Cavitation Technology - A Greener Processing Technique For The Generation of Pharmaceutical Nanoemulsions

Ultrasonics Sonochemistry xxx (2014) xxxxxx
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultson
Cavitation technology A greener processing technique

for the generation of pharmaceutical nanoemulsions
Manickam Sivakumar a,, Siah Ying Tang b, Khang Wei Tan c
a
Manufacturing and Industrial Processes Research Division, Faculty of Engineering, University of Nottingham Malaysia Campus, 43500 Semenyih, Selangor, Malaysia
Chemical Engineering Discipline, School of Engineering, Monash University Malaysia, Jalan Lagoon Selatan, 46150 Bandar Sunway, Selangor, Malaysia
c
Department of Chemical Engineering, UCSI University, Kuala Lumpur, Malaysia
b
a r t i c l e
i n f o
Article history:
Received 30 November 2013
Received in revised form 24 March 2014
Accepted 24 March 2014
Available online xxxx
Keywords:
Nano
Emulsion
Ultrasound
Cavitation
Pharmaceutical
Hydrodynamic
a b s t r a c t
Novel nanoemulsion-based drug delivery systems (DDS) have been proposed as alternative and effective
approach for the delivery of various types of poorly water-soluble drugs in the last decade. This nanoformulation strategy signicantly improves the cell uptake and bioavailability of numerous hydrophobic
drugs by increasing their solubility and dissolution rate, maintaining drug concentration within the therapeutic range by controlling the drug release rate, and reducing systemic side effects by targeting to specic disease site, thus offering a better patient compliance. To date, cavitation technology has emerged to
be an energy-efcient and promising technique to generate such nanoscale emulsions encapsulating a
variety of highly potent pharmaceutical agents that are water-insoluble. The micro-turbulent implosions
of cavitation bubbles tear-off primary giant oily emulsion droplets to nano-scale, spontaneously leading
to the formation of highly uniform drug contained nanodroplets. A substantial body of recent literatures
in the eld of nanoemulsions suggests that cavitation is a facile, cost-reducing yet safer generation tool,
remarkably highlighting its industrial commercial viability in the development of designing novel nanocarriers or enhancing the properties of existing pharmaceutical products. In this review, the fundamentals of nanoemulsion and the principles involved in their formation are presented. The underlying
mechanisms in the generation of pharmaceutical nanoemulsion under acoustic eld as well as the advantages of using cavitation compared to the conventional techniques are also highlighted. This review
focuses on recent nanoemulsion-based DDS development and how cavitation through ultrasound and
hydrodynamic means is useful to generate the pharmaceutical grade nanoemulsions including the complex double or submicron multiple emulsions.
2014 Elsevier B.V. All rights reserved.
1. What is nanoemulsion?
Nanoemulsions are isotropic colloidal systems composed of oil
droplets dispersed in continuous aqueous media and stabilized
by surfactant molecules. They are also frequently known as nedispersed emulsions, miniemulsions, ultrane emulsions and submicron emulsions [1]. The nanoemulsions can be in the form of
simple emulsion of oil-in-water, O/W or water-in-oil, W/O types.
Typically the particle size or the mean droplet diameter covers a
size range of 20500 nm [2]. They are a class of transparent, translucent or sometimes milky emulsion systems which cannot be
formed spontaneously as being non-equilibrium systems. Unlike
microemulsions, which are also transparent and thermodynamically stable, nanoemulsions have a higher solubilization capacity
Corresponding author. Tel.: +60 3 8924 8156; fax: +60 3 8924 8017.
E-mail address: Sivakumar.Manickam@nottingham.edu.my (M. Sivakumar).
for lipophilic drugs and better resistance toward droplet collisions

induced by Brownian motion, thus giving rise to an excellent
kinetic colloidal stability. Although they are kinetically stable,
nanoemulsions are thermodynamically unstable dispersions as
their free energy of formation is greater than that of their phase
separated state. However, due to their nanometer-sized droplets,
the long-term physical stability of nanoemulsions makes them
unique without any apparent occulation or coalescence during
storage. Therefore these tiny emulsions of nano-dimension are
sometimes referred to as approaching thermodynamic stability
[3]. In the eld of pharmaceuticals, nanoemulsion is usually a
homogeneous mixture consisting of oil droplets encapsulating bioactive ingredients that are well-dispersed in an aqueous medium
in the presence of a surfactant or emulsier. In pharmaceutical
nanoemulsions, the oil droplets serve as the reservoir for hydrophobic drugs. The most widely used oils include ax-seed oil, olive
oil, castor oil, soybean oil, and other vegetable oils that are rich in
http://dx.doi.org/10.1016/j.ultsonch.2014.03.025
1350-4177/ 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: M. Sivakumar et al., Cavitation technology A greener processing technique for the generation of pharmaceutical nanoemulsions, Ultrason. Sonochem. (2014), http://dx.doi.org/10.1016/j.ultsonch.2014.03.025
M. Sivakumar et al. / Ultrasonics Sonochemistry xxx (2014) xxxxxx
Omega-3 and Omega-6-fatty acids and contain useful vitamins and

minerals. Non-ionic surfactants are preferred since they are of low
toxicity and known to be less affected by pH and ionic strength,
and they are generally regarded as safe (GRAS) and are biocompatible. Combination of various surfactants has also been used to control droplet size and improve the stability of nanoemulsions. These
pharmaceutical nanoemulsions generally appear to be clear or
transparent with the mean droplet diameter no larger than
200 nm while some appear optically milky with the droplet size
up to 500 nm [4].
2. Why are pharmaceutical nanoemulsions?

Nanoemulsions are useful means of encapsulating, protecting
and delivering the poorly water-soluble bioactive components for
both functional food and pharmaceutical applications [5,6].
Although nanoemulsions have applications in wider technological
areas (Fig. 1), their vital importance could be felt more in the pharmaceutical eld. Admittedly, innovations in material chemistry
and nanotechnology have synergistically fuelled the development
of novel drug delivery systems and nanocarriers that are biodegradable, biocompatible, targeting and stimulus-responsive [7].
Increasing attention has been devoted to these systems due to
their unique structure and properties, such as extremely smaller
droplet size with larger surface area to volume ratio, increasing
drug solubility and dissolution rate, protecting the bioactive compounds against degradation, improving diffusion across intestinal
membrane and enhancing mucosal permeability and bioavailability [813]. Nanoemulsion formulations offer appealing alternative
for the easy administration of poorly water-soluble drugs (hydrophobic bioactive agents) with reduced dosing frequency and drug
originated systemic toxic effects and thus they could be considered
as a promising drug delivery technology. The outstanding advantages of nanoemulsions over microemulsions in the pharmaceutical
area could be mentioned in terms of enhanced drug properties
and enhanced dosing requirements as shown in the Table 1. Overall nanoemulsions represent an effective, convenient, exible formulation strategy and in fact, they are more patient compliant as
compared to other existing dosage forms which make them a
promising candidate for interesting pharmaceutical applications.
Approximately 40% of the newly discovered drugs or bioactive
agents intended for transdermal, parenteral, intravenous route or
oral ingestion are highly hydrophobic compounds with low
water solubility which reduce their dissolution-rate limited cell
absorption. The in vivo bioavailability of these drugs remains problematic due to their extremely poor solubility in the body uids,
thus greatly hinders their clinical translations. Several strategies
and formulations have been employed to overcome this limitation.
For these reasons, many of the hydrophobic drugs are frequently
formulated in the conventional dosage forms such as tablets, capsules, pellets and injectable suspensions. Despite their established
manufacturing techniques and good reproducibility, these pharmaceutical dosage forms suffer from the disadvantages of low drug
absorption rate across gastrointestinal (GI) tract due to the low
surface area, uncontrolled drug release prole due to the fast dissolution rate, non cell/tissue-specic drug delivery due to the
absence of targeting ligands, higher doses and frequent dosing
due to rapid metabolism rate of drugs in gastric uid. The gastric
uid is essentially a colorless digestive uid which is produced
from the mucous membrane of the stomach, consisting of hydrochloric acid, pepsin, rennin and mucin whereas for GI tract, it is a
9-meter long, hollow digestive tube inside the human body, starting from mouth where food enters, to the rectum and anus where
food is expelled, which is also known as alimentary canal. Nanoemulsions, on contrary, offer many crucial benets over the existing solid dosage forms. By virtue of their ne droplet diameter,
nanoemulsions provide ultra low interfacial tension and extremely
large surface area that could signicantly enhance the drug absorption in GI tract [14]. Therefore, nanoemulsion technology could
improve the therapeutic index of drugs by enhancing their efcacy
and increasing their tolerability in the human body. Nanoemulsion
could also carry large payloads (e.g. drugs, protein, peptides,
nucleic acids), protect the therapeutic agents from physiological
barriers, as well as enable the development and synthesis of novel
classes of polysaccharide nanoparticles [1517].
The efciency of drug delivery via different routes of administration is of vital importance in medicine and healthcare. Parenteral route is generally regarded as one of the major routes of
drug administration due to its quickest onset of action caused by
rapid access to blood circulation. However, it has been proven to
be a challenging task to deliver hydrophobic drugs via parenteral
route. For a majority of the existing hydrophobic drugs, solvents
such as ethanol and propylene glycol are often used to solubilize
water-insoluble drugs prior to parenteral administration [18]. Nevertheless, drug precipitation caused by co-solvent [19], severe pain
during injection and also hemolysis at injection site often occur
which strongly limits its application practically. One strategy
to tackle these problems is through intravenous fat emulsion
therapy. Commercially available intravenous fat emulsions such
Fig. 1. Applications of nanoemulsions.

Table 1
Advantages of pharmaceutical nanoemulsions.
liver and the spleen within minutes [26]. Many studies have
shown that positively charged nanoemulsions possess improved
transdermal permeation of anti-inammatory drugs over the conventional emulsions and gels due to their enhanced interaction
with negatively charged skin epithelia [27,28]. Briey, in improving therapeutic efcacy, nanotechnology based DDS (nanoemulsions/liposomes/nanoparticles) has beneted tens of millions of
patients by means of relieving the suffering and prolonging life
[7]. They have also changed the economics of drug development.
Making an existing drug into nanoemulsion-based formulations
may not only improve its performance but also extend its patent
life as a new pharmaceutical product. Not surprisingly the world
market for advanced DDS utilizing nanomaterials is expected to
reach $2.6 trillion by 2015 [29].
3 Principles of nanoemulsion formation
The dispersion of oil into water can be explained with the help
of Gibbs free energy, DG, based on thermodynamic theory as
expressed in the following Eq.(1) [1]:
as Intralipid are oil-in-water emulsion consisting of one or more

medium chain triglyceride, a phospholipid emulsier and glycerin.
The potential shortcoming of this therapy is that fat emboli may, if
coalescing of emulsion droplets occurs, be produced leading to
pulmonary embolism and potentially fatal consequences. It had
been reported that the droplets greater than 5 lm are large enough
to occlude small blood capillaries and risk of pulmonary emboli
[20]. Nanoemulsions seem to be ideal liquid vehicles for various
routes of drug delivery since they provide all the possible requirements of a therapeutic liquid system including easy formation, low
viscosity with Newtonian behavior, high drug loading and very
small droplet size [21]. For oral administration, dilution or degradation of the drug vehicle in the body uids is not desirable before
a particular site of action is reached. The delay of vehicle degradation and drug release could be achieved by using nanoemulsions as
drug vehicle. In nanoemulsion, the drug moieties are encapsulated
in the oil droplets to preserve drug activity and particle integrity,
as well as to prevent partitioning of drug from inner oil phase to
external aqueous phase during the delivery through GI tract.
Lipophilic antineoplastic agents such as paclitaxel, curcumin,
tamoxifen, and dacarbazine have been encapsulated in nanoemulsions to increase cytotoxicity and to overcome multi-drug resistance [9,12,22,23].
Nanoemulsions, on account of their higher ratio of surface
area to volume, with the intestine provide high concentration
gradient and improved pharmacokinetics and biodistribution of
therapeutic agents and thus minimize toxicity by their preferential accumulation at the target site. They improve the solubility of
hydrophobic compounds and render them suitable for oral,
parenteral, ocular and transdermal administration. Furthermore,
they increase the stability of a variety of therapeutic agents, like
peptides, and oligonucleotides. In particular, the bioavailability of
compounds encapsulated into emulsions is enhanced when
emulsion droplets are of nanometric size [24]. Pharmaceutical
scientists have shown that reducing the droplet size to values
below cell size (500 nm) produces higher absorption of the active
ingredient and higher particle uptake, by enhancing the mechanisms of passive transport through the intestinal walls [25].
Due to their extremely smaller droplet size, injectable liquid
nanoemulsions meet no difculty to pass through the biological
barrier in the blood vessel, eliminating the risk of emboli. It has
been reported that droplets smaller than 20 nm will be cleared
from circulation via reticuloendothelial system (RES) within few
hours when injected intravenously, larger ones trapped in the
DG l2 l1
where l1 and l2 are the chemical potentials of state 1 and 2. It suggests that, when DG > 0, the phase transformation is thermodynamically impossible. Whereas, when DG = 0, oil and water mixture is in
thermodynamic equilibrium. But, when DG < 0, the transformation
from heterogeneous multi-phase oil and water mixture to single
phase emulsion is possible, which is spontaneous and reversible.
When DG < 0, one bulk phase is dispersed into another bulk phase.
The congurational entropy change, DSconf can be described as
below Eq. (2) [30]:
DSconf nkB ln / f1 /=/gln 1 /
where n is the number of droplets of dispersed phase, kB is the

Boltzmann constant, and / is the dispersed phase volume fraction.
By combining the above two equations, Gibbs free energy can be
expressed as the sum of free energy (to form new interfacial area)
(DAc12) and congurational entropy as follows Eq. (3):
DG DAc12 T DSconf
From the above equation, DAc12 has to be much lower than

TDSconf in order to full DG < 0. Owing to this, surfactants are
always required to achieve an ultra-low interfacial tension,
DAc12. However, the formation of nanoemulsion is not spontaneous and requires an intensive external energy. As a result, high
energy emulsication devices such as high pressure homogenizer
or Microuidizer are always in order. The high amount of external
energy needed for the formation can be described by using the following Eq. (4),

1
1
pc
R1 R2
where p indicates the Laplace pressure, R1 and R2 are the principal

radii of curvature of the droplets and c is the interfacial tension.
Theoretically, this happens only when the subjected shear rate is
much higher than the Laplace pressure of tiny droplets. As a result,
this partly supports the existence of a surfactant, as its employment
can signicantly reduces the interfacial tension, c. Therefore, the
applied stress can be reduced and the deformation of tiny droplets
can be avoided. A parameter that has been widely used to describe
the droplet deformation is Weber number (We) which can be
expressed as below Eq. (5):
We
Gg gc R
2c
where Gg is the velocity gradient, gc is the viscosity of continuous

phase, and R is radius of curvature of the droplet. It suggests that
an increase in Weber number could increase the possibility for
the deformation of droplets and when it reaches a specic value
called as critical Weber number, the breakdown of droplets
occurs.
4. Synthesis and basic processes for the fabrication of

nanoemulsions
To synthesize nanoemulsion, it requires, in general, four components: (a) oil phase (b) water phase (c) surfactant and (d) energy.
Fig. 2 shows the components involved and their role in the generation of nanoemulsions. Nanoemulsions cannot be formed spontaneously and consequently higher energy input is required.
Although the importance and promise of this nanoscale therapeutic system have been recognized in the past decade, the preparation of extremely ne emulsions could be a key challenge, as the
pharmacological properties of nanoemulsions can be largely inuenced by the physicochemical characteristics of the droplets i.e.
droplet size, size distribution, morphology, viscosity etc. Conventionally, different homogenizing/dispersing technologies such as
simple agitation, colloidal mills, static mixers and high shear mixers have been employed and are useful to generate emulsions. As
intense shear should be applied in order to overcome the Laplace
pressure so that larger droplets are broken into smaller droplets
of nanoregime, the formation of nanoemulsion is not possible with
these conventional mixing systems. The preparation of nanoemulsions with the uniform droplet size as well as the choice of its preparation method is of crucial importance in the current
pharmaceutical industries. This is because both the physicochemical and organoleptic properties of nanoemulsions such as stability,
color, appearance, texture, and rheology are greatly affected by the
droplet size of nanoemulsions. More often than not, smaller droplet size leads to a creamier mouth feel and greater emulsion stability [31]. In general, the basic processes used to fabricate the
nanoemulsions are classied under (a) low-energy emulsication
methods that include phase inversion temperature, solvent-diffusion and spontaneous emulsication and (b) high-energy emulsication methods that require larger mechanical energy generated
by high-pressure homogenizer, ultrasonicator and Microuidizer.
Of the emulsifying methods used to design and formulate pharmaceutical naonoemulsions, the most common formulation technique
is focused on low-energy emulsication method i.e. phase inversion temperature (PIT) technique. PIT method generates chemical
potential through the use of surfactants. However, several limitations have been coupled with PIT method such as, the use of a large
quantity of surfactant, careful selection of both surfactant-cosurfactant, high polydispersity index (PDI) induced instability after
long-term storage and relatively heavy and tedious workload to
identify the system inversion temperature. In comparison, nanoemulsions prepared by ultrasonic cavitation offers a greater
improvement in terms of stability with lower Ostwald ripening
rate than the systems prepared using PIT method. The high energy
input originating from micro-turbulent implosions of cavitation
bubbles provides enormous forces that are able to deform and
break-off droplets into nanometer scale, provided the Laplace pressure is overcome. However, in order to obtain smaller droplet sizes,
higher energy input is required for further droplet break-off [32]. It
was found that the droplet sizes of ultrasonically-induced nanoemulsions are much smaller with superior physical stability than
the dispersion systems prepared by homogenizer [33]. Although
nanoemulsions with much smaller droplet sizes can be produced
by applying Microuidizer, a comparative study revealed that
microuidization is not convenient as compared to using an
ultrasound probe sonicator. The latter uses a probe and is much

easier to clean and is free of line blockage whereas for Microuidizer, the contamination of materials still remains a main issue [34].
Furthermore, they are also less viable with respect to production
and maintenance costs. Besides, most of the conventionally
employed technologies are less energy intensive as only a small
part of the applied energy is effective for the droplet break-off
[35]. All these facts continue to make ultrasonic cavitation the
most effective and promising method in the preparation of
pharmaceutical nanoemulsions.
5. Why ultrasonic cavitation in the generation of

nanoemulsions?
Introducing a large amount of mechanical energy is essential to
produce ne emulsion droplets. In general, the mechanical mixing
could be achieved by using inline rotor/stator mixers, colloid mills
and high pressure homogenizers, etc. However, most of the traditional methods usually fail to provide a satisfactory control over
the particle size distribution and often result in poor dispersion
stability. Compared to mechanical agitation, high intensity ultrasound offers a better alternative yet energy efcient technique in
the generation of nanoemulsions. Ultrasound cavitation is dened
as a combined phenomenon of bubble formation, growth and
implosive collapse of the bubbles in a liquid medium. A transient
collapse of bubbles initiated by compressed air generates localized
hot spots with the temperatures up to 5000 K, pressure of approximately 1000 bar and heating/cooling rates above 1010 K/s [36].
Ultrasound emulsication was rst reported in 1927 by Wood
and Loomis [37], yet the rst patent was only granted in 1944
[38]. Li and Fogler [39,40] proposed two-stage ultrasound emulsication mechanism (Fig. 3). First stage is the generation of primary
droplets, where the acoustic eld produces the interfacial waves,
the instability of which causes eruption of oil phase into water in
the form of droplets. Second stage involves the break-up of primary droplets where the acoustic cavitation causes localized
intense turbulence and shear forces that produces violently and
asymmetrically imploding bubbles and causes microjets which
effectively further breaking the primary droplets of dispersed oil
generated in the rst stage into droplets of nanometric-sized. The
rst stage of break-up of droplets is primarily controlled by the
type and amount of shear applied to droplets. Resistance of droplets to deformation is determined by the surfactant. In the second
stage (coalescence of droplets) where the rate at which the surfactant is adsorbed into the newly formed droplets is controlled by
the surfactant surface activity and its concentration. Thus, selection of appropriate surfactant is of paramount importance in producing nanoemulsions with high stablity. HLB (HydrophilicLipophilic balance) serves as an useful parameter in the selection
of surfactant. HLB is an empirical expression to indicate which surfactant is hydrophilic or hydrophobic. The lower the HLB value the
more lipophilic or oil soluble the surfactant is. The higher the HLB
value, the more hydrophilic or water soluble the surfactant is. In
general, surfactants with a HLB range of 27 are used for the formation of water-in-oil emulsion systems, whereas in producing
oil-in-water emulsions, surfactants with a HLB range of 816 is
preferred.
Many studies have revealed that ultrasonic emulsication could
serve as a feasible and energy efcient tool in the generation of
pharmaceutical grade nanoemulsions. For instance, parenteral
nanoemulsions had been successfully produced by Wulff-Prez
et al. via low frequency ultrasound (20 kHz) using three different
types of natural oils: olive, sesame and soybean oils [41]. The
resulting mean droplet diameters for olive, sesame and soybean
oil nanoemulsions were found to be 379 nm, 368 nm and 380 nm
Fig. 2. Components and their role in the formation of nanoemulsions.
respectively. Stability of droplets against coalescence was conrmed using Turbiscan MA 2000 even with a relatively small
amount of surfactant (7.8 1043.1 103 mol/L) and with volumes of oil phase as high as 25% (v/v). In a comparative study with
a Microuidizer, Kentish et al. proved that nanoemulsions with the
mean droplet size as low as 135 nm could be achieved by using a
ow-through ultrasonic cell (2024 kHz) [35]. The obtained droplet sizes are comparable to those for nanoemulsions prepared
using a Microuidizer operated at 100 MPa. With ultrasonic cavitation, Abismail et al. successfully prepared nanoemulsion in a
water/kerosene/Tween 60 model system having droplets with
the average size no larger than 300 nm [33]. They suggested that
ultimate droplet size of nanoemulsion was greatly inuenced by
the time of emulsication, concentration of emulsier, ultrasonic
power and volume of oil fraction when low frequency ultrasound
(20 kHz, 130 W) was applied. Their results showed that the desirable nanoemulsion could be obtained with 30 s of emulsication
time, with 6% oil fraction and 10 g/L of Tween 60. Another study
conducted by Abismail et al. demonstrated that ultrasound was
more efcient and superior than rotorstator systems in terms of
producing ner emulsion droplets [42]. Similarly, Behrend et al.
applied ultrasonic waves to an emulsion system consisting of
water/vegetable oil/sodium dodecyl sulfate and successfully produced nanodroplets with minimum sizes of below 200 nm in the
presence of glycerine or polyethylene glycol as stabilizers [43].
Recently, novel dextrin nanoparticles had been successfully developed by Manchun et al. from nanoemulsion templates utilizing a
high power ultrasonicator [15]. Where, nanoemulsions with droplet sizes of about 200 nm were achieved using mixed surfactants
(Span 80/Tween 80) at HLB 6 after subjecting to sonication for
30 min. The nal droplet size of nanoemulsion templates was
found to decrease with increasing emulsication time, surfactant
concentration, and water content. On the other hand, a topical
nanoemulsion encapsulating eucalyptus oil has also been designed
and reported recently [44]. It has been observed that the transparency and stability of nanoemulsion were enhanced with sonication
time as compared to the emulsion generated using hand blender.
The most stable nanoemulsion with the mean droplet diameter
of 3.8 nm was obtained after 30 min of ultrasonication.
Many authors have reported that in the emulsication process
ultrasound has emerged as an excellent yet powerful emulsifying
tool as compared to that of other mechanical alternatives in terms
of obtaining a smaller droplet size and high energy efciency
[3,33,35]. Additionally, under the same conditions, in case of
producing a nanoemulsion with desired diameter, the required

amount of surfactant was signicantly reduced; the energy consumption was considerably lowered than other classical mechanical devices. It would then appear that ultrasound emulsication
may be used in place of high-pressure homogenization and microuidization as it is capable of achieving similar local power densities with lower operating costs, if a suitable treatment chamber is
used. However, it is worth mentioned here that the nal droplet
size distribution of a nanoemulsion is mainly controlled by the rate
between two opposing processes; droplet break-up and droplet recoalescence [45]. Studies of the effect of ultrasonic operating
parameters and the nanoemulsion composition on the droplet
break-up and coalescence are particularly important in obtaining
smaller nano-sized emulsion droplets with narrower distribution.
The balance between these two dominant processes strongly
depends on the energy input during emulsication and the geometry of design of the ultrasound emulsication device. For this reason, several ultrasonic parameters such as irradiation power,
irradiation time, volume ratio of phases, surfactant concentration,
viscosity, liquid purity, gas content, position of the ultrasonic
source with respect to the liquidliquid interface, tip diameter
and vessel geometry must be properly controlled and optimized,
so that the effectiveness of ultrasound-engineered nanoemulsions
and their physiochemical properties could be guaranteed [46].
6. Examples of pharmaceutical nanoemulsions generated using

ultrasonic cavitation
In general, especially in the pharmaceutical and cosmetic industries, emulsions with mean droplet size of less than 1 lm are
essential in order to impart an enhanced bioavailability, as well
as high physical stability of the emulsion [47]. However, an efcient approach to produce such nanocarriers still remains ambiguous in the last two decades. To date, self-nanoemulsifying drug
delivery systems (SNEDDS) have been emerged to be one of the
most promising approaches to provide the transient formation of
hydrophobic drug encapsulated nanoemulsions. Several successful
cases had been reported such as Cefpodoxime proxetil [48], Ibuprofen [49], Ramipril [50], CoQ10 [51], Oridonin [52], b-lactamase
[53], etc. However, a higher concentration of surfactant was always
required (normally in the range of 2050%), and this may lead to an
increased incidence of unwanted side-effects in the gastrointestinal (GI) tract. A transient formation of nanoemulsion without
Fig. 3. Two-stage ultrasound emulsication: droplet formation and break-up.
introducing surplus stabilizer to the drug capsule could be easily

achieved using ultrasonic transducer [35,54]. In fact, the development of such energy-intensive techniques for the preparation of
pharmaceutical grade nanoemulsions is a much more recent phenomenon [2,14,5558].
Li et al. had successfully produced two types of Bufadienolidesloaded nanoemulsions which were separately prepared by ultrasonication at an intensity of 40 W at 40 C for 60 min via a high
intensity ultrasonic processor [58]. The mean diameter, PDI and
zeta potential of both the Bufadienolides-loaded nanoemulsions
were 43.5 nm versus 161.4 nm, 0.100 versus 0.143 and 19.7 to
26.2 mV versus 29.4 to 35.3 mV, respectively. The study
showed that both the lyophilized nanoemulsions were stable over
a period of up to 3 months with no change in the appearance,
reconstitution ability, particle size, drug concentration and entrapment efciency when maltose (20%) and trehalose (20%) were used
as cryoprotectants. Using combined technique of solvent diffusion
with ultrasonication, Araujo et al. successfully achieved a novel
cationic nanoemulsion formulation containing 2-(butylamino)-1phenyl-1-ethane thiosulfuric acid (BphEA), a schistosomicidal
agent [59]. The cationic nanoemulsion was formulated with a combination of surfactants where the emulsion was generated by
slowly adding the organic phase to the aqueous phase under magnetic stirring at 150 rpm for 30 min at 25 C. The formation of
coarse oil-in-water emulsion occurred via diffusion of the organic
solvent into external phase and the solvent was then evaporated
under reduced pressure at the end of the process. The nal step
was accomplished by the size reduction using an ultrasonic processor with a tapered microtip probe of 1/8 (3 mm) diameter. This
combined approach had effectively rendered the emulsion to be
homogenous with a smaller droplet size in the nanometric range
around 225 nm with the PDI of 0.294. In vitro schistosomiasis study
showed that Schistosoma mansoni worms incubated with nanoformulation (3 h) could gradually reduce their activity, and all female
worms were died after 48 h of incubation with the formulation.
Table 2 shows the details of representative nanoemulsions of
water-insoluble drugs that have been generated by ultrasonication.
By employing ultrasound probe sonicator alone, Doh et al. had
successfully developed a novel oral lipid nanoemulsion system
containing Granisetron, an antiemetic drug and the mean diameters of ultrasonically-induced nanoemulsion were around 50 nm
with the PDI less than 0.2 [14]. The resulting nanoemulsion exhibited a higher drug dissolution prole and in vitro drug permeation
rate compared to Granisetron powder. For topical applications,
Kong et al. had successfully fabricated a new hyaluronic acid
(HA) based nanoemulsions with higher degree of substitution
using combined solvent evaporation and ultrasonic cavitation
approach [2]. The acoustically-formed HA nanoemulsions showed
smaller droplet sizes of approximately 50 nm. The size distribution
and morphology qualities of obtained nanoemulsions were found
to be signicantly improved to be more uniform and the droplet

occulation was also alleviated with the addition of Ca2+ as a crosslinker. In addition, the highest encapsulation efciency of about
94% was achieved by using an ultrasonic probe. It is worth mentioned here that without using any chemical enhancer, ultrasound-engineered HA nanoemulsion showed desirable skin
permeability with no irritation in dermis compared with the control group, suggesting that it could be a potential colloidal transdermal carrier for the targeted delivery of active lipophilic drugs.
An O/W nanoemulsion had also been formulated and characterized
by Sandig et al. for the percutaneous delivery of Imipiramine and
Doxepin [27]. The mean droplet size of Imipramine loaded nanoemulsion was 17.8 nm, and for Doxepine loaded nanoemulsion it
was 19.9 nm. It was found that the average droplet size was
slightly but not signicantly decreased after loading the drug.
PDI values were observed to be 0.216 for Imipramine nanoemulsion and 0.133 for Doxepine nanoemulsion. The stability test
showed that both the nanoemulsions had an excellent physical stability with no phase separation, creaming, cracking or precipitation
being observed upon centrifugation. More importantly, the in vivo
analgesic and antiallodynic active ex vivo studies suggested that
topically applied Imipramine and Doxepin loaded nanoemulsions
were safe and an alternative analgesic therapy. Sood et al. suggested that an anionic surfactant could provide an electrostatic
barrier on the droplets surface against coagulation, and also retards
molecular diffusion of monomer from the particle surface, thereby
lowering down the effect of Ostwald ripening [45]. Wulff-Perez
et al. reported that the concentration of surfactant in the formulation could be further reduced at the expense of an increased ultrasonic power [41]. Interestingly, a reversible destabilization was
observed when higher amount of surfactant was employed. In
some of the cases, phase diagram has been used as a useful schematic guideline as it provides the most straightforward solution
to identify the minimum surfactant needed to form a nanoemulsion with desirable droplet sizes [60,61].
Besides, a novel nanoemulsion encapsulating the natural avonoid has been recently reported by Ragelle et al. [57]. They have
successfully formulated a nanoemulsion of Fisetin with high loading capacity (5 mg/ml with the use of combined surfactants, Tween
80 and Labrasol). Where, after subjecting to ultrasound and subsequent ltration, the nanoemulsion possessed an oil droplet diameter of 153 nm, a negative zeta potential of 28.4 mV and a PDI of
0.129. The dispersion was stable at 4 C for 30 days. Interestingly,
when the Fisetin nanoemulsion was administered intraperitoneally, a 24-fold increase in Fisetin relative bioavailability was noted
as compared to free Fisetin. Additionally, the antitumour activity of
Fisetin nanoemulsion in Lewis lung carcinoma bearing mice
occurred at lower doses (36.6 mg/kg) compared to free Fisetin
(223 mg/kg). A similar nding has been reported by Gao et al.
[56] who have performed a modied emulsication solvent
evaporation to produce a Candesartan cilexetil-loaded nanoemulsion to improve the oral bioavailability of this inactive racemic prodrug. The ultrasound prepared ne emulsion was nanometer-sized
(35.5 nm) with the negative zeta potential. It was found that the
absorption of nanoemulsion containing Candesartan cilexetil was
signicantly improved as compared to free dug solution. In particular, the area under concentrationtime curve (AUC0 ? t) of Candesartan was improved over 10-fold with the oral administration of
formulated nanoemulsion. Exciting advances in nanoemulsionbased technology have been witnessed by Shiraishi et al., where
they have successfully designed a novel nano-sized emulsion containing Peruoropentane (PFC5) in a diameter range of 200 nm by
using a bath-type sonicator [55]. Additionally, the PFC5 nanoemulsions were prepared in high yield at 40 C, which is higher than the
boiling temperature of PFC5. This ultrasonically prepared nanoemulsion was delivered into tumor tissue which was transformed
into a micron-sized bubble upon ultrasound irradiation through
the phase transition of PFC5. This very facile preparation method
using ultrasound offers immediate and realistic potential for a
large-scale production of this pharmaceutically valuable nanoemulsion for efcient theranostics of solid tumors.
7. Nanoemulsions from our sonochemical engineering
laboratory
The aim of a good nanoemulsion should be towards high loaded
drug capacity stabilized with a very low concentration of surfactant with high homogeneity and excellent stability over long-term
storage. In our laboratory, we have successfully generated a variety
of nanoemulsions encapsulated with pharmaceutically active
ingredients such as ganoderic acid, curcumin, and aspirin using
cavitation.
7.1. Nanoemulsions encapsulated with ganoderic acid
Ganoderic acid (GA), a major bioactive ingredient isolated from
oriental medicinal mushroom ganoderma tsugae, has been found to
have signicant benecial effects either in the prevention or in the
treatment of a variety of diseases such as hepatitis B, hypertension,
AIDS, and cancers. However, the insolubility of GA in water poses
difculty in the formulation and in oral administration. The limitations of exisiting approach via reverse microemulsion process
often involves the addition of a toxic solvent (e.g. hexane or chloroform), and results in a lower product yield. To overcome this, we
have successfully encapsulated crude ganoderic acids by means of
nanoemulsication using ultrasound cavitation [62,63]. By taking
advantage of the surfactants chemical potential at oilwater interface, the free energy required to full the entropy of micelles formation (S) had been minimized, which subsequently led to
shorter emulsication time needed to generate the nanometricsized emulsion. The resultant formulations consisting of water,
surfactants and ganoderic acid solution were subjected to 5, 10,
20, 30 and 60 min of ultrasonication in an ultrasonic bath at room
temperature. In our studies, only 5 min of sonication time was
required to form tiny droplets and the generation of minimum
droplet sizes had been conrmed though DLS particle size analysis.
The resultant nanodispersions containing ganoderic acid in the
hydrophobic oil core were found to have a mean droplet no larger
than 200 nm. An increase in the time of ultrasound did not have a
signicant inuence on the size reduction of droplets. This may
represent the limiting value for the minimum droplet size for these
nanoemulsions. However, a slightly narrower particle size distribution was observed, as the PDI of droplets decreased from 0.187
to 0.158 after 5 min of ultrasonication. In general, under a given
set of emulsication conditions at xed emulsion composition,
there exists a minimum emulsion droplet size which cannot be

reduced with repeated or prolonged ultrasound treatment time,
and therefore any longer application of ultrasound for the emulsication did not lead to any further reduction in the droplet size. It
should however be noted that the ultimate or minimum droplet
diameter is also the function of the physical and interfacial properties of the oil phase and the emulsier present in the emulsion system. Ganta et al. observed a similar trend and reported that after
reaching a critical droplet size, extending the ultrasonication further did not reduce the size of emulsion droplets [64].
7.2. Nanoemulsions encapsulated with curcumin
Curcumin, a yellow pigment extracted from curcuma longa dried
rhizome, has been reported to have signicant pharmaceutical
activities such as anti-cancer, anti-carcinogenic, anti-inammatory
and anti-oxidant properties [65]. However, the bioavailability of
curcumin after administration is intrinsically low due to its extremely low water solubility. In order to improve the absorption rates
of curcumin in vivo, attempts to incorporate curcumin into the
nanoemulsion systems have been made. The formation of curcumin-loaded nanoemulsions has been achieved using an ultrasonic
bath (38 kHz) [63]. Colloidal stability of the resulting formulations
has been measured in terms of particle size distribution and PDI.
The mean droplet diameters and PDI of the nanoformulations were
approximately 120 nm and 0.35 respectively. MTS assay test shows
encouraging inhibition activity levels on MCF-7 human breast adenocarcinoma cell lines after administration of 20 ll of curcumin
nanoformulation. Approximately 68% inhibition has been recorded
in the cultured cell line after an incubation period of 3 days with
the drug formulation.
Fig. 4 shows the SEM images of unhomogenized curcumin oily
droplets in water prior to ultrasound treatment. Figs. 5 and 6 illustrate the SEM images of generated curcumin nanoemulsions after
subjected to ultrasonic cavitation. The microscopic results show
that with merely 5 min of ultrasonication, curcumin-loaded nanoemulsions were produced. Effect of ultrasonication time i.e. 5, 10,
20 and 30 min on the droplet size of nanoemulsion has been investigated. The study suggests that the mean droplet diameter of
nanoemulsions readily decreased with an increase in the duration
of sonication, and a more uniform particle size distribution could
be obtained. It is also interesting to note that the rate of size reduction was not affected by the weight percentage of isopropyl palmitate which acts as an organic oil phase.
7.3. Nanoemulsions of O/W and multiple W/O/W encapsulated with
aspirin
Aspirin (acetylsalicylic acid) is a well-known non-steroidal antiinammatory drug (NSAID) widely used for its anti-inammatory,
anti-pyretic, analgesic, and platelet anti-aggregation properties.
Although adequate inammation and pain relief could be achieved
with the currently available aspirin dosage forms such as tablets or
capsules, some of their serious side effects in the GI, kidney and
platelets are major limitations to their routine use in therapy.
Due to the small droplet size, nanoemulsions are expected to afford
an efcient delivery of therapeutic agents to target sites in the
body and increase the oral bioavailability. On the other hand, the
development of complex multiple nanoemulsion system is aimed
to facilitate a sustained release and transport of entrapped active
aspirin drug, thereby reducing transient drug overload and severity
of drug-related gastrointestinal adverse effects. Hence, incorporating aspirin in the core nanoemulsion and multiple nanoemulsion
formulations could be useful in the treatment of inammation
and pain. Most importantly, both nanoformulations would be efcient, convenient, exible and more patient compliant approaches
Table 2
Representative nanoemulsions of water-insoluble drugs that are generated by ultrasonication.
Drug and route of
administration
Dosage
Oil
Surfactant
Co-surfactant/ solvent
Indication
Mean
droplet
diameter
(nm)
Stability
References
Saquinavir (SQV) (oral)
400 lg/
ml
Flaxseed oil
Lipoid E80
Deoxycholic acid
HIV/AIDS
218.0 13.9
[13]
Bufadienolides (mBU)
(i.v.)
0.28 mg/
ml
Soybean oil
Lipoid E80,
pluronic F68,
Tween 80
Egg lecithin
Sodium oleate, glycerine
Antitumor
analgesic
43.5 13.8
2 months (stored at
4 C in the dark
place)
3 months (stored in
a dessicator with
silica-gel at 25 C)
Stearylamine,
deoxycholic acid
Pluronic F68,
hydroxypropyl-bcyclodextrin,
polyvinylpyrrolidone K25
Ethanol, glycerol
Anticancer
90120
Antiemetic
50
3 months (stored at
4 C in the dark
place)
[14]
Schistosomiasis
225.8 32.1
3 months (stored at
4 C in the dark
place)
[59]
Analgesic antiallodynic
1820
3 months (stored at
room temperature)
[27]
Antitumor
153 2
1 month (stored at
4 C in the dark
place)
[57]
Paclitaxel (oral)
Pine nut oil
Granisetron (GRN)(oral)
0.4 mg/
ml
Isopropyl
myristate,
lauroglycol
90
Medium
chain
triglyceride
2-(Butylamino)-1 phenyl-1ethanethiosulfuric
acid (BphEA) (i.n.)
Imipramine /doxepin
(topical)
10 mg
3% w/w
D-limonene
Fisetin (i.p)
36.6 mg/
kg
Miglyol 812
Lipoid E80
Tween 80,
Span 80,
stearylamine
Labrasol,
plurol
oleique
Tween 80,
labrasol
Propylene glycol,
transcutol, oleic acid,
isostearyl isostearate
Lipoid E80
in comparison to the conventional drug tablets and capsules. Generation of novel nanoemulsions and multiple nanoemulsions containing aspirin using ultrasonic cavitation approach has been
presented [46]. For the former, response surface methodology
(RSM) has been adopted to produce an optimal cremophore-EL
based oil-in-water (O/W) nanoemulsion with the desired droplet
size and PDI [66,67]. As to the generation of new water-in-oil-inwater (W/O/W) multiple nanoemulsion, a modied two-step cavitational emulsication technique has been employed [68]. Besides,
the impact of gelling and osmotic pressure in the stabilization of
highly stable single core water-in-oil-in-water (W/O/W) multiple
nanoemulsions of aspirin through this two-stage ultrasonic assistance has also been studied [69].
Fig. 7 shows the microscopic observations of aspirin nanoemulsions and reveals that the droplets were almost spherical in shape
by the employed three different processes. More interestingly, it
shows that the nanoemulsion generated by ultrasonic probe sonicator exhibited superior homogeneity with its nanosized oil droplets, as compared to other emulsions prepared by both the
magnetic stirrer and high-speed homogenizer (Ultra-Turrax T18,
IKA, Labortechnik, Germany). In addition to this, the oil droplets
of ultrasonic-treated emulsion were all nely dispersed in the
water medium in a more uniform manner relative to the emulsion
prepared by homogenizer. The result is in line with dynamic light
scattering (DLS) particle size analysis, showing that the aspirin
emulsion droplets are present in the nanometer scale (ranging
around 200 nm) (Table 3).
Fig. 8(AD) images reveal that aspirin-containing nanoemulsion
droplets were almost spherical in shape with homogenous nanometric size distribution. The STEM measured droplet size corroborates with the results obtained from the droplet size analysis using
Zetasizer, showing that emulsion droplets are present in the nanometer range, varying from about 200 to 300 nm. Furthermore,
there is no signicant difference in terms of droplet size between
aspirin-containing nanoemulsion and the free formulation without
aspirin (control) (Fig. 8C). No change in the droplet size due to occulation, coalescence, and drug degradation was observed over a
[58]
[23]
storage period of 15 days (Fig. 8D). It clearly shows that the incorporation of drug into oily core phase has no signicant inuence on
the droplet size and the stability of formulated nanoemulsion.
The performance of industrial scale high intensity ultrasound in
the generation of nanoemulsion has been compared with a benchtop Microuidizer. In this study, for both of these techniques, the
importance of pre-homogenization on the resultant characteristics
of nanoemulsions has been studied [70]. With the pre-homogenized emulsion feed, the morphology from the images revealed
that all the nanoemulsions containing aspirin produced by ultrasonic processor and Microuidizer were comprised of spherical
droplets and almost of uniform size (Fig. 9C and D). In comparison
with the emulsion generated by ultrasound or Microuidizer in the
absence of pre-homogenization (Fig. 9A and B), it could be seen
that there is a variation in the size distribution which was considerably reduced with pre-homogenized emulsion feed. The droplet
size measurements by SEM indicated that the oil droplets in the
aspirin-loaded nanoemulsions were primarily between 200 and
250 nm in diameter, which is in agreement with the DLS particle
size analysis. In contrast, much larger droplets were observed in
both the non pre-homogenized/coarse emulsions treated by high
power ultrasound and Microuidizer where the measured droplet
diameters ranging from 300 to 450 nm (Fig. 9A and B). However, in
non pre-homogenized nanoemulsions, they appeared to be
clumped together in clusters (Fig. 9B and C), with few groups of
densely populated oil droplets. It has been observed that to achieve
a similar droplet size of 160 nm, ultrasound (60% amplitude, 12.5 J/
cm3) is 18 times more energy efcient than a Microuidizer
(200 bar, 226 J/cm3). STEM images of the ultrasonically-induced
and microuidized nanoemulsions using standard negative-staining procedure have been shown in Fig. 9AD.
Besides, the anti-inammatory activities of acoustically formed
nanoemulsion were determined using the k-carrageenan-induced
paw edema model. The analgesic activities of both the nanoformulations were determined using acetic acid induced writhing
response and hot plate assay. For comparison, the effect of
pretreatment with blank nanoemulsion and reference aspirin
Fig. 4. Unhomogenized curcumin emulsion droplets prior to ultrasonication.
Fig. 5. (Left) Curcumin nanodroplets in ethanolic solution (micellar solution) prepared by ultrsonication with surfactant concentration of 0.2 wt%. (Right) Curcumin coarse
emulsion droplets using isopropyl palmitate (IPP) as an organic oil phase.
Fig. 6. Scanning transmission electron microscopy (STEM) images of curcumin nanoemulsions obtained after 5 min of ultrasonication.
suspension were also studied for their anti-inammatory and

antinociceptive activities. The results showed that oral administration of nanoemulsion containing aspirin (60 mg/kg) signicantly
reduced paw edema induced by k-carrageenan injection [71].
Nanoformulations decreased the number of abdominal constriction in acetic acid induced writhing model. Pretreatment with
nanoformulations led to a signicant increase in reaction time in
the hot plate assay. Nanoemulsion demonstrated an enhanced
anti-inammatory and analgesic effects compared to reference

suspension. These experimental studies suggest that nanoemulsion produced a pronounced anti-inammatory and analgesic
effect in rats and may be candidates as new nanocarriers for pharmacological NSAIDs in the treatment of inammatory disorders
and alleviating pains. Briey, the aspirin-loaded nanoemulsion
exhibits enhanced anti-inammatory and analgesic properties
while multiple nanoemulsion demonstrated mild or sustained
10
Fig. 7. Microscopic views (200) of emulsions obtained through three different methods (after 2-weeks of storage): (A) magnetic stirring (7 h); (B) high-speed
homogenization (5 min at 13,500 rpm); (C) ultrasonic emulsication (1 min using 25% amplitude).
Table 3
Comparison of droplet size of emulsions of aspirin produced by three different methods.
Emulsion preparation method
Magnetic stirring
High-speed homogenization
Ultrasonic emulsication
Droplet size (d.nm)

Polydispersity index (PDI)
1160
0.971
359
0.379
232
0.309
anti-inammatory and analgesic activities. Fig. 10 shows the overall anti-inammatory and analgesic activity rank among the aspirin formulations.
7.4. Submicron multiple emulsion encapsulated with ferrous fumarate
Ferrous fumarate, [C4H2FeO4] is widely used in the effective
treatment and prevention of iron deciency anemia (IDA), but its
administration has been oftentimes linked with quite a few side

effects than ferric products. For this reason, multiple or double
emulsion of water-in-oil-in-water (W/O/W) type formulation had
been proposed as an alternative drug delivery system to reduce
the transient drug overload and to overcome drug-related side
effects caused by daily iron supplementation as well as masking
the unpleasant taste of the iron supplements. However, the
production of multiple emulsions with controlled droplet sizes
Fig. 8. Scanning transmission electron microscopy (STEM) images of aspirin-containing nanoemulsion (A) 5000 (B) 10,000 (C) blank and (D) aspirin-containing
nanoemulsions prepared via ultrasonication after 15-days of storage at room temperature (30,000).
11
Fig. 9. Scanning transmission electron microscopy (STEM) images of formulation of aspirin-containing nanoemulsions prepared by (A) ultrasound, and (B) Microuidizer,
with coarse emulsion feed (20,000) (C) ultrasound and (D) Microuidizer, with pre-homogenized emulsion feed (50,000).
Overall Anti-inflammatory and Analgesic Activity Rank

Nanoemulsion
Drug Suspension
Multiple
Nanoemulsion
Blank
Nanoemulsion
Decreasing Activity Order
Fig. 10. Overall anti-inammatory and analgesic activity rank of aspirin formulations.
Large amount of
surfactant
Broad size
Less stable
High
manufacturing &
maintenance cost
Less homogenous
Less Stable
Phase
Invesion
Two-step
Membrane
Microchannel
High
manufacturing &
maintenance cost
Fig. 11. Preparative methods of multiple emulsions with their characteristics.
12
and internal structures could be a major challenge and there have

been intensive studies of emulsication techniques for producing
uniform and stable multiple emulsion droplets in the past decade
[7275]. Recently, a major breakthrough that has been achieved
is the controlled preparation of ne and monodispersed multiple
emulsions by various microstructured processing techniques, such
as microchannel and membrane emulsication but only on the
smaller scale of product throughput. Fig. 11 shows the conventional preparative methods that are employed in the generation
of multiple emulsions with their characteristics.
We have employed a novel yet alternative strategy of hydrodynamic cavitation reactor of liquid whistle type, called Sonolator, for
the generation of stable and highly monodispersed submicron
multiple emulsions (600 nm) with the droplet size distribution
(PDI) in the range of 0.350.40 containing pharmaceutical grade
ferrous fumarate via a two-stage method of droplet formation
[76]. The inuence of variation in the operating conditions of such
unique liquid whistle hydrodynamic cavitation based reactor
(LWHCR) on the generation of submicron multiple emulsions has
been investigated. An increase in the number of passes has been
proved to be capable of producing smaller and stable W/O/W submicron multiple emulsions with the narrow droplet size distribution. Although an increase in the inlet pressure and number of
emulsication passes led to enhanced stability of the W/O/W multiple emulsion, but, extreme pressure was not recommended for
preparing W/O/W submicron multiple emulsions in the second
stage since the intense cavitational bubble collapse could promote
the rupture of internal aqueous droplets, which subsequently led
to the loss of inner water phase encapsulating the active pharmaceutical or nutraceutical ingredients.
Unlike primary W/O emulsion, an excess or intense cavitational
forces caused by high pressure and uid acceleration can lead to
the eventual rupture of the oil lm separating the internal droplets
and the outer continuous phase in the multiple emulsion preparation. For this reason during the secondary emulsication, the
LWHCR was operated at three very low inlet pressures: 100, 160
and 200 psi. The resultant primary W/O coarse emulsion and secondary W/O/W multiple submicron emulsion containing ferrous
fumarate have been shown in Fig. 12.
The microscopic results demonstrated that variation in the multiple globule size distribution is greatly reduced when the
operating pressures were increased from 100 to 200 psi, indicating
an improved homogeneity of the ne dispersion. Selection of an

optimum set of operating parameters including operating pressure,
number of treatment passes, temperature of the continuous phase
and the distance between the blade and orice is essential to
achieve maximum benets in the emulsication process. Thus,
LWHCR is an important technological key for large-scale production of these medicinally valuable multiple emulsions.
7.5. Nanoemulsion encapsulated with curcumin using LWHCR
Besides ferrous fumarate, the encapsulation of curcumin in a
palm oil-based nanoemulsion has been achieved by employing
LWHCR [77]. At rst, the effect of premixing on the size of
generated droplets was also investigated using a high-speed
homogenizer. Different orice plate-blade distances i.e. 0.5 cm,
0.6 cm and 0.8 cm for each of the inlet operating pressures i.e.
400, 600 and 800 psi have been considered. It has been reported
that for the orice plate-blade distance of 0.5 cm at 800 psi, the
lowest droplet size of 415 nm with a PDI of 0.5 was observed.
Effect of co-surfactant, Span 80 on the generation of nanoemulsions was also examined and it has been observed that its
addition did not have any inuence on the nal droplet size.
Finally, the nanoencapsulation of curcumin and its efciency
were studied using the optimized conditions of nanoemulsion
generation. The nanoencapsulation efciency of curcumin was
found to be 88%, indicating the superiority of LWHCR. The stability studies conrmed that the particle size was found to be
decreasing from 740 nm to 560 nm for Span 80 nanoemulsions
and from 708 nm to 532 nm for curcumin based nanoemulsions
over a storage period of 30 days.
8. Future works
Following our investigations as described above, three main
potential research areas need to be explored for future works in
the formulation development and evaluation of the new nano/multiple emulsion-based drug delivery systems using cavitation
approach. (1) Kinetic modelling of in vitro drug release proles of
O/W nanoemulsion and W/O/W multiple nanoemulsions generated using ultrasonic cavitation: aspirin nanoemulsion and its
multiple nanoemulsion intended for oral administration have been
Fig. 12. Primary W/O coarse emulsion (A) and secondary W/O/W submicron multiple emulsion (B) containing ferrous fumarate produced by LWHCR technology.
developed using ultrasonic cavitation approach. Besides, the antiinammatory and analgesic activities of both the nanoformulations have been evaluated and compared to the control. However,
the release mechanisms and drug release kinetics from both nanoemulsion and multiple nanoemulsion have not yet been explored.
Thus, a proper study and verication of the drug release models for
both nanoformulations should be considered. Besides, the therapeutic efcacy of W/O/W multiple nanoemulsion is reported to
be different from the simple O/W nanoemulsion. Hence, further
investigation on the drug release mechanisms and kinetics of both
the ultrasonically-formed nanoformulations should be carried out.
(2) Comparative study of the continuous emulsication process by
ultrasonic cavitation and microuidization in the generation of
pharmaceutical nanoemulsions: A comparison between an industrial scale high power ultrasound horn and a bench-top air-driven
microuidizer in the batch production of aspirin nanoemulsions
has been investigated. However, a detailed comparative work of
both emulsifying techniques in the generation of pharmaceutical
grade nanoemulsion in continuous mode has not been reported
in the open literature. This study is of highly relevance and in fact
it merits further investigation as it would then allow pharmaceutical scientists in selecting an appropriate production method to be
applied to develop and manufacture of a new nanoemulsion based
drug delivery system in a continuous manner. (3) Optimization of
process parameters in the generation of highly stable pharmaceutical W/O/W submicron multiple emulsions produced via novel
LWHCR technology: Application of a very interesting yet novel
Sonolator technology in the emulsication process where a liquid
whistle hydrodynamic cavitation based reactor (LWHCR) was
employed to produce W/O/W submicron multiple emulsions containing ferrous fumarate via two-stage droplet formation in a cavitation chamber. The effect of operating pressure and number of
emulsication passes on the mean droplet size and stability of
W/O/W multiple emulsions had been investigated and analyzed
thoroughly. Apart from the operating pressure and number of
emulsication passes, other important parameters such as
orice diameter, distance between blade and orice, processing
temperature, and viscosity of emulsion should be explored in the
future work to explain how different processing conditions of
LWHCR affect the physicochemical properties of the resultant multiple emulsions. In this aspect, a standard RSM could be used as an
optimization tool in conjunction with the design and manufacture
of optimum submicron multiple emulsion formulation with
desired properties. Furthermore, this should allow a better interpretation of spectra of the variations of W/O/W multiple emulsion
properties caused by different processing parameters used in
LWHCR system.
9. Conclusions
This review has outlined the principles relating to the cavitational emulsication and its potential use in producing the pharmaceutical nanoemulsions in the current drug delivery system.
In the generation of nanoemulsion, cavitation technology is proved
to be a powerful and promising approach for the efcient production of droplets with smaller size compared to other mechanical
alternatives. It is competitive or even superior in terms of energy
efciency and thus more economical compared to classical homogenizing systems. Most importantly, by using cavitation technique,
the requirement of surfactant is signicantly reduced and equipment contamination is less and thus aseptic processing is feasible
and appropriate for pharmaceutical processing. Additionally, the
acoustically formed nanoemulsions were all found to be stable
excellently and more homogeneous as compared to those dispersions produced by conventional mechanical methods.
13
However, in most of the pharmaceutical technology operations,

the achievement of size reduction by ultrasonic cavitation technique still requires proper study. This is due to the fact that it is
usually difcult, in pharmaceutical industry, to alter one processing parameter without adversely affecting another. Besides, the
quality of nanoemulsion for pharmaceutical use or application
must be monitored. Monitoring the critical parameters of ultrasonication process will ensure that the product specications are met.
A clear understanding of the ultrasonic processing parameters, the
choice of recipients (including oils and surfactant), and compatibility of formulations and the overall efcacy of formulated nanoemulsion is therefore necessary to carry out a successful
optimization endeavor in the design and manufacture of pharmaceutical nanoemulsions. To fully realize the potential of nanoemulsion-based drug delivery system with controlled size and shape,
nanofabrication and nanomanufacturing by means of cavitation
approach will play a prominent role in the future. Overall, ultrasonic cavitation is simple, energy efcient and cost-effective in
the generation of ne pharmaceutical nanoemulsions and multiple
nanoemulsions with improved efcacy. Whereas, hydrodynamic
cavitation is facile, highly exible and scalable in the production
of monodispersed multiple submicron emuslion for the pharmaceutical industries. Conclusively, cavitation technology provides
innovating and exciting perspectives for modern pharmaceutical
industries which are looking for signicant and competitive process improvements with sonochemistry.
Acknowledgements
Our sincere gratitude goes to the Malaysian Ministry of Science,
Technology & Innovation (MOSTI) for their nancial support
through eScience (M0058.54.01).
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Cavitation Technology - A Greener Processing Technique For The Generation of Pharmaceutical Nanoemulsions

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Ultrasonics Sonochemistry xxx (2014) xxxxxx

Contents lists available at ScienceDirect

Cavitation technology A greener processing technique

for lipophilic drugs and better resistance toward droplet collisions

M. Sivakumar et al. / Ultrasonics Sonochemistry xxx (2014) xxxxxx

Omega-3 and Omega-6-fatty acids and contain useful vitamins and

2. Why are pharmaceutical nanoemulsions?

Fig. 1. Applications of nanoemulsions.

M. Sivakumar et al. / Ultrasonics Sonochemistry xxx (2014) xxxxxx

as Intralipid are oil-in-water emulsion consisting of one or more

DSconf nkB ln / f1 /=/gln 1 /

where n is the number of droplets of dispersed phase, kB is the

From the above equation, DAc12 has to be much lower than

where p indicates the Laplace pressure, R1 and R2 are the principal

M. Sivakumar et al. / Ultrasonics Sonochemistry xxx (2014) xxxxxx

where Gg is the velocity gradient, gc is the viscosity of continuous

4. Synthesis and basic processes for the fabrication of

ultrasound probe sonicator. The latter uses a probe and is much

5. Why ultrasonic cavitation in the generation of

M. Sivakumar et al. / Ultrasonics Sonochemistry xxx (2014) xxxxxx

Fig. 2. Components and their role in the formation of nanoemulsions.

producing a nanoemulsion with desired diameter, the required

6. Examples of pharmaceutical nanoemulsions generated using

M. Sivakumar et al. / Ultrasonics Sonochemistry xxx (2014) xxxxxx

Fig. 3. Two-stage ultrasound emulsication: droplet formation and break-up.

introducing surplus stabilizer to the drug capsule could be easily

to be signicantly improved to be more uniform and the droplet

M. Sivakumar et al. / Ultrasonics Sonochemistry xxx (2014) xxxxxx

there exists a minimum emulsion droplet size which cannot be

M. Sivakumar et al. / Ultrasonics Sonochemistry xxx (2014) xxxxxx

Saquinavir (SQV) (oral)

Sodium oleate, glycerine

Pine nut oil

M. Sivakumar et al. / Ultrasonics Sonochemistry xxx (2014) xxxxxx

Fig. 4. Unhomogenized curcumin emulsion droplets prior to ultrasonication.

suspension were also studied for their anti-inammatory and

anti-inammatory and analgesic effects compared to reference

M. Sivakumar et al. / Ultrasonics Sonochemistry xxx (2014) xxxxxx

Droplet size (d.nm)

administration has been oftentimes linked with quite a few side

M. Sivakumar et al. / Ultrasonics Sonochemistry xxx (2014) xxxxxx

Overall Anti-inflammatory and Analgesic Activity Rank

Decreasing Activity Order

Fig. 11. Preparative methods of multiple emulsions with their characteristics.

M. Sivakumar et al. / Ultrasonics Sonochemistry xxx (2014) xxxxxx

and internal structures could be a major challenge and there have

an improved homogeneity of the ne dispersion. Selection of an

M. Sivakumar et al. / Ultrasonics Sonochemistry xxx (2014) xxxxxx

However, in most of the pharmaceutical technology operations,

M. Sivakumar et al. / Ultrasonics Sonochemistry xxx (2014) xxxxxx

[15] S. Manchun, C.R. Dass, P. Sriamornsak, Designing nanoemulsion templates for

M. Sivakumar et al. / Ultrasonics Sonochemistry xxx (2014) xxxxxx

[75] J. Weiss, I. Scherze, G. Muschiolik, Polysaccharide gel with multiple emulsion,

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