Classification of liquids:LIQUIDS
Used in Oral
Oral use
Used in other
than oral cavity EMULSION
External use
Which are the novel innovations in
liquid dosage forms??
Nanosuspensions in drug delivery
Nanoemulsions in drug delivery
Multiple emulsions in drug delivery
Self emulsifying drug delivery system
Self microemulsifying drug delivary system
Dry emulsion
Recent innovation in suspension
• More than 40 per cent of the drugs coming from
high-throughput screening are poorly soluble in
• There are number of formulation approaches to
resolve the problems include micronization,
solublization using co-solvents, use of permeation
enhancers, oily solutions, surfactant dispersions, salt
formation and precipitation techniques.
• Other techniques like liposome's, emulsions, micro
emulsions, solid-dispersions and inclusion complexes
using Cyclodextrins show reasonable success but
they lack in universal applicability to all drugs.
Method of preparation
1. Bottom Up technology(precipitation technique)
2. Top Up technology(disintegration technique)
A)Media Milling (Nanocrystals or Nanosystems)
B)Homogenization In Water (Dissocubes)
C)Homogenisation In Nonaqueous Media (Nanopure)
D)Combined Precipitation And Homogenization (Nanoedege)
E)Emulsification-solvent evaporation technique
Precipitation technique
Drug + solvent
added to non-solvent which gives pptn
Rapid addition of a drug solution to an antisolvent
super saturation of the mixed solution
generation of fine crystalline or amorphous
The NANOEDGE process (is a registered trademark of Baxter International
Inc. and its subsidiaries) relies on the precipitation of friable materials for
subsequent fragmentation under conditions of high shear and/or thermal
energy .
Precipitation of an amorphous material may be favored at high
supersaturation when the solubility of the amorphous state is exceeded.
• Simple process
• Low cost equipment
• Ease of scale up
• Drug has to soluble at least in one solvent and
that this solvent needs to be miscible with a
non-solvent Growing of drug crystals needs to
be limit by surfactant addition.
A) Media Milling (Nanocrystals or Nanosystems)
Principle :
The high energy and shear forces generated as a
result of the impaction of the milling media with the
drug provide the energy input to break the micro
particulate drug into nano-sized particles.
The milling medium is composed of glass,
zirconium oxide or highly cross-linked polystyrene
In batch mode, the time required to obtain dispersions
with unimodal distribution profiles and mean
diameters<200nm is 3060 min(51 hr).
Figure 1 Schematic representation of the media milling process
• Easy to scale up.
• Media milling is applicable to the drugs that are poorly soluble in
both aqueous and organic media.
• High flexibility in handaling of large quantity of drug.
• Very dilute as well as highly concentrated nanosuspensions can be
prepared by handling 1mg/ml to 400mg/ml drug quantity.
• Nanosize distribution of final nanosize products.
• Genaration of residue of milling media.
• Nanosuspensions contaminated with materials eroded from balls
may be problematic when it is used for long therapy.
• The media milling technique is time consuming.
• Some fractions of particles are in the micrometer range.
• Scale up is not easy due to mill size and weight.
B) Homogenization In Water (Dissocubes)
• R.H.Muller developed
Dissocubes technology
in 1999.
• The instrument can be
operated at pressure
varying from 100 –
1500 bars (2800 –
21300psi) and up to
2000 bars with volume
capacity of 40ml (for
laboratory scale).
3mm diameter
Principle:• In piston gap homogeniser particle size reduction is based on the cavitation
principle. Particles are also reduced due to high shear forces and the collision of
the particles against each other.
• According to Bernoulli’s Law the flow volume of liquid in a closed system per
cross section is constant.
• The reduction in diameter from 3mm to 25µm leads to increase in dynamic
pressure and decrease of static pressure below the boiling point of water at room
• Due to this water starts boiling at room temperature and forms gas bubbles,
which implode when the suspension leaves the gap (called cavitation) and normal
air pressure is reached.
• The size of the drug nanocrystals that can be achieved mainly depends on factors
like temperature, number of homogenization cycles, and power density of
homogeniser and homogenization pressure.
• Ease of scale-up and little batch-to-batch variation (Grauetal2000).
• It does not cause the erosion of processed materials.
• Very dilute as well as highly concentrated nanosuspensions can be
prepared by handling 1mg/ml to 400mg/ml drug quantity.
• Narrow size distribution of the nano particulate drug Present in the final
product (Muller&Bohm1998).
• It is applicable to the drugs that are poorly soluble in both aqueous and
organic media.
• It allows aseptic production of nanosuspensions for parentral
• Preprocessing like micronization of drug is required.
• High cost instruments are required that increases the cost of dosage form.
Parenteral administration
Peroral administration
Ophthalmic drug delivery
Pulmonary drug delivery
Target drug delivery
Topical formulations
Evaluation of nanosuspensions:–
A) In-Vitro Evaluations
1. Particle size and size distribution
2. Particle charge (Zeta Potential)
3. Crystalline state and morphology
4. Saturation solubility and dissolution velocity
B) In-Vivo Evaluation
C) Evaluation for surface-modified Nanosuspensions
1.Surface hydrophilicity
2. Adhesion properties
3. Interaction with body proteins
Self emulsifying drug delivery system
• Self-emulsifying drug delivery systems (SEDDSs) have gained exposure
for their ability to increase solubility and bioavailability of poorly soluble
• SEDDSs are mixtures of oils and surfactants, sometimes containing
cosolvents, and can be used for the design of formulations in order to
improve the oral absorption of highly lipophilic compounds.
• SEDDSs emulsify spontaneously to produce fine oil-in-water emulsions
when introduced into an aqueous phase under gentle agitation.
The self-emulsifying process is depends on:
• The nature of the oil–surfactant pair
• The surfactant concentration
• The temperature at which self-emulsification occurs.
Mechanism of self-emulsification
• According to Reiss, self-emulsification occurs when the entropy
change that favors dispersion is greater than the energy required to
increase the surface area of the dispersion. The free energy of the
conventional emulsion is a direct function of the energy required to
create a new surface between the oil and water phases and can be
described by the equation:
DG = free energy
N =number of droplets
r= redius
s= interfacial energy
Evaluation of SEDDS:
Visual assessment
Turbidity Measurement
Droplet Size
Zeta potential measurement
Determination of emulsification time
• The system has the ability to form an oil-in-water
emulsion when dispersed by an aqueous phase
under gentle agitation.
• SEDDSs present drugs in a small droplet size and
well-proportioned distribution, and increase the
dissolution and permeability.
SMEDDS are defined as isotropic mixtures of natural or synthetic oils,
solid or liquid surfactants, or alternatively, one or more hydrophilic solvents and
co-solvents/surfactants that have a unique ability of forming fine oil-in-water
(o/w) micro emulsions upon mild agitation followed by dilution in aqueous
media, such as GI fluids.
• droplet size between
100 and 300 nm
• Oil phase 40-50%
• droplet size < 50 nm
• Oil phase <20%
•When compared with emulsions, which are sensitive and metastable
dispersed forms, SMEDDS are physically stable formulations that are easy
to manufacture.
•The SMEDDS mixture can be filled in either soft or hard gelatin capsules.
• Improvement in oral bioavailability:
SMEDDS to present the drug to GIT in solubilised and micro emulsified
form (globule size between 1-100 nm) and subsequent increase in
specific surface area
E.g. In case of halofantrine approximately 6-8 fold increase in BA of
drug was reported in comparison to tablet formulation.
• Ease of manufacture and scale-up:
Ease of manufacture and scale up is one of the most important
advantage that makes SMEDDS unique when compared to other drug
delivery systems like solid dispersions, liposomes, nanoparticles, etc.,
dealing with improvement of BA.
• Reduction in inter-subject and intra-subject variability and food
Several research papers specifying that, the performance of SMEDDS is
independent of food and, SMEDDS offer reproducibility of plasma
profile are available.
Ability to deliver peptides that are prone to enzymatic hydrolysis
in GIT:
• SMEDDS ability to deliver macromolecules like peptides, hormones,
enzyme substrates and inhibitorsand their ability to offer protection
from enzymatic hydrolysis.
No influence of lipid digestion process:
• SMEDDS is not influenced by the lipolysis, emulsification by the bile
salts, action of pancreatic lipases and mixed micelle formation.
Increased drug loading capacity:
• SMEDDS also provide the advantage of increased drug loading capacity
when compared with conventional lipid solution as the solubility of
poorly water soluble drugs with intermediate partition coefficient (2<log
P>4) are typically low in natural lipids and much greater in amphilic
surfactants, co surfactants and co-solvents.
Advantages of SMEDDS over emulsion:
The drawback of the layering of emulsions after sitting for a long time SMEDDS can be easily
stored since it belongs to a thermodynamics stable system.
The size of the droplets of common emulsion ranges between 0.2 and 10 μm, and that of
the droplets of microemulsion formed by the SMEDDS generally ranges between 2 and 100
nm (such droplets are called droplets of nano particles).
Since the particle size is small, the total surface area for absorption and dispersion is
significantly larger than that of solid dosage form and it can easily penetrate the
gastrointestinal tract and be absorbed.
So, The bioavailability of the drug is therefore improved.
SMEDDS offer numerous delivery options like filled hard gelatin capsules or soft gelatin
capsules or can be formulated in to tablets whereas emulsions can only be given as an oral
Emulsion can not be autoclaved as they have phase inversion temperature, while SMEDDS
can be autoclaved.
Nano emlsion are submicron sized, the thermodynamically stable
isotropic system in which two immiscible liquid (water and oil) are
mixed to form a single phase by means of an appropriate
surfactants or its mix with a droplet diameter approximately in the
range of 0.5-100 um. Nanoemulsion droplet sizes fall typically in
the range of 20-200 nm and show narrow size distributions.
NE in cosmetics
NE in mucosal vaccines system.
Antimicrobial NE.
NE in non-toxic disinfectant cleaner.
NE in cancer therapy & in targeted drug delivery.
NE in various disease condition.
NE formulations for improve oral delivery of poorly
soluble drugs.
NE as a vehicle for TDDS.
Solid SNEDS as a platform tech. for formulation of
poorly solubal drugs
Nanoemulsion in cosmetics
• They can form a optimum dispersion of active
ingrediant .
• Due to their lipophilic interior,NEs are more
suitable for trasport of lipophilic drug then
• NJ –TRI K indusry & its perant company
Kemira have launched a new nano-based gel
for skin care .In that NE is carrier system .
Antimicrobial NE
• Antimicrobial NEs are oil-in-water droplets
that range from 200 to 600 nm. They are
composed of oil and water and are stabilized
by surfactants and alcohol.
• This fusion is enhanced by the electrostatic
attraction between the cationic charge of the
emulsion and the anionic charge on the
NE in cancer therapy & in targeted drug delivery.
• In order to achieve absorption of Paclitaxel , formulatad in NE increase the
BA of 70.62% .
• Inhibition of P-glycoprotein efflux by D-tocopheryl polyethyleneglycol 1000
succinate and labrasol would have contributed to the enhanced peroral
bioavailability of PCL.
• Camptothecin is a topoisomerase I inhibitor that acts against a broad
spectrum of cancers. However, its clinical application is limited by its
insolubility, instability, and toxicity .
• The NEs were prepared using liquid perfluorocarbons and coconut oil as the
cores of the inner phase. These NEs were stabilized by phospholipids and/or
Pluronic F68 (PF68). The NEs were prepared at high drug loading of
approximately 100% with a mean droplet diameter of 220-420 nm.
Nanoemulsions as a vehicle for
transdermal delivery
• NEs have great potential for transdermal drug
delivery of aceclofenac.
• The NEs of the system containing ketoprofen
evidenced a high degree of stability. Ketoprofenloaded Nes enhanced the in vitro permeation
rate through mouse skins as compared to the
• The study was developed to evaluate the
potential of NEs for increasing the solubility and
the in vitro transdermal delivery of carvedilol.
Nanoemulsions as a vehicle for
transdermal delivery
• From in vitro and in vivo data, it was
concluded that the developed NEs have great
potential for transdermal drug delivery of
• The NEs of the system containing ketoprofen
evidenced a high degree of stability &
enhanced the in vitro permeation rate
through mouse skins a compared to the
Nanoemulsion formulations for improved oral
delivery of poorly soluble drugs
• NE formulations were developed to enhance oral
bioavailability of hydrophobic drugs.
• Paclitaxel was selected as a model hydrophobic
• The oil-in-water (o/w) NEs were made with pine
nut oil as the internal oil phase, egg lecithin as
the primary emulsifier, and water as the external
• particle size range of 90-120 nm and zeta
potential ranging from 134 mV to 245 mV.
Self-nanoemulsifying drug delivery
• The research project was done to develop a
self-nanoemulsifying drug delivery system
(SNEDDS) for non-invasive delivery of protein
• Eg. Fluorescent-labeled beta-lactamase (FITCBLM), a model protein, was loaded into
SNEDDS through the solid dispersion
Multiple emulsions are complex polydispersed systems where both oil in water and
water in oil emulsion exists simultaneously which are stabilized by lipophillic and
hydrophilic surfactants respectively.
The ratio of these surfactants is important in achieving stable multiple emulsions.
Among water-in-oil-in-water (w/o/w) and oil-in-water-in-oil (o/w/o) type multiple
emulsions, the former has wider areas of application and hence are studied in great
It finds wide range of applications in controlled or sustained drug delivery, targeted
delivery, taste masking, bioavailability enhancement, enzyme immobilization, etc.
Multiple emulsions have also been employed as intermediate step in the
microencapsulation process and are the systems of increasing interest for the oral
delivery of hydrophilic drugs, which are unstable in gastrointestinal tract like proteins
and peptides.
With the advancement in techniques for preparation, stabilization and rheological
characterization of multiple emulsions, it will be able to provide a novel carrier
system for drugs, cosmetics and pharmaceutical agents.
Multiple emulsions, either W/O/W or O/W/O
emulsions, are generally prepared using a 2-step
• For W/O/W emulsions, the primary emulsion (W/O) is
first prepared using water and a low-HLB surfactant
solution in oil. In the second step, the primary emulsion
(W/O) is reemulsified in an aque-ous solution of a highHLB surfactant to produce a W/O/W multiple emulsion.
• The first step is usually carried out in a high-shear device
to produce very fine droplets. The second emulsification
step is carried out in a low-shear device to avoid
rupturing the multiple droplets.
Multiple emulsion microbubbles for ultrasound imaging
(Materials Letters 62 (2008) 121–124 )
• Air or N2 or perfluorocarbon only encapsulated microbubbles which
are currently used have lower efficiency and short imaging time.
• So the novel contrast agents with a higher efficiency are required.
• To achieve this objective, the strategy that we have explored
involves the use of superparamagnetic iron oxide (SPIO) Fe3O4
nanoparticles multilayer emulsion microbubbles.
• This multilayer structure consists of three layers.
The core is poly-D, L-lactide (PLA) encapsulated N2 nanobubble
with the SPIO nanoparticles forming oil-in-water (W/O) layer.
• The outermost is water-in-oil-in-water ((W/O)/W) emulsion layer
with PVA solution.
• An overall diameter of around 2μm–8μm.
• On the one hand, the stable gas encapsulated microstructure can
provide a high scattering intensity resulting in high echogenicity, On
the other hand, SPIO nanoparticles have shown the potential of
high resolution sonography.
• So the multiple emulsion microbubbles with SPIO can have double
action to enhance the ultrasound imaging.
Besides, because SPIO can also serve as magnetic resonance
imaging (MRI) contrast agents, such microstructure may be useful
for multimodality imaging studies in ultrasound imaging and MRI.
• Combining SPIO Fe3O4 nanoparticles with ultrasound imaging
technique may be more attractive in ultrasound molecular imaging
and also may provide a dramatic increase in resolution over
conventional clinical diagnostic ultrasound scanners.
Preparation of multiple emulsion microbubbles
The methylene chloride organic solution (10.00ml) was prepared
containing PLA (0.50g) and hydrophobic SPIO Fe3O4 nanoparticles
(0.5g) at 25°C.
To generate the first W/O microbubble emulsion, 1.00mL deionized
water and a few Tween 80 (about 1.00ml) were added to the
organic solution and sonicated continuously by ultrasound probe at
100W with constant purging using a steady (4ml/min) stream of N2
gas for 5min.
The W/O microbubble emulsion is brown and visibly homogeneous.
The dissociated Fe3O4 can be separated from the first emulsion
microbubbles solution under an external magnetic field.
The first W/O microbubble emulsion was then poured into a 1%
PVA(w/v) solution and mixed mechanically for 2h to form(W/O)/ W
multiple emulsion microbubbles and to eliminate the organic
solution. After reaction, the final emulsion became milk-white.
Preparation of multiple emulsion microbubbles
methylene chloride containing PLA (0.50g)
hydrophobic SPIO Fe3O4
nanoparticles (0.5g)
W/O microbubble emulsion
Tween 80 (1 ml) & deionized water (1 ml)
sonicated continuously by ultrasound probe at 100W with constant purging using a steady
(4ml/min) stream of N2 gas for 5min
brown and visibly homogeneous W/O emulsion
poured into a 1% PVA(w/v) solution and mixed mechanically for 2h
eliminate the organic solution.
(W/O)/ W multiple emulsion microbubbles is ready and the final emulsion became milk-white.
Dry emulsion
• A novel oral dosage formulation of insulin consisting of a surfactant, a
vegetable oil, and a pH-responsive polymer has been developed. First, a
solid-in-oil (S/O) suspension containing a surfactant–insulin complex
was prepared.
• Solid-in-oil-in-water (S/O/W) emulsions were obtained by
homogenizing the S/O suspension and the aqueous solution of
hydroxypropylmethylcellulose phthalate (HPMCP).
A microparticulate solid emulsion formulation was successfully
prepared from the S/O/W emulsions by extruding them to an acidic
aqueous solution, followed by lyophilization.
• The insulin release from the resultant dry emulsion responded to the
change in external environment simulated by gastrointestinal
conditions, suggesting that the new entericcoated dry emulsion
formulation is potentially applicable for the oral delivery of peptide and
protein drugs.
Homogenization and membrane emulsification
Dropwise extrusion through a syringe
Recovery and lyophilization.
Suryakanta Nayak et.al., Nanosuspension:A novel drug delivery system,
Journal of Pharmacy Research 2010, 3(2),pp.241-246.
V. B. Patravale et.al., Nanosuspensions: a promising drug delivery
strategy jpp,2004,56,pp.-827 – 840
Jiraporn CHINGUNPITUK, Nanosuspension Technology for Drug Delivery
Walailak J Sci & Tech 2007; 4(2) pp. 139-153.
Shah P et.al., Nanoemulsion: A Pharmaceutical Review, Sys Rev Pharm ,
January-June 2010 ,Vol 1 , Issue 1,pp.24-32.
Fang Yang et.al., Multiple emulsion microbubbles for ultrasound imaging,
www.sciencedirect.com, Materials Letters 62 (2008) pp.121–124
Fabienne Cournarie et.al., Insulin-loaded W/O/W multiple emulsions,
European Journal of Pharmaceutics and Biopharmaceutics 58 (2004)
Ritesh B. Patel, Self-Emulsifying Drug Delivery Systems, Jul 2, 2008
Eiichi Toorisaka et.al, An enteric-coated dry emulsion formulation for oral
insulin delivery Journal of Controlled Release 107 (2005) pp.91–96
Anand U. Kyatanwar et al. Self micro-emulsifying drug delivery system
(SMEDDS) : Review Journal of Pharmacy Research 2010, 3(1),pp.75-83