multiple and microemulsions
TRANSCRIPT
PESENTED BY,K.SAILAKSHMI,M.PHARMACY,(Pharmaceutics),256213886016.
UNDER THE GUIDENCEOF
Dr . YASMIN BEGUMM.pharm , Ph.d
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CONTENTS
• INTRODUCTION
• MICRO EMULSIONS
TYPES OF MICRO EMULSIONS
DIFFERENCE BETWEEN MICRO AND MACRO
PREPARATION AND CHARACTERISATION
ADVANTAGES
STABILITY STUDIES
USES
• EQUIPMENTS
• MUTIPLE EMULSIONS
TYPES
PREFORMULATION OF DOUBLE EMULSIONS
PREPARATION OF MULTIPLE EMULSIONS
MECHANISMS AND EVALUATION
STABILITY
USES
• CONCLUSION
An emulsion is a thermodynamically unstable system consisting
of atleast two immisible liquid phases one of which is dispersed
as a globules in the other liquid phase stabilised by a third
substance called emulsifying agent
An emulsion is a mixture of two or more
immiscible(unblendable) liquids
Emulsions are a part more general classes of two phase systems
of matter called Colloids
In an emulsion one liquid(the dispersed phase) is dispersed in
the other (the continuos phase)
EMULSION
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MICRO EMULSIONS
DEFINITION: (Danielsson and Lindman)
“ A micro emulsion is a system, of water ,oil and an
amphiphile which is a single optically isotropic and
thermodynamically stable liquid solution.”
In some aspects, micro emulsions can be considered as
small scale versions of emulsions ,i.e , droplet type dispersions
either of oil-in-water (o/w) or of water in oil (w/o) with a size
range in the order of 5-50nm in drop radius.
TYPES OF MICROEMULSIONS
Three types of micro emulsions are most likely to be formed depending on the composition:
• Oil in water micro emulsions wherein oil droplets are dispersed in the continuos aqueous phase
• Water in oil micro emulsions wherein water droplets are dispersed in the continuous oil phase
• Bi-continuous micro emulsions where in micro domains of oil and water are inter dispersed within the system.
In all three types of microemulsions, the interface is stabilized by an appropriate combination of surfactants and/or co-surfactants.
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The term micro emulsion introduced by Schulman and co-works.
The term "micro emulsion" refers to a thermodynamically stable
isotropically clear dispersion of two immiscible liquids, such as oil
and water, stabilized by an interfacial film of surfactant molecules.
A micro emulsion is considered to be a thermodynamically or
kinetically stable liquid dispersion of an oil phase and a water
phase, in combination with a surfactant.
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The key difference between emulsions andmicro emulsions are that the former, whilst they mayexhibit excellent kinetic stability, are fundamentally thermodynamically unstable and will eventually phase separate.
Another important difference concerns their appearance;emulsions are cloudy while micro emulsions are clear or translucent.
In addition, there are distinct differences in their methodof preparation, since emulsions require a large input of energy while micro emulsions do not.
Micro emulsion formation and stability can be explained on the basis of a simplified thermodynamic rationalization.
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Microemulsions and (Macro) emulsions are
Different
Microemulsion
• Thermodynamically Stable
• Droplet size 10 - 100 nm
(transparent)
• High surface area: 200 m2/g
• Ultra Low O/W IFT (10-2 –
10-3 mN/m)
• W/O , O/W and
Bicontinuous types
• Forms at CPP = 1
Macroemulsion
• Kinetically Stable
• 1-10 m (opaque)
• Low surface area: 15 m2/g
• O/W IFT 1-10 mN/m
• W/O or O/W types
• Forms at CPP > or < 1
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PREPARATION OF MICROEMULSION:
Microemulsions were prepared at 27°C by a titration
method.
The drug is be dissolved in the lipophilic part of the microemulsion
i.e. Oil and the water phases can be combined with surfactant and
a cosurfactant is then added at slow rate with gradual stirring until
the system is transparent.
The amount of surfactant and cosurfactant to be added and the
percent of oil phase that can be incorporated shall be determined
with the help of pseudo-ternary phase diagram.
Ultrasonicator can finally be used so to achieve the desired size
range for dispersed globules. It is then be allowed to equilibrate. 9
Oil-in-water microemulsions were prepared by the titrationmethod.
A mixture of fatty acid and oil was added to a caustic solutionto produce a microemulsion, which was then titrated with a cosurfactant, an alcohol, until the system turned clear.
It was found that as the chain length of the surfactant increased, microemulsions with significant transmittances by visible spectrum could be formed with oils of longer chain lengths.
It was also found that different alcohols affected the formationof microemulsions in different ways.
The best results, in terms of the greatest percent transmittance coupled with the widest range of oil (dispersedin water) concentration, were obtained from short or branched alcohols.
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The free energy of microemulsion formation can beconsidered to depend on the extent to which surfactant lowers the surface tension of the oil–water interface andthe change in entropy of the system such that,
DG f = γDA - T DS
where DG f is the free energy of formation,
γ is the surface tension of the oil–waterinterface, DA is the change in interfacial area on
microemulsification, DS is the change in entropy of the system which is
effectively the dispersion entropy,and T is the temperature.
It should be noted that when a microemulsion is formed the change in DA is very large due to the large number of very small droplets formed.
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Though it has been know that several factors determine whether a w/o or o/w system will be formed but in generalit could be summarised that the most likely microemulsionwould be that in which the phase with the smaller volumefraction forms the droplets i.e. internal phase.
The surfactants used to stabilise such systems may be:
(i) Non-ionic
(ii) Zwitterionic
(iii) Cationic
(iv) Anionic surfactants
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Various pharmaceutically acceptable availablethat can be used in microemulsion formulation exicipents are:
Long chain or high molecular weight (>1000) surfactantsinclude
Gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, polyoxyethylene alkyl ethers,
e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters,
e.g., the commercially available Tweens, polyethylene glycols, polyoxyethylene stearates.
The low molecular weight (<1000) surfactants include: Stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, and sorbitan esters.
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Characterization Of Microemulsion
The droplet size, viscosity, density, turbidity, refractive index, phase separation and pH measurements shall be performed to characterize the microemulsion.
The droplet size distribution of microemulsion vesicles canbe determined by either light scattering technique or electron microscopy. This technique has been advocated as the best method for predicting microemulsion stability.
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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
· Rapid and efficient penetration of the drug moiety
· Helpful in taste masking
· Liquid dosage form increases patient compliance.
· Less amount of energy requirement.
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Stability Studies
The physical stability of the microemulsion must be determined under different storage conditions (4, 25 and 40 °C) during 12 months.
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.
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Uses
Microemulsions have many commercially important uses:
Water-in-oil microemulsions for some dry cleaning processes
Floor polishers and cleaners.
Personal care products
Pesticide formulations
Cutting oils.
Pharmaceutical applications of microemulsionsIncrease bioavailability of drugs poorly soluble in water.
Topical drug delivery systems
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Applications of microemulsions
Microemulsions in enhanced oil recovery
Microemulsions as fuels
Microemulsions as coatings and textile finishing
Microemulsions as lubricants, cutting oils and corrosioninhibitors
Microemulsions in detergency
Microemulsions in cosmetics
Microemulsions in agrochemicals
Microemulsion in pharmaceuticals
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EQUIPMENT USED IN PREPARATION OF
EMULSIONS
COLLOIDAL MILLAPPLICATION:
Product is feed to the operating area of a rotor,
having a speed of 2800 R.P.M by specially
designed feed device. The product is processed
by high sheer, pressure and friction between the
stator and rotor, the angular gap becomes
narrower towards the discharges section. This
processed product continuously leaves the mill
through the drain pipe, if required, it can be re-
circulated.
SALIENT FEATURES
All contact parts can be easily and quickly
dismantled and cleaned.
Machine is designed for continuous operation.
Cylindrical screen for higher output.
Flame proof electrical can be provided at extra
cost. 19
HOMOGENISER
High Speed Homogenizer
Vats & Vessels Homogenizer is used to
homogenize, emulsify, and disperse
material in pharmaceutical, cosmetics,
food, chemical, petrochemical industry, etc.
Working Principle -
High speed mechanical and hydraulic shear
forces are the real key to the success of this
machine. Rotor & stator generates a
shearing action which insures that materials
being processed are subjected to thousands
of shearing actions each minute.
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ROTORSTATOR
High speed rotor operating at close clearance
to stator draws material in from the bottom of
the mixing vessel and subjects it to intense
mixing and shearing action.
The rotor accelerates the product towards the
blades periphery. There it is expelled through
the stator openings into the body of the mix
while undergoing an intensive mechanical and
hydraulic shearing action.
Simultaneously new material is drawn in.
The expelled mixture is deflected by the tank
wall completing the circulation pattern.
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DEFINITION
Multiple emulsions are the emulsion system in which thedispersed phase contain smaller droplets that have the same composition as the external phase.
This is made possible by double emulsification hence thesystems are also called as “double emulsion”.
Like simple emulsions, the multiple emulsions are also considered to be of two
types:
•Oil-in-Water-in-Oil (O/W/O) emulsion system
•Water-in-Oil-in-Water (W/O/W) emulsion system
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O/W/O EMULSION
In O/W/O systems an aqueous phase (hydrophilic)separates internal and external oil phase.
In other words, O/W/O is a system in which water dropletsmay be surrounded in oil phase, which in true encloses oneor more oil droplets.
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W/O/W EMULSION
In W/O/W systems, an organic phase (hydrophobic) separates internal and external aqueous phases.
In other words, W/O/W is a system in which oil droplets maybe surrounded by an aqueous phase, which in turn encloses one or several waterdroplets.
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These systems are the most studied among the multiple emulsions.
The immiscible oil phase, which separates two miscible aqueous phases is known as “liquid membrane” and acts as a different barrier and semi-permeable membrane for the drugs or moieties entrapped in the internal aqueous phase.
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Schematic Diagram of W/O/W & O/W/O
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Pre-Formulation of Double Emulsion
The formulate a double emulsion, it is necessary to
choose, at least, an oil and two surfactants, one low in HLB
and one high in HLB.
In the example mentioned here, we have been working
with span surfactants (HLB<5) and
Tween surfactants (HLB>10) and
with a vegetable oil (caprylic/ capric triglyceride).
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Methods of Preparation
Multiple emulsions are best prepared by
re- emulsification of primary emulsion.
The following are the method of multiple emulsions:
Two Steps Emulsification (Double Emulsification)
Phase Inversion Technique (One Step Technique)
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Two Steps Emulsification
(Double emulsification)
Two steps emulsification methods involve
re-emulsification of primary W/O or O/W emulsion
using a suitable emulsifier agent.
The first step involves, obtaining an ordinary W/O or
O/W primary emulsion wherein an appropriate
emulsifier system is utilized.
In the second step, the freshly prepared W/O or
O/W primary emulsion is re-emulsified with an excess
of aqueous phase or oil phase.
The finally prepared emulsion could be W/O /W or
O/W/O respectively. 30
Two Steps Emulsification
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Modified Two Steps Emulsification
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Phase Inversion Technique
(One Step Technique)
An increase in volume concentration of dispersed phase
may cause an increase in the phase volume ratio, which
subsequently leads the formation of multiple emulsions.
The method typically involves the addition of an aqueous phase
contains the hydrophilic emulsifier
[ Tween 80/sodiumdodecylsulphate (SDS) or Cetyl trimethyl
ammonium salt CTAB)] to an oil phase consisted of liquid
paraffin and containg lipophilic emulsifier (Span80).
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A well-defined volume of oil phase is placed in a vessel of
pin mixer.
An aqueous solution of emulsifier is then introduced
successively to the oilphase in the vessel at a rate of 5 ml/min,
while the pin mixer rotates steadily at 88 rpm at room
temperature. When volume fraction of the aqueous solution
of hydrophilic emulsifier exceeds 0.7, the continuous oil
phase is substituted by the aqueous phase containing a
number of the vesicular globules among the simple oil
droplets, leading to phase inversion and formation of
W/O/W multiple emulsion.
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Phase Inversion Technique
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POSSIBLE MECHANISMS OF DRUG RELEASE
FROM MULTIPLE EMULSIONS
Diffusion mechanism.
Micellar transport.
Thinning of oil membrane.
Rupture of oil phase.
Faciliated diffusion (carrier mediated transport).
Photo -osmotic transport.
Solubilization of internal phase in the oil membrane.
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EVALUATION OF MULTIPLE EMULSIONS
Characterization
Average globule size and size distribution
No.of globules
Percentage drug entrapment
Rheological evaluation
Zeta potential
In-vitro stability studies
In-vitro drug release
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Characterization :
Emulsions are mostly characterized by the size distribution
of the droplet and other physical properities such as dielectric
properities thermal behaviour, rheological properities and other
microscopic and macroscopic observation.
Macroscopic examination:
Primary observations like color, consistency, and
homegeneity are frequently used to ensure type of multiple
emulsions formed (w/o/w or o/w/o) can be validated by dilution
with the external phase.
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• Various other techniques used to characterize emulsions like
coulter counter, freeze-fracture electron microscopy and scanning
electron microscopy and are also used to determine average
globule size and size distribution of multiple emulsions droplets.
Number of globules
• Number of globules per cubic millimeter can be measured using
a haemocytometer cell after approriate dilution of the multiple
emulsions.
• The globules in five groups of 16 small squares (total 80 small
squares) can be counted and the total number of globules in per
cubic mm is calculated using the formula
No . of Globules/mm3 =No . of globules x Dilution x 4000
No . of small squares counted
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Percentage Drug Entrapment:
• Percent entrapment of drug or active moiety in the multiple
emulsion is generally determined using dialysis , centrifugation,
filtration and conductivity measurements.
• However , recently an internal tracer /marker was used to
evaluate the entrapment of an impermeable marker molecule
contained in the inner aqueous phase of w/o/w emulsion.
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The % Entrapment can be calculated using the following
equation :
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Rheology : (Jim et al, 2003)
By increasing the shear rate and shear time the apparent
viscosity increased.
Further shearing caused increase in shear stress of
emulsion and induced phase inversion
Reasons of phase inversion:
Increase in volume fraction of oil droplets by
entrapment of water molecules
Coalescence of oil droplets upon shearing
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Zeta- potential
• The zeta-potential and surface charge can be calculated using
smoluchowski’s equation from the mobility and electrophoretic
velocity of dispersed globules using the zeta-potentiometer.
• The apparatus consists of cylindrically bored micro-
electrophoresis cell equipped with platinum-iridium electrodes
to measure the electrophoretic mobility of the diluted w/o/w
emulsion.
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Zeta-potential was calculated using following formula:
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In vitro stability studies
• Phase separation is a phenomenon by which one phase of
emulsion gets separated due to colescence.
• Percentage phase separation is the volume of phase in
percentage separated from the total volume of emulsion after
storage .
• 20ml of freshly prepared w/o/w emulsion is kept in 25ml of
graduated cylinder and allowed to stand for defined period at
40˚c.
• The volume of separated aqueous phase (V sep) is observed
periodically at regular intervals.
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Percent phase separation is calculated using following
formula:
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In Vitro Drug Release
• The drug released from the aqueous inner phase of a w/o/w
emulsion can be estimated using the conventional dialysis
method using a cellophane tubing.
• Typically, 5ml of (w/o/w) multiple emulsion is placed in the
dialysis tube which is then tied at both ends by thread and
placed in basket (usually 100rpm) and dialyzed against
specified dissolution media (usually 200ml) at 37±1˚C.
•Aliquots were withdrawn at different time intervals and
replaced with fresh dissolution media and estimated using
standard procedure and the data were used to calculate
cumulative drug release profile.
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Fig: Assembly use for invitro drug release.
Stability of Multiple Emulsions
Emulsion stability is a phenomenon, which depends upon theequilibrium between water, oil and surfactant.
Unfortunately multiple emulsions are thermodynamically unstable.
The possible indications of instability includes:
Leakage of the contents from the inner aqueous phase.
Expulsion of internal droplets in external phase.
Constriction or distension of the internal droplets due toosmotic gradient across the oil membrane.
Flocculation of internal aqueous phase and multiple emulsion droplets.
Disruption of oil layer on the surface of internal droplets. Phase separation.
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Methods to Stabilize Multiple
Emulsions The followings are some of the attempt or studies made to restore or strengthen the stability of multiple emulsions :
Liquid crystal stabilized multiple emulsion.
Stabilization in presence of electrolytes.
Stabilization by forming polymeric gel.
Stabilization by interfacial complexation between non- ionic surfactant and macromolecules.
Steric stabilization
Phase-inversion stabilization of W/O/W emulsion
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Fig; Various approaches to stabilize w/o/w multiple emulsion.
A-stabilizing through liquid crystal formation
B-stabilization by interfacial polymerization
C-stabilization by adsorption of electrolyte or adsorption or covalent
anchoring of polymer
D-gelation of either internal or external phase or oil core
Applications in Therapeutics & Cosmetics:
Multiple emulsion systems are finding unlimited
uses because of their vesicular structure with
innermost phase closely similar to that of
liposomal vesicles and the selective permeability
characteristic of liquid membrane.
In cancer therapy.
In herbal drugs.
In taste masking.
In food industry.
In drug over dosage treatment.
In inverse targeting.
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APPLICATIONS
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• Micro emulsion properties are extremely varied. The extreme diversity of their practical applications is one consequence.
One of their disadvantages is the large amount of surfactant required to stabilize them because of the small dispersion size.
Although micro emulsion properties are beginning to be satisfactorily understood, especially the droplet structure, large research domains remain to be clarified.
With evaluation of newer techniques of preparation, stabilization, rheological properties can serves as potential carrier for drugs ,cosmetics ,pharmaceutical agents
CONCLUSION
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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 applications.
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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
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S.P. Vyas , R.K. Khar. Targeted & Controlled drug
delivery: novel carrier systems , 1st ed. New Delhi: CBS
publishers ; 2004,page no 303-303
Micro emulsions as drug delivery system,A.N
Lalwani,T.J shah&N.S Parmar-309
Targeted &Controlled Drug delivery vyas/khar-303
Progress in controlled and novel drug delivery system-nk
jain
Advance in controlled &drug delivery A.j khapae&N.K
jain-381
Remington the science and practice of pharmacy 21st ed.
page no-745
Martin’s physical pharmacy and pharmaceutical sciences
6th ed. Page no- 410
Journals.
REFERENCES
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