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145
Dosage Forms
Fig. 5.15: Hand operated hard gelatin capsule filling machine.
simple to operate can be easily dismantled and reassembled.
Even an unskilled worker can fill the capsules without much
difficulty.
Working
The empty capsules are filled into the loading tray which is
then placed over the bed. By operating the handle, the bodies
of the capsules are locked and caps separated in the loading
tray itself which is then removed by operating the lever. The
weighed amount of the drug to be filled in the capsules is
placed in powder tray already kept in position over the bed.
Spread the powder with the help of a powder spreader so as
to fill the bodies of the capsules uniformly. Collect excess of
the powder on the platform of the powder tray. Lower the pin
plate and move it downward so as to press the powder in the
bodies. Remove the powder tray and place the caps holding
tray in position. Press the caps with the help of plate with
rubber top and operate the lever to unlock the cap and body
of the capsules. Remove the loading tray and collect the filled
Introduction to Pharmaceutics
146
capsules in a tray. With 200 hole machine about 5000 capsules
can be filled per hour and with 300 hole machine 7500 capsules
can be filled per hour.
On large scale manufacturing various types of
semiautomatic and automatic machines are used. They operate
on the same principle as manual filling, namely the caps
are removed powder filled in the bodies, caps replaced and
fliled capsules are ejected out. With automatic capsule filling
machines powders or granulated products can be filled into
hard gelatin capsules. With accessory equipment, pellets or
tablets along with powders can also be filled into the capsules.
Depending upon the make and model, operator and the type
of the materials to be filled, a machine can fill 9000 to 150,000
capsules per hour.
Since the primary reason of filling the drug in capsules is
to avoid odour and taste of the drug. The whole aim is lost
even if a small amount of the drug remains sticking outside the
capsules. Therefore, all the capsules whether filled by hand or
by machine must be thoroughly cleaned. Small quantities of
capsules can be cleaned by wiping each capsule with surgical
gauze or clean cloth. On large scale they can be rolled lightly
in the folds of a clean towel or cloth forward and backward
until cleaned. Still another method is to rotate or shake gently
the capsules with granular sodium chloride contained in a
container. Then the sticking sodium chloride is removed by
rolling them on a clean cloth surface.
The cleaned capsules may be polished by rolling them in a
towel which has been previously sprinkled lightly with liquid
paraffin. This gives very good shine to the capsules.
Difficulties in Filling the Capsules
Deliquescent or Hygroscopic Powders
A gelatin capsule contains water which is extracted or taken
up by a hygroscopic drug and renders the capsule very brittle
which leads to cracking of the capsule. The addition of an
absorbent like magnesium carbonate, heavy magnesium oxide
or light magnesium oxide overcomes this difficulty provided
the capsules are packed in tightly closed glass capsule vials.
147
Dosage Forms
Eutectic Mixtures
Certain substances when mixed together tend to liquefy or
form a pasty mass due to the formation of a mixture which
has a lower melting point than room temperature. For filling
these types of substances each troublesome ingredient is
mixed with an absorbent separately then mixed together and
filled in capsules. The absorbents used are magnesium oxide
and kaolin. Heavy magnesium oxide is less effective. The use
of heavy and light magnesium oxide is restricted because it
forms a very hard cement like mass which passes through the
GIT without disintegration. But this type of mass is not formed
when magnesium carbonate is used as an absorbent.
Another method in dealing with such type of difficulty is
that the substances are mixed together so as to form a eutectic
mixture, then an absorbent like magnesium carbonate or
kaolin is added.
Addition of Inert Powders
When the quantity of the drug to be filled in capsules is very
small and it is not possible to fill this much small amount in
capsules then inert substance or a diluent is added so as to
increase the bulk of the powder which can be filled easily in
capsules. Generally smallest capsule requires at least 65 mg of
the substance to fill it.
Filling of Granular Powders
Some powders which lack adhesiveness and most granular
powders are difficult to fill in the capsules by punch method
because they are not compressible and flow out of the capsule
as soon as they are lifted from the pile of the powder into which
they are punched. To overcome this difficulty the nonadhesive
powders should be moistened with alcohol and the granular
powders should be reduced to powder before filling into
capsules.
Use of Two Capsules
Some of the manufacturers separate the incompatible
ingredients of the formulation by placing one of the ingredients
Introduction to Pharmaceutics
148
in smaller capsule and then placing this smaller capsule
in a larger capsule containing the other ingredients of the
formulation.
Liquids
Oils and liquids which will not dissolve gelatin may be filled
into hard gelatin capsules. A measured quantity of the liquid is
filled in the body of the capsule and the cap, the lower portion
of which has been moistened with hot water is placed over the
body with a rotary motion so as to seal the capsule.
When the quantity of the liquid to be incorporated is small,
it is first mixed with an inert absorbent which is then added to
another ingredient, mixed thoroughly and filled into capsules
in the usual manner.
Viscous liquids and semisolids are mixed with an absorbent
like powdered glycyrrhiza so as to form a soft mass. This soft
mass is cut into desired number of pieces which are then put
into capsules.
Soft Gelatin Capsules or Soft Capsule
These capsules are soft and elastic in nature which are prepared
from gelatin and water to which glycerin, sorbitol or propylene
glycol has been added as a plasticizer which make the capsules
flexible. They usually contain a preservative to pevent the
growth of bacteria and fungi. These capsules are available in
a number of shapes and sizes, e.g. spherical, ovoid, cylindrical
and tubes. The spherical capsules are also known as “pearls”.
The contents of the soft capsules may very from 0.1 to 30 ml.
The soft gelatin capsules differ from hard capsules that
the latter are manufactured in two stepes where the shells are
made on one type of machine and filling is done on another
machine. Whereas soft capsules are formed and filled in
one conti nuous operation on semi-automatic and automatic
machines. They are hermetically sealed.
The capsules are used for filling liquids and semi-solids.
Vitamin preparations such as halibut liver oil, vitamin A and D
and multivitamins are conveniently dispensed in soft capsules.
149
Dosage Forms
They are also used for containing eye, ear, nose and throat
preparations. Ophthalmic ointments are frequently packed
in unit dose capsules. They are also being used as substitutes
for suppositories. Nowadays soft capsules are also used for
packing cosmetics, flavours and food concentrates.
Preparation of Soft Capsules
Soft capsules are generally manufactured by two methods:
1. Plate process.
2. Rotary die process (Fig. 5.16).
In the plate process a wanned sheet of plasticized gelatin is
placed over a plate having a number of depressions or moulds,
the sheet is drawn into these depressions by applying vacuum.
Fig. 5.16: Rotary die machine.
Introduction to Pharmaceutics
150
A measured quantity of liquid medicament is poured over it,
then another sheet of gelatin is placed on it. Over this another
plate of the mould is placed and the pressure is then applied
to the combined plates. The capsules are then simultaneously
shaped, filled, sealed and cut into individual units.
In the rotary die process filled capsules are produced conti-
nuously and automatically. Two continuous sheets of gelatin are
supplied to the two die rolls of the machine which has a number
of matching dies and rotate at the same speed and in the opposite
direction. As the gelatin sheets comes in between the rollers
the material to be filled in is injected through a metering
device. The pressure exerted by the material forces the gelatin
sheet to go in the cavities of the die rolls to form two halves
of the capsule and fill them. The heat and pressure exerted
by the die rolls seals and cuts out the capsules. The finished
capsules are then passed through a series of naphtha baths to
remove lubricants and then dried. These rotary die machines
can produce 25,000 to 30,000 capsules per hour.
Packaging and Storage of Capsules
Capsules should be packed in well closed glass or plastic
containers and stored in a cool place. These types of containers
have advantage over cardboard boxes that they are more
convenient to handle and transport and protect the capsules
from moisture and dust. To prevent the capsules from rattling
a tuft of cotton is placed over and wider the capsules in the
vials. In vials containing very hygroscopic capsules a packet
containing dessicant like silica gel or anhydrous calcium
chloride may be placed to prevent the absorption of excessive
moisture by the capsules. Nowadays capsules are strip
packaged which provide sanitary handling of medicines, ease
in counting and identification.
Special Types of Capsules
Enteric Coated Capsules
An enteric coated capsule does not disintegrate in the stomach
or acidic medium but breaks up in the intestine or alkaline
medium. They are given special type of treatment or coating
which makes the medicine to pass unchanged through the
151
Dosage Forms
stomach but set free in the intestine. Entenc coating may be
given to following categories of drugs:
Which cause irritation to the gastric mucosa and lead to
nausea and vomiting.
Which interfere with digestion, e.g. tannins, silver nitrate
and other salts of heavy metals.
Which are unstable in the gastric fluids.
Which are specially needed for treatment of intestine, e.g.
santonin, extract male fern, etc.
Which are required to produce delayed action of the drug.
Formaldehyde, cellulose acetate phthalate and mixture
of waxes with fatty acids or their esters are used for enteric
coating of capsules. For extemporaneous enteric coating of
capsules cellulose acetate phthalate (cellacephate) is widely
used. The capsules are dropped in a 10% solution of cellulose
acetate phthalate in acetone, they are removed with forceps
and excess of the liquid is removed. The capsules are dried on
a muslin strainer then second and third coats are applied after
thorough drying each time.
Sustained Release Capsules
These types of capsules release the drug slowly and conti-
nuously for a prolonged duration of action, thus maintaining
a minimum effective concentration (MEC) of the drug in the
blood at a constant level throughout the treatment period.
Whereas in the conventional therapy, i.e. administration of the
drug in divided doses at specified intervals of time, a constant
blood concentration is not maintained and there is considerable
fluctuation in drug concentration.
The finely powdered drug is converted into pellets of
suitable size (1–2 mm in diameter). These pellets are divided
into a number of groups (generally 10 groups). The first group
is kept untreated to produce rapid therapeutic effect and the
other groups are coated with selected materials one by one
to produce thickness of varying degrees. This can be done by
giving two coatings to the 2nd group, 3 coatings to the 3rd
group, four to the fourth group and so on. The total thickness
of these coatings should be about 0.1 mm. All these groups,
i.e. coated and uncoated are then mixed together and filled
Introduction to Pharmaceutics
152
into capsules. For coating, the materials may include cellulose
esters, fats, keratin, gluten, mixtures of bees wax, carnauba
wax with glyceryl monostearate.
Rectal Capsules
Soft gelatin capsules may be used as substitutes for rectal and
vaginal suppositories. Various shapes and sizes are used for
this purpose. They are generally wider at one end which is
inserted first, the movement of the sphincter muscles forces
the capsules forward into the rectum. Liquids or solids can be
filled into rectal capsules but the base in which the medicament
have been incorporated must be non-toxic, non-irritant and
compatible with the capsule shell.
Capsules for Packing of Ophthalmic Ointments
It is very important that the ophthalmic ointments should
be sterile and free from irritant effect. Therefore they must
be packed in such a manner that the product remains sterile
until whole of it is used up. The best method to keep the
preparation free from contamination during use is to pack it
in single dose containers. Nowadays soft gelatin capsules are
very commonly used for filling ophthalmic ointments. These
capsules are meant for single application to the eye. Just before
application, the capsule is punctured with a sterile needle, the
contents instilled into the eye and the shell discarded.
Standardization of Capsules
Whether capsules are produced on a small or large scale all
of them are required to pass not only the disintegration test,
weight variation test and percentage of medicament test but
a visual inspection must be made as they roll off the capsule
machine onto a conveyor belt regarding uniformity in shape,
size, colour and filling. As the capsules move in front of the
inspectors the visibly defective or suspected of being less than
perfect are picked out. If the number of defective capsules is
large it may be due to some fault in the capsule filling machine
which must be corrected.
The hard and soft gelatin capsules should be subjected to
following tests for their standardization:
153
Dosage Forms
Shape and size
Colour
Thickness of capsule shell
Leaking test for semi-solid and liquid ingredients from soft
capsules
Disintegration test
Weight variation test
Percentage of medicament test
In official books the following quality control tests are
recommended for capsules.
Disintegration Test
For performing disintegration test on capsules the tablet
disintegration test apparatus is used but the guiding disc may
not be used except that the capsules float on top of the water.
One capsule is placed in each tube which are then suspended
in the beakers to move up and down for 30 minutes, unless
otherwise stated in the monograph. The capsules pass the test
if no residue of drug or other than fragments of shell remains
on No. 10 mesh screen of the tubes.
Weight Variation Test
Twenty capsules are taken at random and weighed. Their
average weight is calculated, then each capsule is weighed
individually and their weight noted. The capsules pass the test
if the weight of individual capsule falls within 90–110% of the
average weight. If this requirement is not met, then the weight
of the contents for each individual capsule is determined and
compared with the average weight of contents. The contents
from the shells can be removed just by emptying or with the
help of small brush. From soft gelatin capsules the contents
are removed by squeezing the shells which has been carefully
cut. The remainder contents are removed by washing with a
suitable solvent. After drying the shells, they are weighed and
the content weights of the individual capsules are calculated.
The requirements are met if (a) not more than 2 of the differences
are greater than 10% of the average net content and (b) in no
case the difference is greater than 25%.
Introduction to Pharmaceutics
154
Contents Uniformity Test
This test is applicable to all capsules which are meant for
oral administration. For this test a sample of the contents is
assayed as described in individual monographs and the values
calculated which must comply with the prescribed standards.
LIQUID ORAL PREPARATIONS
A solution is a clear, homogeneous mixture that is prepared by
dissolving a solid, liquid or gas in another liquid. The component
of a solution present in large amount is known as solvent and
the component present in lesser amount is known as solute.
A solution is homogeneous because the soluble is in a molecular
or ionic state of subdivision, therefore, a true solution is a one
phase system. Solutions may be used internally or applied
externally whereas mixtures are meant for oral administration.
Mixtures are mainly prescribed for acute conditions such as
cough, indigestion, diarrhoea, constipation and rheumatism.
They are prepared extemporaneously and supplied only for a
few days treatment because if they are stored for more than a
few weeks even under normal conditions they may deteriorate.
Advantages
They are homogeneous, therefore, the medicament is uni-
formly distributed throughout the liquid.
The doses can be easily adjusted according to the need of
the patient.
They can be easily measured with the household measures.
They are more quickly effective than tablets or capsules
because they are already in the solution form and absorption
starts quickly.
Some drugs like potassium iodide and bromide leads to
gastric pain if taken in the tablet or capsule form but this
pain may be reduced when these drugs are administered in
the solution form because of dilution factor.
They can be easily coloured, flavoured or sweetened.
Children or patients who cannot swallow tablets or capsules
can easily ingest solutions.