A seminar on MULTIPLE EMULSIONS - PowerPoint Presentation

Slide1

A seminar onMULTIPLE EMULSIONS

byM. NALINI KRISHNA REDDY(M.Pharm. I Semester)Department of PharmaceuticsBLUE BIRDS COLLEGE OF PHARMACY(Affiliated To Kakatiya University)WARANGAL-506 009Slide2

INTRODUCTION

FORMULATION OF MULTIPLE EMULSIONSPREPARATION OF MULTIPLE EMULSIONS

CHARACTERISATIONOFMULTIPLEEMULSIONS

STABILITY OF MULTIPLE EMULSIONSSTABILITY ASSESSMENT STUDIESDRUG RELEASE FROM MULTIPLE EMULSIONSBIOAVAILABILITY APPLICATIONSCONCLUSIONREFERENCES

CONTENTSSlide3

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.INTRODUCTIONSlide4

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 emulsiono/w/o multiple emulsionAccording 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 

MULTIPLE EMULSIONSSlide5

(Jim

et al

, 2003)Slide6

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 (Shende et al, 2006)Slide7

Selection of oil phase can affect various emulsion parameters. Like :

Yield Release profileParticle sizeEmulsion 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 EMULSIONSSlide8

Aqueous phase (Sinha et al,

2002): The two aqueous phases of w/o/w emulsions can be Simple aqueous solution of drugsBuffer solutionsAqueous suspensions of drugGelled aqueous phase andAqueous phases containing viscosity enhancersIncrease 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 EMULSIONSSlide9

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 EMULSIONSSlide10

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.…….FORMULATION OF MULTIPLE EMULSIONSSlide11

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 emulsionA 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 EMULSIONSSlide12

PREPARATION OF MULTIPLE EMULSIONS

Fig. Preparation of w/o/w type of multiple emulsions by two step methodSlide13

Phase Inversion or one step method:

PREPARATION OF MULTIPLE EMULSIONS

Fig. Preparation of multiple emulsions using phase

inversion techniqueSlide14

Membrane Emulsification Method

(Charcosset et al,

2004)

PREPARATION OF MULTIPLE EMULSIONS

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 sizeSlide15

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 (Shende et al, 2006)Slide16

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 diameterή = viscosity of the mediumdp & dm = densities of particles and mediumg = gravitational constant

……CHARACTERIZATION OF MULTIPLE EMULSIONSSlide17

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. & D- diameter 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 EMULSIONSSlide18

Yield or Entrapment Efficiency (Sinha

et al, 2002)  Yield is expressed in two waysPercentage of multiple droplets relative to simple dropletsFraction of internal aqueous phase entrapped as multiple droplets.Factors affecting the yield of multiple emulsionsPrimary phase volume ratioSecondary emulsification timeMixing speedSecondary phase volume ratioAdditives

……CHARACTERIZATION OF MULTIPLE EMULSIONSSlide19

Determination of entrapment efficiency

Internal phase tracer technique DialysisCentrifugationConducirtivty measurementsPer cent of drug entrapped = amount of drug entrapped/total amount of drug X 100.……CHARACTERIZATION OF MULTIPLE EMULSIONSSlide20

By increasing the shear rate and shear time the apparent viscosity increased.

Further shearing caused increase in shear stress of emulsion and induced phase inversionReasons of phase inversion:Increase in volume fraction of oil droplets by entrapment of water moleculesCoalescence of oil droplets upon shearing.……CHARACTERIZATION OF MULTIPLE EMULSIONS

Rheology :

(Jim

et al,

2003)Slide21

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 areCoalescence of internal droplets Coalescence of multiple dropletsExpulsion of internal dropletsShrinkage of internal droplets The causes for the instability of multiple emulsions areMigration of emulsifierOsmotic instabilityCreaming

STABILITY OF MULTIPLE EMULSIONSSlide22

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 moleculesGelation of oil or aqueous phases of the emulsionLiquid crystal stabilized multiple emulsion

Stabilization in the presence of electrolytes

METHODS TO STABILISE MULTIPLE EMULSIONSSlide23

 Fig; Various approaches to stabilize w/o/w multiple emulsion

.A-stabilizing through liquid crystal formationB-stabilization by interfacial polymerizationC-stabilization by adsorption of electrolyte or adsorption or covalent anchoring of polymerD-gelation of either internal or external phase or oil coreSlide24

Stability of multiple emulsions can be assessed in various aspects likeDetermination of particle sizeDetermination of phase separationMeasurement entrapped percentage and viscosityIn – vitro release studies:Dialyzing the multiple emulsion packed in a dialysis tube against a suitable dissolution media

Conductometric method

STABILITY ASSESSMENT STUDIESSlide25

Fig: Assembly use for

invitro

drug release

. In –vivo evaluation:

Blood concentration data in rats and rabbits

Urinary excretion data in manSlide26

Release of drug from multiple emulsions occurs from various mechanisms

(Pandit et al, 1987).

Diffusion of unionized drugs through the oil layerCarrier mediated transportMicellar transportRapture of oil membraneThinning of oil membraneSwelling and breakdown behaviorDRUG RELEASE FROM MULTIPLE EMULSIONSSlide27

 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.

BIOAVAILABILITY OF MULTIPLE EMULSIONSSlide28

Multiple emulsions are formulated for intravenous, topical and oral administration.Controlled and sustained drug delivery

Improve in the bioavailability

Drug targetingVaccine adjuvantHemoglobin multiple emulsionMasking of tasteDrug overdose treatmentImmobilization of enzymesTropical and cosmetic use.

APPLICATIONS OF MULTIPLE EMULSIONS:Slide29

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.

CONCLUSIONSlide30

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.

CONCLUSIONSlide31

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).

REFERENCESSlide32

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 water-in-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).

……REFERENCESSlide33

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).

……REFERENCESSlide34

Thank you