Recent innovation in liquid dosage form 1by sachin

A SEMINAR ON
Recent Innovations in
ORAL LIQUIDS
Presented by:
 Sachin Prajapati
Roll No. : 15
M.Pharm Sem-II
PHARMACEUTICS
1
NOOTAN PHARMACY COLLEGE,VISNAGAR

Co ntents
 Suspension as oral
Nano suspension
Micro suspension
 Emulsion as oral
Micro emulsion
Nano emulsion
Multiple emulsion
Dry emulsion
2

liquids
 Definition
This is a general term used to describe a solution, suspension or emulsion
in which the active ingredient is dissolved or dispersed in a suitable
liquid vehicle.
“A solution is a liquid-preparation that contains one or more soluble
chemical substances dissolved in a specified solvent.”
 Advantages
 Immediately available for absorption.
 Administration convenient, particularly for infants, psychotic patients.
 Easy to color, flavor & sweeten.
 Liquids are easier to swallow than solids and are therefore particularly
acceptable for pediatric patient.
 A solution is an homogeneous system and therefore the drug will be
uniformly distributed throughout the preparation.
 Some drugs like aspirin, KCl can irritate gastric mucosa if used orally as a
solid dosage forms. But this effect can be reduce by solution system.
3

 Disadvantages
 Bulky than tablets or capsule, so difficult to carry transport.
 Less stable in aqueous system. Incompatibility is faster in
solution than solid dosage form.
 Patients have no accurate measuring device.
 Accident breakage of container results in complete loss.
 Solution often provide suitable media for the growth of
microorganisms.
 The taste of a drug, which is often unpleasant, is always
more pronounced when in solution than in a solid form.
4

Classification of liquids
5
LIQUID
Monophasic
Oral
use
Solution
Draught
Drops
Linctuses
Syrups
Elixirs
External use Parenteral Special use
Used in
Oral cavity
THROAT
PAINTS
GLYCERITES
MOUTH
WASHES
THROATSPRAY
S
Used in other
than oral cavity
DOUCHES
ENEMAS
EYE DROPS
EYE LOTIONS
NASAL DROPS
INHALANTS
Biphasic
Liquid in
liquid
Oral use
EMULSION
External
use
Liniments
Solids in
liquid
Parenteral Oral
SUSPENSION
External
Lotion

SUSPENSION AS ORAL
6
Nano suspension
Micro suspension

Suspension
8
 Mixture of two substances, one of which is finely divided and
dispersed in the other.
 Suspensions:
S-S,
L-S (OR S-L),
G-S
 Colloidal suspension 1 nm to 0.5 µm
 Coarse suspension 1 to 100 µm
 A suspension of liquid droplets or fine solid particles in a gas is
called an aerosol.
 Blood is an example of suspensions
 Suspensions are useful for administering insoluble or poorly
soluble drugs or in situations when the presence of a finely
divided for the material in the GI tract is required.

The Difference Between Solution & Suspensions
 When the 2 substances totally mix it is called a solution.
 E.g. Solute + Solvent = Solution
(sugar) + (water) = Solution
 Then, We can say sugar is soluble in water, it has dissolved.

Contd…
 Suspensions
 Sometimes when we mix substances they stay in
clusters. We therefore say it is insoluble in water.
 E.g. Chalk + Water = Suspension
 Eventually the particles sink to the bottom to form
sediment.

More than 40% of drugs are poorly soluble in water, so they show problems in
formulating them in conventional dosage forms.
For class II drugs (e.g.-Itraconazole & carbamazepine), WHICH ARE
POORELY SOLUBLE IN AQUEOUS AND ORGANIC MEDIA, THE
PROBLEM IS MORE COMPLEX.
Various approaches to resolve problems of low solubility and low
bioavailability
- Micronization, co-solvancy, oily solution, salt formation
- SOME OTHER TECHNIQUES ARE LIPOSOMES, EMULSIONS,
MICROEMULSION, SOLID DISPERSION, ß- CYCLODEXTRIN
INCLUSION COMPLEX etc.
Many of these techniques are not universally applicable to all drugs or are not
applicable to drugs which are not soluble in both aqueous & organic media.
A different but simple approach is needed to tackle the formulation problem
to improve their efficacy and to optimize the therapy with respect to
pharmacokinetics.
11

 A pharmaceutical nanosuspension is defined as very finely
dispersed solid drug particles in an aqueous or organic vehicle
for either oral and topical use or parenteral and pulmonary
administration.
 The particle size distribution of the solid particles in
nanosuspensions is usually less than one micron with an
average particle size ranging between 200 and 600 nm.
 Nanosuspensions differ from nanoparticles.
Nanoparticles are commonly polymeric colloidal carriers of
drugs whereas solid lipid nanoparticles are lipidic carriers of
drugs. In nanosuspension technology, the drug is maintained in
the required crystalline state with reduced particle size, leading
to an increased dissolution rate and therefore improved
bioavailability.
12
Nanosuspension

Nanosuspension
preparation
Top down
Media Milling
(Nanocrystals)
HPH in water
(Dissocubes)
HPH in non
aqueous media
(Nanopure)
Combination of
precipitation and
HPH (Nanoedge)
Bottom up
Precipitation
13

Drug
dissolved in
the solvent
Added to
non -solvent
Precipitation
Of
Crystals
14

Main advantage is the use of simple and low cost equipments.
Basic challenge is that during the precipitation procedure
growing of the crystals need to be controlled by addition of
surfactant to avoid formation of microparticles.
Limitation of this precipitation technique is that the drug
needs to be soluble in at least one solvent and the solvent
needs to be miscible with non-solvent.
Moreover,
It is not applicable to the drugs, which are poorly soluble in
both aqueous and non-aqueous media.
15

The nanosuspensions are prepared by using high shear media
mills. The milling chamber charged with milling media,
water,drug & stabilizer is rotated at very high shear rate under
controlled temp. for 2-7 days.
The major concern with this method is the residues of milling
media remaining in the finished product could be problematic for
administration.
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 resin.
17

19
Coolant Large
drug
crystals
Charged
with
drug, water
and
stabilizer
Re-circulation
chamber
Milling chamber
Screen
retaining
milling media
in chamber
Milling
shaft
Nanocrystals
Milling media
Motor

ADVANTAGES OF MEDIA MILLING
1. applicable to the drugs that are poorly soluble in both aqueous and
organic media.
2. Very dilute as well as highly concentrated nanosuspensions can be
prepared by handling 1mg/ml to 400mg/ml drug quantity.
DISADVANTAGES OF MEDIA MILLING
1. Nanosuspensions contaminated with materials eroded from balls
may be problematic when it is used for long therapy.
2. The media milling technique is time consuming.
3. Some fractions of particles are in the micrometer range.
4. Scale up is not easy due to mill size and weight.
20

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).
Have to be started with micronized drug particle size less than
25μ to prevent blocking of homogenization gap.
So it is essential to prepare a presuspension of the micronized
drug in a surfactant solution using high speed stirrer.
21

High pressure homogenizer
-Cavitation, High shear forces and
collision of particles against each other
-The drug suspension, contained in a
cylinder of diameter about 3 mm, passes
suddenly through a very narrow
homogenization gap of 25 μm, which leads
to a high streaming velocity.
-In the homogenization gap, according to
Bernoulli’s equation, the dynamic pressure
of the fluid increases with the
simultaneous decrease in static pressure
below the boiling point of water at room
temperature.
22

- water starts boiling at room temperature, leading to the
formation of gas bubbles, which implode when the
suspension leaves the gap (called Cavitation) and
normal air pressure is reached again.
- The implosion forces are sufficiently high to break
down the drug microparticles into nanoparticles.
- Additionally, the collision of the particles at high speed
helps to achieve the nano-sizing of the drug.
23

• Drugs that are poorly soluble in both aqueous and organic
media can be easily formulated into nanosuspensions.
• Ease of scale-up and little batch-to-batch variation.
• Narrow size distribution of the nanoparticulate drug present in
the final product.
• Allows aseptic production of nanosuspensions for parenteral
administration.
• Flexibility in handling the drug quantity, ranging from 1 to
400mg/mL, thus enabling formulation of very dilute as well as
highly concentrated nanosuspensions.
• Prerequisite of micronized drug particles.
• Prerequisite of suspension formation using high-speed mixers
before subjecting it to homogenization.
24
Advantages
Disadvantages

The drugs that are chemically labile can be processed in
such non-aqueous media or water-miscible liquids like
polyethyleneglycol-400 (PEG), PEG1000 etc. The
homogenization can be done at room temperature, 0o C and
below freezing point (-20o C).
25

Precipitated
drug particles
(nanosize
desired)
Continues to
grow till
microcrystal
size
So the precipitated particle suspension is subsequently
homogenized which preserve the particle size obtained
after the precipitation step.
26

Evaluation of Nanosuspensions
In-Vitro Evaluation
-Particle size & Size Distribution
-Particle Charge (Zeta potential)
-Crystalline state & Morphology
-Saturation Solubility & Dissolution Velocity
In- Vivo Evaluation
-Surface Hydrophobicity
-Interaction with Body Protein
28

Mean particle
size and size
distribution
Photon correlation
Spectroscopy
Laser
Diffractometry
Atomic Force
Microscopy
29

Particle Charge ( zeta potential)
Gives idea about physical stability of the Nanosuspension
30
“Potential difference between the ions in the tightly bound layer
and the electroneutral region, referred to as zeta potential.”

Crystalline State and Particle Morphology
Differential
Scanning
Calorimetry
Crystalline Structure
X- Ray Diffraction
Change in physical state and
extent of amorphous drug.
31
SCANNING ELECTRON MICROSCOPY

Saturation solubility & Dissolution Velocity
Help to anticipate In-vivo performance
blood profiles,
plasma peaks,
bioavailability
32

e.g.:
IMPROVED BIOAVAILABILITY
1) Atovaquone  10-15% bioavailable  high dose (750mg, twice a day)
NANOSUSPENSION 2.5 FOLD INCREASE IN BIOAVAILABILITY
2) Danazole poorly soluble gonadotropin inhibitor
Marketed Suspension(Danocrine)  5.2% Bioavailability
NANOSUSPENSION 82.5% BIOAVAILABILITY
QUICK ONSET OF ACTION:
3) NAPROXEN, an NSAID
Nanosuspension
• Tmax= 1.69 hr
Naprosyn
(Suspension)
• Tmax= 3.33 hr
Anaprox
(Tablet)
• Tmax= 3.2 hr
34

 Patented technologies for Preparation:
35

37
 Microsuspension® is a registered trademark used for Aqueous Solutions
Sold As a Component of Veterinary Pharmaceutical Preparations For Use In
the Treatment of Respiratory Disease In Livestock and owned by G. C.
Hanford Manufacturing Company.
 Drug is in micro size range.
 No significant advantages over the macrosuspension or Nanosuspension.
 Same methods of preparation as the Nanosuspension.
MICROSUSPENSION (?)

Emulsion as Oral
MICROEMULSION
NANOEMULSION
MULTIPLE EMULSION
DRY EMULSION 39

40
EMULSION
 An emulsion is a mixture of two or more liquids that are
normally immiscible (nonmixable or unblendable).
 In an emulsion, one liquid (the dispersed phase) is dispersed in
the other (the continuous phase).
 Examples of emulsions include vinaigrettes, milk, and some
cutting fluids for metal working.
 The word "emulsion" comes from the Latin word for "to
milk", as milk is (among other things) an emulsion of milk fat
and water.

MICROEMULSION
 “Microemulsions are dispersions of nanometer-
sized droplets of an immiscible liquid within
another liquid. Droplet formation is facilitated by
the addition of surfactants and often also co
surfactants.”
 Microemulsions can have characteristic properties such
as ultralow interfacial tension, large interfacial area and
capacity to solubilize both aqueous and oil-soluble
compounds.
41

• Microemulsions are clear, stable, liquid mixtures of oil,
water and surfactant, frequently in combination with a co
surfactant like short chain alcohol or amine.
• Diameter of the droplets in a microemulsion is in the range
of 0.1 to 10 µm.
• The two basic types of microemulsions are
(1) o/w (oil dispersed in water) and
(2) w/o (water dispersed in oil).
42

Difference between Ordinary emulsion and Microemulsion:
Ordinary emulsion Microemulsion
Size of globule: 0.5-50 µm 0.1-10 µm
Appearance: Turbid Clear
Thermodynamically: Stable but coalesce
finally.
More stable
Viscosity: - Less compared to other
emulsion.
Preparation: It require high shear
condition
By simple mixing of the
component and do not
require high shear
condition
Surfactant concentration: 2-3 %Waight 6-8 %Waight
Phases: 2 1
43

Types of microemulsion systems
 According to Winsor, there are four types of microemulsion
phases exists in equilibria , these phases are referred as Winsor
phases. They are,
 Winsor I: With two phases, the lower (o/w)
Microemulsion phases in equilibrium with the upper excess oil.
 Winsor II: With two phases, the upper (w/o)
Microemulsion phase in equilibrium with lower excess water.
 Winsor III: With three phases, middle
Microemulsion phase (o/w plus w/o, called bi continous) in equilibrium
with upper excess oil and lower excess water.
 Winsor IV: In single phase, with oil, water and
Surfactant homogenously mixed.
45

46
 Advantages Of Microemulsion Over Other Dosage Forms
• Increase the rate of absorption.
• Eliminates variability in absorption.
• Helps solublize lipophilic drug.
• Provides a aqueous dosage form for water insoluble drugs.
• Increases bioavailability.
• Various routes like tropical, oral and intravenous can be used to
deliver the product.
• Rapid and efficient penetration of the drug moiety.
• Helpful in taste masking.
• Provides protection from hydrolysis and oxidation as drug in oil
phase in O/W microemulsion is not exposed to attack by water and
air.
• Liquid dosage form increases patient compliance.
• Less amount of energy requirement.

47
 A large number of oils and surfactant are available but their use in the
microemulsion formulation is restricted due to their toxicity, irritation
potential and unclear mechanism of action.
 Oils and surfactant which will be used for the formulation of microemulsion
should be biocompatible, non-toxic, clinically acceptable, and use emulsifiers
in an appropriate concentration range that will result in mild and non-
aggressive microemulsion.
 The emphasis is, excipients should be generally regarded as safe.
Component of Microemulsion System

48
1. Oil phase
2. Surfactant
3. Aqueous Component
 If a cosurfactant is used, it may sometimes be represented at a fixed ratio
to surfactant as a single component, and treated as a single "pseudo-
component".
 The relative amounts of these three components can be represented in a
ternary phase diagram.
 Gibbs phase diagrams can be used to show the influence of changes in the
volume fractions of the different phases on the phase behavior of the
system.
Main three components

 In case turbidity appears followed by a phase
separation, the samples shall be considered as
biphasic.
 In case monophasic, clear and transparent
mixtures are visualized after stirring; the samples
shall be marked as points in the phase diagram.
The area covered by these points is considered as
the microemulsion region of existence.
50
contd….

Oil Component
 The oil component influences curvature by its ability to
penetrate and swell the tail group region of the surfactant
monolayer.
 Following are the different oil are mainly used for the
formulation of microemulsion:
 Saturated fatty acid-lauric acid, myristic acid,capric acid
 Unsaturated fatty acid-oleic acid, linoleic acid,linolenic acid
 Fatty acid ester-ethyl or methyl esters of lauric, myristic and
oleic acid.
 The main criterion for the selection of oil is that the drug
should have high solubility in it.
 This will minimize the volume of the formulation to deliver
the therapeutic dose of the drug in an encapsulated form.
51

Surfactants
 The role of surfactant in the formulation of microemulsion is to
lower the interfacial tension.
 The surfactant should have appropriate lipophilic character to
provide the correct curvature at the interfacial region.
 Generally, low HLB surfactants are suitable for w/o microemulsion,
whereas high HLB (>12) are suitable for o/w microemulsion.
 Following are the different surfactants are mainly used for
microemulsion-
 Polysorbate (Tween 80 and Tween 20), Lecithins, Decyl
polyglucoside (Labrafil M 1944 LS), Polyglyceryl-6-dioleate
(Plurol Oleique), Dioctyl sodium sulfosuccinate (Aersol OT),
PEG-8 caprylic /capril glyceride (Labrasol).
52

Co surfactants
 Cosurfactants are mainly used in microemulsion formulation for
following reasons:
 They allow the interfacial film sufficient flexible to take up different
curvatures required to form microemulsion over a wide range of
composition.
1. Short to medium chain length alcohols (C3-C8) reduce the
interfacial tension and increase the fluidity of the interface.
2. Surfactant having HLB greater than 20 often require the presence
of cosurfactant to reduce their effective HLB to a value within the
range required for microemulsion formulation.
 Following are the different co surfactant mainly used for
microemulsion:
sorbitan monoleate, sorbitan monosterate, propylene glycol,
propylene glycol monocaprylate (Capryol 90), 2-(2-
ethoxyethoxy)ethanol (Transcutol) and ethanol.
53

Preparation of Microemulsion
 Following are the different methods are used
for the preparation of microemulsion:
1. Phase titration method
2. Phase inversion method
54

 Microemulsions are thermodynamically stable, so they
can prepared simply by blending oil, water, surfactant
and cosurfactant with mild agitation or mild heat.
 Titrating the mixer of surfactant ,cosurfactant,and oil
against the water till the clear solution is obtained.
 If solution is still slight turbid then add some more
amount of cosurfactant to get the clear solution.
55
Contd…

Phase inversion method
 Phase inversion of microemulsion is carried out upon addition of
excess of the dispersed phase or in response to temperature.
 During phase inversion drastic physical changes occur including
changes in particle size that can ultimately affect drug release
both in vitro and in vivo.
 For non-ionic surfactants, this can be achieved by changing the
temperature of the system,
forcing a transition from an o/w microemulsion at low
temperature to a w/o microemulsion at higher temperatures
(transitional phase inversion).
57

 During cooling, the system crosses a point zero spontaneous
curvature and minimal surface tension, promoting the formation
of finely dispersed oil droplets.
 Apart from temperature, salt concentration or pH value may
also be considered.
 A transition in the radius of curvature can be obtained by
changing the water volume fraction.
 Initially water droplets are formed in a continuous oil phase by
successively adding water into oil. Increasing the water volume
fraction changes the spontaneous curvature of the surfactant
from initially stabilizing a w/o microemulsion to an o/w
microemulsion at the inversion.
58
Contd…

 Many examples of microemulsion based formulations
are now on the market ;
Among them, the performances of microemulsions
are well demonstrated in the reformulation of
Cyclosporin A by Novartis into a microemulsion
based formulation marketed under the trade mark
Neoral®
59
Contd..

Characterization Of Microemulsion
1. The droplet size,
2. viscosity,
3. density,
4. turbidity,
5. refractive index,
6. phase separation and
7. pH measurements shall be performed to
characterize the microemulsion.
60

The droplet size
 The droplet size distribution of microemulsion vesicles can be
determined by either light scattering technique or electron
microscopy.
 This technique has been advocated as the best method for
predicting microemulsion stability.
Dynamic light-scattering measurements.
The DLS measurements are taken at 90 in a dynamic
light-scattering spectrophotometer which uses a neon
laser of wavelength 632 nm. The data processing is done
in the built-in computer with the instrument.
61

Phase analysis and viscosity measurement
 Polydispersity
Studied using Abbe refractometer.
 Viscosity measurement
The viscosity of microemulsions of several compositions can be
measured at different shear rates at different temperatures using
Brookfield type rotary viscometer.
The sample room of the instrument must be maintained at 37
0.2 C by a thermobath, and the samples for the measurement are
to be immersed in it before testing.
62

63
Bulb glows with O/W Bulb doesn’t glow with W/O
Emulsion Emulsion
Phase analysis
To determine the type of microemulsion that has formed, the
phase system (o/w or w/o) of the microemulsions is determined by
measuring the electrical conductivity using a conductometer.

Stability Studies
 The physical stability of the microemulsion must be determined
under different storage conditions (4 C, 25 C and 40 C) during
12 months.
 Depending on different regulatory agency requirement it’ll vary
according to them.
 Fresh preparations as well as those that have been kept under
various stress conditions for extended period of time is subjected
to droplet size distribution analysis.
 Effect of surfactant and their concentration on size of droplet is
also be studied.
64

Application of microemulsion in delivery of drug
 Oral delivery
 Microemulsions have the potential to enhance the solubilization
of poorly soluble drugs (particularly BCS class II or class IV)
and overcome the dissolution related bioavailability
problems.
 These systems have been protecting the incorporated drugs
against oxidation, enzymatic degradation and enhance
membrane permeability.
 Presently, Sandimmune Neoral(R) (Cyclosporine A),
Fortovase(R) (Saquinavir), Norvir(R) (Ritonavir) etc. are the
commercially available microemulsion formulations.
 Microemulsion formulation can be potentially useful to improve
the oral bioavailability of poorly water soluble drugs by
enhancing their solubility in gastrointestinal fluid. 65

Topical delivery
 Topical administration of drugs can have advantages over other
methods for several reasons, one of which is the avoidance of hepatic
first-pass metabolism of the drug and related toxicity effects.
 Another is the direct delivery and target ability of the drug to affected
areas of the skin or eyes.
 Now a day, there have been a number of studies in the area of drug
penetration into the skin.
 They are able to incorporate both hydrophilic (5-flurouracil,
apomorphine hydrochloride, diphenhydramine hydrochloride,
tetracaine hydrochloride, methotrexate) and lipophilic drugs
(estradiol, finasteride, ketoprofen, meloxicam, felodipine, triptolide)
and enhance their permeation.
66

Evaluation of Microemulsion
1)Percentage Transmittance:
 Transparency of microemulsion formulation was determined by
measuring percentage transmittance through U.V. Spectrophotometer.
2)Droplet Size Analysis:
By microscopic method
3)Zeta-Potential Determination:
4)Viscosity
5)Stability Studies:
The optimized ME was stored at three different temperature ranges
for 6 months i.e., refrigerating condition (20C – 80C), room
temperature and elevated temperature (50 20C) and shelf life of the
stored microemulsion system was evaluated by visual inspection
(phase separation), % transmittance, Particle size and % Assay.
67

68
Drug Name Route Purpose/Result
Flurbiprofen Parenteral Increased the solubility
Apormorphine HCl Transdermal Increased the permeability
Ketoprofen Transdermal Enhancement of permeability
Prilocainne-HCL Transdermal Increased the solubility
Estradiol Transdermal Improvement in solubilization
Aceclofenac Dermatological Increased the solubility
Piroxicam Oral Increased the solubility
Diclofenac Transdermal Permeability enhancement
Dexamethasone Topical Ocular Enhanced the Bioavailability
Chloramphenicol Ocular Increased the solubility
Ibuprofen Parenteral Increased the solubility
Sumatriptan Intranasal Enhanced the Bioavailability
Ibuprofen Topical Increasing the solubility
Research Work carried out on Microemulsions

NANOEMULSION
• Nanoscale emulsion having size less than 100nm.
• Due to their small droplet size, nano-emulsions may appear
transparent, and Brownian motion prevents sedimentation or
creaming, hence offering increased stability.
• In contrast to microemulsions, nanoemulsions are
metastable and can be diluted with water without changing
the droplet size distribution.
• Nanoemulsion are thermodynamically stable system in
which the two immisible liquid (water and oil)are mix to
form a single phase by means of appropriate surfactant .
69

Method of preparation
1)High pressure homoginization:
• By high pressure homoginizer or piston homoginizer which
produce NEs of exrtemly low particle size upto 1 nm.
2)Microfluidization:
• This make use of microfluidizer.
• This device use high pressure positive displacement
pump(500-20000 psi) which force the product through the
interaction chamber which consist of small micro channel.
• Product flow throgh the micro channel on to the impigment
resulting in the formation of nano size droplet.
70

CHARACTERIZATION OF NANOPARTICALS
• Nano-emulsions are not thermodynamically stable, and because of
that, their characteristics will depend on preparation method. Here
some parameters are discussed which should be analysed at the
time of preparation of nanoemulsion.
• Phase Behavior Study
This study is necessary in characterization and optimization of
ingredients. This is used in case of NE formulation prepared by
phase inversion temperature method and self-emulsification
method.
• Particle Size Analysis
Generally Dynamic Light Scattering(DLS) method are used.
• Surface Charge Measurement
Surface zeta potential of NE droplets should be measured with the
help of mini electrode to predict the surface properties of NEs. .72

• Transmission Electron Microscopy
TEM is used to observe the morphology in Nano-emulsion.
• Viscosity
Viscosity should be measured to ensure the better delivery of
the formulation.
• Morphology & structure
Morphology and structure of nanoemulsion can be studied
using TEM. The study of globule shape and surface can be
observed by TEM. To perform TEM observations, a drop of
the nanoemulsion is deposited on the holey film grid and
observed after drying.
73
Contd…

Advantages of nanoemulsion
• Reduction of globules: Increase surface area,
Enhance solubility, Increase bioavailability
• They do not show the problems of flocculation,
coalescence and sedimentation.
• They are non-toxic ,non-irritant
74

Limitations Of Nanoemulsions
• The manufacturing of nanoemulsion formulation is an expensive
process because size reduction of droplets is very difficult as it
required a special kind of instruments and process methods.
• For example, homogenizer (instruments required for the
nanoemulsion formulation) arrangements is an expensive process.
Again microfluidization and ultrasonication (manufacturing
process) required high amount of financial support.
• Stability of nanoemulsion is quite unacceptable and creates a big
problem during the storage of formulation for longer time of
period. Ostwald ripening is the main factor associated with
unacceptability of nanoemulsion formulations. This is due to high
rate of curvature of small droplets show greater solubility as
compared to large drop with a low radius of curvature.
75

APPLICATIONS OF NANO-EMULSIONS
76
 The compositional flexibility of nanoemulsions offers a wide range of
applications.
 The incorporation of fluorescent dyes and other molecules into nanoemulsions
makes the interesting probes for exploring properties of living cells and for
drug delivery.
 Nanoemulsion vaccine could inactivate and kill the virus and then
subsequently induce immunity to the virus that includes cellular immunity,
antibody immunity and mucosal immunity.
 The deformable and liquid nature of the droplets may lead to discoveries of
new pathways for cellular uptake and dispersal. Both oil-soluble and water-
soluble drug molecules can be incorporated into the nanodroplets of direct and
inverse nanoemulsions for potential pharmaceutical uses.
 In the printing and data storage industries, one may imagine the resolution of
droplets.

 In the personal care and food industries, nanoemulsions may
provide interesting alternatives as pleasantly transparent and soft
solids that possess plastic-like rheological properties. While being
appealing from an optical and rheological point of view,
nanoemulsion also can deliver moisturizers to the skin quite
efficiently and also block ultraviolet light without leaving a white
residue.
 The small size of the nano droplets will likely increase transport
efficiency of any active drugs or other molecules inside the
droplets across biological membranes, including the skin. Thus,
nanoemulsions may have significant applications in medical
patches.
 High-throughput production methodologies make nanoemulsions a
realistic commercial-scale alternative for diverse areas, including
lotions and pharmaceuticals.
77
Contd…

Marketed products:
Drug Brand Manufacturer Indication
Propofol Diprivan Astra zeneca Anesthatic
Dexamethazone Limethasonn Mitsubishi
pharmaceutical,
Japan
Steroids
Palmitate
alprostadil
Liple Mitsubishi
pharmaceutical,
Japan
Vasodilator
Flubriprofen axetil Ropion Kaken
pharmaceutical,
Japan
NSAIDS
Vitamines A,D,E,K Vitalipid Fresenius
kabi,Europe
Parenteral
nutrition
78

Introduction
 Multiple emulsion systems are novel developments in the field of
emulsion technology and are more complex type of dispersed
system.
 These are the emulsion systems in which the dispersed phase
contain smaller droplets that have the same compositon as the
external phase.
 These made possible by the double emulsification hence the
systems are also called as “double emulsion”.
 Diameter of the droplets in a Multiple emulsion is in the range of
0.5 to 3µm.
 Multiple emulsions are defined as emulsions in which both
types of emulsions, i.e. water-in-oil (w/o) and oil-in-water
(o/w) exist simultaneously.
 They combine the properties of both w/o and o/w emulsions
 These two liquids forming a system are characterized by their
low thermodynamic stability .
80

 Like simple emulsion multiple emulsion are
classified into two type.
1)O/W/O type
2)W/O/W type
 The immiscible phase ,which separates the two
miscible phase is known as “liquid membrane” and
act as a diffusion barrier and semipermeable
membrane for drugs or moities entrapped in the
internal aqueous phase.
81

Preparation
 Multiple emulsions, either W/O/W or O/W/O emulsions, are
generally prepared using a 2-step procedure.
 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 re-emulsified
in an aqueous solution of a high-HLB 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.
82

Multiple emulsion (w/o/w or o/w/o), Prepared by two step procedure
First step (o/w)
Primary emulsion
Second step (o/w/o)
Secondary emulsification
phase
83
Oil + Aqueous phase Low HLB surfactant + Oil
Blend and heat up to
70-80º C
Formation of very fine droplets
Heat and blend with
low shear
Oil
Multiple emulsion
Blend with low shear

84
 Viscosity
 surface tension
 conductivity
 pH
 Globule size
 Test for sterility
 Microscopic method
 Particle size distribution
EVALUATION OF MULTIPLE EMULSION

86
Application :
 Controlled and sustained drug delivery.
 Vaccine adjuvant.
 Cosmetic application.
 As a preparative tool for microencapsulation
technology.
 Miscellaneous.
Protection action.
Taste masking.
Absorption enhancement through GIT.

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 hydroxy propyl methyl cellulose
phthalate (HPMCP).
 A micro-particulate 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 enteric coated dry emulsion formulation is potentially applicable
for the oral delivery of peptide and protein drugs.
87

Homogenization and membrane emulsification
Dropwise extrusion through a syringe
Recovery and lyophilization.
88

89
Jiraporn CHINGUNPITUK,
Nanosuspension Technology for Drug Delivery,
Walailak J Sci & Tech 2007; 4(2): 139-153.
V. B. Patravale, Abhijit A. Date and R. M. Kulkarni,
Nanosuspensions: a promising drug delivery strategy
JPP 2004, 56: 827–840
Rong Liu
Water-Insoluble Drug Formulation
Second Edition, page no. 122-123
Nanoparticle Technology for Drug Delivery,
edited by Ram B. Gupta and Uday B. Kompella

90
Advances in controlled and novel drug delivery.
By N.K.Jain.
Targeted and controlled drug delivery
By S.P.Vyas and R.K.Khar
Nano emulsion: A pharmaceuticle review.
http:/www.sysrevpharm.org
Review Article :Microemulsions: a novel drug carrier
system.International Journal of Drug Delivery Technology
2009; 1(2): 39-41 www.ijddt.com
TOPICAL REVIEW: nanoemulsions:
Formation, structure, and physical properties. Journal of
physics: condensed matter 18 (2006) r635–r666
Stacks.Iop.Org/jphyscm/18/R633

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