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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5724_Библиотеки_им_академика_М_И_Перельмана.pdf
175
Dosage Forms
Fig. 5.19: QP emulsifier.
and their uniform distribution throughout the continuous
phase. Emulsions should be chemically stable and they should
not allow any bacterial growth to take place.
In the present discussion only the physical stability will be
discussed in detail. The three major changes associated with
physical stability are as follows:
1. Upward or downward movement of dispersed globules
in the continuous phase referred to as creaming or sedi-
mentation of emulsions.
2. Aggregation of the dispersed globules forming a separate
phase referred to as cracking of emulsions.
3. Phase inversion.
Creaming and Sedimentation
In creaming the dispersed globules move upward and
form a thick layer at the surface of the emulsion whereas in
sedimentation the dispersed globules move downward towards
the bottom and form a layer over there. A good example of
Introduction to Pharmaceutics
176
creaming is when milk is set aside for a few hours, a thick layer
of cream forms at the surface. Creaming is a temporary phase
because it can be re-distributed by mild shaking or stirring
to get a homogenous product. At the same time creaming is
undesirable because a badly creamed emulsion may lead to
cracking with complete separation of the two phases. There are
many factors which lead to creaming of emulsions but the chief
factor is the rising of dispersed globules to the surface of the
emulsion. The rate at which the globules will rise to the surface
or the rate of creaming is governed by Stoke’s law, which may
be expressed as follows:
V
rd
dg
=
−2
9
2
12
()
η
=
dd
dg
2
12
18
()
−
η
where V = rate of creaming
r = radius of globules
d
1
= density of dispersed phase
d
2
= density of continuous phase
g = gravitational constant
h = viscosity of the dispersion medium.
It is evident from the equation that the rate of creaming
depends upon the radius of globules, the difference between
the densities of the dispersed phase and continuous phase
and the viscosity of the dispersion medium. Larger the size
of the globules more will be creaming and smaller the size of
the globules lesser will be creaming because small globules
will rise less quickly than large globules. Therefore creaming
can be reduced by reducing the size of globules by passing the
emulsion through a homogeniser.
The rate of creaming depends upon the difference between
the densities of dispersed phase and continuous phase. Greater
the difference more will be creaming. Therefore this difference
can be reduced but this is rarely possible in practice because it
is therapeutically undesirable.
The rate of creaming is inversely proportional to the
viscosity of the dispersion medium, therefore, this is the most
suitable approach for preparing a stable emulsion. The viscosity
of the emulsion can be increased, but too high a viscosity is
177
Dosage Forms
undesirable because it may become difficult to redisperse the
materials which have settled and pouring of the too viscous
product from its container may be a problem.
The high temperature reduces viscosity which encourages
creaming, therefore, emulsions should be stored in a cool place.
Freezing should be avoided which may lead to cracking.
Cracking
In cracking the coalescence of the dispersed globules takes place
and two separate layers of the dispersed phase and continuous
phase are formed which are difficult to redisperse by shaking
or stirring to get the original product. Hence cracking is more
serious in comparison to creaming. Cracking may take place
due to following reasons:
By Addition of Emulsifying Agent of Opposite Type
As discussed earlier soaps of monovalent metals produce O/W
type emulsions whereas soaps of divalent metals produce
W/O type emulsions. But the addition of monovalent soap
to an emulsion prepared with divalent soap or vice versa will
lead to instability and cracking of emulsion.
By Decomposition or Precipitation of Emulsifying Agents
The addition of an acid to an alkali soap emulsion, e.g., tur-
pentine liniment, leads to decomposition of the emulsifying
agent with the liberation of fatty acid and alkali salt of the
added acid, neither of which has emulsifying properties thus
causing cracking.
The addition of sodium chloride and certain other
electrolytes to sodium soap or potassium soap emulsions leads
to the precipitation of emulsifying agent thus causing cracking.
By Addition of a Common Solvent
The addition of a solvent to an emulsion, which is either miscible
with or can dissolve the dispersed phase, the emulsifying
agent and the continuous phase leads to the formation of one
phase system or clear solution thus destroying the emulsion.
Introduction to Pharmaceutics
178
For example, when alcohol is added to turpentine oil liniment
it forms a clear solution because turpentine oil, soft soap and
water gets dissolved in alcohol.
By Micro-organisms
The emulsions which are stored for a long time may develop
bacterial and mold growth which may destroy the emulsifying
agent and cause cracking. Therefore, the emulsions which are·
not meant for immediate use must be suitably preserved.
By High Temperature
When emulsions are stored for a long time an increase in
temperature may reduce viscosity of the emulsion and
encourage creaming.
By Creaming
A badly creamed emulsion is more liable to crack than a homo-
geneous emulsion therefore steps should be taken to retard
creaming as for as possible.
Phase Inversion
In phase inversion the oil in water type emulsion changes into
water in oil type and vice versa. It is a physical instability. It
may be brought about by the addition of an electrolyte or by
changing the phase-volume ratio or by temperature changes,
etc. Phase inversion can be minimised by using the proper
emulsifying agent in adequate concentration, keeping the
concentration of dispersed phase between 30 and 60 percent
(higher concentration may lead to phase inversion) and by
storing the emulsion in a cool place.
Preservation of Emulsions
Since emulsions are prepared by using emulsifying agents such
as carbohydrates, proteins, sterols and non-ionic surfactants
which lead to the growth of bacteria, fungi, molds and yeasts,
specially in the presence of water. The contamination of
179
Dosage Forms
emulsions by these micro-organisms may cause unpleasant
odour, taste and discolouration. The eating up of the emulsi-
fying agent by the microorganisms will lead to changes in
consistency and ultimately may cause cracking. Even if the
emulsion does not crack it will become unfit for consumption.
Other factors affecting growth of microorganisms in emulsions
include:
Deionised water and purified water if not stored properly
after collection. ·
Carelessly cleaned equipment.
Type of container and closure used.
The ratio of oil and water and the type of emulsion.
pH of the preparation.
The above mentioned factors can be minimized to a great
extent by:
Using ingredients of high quality.
Using boiling water to destroy the microorganisms.
Using thoroughly cleaned equipment and paying particular
attention to hidden parts of the equipment which are
generally a major source of contamination.
Using containers and closures of high quality and closures
should fit well in the containers. .
Maintaining the prescribed ratio of oil and water.
Maintaining the prescribed pH of the preparation.
The above mentioned precautions will not completely
exclude the contamination therefore a suitable preservative
will have to be included in the emulsion. The preservative
used should have the following qualities:
It should be non-toxic.
It should be water soluble.
It should be effective in low concentrations.
It should be compatible with other ingredients of the
preparation.
It should be effective against wide range of microorganisms.
It should be free from odour and taste.
Introduction to Pharmaceutics
180
Some of the commonly used preservatives in emulsions
include benzoic acid, p-hydroxybenzoic acid, sodium benzoate,
esters of p-hydroxybenzoic acid, chloroform, chlorocresol, and
quaternary ammonium compounds, etc. Generally combi-
nations of preservatives are used because they increase the
preservation action by their synergistic effect.
Benzoic acid is commonly used for oral preparations the
action of which is enhanced by the addition of chloroform as
in liquid paraffin emulsions. Esters of p-hydroxybenzoic acid
are popular preservatives which are used for oral as well as
for external preparations. They are stable, inert, non-toxic,
odourless and tasteless. They are effective against molds
and yeasts, but less effective against bacteria. Sometimes the
drug itself has a preservative action as in the cetrimide cream
but in other preparations chloroeresol is the most suitable
preservative.
SUSPENSIONS
Suspensions are the biphasic liquid dosage form of medicament
in which the finely divided solid particles ranging from 0.5 to
5.0 micron are suspended or dispersed in a liquid or semi-solid
vehicle. The solid particles constitutes the discontinuous phase
whereas the liquid vehicle constitutes the continuous phase.
Suspensions are mainly used for oral administration, external
application or parenteral use. Oral suspensions can be made
more palatable by using derivative of the drug as in the case
of chloramphenicol palmitate. Suspensions are also chemically
more stable than solutions. That is why nowadays many
suspensions are marketed as dry powders and the patient or
pharmacist is asked to incorporate a specified amount of the
vehicle to constitute the suspension before its use. Suspension
is an ideal dosage form for patients who cannot swallow
tablets or capsules. Suspensions meant for external application
should have very small particle size to avoid gritty feeling to
the skin. Similarly suspensions meant for introduction into
the ophthalmic cavity should be free from gritty particles
to avoid irritation, pain and discomfort. In some cases,
sterile suspensions are injected hypodermically to produce
181
Dosage Forms
sustained action of the drug which will not be produced by a
true solution of the same drug.
Qualities of Good Suspension
A well formulated suspension should have the following
properties:
The dispersed particles should not settle readily and the
settled particles should redisperse immediately on shaking.
The particles should not form a cake· on settling.
The viscosity should be such that the preparation can be
easily poured.
It should be chemically stable.
Suspensions for internal use must be palatable and suspen-
sions for external use must be free from gritty particles
and possess other characteristics required for external
preparations.
Flocculated and Non-Flocculated Suspensions
In flocculated suspensions the individual particles are in contact
with each other to form loose aggregates and create a network
like structure. Although the rate of sedimentation is high but
the sediment is loosely packed which can redisperse easily on
shaking so as to reform the original suspension. However, the
flocculated suspensions meant for oral, parenteral, ophthalmic
or external use may not be elegant because they are difficult
to remove from bottles or vials and on transferring from the
bottle the floccules remain sticking to the sides of the bottle.
These properties can be improved by adding protective
colloids.
In non-flocculated or de-flocculated suspensions all
individual particles exist as separate entities. The rate of
sedimentation is slow and a sediment is formed slowly but the
sediment is closely packed due to weight of upper layers of
sedimenting materials. A hard cake is formed which is difficult
to redisperse to get original suspension. The non-flocculated
suspensions have pleasing appearance as compared to floccu-
lated suspensions because the substances remain suspended
for a sufficiently long time.
Introduction to Pharmaceutics
182
Formulation of Suspensions
Before selecting the additives to be used in the formulation
of suspensions it is very important to decide whether the
particles in suspension are to be flocculated or to remain non-
flocculated. Following are the additives which are generally
used in the formulation of suspensions:
Flocculating agents
Suspending agents/thickening agents
Wetting agents
Dispersing agents
Preservative
Organoleptic additives
Flocculating Agents
When formulating suspensions it must be ensured that the
particles are well dispersed in the vehicle. The dispersion can
be improved by adding a surfactant which will act by reducing
the interfacial tension. For example, if surfactants with
negative charges are adsorbed on the particles, prevents or
minimises flocculation in the presence of positive ions because
of natural repulosion of like charges. Sodium lauryl sulphate
and sodium dioctyl sulphosuccinate are examples of this type
of surfactants. Non-ionic surfactants also usually assume a
Relative properties of flocculated and non-flocculated suspensions
Flocculated Non-flocculated
Particles form loose aggregates and
form a network like structure
Particles exist as separate entities
Rate of sedimentation is high Rate of sedimentation is slow
Sediment is rapidly formed Sediment is slowly formed
Sediment is loosely packed and does
not form a hard cake
Sediment is very closely packed
and a hard cake is formed
Sediment is easy to redisperse Sediment is difficult to redisperse
Suspension is not pleasing in
appearance
Suspension is pleasing in
appearance
The floccules stick to the sides of the
bottle
They do not stick to the sides of
the bottle
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Dosage Forms
negative charge in solution thereby act as effective flocculating
agents. Generally non-ionic surfactants are used for dispersing
the insoluble particles. Tweens, spans and carbowaxes are
frequently used in this manner.
Protective colloids can also be used as flocculating agents.
They differ from surfactants in that they do not reduce the
interfacial tension. Their solutions differ in viscosity and are
used in higher concentration than surfactants.
Suspending Agents/Thickening Agents
Suspending agents are the substances which are added to a
suspension to increase the viscosity of the continuous phase so
that the particles remain suspended for a sufficiently long time
and it becomes easy to measure an accurate dose.
While selecting a suspending agent it is not only important
that it should increase the viscosity of the system but the
pourability, spread-ability, etc., of the final product must also
be taken into consideration. Some of the thickening agents
used in formulations include acacia, tragacanth and sodium
alginate. As these are natural products therefore vary in
qualities and properties hence not very commonly used. The
semi-synthetic thickening agents widely used include methyl
cellulose, carboxy methyl cellulose, hydroxypropyl methyl
cellulose, synthetic polymers and gelatin. Sodium carboxy
methyl cellulose in concentration of about 3.5% is used in
injectable suspensions. Clays such as hydrated aluminium
silicate or magnesium silicate are also used as suspending
agents. Non-ionic substances such as sorbitol, glycerin, sugar
or polyethylene glycols may be included to adjust the viscosity
of the medium.
Wetting Agents
Wetting agents are the substances which reduce the interfacial
tension between the solid particles and liquid medium thus
producing a suspension of desired quality. This may be
achieved by adding a suitable wetting agent which is adsorbed
at the solid/liquid interface in such a way that the affinity of
the particles for the surrounding medium is increased and
the interparticular forces are decreased. Examples of wetting
Introduction to Pharmaceutics
184
agents are alcohol in tragacanth mucilage, glycerin and glycols
in sodium alginate or bentonite dispersions and polysorbates
in oral and parenteral suspensions.
Only a minimum amount of wetting agent should be
used; excessive amounts may lead to foaming or impart an
undesirable taste or odour to the suspension.
Dispersing Agents
The first step in the formulation of any suspension is to ensure
that the particles are dispersed in and wetted by the dispersion
medium. In some substances where the surface energy is not
sufficient the particles may come together and form larger
particles. To overcome this difficulty the substances which are
used are known as dispersing agents. They carry good charge
and are easily adsorbed onto the disperse phase particles.
These substances increase the zeta potential and do not allow
the particles to come together to form large particles.
Preservative
The presence of suspending agents and medicaments which
are liable for bacterial growth makes it necessary to incorporate
a preservative in suspensions. Preservatives selected should be
effective against a wide range of micro-organisms and should
be chemically and physically stable. It should be non-toxic
and compatible with other added substances. The commonly
used preservatives are benzoic ·acid, sodium benzoate, methyl
paraben and propyl-paraben.
Organoleptic Additives
Colours, sweetening agents and flavouring agents are used
in oral suspensions. Similarly colours and perfumes are
incorporated in suspensions meant for external application
but these must be compatible with other ingredients.
Preparation of Suspensions
These preparations are generally of two types:
1. Those in which the insoluble substances are added to the
vehicle or the vehicle is added to the insoluble substances.