulsion product.
Thus, energy is required for microemulsion dissociation into the
original components. Microemulsion formation is therefore a
forward-driven process and, in fact, most microemulsion systems
form spontaneously without the input of energy. Micellar, rod-like,
lamellar and sponge-like structures are all possible depending on
the type of microemulsion formed and in particular, the proportion
of surfactant, oil and water used (McClements, 2012). Fig. 5
displays the various packing arrangements that can be obtained
depending on the concentration of oil, water and surfactant
utilized. In contrast to nanoemulsions, microemulsions usually
require a higher percentage of surfactant or emulsifier (i.e., 15–30%
w/w of the oil phase) for formation (Rosen and Kunjappu, 2012).
Additionally, the co-surfactant required is usually of a shorter
carbon chain length than that required in nanoemulsions (Rosen
and Kunjappu, 2012).
1.1.4.4. Stability. Given the reverse energy profile of
microemulsions as compared to nano and macroemulsions,
microemulsions are thermodynamically stable. This means that
their phases are not prone to separation over time and most
microemulsion formulations remain stable for many years. Fig. 6
illustrates the energetic differences between macro, nano- and
microemulsions.
1.1.5. Self-emulsifying drug delivery systems (SEDDS)
SEDDS are isotropic mixtures of oil, surfactant and sometimes
co-solvent that are able to self-emulsify upon mild agitation and
dilution with aqueous media to form O/W emulsions. These fine
oil/water dispersions are able to spread throughout the GI tract, as
the digestive system provides the agitation needed for the
microemulsion to form (Rahman et al., 2013). SMEDDS (referred
to as self-microemulsifying drug delivery systems) are often
distinguished by their inclusion of water-soluble components
(Rahman et al., 2013) and tend to form microemulsions upon self-
emulsification while SNEDDS (self-nanoemulsifying drug delivery
systems) tend to form nanoemulsions upon self- emulsification.
According to the lipid formulation classification system (LFCS),
SEDDS consisting of water-insoluble surfactants and oil are
regarded as Type II LFCS formulations while those with oil,
surfactant and a co-solvent and are regarded as Type III LFCS
formulations with optical clarity and smaller droplet sizes (Rah-
man et al., 2013). SEDDS are a common emulsion dosage form of
choice for drug delivery as can be seen in Section 3 (ii).
1.2. Advantages and disadvantages of microemulsion sub-class in drug
delivery
Microemulsions possess a number of unique characteristics
that render them suitable for drug delivery. Unfortunately, their
complex nature does not always make them a viable option for
drug delivery. Understanding the key advantages and disadvan-
tages of microemulsion drug delivery systems is essential in
making informed decisions regarding the delivery of the active
pharmaceutical ingredient (API) in question.
1.2.1. Advantages
Microemulsions are uniquely equipped for drug delivery. In
particular, microemulsions are able to: i) administer APIs in liquid
form, ii) improve bioavailability and stability via small droplet
sizes, iii) solubilize and delivery both hydrophilic and lipophilic
drugs, (iv) form spontaneously with relatively simple starting
ingredients

Fig. 6. Schematic of the energetics involved in a typical microemulsion system. It is clear that the microemulsion product is at a lower energy state than that of its separated
phases or starting components. This contributes to its thermodynamic stability. Nanoemulsions have a reversed profile with the nanoemulsion product at a higher energy
state than the starting components. This not only results in an input of energy to form the nanoemulsion, but also in a kinetically, rather than thermodynamically, stable state
Adapted from McClements (2012).
 S.P. Callender et al. / International Journal of Pharmaceutics 526 (2017) 425–442
i) Drugs Administered in Liquid Form
It is generally well established that drugs in solid form must
undergo an extra dissolution step before they can be absorbed.
There are three main processes necessary for solid drug absorption
for oral delivery: a) disintegration, b) dissolution and c) absorption
(McCuistion et al., 2014). Disintegration is necessary in order for
the solid particles to dissolve in liquid media before being absorbed
(McCuistion et al., 2014). Microemulsions are liquid in nature and
thus, are able to bypass this additional disintegration step
(McCuistion et al., 2014). The overall result is that microemulsions,
and liquids in general, experience faster drug absorption rates
independent of any effect of disintegration (McCuistion et al.,
2014). In the context of drug formulations, this is beneficial to the
consumer especially for fast-acting relief purposes. Though liquid
formulations are often encapsulated in solid dosage forms such as
gelatin capsules, dissolution for a solid capsule containing drugs in
liquid form is still faster than dissolution for a solid capsule
containing drugs in solid form.
The presence of drug in liquid form is also advantageous in
terms of gastrointestinal (GI) stability (Brandlin, 2013). While
liquids may take 20–30 min to pass completely through the
digestive system, solids may take up to 3 h depending on their
composition (Brandlin, 2013). These solids remain in the stomach
for a longer period of time and thus, are subjected to GI enzymatic
degradation for longer periods of time (Paradkar and Bakliwal,
2008). This may greatly affect drug stability within the GI tract,
causing premature drug degradation (Paradkar and Bakliwal,
2008).
ii) Small Droplet Sizes
Microemulsions possess droplet sizes in the diameter range 10–
100 nm (Rosen and Kunjappu, 2012; McClements, 2012). These
small droplet sizes increase the surface area to volume ratio for
drug absorption leading to improved bioavailability (Liu et al.,
2016; Cerpnjak et al., 2013; He et al., 2010; McClements, 2015).
Additionally, these small droplet sizes are able to resist gravita-
tional separation and hence, enhance stability of the micro-
emulsion system. The factors influencing droplet size in
microemulsion systems have been discussed earlier in Section
1.1.4 but generally include alkyl chain length of the oil, the length
and type of surfactant chosen and the rigidity of the resulting
interfacial film. Many studies conducted over the past 5 years
Fig. 7. Pie chart depicting the various types of drugs delivered via microemulsion systems over the past five years. Due to the fact that poorly water-soluble and lipophilic
compounds are most challenging in terms of drug delivery (Kwon, 2002; Niazi, 2015; Gupta et al., 2013; Shargel et al., 2012), it is not surprising that almost 80% of
microemulsions have been used to deliver these types of compounds. The section classified as ‘other’ is representative of compounds that are classified as neither lipophilic
nor hydrophilic and/or may be pH sensitive.
431
credit the small droplet sizes of microemulsions for the resulting
stable and highly bioavailable formulations. In particular, micro-
emulsions have improved the stability and bioavailability of many
drugs including Aprepitant (a chemotherapy-induced nausea and
vomiting preventer (Kamboj et al., 2015)), Troxerutin (Xu et al.,
2016) (a hydrophilic vasoprotector), Fenofibrate (Hu et al., 2011) (a
cholesterol-lowering agent), Pranlukast Hemihydrate (Baek et al.,
2013), (an asthma medication), Leuprorelin (Hintzen et al., 2014) (a
hormone mimicking agent used for treatment of numerous
illnesses), Ritonavir (Deshmukh and Kulkarni, 2014) (a HIV anti-
retroviral), Sirolimus (Cho et al., 2013) (an immunosuppressant),
and Gatifloxacin (Kalam et al., 2016) (an antibiotic). The small
droplet sizes of microemulsions also afford delivery via a wide
variety of administration routes.
iii) Solubilization & Delivery of Hydrophilic and Hydrophobic
Drugs
Another major advantage of microemulsion systems is their
ability to solubilize poorly water-soluble drugs (PWSDs). More
than 40% of drugs in the development phase fail to reach the
market due to poor biopharmaceutical properties, including poor
water solubility (Dahan and Hoffman, 2011; Gullapalli, 2010;
Jambhekar and Breen, 2013). PWSDs often experience unfavour-
able dissolution profiles in vivo leading to dissolution being the
rate-limiting step with respect to absorption (Kwon, 2002; Niazi,
2015; Gupta et al., 2013; Shargel et al., 2012). With microemulsions
containing both a hydrophilic and a hydrophobic phase, the
incorporation and delivery of both hydrophilic and hydrophobic
APIs is possible. Oil-in-water microemulsions are well suited for
lipophilic drug delivery while water-in-oil microemulsions are
well suited for hydrophilic drug delivery. Hydrophilic and
hydrophobic drugs may also be delivered via microemulsion gel
systems.
iv) Spontaneous Formation and Simple Starting Ingredients
The ability of microemulsions to form spontaneously (McCle-
ments, 2012; Mason et al., 2006) due to the ingredients being
driven to an energy state favourable to microemulsion formation
(McClements, 2012, 2015; Tong et al., 2015; Fast and Mecozzi,
2009; Ngan et al., 2014; Lawrence and Warisnoicharoen, 2006)
results in an economical formation process. This means that in
many cases, energy is not required for microemulsion formation
(unlike nano- and macroemulsions) resulting in a cost-effective
432 S.P. Callender et al. / International Journal of Pharmaceutics 526 (2017) 425–442

production method. Additionally, the simplicity of the components

comprising microemulsion systems renders them suitable for drug
Type of Microemulsions Formulated 2011-2016
delivery of almost any route of administration. Surfactants and oil
components are readily available and mostly economical for
40

Percentage of Publications
formulation purposes.

1.2.2. Disadvantages 30
The presence of both an organic and aqueous phase allows for
the delivery of both hydrophobic and hydrophilic APIs; however,
this becomes problematic when dealing with APIs that do not fall 20
into either category. Minerals are a prime example of this. APIs
such as iron and calcium do not fall into either of these categories 10
and if added to a microemulsion system, would likely result in a
suspension. In cases like this, a solid dosage form such as a tablet
may be a better option. Thus, microemulsion systems may not 0
always be a favourable method of delivery for ingredients that are

s
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insoluble in either hydrophilic or hydrophobic environments. It is

O
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also important to remember that in the case of microemulsions,

l(
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APIs must be solubilized in their respective phases. As a result, the

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in
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This could prove to be a limiting factor depending on the amount of

ic
B
API necessary for delivery.
Microemulsions also require the presence of emulsifiers at a
Type of Microemulsion
slightly higher concentration than their nanoemulsion counter- Fig. 8. Types of microemulsion systems used in drug delivery over the past five
parts (McClements, 2012). Some emulsifiers demonstrate toxicity, years. Due to the challenging nature of lipophilic drug delivery (Kwon, 2002; Niazi,
as explained later on, and as a result are heavily regulated. This 2015; Gupta et al., 2013; Shargel et al., 2012), it can be seen that oil-in-water
reduces the list of available surfactants for use in oral formulations. microemulsions are considered appropriate vehicles for this type of delivery,
comprising over 50% of publications over the last five years. Gel formulations are
Those surfactants that are considered acceptable are only also quite common. Microemulsion systems have also been used as a basis for
acceptable up to certain concentrations. This rule also applies to nanoparticle formation.
certain oils demonstrating toxicity.
Finally, microemulsions are sensitive to temperature and
salinity changes and may undergo phase changes when exposed
comparison to hydrophilic drug delivery (15.9%). Negligible
to higher or lower than normal temperatures or salinity concen-
amounts were seen for amphiphilic (1.2%) and other drugs such
trations. This could lead to ‘breaking’ of the microemulsion and
as basic or pH-sensitive drugs (3.5%). This high lipophilic
eventually, phase separation.
representation may be largely attributed to the fact that poorly
water-soluble drugs require modification for delivery given their
2. Materials and methods
poor absorption profiles (Kwon, 2002; Niazi, 2015; Gupta et al.,
2013; Shargel et al., 2012). Lipophilic components can be hidden
In this review, a literature search of the database PubMed
and solubilized within the hydrophobic surfactant tail core of an
revealed that over 431 microemulsion formulation articles were
oil-in-water microemulsion for effective delivery.
published from January 1, 2011 to April 30, 2016. The following
ii) Type of Microemulsion Formulated
search criterion was used: ‘((((microemulsi*) OR micro-emulsi*)
The type of microemulsion most commonly formulated over
OR micro emulsi*) AND drug delivery) NOT cosmetic*’. These
the past five years is a direct result of the type of drug most
publications were screened for drug, microemulsion and surfac-
commonly delivered during this period. Fig. 8 depicts that of the
tant type along with a number of other factors including preferred
more than 400 publications regarding microemulsion drug
routes of administration for delivery. Given the current gap in
delivery over the last five years, over 50% (55.8%) can be attributed
theoretical understanding, the results from this analysis may shed
to oil-in-water whether via Type I microemulsion delivery or
insight into how well theoretical knowledge is put into practice.
through SEDDS. O/W microemulsions are well suited for the
delivery of lipophilic compounds; thus, these results are in direct
3. Results and discussion
agreement with the results from Fig. 7. Type I microemulsions are
able to effectively solubilize these drugs in their hydrophobic core.
Microemulsions are comprised of at least three important
Second to O/W microemulsions are gel formulations (16.6%) and
ingredients: an aqueous component, an oil component and an
solid nanoparticles (10.1%). Surprisingly, water-in-oil, including
emulsifier. Given the multi-component nature of microemulsions,
Type II microemulsion drug delivery accounts for less than 10%.
information gathered over the past five years indicates interesting
This may be attributed to the highly water-soluble and readily
trends in the areas of type of drug delivery, surfactant use and even
dissolvable nature of the hydrophilic compounds that these types
country of publication. These results will be discussed below:
of microemulsions strive to deliver, eliminating the necessity for
i) Type of Drug Delivery
microemulsion formulation. Bicontinuous or Type III micro-
One of the most important properties of microemulsions is
emulsions account for just over 1% of formulations. This is
their ability to encapsulate and deliver both hydrophilic and
remarkable given that these microemulsions are considered
hydrophobic compounds. Fig. 7 depicts the classes of drugs that
‘optimum’ in nature due to their equal preference for both the
have been delivered via all types of microemulsion systems,
hydrophilic and hydrophobic phases of the microemulsion. Type IV
including self-microemulsifying systems, over the past five years.
or monophasic microemulsions are non-existent, perhaps due to
It can be seen that of the more than 400 publications regarding
the high surfactant content required in these formulations
microemulsion drug delivery over the past five years, lipophilic
rendering them less suitable for delivery.
drugs are the preferred drug class for delivery (79.4%) in
 S.P. Callender et al. / International Journal of Pharmaceutics 526 (2017) 425–442 433

can be readily solubilized and absorbed in the digestive system.

Routes of Administration Utilized in Microemulsion
Formulations 2011-2016 The nanoscale size of microemulsion droplets also renders them
suitable for dermal/topical delivery (>30%) followed by parenteral
50
delivery (14.25%). Parental delivery and formulation is especially
challenging given the close monitoring of acceptable excipients
Percentage of Publications

40 due to the nature of the administration route. Of notable interest,

however, is the presence of microemulsion formulations suitable
for intranasal (3.3%), ocular (3%) and intrathecal/brain delivery
30
(1.2%). These three routes of administration all depend on the small
droplet sizes of microemulsions while the transparent nature of
20 microemulsion systems is particular attractive in ocular formu-
lations.
iv) Diseases Preferentially Treated
10 The evolution and usefulness of a particular technology can be
evidenced by the disease states often chosen for treatment. The
0 pathologies treated using microemulsion formulations over the
past five years are depicted in Fig. 10. It can be seen that cancer is
m ry

al
ar

lm al
de al

l
en l
l/b tra a

le

l/d a l
to b l i r y

va a l
na
a

pa he
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or

pu ter
in as
cc

m
ca g u
tip
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ul

su na

the leading disease state treated, accounting for over 16% of

gi
liv

ot

er
oc
n
bu

n
ul

o
re

publications. This is closely followed by inflammatory diseases

ra

pi

(14.7%), microbial diseases (10.9%) and cardiovascular diseases

ca

(9.7%). As discussed in Section 3.1.1, with the exception of microbial

he
at

diseases, these are the most common chronic ailments affecting

tr
in

Routes of Administration the Canadian population to date and often occur concurrently with
other illnesses. The formulation of successful microemulsion
Fig. 9. Microemulsion drug delivery publications separated by route of adminis- formulations to treat these disease states holds great promise in
tration. Most microemulsion formulations contain non-ionic surfactants, which are the field of chronic disease treatment and multi-drug delivery.
generally regarded as the safest type of surfactant for ingestion purposes. Hence,
v) Surfactant Class Preferred
most microemulsions are delivered via the oral route. The small droplet sizes of
microemulsions also allow for favourable penetration necessary in topical and Microemulsions cannot form without emulsifiers. The four
parenteral delivery, as well as pulmonary and intranasal delivery to a lesser extent. classes of surfactants (non-ionic, anionic, cationic and zwitterion-
ic) allow for a wide selection pool. Unlike ionic surfactants, non-
iii) Routes of Administration Preferred ionic surfactants do not possess charged head groups. This affords
According to microemulsion drug delivery literature over the them a lower critical micelle concentration than their ionic
past five years (Fig. 9), oral delivery is preferred, accounting for counterparts due to an absence of electrostatic repulsion between
over 42% publications. This is not surprising given that micro- head groups (Attwood and Florence, 2012; Tadros, 2005). Non-
emulsions have the advantage of being present in liquid form and ionic surfactants are also more resistant to the effect of charge and

Microemulsion-treated Pathologies 2011-2016

20
Percentage of Publications

15

10

0
or se s
rs
yp s t h s

A ing s

s
s

ea s

ea r
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eu

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Im

Pathology

Fig. 10. Graphic depicting the various pathologies treated by microemulsion systems over the past five years. Cancer, inflammatory diseases, neurological disorders and
cardiovascular diseases are amongst the leading pathologies treated by single drug, microemulsion systems. These diseases typically occur concurrently with a wide variety of
other illnesses.
434 S.P. Callender et al. / International Journal of Pharmaceutics 526 (2017) 425–442
Fig. 11. Classes of surfactants utilized in microemulsion formulations within the
last five years. Of the 607 surfactants used in over 400 publications, almost 90% of
these are non-ionic due to their uncharged nature, insensitivity to salt/pH changes
and favourable safety profile. Amphoteric surfactants (mainly natural oils such as
lecithins and phospholipids) containing both a positive and negative charge are the
second most popular choice comprising almost 7%. This is likely due to its overall
neutrality attributed to the cancellation of charges near the isoelectric point.
Cationic surfactants are considered the most toxic due to their positive charges,
which interfere with the negative cell membranes of mammalian cells. This
explains their low occurrence in many microemulsion formulations.
pH changes compared to the other surfactant classes (Myers,
2005). In addition, they are known to have a better oral safety
profile than ionic surfactants (Malmsten, 1999; Grove et al., 2007;
Liu et al., 2008; Hauss, 2007; Balazs, 2011) and many are generally
regarded as safe for ingestion. These advantages often result in
non-ionics being preferred for use in oral pharmaceutical
formulations. Anionic surfactants are slightly more toxic than
non-ionics while cationic surfactants are hardly used due to their
high toxicity (Liu et al., 2008; Atwood and Steed, 2004). Near to the
isoelectric point, zwitterionic surfactants may possess a neural net
charge, leading them to behave similar to non-ionic surfactants
(Myers, 2005). Fig. 11 illustrates the classes of surfactants used in
microemulsion formulations over the past five years. It can be seen
that almost 90% of microemulsion formulations in the past five
years have utilized non-ionic surfactants followed by amphoteric
(7%) and anionic surfactants (2.5%). Cationics are hardly used in
drug delivery (0.6%) due to their toxic nature.
A good emulsifier depends on, and must match, the continuous
phase of the microemulsion system (Bancroft, 1913). Therefore, it is
crucial to understand the type of microemulsion, i.e., oil-in-water
versus water-in-oil, suitable for a particular application. This
usually depends on the type of drug that must be solubilized. For
example, a hydrophobic drug should partition into oil droplets
within an aqueous phase. Hence, O/W formulations are preferred
and a hydrophilic surfactant will be the surfactant of choice. For
formulators, the hydrophilic-lipophilic balance (HLB) is a very
important parameter that can help select the right surfactant for
the formulation in question. The HLB takes into account the
structure of the surfactant with respect to its hydrophilic and
hydrophobic structure and can very generally be calculated as
follows: (Rosen and Kunjappu, 2012)
P P
HLB = 7 + (hydrophilic group numbers)  (hydrophobic group
numbers)
From the equation above, it can be seen that a high HLB
corresponds to a higher degree of hydrophilicity and vice versa for
a low HLB. It is also important to note that the HLB is summative
and can be obtained by mixing various ratios of more than one
surfactant. In this case, the additional surfactant will serve as a
linker or co-surfactant.
Two additional parameters to consider are the efficiency and
effectiveness in the formulation in which it is meant to be active.
Efficiency in the context of emulsifiers is the ability of the
surfactant to reduce the interfacial tension by 20 mN/m. Effective-
ness is the maximum reduction in interfacial tension that the
surfactant can achieve. Surfactant efficiency can be controlled by
increasing the number of carbon atoms in a straight-chain
hydrophobic group or through the addition of a fluorocarbon
(Rosen and Kunjappu, 2012). Branching within the surfactant or
the addition of a phenyl group decreases efficiency (Rosen and
Kunjappu, 2012). Effectiveness can be controlled by an increase in
the ionic strength of solution for ionic surfactants, or with the
increase of the hydrophobic tail for POE non-ionic surfactants
(Rosen and Kunjappu, 2012). In general, emulsifier properties are
instrumental in deciding which surfactant to choose. Values such
as HLB, efficiency and effectiveness are important and must be
taken into consideration.
vi) Non-ionic Surfactants Preferred
Of the 90% of non-ionic surfactants used in microemulsion
formulations, Fig. 12 indicates that the most common are the
Tweens or polyoxyethylene sorbitan esters ( > 28%), Cremophor or
a castor oil derivative of polyoxyethylene alkyl ethers (19.8%) and
Transcutol or diethylene glycol ethers (11.6%). The least commonly
used non-ionic surfactant was Gelucire, perhaps due to its solid
nature and need for heat during the formulation process. Fig. 13
depicts the structures of the three most commonly used non-ionic
surfactants in microemulsion drug delivery formulations over the
past five years.
vii) Anionic Surfactants Preferred
Non-ionic Surfactants Utilized in
Microemulsion Formulations 2011-2016
Other
Gelucire
TPGS
Labrafil
Non-ionic Surfactant
Triton X 100
Brij
Solutol
Poloxamers
Spans
Labrasol
Transcutol
Cremophor
Tweens
0
10
20
30
Percentage of Publications
Fig. 12. Various types of non-ionic surfactants used in peer-reviewed publications
over the past five years. Tweens or polyoxyethylene glycols are the most common,
representing almost one-third of publications. This group includes Tween 20,
Tween 40, Tween 60 and Tween 80. The number at the end denotes the number of
polyoxyethylene groups. Cremophor, a castor oil derivative, is the second most
commonly used non-ionic surfactant followed by Transcutol.
 S.P. Callender et al. / International Journal of Pharmaceutics 526 (2017) 425–442 435

Fig. 13. Structures of some of the most common non-ionic surfactants used in the preparation of microemulsion dosage forms for the delivery of multiple APIs.

versatile surfactant despite aggregation and adsorption behaviours

Anionic Surfactants Utilized in Microemulsion not unlike typical sulfosuccinates (Nave and Estoe, 2000).
50 Formulations 2011-2016 viii) Commonly Utilized Surfactants in Microemulsion For-
mulations
Of all surfactants utilized in microemulsion formulations over
40 the past five years, those most commonly utilized include Tween
Percentage of Publications

80, Labrasol, Cremophor RH 40, Cremophor EL and Transcutol- all

non-ionic surfactants (Fig. 15). Second to the non-ionic surfactants
30 class is Lecithin, an amphoteric surfactant. Lecithin consists of a
mixture of phospholipids and is naturally derived from plant
products such as soybeans and animal products such as eggs (Jala
20 and Prasad, 2015). They offer a natural alternative to synthetic
surfactants as they consist of a mixture of natural lipids such as
phosphatidylcholine, phosphatidylethanolamine and phosphati-
10 dylinositol (Jala and Prasad, 2015). Their lipid nature allows them
to act as ideal emulsifiers and solubilizers of hydrophobic material
(Jala and Prasad, 2015).
0 ix) Single vs. Multi-drug Formulations
12
te

e
e
T

Despite the unique advantages posed by microemulsion

at

at
O

la

61
A

in

le
ho

O
cc

ul

systems for multi-drug delivery, there is surprisingly very little

C

em
su
lt/
Sa

lfo

ax

information regarding this type of delivery. Fig. 16 depicts the

M
Su
ile

distribution of single versus multi-drug formulations published

B

Anionic Surfactant over the past five years.

The lack of microemulsion, multi-drug delivery publications
Fig. 14. Anionic surfactants used in the preparation of microemulsion drug delivery
systems from a review of 2011–2016 publications. AOT, in particular, represents may be a result of the complex and challenging nature of
almost half of this category followed by bile salts or cholate. General sulfosuccinates microemulsion drug delivery in general, as discussed later in
follow with almost 20%. Section 3.2. Despite the multi-component and dynamic nature of
these systems, there are a limited number of studies where drugs
have been co-administered for a variety of reasons. Ding et al.
Although anionic surfactants are not utilized as commonly in
(2015) successfully co-administered sirolimus with honokiol.
drug delivery formulations due to their somewhat toxic nature,
Sirolimus is a p-glycoprotein substrate with poor water solubility
their negative charge may be advantageous in the delivery of
while honokiol is a p-glycoprotein inhibitor (Ding et al., 2015).
oppositely-charged compounds. Of the anionic surfactants utilized
Though the addition of honokiol had no effect on drug release
in microemulsion formulations over the past five years, AOT
rates, the higher the amount of honokiol, the higher the
(Aerosol-OT) or sodium bis-2-ethyl hexyl sulfosuccinate accounted
permeability coefficient (Ding et al., 2015). It should also be noted
for almost 40% followed by cholates with 23% (Fig. 14). The high
that both sirolimus and honokiol are lipophilic compounds.
usage of Aerosol-OT may be attributed to its reputation as a very
436 S.P. Callender et al. / International Journal of Pharmaceutics 526 (2017) 425–442

lycopene, into a microemulsion formulation with ascorbic acid, a

Most Common Surfactants Used in Microemulsion
Formulations 2011-2016 lycopene stabilizer. It should be noted that these two drugs are of
opposing polarity- lycopene is highly lipophilic while ascorbic acid
Other
Unknown is hydrophilic. Similarly, in 2014, Kaur and Mehta successfully
Tween 80 incorporated two anti-TB drugs of opposite lipophilicity into a
Transcutol Type I microemulsion system for oral delivery (Kaur and Mehta,
Cremophor RH 40 2014). Other studies have formulated anti- inflammatory and
Cremophor EL analgesic agents successfully (El Maghraby et al., 2014; Zhang et al.,
Labrasol
2011; Negi et al., 2016) or specifically in the case of psoriasis, an
Tween 20
Span 80 anti-inflammatory and keratolyic agent, salicylic acid (Baboota
Lecithin et al., 2011). Gupta et al. (2014) formulated caffeine and green tea
Solutol HS 15 catechins for their antimicrobial activity (Gupta et al., 2014) while
Span 20 others have successfully co-administered apoptosis triggers for
Surfactants

Soy Lecithin cancer treatment (Qu et al., 2015; Ujhelyi et al., 2015).
Poloxamer
Finally, with respect to neurological disorders, multi-drug
Pluronic
Triton X 100 microemulsions have been successfully formulated for Alzheimer’s
TPGS disease (Shi et al., 2012) and neurocysticercosis or NCC (Shinde
Labrafil M 1944 et al., 2015). Chemelli et al. (2012) was also able to load two
Gelucire hydrophilic proteins, cytochrome c and bovine serum albumin
AOT (BSA) concurrently into a single water-in-oil microemulsion
Brij 30/35
(Chemelli et al., 2012). Table 2 summarizes these studies.
Tween 85
Span 85
Tween 60 3.1. Relevance of microemulsions in multi-drug delivery
Brij 97
Brij 96 Microemulsion systems hold great potential for multi-drug
Brij delivery due to their amphiphilic nature. Concurrent disease in
Canada and the resulting pill burden has a number of economic
0

10

15

20

Percentage of Publications and social implications that may be alleviated through the use of
microemulsions. In addition, microemulsions are suitable for
Fig. 15. Most commonly used surfactants in the preparation of microemulsion combinatorial therapy which has been shown to improve clinical
dosage forms, as described in peer-reviewed publications over the past five years.
effectiveness and economic outcomes. These implications are
Tween 80, Transcutol and Cremophor RH 40, all non-ionic surfactants are the most
common. Second to all non-ionics is lecithin, an amphoteric surfactant represented discussed in greater detail, below.
in almost 5% of publications.
3.1.1. Concurrent disease in Canada and the resulting pill burden
Many chronic diseases occur concurrently. By definition, this is
Single and Multi-drug Formulations Published 2011-2016 the occurrence of more than one chronic disease simultaneously. A
2015 study by Osmun, Kim and Harrison revealed that concurrent
150
Percentage of Publications

diseases account for over 50% of family physician caseloads

(Osmun et al., 2015). According to the Public Health Agency of
Canada (PHAC), 14.8% of Canadians over the age of 20 suffer from
100
two or more chronic diseases concurrently.
The PHAC also reports that the most prevalent chronic diseases
50
in Canada include mental illness (33.3% of Canadians over the age
of 15), obesity (26.4% of Canadians over 18 years old), hypertension
(24.2% in Canadians over the age of 20) and arthritis (17.9% of
0 Canadians over the age of 20) (Anonymous Economic Burden of
Illness in Canada, 2005). These conditions are known to occur
ns

ns
io

io

concurrently with a variety of other illnesses (Nousen et al., 2013;

at

at
ul

ul

Sajatovic et al., 2016; Lee et al., 2015; Martin-Rodriguez et al., 2015;

rm

rm
Fo

Fo

Katsareli and Dedoussis, 2014; Castanon et al., 2014; Hajjar et al.,

PI

PI

2011; Lee et al., 2008; Michaud and Wolfe, 2007; Ogdie et al., 2014;
-A

A
ti-
le

ul
ng

Uutela et al., 2014; Innala et al., 2016).

M
Si

As a consequence of the high incidence of concurrent disease,

Type of Formulation
patients are often prescribed multiple medications that must be
Fig. 16. The distribution of single and multi-drug microemulsion formulations taken within a 24-h period. This may be quite overwhelming for
published in peer-reviewed journals within the past five years. Due to their complex the patient and a variety of studies have shown that medication
nature, multi-drug formulations are rare, comprising a mere 4.6% of total
adherence decreases as the number of medications increases
publications in this period.
(Pasina et al., 2014). Some studies suggest that dose frequency
rather than medication number is more influential on adherence
Several studies have also successfully formulated curcumin, a
(Jin et al., 2008). Despite this, there is overall agreement that
highly lipophilic anti-cancer and anti-inflammatory agent with
complex treatment regimens decrease adherence (Jin et al., 2008).
absorption enhancers and metabolic clearance inhibitors (Grill
Farrell et al. (2013) suggest that within Ontario, the solution to pill
et al., 2014; Li et al., 2015). Others have studied the co-delivery of
burden is to utilize combination formulations. Such treatments
statins (cholesterol-lowering agents) with agents that limit
may improve adherence by up to 26% (Farrell et al., 2013).
cholesterol uptake (Fisher et al., 2013; Hwang et al., 2015). In
Increased adherence would reduce the economic burden of re-
addition, Pepe et al. (2012) successfully loaded the oxidative agent,
hospitalizations or subsequent medical consultation as a result of
 S.P. Callender et al. / International Journal of Pharmaceutics 526 (2017) 425–442 437

Table 2
Publications regarding multi-drug delivery Jan 2011–April 2016. The majority of these publications involved type I oil-in-water microemulsion drug delivery systems.

APIs Function Formulation Ingredients Microemulsion Observations Ref.

Type
 Honokiol (p-gp inhibitor) Immunosuppressant Cremophor1 EL (emulsifier), I (SMEDDS) Improved oral absorption and (El Maghraby
 Sirolimus (p-gp substrate) Propylene glycol (co-emulsifier) and transport of sirolimus et al., 2014)
Medium chain triglycerides (MCT)
[9:2:9 w/w/w]
 Curcumin Antioxidant Cremophor1 EL (emulsifier) and I (SMEDDS) Improved curcumin (Zhang et al.,
 Silibinin (UGT-mediated clearance Antiinflammatory CarbitolTMin 2:1 w/w with bioavailability in vivo 2011)
inhibitor) Captex1355 as oil (10:1 w/w
surfactants to oil)
 Curcumin Antioxidant Cremophor1 RH40 (emulsifier), I (SMEDDS) Improved local concentration of (Negi et al.,
 Piperine (clearance inhibitor) Antiinflammatory Transcutol1 HP (co-emulsifier), curcumin in colonic lesion site 2016)
CapryolTM 90 (oil)
 Simvastatin Statin Sucrose ester (surfactant) an 1,2- Lipophilic Favourable solubilization for (Baboota
 Phytosterols (reduce cholesterol propanediol (co-surfactant) [2:1 w/ dispersed in both compounds in 1,2- et al., 2011)
absorption) w] and oleyl lactate as oil (9:1 w/w hydrophilic propanediol + nonionic + anionic
surfactants to oil) compounds surfactant
(without water)
SMEDDS
 Atorvastatin Statin Tween1 80 (surfactant), PEG 600 I (SMEDDS) Higher bioavailability and faster (Gupta et al.,
 Ezetimibe (inhibits cholesterol up- (co-surfactant) [5:1 w/w], ethyl dispersion 2014)
take) oleate as oil (4:1 w/w surfactants to
oil)
 Lycopene Antioxidant Decylglucoside: propylene glycol I or III Additive rather than synergistic (Qu et al.,
 Ascorbic acid (protects against ly- UVB- inhibitor (1:1 w/w surfactant blend) and effect observed; monocaprylin as 2015)
copene degradation) monocaprylin as oil [50:20:30 w/w/ the oil choice increased
w surfactant:oil:water] cutaneous delivery
 Rifampicin Anti-tuberculosis Brij1 96 (surfactant), butanol (co- I Rifampicin (lipophilic) localized (Ujhelyi
 Isoniazid surfacatant), ethyl oleate as oil [1.2:2 near to oil interface; Isoniazid et al., 2015)
 Pyrazinamide oil to surfactant w/w] and pyrazinamide (hydrophilic)
near to hydrophilic interface
 Indomethacin Anti-inflammatory Tween1 80 (surfactant), ethanol (co- I Synergistic effect obtained (Shi et al.,
 Benzocaine Anesthetic surfactant), eucalyptus oil and water 2012)
[30:30:20:20 w/w, respectively]
 Evodiamine Anti-inflammatory Cremophor1 EL (emulsifier), PEG I Enhanced permeation and (Shinde et al.,
 Rutaecarpine & antinociceptive 400 (co-emulsifier) and ethyl oleate absorption when abdominally 2015)
[surfactant:co-surfactant:oil:water applied
30:15:5:50 w/w/w/w]
 Lidocaine Anesthetic Tween1 80 (surfactant), ethanol (co- I Enhanced skin permeation and (Chemelli
 Prilocaine surfactant), saturated lipids absorption et al., 2012)
1
(Labrasol and LauroglycolTM 90);
isopropyl myristate as oil; water and
API mix [30%:5%:60%:5%,
respectively]
 Betamethasone dipropionate Antiinflammatory Tween1 20 (surfactant), isopropyl I Enhanced permeation, reduced (Osmun
 Salicylic acid Keratolytic alcohol (co-surfactant); oleic acid dosage frequency, sustained drug et al., 2015)
and sefsol (1:1) as oil and water. release
[Surfactant mix (1:1): oil: water
38:15:47]
 Green tea catechins Antimicrobial Cremophor1 EL (emulsifier), I Synergistic effect against E.coli (Anonymous
 Caffeine glycerol (co-emulsifier) [6:1 w/w] Economic
and Labrasol as oil Burden of
Illness in
Canada,
2005)
 Bleomycin All Cremophor1 RH40 (surfactant): I (SMEDDS) Increased inhibitory effect on (Nousen
 Cisplatin chemotherapeutics Labrasol1 (surfactant): Transcutol1 human cervical HeLa cells et al., 2013)
 Ifosfamide HP (cosurfactant): CapryolTM90 (co-
surfactant): Isopropyl myristate (oil)
(2:2:6:1:1)
 Coix seed oil Ancillary drug for Cremophor1 RH40 (surfactant); PEG I Enhanced cytotoxicity against (Sajatovic
chemotherapeutics 400 (co-surfactant); Coix seed oil A549 cells; promoted significant et al., 2016)
to improve (oil) internalization of etoposide
undesirable
immunologic
suppression
 Etoposide Chemotherapeutic

 Huperzine A Acetylcholine Cremophor1 RH40 (surfactant), I Demonstrated slowed (Lee et al.,

esterase inhibitor for ethanol (co-surfactant), oleic acid progression of Alzheimer’s 2015)
Alzheimer’s (OA), water [12:4:1:80 w/w/w/w] disease in rats
treatment
 Ligustrazine Antioxidant

 Albendazole sulphoxide Neurocysticercosis Tween1 80 (surfactant), ethanol (co- I Enhanced intranasal delivery (Martin-
 Curcumin treatment surfactant), DHA:Capmul 1:1 (oil), when formulated with DHA Rodriguez
Antiinflammatory (docosahexaenoic acid) et al., 2015)
438 S.P. Callender et al. / International Journal of Pharmaceutics 526 (2017) 425–442
Table 2 (Continued)
APIs Function Formulation Ingredients
water [surfactant:oil:water
60:30:10 w/w/w)
 Bovine serum albumin High-molecular Pluronic F127 (surfactant);
 Cytochrome c weight model monoglyceride, polyglycerol ester,
hydrophilic proteins and tetradecane as oil mix
non-adherence. Microemulsions provide a medium in which both
hydrophilic and hydrophobic drugs may be delivered concurrently.
Though there are no publications documenting increased adher-
ence from a multi-drug, single dose microemulsion formulation, it
can be inferred that such formulations have the potential to
improve medication adherence outcomes given that adherence
decreases with increased pill burden (Pasina et al., 2014).
3.1.2. Clinical effectiveness and economic impact
According to the Public Health Agency of Canada (PHAC),
malignant neoplasms or cancer and cardiovascular disease
together account for over 50% of the mortality rate in Canada
(Anonymous Economic Burden of Illness in Canada, 2005). The
PHAC reports economic burden in terms of direct and indirect
costs. Direct costs refer to health care expenditures to improve or
prevent deterioration of health statuses such as physician care
expenditures while indirect costs refer to the dollar value as a
result of loss of productivity such as labour (Anonymous Economic
Burden of Illness in Canada, 2005). In terms of total direct and
indirect costs associated with the treatment of disease states,
neuropsychiatric diseases and cardiovascular diseases are first and
second, respectively, with over $12 B spent, nationally, on each
(Anonymous Economic Burden of Illness in Canada, 2005). Recall
that these are diseases that occur concurrently with other illnesses,
implying that total direct and indirect costs may actually be much
higher. Microemulsions are a potential solution to the treatment of
such concurrent diseases. Combinatorial treatment has been
thought to improve clinical effectiveness and this can be achieved
through the use of microemulsion delivery systems. A number of
reviews published within the last five years detail the use of
combinatorial treatment in cancer and its resulting effectiveness
(Linton et al., 2016; Fleeman et al., 2011). Several recent reviews
have also pointed out the effectiveness of combinatorial treatment
in the prevention of CVD (Yusuf et al., 2014; Lee et al., 2014; Athyros
et al., 2014). In addition, Andreazza and Young (2014) and Floyd
et al. (2013) suggest that combinatorial treatment is also effective
for neuropsychiatric conditions. Thus, microemulsions are a
potential combinatorial treatment option which may reduce the
economic burden of these diseases.
3.2. Considerations in multi-drug delivery
Delivering multiple drugs simultaneously is a challenge in
itself. The inclusion of an organic phase, aqueous phase, emulsifier,
co-surfactant along with a number of APIs of varying physical and
chemical properties only serves to further complicate this system.
There are, however, a number of primary considerations that may
be taken into account for multi-drug delivery using micro-
emulsions: (i) the overall conditions and components of the
microemulsion system, including emulsifying agents (as discussed
above) and (ii) drug–drug interactions.
3.2.1. Components of the microemulsion system
Microemulsion systems are dynamic and may vary significantly
with environmental changes. Though the HLB parameter is useful
Microemulsion Observations Ref.
Type
II Promoted sustained release (Katsareli
and
Dedoussis,
2014)
for identifying the suitability of an emulsifier for a particular
formulation, it does not account for formulation variables. Salager
et al. (1979) first linked four major formulation variables to
microemulsion type. This led to the development of the
hydrophilic-lipophilic deviation (HLD) equation which was also
based on principles from previous works including those of
Winsor. Prior to this, microemulsion formation relied on trial and
error to a greater extent. The HLD equations for non-ionic and ionic
surfactants are:
HLD = b(S)  K (EACN)  f (A) + aT DT + Cc for non-ionic surfac-
tants
HLD = ln (S)  K (EACN)  f (A) + CT DT + Cc for ionic surfactants
where S is the concentration of the surfactant in g/100 ml, EACN is
the effective alkane number of the oil used (related to lip-
ophilicity), DT is the change in temperature within the system, A
depends on the co-surfactant or alcohol added, Cc is the
characteristic curvature of the surfactant reflecting its hydrophil-
ic/lipophilic nature and b, f, f; and K are constants (Salager et al.,
2008). The HLD equation takes into account important aspects of
the microemulsion system including temperature, salinity, alcohol
addition, and lipophilicity of the oil phase. An HLD of zero
corresponds to a Type III microemulsion, a negative value
corresponds to a Type I microemulsion and a positive value
corresponds to a Type II microemulsion (Salager et al., 2008). Thus,
increasing or decreasing temperature, oil lipophilicity and other
parameters affect the type of microemulsion obtained (Salager
et al., 2008).
Though this equation is an important tool when developing
microemulsions for single drug incorporation, it is even more
essential in formulations containing multiple drugs. This is
because when more than one API is involved, temperature, salinity
and oil lipophilicity changes may have significant effects on some
but not all of the APIs. One potential solution to this problem is to
group APIs based on certain physicochemical properties and treat
this multi-API group as a single entity; however, nothing in the
literature suggests that this approach has been used to date.
3.2.2. Drug-drug and other interactions
Drug-drug interactions are an important consideration in any
formulation containing more than one API. Microemulsion
systems, however, are significantly more complex. The multi-
component, dynamic nature of these systems leads to a number of
challenges. Their oil, emulsifier and water composition means that
not only must their fluidic nature be taken into account, but also
their propensity to interact with each other and with various APIs
present in the formulation. As a result, compatibility is an
important consideration and challenge for multi-drug micro-
emulsion formulations. In addition, the possibility of compound
degradation as a result of these interactions cannot be understated.
To screen for compatibility issues, calorimetry is often
performed with various combinations of emulsifier, oil and API
(s) to determine interactions and thermodynamic energy profiles
 S.P. Callender et al. / International Journal of Pharmaceutics 526 (2017) 425–442 439

of each component. Differential Scanning Calorimetry (DSC)
(Brown and Burlett, 2011) and Isothermal Titration Calorimetry
(ITC) (Klump, 1999) are, on average, the methods of choice.
Unfortunately, these techniques (and other strategies) do not
guarantee predictability in complex formulations, where a large
number of components increases the probability for interactions to
occur.
3.3. Challenges in multi-drug delivery
Even through consideration of the many factors involved in the
formulation of microemulsion based multi-drug dosage forms,
there still remains a number of inevitable challenges:
3.3.1. Lack of understanding
Despite the advantages associated with the use of micro-
emulsion systems in the pharmaceutical industry, the major
challenge impeding their use has been and continues to be the lack
of understanding of these systems. There are approximately 1200
publications regarding microemulsion drug delivery since their
introduction in the 1940s. Despite the fact that more than one third
of these have been published within the last five years, much of this
information is on successful formulation combinations rather than
fundamental understandings of these complex systems. To combat
this, it is imperative to combine theoretical knowledge with the
practical use of various emulsifiers and solubilized APIs in the
microemulsion drug delivery arena.
3.3.2. Characterization 6¼ The full picture
Microemulsion formulation is still currently performed on a
trial and error basis, relying on characterization techniques such as
interfacial tension, droplet size, zeta potential, conductivity,
viscosity and turbidity. These characterization techniques though
not fully comprehensive, may provide the formulator with
important information about the microemulsion system.
(i) Interfacial Tension
Interfacial tension is used to evaluate the emulsifier’s ability to
reduce the tension existing at the oil and water interface. These
results are then consulted when determining whether modifica-
tions to further reduce the tension are necessary- for example, the
addition of co-surfactant. In general, regarding true microemulsion
systems, interfacial tensions are expected to be ‘ultralow’
(Tongcumpou et al., 2003). For Type III systems in particular, the
middle phase can possess interfacial tension values as low as
103 mN/m (Tongcumpou et al., 2003; Huh, 1979). However, these
values vary depending on the type of oil and surfactant used, as
well as the inclusion of co-surfactants or salt in the formulation. A
number of older publications seeking to unravel fundamental
understandings of microemulsion IFT point to a general interfacial
tension value of between 101 and 102 mN/m (Phan et al., 2011;
Fletcher, 1987; Ruckenstein, 1985; Pouchelon et al., 1981; Langevin
et al., 1986). Consequently, the spontaneous formation of a stable
micro- emulsion with drops in the observed size range (100–
1000 A) is possible only in the case of low interfacial tension, e.g.
0.1 dyn/cm” (Ostrovsky and Good, 1984).
(ii) Droplet Size
Droplet size is used as an indication of the type of emulsion
formed. As discussed above, macroemulsions usually consist of
droplets over 400 nm in diameter, nanoemulsions 100–400 nm
and microemulsions 10–100 nm. The factors influencing droplet
size have been discussed previously. However, studies attempting
to improve delivery of two famous SMEDD-incorporated drugs,
cyclosporine A (an immunosuppressant) and saquinavir (an HIV
protease inhibitor) report droplet sizes below 100 nm (Gao et al.,
1998) and at approximately 200 nm (Shah and Amiji, 2006; Dodiya
et al., 2011).
(iii) Zeta Potential
Zeta potential reflects the surface charge of emulsion droplets.
As such, it provides insight into the charge–charge interactions
that may occur between the droplets in an emulsion system, i.e.
electrostatic repulsion or attraction. As discussed previously,
electrostatic repulsion delays coalescence and flocculation and
hence, phase separation. This is why zeta potential is often looked
at as an emulsion stability indicator. A common misconception is
that zeta potential alone (and in particular, values higher than
30 mV) (Rozentur et al., 2010) indicate stability. However, a more
accurate indication of stability can be obtained from the zeta
potential of the droplets with respect to time or the zeta potential
rate (Sepeur, 2008).
(iv) Electrical Conductivity
Electrical conductivity is used to confirm the type of micro-
emulsion obtained. Water is a good conductor of ions and as such,

Microemulsion Formulation Publications by Country 2011-2016

30
Percentage of Publications

20

10

0
ch B ol sia

a
d

ew C t a

ki and

Pa orpan

Si omtug e

Ua
U ia

G hai anl

A Se taly

Paeal da

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do a c

Sl ap nia
M ng ce

R lg d
D puium

ak e
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B keyt

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I a

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n rk

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Tasra n

Soud Au any

A lovral a

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Eg SA

K
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K azi
r p

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i
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e

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Sa ermlan

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us rb
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i

a
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r
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e
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Country

Fig. 17. Microemulsion publications by country over the past five years. China and India together account for almost 50% of publications.
440 S.P. Callender et al. / International Journal of Pharmaceutics 526 (2017) 425–442
Number of Microemulsion Formulation Publications
Available on PubMed 2011-2016
30
Number of Publications
20
10
0
2011 2012 2013 2014
Year
Fig. 18. Number of microemulsion-related publications over the past five years.
There has been a steady increase in these numbers leading to the conclusion that
microemulsion systems are slowly being recognized as efficient drug delivery
vehicles.
the higher the water content, the higher the conductivity value
(Ramli et al., 2009; Kahlweit et al., 1993). Though the exact
conductivity value depends on the specific oil or surfactant used in
the microemulsion, some useful generalizations can be made. In
general, inverse microemulsions or water-in-oil types have very
low, almost zero electrical conductivity values of as low as 105–
102 Sm1 (Clausse et al., 1987) and even, as reported more
recently, 107–109 V1 cm1 (Mehta and Kaur, 2011). Oil-in-
water microemulsions may have electrical conductivity values of
102–103 higher (Clausse et al., 1987). Again, exact values depend on
the constituents. For microemulsions containing ionic surfactants,
this trend is obvious. For microemulsions containing non-ionic
surfactants, a salt such as sodium chloride must be added for
electrical conductivity (Ramli et al., 2009).
As microemulsions transition from a Type I to Type III to Type II
due to salt or temperature increases, the lipophilicity increases.
Thus, conductivity may be used to evaluate breaking points in this
transition. In this case, the formulator will be able to see a steady
decrease in conductivity with a large decrease at each breaking
point.
(v) Viscosity
Viscosity measurements may shed insight into stability of a
microemulsion system based on the diffusion constant and
droplet–droplet interactions as explained below. The viscosity of
the continuous phase is closely related to the diffusion constant of
the system (Rosen and Kunjappu, 2012). Given that the diffusion
constant, D:
D = kT/6phr
where k = the Boltzmann constant, T = temperature, h= viscosity
and r = radius of the droplets, it can be seen that viscosity is
inversely proportional to the diffusion constant (Rosen and
Kunjappu, 2012). As viscosity increases, the diffusion constant
decreases resulting in an overall decrease in the frequency of
droplet–droplet collisions that can later result in phase separation.
Hence, increased viscosity limits these collisions and increases
stability. Though exact values cannot be stated as they vary greatly
depending on the emulsion ingredients, it is well established that
as surfactant concentration increases, various micellar shapes are
obtained that result in increased overall viscosity (Kamranfar and
Jamialahmadi, 2014).
(vi) Turbidity
Turbidity is often an indication of droplet size. Larger droplet
sizes result in increased turbidity due the increased ability of these
droplets to scatter light. Though macroemulsions are often turbid
and opaque in nature, microemulsions are usually clear or slightly
turbid due to their small droplet sizes that are unable to scatter
light. There is a distinction between O/W and W/O micro-
emulsions, however. O/W microemulsions consist of oil droplets
surrounded by a surfactant film while W/O microemulsions consist
of water droplets surrounded by a surfactant film. This often leads
to O/W microemulsions having a bluish appearance rather than the
clear appearance in W/O microemulsions (Fletcher and Morris,
1995).
Despite the fact that the above techniques are well established,
and that there are some generalizations that can be made with
regard to microemulsion formation, the fact remains that these
2015 systems by nature are highly complex and dynamic. Thus, there is
no defined set of values that microemulsion formation can be held
to. As a consequence, characterization of such a system, no matter
how thorough, may never fully explain what is occurring or what
will occur over time.
3.4. Funding/dedication to research
The final major challenge lies in the lack of microemulsion
research being conducted in regions such as North America and
Europe over the past five years. Fig. 17 shows that of the over 400
microemulsion-related publications put forward in the last five
years, only 3 of those have originated from Canada. Leading the
way in microemulsion formulation publications is China with over
27% followed by India with over 21%. Together, China and India
account for almost half of all microemulsion-related publications
over the past five years. Microemulsion drug-delivery related
publications originating in Canada account for a mere 0.7%.
Given the potentially substantial economic benefits that could
be associated with microemulsion use in multi-drug delivery in
Canada, this is an area warranting greater investment and further
investigation. The future, however, looks bright, as the rate of
microemulsion-related formulations has increased steadily over
the past five years (Fig. 18).
4. Conclusions
Research into microemulsions over the past five years has
resulted in the following conclusions: (i) non ionic surfactants are
mostly preferred due to their safety profiles and uncharged nature;
(ii) oil and water (type I) microemulsions have been most
commonly used to encapsulate lipophilic drugs for oral adminis-
tration; (iii) cancer is the most common disease targeted for
treatments that use microemulsion formulations; (iv) China and
India have produced the most microemulsion-related publications
in the past five years; (v) the number of publications regarding
microemulsions has steadily increased over the past five years.
Microemulsion systems are a great pharmaceutical tool for the
delivery of formulations containing multiple hydrophilic and
hydrophobic ingredients of varying physicochemical properties,
but are still poorly understood. This review has provided
information regarding the considerations for multi-drug delivery
via microemulsion systems. Although progress in this field is slow,
a sound understanding of the emulsifier, microemulsion system,
and drug–drug interactions is crucial. Given that emulsifiers are
the heart of all microemulsion systems, there is the need for the
development of a predictive tool for microemulsion formation via
emulsifier selection.
 S.P. Callender et al. / International Journal of Pharmaceutics 526 (2017) 425–442 441

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Funding: This work was supported by MITACS Accelerate (grant Fleeman, N., Bagust, A., Boland, A., Dickson, R., Dundar, Y., Moonan, M., Oyee, J.,
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