Emulsion consistency

The texture or feel of a product intended for exter-

nal use must also be considered. A w/o preparation

will have a greasy texture and often exhibits a higher

apparent viscosity than o/w emulsions. This fact is

often used to convey a feeling of richness to many

cosmetic formulations. Oil-in-water emulsions will,

however, feel less greasy or sticky on application to

the skin, will be absorbed more readily because of

their lower oil content, and can be more easily

washed from the skin surface.

Ideally emulsions should exhibit the rheological

properties of plasticity/pseudoplasticity and thixo-

tropy (see Chapter 4). A high apparent viscosity at

the very low rates of shear caused by movement of

dispersed phase globules is necessary in order to

retard this movement and maintain a physically

stable emulsion. It is important, however, that these

products should flow freely when shaken, poured

from the container or injected through a hypodermic

needle. Therefore, at these high rates of shear, a

lower apparent viscosity is required. This change in

apparent viscosity must be reversible after a suitable

time delay so as to retard creaming and coalescence.

For an externally applied product a wide range

of emulsion consistencies can be tolerated. Low-

viscosity lotions and liniments can be formulated

that are dispensed from a flexible plastic container

via a nozzle on to the skin. Only light shearing is then

required to spread this type of product over the skin

surface. This is particularly advantageous for painful

or inflamed skin conditions.

The main disadvantage with low-viscosity emul-

sions is their tendency to cream easily, especially if

formulated with a low oil concentration. It is rarely

possible to formulate low-viscosity w/o products

because of the consistency of the oil phase.

Emulsions of high apparent viscosity for external

use are termed creams and are of a semisolid consis-

tency. They are usually packed into collapsible

plastic or aluminium tubes, although large volumes

or very high-viscosity products are often packed into

glass or plastic jars.

It is important not to ignore the patient/consumer

acceptability of topically applied preparations, par-

ticularly in a competitive market.

There are several methods by which the rheologi-

cal properties of an emulsion can be controlled.

Volume concentration of the dispersed phase

As discussed in Chapters 4 and 6, Einstein developed

an equation relating the viscosity of a suspension to

the volume fraction of the particles in that suspen-

sion. A qualitative application of this equation to the

behaviour of emulsions shows that the viscosity of the

product as a whole would be higher than the viscos-

ity of the continuous phase on its own. So, as the con-

centration of dispersed phase increases, so does the

apparent viscosity of the product.

Care must be taken to ensure that the dispersed

phase concentration does not increase above about

60% of the total, as phase inversion may occur.

Particle size of the dispersed phase

It is possible, under certain conditions, to increase

the apparent viscosity of an emulsion by a reduction

in mean globule diameter. This can be achieved by

homogenization. There are two postulated mecha-

nisms for this occurrence:

1. A smaller mean globule size can cause increased

flocculation. In a flocculated system a significant

part of the continuous phase is trapped within

aggregates of droplets, thus effectively increasing

the apparent disperse phase concentration.

Emulsions consisting of polydispersed droplets

will tend to exhibit a lower viscosity than a

monodispersed system, due to differences in

electrical double-layer size and thus in the

energy of interaction curves. These variations in

interaction between globules during shear may

be reflected in their flow behaviour,

2. If a hydrophilic colloid is used to stabilize the

emulsion it will form a multimolecular film

round the dispersed globules. A reduction in

mean globule size will increase the total surface

area, and therefore more colloid will be adsorbed

on to the droplet surface. This will effectively

increase the volume concentration of the

dispersed phase.

The particle size of the dispersed phase is therefore

controlled mainly by the method and conditions of

manufacture of the emulsion, and by the type of

emulgent used and its concentration.

Viscosity of the continuous phase

It has been well documented that a direct relation-

ship exists between the viscosity of an emulsion and

the viscosity of its continuous phase. Syrup and glyc-

erol, which are used in oral emulsions as sweetening

agents, will increase the viscosity of the continuous

phase. Their main disadvantage is in increasing the

density difference between the two phases, and thus

possibly accelerating creaming.

Hydrocolloids, when used as emulsifying agents in

o/w emulsions, will stabilize them not only by the for-

mation of multimolecular layers around the dispersed

globules, but also by increasing the continuous phase

viscosity. They do not have the disadvantage of alter-

ing the density of this phase. If oil is the continuous

phase, then the inclusion of soft or hard paraffin or

certain waxes will increase its viscosity.

Viscosity of the dispersed phase

For most practical applications it is doubtful

whether this factor would have any significant effect

on total emulsion viscosity. It is possible, however,

that a less viscous dispersed phase would, during

shear, be deformed to a greater extent than a more

viscous phase, and thus the total interfacial area

would increase slightly. This may affect double-layer

interactions and hence the viscosity of the emul-

sion.

Nature and concentration of the emulsifying

system

It has already been shown that hydrophilic colloids,

as well as forming multimolecular films at the

oil/water interface, will also increase the viscosity of

the continuous phase of an o/w emulsion. Obviously,

as the concentration of this type of emulgent

increases so will the viscosity of the product.

Surface-active agents forming condensed

monomolecular films will, by the nature of their

chemical structure, influence the degree of floccula-

tion in a similar way, by forming linkages between

adjacent globules and creating a gel-like structure. A

flocculated system will exhibit a greater apparent vis-

cosity than its deflocculated counterpart and will

depend on surfactant concentration.

Choice of emulsifying agent

Toxicity and irritancy considerations

The choice of emulgent to be used will depend not

only on its emulsifying ability, but also on its route of

administration and, consequently, on its toxicity.

Although there is no approved list of emulsifying

agents for use in pharmaceutical products there is an

approved list of emulsifiers as food additives for use

in the European Union. It can be assumed that

emulsifiers contained in this list would be suitable

for internally used pharmaceutical emulsions. The

regulations mainly include naturally occurring mate-

rials and their semisynthetic derivatives, such as the

polysaccharides, as well as glycerol esters, cellulose

ethers, sorbitan esters and polysorbates.

It will be noted that most of these are non-ionic,

having a tendency to be less irritant and less toxic

than their anionic, and particularly their cationic

counterparts. The concentrations of ionic emulsify-

ing agents necessary for emulsification will be irri-

tant to the gastrointestinal tract and have a laxative

effect, and should not be used for oral emulsions.

Cationic surfactants in general are toxic even at

lower concentrations. The emulgent cetrimide is

limited to externally used preparations, where its

antiseptic properties are of use.

Some emulgents, such as the anionic alkali soaps,

often have a high pH and are thus unsuitable for

application to broken skin. Even on normal intact

skin with a pH of 5.5, the application of such alka-

line materials can cause irritation. Some emulsifiers,

in particular, wool fat can cause sensitization reac-

tions in susceptible people.

When choosing an emulgent for parenteral use it

must be realized that only certain types of non-ionic

material are suitable. These include lecithin,

polysorbate 80, methylcellulose, gelatin and serum

albumin.

Formulation by the HLB method

It has already been shown that physically stable

emulsions are best achieved by the presence of a

condensed layer of emulgent at the oil/water inter-

face, and that the complex interfacial films formed

by a blend of an oil-soluble emulsifying agent with a

water-soluble one produces the most satisfactory

emulsions.

A useful method has been devised for calculating

the relative quantities of these emulgents necessary

to produce the most physically stable emulsion for a

particular oil/water combination. This is called the

hydrophile-lipophile balance (HLB) method.

Although originally applied to non-ionic surface-

active agents, its use has been extended to ionic

emulgents. Each surfactant is allocated an HLB

number representing the relative proportions of the

lipophilic and hydrophilic parts of the molecule.

High numbers (up to a theoretical maximum of 20)

therefore indicate a surfactant exhibiting mainly

hydrophilic or polar properties, whereas low

numbers represent lipophilic or non-polar character-

istics. Table 23.2 gives HLB values for some com-

monly used emulsifying agents. The concept of HLB

values is discussed more fully in Chapter 6.

Each type of oil used will require an emulgent of a

particular HLB number in order to ensure a stable

assess the suitability of other emulgent blends that

may give a better emulsion than the one containing

the emulgent used for the initial trials.

It must be remembered that, in choosing an

emulsifier blend, the effect of chemical structure on

the type of interfacial film must be taken into account.

Condensed films are produced by emulgents having

long, saturated hydrocarbon groups, thus providing

maximum cohesion between adjacent molecules. In

most cases it has been found that the most stable

emulsions are formed when both emulsifying agents

are of the same hydrocarbon chain length.

The use of phase inversion temperature

The use of the HLB system has several disadvan-

tages, including the inability to take into account the

effects of temperature, the presence of additives and

the concentration of the emulsifier. It is possible to

overcome some of these problems.

An o/w emulsion stabilized by non-ionic emulgents

will, on heating, invert to form a w/o product. This is

because, as the temperature increases, the HLB value

of a non-ionic surfactant will decrease as it becomes

more hydrophobic. At the temperature at which the

emulgent has equal hydrophilic and hydrophobic

tendencies (the phase inversion temperature) the

emulsion will invert.

The stability of an emulsion has been related

to the phase inversion temperature (PIT) of its

emulsifying agent (see Chapter 6).

CLASSIFICATION OF EMULSIFYING
AGENTS

The inclusion of an emulsifying agent or agents is

necessary to facilitate actual emulsification during

manufacture, and also to ensure emulsion stability

during the shelf-life of the product.

The different methods by which emulsifying

agents (also called emulsifiers or emulgents) exert

their effects have been detailed in Chapter 6, but the

one factor common to all of them is their ability to

form an adsorbed film around the dispersed droplets

between the two phases. There are many types of

emulgent available, but for convenience they can be

divided into two main classifications: synthetic or

semisynthetic surface-active agents, and naturally

occurring materials and their derivatives.

These divisions are quite arbitrary and some materi-

als may justifiably be placed in more than one category.

Synthetic and semisynthetic surface-

active agents

There are four main categories of these materials,

depending on their ionization in aqueous solutions:

anionic, cationic, non-ionic and amphoteric.

Anionic surfactants

In aqueous solutions these compounds dissociate

to form negatively charged anions that are respon-

sible for their emulsifying ability. They are widely

used because of their cheapness, but because of

their toxicity are only used for externally applied

preparations.

Alkali metal and ammonium soaps Emulgents in

this group consist mainly of the sodium, potassium

or ammonium salts of long-chain fatty acids, such as:

347

They produce stable o/w emulsions but may in some

instances require the presence of an auxiliary non-

ionic emulsifying agent in order to form a complex

monomolecular film at the oil/water interface.

Because in acidic conditions, these materials will

precipitate out as the free fatty acids, they are most

efficient in an alkaline medium.

This type of emulgent can also be formed in situ

during the manufacture of the product by reacting

an alkali such as potassium, sodium or ammonium

hydroxide with a fatty acid. The latter may be a

constituent of a vegetable oil. Oleic acid and

ammonia, for example, are reacted together to form

the soap responsible for stabilizing White Liniment.

These emulgents are incompatible with polyvalent

cations, often causing phase reversal, and it is there-

fore essential that deionized water is used in their

preparation.

Soaps of divalent and trivalent metals Although

many different divalent and trivalent salts of fatty

acids exist, and would produce satisfactory emulsions,

only the calcium salts are commonly used. They are

often formed in situ during preparation of the product

by interacting the appropriate fatty acid with calcium

hydroxide. For example, oleic acid is reacted with

calcium hydroxide to produce calcium oleate, which is

the emulsifying agent for both Zinc Cream BP and

some formulations of oily calamine lotion.

These emulgents will only produce w/o emulsions.

Amine soaps A number of amines form salts with

fatty acids. One of the most important of those used

is based on triethanolamine N(CH2CH2OH)3 and is

widely used in both pharmaceutical and cosmetic

products. For example, triethanolamine stearate

DOSAGE FORM DESIGN AND MANUFACTURE

forms stable o/w emulsions and is usually made in

situ by a reaction between triethanolamine and the

appropriate fatty acid. Although these emulgents are

usually pH neutral they are still restricted to exter-

nally used preparations. They are also incompatible

with acids and high concentrations of electrolytes.

Sulphated and sulphonated compounds The alkyl

sulphates have the general formula ROSO3 M+

where R represents a hydrocarbon chain and M+

is

usually sodium or triethanolamine. An example is

sodium lauryl sulphate, which is widely used to

produce o/w emulsions. Because of its high water

solubility and its inability to form condensed films at

the oil/water interface, it is always used in conjunc-

tion with a non-ionic oil-soluble emulsifying agent in

order to produce a complex condensed film. It is

used with cetostearyl alcohol to produce Emulsifying

Wax, which stabilizes such preparations as Aqueous

Cream and Benzyl Benzoate Application.

Sulphonated compounds are much less widely

used as emulgents. Materials of this class include

sodium dioctylsulphosuccinate, and are more often

used as wetting agents or for their detergency.

Cationic surfactants

In aqueous solutions these materials dissociate to

form positively charged cations that provide the

emulsifying properties. The most important group of

cationic emulgents consists of the quaternary ammo-

nium compounds. Although these materials are

widely used for their disinfectant and preservative

properties, they are also useful o/w emulsifiers. Like

many anionic emulgents, if used on their own they

will produce only poor emulsions, but if used with

non-ionic oil-soluble auxiliary emulgents they will

form stable preparations.

Because of the toxicity of cationic surfactants they

tend to be used only for the formulation of antiseptic

creams, where the cationic nature of the emulgent is

also responsible for the product's antiseptic properties.

Cationic emulsifying agents are incompatible with

anionic surface-active agents and polyvalent anions,

and are unstable at high pH.

Cetrimide The most useful of these cationic

emulgents is cetrimide (cetyl trimethylammonium

bromide) CH3(CH2)15N

(CH3)3Br~. Cetrimide is

used at a concentration of 0.5% with 5% cetostearyl

alcohol for the formulation of Cetrimide Cream BP.

Non-ionic surfactants

These products range from oil-soluble compounds

stabilizing w/o emulsions to water-soluble materials

giving o/w products. It is usual for a combination of

a water-soluble with an oil-soluble emulgent to be

used in order to obtain the complex interfacial film

necessary for optimum emulsion stability. Non-ionic

emulgents are particularly useful because of their

low toxicity and irritancy; some can therefore be

used for orally and parenterally administered prepa-

rations. They also have a greater degree of compati-

bility with other materials than do anionic or

cationic emulgents, and are less sensitive to changes

in pH or to the addition of electrolytes. They do,

however, tend to be more expensive.

Being non-ionic, the dispersed globules may not

possess a significant charge density. To reduce the

tendency for coalescence to occur in an oil-in-water

emulsion, it is necessary that the polar groups be

well hydrated and/or sufficiently large to prevent

close approach of the dispersed droplets in order to

compensate for the lack of charge.

Most non-ionic surfactants are based on:

• a fatty acid or alcohol (usually with 12-18 carbon

atoms), the hydrocarbon chain of which provides

the hydrophobic moiety;

• an alcohol (-OH) and/or ethylene oxide grouping

(-OCH2CH2-), which provide the hydrophilic

part of the molecule.

By varying the relative proportions of the hydrophilic

and hydrophobic groupings many different products

can be obtained.

If the hydrophobic part of the molecule predom-

inates, then the surfactant will be oil-soluble. It will

not concentrate at the oil/water interface but rather

tend to migrate into the oil phase. Similarly, a

water-soluble surfactant will migrate into the

aqueous phase and away from the oil/water inter-

face. The best type of non-ionic surfactant to use is

one with an equal balance of hydrophobic and

hydrophilic groupings. An alternative would be to

use two emulgents, one hydrophilic and one

hydrophobic. The cohesion between their hydrocar-

bon chains will then hold both types at the oil/water

interface.

Glycol and glycerol esters Glyceryl monostearate

(a polyhydric alcohol fatty acid ester) is a strongly

hydrophobic material that produces weak w/o emul-

sions. The addition of small amounts of sodium,

potassium or triethanolamine salts of suitable fatty

acids will produce a 'self-emulsifying' glyceryl mono-

stearate, which is a useful o/w emulsifier. Self-emul-

sifying monostearin is glyceryl monostearate to

which anionic soaps (usually oleate or stearate) have

been added. This combination is used to stabilize

Hydrocortisone Lotion.

348

SUSPENSIONS AND EMULSIONS

Other polyhydric alcohol fatty acid esters are also

available either in the pure form or in the 'self-emul-

sifying' form containing small proportions of a

primary emulsifier, and include glyceryl mono-

oleate, diethylene glycol monostearate and propylene

glycol mono-oleate.

Sorbitan esters These are produced by the

esterification of one or more of the hydroxyl groups of

sorbitan with either lauric, oleic, palmitic or stearic

acids. The structure of sorbitan monostearate is shown

below.

This range of surfactants exhibits lipophilic proper-

ties and tends to form w/o emulsions. They are,

however, much more widely used with polysorbates

to produce either o/w or w/o emulsions.

Polysorbates Polyethylene glycol derivatives of the

sorbitan esters give us polysorbates. These have the

general formula:

where R represents a fatty acid chain. Variations in

the type of fatty acid used and in the number of

oxyethylene groups in the polyethylene glycol chains

produce a range of products of differing oil and

water solubilities. Polyoxyethylene 20 sorbitan

mono-oleate, for example, contains 20 oxyethylene

groups in the molecule. This number must not be

confused with the one given as part of the official

name (Polysorbate 80) or in the trade name (Tween

80), which is included in order to identify the type of

fatty acid in the molecule.

Polysorbates are generally used in conjunction

with the corresponding sorbitan ester to form a

complex condensed film at the oil/water interface

(see Formulation by the HLB method, earlier).

Other non-ionic oil-soluble materials, such as

glyceryl monostearate, cetyl or stearyl alcohol or

propylene glycol monostearate, can be incorporated

with polysorbates to produce 'self-emulsifying'

preparations. For example, Polawax contains cetyl

alcohol with a polyoxyethylene sorbitan ester.

Polysorbates are compatible with most anionic,

cationic and non-ionic materials. They are pH neutral

and are stable to the effects of heat, pH change and

high concentrations of electrolyte. Their low toxicity

renders them suitable for oral use and some are also

used in parenteral preparations. They have the disad-

vantage, however, of an unpleasant taste, and care

must be taken when selecting a suitable preservative

as many are inactivated by complexation with

polysorbates.

Fatty alcohol polyglycol ethers These are conden-

sation products of polyethylene glycol and fatty

alcohols, usually cetyl or cetostearyl:

349

and comprise a very large group of compounds,

some of which are used as emulsifying agents for

intravenous fat emulsions.

Higher fatty alcohols The hexadecyl (cetyl) and

octadecyl (stearyl) members of this series of satu-

rated aliphatic monohydric alcohols are useful auxil-

iary emulsifying agents. Part of their stabilizing effect

where R is a fatty alcohol chain.

Perhaps the most widely used is macrogol

cetostearyl ether (22) or cetomacrogol 1000, which

is polyethylene glycol monocetyl ether. This is a very

useful water-soluble o/w emulgent, but because of

its high water solubility it is necessary to include an

oil-soluble auxiliary emulsifier when formulating

emulsions. Cetomacrogol Emulsifying Ointment

includes cetomacrogol 1000 and cetostearyl alcohol

and is used to stabilize cetomacrogol creams.

They can also be produced with shorter poly-

oxyethylene groups as lipophilic w/o emulsifiers.

Combinations of lipophilic and hydrophilic ethers

can be used together to produce stable emulsions.

These materials can be salted out by the addition

of high concentrations of electrolyte, but are stable

over a wide pH range.

Fatty acid polyglycol esters The stearate esters or

polyoxyl stearates are the most widely used of this

type of emulgent. Polyoxyethylene 40 stearate (in

which 40 represents the number of oxyethylene

units) is a water-soluble material often used with

stearyl alcohol to give o/w emulsions.

Poloxalkols Poloxalkols are polyoxyethylene/

polyoxypropylene copolymers with the general

formula:

DOSAGE FORM DESIGN AND MANUFACTURE

comes from their ability to increase the viscosity of

the preparation, thereby retarding creaming.

Cetostearyl alcohol will also form complex interfa-

cial films with hydrophilic surface-active agents such

as sodium lauryl sulphate, cetrimide or cetomacro-

gol 1000, and so stabilize o/w emulsions.

Amphoteric surfactants

This type possesses both positively and negatively

charged groups, depending on the pH of the system.

They are cationic at low pH and anionic at high pH.

Although they are not widely used as emulsifying

agents, one example, lecithin, is used to stabilize

intravenous fat emulsions.

Naturally occurring materials and their

derivatives

Naturally occurring materials often suffer from

two main disadvantages: they show considerable

batch-to-batch variation in composition and hence

in emulsifying properties, and many are susceptible

to bacterial or mould growth. For these reasons they

are not widely used in manufactured products

requiring a long shelf-life, but rather for extempora-

neously prepared emulsions designed for use within

a few days of manufacture.

Polysaccharides

The most important emulsifying agent in this group

is acacia. This stabilizes o/w emulsions by forming a

strong multimolecular film round each oil globule,

and so coalescence is retarded by the presence of a

hydrophilic barrier between the oil and water

phases.

Because of its low viscosity, creaming will occur

readily, and therefore a suspending agent such as

tragacanth or sodium alginate can also be included.

Because of its sticky nature the use of acacia is

limited to products for internal use.

Sem /synthetic polysaccharides

In order to reduce the problems associated with

batch-to-batch variation, semisynthetic derivatives

are available as o/w emulgents or stabilizers.

Several grades of methylcellulose and carmellose

sodium are available and exert their action in a

similar way to that of acacia.

Methylcellulose 20, for example, is used at a

concentration of 2% to stabilize Liquid Paraffin Oral

Emulsion.

Sterol-containing substances

Beeswax, wool fat and wool alcohols are all used in

the formulation of emulsions. Beeswax is used

mainly in cosmetic creams of both o/w and w/o type,

in conjunction with borax. Because of the systemic

toxicity of boric acid and its salts, however, the use of

beeswax/borax preparations is limited, although

beeswax is used as a stabilizer for w/o creams.

Wool fat (anhydrous lanolin) consists chiefly of

normal fatty alcohols with fatty acid esters of choles-

terol and other sterols. It will form w/o emulsions of

low dispersed phase concentration, and it can also be

incorporated for its emollient properties. Some indi-

viduals exhibit sensitization to this material and,

because of its characteristic odour and the need to

incorporate antioxidants, it is not widely used. It is,

however, to be found in low concentrations in many

ointments, where its water-absorbing properties are

of great value. It can be employed as an emulsion sta-

bilizer with a primary emulsifying agent, for example

with calcium oleate in oily calamine lotion, with

beeswax in Proflavine Cream, and with cetostearyl

alcohol in Zinc Cream and ichthammol cream.

Because wool fat has some ideal properties,

attempts have been made to improve its other, less

desirable, characteristics by physical and chemical

modification. Processes including hydrogenation and

fractionation have been carried out with some

success. It has also been converted, by a reaction with

ethylene oxide, to give a range of polyoxyethylene

lanolin derivatives. These non-ionic products are

mainly water soluble and are used as o/w emulgents

possessing the properties of emollience.

The principal emulsifying agent in wool fat is wool

alcohols, which consists mainly of cholesterol

together with other alcohols. It is an effective w/o

emulgent, being more powerful than wool fat, and is

used in the formulation of Hydrous Ointment. It is

also incorporated as Wool Alcohols Ointment into

other ointment bases which, although not emulsions,

will readily mix with aqueous skin secretions and

easily wash off the skin. Wool alcohols does not have

the same strong odour as wool fat but does require

the presence of an antioxidant.

Finely divided solids

Certain finely divided solids can be adsorbed at the

oil/water interface, forming a coherent film that

physically prevents coalescence of the dispersed

globules. If the particles are preferentially wetted by

the aqueous phase then o/w products will result,

whereas preferential wetting by the oil will produce

w/o emulsions.