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Pharmaceutical sciences

Novel Drug Delivery Systems II

Introduction ofMultiple Emulsions

Paper No. : 08 Novel Drug Delivery Systems II

Module No : 18 Introduction ofMultiple Emulsions

Development Team

Principal Investigator

Dr. Vijaya KhaderFormer Dean, Acharya N G Ranga Agricultural University

Paper Coordinator

Content Writer

Content Reviewer

Prof. Farhan J Ahmad Jamia Hamdard, New Delhi

Dr. SushamaTalegaonkarJamia

Hamdard, New Delhi

Dr. SushamaTalegaonkarJamia

Hamdard, New Delhi

Prof Gurpreet Kaur

Punjabi University, Patiala, Pun jb

Prof. Farhan J Ahmad Jamia Hamdard, New Delhi

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Description of Module

Subject Name Pharmaceutical Sciences

Paper Name Novel Drug Delivery Systems II

Module Name/Title Introduction ofMultiple emulsions

Module Id

Pre-requisites

Objectives Basic Introduction to multiple Emulsion

Advantages and Disadvantages of Multiple Emulsions

Formulation Components

Keywords Emulsion, Multiple emulsion , micro and nanoemulsion Surface

active agents, HLB

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1. INTRODUCTION

Emulsions are the dispersed systems containing undissolved or immiscible drug distributed

throughout a vehicle. It is almost universally accepted that the term emulsion should be

limited to liquid-in- liquid systems in which dispersed phase is liquid that is neither soluble

nor miscible with the liquid of the dispersing phase. The particles of the dispersed phase are

usually solid materials that are insoluble in the dispersion medium. Emulsification results in

the dispersion of liquid drug as fine droplets throughout the dispersing phase. Since

approximately 1978, an additional type of emulsion classified as multiple emulsion with the

characteristics of oil- in-water- in-oil or water- in-oil- in-water emulsions was introduced. Such

emulsions also can invert, however, during inversion they usually form simple emulsions.

“An emulsion is thermodynamically unstable two phase system consisting of

atleast two immiscible liquids, one of which is finely sub-divided and uniformly

distributed as droplets throughout the other. The system is stabilized by the presence of an

emulsifying agent. The dispersed liquid or internal phase usually consists of globules of

diameters 0.1 to 10µm, although particle diameters as small as 0.01µm and as large as 100µm

are not uncommon in some preparations”.

2. TYPES OF EMULSION

i. Simple emulsions

a) Oil- in-water (O/W) Type: If the oil droplets are dispersed throughout the aqueous

phase the emulsion is termed as oil- in-water (o/w) type emulsion.

b) Water- in-oil (W/O): A system in which the water is dispersed throughout the oil is a

water-in-oil (w/o) emulsion.

ii. Multiple emulsions: Many small water droplets can be enclosed within larger oil

droplets, which are themselves then dispersed in water. This gives a water- in-oil- in-

water (w/o/w) emulsion. The alternative o/w/o emulsion is also possible.

iii. Micro emulsions: If the dispersed globules are of colloidal dimensions (1nm to 1µm

diameter) the preparation which is quite often transparent or translucent is called a

Microemulsion.

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iv. Nanoemulsions:Nanoemulsion is considered to be a thermodynamically or kinetically

stable liquid dispersion of an oil phase and a water phase, in combination with a

surfactant. The dispersed phase typically comprises small particles or droplets, with a

size range of 5 nm-200 nm, and has very low oil/water interfacial tension.

3. MULTIPLE EMULSIONS

There are different types of specialized emulsions such as Multiple emulsions,

Microemulsions and Nanoemulsions.

These are complex polydispersed system where both oil in water and water in oil emulsion

exists simultaneously. These are stabilized by hydrophobic and hydrophilic surfactants

respectively. Multiple emulsions are also called as “emulsions of emulsions”, “double or

triple emulsions” because this type of emulsion itself contains dispersed globules, which are

miscible with the continuous phase. Sometimes certain multiple emulsions also termed as

“liquid membrane system” because the two miscible phases are separated by an immiscible

phase (liquid membrane) which acts as a semipermeable film through which solute must

diffuse in order to traverse from one phase to another.

These complex emulsions are covered by the broader definition of emulsions given by

International Union of Pure and Applied Chemistry (IUPAC) which extends the classical

definition to include “liquid droplets and/or liquid crystals dispersed in a liquid”. Several

modifications can be made in the development of the liquid membrane system depending on

the purpose for which it has to be prepared. Various additives can also be used to control the

stability, permeation and selection of membrane. Multiple emulsion has shown promises in

several technologies particularly in several pharmaceuticals and in separation science.

Multiple emulsions are commonly of two types (fig 1)

i. Water-in-oil-in-water (W/O/W)

In W/O/W systems, an organic phase (hydrophobic) separates internal and external aqueous phases or in other words, oil droplets may besurrounded by an aqueous phase, which in turn

encloses one or several water droplets.

ii. Oil-in-water-in-oil (O/W/O)

In O/W/O systems an aqueous phase (hydrophilic) separates internal and external oil phase or

in other words, water droplets may besurrounded in oil phase, which in turn encloses one or

more oil droplets.

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MULTIPLE EMULSIONS

water phase = oilphase

W/O/W SYSTEM O/W/O SYSTEM

HYDROPHOBIC SURFACTANT

HYDROPHILIC SURFACTANT

O/W/O

Fig.1 W/O/W and O/W/O type emulsions

Multiple emulsions are complex system which consist of both w/o and o/w at the same

time.There are potential matrices for the encapsulation of bioactive compounds and for the

controlled release compounds.W/O/W multiple emulsion are system where small water

droplets are surrounded by larger oil droplets and they are dispersed in continuous water

phase. Diameter of the droplets in a multiple emulsion is in the range of 0.5 to 3µm.Because

of presence of reservoir phase these can be used to prolong release of active ingredients.

Multiple emulsion w/o/w contain two emulsifiers:

Low HLB surfactant (Hydrophobic in nature), used in disperse phase.

High HLB surfactant (Hydrophilic in nature), used in continuous phase

The basic rationale for the use of W/O/W & O/W/O type multiple emulsions as a means of

prolonged delivery of drugs is that the drug present in the innermost phase is forced to

partition itself through different phases beforeits release at the absorption site. Thusthe drug

release from these systems is controlled by partition & diffusion coefficient of the drug & the

strength of the middle membrane phase, which is a multimolecular layer of oil, water &

emulsifier molecules at both the interfaces of multiple emulsion system.

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4. ADVANTAGES AND DISADVANTAGES OF MULTIPLE EMULSION

Advantages:

i. Masking of unpleasant taste: Although liquid dosage forms may be ideal for small

children who are unable to swallow solid dosage forms, many drugs taste unlikable

when formulated into a solution. It is possible to attempt to mask any unpleasant tastes

by the addition of a flavouring agent, but this will not always be successful. Such drugs

can be incorporated in the dispersed phase so that the external phase keeps them from

directly contacting to taste buds and taste can be masked. Examples are laxatives,

phenolphthalein, vitamin A, Castor oil, Cod- liver oil, Chloroquine Phosphate etc.

ii. Improved bioavailability: Absorption of drugs has been found to be faster and better

when formulated as emulsions. Small particle size of the drug present in disperse

systems result in a large specific area this leads to higher rate of drug dissolution and

possibly a superior bioavailability. Bioavailability of lipophilic drugs which have high

first pass metabolism can be increased by protecting drugs from GIT enzymes by

formulating multiple emulsions and placing the drugs in internal phase of the emulsion.

Eg. Atorvastatin, Lamotragine etc.

iii. Sustained release medication: Water soluble antigenic materials are dispersed in

mineral oil and are given as intramuscular injections. These preparations act as depots in

the muscle and release antigen from the oil slowly, over a long period. For sustained

release medication multiple emulsions are formulated in which drug present in

innermost phases has to cross several phases before it is available for absorption for the

system.

iv. Biocompatability and Biodegradability.

Since in multiple emulsions components used to produce hydrophobic and hydrophilic

phases are biodegradabletherefore this system have remarkable degree of

biocompatability and biodegradability.

v. Versatile drug carrier:bothhyrophilic as well as hydrophobic drugs can be entrapped

within multiple emulsion.

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vi. Protection from inactivation by endogenous factors.Emulsions provide protection to

drugsthat are susceptible to oxidation or hydrolysis.

vii. Nutritional supplement: Terminally ill-patients are given nutrients parenterally. Fats

are dissolved in the oil phase and water soluble nutrients are incorporated in the aqueous

phase. Essential nutrients like carbohydrates, fats and vitamins can all be emulsified and

can be administered to bed ridden patients as sterile intravenous emulsions.

viii. Diagnostic Purposes: Radio-opaque emulsion are used as diagnostic materials in X-ray

examination. Intravenous emulsions of contrast media have been developed to assist in

diagnosis.

ix. Topical use:multiple emulsions are used in topical delivery as semisolid vehicles for

theenhancement of enteric or dermal absorption. examples are cold cream, vanishing

cream, benzyl benzoates, lotions, liniments, etc..

x. Economical: Expensive solvents are required to dissolve the lipids(oil soluble drugs).

Such substances can be easily dispersed in a less expensive vehicle such as water.

Hence emulsions can be made available at cheaper cost.

Disadvantages:

i. The main problem associated with multiple emulsions is their thermodynamic instability and their complex structure, because of which they are unstable and the insoluble phase separates slowly. Condition of storage may adversely affect the

disperse systems leading to creaming and cracking which has severely limited their usefulness in the many applications of multiple emulsions, so there is a need to

formulate stable emulsions such as microemulsions and nanoemulsions.

ii. Partitioning effect of emulsifiers, Phase inversion, Coalescence, Swelling and

shrinking of the internal droplets affect stability by influencing osmotic gradient for the passage of water across the oily membrane

iii. Being liquid dosage forms, they are much more bulky than their comparable solid

dosage forms.These makes emulsion heavier and difficult to transport.

iv. These are packed in glass or plastic containers thus care should be taken in hand ling

and storage.

5. PHYSICAL PROPERTIES OF WELL FORMULATED MULTIPLE EMULSION

The product must remain sufficiently homogenous for at least the period between shaking the

container and removing the required amount.

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i. The sediment or creaming produced on storage, if any, must be easily re-suspended by

moderate agitation of the container.

ii. The product may be required to be thickened in order to reduce the rate of settling of the

particles or the rate of creaming of oil globules. The resulting viscosity must not be so

high that removal of the product from the container and transfer to the site of

application are difficult.

iii. Any suspended particles should be small and uniformly sized in order to give a smooth,

elegant product, free from a gritty texture.

6. FORMULATION INGREDIENTS OF MULTIPLE EMULSION SYSTEM

i.Oils

Oils used in the preparation of pharmaceutical emulsion are of various chemical types,

including simple esters, fixed and volatile oils, hydrocarbons, and terpenoid derivatives. The

oil itself may be the medicament or it may function as a carrier for a drug, or even form part

of a mixed emulsifier system as in the case of some fixed oils that contain sufficient free

acids. Many oils, particularly those of vegetable origin, are liable to autooxidation with

subsequent rancidity, so it is frequently necessary to add an antioxidant and/or preservative to

inhibit this degradation process. Selection of oil phase can effect various emulsion parameters

like yield, release profile, particle size and emulsion stability. The mineral oils give much

higher yield than the vegetable oils.

Table 1. Types of oil

Types of oil Examples

Fixed oil Arachis oil BP, Cod liver oil BP, Castor oil

BP

Mineral oil Liquid Paraffin BP ,

Liquid petrolatum

Volatile oil Cinnomon oil BP, Peppermint oil BP

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ii. Pharmaceutical Emulsifiers

Emulsifying agents are used both to promote emulsification at the time of manufacturing and

to impart stability during the shelf life that can vary from days for extemporaneously

prepared emulsions to months or years for commercial preparations. In practice, combination

of emulsifiers rather than single agent is used.

The optimum concentration of surfactant required to emulsify given oil is determined by the

use of hydrophilic- lipophilic balance (HLB) system. In a W/O/W emulsion, the optimal HLB value of primary surfactant is usually in the range of 2-7 while it is 6-16 for the secondary

surfactant. The concentration of the emulsifiers can also be varied. Too little emulsifier may result in unstable systems,whereas too much emulsifier may lead to toxiceffects and can even cause destabilization. Anexcess of lipophilic surfactant can cause theinversion of w/o/w

emulsion to simple o/wemulsion.It is beneficial to use hydrophobic emulsifier in excess i.e. about 10-30% w/w of oil phase or primary emulsion whereas hydrophilic emuls ifier is used

in low concentration i.e. about 0.5%-5% w/w of external phase.

Table 2. Classification of emulsifying agent

EMULSIFYING AGENTS

Synthetic surfactants Hydrocolloid

emulsifying agents

Finely

Divided

Solids

anionic cationic nonionic amphoteric natural Semi-

synthetic

Colloidal

clays

Bentonite,

veegum

(Soaps ,Sulphates,Sul

phonates (CH3(CH2)n

CH2SO3Na+)

Quaternary ammonium

compounds

Tweens. Spans,

Lanolin alcohols

and ethoxylated lanolin

alcohols

lecithin Plant

origin

Polysacch- arides

(acacia, tragacanth, agar,

pectin)

Methyl cellulose,

Carboxy-methyl

cellulose Metallic

hydroxides

magnesium and

aluminum hydroxides

animal

origin

Gelatin,LecithinCholesterol, Wool

fat

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iii. Preservatives

It is essential that emulsions formulated should resist microbial attack, as this not only can

affect the physicochemical properties of the formulation, causing color, odor, or pH changes

and even phase separation, but may also constitute a health hazard. The potential sources of

contamination can be from raw materials (especially if these are natural products), water,

manufacturing and packaging equipment. O/W/O emulsions are less susceptible to attack

than W/O/W emulsions because the external aqueous phase can produce ideal conditions for

the growth of bacteria and fungi.

There is no simple way of predicting the ideal preservation for particular emulsion. In

addition a wide spectrum of activity against bacteria, yeast, and molds, the preservative

should be free from toxic, irritant, or sensitizing activity. Some commonly used preservatives

in oral and topical preparations include phenoxyethanol, benzoic acid, parabenzoates, and

chlorocresols. Emulsions are heterogenous products, and the preservative partitions between

the oil and the aqueous phases. A sufficient aqueous concentration of the active (usually

unionized) form must be present to ensure proper preservation. Problems often arise because

many of the materials used in emulsion formulation, for example hydrocolloids or

polyoxyethylene surfactants, can interact with the preservatives, thus depleting their activity.

iv. Antioxidants

Antioxidants are added to many pharmaceutical preparations to prevent oxidatitive

deterioration on storage of the oil, emulsifier, or the drug itself. Such deterioration, as well as

destabilization of the formulation, imparts an unpleasant odour or taste. Some oils are

supplied containing antioxidatnts already. Those commonly used in pharmacy include

butylatedhydroxyanisole(BHA) and butylated hydroxyl toluene(BHT) at concentration upto

0.2%, and the alkyl gallates, Propyl, octyl and dodecyl esters of gallic acid etc.

v. Other formulation additives:

a) Density modifiers; eg. Dextrose, sucrose, propylene glycol, glycerol, etc.

b) Humectants; eg. Glycerol, PEG, propylene glycol,etc.

c) Flavours, colours and perfumes; eg. Fruit juices, aromatic oils (peppermint, lemon),

carotenoids, anthocyanin, amaranth, etc.

d) Sweetening agents; eg.sucrose sorbitol, mannitol, aspartame etc.

e) Cosurfactants;eg. Glycerin, Ethylene glycol, Propylene glycol, Ethanol, Propanol,

Transcutol

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7. FACTORS TO BE CONSIDERED BEFORE PREPARING MULTIPLE EMULSIONS

i) Hydrophilic-lipophilic balance (HLB)

The HLB number is an index describing the hydrophilic- lipophilic balance.A hydrophilic

emulsifier possess an high HLB number these are O/W emulsifiers.eg; Tween80(HLB 15),

Sodium oleate(HLB 18). On the other hand a lipophilic emulsifier has a low HLB number &

belongs to the W/O emulsifier group. Eg. Span80 (HLB 4.3)

GRIFFIN SCALE: Used For measurement of HLB of surfactants

SOLUBILISING AGENTS (16-20)

DETERGENTS(13-16)

O/W EMULSIFYING AGENTS (9-16)

WETTING & SPREADING AGENTS(7-9)

W/O EMULSIFYING AGENTS(4-8)

ANTIFOAMING AGENTS(1-3)

Fig.2 HLB Scale

HLB methods for selection of emulsifying agents

This method has been devised for calculating the relative quantities of the emulgents necessary to

produce the most physically stable emulsion for a particular oil/water combination. This is called the

hydrophilic- lipophilic balance (HLB) method.

for two surfactant mixture,

18

15

12

9

6

3

0

HLB blend = f x HLB (A) + (1-f) x HLB (B)

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f = fraction of surfactant (A) in the blend

For simple alkyl ethers in which the hydrophile consists only of ethylene oxide,

E = weight percentage of ethylene oxide groups

The HLB of polyhydric alcohol fatty acid esters such as glycerylmonostearate may be obtained

from the equation:

whereS is the saponification number of the ester and A is the acid number of the fatty acid.

HLB values can also be calculated from group contributions using:

ii) Bancroft’s rule:Bancroft’s rule describes the relationship between the nature of

emulsifying agent and type of emulsion formed. Though emulsifying agents have affinity

towards polar and nonpolar liquids they have preferential solubility in one of the liquids.

The phase in which an emulsifier is more soluble constitutes the continuous phase-

In O/W emulsions – emulsifying agents are more soluble in water than in oil (High HLB

surfactants).

In W/O emulsions – emulsifying agents are more soluble in oil than in water (Low HLB

surfactants).

Based on the Bancroft’s rule, it is possible to change an emulsion from O/W type to W/O

type by inducing changes in surfactant HLB.

HLB = E/5

HLB = ∑(hydrophilic group numbers) – ∑(lipophilic group numbers)+7

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iii) Energy barrier and zeta potential

DLVO THEORY(Derjaguin Landau VerweyOverbeek Theory)

FIGURE-8 The two potentials involved in the DLVO theory are from an overlap of the

electric double layer(top line) and from the Vander Waals interaction(lower line). A sufficient

positive value of the total interaction(continuous line) gives particle stability.

Electric double layer: An ionic surfactant adsorb at the interface by orienting their

hydrophilic and hydrophobic parts towards polar and nonpolar phases of emulsion but some

counterions of the surfactant(eg. Sodium ion from sodium dodecyl sulfate) will separate from

the surface and form diffuse cloud reaching out in the continuous phase. Charged droplet

surface shows a diffuse layer of counterions. The surface and the co unterions called electric

double layer. When two droplets approach electrical double layer overlap, electric potential

between droplets increased which means that increased energy must be added with reduced

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distance between droplets. An increase in energy means a repulsive force between droplets.

Since droplets are different from continuous medium a vanderwaals attraction potential is

also developed. The interaction between droplets is decided by total potential. On the other

hand, for small distances the resulting force is always negative and the particles will

spontaneously move towards each other.

The zeta potential is the electric potential in the interfacial double layer (DL). It is the

potential difference between the dispersion medium and the stationary layer of fluid remain

in touchwith the dispersed globules. The zeta potential is a key indicator of the stability of

multiple emulsions. The magnitude of the zeta potential indicates the degree of electrostatic

repulsion between similarly charged globules in a dispersion. For molecules and particles that

are small enough, a high zeta potential will impart stabilityby resisting aggregation in the

dispersion. When the potential is small, attractive forces may surpass this repulsion and the

dispersion may break. So emulsions with high zeta potential (negative or positive) are

electrically stabilized while with low zeta potentials tend to coalesce or aggregate.

Conclusion

The development and production of excellent pharmaceutical emulsions depends on the basic

knowledge of physicochemical properties and stability. Emulsifying agents play important

role in manufacturing of emulsions as they stabilize emulsion by preventing coalescence of

dispersed globules. They act as a bridge between the polar and nonpolar phases and reduce

the interfacial tension so its nature and concentration is important factor.Simple emulsion has

been advanced to multiple emulsion which is novel formulation for thebetterment of the drug

administration &improvement in the palatability of the drug.by incorporating them into the

variousformulations. Till date multiple emulsions have been shown to be able to protect labile

drug, delivering the unstable drug ,prevention of the drug from theenvironment, for

theimprovement of the various characteristicsof the drugslike taste masking,control drug

release, increase drug solubility, increase bioavailability and reduce patient variability.

Furthermore, it has proven possible to formulate preparations suitable for most routes of

administration.

https://en.wikipedia.org/wiki/Electric_potential

https://en.wikipedia.org/wiki/Double_layer_(interfacial)

https://en.wikipedia.org/wiki/Dispersion_medium

https://en.wikipedia.org/wiki/Dispersed_particle

https://en.wikipedia.org/wiki/Dispersion_stability

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