Capsules are solid dosage forms in which one or more

medicinal and/or inert substances are enclosed within

a small shell or container generally prepared from a
suitable form of gelatin.
Depending upon their formulation, the gelatin capsule
shells may be hard or soft.
Hard Gelatin Capsules
The hard gelatin capsule
consists of a base or body
and a shorter cap, which
fits firmly over the base of
the capsule .
Hard Gelatin Capsules
1. Mask the unpleasant tastes of a drug.
2. Allow powders to be dispensed in an uncompressed form,
thus allowing for quicker dissolution and absorption of the
drug following oral dosing
3. Have the flexibility which permit a wide prescribing
opportunity by the physician in that the pharmacist may
prepare capsules containing a single chemical substance
or a combination of drugs at the accurate dosage level for
the individual patient.
4. Be easier than tablets for some people to swallow.
5. Can alter the release rate of the drug.
Advantage of Hard gelatin capsules
Disadvantages or limitations include the following :

1. They are subject to the effects of relative humidity and to
microbial contamination .
2. They may be difficult for some people to swallow .
3. More expensive (commercially) .

Opaque capsules may be prepared by adding an insoluble
substance as titanium dioxide to the gelatin mixture.
Colored, opaque capsules may be prepared by using both a
colorant and the opaque-producing substance.
Gelatin, NF, is a product obtained by partial hydrolysis of
collagen obtained from the skin, white connective tissue,
and bones of animals.
It is found in commerce in the form of a fine powder, a
coarse powder, shreds, flakes, or sheets
The basic empty capsule shells are
made from a mixture of gelatin,
sugar, and water and are clear,
colorless, and essentially tasteless.
Colorants may be used to prepare
distinctive capsules.
depending upon the environmental conditions, in high
humidity, capsules absorb moisture and become
distorted and lose their rigid shape.
but in extreme dryness, some of the moisture normally
present in the gelatin capsules may be lost, and the
capsules become brittle and crumble.
Thus capsules should be stored in areas of low
humidity.
Normally, hard gelatin capsules
contain between 13 and 16% of
moisture.
moisture may be absorbed or
released by gelatin capsules,
Gelatin is insoluble in cold water but soluble in hot
water, and in gastric fluid where a gelatin capsule
rapidly releases its contents.
Gelatin, being a protein, is digested and absorbed.
Hard gelatin capsule shells are manufactured mechanical
dipping of manganese bronze pins of the desired shape and
diameter to the desired depth and time into a reservoir of
the melted gelatin mixture, maintained at a constant
temperature to achieve the desired degree of fluidity.
Then the plate and the pins slowly lifted from the gelatin
bath and gently dried by a flow of temperature and
humidity controlled air
Capsule Sizes
Empty gelatin capsules are manufactured in various
sizes, varying in length, in diameter, and capacity.
For human use, empty capsules ranging in size from
000 the largest, to 5 the smallest are commercially
available.
Preparation of Filled Hard Gelatin Capsules
The preparation of filled hard gelatin capsules may be
divided into the following steps:
1. Preparing the formulation
2. Selecting the capsule size.
3. Filling the capsule shells.
4. Cleaning and polishing the filled capsules.


Preformulation studies are used to determine if the bulk
powders may be blended together as such, or if they
require reduction of particle size or processing into formed
granules.
I. Preparing the formulation
Milling
To achieve uniform drug distribution through out a powder
mix, it is advantageous that the density and particle size of
the drug and non-drug components are similar. This is
achieved by particle size reduction (milling).
Dry Powder
Diluent
Generally, hard gelatin capsules are used to encapsulate
between about 65 mg and 1 g of powdered material,
including drug and any diluent required.
If the dose of the drug to be placed in a single capsule is
smaller than 65 mg to produce the proper fill, lactose,
microcrystalline cellulose, and pregelatinized starch are
common diluents used in capsule filling. But when the
amount of drug is large enough to fill a capsule completely,
a diluent may not be required.
Lubricant
a lubricant as 1% Magnesium stearate is utilized to
prevent adhesion and facilitate the flow of the powder in
capsule filling machine.
Glidant
The powder mixture or granules must be free-flowing to
allow passage from the hopper by the addition of a glidant
such as 1% silicon dioxide.
Lubricant and Glidant are used to improve filling
properties.


Wetting agent
Addition wetting agents, as sodium lauryl
sulfate, in capsule facilitate the wetting
of the drug substance by gastrointestinal fluids to
enhance dissolution, and overcome the problem
associated with water-insoluble lubricant as
magnesium stearate which can delay the dissolution of
the drug and its absorption.
Eutectic mixtures or mixtures that tend to liquefy, may
require a diluent or absorbant such as magnesium
carbonate, kaolin, or light magnesium oxide to separate
physically the interacting agents and to absorb any liquefied
material.
Eutectic mixtures
However, some liquids such as fixed or volatile oils that do
not interfere with the stability of the gelatin shells may be
placed in gelatin capsules which then may be sealed to
ensure the retention of the liquid (soft gelatin capsules)
Gelatin capsules are
unsuitable for the
encapsulation of aqueous
liquids, because water
softens the gelatin to
produce distortion of the
capsules.
Liquids
Semisolids
This system can be used for both
liquid and solid active ingredients.
Mixtures for filling need only be
liquid when filled and should be
semisolid after being inside the capsules.
The materials to be filled must be either thermosoftening or
thixotropic in nature to be liquefied by heating or shearing
forces using heated hopper with a stirrer and revert to the
solid state within the capsule shell.
Used for potent drugs to improve uniformity of filling.
Used for safely handling toxic drugs to reduce
contamination with filling of powders.


Granules and Pellets
Granules are produced by
granulation and are more
irregular than pellets which
are spherical and produced
by microencapsulation
technique
Granules and Pellets are
packed in capsules instead of
powder to produce modified
release patterns.
Capsules within capsules:






Tablets within capsules:




This small tablet can be placed inside the capsule following the
addition of a small quantity of the powder and the filling
completed.
Small tablets are filled into capsules to
produce special release forms or to separate
incompatible ingredients.
If one ingredient must be separated from
others in the formulation, a small capsule,
such as a No. 5, may be filled with one
powder and placed into a larger capsule
with the remaining ingredients in the
formulation.






Beads








Granules






Powders




Pastes



Capsules




Tablets



Liquids


The selection of capsule size is best done during the
development of the formulation, because the amount of
inert materials to be employed is dependent upon the size or
capacity of the capsule to be selected.
II. SELECTION OF CAPSULE SIZE
The density and compressibility of a powder or a powder
mixture will largely determine to what extent it can be
packed into a capsule shell.
The amount may vary according to the degree of pressure
used in filling the capsules.
Determination of capsule fill weight
To determine the size of capsule to be used or the fill
weight for a formulation the following relationship is
used:
Capsule fill weight =
Tapped Bulk Density of Formulation X Capsule Volume

III. Filling the capsule shells
1."Punch" Method
2. Hand-Operated Capsule Filling Machines
3. Automatic-Operated Capsule Filling Machines
Used for filling a small number of capsules in the
pharmacy, at the prescription counter.
The ingredients are triturated to the same particle size
and then mixed by geometric dilution.
The powder is placed on a powder paper or ointment slab
and smoothed with a spatula to a height approximately
half the length of the capsule body.
"Punch" Method
The base of the capsule is held vertically and the open end
is repeatedly pushed or "punched" into the powder until
the capsule is filled;
The cap is then replaced to close the capsule. Each filled
capsule is weighed using an empty capsule as a
counterweight.
Powder is added or removed until the correct weight has
been placed in the capsule.
The filled capsule is tapped so that no air spaces are
visible within the contents.
Pharmacists that prepare capsules on a regular or
extensive basis may use hand-operated capsule
machines.
These machines are available in capacities of 24, 96, 100,
and 144 capsules.
First, the plates are adjusted to hold the capsule bodies in
place while the caps are removed all at one time.
The caps remain in place in the top of the machine for
later use.
hand-operated capsule machines
Then the plates are adjusted again so that the capsule
bodies will "drop" into place so that the tops are flush
with the working surface of the plate.
The formulation powder is poured onto the plate and
special spreaders are used to fill the individual capsules.
The combs are used to tamp (compress) and pack the
powder into the capsules.
All of the caps are then returned to the capsule bodies,
and the closed capsules are removed from the machine.
Automatic-Operated Capsule Filling Machines
Machines developed for industrial use can automatically
remove the caps from empty capsules, fill the capsules,
replace the caps, and clean the outside of the capsules at a
rate of up to 165,000 capsules and greater per hour.
In this process, the two capsule parts are sealed with a
gelatin or polymer band at the joint of the cap and body.
A tamper-resistant seal on hard gelatin capsules was
SEALING of Gelatin capsules
developed in which the
contact areas of the cap
and body are wetted
with a mixture of water
and ethanol to soften
the gelatin and then
thermally bonded at
104 to 113
o
F to form
the seal.
CONI-SNAP Hard gelatin capsule
A recent innovation in capsule shell
design, where the two halves of the
capsule shells are enable to be
positively joined through locking
grooves in the shell walls.
The two grooves fit into each other
and ensure reliable closing of the
filled capsule.
Opening of such capsule is difficult
with increasing security of the
contents of the capsule.
IV. Cleaning and polishing the filled capsules
Capsules prepared on a small scale or on a large scale may
have small amounts of the powder adhering to the outside
of the capsules.
This powder should be removed before packaging or
dispensing to improve the appearance of the capsules and to
preserve their quality of being tasteless on administration.
On a large scale, many capsule-filling machines are affixed
with a cleaning vacuum that removes any extraneous
material from the capsules.
Another proposed cleaning method is to put the capsules in
a container filled with sodium bicarbonate, sugar, or sodium
chloride, and gently roll the container.
Then the container contents can be poured into a ten-mesh
sieve where the "cleaning salt" will pass through the sieve.
Soft gelatin capsules (soft elastic gelatin capsules) or (softgels)
are prepared from continuous gelatin shells to which glycerin or a
polyhydric alcohols such as sorbitol has been added to render
gelatin elastic or plastic-like.
Soft gelatin capsules may be oblong, elliptical (oval), or spherical
round, oval, oblong, tube in shape., They may also be prepared of
single or two-tone color,
Application of Soft Gelatin Capsules
1. Water immiscible, volatile and nonvolatile liquids such as
vegetable and aromatic oils, aromatic and aliphatic
hydrocarbons, chlorinated hydrocarbons, ethers, esters,
alcohols, and organic acids.
2. Water miscible, nonvolatile liquids such as polyethylene
glycols, and nonionic surface active agents as tween 80.
3. Solids may be encapsulated into soft gelatin capsules as
solutions in one of the suitable liquid solvents, as
suspensions, or as dry powders, granules, or pelletized
materials.
Liquids which can easily migrate through the capsule
shell cannot be encapsulated into soft gelatin
capsules.
These materials include:
Water, above 5%, and low molecular weight water
soluble and volatile organic compounds such as
alcohols, ketones, acids, amines, and esters.
1. They permit liquid medications to become easily
portable.
2. Comparing the degree of irritation or ulcerogenic
potential of soft gelatin capsule formulations with a
tablet formulation, Capsule formulations had a reduced
ulcerogenic potential when compared to the tablet
formulation.
3. Dose uniformity is optimized, because the drug is
dissolved or dispersed in a liquid which is then dosed
volumetrically into the capsule accurately.
Advantages of Soft Gelatin Capsules
4. Improve drug stability by resist gaseous diffusion and
contain no water, thus protect drugs sensitive to
oxidation or hydrolysis on long term storage.

5. Good bioavailability of drugs than from the commercial
tablets or capsules, that dissolved or dispersed in a
water miscible or oily liquids, thus when the capsule
ingested, the drug dispersed as solution or emulsion to
give a drug dispersion of high surface area
Preparation of Soft Gelatin Capsules
In a soft gelatin capsule formulation the medicament is in
solution or is dispersed as a fine suspension in either a
hydrophilic vehicle or a hydrophobic base.

Formulation of soft gelatin capsules
There are two main aspects to be considered during the
formulation of soft gelatin capsules:
The composition of the gelatin shell and the composition of
the fill material.
The composition of the soft capsule shell consists of two
main ingredients: gelatin and a plasticize (e.g. glycerol).
Water is used to form the capsule and it may be desirable or
even necessary to add other additives such as preservatives,
dyes, opacifiers and, rarely, flavours and drugs.
Formulation of the gelatin shell
To produce shells with a greater flexibility than hard gelatin
capsules it is necessary to control carefully the viscosity and
strength of the gelatin used in production.







The mechanical properties of the gelatin shells are controlled
by choice of gelatin grade and by adjusting the concentration
of plasticizer in the shell.
Gelatin
If the viscosity of aqueous gelatin solution is too low, a thin,
low strength shell is produced which has the disadvantage of
requiring prolonged drying.
If the viscosity of the gelatin solution is too high, a thick
film is produced which may be too hard and brittle. also
require higher sealing temperatures during manufacture.
The main plasticizer used for soft gelatin capsules is
glycerol.
Sorbitol and propylene glycol have also been used but they
are normally added in combination with glycerol.
Plasticizers are added in relatively large concentrations.
The greater the plasticizer content the greater the
flexibility of the shell. (0.3-1.0 parts of dry plasticizer to 1
part of dry gelatin).
Low ratios 0.3-0.5 are used for oily liquid fills,
(0.4-0.6) for oily fills with added surfactant,
(0.6-1.0) for water-miscible fills and chewable capsules.
Plasticizers
Water
The demineralized water content of gelatin solution used
to produce a soft gelatin capsule shell depends on the
viscosity of gelatin used (0.7-1.3 parts of water to each
part of dry gelatin), 1: 1 ratio being typical.

Preservatives
Preservatives are added to prevent mould growth in the
gelatin shell. Potassium sorbitate and methyl, ethyl and
propyl hydroxybenzoate (methyl-, ethyl- and
propylparaben) are common additives.
Colours
A wide range of colours can be incorporated into soft
gelatin shells
Water-soluble dyes (synthetic and vegetable), insoluble
inorganic and organic pigments and lakes.

Opacifiers
Titanium dioxide is the most common. It is added in
concentrations of about 0-0.5%.

Enteric treatment
Enteric properties can be imparted to soft gelatin shells by
coating with 4% cellulose acetate phthalate.
Any non-aqueous liquid or powdered solid in suspension
can be filled into soft gelatin capsules.
It is possible to fill soft gelatin capsules with a very wide
range of materials.
Suspensions, pastes, drugs in solution in either oils, self-
emulsifying oils or water-miscible liquids.
Formulation of the capsule contents
Limitations for fill materials
Drugs or excipients containing large amounts of water or
other gelatin solvents cannot be incorporated.
It is not recommended to fill emulsions (whether they be o/w
or w/o) since they are unstable and will crack as the water is
lost from the shell in the manufacturing process.
Surfactants may have a deleterious effect on the capsule seal.
Extremes of pH must be avoided. pHs below about 2.5 attack
the gelatin leading to hydrolysis and leakage and pHs above
about 7.5 have a tanning effect on the gelatin, and affecting
the solubility of the shell.
Aldehydes must also be avoided since these have a tanning
action on the proteins of the gelatin shell.
Liquid vehicles
Water-immiscible oils or water-miscible liquids.
Water-immiscible oils:
Either volatile or non-volatile oils,
Fixed aromatic vegetable oils,
Aliphatic, aromatic and chlorinated hydrocarbons,
Liquid ethers and esters.
Water-miscible liquids (hydrophilic)
Polyols as Polyethylene glycols with low molecular weight
(400-600) since they are liquid at ambient temperatures.
Alcohols as isopropyl alcohol, polyglycerols, triacetin,
glyceryl esters, sorbitan esters, sugar esters and
polyglyceryl esters.
Propylene glycol and glycerol can be used, but the
concentration must be low, (5-10%), in order to prevent
migration into the gelatin and softening of the shell.
Suspensions
The particle size of the solid should be reduced to less than
180 m to pass through the filling head.
Insoluble drugs can be dispersed (with suspending agents
and surfactants) in the above vehicles or combinations of
vehicles.
Suspending agents are added to prevent settling and
maintain homogeneity
For oily bases (beeswax, paraffin wax, ethylcellulose
and hydrogenated vegetable oil)
For non-oily bases (solid glycol esters as PEG 4000 and
PEG 6000).
Surfactants as polysorbate 80 (Tween 80) are often added
as wetting agent.
Caking of suspensions in soft gelatin capsules can be
avoided by rheological control of the vehicle.
Preparation of Soft Gelatin Capsules
Preparation of Soft Gelatin Capsules
Soft gelatin capsules may be prepared by:
The plate process, using a set of molds to form the capsules.
The die processes (rotary or reciprocating processes)
more efficient and productive processes
A warm sheet of gelatin (plain or colored) is placed on
the bottom plate of the mold.
The liquid medication is poured on it.
Then a second sheet of the prepared gelatin is carefully
laid in place on top of the medication, and the top plate
of the mold is put in place.
The entire mold is then subjected to a press where
pressure is applied to form, fill, and seal the capsules
simultaneously.
The capsules are then removed and washed with a
solvent harmless to the capsules.
the plate process
Liquid gelatin flowing from an
overhead tank is formed into two
continuous ribbons by the rotary
die machine and brought together
between twin rotating dies.
the rotary die process
At the same time, metered fill material is injected
between the ribbons at the moment that the dies form
pockets of the gelatin ribbons.
These pockets of fill-containing gelatin are then sealed
by pressure and heat.
The soft gelatin capsules may be prepared of single or
two-tone color, the latter resulting from the employment
of two different colored ribbons of gelatin to form the
sides of the capsule.
Manufacturing process
The reciprocating die process is similar to the rotary
process in that ribbons of gelatin are formed and used to
encapsulate the fill,
But it differs in that the gelatin ribbons are fed between a
set of vertical dies that continually open and close to form
rows of pockets in the gelatin ribbons.
These pockets are filled with the medication and are
sealed, shaped, and cut out of the film as they progress
through the machinery.
As the capsules are cut from the ribbons, they fall into
refrigerated tanks which prevent the capsules from
adhering to one another.
The reciprocating die process
Capsules are usually packaged in glass or in plastic
containers
Some containing packets of a desiccant to prevent the
absorption of excessive moisture by the capsules.
Soft capsules have a greater tendency than do hard
capsules to soften and adhere to one another, and they
must be maintained in a cool, dry place.