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Taibah University
College of Health Sciences
Department of Pharmacy
Pharmaceutics II
PHR 206
College of Health Sciences
2009 – 2010
1
TOC
Table of Contents
1. MIXTURES..................................................................................................................... 3
• Definition: .................................................................................................................... 3
• Advantages: ................................................................................................................. 3
• Containers for mixtures: ............................................................................................. 3
• Classification: .............................................................................................................. 4
Class 1: Simple mixtures containing soluble substances only .......................................... 4
Class 2: Mixtures containing diffusible solids .................................................................. 4
Class 3: Mixtures containing indiffusible solids ............................................................... 5
Class 4: Mixtures containing precipitate forming liquids ................................................. 6
Class 5: Mixtures containing slightly-soluble liquids or solids ........................................ 7
Class 6: Effervescent mixtures.......................................................................................... 8
Class 7: Miscellaneous mixtures ....................................................................................... 9
• Protective effect of gums on colloidal precipitates: ................................................ 14
• Stock solutions:.......................................................................................................... 14
• Stock mixtures: .......................................................................................................... 15
• Suspending Agents .................................................................................................... 16
o Polysaccharides ...................................................................................................... 16
o Water-soluble celluloses ......................................................................................... 18
o Hydrated silicates ................................................................................................... 20
o Carbomers (carboxypolymethylene) ....................................................................... 22
o Colloidal silicon dioxide (Aerosil) .......................................................................... 22
2
Chapter 1 Mixtures
1. MIXTURES
• Definition:
Liquid medicine for internal use of which several doses are contained in
one bottle.
• Advantages:
1. They are more quickly effective than, for example, tablets,
which require previous disintegration-in the body before absorption
can begin.
2. Certain substances can only be given in liquid form, the character
of the remedy, or the large dose, makes administration in any
other from inconvenient, e. g. castor oil, liquid paraffin,
ammonium acetate solution.
3. The usefulness of some substances is largely dependent upon
administration in a diffused form. For example, light kaolin is used
to adsorb toxic substances in the gut, the great surface area of the fine
powder giving Maximum adsorbent effect.
4. Certain chemical substances, e. g. potassium iodide and potassium
bromide, may cause pain if taken in the dry state as a powder or
tablet.
• Containers for mixtures:
o Plain white bottles should be used for preference. The bottle selected
should then be fitted with a cork. This fitting should be done before
the medicine is put into the bottle, so that unsuitable corks may be
returned to stock for later use. The ideal fit should leave about two -
thirds of the cork projecting from the neck of the bottle, to ensure easy
removal. A white label indicating the dose is affixed on the bottle.
3
Chapter 1 Mixtures
• Classification:
Class 1. Simple mixtures containing soluble substances only.
Class 2. Mixtures containing diffusible solids.
Class 3. Mixtures containing indiffusible solids.
Class 4. Mixtures containing precipitate forming liquids.
Class 5. Mixtures containing slightly soluble liquids or solids.
Class 6. Effervescent mixtures.
Class 7. Miscellaneous mixtures.
Class 1: Simple mixtures containing soluble substances only
Mixtures containing soluble substances such as sodium citrate,
potassium citrate, magnesium sulphate, sodium sulphate and
ephedrine hydrochloride are prepared by dissolving the solid in a
portion of the vehicle which may be water or aromatic water as
chloroform water or an infusion as infusion of senege or a decoction
as decoction of ammi visnaga and straining the prepared solution.
The other liquid ingredients (spirit, syrup, tincture, extract) are then
added and the mixture completed with the vehicle to volume.
Class 2: Mixtures containing diffusible solids
Diffusible solids are those which do not dissolve in water, but may be
mixed therewith so that, upon shaking, the powder is evenly diffused
throughout the liquid for sufficient time to ensure uniform
distribution in each dose.
Examples of diffusible solids include: Rhubarb powder, aromatic
chalk powder, compound rhubarb powder, bismuth subnitrate
compound bismuth powder, compound kaolin powder,, compound
liquorice powder, compound magnesium trisilicate powder, light kaolin,
light and heavy magnesium oxide, light and heavy magnesium
4
Chapter 1 Mixtures
trisilicate, phenolphthalein, quinine sulphate, and compound jalap
powder are diffusible insoluble .
Diffusible substance when introduced into mixtures requires no
suspending agents.
The presence of air in the interstices of many powders, particularly those
of vegetable origin, causes some of the powder to float on the water. To
prevent this tendency, make a smooth cream first, by adding only a small
quantity of vehicle, and then-diluting.
Class 3: Mixtures containing indiffusible solids
A solid is regarded as indiffusible when it will not remain evenly
distributed in the vehicle long enough to ensure uniformly of the
measured dose.
The vehicle must, therefore, be increased in viscosity, and it should be
noticed that the viscosity required to hold a given powder in suspension
for a stated period is independent of the quantity of the powder. Therefore,
the amount of suspending agent required depends upon the volume of the
mixture.
Examples of insoluble indiffusible solids include: Acetylsalicylic acid
(aspirin) benzoic acid, bismuth oxychloride, bismuth salicylate, calomel,
chlorbutol, phenacetin, phenobarbitone, prepared chalk, quinidine
sulphate, Quinine salicylate, Salicylic acid, salol, succinylsulphathiazole,
sulphadimidine, acetanilide, and resins of guaiacum, Jalap, podophyllum
and scammony. All of these solids require a suspending agent when
prescribed in mixtures
Suspending agents:
5
Chapter 1 Mixtures
There are many suspending agents which can be used. The best
suspending agents for general use are:
1. Compound powder of tragacanth: 2% w/v
2. Powder of tragacanth: 6.25% to 6.32% w/v
3. Powder of acacia 6% to 10% w/v
4. Mucilage of tragacanth; 1/4 the volume of the mixture.
5. Mucilage of acacia: 1/4 the volume of the mixture.
For bismuth salts in mixtures, the suspending agents that can be used
are compound powder of tragacanth, powder of tragacanth and
mucilage of tragacanth, but not powder of acacia or mucilage of
acacia because they tend to form Cement - like mass at the bottom of
the bottle.
Class 4: Mixtures containing precipitate forming liquids
Certain liquid preparations contain resinous matter, when mixed with
water, the resin is precipitated and may adhere to the sides of the bottle,
or form a clotted precipitates which will not rediffuse upon shaking. This
happens particularly when salts are present.
Resins of scammony, podophyllum, jalap, guaiacum are insoluble and
form indiffusible masses, particularly when salts are present. Resinous
tinctures and extracts as ammoniated tinctures of guaiacum, and of
quinine, compound tincture of benzoin, liquid extract of hydrastis,
tinctures of asafetida, of tolu and of podophyllum when mixed with water,
the resin is precipitated and may adhere to the bottle to form a clotted
precipitate, which will not rediffuse upon shaking.
A suspending agent must be added such as compound powder of
tragacanth ( 2% w/v) or mucilage of tragacanth (25% w/v).
6
Chapter 1 Mixtures
Tinctures of cubebs, of jalap and of myrrh when added to water,
their resins precipitated in a diffusible state, and thus they do not
need a suspending agent except when salts are present in
appreciable proportions.
If the mixture contains other tinctures or spirits, they are mixed
with the resinous tinctures first before adding to water or to the
vehicle. The suspending agent is added before adding the precipitate
forming liquids.
Class 5: Mixtures containing slightly-soluble liquids or solids
1. Slightly soluble liquids
The insoluble portion of slightly soluble liquids is not readily
diffusible, and a suspending agent is therefore necessary.
Compound tragacanth powder (2% w/v) and tragacanth mucilage
(25% v/v) are used for this purpose.
Examples: Creosote is soluble (1 in 150), guaiacol (1 in 80),
paraldehyde (1 in 9), and amyl nitrite (almost insoluble). Alcohol,
alcoholic tinctures, spirits and extracts facilitate their solution if
present in favorable proportions.
2. Slightly soluble solids:
The insoluble portion of slightly soluble solids is diffusible and if
presented in the form of a fine powder, it requires no suspending
agent.
Examples of substances commonly prescribed in a quantity greater
than will dissolve: Borax (1 in 20) boric acid (1 in 20), caffeine
citrate (1 in 32) calcium lactate (1 in 20) and potassium chlorate (1
in 14).
7
Chapter 1 Mixtures
Class 6: Effervescent mixtures
An effervescent mixture is one containing a recently prepared salt
by combining an acid (citric, tartaric) and a bicarbonates or
carbonate ( K, Na or NH4 ) at the time of dispensing and
producing by this means a mixture charged with carbon dioxide.
The substance that produces the effervescence may be added last
without powdering.
Effervescent preparations are more agreeable to the taste when
slightly acid, and thus it is better to arrange for a slight excess of the
acid.
Examples:
1.Limonade purgative E.P. (Magnesium citrate).
2. Effervescent mixture.
Effervescent mixture E.P.
Solution no. 1
Sodium bicarbonate 40 g
Simple syrup 170 ml
Distilled water to 1000 ml
Solution no. 2
Citric acid 33 g
Simple syrup 170 ml
Spirit of lemon 10 ml
Distilled water to 1000 ml
8
Chapter 1 Mixtures
• The two solutions are freshly prepared in separate bottles.
Class 7: Miscellaneous mixtures
1. Mixtures containing small doses of potent medicaments:
Substances like hyoscine hydrodromide, arsenic trioxide and "strychnine
hydrochloride require great care in dispensing the volume to be used.
2. Use of official solutions to obtain small doses:
The pharmacopoeia includes few solutions of potent substances, e.g. Arsenical
solution, containing 1% w/v of arsenic trioxide, adrenaline solution containing
0.1 % w/v of adrenaline, and morphine hydrochloride solution, containing, ,1%
w/v of morphine hydrochloride. These are convenient unsuitable cases where
fractions of a mg. are required.
3. Calcium lactate mixtures:
Samples of calcium lactate differ in the extent of solubility. This causes a
variation in the appearance of a mixture; sometimes it may be clear and
sometimes there may be a diffused powder. Some commercial specimens have
the objectionable odour of sour milk to an undesirable extent. When freshly
made, this odour is not so apparent, and solubility is also good. Calcium
carbonate and lactic acid are allowed to interact and boiled together for about
20 minutes in order to hydrolyze any lactide present in lactic acid to form lactic
acid which will react with calcium carbonate.
9
Chapter 1 Mixtures
4. Other forms of mixtures:
a. DROUGHT
o A draught is a liquid medicine which is usually ordered in from one to
three doses sent in a separate bottle.
b. LINCTUSES
o Linctuses are viscous preparations usually containing medicaments
having a local action on the mucous membrane of the throat and are
usually prescribed for the relief of cough.
o The vehicle is some mucilaginous syrupy or viscous substance. They
are sipped or swallowed slowly without dilution in orders that they
may have a prolonged action.
o It usually consists of a simple solution of the active agent in a high
concentration of sucrose often with other sweetening agents.
o This type of products, which is also designed to be administered in
multiples of 5 ml should be sipped slowly and do not diluted
beforehand.
o The syrup content has a demulcent action on the mucous membranes
of the throat.
o For diabetic use the sucrose is usually replaced by sorbitol and /or
synthetic sweeteners.
o Examples are Codeine Linctus in sucrose syrup PC (11 th ed) &
Diabetic Codeine Linctus in sorbitol solution, PC (11 th ed).
c. ELIXIRS
o Elixirs are clear, pleasantly flavored, sweetened hydroalcoholic
liquids intended for oral use.
o The main ingredients in elixirs are ethanol and water but glycerin,
sorbitol propylene glycol, flavoring agent, preservatives, and syrups
10
Chapter 1 Mixtures
often are used in the preparation of the final product. The solvents are
often used to increase the solubility of the drug substance in the
dosage form.
o Elixirs are more fluid than syrups, due to the use of less viscous
ingredients such as alcohol and the minimal use of viscosity-
improving agents such as sucrose.
o They are used as flavors and vehicles for drug substances (e.g.
aromatic elixir USP).
o Examples of medicated elixirs:
Dexamethasone elixir USP
Phenobarbital elixir USP
o Occasionally, certain adverse effects (e.g., mucosal erosions) may be
eliminated or reduced if the active drug (e.g. potassium chloride) is
administered in elixir rather than in a solid dosage form.
o The distinction between some of the medicated syrups and elixirs is
not always clear however elixir must contain alcohol.
o Elixirs also may contain glycerin and syrup. These may be added to
increase the solubility of the medicinal agent, for sweetening purposes
or to decrease the pharmacological effects of the alcohol. Some elixirs
contain propylene glycol. Claims have been made for this solvent as a
satisfactory substitute for both glycerin and alcohol.
o An elixir may contain both water- and alcohol-soluble ingredients. If
such is the case, the following procedure is indicated:
Dissolve the water-soluble ingredients in part of the water.
Add and solubilize the sucrose in the aqueous solution.
Prepare alcoholic solution containing the other ingredients.
Add the aqueous phase to the alcoholic solution, filter, and make
to volume with water.
11
Chapter 1 Mixtures
Sucrose increases viscosity and decreases the solubilizing
properties of water and so must be added after primary
solution has been affected.
A high alcoholic content is maintained during preparation by
adding the aqueous phase to the alcoholic solution.
o Elixirs that contain therapeutically active compounds are known as
medicated elixirs. Phenobarbital elixir is considered a medicated
elixir.
Phenobarbital 4.00 g
Orange oil 0.75 ml
Amaranth solution 10.00 ml
Alcohol 150.00 ml
Glycerin 450.00 ml
Syrup 150.00 ml
Purified water, q.s. 1000.00 ml
Sig.: Phenobarbital elixir.
In preparing Phenobarbital elixir, the Phenobarbital and the
orange oil are dissolved in alcohol.
The remaining ingredients are then added, and the solution
is adjusted to final volume by the addition of water.
If all the ingredients were mixed and the Phenobarbital was
added last, the Phenobarbital would dissolve with difficulty.
The 15% alcohol in the Phenobarbital elixir is not sufficient
to maintain the Phenobarbital in solution. It is the aqueous
12
Chapter 1 Mixtures
alcohol and glycerin solution that maintains the drug in
solution.
The addition of aqueous solutions to Phenobarbital elixir
may cause precipitation of the Phenobarbital.
o Incompatibilities:
Because elixirs contain alcohol, incompatibilities of this solvent
are an important consideration during formulation.
Alcohol precipitates tragacanth, acacia, and agar from aqueous
solutions.
If an aqueous solution is added to an elixir, a partial
precipitation of alcohol soluble ingredients may occur. This is
due to reduced alcoholic content of the final preparation.
d. DROPS
o A mixture is designated “Drops” when it is ordered in doses of less
than one teaspoonful. Drops may be remedies given in their original
form without dilution. Sometimes the remedy decomposes in aqueous
media. Tincture of strophanthus contains the active principle
strophanthin, a glycoside which is readily hydrolyzed by water to
Strophanthidin which is inactive. To avoid this, it is prescribed
generally in an alcoholic medium sometimes with compound tincture
of cardamom.
o Care must be taken to note the considerable difference between drops
and minims. The weight of the minim of water is always constant
while the weight of drop is variable with different substances. One
minim approximately gives three drops of alcohol, five drops of
chloroform, two and a half drops of tincture of belladonna, tincture of
digitalis and tincture of opium.
13
Chapter 1 Mixtures
o Drops are usually sent out in bottles, accompanied by a standard
dropper or a measure graduated in minims.
• Protective effect of gums on colloidal precipitates:
o The addition of an electrolyte, e.g. potassium bromide, and magnesium
sulphate to certain colloidal solutions (e.g. resins) cause rapid
agglomeration of the particles, with the formation of large visible
particles, the colloid is then said to be precipitated. With other colloidal
solutions, e.g. a solution of acacia or tragacanth no such precipitation
takes place.
o A solution of acacia is a protective colloid, i.e. not only is it stable with
electrolytes,
but it also prevents precipitation of other colloids when an electrolyte is
added thereto.
o The protective effect maybe explained by saying that the colloidal
particles of acacia surround the particles of the other colloid, forming an
effective barrier against the electrolyte.
• Stock solutions:
o It is quicker to measure a liquid than to weigh a solid, hence stable
soluble salts in frequent use are often made into solutions of known
strength.
o A common strength for very soluble substances is 1 in 3, meaning that 1
gram contained in 3 milliliters of solution. Less soluble substances are
necessarily stocked in weaker solutions, e.g. 1 in 6 or 1 in 8.
o It must be remembered, however, that measuring is less accurate than
weighing and great care must be taken to ensure a satisfactory degree of
accuracy.
14
Chapter 1 Mixtures
• Stock mixtures:
o These are mixtures prepared in bulk, to enable small volumes to be
dispensed quickly when required.
15
Chapter 1 Mixtures
• Suspending Agents
The following materials are those most widely used for the modification of
suspension viscosity.
o Polysaccharides
1. Acacia
Acacia This natural material is often used as a suspending agent
for extemporaneously prepared suspensions.
Acacia is not a good thickening agent and its value as a
suspending agent is largely due to its action as a protective
colloid. It is therefore useful for preparations containing
tinctures of resinous materials that precipitate on addition to
water.
It is essential to ensure that any precipitated resin is well coated
by the protective colloid before any electrolyte (which should be
well diluted) is added.
Acacia is not very effective for dense powders, and for these it
is often combined with other thickeners such as tragacanth,
starch and sucrose in compound tragacanth powder.
Unfortunately, acacia mucilage becomes acidic on storage as a
result of enzyme activity, and it also contains an oxidase
enzyme which may cause deterioration of active agents that are
susceptible to oxidation. This enzyme can, however, be
inactivated by heat.
Because of the stickiness of acacia it is rarely used in
preparations for external use.
16
Chapter 1 Mixtures
2. Tragacanth
Tragacanth This product will form viscous aqueous solutions.
Its thixotropic and pseudoplastic properties make it a better
thickening agent than acacia and it can be used both for internal
and external products.
Like acacia it is mainly used for the extemporaneous
preparation of suspensions with a short shelf-life.
Tragacanth is stable over a pH range of 4-7.5 but takes several
days to hydrate fully after dispersion in water. The maximum
viscosity of its dispersions is not, therefore, achieved until after
this time, and can also be affected by heating.
There are several grades of this material and only the best
quality is suitable for use as a pharmaceutical suspending agent.
3. Alginates
Alginic acid, a polymer of D-mannuronic acid, is prepared
from kelp, and its salts have suspending properties similar to
those of tragacanth.
Alginate mucilages must not be heated above 60°C as
depolymerization occurs, with a consequent loss in viscosity.
They are most viscous immediately after preparation, after
which there is a fall to a fairly constant value after about 24
hours.
Alginates exhibit a maximum viscosity over a pH range of 5-9,
and at low pH the acid is precipitated.
Sodium alginate (Manucol) is the most widely used material in
this class but it is, of course, anionic and will be incompatible
with cationic materials and with heavy metals. The addition of
calcium chloride to sodium alginate dispersion will produce
17
Chapter 1 Mixtures
calcium alginate, which has a much higher viscosity. Several
different viscosity grades are commercially available.
4. Starch
Starch is rarely used on its own as a suspending agent but is one of
the constituents of compound tragacanth powder, and it can also be
used with carmellose sodium.
Sodium starch glycolate (Explotab, Primojel), a derivative of
potato starch, has also been evaluated for its use in the
extemporaneous preparation of suspensions.
5. Xanthan gum (keltrol)
This is an anionic heteropolysaccharide produced by the action of
Xanthomonas campestris on corn sugars. It is very soluble in cold
water and is one of the most widely used thickening agents for the
extemporaneous preparation of suspensions for oral use.
It is used in concentrations up to about 2% and is stable over a
wide pH range.
o Water-soluble celluloses
Several cellulose derivatives are available that will disperse in water
to produce viscous colloidal solutions suitable for use as suspending
agents.
1. Methylcellulose (Celacol, Methocel)
This is a semisynthetic polysaccharide of the general formula:
and is produced by the methylation of cellulose.
Several grades are available, depending on their degree of
methylation and on the chain length. The longer the chain, the
more viscous is its solution. For example, a 2% solution of
18
Chapter 1 Mixtures
methylcellulose 20 exhibits an apparent viscosity of 20 millipascal
seconds (mPa s) and methylcellulose 4500 has value of 4500 mPa
s at 2% concentration.
Because these products are more soluble in cold water than in hot,
they are often dispersed in warm water and then, on cooling with
constant stirring, a clear or opalescent viscous solution is
produced.
Methylcelluloses are non-ionic and therefore stable over a pH
range of 3-11, and are compatible with many ionic additives.
When these dispersions are heated, the methylcellulose molecules
become progressively dehydrated and eventually gel at about
50°C; on cooling the original form is regained.
2. Hydroxyethylcellulose (Natrosol)
This compound has hydroxyethyl instead of methyl groups
attached to the cellulose chain and is also available in different
viscosity grades. It has the advantage of being soluble in both hot
and cold water and will not gel on heating. Otherwise it exhibits
the same properties as methylcellulose.
3. Carmellose sodium (sodium carboxymethylcellulose)
This material can be represented by:
where x represents the degree of substitution, usually about 0.7,
which in turn affects its solubility.
The viscosity of its solution depends on the value of n, which
represents the degree of polymerization. The numerical suffix
gives an indication of the viscosity of a 2% solution. For example
19
Chapter 1 Mixtures
sodium carboxymethylcellulose 50 at a concentration of 2% will
have a viscosity of 50 mPa s.
This material produces clear solutions in both hot and cold water,
which are stable over a pH range of about 5-10.
Being anionic, this material is incompatible with polyvalent
cations and the acid will be precipitated at low pHs. Heat
sterilization of either the powder or its mucilage will reduce the
viscosity, and this must be taken into account during formulation.
It is widely used at concentrations of up to 1 % in products for
oral, parenteral or external use.
4. Microcrystalline cellulose
This material consists of crystals of colloidal dimensions which
disperse readily in water (but are not soluble) to produce
thixotropic gels.
It is a widely used suspending agent and the rheological properties
of its dispersions can often be improved by the incorporation of
additional hydrocolloid, in particular carboxymethylcellulose,
methylcellulose and hydroxypropylmethylcellulose. These will aid
dispersion and also stabilize the product against the flocculating
effects of added electrolyte.
o Hydrated silicates
There are three important materials within this classification,
namely bentonite, magnesium aluminium silicate and hectorite,
and they belong to a group called the montmorillonite clays.
They hydrate readily, absorbing up to 12 times their weight of
water, particularly at elevated temperatures. The gels formed are
thixotropic and therefore have useful suspending properties.
20
Chapter 1 Mixtures
As with most naturally occurring materials they may be
contaminated with spores, and this must be borne in mind when
considering a sterilization process and choosing a preservative
system.
1. Bentonite
This has the general formula:
It is used at concentrations of up to 2 or 3% in preparations for
external use, such as calamine lotion.
As this product may contain pathogenic spores it should be
sterilized before use.
2. Magnesium aluminium silicate (Veegum)
It is also known as attapulgite, this is available as insoluble flakes
that disperse and swell readily in water by absorbing the aqueous
phase into its crystal lattice.
Several grades are available, differing in their particle size, their
acid demand and the viscosity of their dispersions.
They can be used both internally and externally at concentrations
of up to about 5%, and are stable over a pH range of 3.5-11.
Veegum/water dispersions will exhibit thixotropy and plasticity
with a high yield value, but the presence of salts can alter these
rheological properties because of the flocculating effect of their
positively charged counter-ions. Some grades, however, have a
higher resistance to flocculation than others.
This material is often combined with organic thickening agents
such as sodium carboxymethylcellulose or xanthan gum to
improve yield values and degree of thixotropy, and to control
flocculation.
21
Chapter 1 Mixtures
3. Hectorite
This material is similar to bentonite and can be used at
concentrations of 1-2% for external use.
It is also possible to obtain synthetic hectorites (Laponite) that do
not exhibit the batch variability or level of microbial contamination
associated with natural products, and which can also be used
internally.
As with other clays it is often advantageous to include an organic
gum to modify its rheological properties.
o Carbomers (carboxypolymethylene)
This material is a totally synthetic copolymer of acrylic acid and
allyl sucrose.
It is used at concentrations of up to 0.5%, mainly for external
application, although some grades can be taken internally.
When dispersed in water it forms acidic, low-viscosity solutions
which, when adjusted to a pH of between 6 and 11, become highly
viscous.
o Colloidal silicon dioxide (Aerosil)
When dispersed in water this finely divided product will aggregate,
forming a three-dimensional network.
It can be used at concentrations of up to 4% for external use, but has
also been used for thickening non-aqueous suspensions.
22
Chapter 2 Suspensions
2. SUSPENSIONS
• Definition of suspension:
Suspensions are preparations that contain fine drug particles distributed
uniformly throughout a vehicle in which the drug exhibits minimum solubility.
A pharmaceutical suspension is usually a coarse dispersion in which insoluble
solid particles are dispersed in a liquid system. The particles usually have
diameter greater than 0.1 μm.
• Physical properties of well formulated suspensions
o The product must remain sufficiently homogenous for at least the period
between shaking the container and removing the required amount.
o The sediment produced on storage, if any, must be easily re-suspended
by moderate agitation of the container.
o The product may be required to be thickened in order to reduce the rate
of settling of the particles. The resulting viscosity must not be so high
that removal of the product from the container and transfer to the site of
application is difficult.
o Any suspended particles should be small and uniformly sized in order to
give a smooth, elegant product, free from a gritty texture.
• Theory of suspension
1. Surface free energy:
For the formulation of suspensions work must be done to reduce a large
solid material into small particles and disperse them in a continuous
medium.
23
Chapter 2 Suspensions
Particle size reduction may be achieved by; Milling, Micro-pulverization,
Fluid energy grinding, jet milling or micronizing, spray drying.
This comminution process results in the generation of surface free energy
that makes the system thermodynamically unstable as the resultant small
particles are highly energetic and tend to regroup in such a way as to
decrease the total area and reduce the surface free energy.
The particles in a liquid suspension therefore tend to form light, fluffy
conglomerates known as floccules that are held together by weak van der
Waals forces. Under certain conditions, the particle may adhere by
stronger forces to form aggregates known as cakes.
The formation of any type of aggregate, either floccules or cakes, is
perceived as a measure of the system's tendency to reach a more
thermodynamically stable state.
An increase in the work, W, or surface free energy, ΔG, brought about by
dividing the solid into smaller particles and eventually increasing the
total surface area, ΔA, is given by:
ΔG = γSL •ΔA
Where γSL , is the interfacial tension between the liquid medium
and the solid particles.
In order to approach a stable state, the system tends to reduce the surface
free energy. This may be achieved either by a reduction of interfacial
tension or by a reduction of the interfacial area.
Interfacial tension can be reduced by the addition of a surfactant.
Reduction of interfacial area, on the other hand, is achieved through
formation of floccules or cakes.
24
Chapter 2 Suspensions
2. Electrical properties:
2.1 Electric Double Layer
o When dispersed particles are in contact with an aqueous solution of an
electrolyte, the particles may selectively adsorb one charge species. If the
adsorbed species is an anion, the particles will be overall negatively
charged.
o The ions that give the particle its charge, anions in this case, are called
potential-determining ions or co-ions.
o Remaining ionic species in the solution are the rest of the anions and the
total number of cations added. This means, there will be excess cations
than anions in the dispersion medium.
o These cations having a charge opposite to that of the potential-
determining ions are known as counter-ions. They are attracted to the
negatively charged surface by electric forces.
o Counter-ions also repel the approach of any further anions to particle
surface, once the initial adsorption is complete.
o These electric forces and thermal motion keeps an equal distribution of
all the ions in solution. It results in an equilibrium condition where some
of the excess cations approach the surface and the rest of the cations will
be distributed in decreasing the amounts as one moves away from the
charged surface. This situation is explained in Fig. 2.1.
o The part of the solvent immediately surrounding the particles will almost
entirely comprise of the counter-ions. This part of the solvent, along with
these counter-ions is tightly bound to the particle surface and is known as
the Stern layer.
o When particles move through the dispersion medium, the Stern layer
moves along with them and thus the shear plane is the one peripheral to
the Stern layer.
25
Chapter 2 Suspensions
o There are fewer counter-ions in the tightly bound layer than co-ions
adsorbed onto the surface of the solid. Therefore, the potential at the
shear plane is still negative.
o Surrounding the Stern layer is the diffuse layer that contains more
counter-ions than co-ions. The ions in this layer are relatively mobile
and, because of thermal energy, they are in a constant state of motion into
and from the main body of the continuous phase.
o Electric neutrality occurs where the mobile diffuse layer ends. Beyond
the diffuse layer, the concentrations of co- and counter-ions are equal,
that is, conditions of electric neutrality prevail throughout the remaining
part of the dispersion medium.
o Thus, the electric distribution at the solid–liquid interface can be
visualized as a double layer of charge. The Stern layer, the first layer is
tightly bound to the solid surface and contains mostly the counter-ions.
The second layer is more mobile containing more counter-ions than co-
ions. These two layers are commonly known as the electric double layer.
o The thickness of the double layer depends upon the type and
concentration of ions in solution. It is important to note that the
26
Chapter 2 Suspensions
suspension, as a whole is electrically neutral despite the presence of
unequal distribution of charges in the double layer.
o Two other situations may arise. Should the concentration of counter-ions
in the tightly bound layer be equal to that of the co-ions on the solid
surface, then electric neutrality will occur at the shear plane and there
will be only one layer of medium and ions, instead of double layer.
o However, if the total charge of the counter-ions in the Stern layer exceeds
the charge due to the co-ions, the net charge at the shear plane will be
positive rather than negative. It means electric neutrality will be achieved
where the electric double layer ends and the diffuse layer, will contain
more co-ions than counter-ions.
o The charge density at any distance from the surface is determined by
taking the difference in concentration between positive and negative ions
at that point.
2.2 Nernst and Zeta Potentials
o The electric double layer is formed in order to neutralize the charged
particles in a suspension.
o As discussed before the electrical potential at any point in a suspension
system depends on its exact location.
o The potential in the diffuse layer gradually changes as one moves away
from a solid particle. This is shown in Fig. 2.2.
o The difference in electric potential between the actual or true surface of
the particle and the electroneutral region is referred to as the surface or
electrothermodynamic or Nernst potential (E).
o Hence, Nernst potential is controlled by the electrical potential at the
surface of the particle due to the potential determining ions.
o The potential difference between the shear plane and the electroneutral
region is known as the electrokinetic or zeta (z) potential (Fig. 2.3).
27
Chapter 2 Suspensions
o While Nernst potential has little influence in the formulation of stable
suspension, zeta potential has significant effect on it.
o Zeta potential governs the degree of repulsion between adjacent,
similarly charged solid dispersed particles. If the zeta potential is reduced
below a certain value, which depends on the specific system under
investigation, the attractive forces between particles due to van der
Waals’ force, overcome the forces of repulsion and the particles come
together to form floccules. This phenomenon is known as flocculation.
o The magnitude of surface and zeta potentials is related to the surface
charge and the thickness of the double layer.
28
Chapter 2 Suspensions
• Rationale for suspensions formulation
o The reasons for preparing a suspension are:
1. Certain drugs are chemically unstable in solution phase but stable in
suspension. In this case, the suspension can assure the stability while
delivering the drugs in liquid dosage form.
2. Many patients prefer the liquid formulation over the solid form of the
same drug since it is easier to swallow.
3. The flexibility in administration of a range of doses for a liquid
dosage form than a solid dosage form (as tablets) for infants, children,
and the elderly.
4. Suspension helps improve the taste of some poor-tasting drugs,
because the dispersion medium can be sweetened and flavored.
5. A suspension is often a suitable dosage form to be given orally, in
dermatology (Topical or on the skin) and for the parenteral (IM, SC)
administration of insoluble drugs.
6. Many antibiotic agents are unstable in solution for a period of time;
therefore, packaging as a dry powder to be reconstituted by adding the
dispersion medium when filling the prescription is a good approach.
o Common pharmaceutical suspensions belong to three groups: (1) Oral
suspensions (syrups) which have the most common application of
suspension, (2) external suspension (lotions), and (3) parenteral
suspensions.
o The following are examples of some common oral suspensions:
♦ Alumina, magnesia, and simethicone oral suspension.
♦ Magnesia and alumina oral suspension.
♦ Sulfamethoxazole and trimethoprim oral suspension.
♦ Amoxicillin for oral suspension.
♦ Ampicillin for oral suspension.
♦ Cefixime for oral suspension.
29
Chapter 2 Suspensions
o The last three preparations consist of specific amounts of dry powder
mixtures or granules, which are intended to be suspended in a specific
quantity of water or some other vehicle prior to oral administration to
produce a specific concentration.
• Formulation of Suspension
1. Particle size control
o It is first necessary to ensure that the drug to be suspended is of a fine
particle size prior to formulation. This is to ensure a slow rate of
sedimentation of the suspended particles.
o Large particles, if greater than about 5 µm diameter, will also impart a
gritty texture to the product, and may cause irritation if injected or
instilled into the eyes.
o The ease of administration of a parenteral suspension may depend upon
particle size and shape, and it is quite possible to block a hypodermic
needle with particles over about 25 µm diameter, particularly if they are
acicular in shape rather than isodiametric.
o A particular particle size range may also be chosen in order to control the
rate of dissolution of the drug and hence its bioavailability.
o Even though the particle size of a drug may be small when the
suspension is first manufactured, there is always a degree of crystal
growth that occurs on storage, particularly if temperature fluctuations
occur. This is because the solubility of the drug may increase as the
temperature rises, but on cooling, the drug will crystallize out. This is a
particular problem with slightly soluble drugs such as paracetamol.
o If the drug is polydispersed, then the very small crystals of less than 1 µm
diameter will exhibit a greater solubility than the larger ones.
o Over a period of time the small crystals will become even smaller,
whereas the diameters of the larger particles will increase.
30
Chapter 2 Suspensions
o It is therefore advantageous to use a suspended drug of a narrow size
range. The inclusion of surface-active agents or polymeric colloids,
which adsorb on to the surface of each particle, may also help to prevent
crystal growth.
o Different polymorphic forms of a drug may exhibit different solubilities,
the metastable state being the most soluble. Conversion of the metastable
form, in solution, to the less soluble stable state, and its subsequent
precipitation, will lead to changes in particle size.
2. The use of wetting agents
o Some insoluble solids may be easily wetted by water and will disperse
readily throughout the aqueous phase with only minimal agitation.
o Most, however, will exhibit varying degrees of hydrophobicity and will
not be easily wetted. Some particles will form large porous clumps within
the liquid, whereas others remain on the surface and become attached to
the upper part of the container.
o The foam produced on shaking will be slow to subside because of the
stabilizing effect of the small particles at the liquid/air interface.
o To ensure adequate wetting, the interfacial tension between the solid and
the liquid must be reduced so that the adsorbed air is displaced from the
solid surfaces by the liquid.
o The particles will then disperse readily throughout the liquid, particularly
if an intense shearing action is used during mixing.
o If a series of suspensions is prepared, each containing one of a range of
concentrations of wetting agent, then the concentration to choose will be
the lowest that provides adequate wetting.
o The following is a discussion of the most widely used wetting agents for
pharmaceutical products.
31
Chapter 2 Suspensions
a. Surface-active agents
Surfactants possessing an HLB value between about 7 and 9 would be
suitable for use as wetting agents. The hydrocarbon chains would be
adsorbed by the hydrophobic particle surfaces, whereas the polar
groups project into the aqueous medium and become hydrated.
Wetting of the solid occurs as a result of a fall both in interfacial
tension between the solid and the liquid and, to a lesser extent,
between the liquid and air.
Most surfactants are used at concentrations of up to about 0.1 % as
wetting agents and include, for oral use, the polysorbates (Tweens)
and sorbitan esters (Spans). For external application, sodium lauryl
sulphate, sodium dioctylsulphosuccinate and quillaia extract can also
be used.
The choice of surfactant for parenteral administration is obviously
more limited, the main ones used being the polysorbates, some of the
poloxamers (polyoxyethylene/polyoxypropylene copolymers) and
lecithin.
Disadvantages in the use of this type of wetting agent include
excessive foaming and the possible formation of a deflocculated
system, which may not be required.
b. Hydrophilic colloids
These materials include acacia, bentonite, tragacanth, alginates,
xanthan gum and cellulose derivatives, and will behave as protective
colloids by coating the solid hydrophobic particles with a
multimolecular layer.
This will impart a hydrophilic character to the solid and so promote
wetting. These materials are also used as suspending agents and may,
like surfactants, produce a deflocculated system, particularly if used at
low concentrations.
32
Chapter 2 Suspensions
c. Solvents
Materials such as alcohol, glycerol and glycols, which are water
miscible, will reduce the liquid/air interfacial tension.
The solvent will penetrate the loose agglomerates of powder
displacing the air from the pores of the individual particles, so
enabling wetting to occur by the dispersion medium.
3. Flocculated and deflocculated systems
o Having incorporated a suitable wetting agent, it is then necessary to
determine whether the suspension is flocculated or deflocculated and to
decide which state is preferable.
o Whether or not a suspension is flocculated or deflocculated depends on
the relative magnitudes of the forces of repulsion and attraction between
the particles.
o In a deflocculated system the dispersed particles remain as discrete units
and, because the rate of sedimentation depends on the size of each unit,
settling will be slow.
o The supernatant of a deflocculated system will continue to remain cloudy
for an appreciable time after shaking, due to the very slow settling rate of
the smallest particles in the product, even after the larger ones have
sedimented.
o The repulsive forces between individual particles allow them to slip past
each other as they sediment. The slow rate of settling prevents the
entrapment of liquid within the sediment, which thus becomes compacted
and can be very difficult to redisperse.
o This phenomenon is also called caking or claying, and is the most serious
of all the physical stability problems encountered in suspension
formulation.
33
Chapter 2 Suspensions
o In a flocculated system, the aggregation of particles will lead to a much
more rapid rate of sedimentation or subsidence because each unit is
composed of many individual particles and is therefore larger.
o The rate of settling will also depend on the porosity of the aggregate,
because if it is porous the dispersion medium can flow through, as well as
around, each aggregate or floccule as it sediments.
o The nature of the sediment of a flocculated system is also quite different
from that of a deflocculated one. The structure of each aggregate is
retained after sedimentation, thus entrapping a large amount of the liquid
phase. The volume of the final sediment will still be large and will easily
be redispersed by moderate agitation.
o In a flocculated system the supernatant quickly becomes clear, as the
large flocs that settle rapidly are composed of particles of all sizes.
The sedimentation behaviour of flocculated and deflocculated suspensions. Within a few minutes of
manufacture (a) there is no apparent change within the deflocculated system compared to its initial
appearance. Even after several hours (b) there is still little obvious change, except that the
concentration of solids in the lower layers has increased at the expense of the upper layers owing to
slow particle sedimentation. There is a small amount of a compact sediment. After prolonged storage
(c), depending on the physical stability of the system, the supernatant has cleared, leaving a compact
sediment. In the flocculated system at (a) there is some clear supernatant with a distinct boundary
between it and the sediment. At (b) there is a larger volume of clear supernatant with a relatively large
volume of a porous sediment, which does not change further even after prolonged storage (c).
34
Chapter 2 Suspensions
o In summary, deflocculated systems have the advantage of a slow
sedimentation rate, thereby enabling a uniform dose to be taken from the
container, but when settling does occur the sediment is compacted and
difficult to redisperse. Flocculated systems form loose sediments which
are easily redispersible, but the sedimentation rate is fast and there is a
danger of an inaccurate dose being administered; also, the product will
look inelegant.
a. Controlled flocculation
A deflocculated system with a sufficiently high viscosity to prevent
sedimentation would be an ideal formulation.
It cannot be guaranteed, however, that the system would remain
homogenous during the entire shelf-life of the product.
Usually a compromise is reached in which the suspension is partially
flocculated to enable easy redispersion if necessary, and viscosity is
controlled so that the sedimentation rate is at a minimum.
So the next stage of the formulation process, after the addition of the
wetting agent, is to ensure that the product exhibits the correct degree
of flocculation.
Underflocculation will give those undesirable properties that are
associated with deflocculated systems. An overflocculated product
will look inelegant and, to minimize settling, the viscosity of the
product may have to be so high that any necessary redispersion would
be difficult.
Controlled flocculation is usually achieved by a combination of
particle size control, the use of electrolytes to control zeta potential,
and the addition of polymers to enable crosslinking to occur between
particles. Some polymers have the advantage of becoming ionized in
35
Chapter 2 Suspensions
an aqueous solution, and can therefore act both electrostatically and
sterically. These materials are also termed polyelectrolytes.
b. Flocculating agents
In many cases, after the incorporation of a non-ionic wetting agent a
suspension will be found to be deflocculated, either because of the
reduction in solid/liquid interfacial tension, or because of the hydrated
hydrophilic layer around each particle forming a mechanical barrier to
aggregation.
The use of an ionic surfactant to wet the solid could produce either a
flocculated or a deflocculated system, depending on any charge
already present on the particles. If particles are of opposite charge to
that of the surfactant then neutralization will occur. If a high charge
density is imparted to the suspended particles then deflocculation will
be the result.
If it is necessary for the suspension to be converted from a
deflocculated to a partially flocculated state, this may be achieved by
the addition of electrolytes, surfactants and/or hydrophilic polymers.
i. Electrolytes
The addition of an inorganic electrolyte to an aqueous suspension will
alter the zeta potential of the dispersed particles and, if this value is
lowered sufficiently, flocculation may occur.
The Schultz-Hardy rule shows that the ability of an electrolyte to
flocculate hydrophobic particles depends on the valency of its
counter-ions.
Although they are more efficient, trivalent ions are less widely used
than mono- or divalent electrolytes because they are generally more
toxic. If hydrophilic polymers, which are usually negatively charged,
36
Chapter 2 Suspensions
are included in the formulation they may be precipitated by the
presence of trivalent ions.
The most widely used electrolytes include the sodium salts of
acetates, phosphates and citrates, and the concentration chosen will be
that which produces the desired degree of flocculation.
Care must be taken not to add excessive electrolyte or charge reversal
may occur on each particle, so forming, once again, a deflocculated
system.
ii. Surfactants
Ionic surface-active agents may also cause flocculation by
neutralizing the charge on each particle.
Non-ionic surfactants will, of course, have a negligible effect on the
charge density of a particle but may, because of their linear
configurations, adsorb on to more than one particle, thereby forming a
loose flocculated structure.
iii. Polymeric flocculating agents
Starch, alginates, cellulose derivatives, tragacanth, carbomers and
silicates are examples of polymers that can be used to control
flocculation.
Their linear branched-chain molecules form a gel-like network within
the system and become adsorbed on to the surfaces of the dispersed
particles, thus holding them in a flocculated state. Although some
settling can occur, the sedimentation volume is large, and usually
remains so for a considerable period.
Care must be taken to ensure that, during manufacture, blending is not
excessive as this may inhibit the crosslinking between adjacent
particles and result in the adsorption of each molecule of polymer on
to one particle only. If this should occur then a deflocculated system
37
Chapter 2 Suspensions
may result, because the formation of the hydrophilic barrier around
each particle will inhibit aggregation. A high concentration of
polymer may have a similar effect if the whole surface of each particle
is coated.
It is essential that areas on each suspended particle remain free from
adsorbate, so that crosslinking can recur after the product is sheared.
Table.1. Relative properties of flocculated and deflocculated suspensions
Character Deflocculated Flocculated
Exist in suspension as Form loose aggregates or
Particles
individual entities. floccules.
Rate of sedimentation Slow high
Very closely packed and loosely packed and easy to
the resulting hard cake is redisperse
The sediment
difficult, if not
impossible, to redisperse
after settling it remains After rapid settling, a
cloudy. clear boundary exists
supernatant
between the sediment and
the supernatant.
• Preparation of suspension
o In the preparation of a suspension, the pharmacist must be familiar with
the characteristics of both the dispersed phase and the dispersion
medium.
o In some cases, the dispersed phase (powder) is readily wetted when
added to the medium. However, sometimes the particles clump together
and float on top of the vehicle and cause an uneven suspension. In these
cases, the powder must be wetted firstly with wetting agent.
o Examples of wetting agents used in case of aqueous vehicle as dispersion
medium are alcohol, glycerol, propylene glycol or other hygroscopic
liquids.
38
Chapter 2 Suspensions
o Once the powder is wetted, the dispersion medium is added and mixed
thoroughly before addition of the vehicle.
o The final product is then passed through a colloid mill or blender to
insure uniformity. A preservative may be added to protect against
bacterial contamination.
• Extemporaneous compounding of suspensions
o Unfortunately, not all medicines are available in a convenient, easy-to-
take liquid dosage form. Therefore, patients who are not able to swallow
solid dosage medicines such as infants and elderly may present a special
need.
o Thus pharmacist may have to use a solid dosage form of the drug and
extemporaneously compound a liquid product.
o The contents of the capsule are to be putted into a mortar; if it is in tablet
form, it will be crushed in a mortar with a pestle. Then the selected
vehicle is slowly added to the powder and mixed well to create a paste
before being diluted to the desired volume.
o The difficulty that confronts the pharmacist is the stability of the drug
when it is incorporated into a liquid vehicle. Drugs in liquid form have
faster decomposition rates than those in solid form. To overcome this, the
pharmacist can contact the pharmaceutical manufacturer to obtain
stability information.
• Settling/Sedimentation in suspensions
o Settling of the suspended particles leading to separation of dispersed
particles and dispersion medium is the most important factor associated
with the physical stability of a suspension.
o Many factors involved in the rate of settling of the particles of a
suspension are summarized in the equation of Stokes' law:
39
Chapter 2 Suspensions
dx d ( ρ p − ρ m ) g
2
=
dt 18η
Where
dx/ dt is the sedimentation rate,
d is the diameter of the particles,
ρp is the density of particles,
ρm is the density of medium,
g is the gravitational constant, and
η is the viscosity of the medium,
o The equation is valid only in an ideal situation in which uniform,
perfectly spherical particles settle in a very dilute suspension (i.e., no
collision of the particles), without effecting turbulence in the medium and
without chemical or physical attraction between the particles and the
medium.
o While in practical cases, conditions are not in strict accord with the
assumptions of Stokes' law, the above equation does give the factors that
influence the rate of settling. It is apparent from the equation that rate of
sedimentation (dx/dt) will be reduced by
A. Decreasing the particle size (d), provided the particles are kept in a
deflocculated state. This may be achieved by communition of the
particles using appropriate techniques (pestle and mortar, colloid
mills, etc.).,
B. Minimizing the difference in densities between the particles and the
dispersion medium (ρp- ρm). In fact control of settling by minimizing
the difference in densities between the particles and the dispersion
medium is not too practical.
C. Increasing the viscosity of the dispersion medium (η). Viscosity of the
dispersion medium can always be increased by the addition of
40
Chapter 2 Suspensions
viscosity building polymers (methyl cellulose, carboxy
methylcellulose, etc.). However, too high a viscosity is undesirable, as
it may affect the redispersability and pourability of the suspension.
41
