A seminar on
MULTIPLE EMULSIONS
by
M. NALINI KRISHNA REDDY
(M.Pharm. I Semester)
Department of Pharmaceutics
BLUE BIRDS COLLEGE OF PHARMACY
(Affiliated To Kakatiya University)
WARANGAL-506 009
CONTENTS
•
INTRODUCTION
•
FORMULATION OF MULTIPLE EMULSIONS
•
PREPARATION OF MULTIPLE EMULSIONS
•
CHARACTERISATIONOFMULTIPLEEMULSIONS
•
STABILITY OF MULTIPLE EMULSIONS
•
STABILITY ASSESSMENT STUDIES
•
DRUG RELEASE FROM MULTIPLE EMULSIONS
•
BIOAVAILABILITY
•
APPLICATIONS
•
CONCLUSION
REFERENCES
INTRODUCTION
 An emulsion “is a thermodynamically unstable system
consisting of at least two immiscible liquid phases, one of
which is dispersed as globules in other liquid phase,
stabilized by presence of an emulsifying agent” (Leon et al,
1991).
 Emulsifying agents are ampiphillic in nature.
 Emulsifiers assist in formation of emulsions by three
mechanisms (Leon et al, 1991).
 Reduction in interfacial tension.
 Formation of rigid interfacial film.
 Electric repulsion.
MULTIPLE EMULSIONS
 These are polydispersed system where the drops of the
dispersed phase themselves contain even smaller
droplets, in most cases identical with a continuous phase.
 Based on dispersed media multiple emulsions are of two
types (James et al, 2002).
w/o/w multiple emulsion
o/w/o multiple emulsion
 According to seifriz even more complex multiple emulsions
may occur like, o/w/o/w/o or w/o/w/o/w but the stability is
delicate.
 Certain multiple emulsions have been termed as liquid
membrane systems
(Jim et al, 2003)
FORMULATION OF MULTIPLE EMULSIONS
(Shende et al, 2006)
 Mainly multiple emulsion are composed of :
Oils:
 For pharmaceutical use oils like refined hydrocarbon oils are
used. Such as, light liquid paraffin and esters of long chain fatty
acids including vegetable oils and mineral oils. Example: ethyl
oleate, isopropyl meristate, olive oil, arachies oil, seasem oil.
 Mixtures of oils can be used.
 To reduce specific gravity
 To alter the viscous nature of the oil.
……..FORMULATION OF MULTIPLE EMULSIONS
• Selection of oil phase can affect various emulsion
parameters. Like :




Yield
Release profile
Particle size
Emulsion stability
 A novel o/w/o emulsion containing castor oil as internal oil
phase and a floro carbon as an external oil phase has
been described for pulmonary delivery of the drug.
…….FORMULATION OF MULTIPLE EMULSIONS
Aqueous phase (Sinha et al, 2002):
 The two aqueous phases of w/o/w emulsions can be
 Simple aqueous solution of drugs
 Buffer solutions
 Aqueous suspensions of drug
 Gelled aqueous phase and
 Aqueous phases containing viscosity enhancers
 Increase and release rate of drug can be modified by changing
the pH of two aqueous phases.
 Increase in difference of pH between two aqueous phases’
leads to instability.
…….FORMULATION OF MULTIPLE EMULSIONS
Surfactants (Florence et al, 1982):
 Reduce interfacial tension between two phases (w/o or o/w
interface)
 At least two surfactants are used for the preparation of multiple
emulsions.
 For w/o/w lipophilic surfactant act as primary emulsifier and
hydrophilic as secondary emulsifier in case of o/w/o it is vice
versa.
 The optimum concentration of the surfactant to emulsify given
oil can be determined by the use of hydrophilic lipophilic
balance (HLB).
…….FORMULATION OF MULTIPLE EMULSIONS
Surfactants (Florence et al, 1982):
 For primary surfactant the HLB valued should be in the range of
2-7 and for secondary surfactant it is between 6-16 for a w/o/w
emulsion.
 Non ionic emulsifiers are preferred due to their low toxicity and
they do not react with ionic compounds.
 Non ionic surfactants like spans and tweens have high HLB
range are used.
PREPARATION OF MULTIPLE EMULSIONS
Two step emulsification or double emulsification method
(James et al, 2002):
 Multiple emulsions may be prepared in a two stage
procedures by the re-emulsification of a primary
emulsions.
 First step is preparation of primary emulsion.
 The second emulsification step is critical, and excess
mixing can fracture the drops, resulting in simple emulsion
 A low sheer mixer may be employed with 1000 rpm for 15
minutes in first step not more than 600 rpm for 5 minutes
for second step.
PREPARATION OF MULTIPLE EMULSIONS
Fig. Preparation of w/o/w type of multiple emulsions by two step method
PREPARATION OF MULTIPLE EMULSIONS
Phase Inversion or one step method:
Fig. Preparation of multiple emulsions using phase
inversion technique
PREPARATION OF MULTIPLE EMULSIONS
Membrane Emulsification Method (Charcosset et al, 2004)
Fig-Schematic diagram of apparatus
used for the multiple emulsion
preparation using
membrane emulsification technique
Y = 5.03X + 0.19
Y-mean globule size
X-membrane pore size
CHARACTERIZATION OF MULTIPLE EMULSIONS
(Shende et al, 2006)
Average globule size and size distribution:
 Optical microscopy,
 Coulter counter method.
 Electron microscopy
• Average globule size of multiple emulsion ranges from
2-5 micrometers.
• Size distribution studies are done to know the movement
of particles i.e., size distribution behaviors with time
(coalescence and flocculation).
……CHARACTERIZATION OF MULTIPLE EMULSIONS
 The critical size of droplets for setting is given from
stokes law.
 Rate of setting or creaming = D2/18 ή (dp -dm) g.




D = particle diameter
ή = viscosity of the medium
dp & dm = densities of particles and medium
g = gravitational constant
……CHARACTERIZATION OF MULTIPLE EMULSIONS
Area of interphases:
 The average globule diameter determined can be used in
the calculation of total area of interphase.
 S = 6/D (S – total area of interphase in sq. cm. & Ddiameter of globule in cm.)
Number of globules:
 Number of globules per cubic millimeter can be measured
using haemocytometer cell.
 Number of globules/mm3 = number of globules x dilution x
4000 / number of small square counted.
 Average droplet size should be in the range of 2-5 µ.m.
……CHARACTERIZATION OF MULTIPLE EMULSIONS
Yield or Entrapment Efficiency (Sinha et al, 2002)
 Yield is expressed in two ways
 Percentage of multiple droplets relative to simple
droplets
 Fraction of internal aqueous phase entrapped as
multiple droplets.
 Factors affecting the yield of multiple emulsions
 Primary phase volume ratio
 Secondary emulsification time
 Mixing speed
 Secondary phase volume ratio
 Additives
……CHARACTERIZATION OF MULTIPLE EMULSIONS
 Determination of entrapment efficiency




Internal phase tracer technique
Dialysis
Centrifugation
Conducirtivty measurements
Per cent of drug entrapped = amount of drug
entrapped/total amount of
drug X 100.
……CHARACTERIZATION OF MULTIPLE EMULSIONS
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.
STABILITY OF MULTIPLE EMULSIONS
 Emulsion stability is a phenomenon which depends upon
the equilibrium between water, oil and emulsifier.
Unfortunately Multiple Emulsions are thermodynamically
unstable (Jim et al, 2003).
 Some of the breakdown pathways that may occur in
multiple emulsions are
 Coalescence of internal droplets
 Coalescence of multiple droplets
 Expulsion of internal droplets
 Shrinkage of internal droplets
 The causes for the instability of multiple emulsions are
 Migration of emulsifier
 Osmotic instability
 Creaming
METHODS TO STABILISE MULTIPLE EMULSIONS
 The following methods can be used for stabilization of
multiple emulsions (Sinha et al, 2002) :
 Use of high viscous oils
 Polymerization and complexation of interfacially
adsorbed surfactant molecules
 Gelation of oil or aqueous phases of the emulsion
 Liquid crystal stabilized multiple emulsion
 Stabilization in the presence of electrolytes
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
STABILITY ASSESSMENT STUDIES

 Stability of multiple emulsions can be assessed in various
aspects like
 Determination of particle size
 Determination of phase separation
 Measurement entrapped percentage and viscosity
 In – vitro release studies:
 Dialyzing the multiple emulsion packed in a dialysis tube
against a suitable dissolution media
 Conductometric method
Fig: Assembly use for invitro drug release.

In –vivo evaluation:
 Blood concentration data in rats and rabbits
 Urinary excretion data in man
DRUG RELEASE FROM MULTIPLE EMULSIONS

Release of drug from multiple emulsions occurs from
various mechanisms (Pandit et al, 1987).






Diffusion of unionized drugs through the oil layer
Carrier mediated transport
Micellar transport
Rapture of oil membrane
Thinning of oil membrane
Swelling and breakdown behavior
BIOAVAILABILITY OF MULTIPLE EMULSIONS
 The administration of emulsions intravenously, presence of
interesting relationship between physicochemical properties
and physiological response (Walster, 1993).
 The clearance of an emulsion from the blood is determined
largely by its interaction with the reteculo endothelial
system. It can be stated that:
 Fine particle size emulsions are cleared more slowly than
coarse particle size emulsions.
 Negatively charged and positively charged particles are
cleared more quickly than natural particles.
 Emulsions stabilized by low molecular weight emulsifiers
are cleared more rapidly than those stabilized by high
molecular emulsifiers.
APPLICATIONS OF MULTIPLE EMULSIONS:
 Multiple emulsions are formulated for intravenous,
topical and oral administration.
 Controlled and sustained drug delivery
 Improve in the bioavailability
 Drug targeting
 Vaccine adjuvant
 Hemoglobin multiple emulsion
 Masking of taste
 Drug overdose treatment
 Immobilization of enzymes
 Tropical and cosmetic use.
CONCLUSION
 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.
 Various factors affecting the stability of multiple emulsions
and the stabilization approaches of multiple emulsions
were discussed in detail.
CONCLUSION
 Favorable drug release mechanisms and rate along with
in-vivo fate of multiple emulsions make them a versatile
carrier. 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.
REFERENCES
• James Swarbrick, James C, Boylan, Encyclopedia of
Pharmaceutical Technology, Marcel Dekker, Inc. Vol.5 (2) :
117-168 (2002).
• Herbert A , Lieberman, Gilberts Banker, ‘ Pharmaceutical
dosage forms, Disperse systems’, vol.2 : 11 – 19 (1995).
• Nissim Garti, Abraham Aserin ‘pharmaceutical Emulsions,
Double Emulsions and Microemulsions’, The Hebrew
University of Jerusalem, Jerusalem, Israel, 494 (2001).
• Leon Lachman, Herbert A. Libertman, Joseph L, Kanig,
The Theory and Practice of Industrial Pharmacy, ( 3) : 501
– 534 (1991).
• Sanjay kumar Goswami, ‘Multiple Emulsions : An auto
processing system for enzymes’, Pharmatimes vol 30 : 17
(1998).
……REFERENCES
• Charcosset c, Limayem I, Fessi H, ‘The membrane
emulsification process – A Review’, J Chem Technol
Biotechnology 79 : 209- 218 (2004).
• Walster P, ‘Emulsion Stability’, Encyclopedia of Emulsion
Technology : Marcel Dekker vol 4 : 1 – 62 (1996).
• Jim Jiao, Diane J, Burgess, ‘Rheology and stability of waterin-oil-in-water multiple emulsions containing span 83 and
tween 80’ , Pharmaceutical R&D, PGRD, Pfizer Inc, Groton,
CT 06340 , AAPS PharmSci, 5: (1) (2003).
• Shende P, Bhattacharya A, 'Formulation and
characterization of Multiple Emulsions‘, Journal of
pharamaceutical research, vol 5:131-136 (2006).
• Ozero, yazan, aydin B, ‘Evaluation of multiple w/o/w
emulsions containing different oils’, Pharmatimes, 3 : 17-21
(2001).
……REFERENCES
• V R Sinha, Kumar A, Multiple Emulsion : An overview of
formulation, characterization, stability and application’,
Indian J Pharm Sci, vol 64 (3) : 191 – 199 (2002).
• Laugel c, A. Baillet ,M P Youenang Piemi , J. P. Marty ,
D. Ferrier, ‘Oil–water–oil multiple emulsions for prolonged
delivery of hydrocortisone after topical application:
comparison with simple emulsions’ ,International Journal of
Pharmaceutics ,vol 160 (1) 109 - 117 (1998).
• Pandit J K , Mishra B, Chand B, ‘Drug release from
multiple w/o/w emulsions’, Indian J Pharm Sci 103-105
(1987).
Thank you