CAPSULES

hard gelatin
 INTRODUCTION
The word capsule is derived from the Latin word Capsula
which means a small box or container. The word is used to
describe various natural and manmade materials in scientific
discipline like in anatomy, as an enclosing membrane, in
botany for fruit and in astrophysics for space vehicle.
In pharmaceutical sciences, the word Capsules are solid oral
dosage forms in which the drug is enclosed within a hard or
soft shell usually made up of gelatin.
They can be either hard or soft depending on the nature of the
capsule shell, with soft capsules possessing a flexible,
plasticized gelatin film where as hard gelatin capsules are
usually rigid two - piece capsules.
 INTRODUCTION
The hard capsule has two parts, the body and the cap which are
closed partially to make it in to a near cylindrical form. The
body is longer and has slightly smaller diameter, while the cap
is shorter and has slightly more in diameter to enable to cap
the body part.
CAPSULE-CAP AND BODY
 GELATIN: HISTORY
Capsules are one of the oldest dosage forms in pharmaceutical
history, dating back to the ancient Egyptians.
In 1730, de Pauli, a pharmacist from Vienna, produced oval-
shaped capsules to cover the unpleasant taste of turpentine he
prescribed for people with gout.
A century later, in 1834 patents were granted to Franois Achille
Barnab Moths and Dublanc for a method to produce a single-
piece gelatin capsule that was sealed with a drop of gelatin
solution. The method used individual iron moulds for the process,
and a dropper to fill the capsules individually. Later on, methods
were developed that used sets of plates with pockets to form the
capsules.
 GELATIN: HISTORY
The concept of preparing gelatin capsules in two parts was first
conceived by James Murdock who patented the two-part
telescoping gelatin capsule in 1847.
In 1931, Arthur Colton, on behalf of Parke, Davis & Co., designed a
machine that simultaneously manufactured both capsule bodies and
caps and fitted them together to form a hard gelatin capsule.
The single piece gelatin capsule concept was later on developed as
modern soft-gel capsules. The process for soft gelatin capsule was
originally developed by R.P. Scherer in 1933 and got modified with
time into the present day technology of using a rotary die to
produce the capsules, with the filling taking place by blow molding.
Commercial production of the capsule started in the United States
during the 1870s and in Europe during the 1950s.
Advantages
Capsules are tasteless, odorless and can easily be
administered.

Combination of powders we can use

There are attractive in appearance.

The drugs having un-pleasant odor and taste are

enclosed in a tasteless shell.

They can be filled quickly and conveniently.

Physician can change the dose and combination of drug

according to patient requirement.

They are economical.

They are easy to handle and carry.

Disadvantages
Hygroscopic drugs are not suitable for filling into
capsules, because they absorb water present in
capsule shell makes shell very brittle and ultimately
lead to crumble into pieces.

The concentrated solutions which require previous

dilution are unsuitable for capsules because if
administered as such lead to irritation into stomach
Capsule size
For human use, empty capsules ranging in size from
000 the largest to 5 the smallest. Generally, hard
gelatin capsule are used to encapsulate between 65 mg
to 1 gram.
Size Volume in ml Size in mm
000 1.37 26.3
00 0.95 23.7
0 0.68 21.8
1 0.50 19.2
2 0.37 18.3
3 0.30 15.3
4 0.21 14.7
5 0.15 11.9
GELATIN
Gelatin is heterogeneous product derived by hydrolytic
extraction of animal's collagen.

The sources of gelatins including animal bones, hide

portions and frozen pork skin.

TYPES OF GELATIN

Type A

Type B
There are two basic
types of gelatin
TYPE A
Derived from acid treated precursor that exhibits an iso electric
point at pH-9. It is manufactured mainly from pork skin.

TYPE B
Derived from alkali treated precursor that exhibits an iso electric
point at pH-4.7. It is manufactured mainly from animal bones
Preparation Of Gelatin
anufacturing of hard gelatin capsules

Steps involved in making empty gelatin capsules

1. Dipping
2. Spinning
3. Drying
4. Stripping
5. Trimming and Joining
6. Polishing
Dipping :
Pairs of the stainless steel pins are dipped into the dipping solution to
simultaneously form the caps and bodies.
The dipping solution is maintained at a temperature of about 50 0C in a
heated, jacketed dipping pan.

Spinning :
The pins are rotated to distribute the gelatin over the pins uniformly and
to avoid the formation of a bead at the capsule ends.

Drying :
The gelatin is dried by a blast of cool air to form a hard shells.
The pins are moved through a series of air drying kilns to remove water

Stripping :
A series of bronze jaws strip the cap and body portions of the capsules
from the pins.
Trimming and joining

The stripped cap and body portions are trimmed to the required length by
stationary knives.

After trimming to the right length, the cap and body portion are joined and
ejected from the machine.

Polishing
Pan Polishing : Acela-cota pan is used to dust and polish.

Cloth Dusting : Capsule are rubbed with cloth.

Brushing : Capsule are feed under soft rotating brush.

 GELATIN: BASIC PROPERTIES

The reason for this is that gelatin possesses the following basic
properties:
It is non-toxic, widely used in foodstuffs and acceptable for use
worldwide.
It is readily soluble in biological fluids at body temperature.
It is good film-forming material, producing a strong flexible film
The gelatin films are homogeneous in structure, which gives them
strength.
 GELATIN: NATURE OF THE CAPSULE
SHELL
Gelatin is a translucent, colorless, brittle, nearly tasteless solid
protein substance, chemically derived by partial hydrolysis of
collagen obtained from the skin, white connective tissue and bones
of animals.
Collagen is a fibrillary protein that contains 18 different amino
acids. The collagen of bones and hides is subject to a maceration
and purification process with acids and alkalis that split it
hydrolytically into an almost unbranched amino acid chain of
variable length. This end product is known as gelatin.
Pork skin gelatin contributes plasticity while bone gelatin gives
firmness in capsule shell.
In commerce, it is available as fine powder, shreds, flakes and
sheets. Different grades of gelatin with E number are available in
the market.
 GELATIN: NATURE OF THE CAPSULE
SHELL
Gelatin melts when heated and solidifies when cooled again.
Together with water, it forms a semi-solid colloid gel.
Gelatin is stable in air in dry form but is subjected to microbial
decomposition on absorption of moisture.
Normally hard gelatin capsules contain 13 to 16% moisture.
The variations in gelatin properties arise because of changes in
molecular weights between 20,000 and 2,00,000.
Two popular grades of gelatin, Pharmagel-A and Pharmagel-B,
are acid processed and alkali processed respectively. They
have differing isoelectric points (Pharmagel-A: pH. 4.8 to 5.2,
Pharmagel-B: pH 6.5 to 9.5).
 GELATIN: BLOOM OR GEL STRENGTH
Gel strength is traditionally referred as Bloom. It is the force,
expressed in grams, necessary to depress by 4 mm the surface of a
gelatin gel (concentration 6.67% kept for 17 hours at 10C) with a
standard plunger (AOAC).
Bloom is linked to mechanical elasticity of the gel and is used to
classify gelatin types. It generally ranges from 50 to 300 Bloom.
We may sometime refer to Low, Medium or High Bloom, with the
following limits:
Low Bloom: gel strength below 120 g.
Medium Bloom: gel strength between 120 and 200 g.
High Bloom: gel strength above 200 g.
Gel strength increases with concentration and time as the gel
matures. It decreases with temperature.
 HYPROMELLOSE: NATURE OF THE
CAPSULE SHELL
Hypromellose is a plant-derived material and, therefore,
answers the need for certain religious, cultural, and dietary
restrictions.
Hypromellose include a moisture content of approximately
4%-6% making it an excellent container for moisture-sensitive
drugs.
Hypromellose capsules are also less prone to brittleness and
have a higher oxygen transmission rate than those made from
gelatin.
Hypromellose has been extensively and successfully
developed into two-piece capsules for use in the
pharmaceutical and nutritional industries.
 ALTERNATIVE MATERIAL FOR HARD-
SHELL CAPSULES
Several materials have been examined as a substitute for the
gelatin in two-piece hard capsules. Hydroxypropylmethyl
cellulose (HPMC) has become a successful alternative material
for two-piece capsules and is actually on the market in the
world. HPMC capsules have been developed for both
pharmaceutical products and dietary supplements. QUALI-V,
developed by Shionogi Qualicaps, is the first HPMC capsule
developed for eventual use in pharmaceutical products.
NATURE OF THE CAPSULE CONTENT
 NATURE OF THE CAPSULE CONTENT
Powders: The most common fill materials for two-piece
capsules are immediate release powders. It is often possible to
go directly from a dry powder blend to the filling machine
with no intermediate steps.
Granules: Granules are useful when a powder formulation
exhibits poor flow or inadequate content uniformity. Granules
may be coated with gastric resistant polymers in cases where
the drug is destroyed by stomach acids. Other polymer
applications can be used to create a delayed release profile and
to improve drug stability.
 NATURE OF THE CAPSULE CONTENT
Pellets/Beads: Pellets can be coated with sustained release and
enteric film coatings to achieve unique release profiles or multiple
release rates in a single dosage unit by mixing pellets with different
film coatings. Pellets also offer the ability to mix multiple active
ingredients or incompatible active ingredients in a single capsule.
Tablets: A common application is the filling of tablets into capsules
for blinding in clinical trials or filling of minitablets coated to
achieve multiple release profiles.
Capsules within capsules: 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.
 NATURE OF THE CAPSULE CONTENT
Pastes: The materials to be filled must be either thermo softening 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.
Liquids: Gelatin capsules are unsuitable for the encapsulation of
aqueous liquids, because water softens the gelatin to produce
distortion of the capsules. 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)
 MANUFACTURING OF HARD GELATIN
CAPSULE SHELL

Fig. A capsule manufacturing machine: (A) gelatin solution storage tank; (B) dip pan; (C) drying
kilns; and (D) Automatic section.
MANUFACTURING OF HARD GELATIN
CAPSULE SHELL

Fig. Dip pan, capsule shell formation.

 MANUFACTURING OF HARD GELATIN
CAPSULE SHELL
Steps involved in making empty gelatin capsules
Dipping: Pairs of the stainless steel pins are dipped into the
dipping solution of manganese bronze to simultaneously form
the caps and bodies. The dipping solution is maintained at a
temperature of about 50C in a heated, jacketed dipping pan.
Spinning: The pins are rotated to distribute the gelatin over the
pins uniformly and to avoid the formation of a bead at the
capsule ends.
Drying: The gelatin is dried by a blast of cool air to form a
hard shells. The pins are moved through a series of air drying
kilns to remove water.
 MANUFACTURING OF HARD GELATIN
CAPSULE SHELL
Stripping: A series of bronze jaws strip the cap and body
portions of the capsules from the pins.
Trimming and joining: The stripped cap and body portions are
trimmed to the required length by stationary knives. After
trimming to the right length, the cap and body portion are
joined and ejected from the machine.
Polishing: Pan Polishing: Acela-cota pan is used to dust and
polish. Cloth Dusting: Capsule are rubbed with cloth.
Brushing: Capsule are feed under soft rotating brush.
 MANUFACTURING OF HARD GELATIN
CAPSULE SHELL- SPECIFICATIONS
Empty gelatin capsules are manufactured in various lengths,
diameters and capacities. The size selected for filling
medicaments is decided by the amount of the material to be
filled. The density and compressibility of the fill will largely
determine to what extent it may be packed into a capsule shell.
Following table (Table 1.1) gives the dimensions of the
universally manufactured capsule shells and weight capacity of
powder of varied density which can be ordinarily filled in
various sizes of capsules. External diameter and length of the
body part are critical dimensions which enables in designing
universal capsule filling machines. Cap part dimensions are
critical and match with the dimensions of the body part to see
that the capsulation is smooth and the filled capsules are intact.
MANUFACTURING OF HARD GELATIN
CAPSULE SHELL- SPECIFICATIONS
 FORMULATION OF CAPSULES
The exclusive use of gelatin for making hard and soft capsules is its
solubility characteristics in stomach fluids.
In addition to gelatin, the shell of hard gelatin capsules contains
plasticizers, preservatives, colorants, opacifying agents, flavours,
sugars, acids, enteric materials, water etc.
The plasticizers used are glycerin, sorbitol etc.
Preservatives, if included, are generally a mixture of methylparaben
(4 part) and propylparaben (1 part) to the extent of 0.2%.
Flavours, if added, should not exceed 2% and are generally
ethylvanillin or essential oils.
Sugar may be added up to 5% to give the gelatin shell desirable
chewable characteristics, if required.
 FORMULATION OF CAPSULES

Capsule colorants must satisfy the following three key

requirements:
Regulatory approval in the countries intended for distribution
Product protection and marketing
Patient acceptance.
For a global presentation, the available palette of colorants is
iron oxides, titanium dioxide, and blue #2.
 PREPARATION OF HARD GELATIN
CAPSULES
The preparation of hard gelatin capsules in large scale or small
scale involves the following steps:
1. Development of formulation and selection of capsule size
2. Filling the capsule shells Empty gelatin capsules are
manufactured in various lengths, diameters and capacities. The
size selected for filling medicaments is decided by the amount of
the material to be filled.
3. Sealing of capsule shells
4. Cleaning and polishing of filled capsules
 PREPARATION OF HARD GELATIN
CAPSULES
1. Development of Formulation and Selection of Capsule Size:
Following are the objectives set in the formulation of a hard
capsule,
Ease of filling and production
Accurate dosage
Stability
Elegance
Bio-availability
In dry formulation, the active and the inactive ingredients are
required to be blended thoroughly to ensure a uniform powder
mix.
 PREPARATION OF HARD GELATIN
CAPSULES
Preformulation study is needed to determine the need for steps
to ensure uniform blending like particle size reduction, bulk
control, need for glidents, lubrication and proper choice of
blending equipment and conditions of blending like sequence
of addition, time of mixing, rotation speed and humidity
control.
Capsule fill mix basically consists of drug, diluents and
lubricant/glidant. However, use of other ingredients like
capsule colorant, capsule opaquants is also inevitable to
improve the look and elegance of capsules. Coating agents,
hardening agents etc., are optional and are used to bring
special characteristics and performance to the product when
needed.
 PREPARATION OF HARD GELATIN
CAPSULES
Diluents or fillers are added to the formulation to increase the
volume of the fill to produce capsules of a standard size. Generally
used diluents include lactose, microcrystalline cellulose, starch etc.
Diluents used should have the following properties;
Provide bulk
Cohesion to the powder, to ensure smooth filling
Overcome hygroscopicity of the drug powder, if they are
hygroscopic
Overcome interaction between incompatible ingredients, if any
Compressibility, in case where pre-compressed compacts are to be
filled Particle size and density of the diluents should match well
with the drug for uniform mixing.
Examples: lactose, microcrystalline cellulose, di-calcium
phosphate, starch.
 PREPARATION OF HARD GELATIN
CAPSULES
Glidants/Lubricants: Glidants are the materials that impart
good flow property to the powder blend but provide poor
lubrication properties. When lubricants are added to a
powder mass, they form a coat around individual particles
which remains more or less intact. Lubricants are mostly
hydrophobic and hence the presence of lubricant coating
may decrease drug dissolution rate. The uniformity of
capsule weights directly depends on how uniformly the
capsule are filled. Addition of lubricant or glidant such as
fumed silicon dioxide, magnesium stearate, calcium stearate,
stearic acid or talc to the powder mix would enhance flow
property.
 PREPARATION OF HARD GELATIN
CAPSULES
Wetting agents: Many other ingredients like surface active
agents, disintegrating agents etc. are used wherever required.
Surface active agents like tweens, sodium lauryl sulphate,
sodium formaldehyde sulfoxilate etc. are used to improve
wetting of hydrophobic drug powder. They are also used to
overcome the problem of dissolution of drugs with
hydrophobic surface.
Disintegrating agents are used in cases where the cohesive
powder released after dissolution of capsule shell fails to
dissolve due to the lack of wetting or penetration of gastric
fluid into it.
 PREPARATION OF HARD GELATIN
CAPSULES
2. Selection of capsule size: 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.
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.
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
 PREPARATION OF HARD GELATIN
CAPSULES
2. Selection of capsule size: Capsules are available in variable sizes.
The hard gelatin capsules, when empty, are numbered from 000, the
largest size which can be swallowed, to 5 which is the smallest.
Ranges from 600mg to 30mg are approximated capsule capacity for
capsules from 000 to 5, respectively. However, the capacity varies
because of varying densities of powdered drug materials and degree of
pressure used in filling the capsules.
 PREPARATION OF HARD GELATIN
CAPSULES
2. Selection of capsule size: Generally, hard gelatin capsules are used
to encapsulate between 65mg and 1g of powdered material, including
the active ingredient and any excipient needed. The caps are meant to
enclose the powder, not to retain additional powder. It is always good
to check the weight of each filled capsules. Aside from choosing the
size of capsule, experienced pharmacist is considering the color of the
hard gelatin capsules to be used. From the transparent, colorless hard
capsule, capsules are also available in various transparent colors such
as blue, yellow, pink green, black or reddish-brown. The pink capsule
is frequently used by pharmacists for prescription where capsule have
been prescribed twice for an individual, or where capsule medication
is given to two persons in the same family. In such cases it is very
important to note the color as well as the capsule size on the
prescription, so that in case of renewals the refilled prescription will
duplicate the original.
 PREPARATION OF HARD GELATIN
CAPSULES
2. Characteristics of a Good Selection of Capsules:
1. A diluent, such as lactose, should be added when drug dose for
a single capsule is inadequate to fill the capsule.
2. Two or more capsules can be required to provide the particular
dose, if the amount of the drug representing a usual dose is too
large to place in a single capsule.
3. Lubricants such as magnesium stearate (frequently less than
1%) are added to facilitate the glow of the powder when an
automatic capsule filling machine is used.
4. Wetting agents such as lithium carbonate are added to capsule
formulations to enhance drug dissolution.
 PREPARATION OF HARD GELATIN
CAPSULES
2. Filling the capsule shells: The filling material must be compatible
with the gelatin shell and, therefore, deliquescent or hygroscopic
materials cannot be used. Conversely, due the moisture content in the
capsule shells, they cannot be used for moisture - sensitive drugs. All
ingredients need to be free of even trace amounts of formaldehyde to
minimize cross - linking of gelatin.
Powders and granules are the most common filling materials for hard -
shell gelatin capsules, although pellets, tablets, pastes, oily liquids,
and non-aqueous solutions and suspensions have been used.
The simplest dependent method of filling is leveling where powder is
transferred directly from a hopper to the capsule body, aided by a
revolving auger or vibration. Additional powder can be added to fill
the space arising, and the fill weight depends on the bulk density of
the powder and the degree of tamping applied.
 PREPARATION OF HARD GELATIN
CAPSULES
Table 1.1 demonstrates the Liquid Excipients Compatible with Hard
Gelatin Capsules. A liquid fill can be useful when manufacturing small
batches if limited quantities of API are available. Two types of liquid
can be filled into hard gelatin capsules: non-aqueous solutions and
suspensions or formulations that become liquid on application of heat
or shear stress.
Peanut oil Paraffin oil
Hydrogenated peanut oil Cetyl alcohol
Castor oil Cetostearyl alcohol
Hydrogenated castor oil Stearyl alcohol
Fractionated coconut oil Stearic acid
Corn oil Beeswax
Olive oil Silica dioxide
Hydrogenated vegetable oil Polyethylene glycols
Silicone oil Macrogol glycerides
Soya oil Poloxamers
PREPARATION OF HARD GELATIN
CAPSULES
Table 1.2 demonstrates the influence of density of drug powder
on variation in the weight of the powder filled in any size of the
capsule.
PREPARATION OF HARD GELATIN
CAPSULES
Formulation types for filling into hard capsules:

Dry Solids Semisolids Liquids

Thixotropic
Powders Oily Liquids
Mixtures
Non-aqueous
Thermo Softening
Granules Solutions
Mixtures
and Suspensions
Pellets Pastes
Tablets
Capsules
TABLE: CAPSULE VOLUMES AND FILLING
CAPACITIES.
PREPARATION OF HARD GELATIN
CAPSULES
Basically any capsule filling operation involve the following
steps:
Loading capsules in the loader tray (Manual or Automatic)
Separation of caps from the body
Filling of the powder into the body
Scraping of the excess powder
Replacing the cap and seal
Cleaning the outside of the filled capsule and polishing
 PREPARATION OF HARD GELATIN
CAPSULES
The following is a list of some of the more important
physicochemical parameters to control for a smooth and efficient
filling run:
Particle size and shape to assure homogeneity and flow
Uniformity of particle size to assure constant fill weights
Homogeneity of the mixture to assure content uniformity
Flow properties to assure accurate fill weights
Appropriate moisture content; too high may result in powder caking
and poor flow, and too low can result in a build-up of electrostatic
charge causing poor flow and a potential safety hazard
Ability to form compacts under pressure in order to meet the
requirements of filling machine dosing mechanisms.
 PREPARATION OF HARD GELATIN
CAPSULES FILLING METHODS
Manual filling or Simple punch method When a prescription calls
for capsules the ingredients are to be mixed by trituration to a fine
and uniform powder. In this method, the powder to be filled is taken
in a glass plate and gently pressed using a spatula to form a cake
having depth approximately equal to one third of the length of the
body of the capsule. The capsule body is held between thumb and
the fore finger and repeatedly pierced/punched vertically into the
cake until filled. The body is then capped. Granular materials which
are not possible to punch are filled into the capsule body by pouring
weighed amount of the powder from a paper fold. Crystalline
materials, especially materials consisting of a mass of filament-like
crystals as with the quinine salts, will not fit into a capsule easily
unless first powdered. Once filled, capsules must be cleaned and
polished. These methods do need cross check by weighing the filled
capsules individually to ensure uniform filling.
PREPARATION OF HARD GELATIN
CAPSULES FILLING METHODS
Hand operated capsule filling machine: (Laboratory Scale):
A hand operated gelatin capsule
filling machine consists of the
following parts and is shown in
figure.
1. A bed with 200-300 holes.
2. A capsule loading tray
3. A powder tray
4. A pin plate having 200 or 300
pins corresponding to the number
of holes in the bed and capsule
loading tray.
5. A lever
6. A handle
7. A plate fitted with rubber top
PREPARATION OF HARD GELATIN
CAPSULES FILLING METHODS
Hand operated capsule filling machine: (Industrial Scale):
 PREPARATION OF HARD GELATIN
CAPSULES FILLING METHODS
Hand operated capsule filling machine Working: The empty capsules
are filled into the loading tray which is then placed over the bed. By
opening the handle, the bodies of the capsules are locked and caps
separated in the loading tray itself which is then removed by operating
the liver. 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 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.
PREPARATION OF HARD GELATIN
CAPSULES - FILLING EQUIPMENT
 PREPARATION OF HARD GELATIN
CAPSULES - FILLING OPERATIONS
The filling machine process involves feeding, rectification,
separation of cap and body, filling, closing of cap and body, and
ejection (Figure).
For high-speed filling machines, these steps may occur at rates up
to 200,000 capsules per hour.
 PREPARATION OF HARD GELATIN
CAPSULES
3. Sealing of Capsule Shell: 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 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 F to form the seal.
 PREPARATION OF HARD GELATIN
CAPSULES
3. Sealing of Capsule Shell:
Many methods have been proposed for the sealing of capsules to
prevent the leakage of liquids. The method proven to be the most
successful is gelatin banding. Two bands of gelatin solution are
applied around the center of the filled capsule, This band is dried
using air at ambient conditions to prevent moisture loss from the
gelatin shells, which would make them brittle. The band can be
colored, permitting a more complicated appearance for product
branding. This band complies with the requirements of the Food and
Drug Administration (FDA). e.g., HicapsealTM 40/100 (Shionogi
Qualicaps Inc.).
Tamper-Evident Packaging Requirements for Over-the-Counter
Human Drug Products for tamper-evident sealed capsules.
 PREPARATION OF HARD GELATIN
CAPSULES
3. Sealing of Capsule Shell:
Through a heat welding process that fuses the capsule cap to
the ring around the capsule where heat welded. Example:
Welds gelatin seal.
Capsule may also be sealed through a heat welding process
that fuse capsule cap to the body.
Lightly coating the inner surface of the cap with a warm
gelatin solution immediately prior to placement on the filled
capsule body.
 PREPARATION OF HARD GELATIN
CAPSULES
4. Cleaning of 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.
 PREPARATION OF HARD GELATIN
CAPSULES
4. Cleaning and polishing of filled capsules:
On small scale, capsules may be cleaned individually or by
rubbing them with a clean gauze or cloth.
On large scale, many capsule filling machines are affixed with
a cleaning vacuum that removes any extraneous material from
the capsules as they exit the equipment. Industrial cleaning and
polishing of filled hard gelatin capsules using the Accela-Cota
apparatus.
Accela-Cota
 PREPARATION OF HARD GELATIN
CAPSULES
4. Polishing of filled capsules:
 PREPARATION OF HARD GELATIN
CAPSULES
4. Polishing of filled capsules: Mode of operation: A major
quantity of capsules to be cleaned and polished is loaded into the
feed hopper. The capsule feed is regulated with the aid of a slide
gate at the opening of the feed hopper and an infinitely adjustable
vibratory conveyor chute. The capsules pass via the vibratory
conveyor chute between two polishing belts while travelling
through the polishing stage. The two contra rotating belts clean
and polish the capsules. The lower belt is running faster than the
upper belt in order to transport the products. Dust is continuously
removed from the polishing fleece by two vacuum units.
PROCESSING PROBLEMS DIFFICULTIES IN
FILLING CAPSULES
1. Deliquescent or Hygroscopic powders a gelatin capsule contain
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 adsorbent like magnesium carbonate,
heavy magnesium oxide or light magnesium oxide overcomes this
difficulty provided the capsules are packed in tightly closed glass
capsule vials.
2. Eutectic mixtures certain substances when mixed together tend to
liquefy and 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. 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.
PROCESSING PROBLEMS DIFFICULTIES IN
FILLING CAPSULES
3. 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.
4. Use of two capsules some of the manufacturers separate the
incompatible ingredients of the formulation by placing one of the
ingredients in smaller capsule, and then placing this smaller capsule in a
larger capsule containing the other ingredients of the formulation.
5. Filling of granular powder 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 powder into which they are
punched. To overcome this difficulty the non-adhesive powders should
be moistened with alcohol and the granular powders should be reduced
to powder before filling into capsules.
 ADVANTAGES OF CAPSULES
1. Capsules mask the taste and odor of unpleasant drugs and can
be easily administered.
2. They are attractive in appearance.
3. They are slippery when moist and, hence, easy to swallow
with a draught of water.
4. As compared to tablets less adjuncts are required.
5. The shells are physiologically inert and easily and quickly
digested in the gastrointestinal tract.
6. They are economical.
7. They are easy to handle and carry.
8. The shells can be opacified (with titanium dioxide) or
colored, to give protection from light.
 DISADVANTAGES OF CAPSULES
1. The drugs which are hygroscopic absorb water from the
capsule shell making it brittle and hence are not suitable for
filling into capsules.
2. The concentrated solutions which require previous
dilution are unsuitable for capsules because if administered
as such lead to irritation of stomach.
CAPSULES
soft gelatin
soft gelatin CAPSULES
 INTRODUCTION soft gelatin
A softgel (a soft gelatin capsule) is a hermetically sealed, one-
piece solid capsule (outer shell) surrounding a liquid or semi-solid
center (inner fill). An active ingredient can be incorporated into
the outer shell, the inner fill, or both without a bubble of air or
gas.
Gelatin soft capsules are made from gelatin and water but with the
addition of a polyhydric alcohol, such as glycerol or sorbitol, to
make them flexible. Sorbitol is less hygroscopic than glycerol.
They usually contain a preservative, such as beta-naphthol. They
are available in variety of shapes and sizes as shown in figure.
Spherical 0.05 -5 ml
Ovoid 0.05 - 7 ml
Cylindrical 0.15- 25 ml
Tubes 0.5 - 0 ml
Pear shaped 0.3 - 5ml
 INTRODUCTION soft gelatin
They are most suitable for liquids and semisolids and are
widely used, in spherical and ovoid forms for vitamin
preparations such as cod liver oil, vitamins A and D and
multiple vitamins.
Content of a softgel capsule is a liquid, or a combination of
miscible liquids, a solution of a solid(s) in a liquid(s) or a
suspension of a solid(s) in a liquid(s).
The liquids include aromatic and aliphatic hydrocarbons, high
molecular weight alcohols, esters or organic acids. The mostly
widely used liquids for human use are oily active ingredients
such as vegetable oils (soybean oil), mineral oil, non-ionic
surface active agents(polysorbate 80) and PEG (400 and 600)
either alone or in combination.
SOFT GELATIN CAPSULES FORMULATION
Gelatin: Obtain from partial hydrolysis of collagen derived from the
skin, connective tissue & Bones of animals.
Important specification of gelatin: Bloom or gel strength: It is a
measure of cohesive strength of cross-linkage that occurs between
molecules and is proportion to the molecular weight of gelatin.
Bloom is determined by measuring the weight in grams required to
move a plastic plunger of 0.5inches in diameter, 4mm into a 6 2/3 %
gelatin that has held at 10C for 17 hrs. The unit of bloom is grams
and it is between 150-250g
Viscosity: Is determined on a 62/3% gelatin of water at 60C and it is
a measure of the molecular chain length. Standard used: 25-45 milli
poise. Iron content: Iron is always present in raw gelatin, and its
concentration usually depends on the iron content of the large
quantities of water used in its manufacture. Amount should not
exceed 15ppm.
SOFT GELATIN CAPSULES FORMULATION
Plasticizers: These are used to make the softgel shell elastic
and pliable. They usually account for 20-30%. The most
common plasticizers used in softgels is glycerol, although
sorbitol and propylene glycol are used frequently often in
combination with glycerol. The amount and choice of the
plasticizer contribute to the hardness of the final product and
may even affect its dissolution or disintegration characteristics,
as well as its physical and chemical stability. Plasticizers are
selected on the basis of their compatibility with the fill
formulation, ease of processing, and the desired properties of
the final soft gel, including hardness, appearance, handling
characteristics and physical stability.
SOFT GELATIN CAPSULES FORMULATION
Plasticizer and Gelatin ratio: In soft gelatin capsule the
plasticizer and gelatin ratio is 0.8: 1 In hard gelatin capsule the
plasticizer and gelatin ratio is 0.4: 1
Water : Water usually accounts for 30-40 % of the wet gel
formulation and its presence is important to ensure proper
processing during gel preparation and softgel encapsulation.
Following encapsulation, excess water is removed from the
softgels through controlled drying. The ratio by weight of
water to dry gelatin can vary from 0.7 to 1.3 (water) to 1.0
(dry gelatin) depending on the viscosity of the gelatin being
used.
Colorants: Colorants (soluble dyes, or insoluble pigments or
lakes) and can be either synthetic or natural, and are used to
impart the desired shell color for product identification.
SOFT GELATIN CAPSULES FORMULATION
Opacifiers: Opacifiers are typically used in the wet gel
formulation. Conc. of opacifier may be up to 0.5%. An
opacifier, usually titanium dioxide may be added to produce an
opaque shell when the fill formulation is a suspension, or to
prevent photo degradation of light-sensitive fill ingredients.
Titanium dioxide can either be used alone to produce a white
opaque shell or in combination with pigments to produce a
colored opaque shell.
Chelating Agents: Iron is always present in raw gelatin, &
should not contain iron more than 15 ppm. Additionally
chelating agent may be used for preventing the reaction of
iron with materials or colors.
PREPARATION OF SOFT GELATIN
CAPSULES FILLING MATERIALS
 PREPARATION OF SOFT GELATIN
CAPSULES FILLING MATERIALS
There are three primary types of inner fill materials:
1) Oily liquids: e.g.. Cod liver oil capsules
2) Solution Fills: Active dissolved in a carrier
Oils such as soybean oil and Miglyol 812 (neutral oil,
triglycerides of medium chain fatty acids)
Polyethylene Glycols: especially PEG 400 -600
Other solvents: Any other solvent, which does not degrade or
solubilize the gelatin shell, i.e., dimethyl isosorbide,
surfactants, diethylene glycol mono ethyl ether.
 PREPARATION OF SOFT GELATIN
CAPSULES FILLING MATERIALS
Optional Ingredients for solution fills:
i. Water or alcohol: up to 10% w/w (if needed for solubility).
ii. Glycerin: 1 to 4% w/w (to retard the migration of the glycerin out
of the shell into the fill).
iii. Polyvinylpyrrolidone: Up to 10% w/w used in combination with
PEG (can increase drug solubility, and also improve stability by
inhibiting drug recrystallization).
3) Suspension Fills: Active dispersed in a carrier.
.Suspensions can accommodate about 30% solids before viscosity
and filling become a problem
.Suspensions can be heated up to 35C to decrease viscosity during
the filling process
.Suspended solids must be smaller than 80 mesh -- mill or
homogenize before filling to prevent needles from clogging during
filling.
 PREPARATION OF SOFT GELATIN
CAPSULES FILLING MATERIALS
Optional Ingredients that can be added in the suspension fill:
Surfactant: sorbitan derivatives such as polysorbate 80 or lecithin.
For hydrophobic drugs dissolved or dispersed in an oily matrix, a surfactant
of HLB 10 will increase the dispersibility of the product in aqueous fluids
and also may improve bioavailability.
Example of suspension fills include drug suspended in the following
carriers:
1. Oily mixtures:
a) Soybean Oil with beeswax (4-10% w/w) and lecithin (2-4% w/w).
b) Gelified Oil, a ready to use system composed of soybean oil, a suspending
agent, and a wetting agent.
2. Polyethylene glycol
.PEG 800 -1000 for semi-solid fills
.PEG 10,000 -100,000 for solid fills
.Or mixtures of the above. (Heat up to 35C to make fluid enough for filling)
 PREPARATION OF SOFT GELATIN MASS
The gel is prepared in a 300-litre stainless steel vessel.
Gelatin powder is mixed with water and glycerin by heating
and stirring.
The molten gelatin mass is formed.
It is decanted into 200-kg mobile vessels by Turbine mixing.
Where colors and flavors can be added.
It ensures consistency of gelatin mass.
This mass is kept at a constant temperature until it is needed
for the next stage of the process.
 MANUFACTURE OF SOFT GELATIN CAPSULE
Soft gelatin capsule is manufactured by five methods Plate process,
Rotary die process, Reciprocating die, Accogel machine, and Droplet
method.
Plate process: Place the gelatin sheet over a die plate containing
numerous die pockets, Application of vacuum to draw the sheet in to the
die pockets, Fill the pockets with liquid or paste, Place another gelatin
sheet over the filled pockets, and Sandwich under a die press where the
capsules are formed and cut out.
Rotary die process: The material to be encapsulated flows by gravity. The
gelatin sheets are feed on rolls contain small orifice lined up with the die
pocket of the die roll. Two plasticized gelatin ribbons are continuously
and simultaneously fed with the liquid or paste fill between the rollers of
the rotary die mechanism where the capsule are simultaneously filled,
shaped, hermetically sealed and cut from the gelatin ribbon. The sealing
of the capsule is achieved by mechanical pressure on the die rolls and the
heating (37-40C) of the ribbons by the wedge.
ENCAPSULATION PROCESS
 ROTARY DIE PROCESS
Tumble Drying: Dry, sterile air is forced across the tumbler and removes the
moisture from the outer surface of the capsules.
Supplemental Drying (curing): After the tumbler dryers, the soft capsules are
placed on special trays for final drying in the drying room. For a period up to
48 hrs.
Sizing: Automatic capsule sizing machine eliminates undersized and
oversized capsules.
Packaging and storage of capsules: Capsules should be packed in a well-
closed glass or plastic containers and stored in a cool place. To prevent the
capsules from rattling a tuft of cotton is placed over and under the capsules in
the vials. In vials containing very hygroscopic capsules a packet-containing
desiccant like silica gel or anhydrous calcium chloride may be placed to
prevent the absorption of excessive moisture by the capsules. Empty gelatin
capsules should be stored at room temperature at constant humidity. High
humidity may cause softening of the capsules and low humidity may cause
drying and cracking of the capsules. Storage of capsules in glass containers
will provide protection not only from extreme humidity but also from dust.
TUMBLE DRYER FOR CAPSULE
PREPARATION OF SOFT GELATIN
CAPSULES
 MANUFACTURE OF SOFT GELATIN CAPSUL E
Reciprocating die: 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.
Accogel Capsule Machine Or Stern machine, it is the only machine that can
successfully fill dry powder into a soft gelatin capsule.
Droplet method: The essential part of the apparatus consists of two
concentric tubes. Through the inner tube flows the medicament and, through
the surrounding outer tube, the gelatin solution. The medicament, therefore,
issues from the tube surrounded by gelatin and forming a spherical drop.
This is ensured by allowing the drop to form in liquid paraffin in which the
gelatin is insoluble. Regular induced pulsations cause drops of the correct
size to be formed, and a temperature of 4C ensures that the gelatin shell is
rapidly congealed. The capsules are subsequently degreased and dried.
DROPLET METHOD
1. Container with medicines
substance
2. Hoper with medicines
substance
3. Container with gelatin
solution
4. Conical nozzle
5. Pulsater
6. Cooler
7. Container with Vaseline
oil
 GELATIN CAPSULES
Packaging and storage of capsules: Capsules should be packed
in a well-closed glass or plastic containers and stored in a cool
place. To prevent the capsules from rattling a tuft of cotton is
placed over and under the capsules in the vials. In vials
containing very hygroscopic capsules a packet-containing
desiccant like silica gel or anhydrous calcium chloride may be
placed to prevent the absorption of excessive moisture by the
capsules. Empty gelatin capsules should be stored at room
temperature at constant humidity. High humidity may cause
softening of the capsules and low humidity may cause drying
and cracking of the capsules. Storage of capsules in glass
containers will provide protection not only from extreme
humidity but also from dust. They should be protected from
light when required, and from excessive moisture or dryness,
and should not be subjected to temperatures above 30 C.
 EVALUVATION OF CAPSULES
Ingredient specifications all ingredients of a soft gel are controlled and tested
to ensure compliance with pharmacopoeial specifications. E.g. Impurities
such as aldehydes & peroxides which may be present in polyethylene
glycols. Presence of high levels of these impurities gives rise to cross-linking
of the gelatin polymer, leading to insolubilization through further
polymerization.
In-process testing: During the encapsulation process the four most important
tests are:
Shape and size
Color
Thickness of capsule shell
Leaking test for semi-solid and liquid ingredients from soft capsules
The gel ribbon thickness;
Soft gel seal thickness at the time of encapsulation;
Fill matrix weight & capsule shell weight;
Soft gel shell moisture level and soft gel hardness at the end of the drying
stage.
 EVALUVATION OF CAPSULES
Finished product testing: These normally includes
Visual inspection: Unpack and inspect at least 20 capsules.
They should be smooth and undamaged. Evidence of physical
instability is demonstrated by gross changes in physical
appearance, including hardening or softening, cracking,
swelling, mottling or discoloration of the shell.
Stability tests for capsules are performed to know the integrity
of gelatin capsule shell and for determining the shelf life of
capsules. The test helps in improving the quality of contents of
capsule shell and for choosing the appropriate retail package.
The capsule shell are to be stabilized to know atmospheric
condition with relative humidity about 20-30 % and
temperature about 21-24c.
 EFFECT OF TEMPERATURE AND HUMIDITY ON CAPSULE
SHELL
Temperature Humidity Effect on Capsule shell
21-24C 60% Capsules become softer, tackier and
bloated
Greater than Greater than 45% More rapid and pronounced effects
24C unprotected capsules melt and fuse
together

Test conditions for accelerated physical stability tests for

capsule dosage forms
Test conditions Observation
80 % RH at room temperature in an Capsules are observed periodically for 2
open container. weeks, both gross and subtle effects of the
storage conditions are noted and recorded.
40 C in an open container.
The control capsule should not be affected
40 C in a closed container (glass except at the 80% RH station.
bottle with tight screw-cap).
 EVALUVATION OF CAPSULES
Shell integrity test: This test is performed to find out the integrity of
capsule shell. The standard capsule shells kept at the room
temperature 40c and 80% RH becomes more soft, sticky and swollen.
Determination of shelf life: Shelf life or the expiry date of packed
capsules is determined under normal storage conditions.
Invariability test: The invariability in the medicaments packed in the
capsule shells can be determined by performing the following tests: a)
Weight variation test: 20 capsules are taken at random and weighed.
Their average weight is calculated, then each capsule is weighed
individually and their weight noted. The capsule passes the test if the
weight of individual capsule falls with in 90-110% of the average
weight. b) Content
uniformity test: The amount of active ingredient should be within the
range of 85% to 115% of the label amount for 9 of 10 capsules, with
no unit outside the range of 70% to 125% of label amount.
 EVALUVATION OF CAPSULES
Moisture permeation test: To assure the suitability of
containers for packaging capsules. The moisture permeating
feature of capsules packaged in single unit containers
blister pack or strip pack unit dose containers glass or
plastic bottles are to be determined.
Disintegration test: Disintegration test is a method to evaluate
the rate of disintegration of solid dosage forms. Disintegration
is defined as the breakdown of solid dosage form into small
particles after it is ingested.
Dissolution test: Dissolution test is an official method to
determine the dissolution rate of a solid dosage form.
Dissolution rate is defined as the rate at which the drug is
released into the systemic circulation from the dosage form.
 ADVANTAGES OF SOFT GELATIN CAPSULES
Easy to administer
Easy to Manufacture
Liquids can be encapsulated ( non water soluble)
Small to large sizes possible
Elegance
Portability
Odour and taste masking
Ready availability of drug hence faster action.
Specialized dosage forms can be made e.g. chewable, extended
release, captabs etc.
Can be used for ophthalmic preparations e.g. aplicaps, vaginal /
rectal suppositories
 DISADVANTAGES OF SOFT GELATIN
CAPSULES

Water soluble material are difficult to incorporate

Highly Moisture sensitive
Efflorescent material cannot be incorporated, they may cause
softening / leaching
Deliquescent materials cannot be incorporated, they may cause
hardening or brittle capsules.

HARD GELATIN CAPSULES
1. Two piece (large body & short
cap)
2. Cylindrical shape.
3. Powder drug or pallets coated
with drug are encapsulated.
4. Gelatin in Hard form is used.
5. Capsules are sealed after they
are filled to ensure that the
medicaments may not come
out of the capsule due to rough
handling.
6. 8 different type of sizes are
available
SOFT GELATIN
CAPSULES
1. One piece & hermetically
sealed.
2. Available in round , oval &
tube like shapes.
3. Liquid & Semi liquid fill &
unstable substances are
encapsulated.
4. Molten gelatin are used.
5. Filling & sealing of soft
gelatin capsules are done in a
combined operation on
machine.
6. No specific sizes are
available.
SPECIAL TYPES OF HARD GELATIN AND SOFT
GELATIN CAPSULES

Altered Release capsules

Enteric-coated capsules
Sustained release capsules
Liquid filled hard gelatin capsules
Rectal capsules
Capsules for packing of Ophthalmic ointments
 RECENT UPDATES IN CAPSULE TECHNOLOGY
Vegicaps Soft capsules are an alternative animal free capsule. The
shell is made from seaweed extract and gluten free starch, and
contains no modified sugars or artificial ingredients. The shell can be
clear or colored and there is a wide range of shapes, sizes and colors
available.
Capsugel these capsules made from all natural fish gelatin derived
from farm-raised fish, they have the same characteristics as
traditional gelatin capsules, including appearance, mechanical
properties, hygroscopic and oxygen properties, chemical stability,
odorless and tasteless.
Licaps new 000 size capsules are ideal for maximizing liquid dosage
with a fill capacity of 1000mg to 1400mg depending on the density of
the liquid fill material. This two-piece capsules has been specially
designed to be sealed for secure containment of liquids and semi-
solids without banding. Available in both gelatin and HPMC capsules
they are available in a variety of colors to meet your specific needs.