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3
UNIT
Pharmaceutical Aids
Pharmaceutical aids are substances that have little or no
pharma cological effect, but are used in the preparation or
compounding of various pharmaceutical dosage forms. They
perform various functions such as enhancing drug solubility,
stability, taste, texture, etc. They can be classified based on
their origin, dosage form, or function:
Origin: Pharmaceutical aids can be derived from animal,
vegetable, mineral, or synthetic sources. For example, lactose,
gelatin, and stearic acid are from animal sources; starch,
acacia, and guar gum are from vegetable sources; calcium
phosphate, talc, and kaolin are from mineral sources; and
baric acid, saccharin, and povidone are from synthetic
sources.
Dosage forms: Pharmaceutical aids can be used in solid,
liquid, or semi-solid dosage forms. For example, diluents,
binders, lubricants, and organoleptic agents are used in
solid dosage forms; solvents, buffers, anti-microbials, and
flavoring agents are used in liquid dosage forms; and
preservatives, antioxidants, and bases are used in semi-
solid dosage forms.
Functions: Pharmaceutical aids can perform various
functions such as acidifying, alkalinizing, buffering,
absorbing, adsorbing, preserving, stabilizing, suspending,
filtering, coloring, tonicity adjusting, etc. For example, acetic
acid and sodium hydroxide are acidifiers and alkalisers;
phosphate buffers are buffers; activated charcoal and
Introduction to Pharmaceutics
46
bentonite are absorbents and adsorbents; benzyl alcohol
and ascorbic acid are preservatives and antioxidants; and
cocoa butter and gelatin are ointment and suppository
bases.
Phramaceutical aids are important for ensuring the quality,
safety, efficacy, and acceptability of pharmaceutical products.
They should be of the same quality as the active ingredients
and are subject to similar quality controls.
ORGANOLEPTIC AGENTS
Colouring Agents
Colouring agents may be defined as the substances used to
impart colour to foods, drugs and cosmetics to increase their
organoleptic properties. In pharmaceutical preparations they
may be used to increase their acceptability by the patients, to
give warning, or to produce standard preparations.
Colours may be obtained from minerals, plants and animals
or they can be prepared by synthesis. Colours obtained from
minerals are also known as pigments. At one time they were
used in cosmetics and lotions meant for external application to
the skin but nowadays their use is restricted and are replaced
by synthetic colours. The examples of mineral colours are
ferric oxide (yellow and red), carbon black, titanium dioxide
and ultramarine.
Different colours obtained from plants include chlorophyll,
indigo, alizarin, carotenoids and flavones. Cochineal was the
only animal colour used in pharmaceutical preparations. But
nowadays the colours obtained from plants and animals are
rarely used, they are replaced by synthetic colours.
The synthetic colours are prepared from coal tar dyes
which include nitro dyes, nitroso dyes, azo dyes, thiazines,
rosanilines, etc. They are mainly used in textile industries. Only
the permitted colours are used in food and pharmaceutical
preparations. Caramel or burnt sugar, an artificial colour is
used to produce brown colour in cough syrups, elixirs and
other oral liquid preparations.
47
Pharmaceutical Aids
Amount of Colouring Agent Required
There is no hard and fast rule regarding the quantity of
colouring agent used in the preparations. It depends upon
the depth of colour required, the thickness of solution to be
viewed and the presence of suspended powders in the
preparation. An approximate quantity of colouring agent used
for liquid preparations is 0.0001 to 0.001% and for powders
is 0.1%.
Flavouring Agents
Flavouring agents are the substances which are used to impart
pleasant smell to the preparation and to mask specific type
of taste of the preparation, thus make them more palatable.
Most of the flavours used in pharmaceutical preparations are
obtained from natural sources but nowadays they are being
replaced by synthetic flavours.
There are a large number of flavouring agents which
are used to impart acceptable smell to pharmaceutical
preparations. Generally the preparations which are taken
orally are flavoured with fruity and spicy flavours and the
preparations which are applied externally are flavoured with
flowery flavouring agents. The flavouring agents obtained
from natural sources include pineapple, banana, cardamom,
ginger, cinnamom, peppermint and volatile oils obtained
from anise, caraway, clove, dill, lemon, orange, rose, jasmine,
lavender, etc. malt extract, glycyrrihiza extract, coffee, vanilla,
chocolate and Tolu balsam are also used as flavouring agents.
Menthol, mannitol, chloroform spirit and chloroform water
are widely used as flavouring agents in liquid formulations.
Synthetic chemicals like certain alcohols, aldehydes, esters,
fatty acids, ketones and lactones are used as flavouring agents.
They are often preferred to natural flavouring agents because:
They are constant in composition;
They are readily available;
They are comparatively cheap;
They are more stable;
Their incompatibilities are more predictable.
Introduction to Pharmaceutics
48
Selection of Flavours
The problem of selection of a flavour for a particular
preparation is quite complicated because flavour and taste
depends on individual preferences. Moreover, it depends on
the qualities of the preparation which is to be flavoured. For
salty preparations, cinnamon flavours are considered the best
flavouring agents followed by orange syrup, cocoa syrup, wild
cherry syrup and raspberry syrup. For bitter taste cocoa syrup,
raspberry syrup, cherry syrup and cinnamon syrup are used.
The acrid taste and sour taste can be masked by raspberry and
other fruit syrups.
Oily taste of fixed oil like that of castor oil can be effectively
masked with aromatic rhubarb syrup and that of cod-liver oil
can be masked by oil of winter green, peppermint oil, malt
extract or glycyrrhiza extract. A blend of flavouring agents
is generally used to effectively mask the odour and taste
sensations. As regards the quantities of flavouring agents used
in formulations. It mainly depends on the formulator. Usually
0.1 to 0.5% of volatile oil is sufficient as flavouring agent for an
emulsion.
Sweetening Agents
Sweetening agents are the substances which are used in the
formulations to mask the objectionable taste of the drug and
make the preparation sweet in taste. Sucrose is the most widely
used sweetening agent. It is obtained from sugar cane. It is quite
soluble in water. It is physically and chemically stable at pH
from 4.0 to 8.0. Simple syrup and liquid glucose are frequently
used in liquid preparations. Sugar is also used in lozenges and
in the coating of pills and tablets. The other sweetening agents
include lactose, mannitol, honey, glycerin and sorbitol.
Artificial or synthetic sweetening agents like saccharin,
sodium saccharin and sodium cyclamate are frequently used in
the preparation of sugar free formulations. These compounds
are soluble in water, alcohol and glycols. They are physically
and chemically stable over a pH range of 3.0 to 8.0. A desired
sweetness can be produced at much lower concentration than
sucrose. Saccharin in dilute solutions is 250–500 times as sweet
49
Pharmaceutical Aids
as sucrose. It but may leave bitter after taste and sometimes
may also considered as carcinogenic. Saccharin sodium is
used in toothpastes and other preparations meant for oral
hygiene because it is less likely to cause dental carries than
carbohydrates. It is also used as a sweetening agent for many
foods for diabetic persons and those who are on slimming
diets. Aspartame is another synthetics agent which is 200 time
more sweet than sucrose but have no bitter after taste.
It is a dipeptide, i.e. methyl ester of the natural amino acids
L-aspartic acid and L-phenylalanine.
PRESERVATIVES
A preservative is a substance which is added to pharmaceutical
formulations to prevent or inhibit the growth of microorganisms
in the preparations. They are added to all formulations which are
to be stored for long periods of time and the ingredients of which
support microbial growth. The emulsions and suspensions
containing water and carbohydrates as emulsifying and sus-
pending agents respectively, must be suitably preserved
because water and carbohydrates provide very good medium
for the multiplication of bacterias and molds. Further, the
parenteral preparations packed in multidose containers must
contain· a preservative to check the growth of microorganisms
which may have accidentally entered the container during the
withdrawal of a dose.
A preservative is unnecessary in multidose containers
prepared by heating with bactericide because they already
contain a lethal substance, nor they are necessary in pre parations
which contain medicaments having bactericidal properties.
Choice of Preservative
The preservative selected should have the following properties:
It should be effective against a wide range of microorganisms.
It should be compatible with other ingredients of the
formulation.
It should be soluble in aqueous phase when used in
emulsions.
It should be nontoxic.
It should be free from odour and taste.
Introduction to Pharmaceutics
50
It should preserve the preparations and remain stable for
the shelf life of the product.
No single preservative possesses all the qualities, therefore,
it becomes necessary to use a combination of preservatives to
prevent the growth of microorganisms.
The most commonly used preservatives in different formu-
lations are as follows:
Types of Preservatives with Examples
TABLE 3.1: Examples of common preservatives used in pharmaceutical preparations
with their concentrations
Class Preservative
Concentration in preparations (in %)
Oral
Liquid Paren teral
Ophthal -
mic/
Nasal
Ointments
and creams
Amino aryl
acid esters
Methyl paraben 0.25 0.01–0.5 0.1 0.001–0.2
Ethyl paraben 0.1–0.25 0.01–0.5 0.1 0.001–0.2
Propyl paraben 0.5–0.25 0.005–0.02 0.1 0.001–0.2
Butyl paraben 0.1–0.4 0.015 0.1 0.001–0.2
Alkyl/aryl
alcohols
Benzyl alcohol 3.0 0.5–10
Chlorobutanol 0.5 0.25–0.5 0.5 0.5
Phenols Phenol 0.1–0.5 0.065–0.02 0.25–0.5
Metacresol 0.15–0.3 0.1–0.25 0.1–0.3
Chlorocresol 0.2 0.1–0.18 0.1–0.3
Alkyl/aryl
acids
Benzoic acid 0.1–0.2
Sorbic acid 0.1–0.2
Organic
mercurial
Thiomersal 0.1 0.01 0.01 0.01
Phenylmercuric
nitrate
0.002–0.1 0.002 0.004 0.002
Diols Bronopol 0.01–0.1
Propylene glycol 15–30
Quaternary
ammonium
compounds
Benzylkonium
chloride
0.002–0.02 0.01 0.004–0.02 0.01
Benzethonium
chloride
0.01–0.02 0.01 0.004–0.01 0.01
4
UNIT
Unit Operations
SIZE REDUCTION
INTRODUCTION
Size reduction is the process of reducing the particle size of
a substance to a finer state of subdivision to smaller pieces,
to coarse particles or to powder. Comminution and grinding
are the synonym terms used for the process of size reduction.
When the particle size of solids is reduced by mechanical
means it is known as milling.
Very rarely, the materials to be used in pharmaceutical
formulations exist in the optimum size, therefore, majority
of them will have to be reduced to a desired size at one
stage or the other during the formulation of a dosage form.
There are a large number of processes which are used in size
reduction, e.g. cutting, chopping, crushing, grinding, milling,
micronizing and trituration which depends on the type of
equipment employed. The selection of an equipment depends
on the properties of the material to be reduced, initial particle
size and degree of size reduction required.
Pharmaceutical Applications of Size Reduction
Size reduction increases the surface area of drugs which
helps in rapid solution formation in the case of chemical
substances.
With increase in surface area the extraction from animal
glands such as liver and pancreas and from crude vegetable
Introduction to Pharmaceutics
52
drugs is facilitated because solvent can easily penetrate
into the tissues resulting in quick extraction of their active
constituents.
The therapeutic effectiveness of certain drugs is increased
by reducing the particle size, e.g. the dose of griseofulvin is
reduced to half than that of originally required.
The mixing of several solid ingredients is easier and more
uniform if ·the ingredients are reduced to same particle size.
In the case of powdered pharmaceutical dosage forms
it is important to powder the crystalline drugs before
mixing them with other drugs in order to mix all the drugs
uniformly and to avoid recognition of crystalline drugs by
the patients.
In the manufacture of tablets relatively few drugs can
be compressed directly, generally they are mixed with
excipients and made in the form of suitable size granules
which are then compressed.
The stability of emulsions is increased by decreasing the
size of the oil globules.
In the case of suspensions the size of the particles play a
great role. If the size of the particles is too small, they may
form a cake which may not re-disperse easily but on the
other hand large size particles settle quickly but form a
loose cake which may re-disperse easily on shaking.
Appropriate particle size is used in the inhalations. Very
small particles may be exhaled out of the bronchioles along
with air without producing its effect.
The physical appearance of ointments, pastes and creams
can be improved by reducing its particle size.
All the ophthalmic preparations and preparations meant
for external application to the skin must be free from gritty
particles to avoid irritation of the area to which they are
applied.
The rate of absorption of a drug depends on the dosage form,
route of administration and particle size. The smaller the
particle size, quicker and greater will be rate of absorption.
Depending on the particle size, the sustained action of a
preparation can be produced.
53
Unit Operations
In certain drugs the colour and texture is changed on
reducing the particle size.
The rate of drying is enhanced if the particle size is reduced.
On reducing the particle size the bulkiness of certain drugs
can be increased.
Disadvantages
On grinding, the aromatic and volatile constituents of crude
drugs may be lost due to increase in temperature during
grinding. Therefore, drugs such as cinnamon, clove, carda-
mom, caraway and other drugs containing volatile oils
must not be subjected to heavy grinding to prevent the loss
of volatile oils.
Since on size reduction the surface area is increased which
when exposed to atmospheric conditions may result in
oxidation and hydrolysis. Therefore, such drugs must be
stored in a well-closed container and at a cool place.
Factors Affecting Size Reduction
The following factors should be taken into consideration while
reducing the particle size of a drug:
Physical properties of drugs such as hardness, toughness,
moisture content, etc.
Melting or softening point of the material: The heat generated
during mechanical grinding present many problems with
materials which tend to liquefy, stick with each other; and
with thermolabile substances.
The size of the starting material: If the size of the original drugs
is too large it may be reduced to small panicles in stages.
The quantity of the material to be reduced.
Size, shape, flow properties and bulk density of the reduced
particles.
The solubility of the drug.
If the material is to be kept free from bacterial contamination.
then the reduction will have to be carried out under aseptic
conditions.
Overall costs of process involved including power con-
sump tion, space occupied, labour expenditure and time
involved.
Introduction to Pharmaceutics
54
Methods of Size Reduction
The processes such as slicing and cutting, bruising and
contusion, rasping or grating, chopping and grinding are
less important today than were in the past. Nowadays
manufacturers use very well developed machines by which
powders of desire degree of fineness can be obtained.
Certain vegetable drugs like stems, roots, barks, fruits
and seeds may require preliminary size reduction, therefore,
following methods may still be used:
A. Slicing and Cutting
Slicing and cutting may be done with a sharp knife, a pair of
scissors, a root cutter or any other sharp instrument. It may
be done either in transverse or longitudinal direction. This
method is usually employed to hasten the drying of crude
vegetable drugs such as leaves and roots. For cutting the drugs
on a large scale a cutter mill is used.
Cutter mill: Cutter mill is fitted with two types of knives, i.e.
stationary and rotating (Fig. 4.1). The stationary knives are
Fig. 4.1: Cutter mill.