SOFT GELATIN CAPSULES

CONTENTS
• INTRODUCTION
• SIZE AND SHAPE OF SOFT GELATIN CAPSULES
• NATURE OF SHELL
• NATURE OF CAPSULE CONTENT
• BASE ADSORPTION & MINIM / GRAM FACTOR
• PRODUCTION OF SOFT GELATIN CAPSULES
• IN PROCESS AND FINAL PRODUCT QUALITY
CONTROL TESTS
• STABILITY TESTING
• PACKAGING AND STORAGE OF CAPSULES
 INTRODUCTION
Soft gelatin capsules, also called as softgels, are one
piece solid capsule, hermetically sealed, soft gelatin shells
(outer shell) containing a liquid, a suspension, or a semi –
solid (inner fill). An active ingredient may be incorporated
in the outer shell, inner fill or both.
 Advantages
• Easy to swallow, tasteless, available in different variety of
shapes, colours, and sizes.
• Unit dose delivery system and tamper proof.
• Accuracy and uniformity of dosage, capsule to capsule and
lot to lot, are predominant advantages.
• Permit liquid medications to become easily portable and
increases the bioavailability.
• Low melting point drugs can also be easily incorporated.
• Safer handling of highly potent or cytotoxic drug
compounds.
• Dissolution rate or disintegration time are better, so they
show an advantage over other solid dosage formulations.
 Disadvantages

• Need special type of equipments for the manufacture

• Not suitable to formulate water soluble compounds.
• Not suitable to formulate highly efflorescent drugs as they
may cause leaking, or softening of shell.
• Not suitable to formulate deliquescent drugs as they may
cause hardening of shell or production of brittle capsules.
• Higher manufacturing costs compared to tablets
 Applications of Soft Gelatin Shell Capsules

• As an oral dosage form for human or veterinary use.

• As a suppository dosage form for rectal or vaginal use
• As a speciality package in the tube shape, for human or
veterinary use of topical, ophthalmic, otic (ear)
preparations.
• In the cosmetic industry, these can be formulated as a
speciality package for breath fresheners, perfumes, bath
oils, various skin creams etc.
Size and Shape of Soft Gelatin Shell Capsules
 PRODUCTION OF SOFT GELATIN
CAPSULES
Originally, soft gelatin capsules are made using leather
mold and later iron mold for shaping the capsules. As
technology advanced, the individual iron molds gave way
to multiple molding units, and theses led to sets of plates
containing pockets.
PREPARATION METHODS

PLATE PROCESS RECIPROCATING

DIE PROCESS

ROTARY DIE ACCOGEL

PROCESS MACHINE
 Plate Process

• Oldest commercial method of manufacture.

• Involves pressing two sheets of wet gelatin together
between two molds provided with die pockets.
• One of the gelatin sheet is placed over the first mold and
application of vacuum produce depressions in the gelatin
sheet into which the active fill is placed.
• A second gelatin sheet is laid over the first gelatin sheet,
and both the gelatin sheet were pressed together with the
fill material sandwiched in between.
 Rotary Die Process
• Gelatin mass is fed in to air cooled rotating drums. Gelatin
ribbons of controlled thickness are formed from the
rotating drums. Thicker shells are used on products
requiring greater gelatin strength. The cost of the product
is directly proportional to the shell thickness.
• Gelatin ribbons are then passed through a mineral oil bath
over oil rolls, and then down between the wedge and the
die rolls with die pockets.
• Material to be capsulated flows by gravity into a pump that
accurately meters the material through the wedge into the
gelatin ribbon between the die rolls. Bottom of the wedge
contains small orifices lined up with the die pockets.
• Filled capsules shaped, hermetically sealed, and cut from
the gelatin ribbons. Capsule sealing is achieved by using
pressure and heat.
• Immediately after manufacture, capsules are automatically
conveyed through a naptha wash unit to remove the
mineral oil lubricant. The washed capsules are subjected
to drying.
• The capsules are then spread on a tray and allowed to
come to equilibrium with forced air conditions :– 20-30%
RH and temperature of 21-24℃.
Softgel formation mechanism (rotary die mechanism)
Schematic
drawing of a
rotary-die
soft gelatin
capsule filler
 Reciprocating Die Process

• Similar to Rotary Die Process.

• Gelatin ribbons are fed into die rolls that continuously
open and close to form rows and pockets in the gelatin
ribbon.
• Pockets are filled with medication, and are sealed, shaped,
and cut out of the film as they progress through the
machine.
• As the capsules are cut from the ribbon, they fall in to
refrigerated tanks which prevent the capsules from
adhering to one another.
 Accogel Machine

• This is the only machine that formulates dry powder in to

soft gelatin capsule.
• Rest of the features are same as rotary die machine.
 NATURE OF CAPSULE SHELL
Capsule shell is composed of gelatin, plasticizers, water,
preservatives, opacifiers, colouring agent, flavours, sugars, and active
ingredient.
• Gelatin :- 150-200 bloom strength, 2.8-4.5 millipoise at 60℃.
• Plasticizers :- added to make the shell elastic, and flexible and to
minimise brittleness and cracking. E.g., polyethylene glycol,
glycerine and sorbitol.
• Water :- demineralised water is used as solvent. Ratio of water to
gelatin is about 0.7-1.3 (water) : 1.0 (gelatin), depending on the
viscosity of gelatin used.
• Preservatives :- added in concentration of 0.2%. Eg. methyl paraben
and propyl paraben.
• Opacifying agent :- titanium oxide used in 0.2 – 1.2%
• Flavouring agent :- used in concentration of 0.1-2%. Eg. ethyl
vanillin.
 NATURE OF CAPSULE CONTENT
Capsule content is individually developed to fulfil the
specifications and requirements of the product. The content of a soft
gelatin capsule can be a liquid, a combination of miscible liquids, a
solution or suspension of solid in a liquid.
All such materials are formulated for capsulation to produce the
smallest possible capsule with maximum ingredient and physical
stability, therapeutic effectiveness and production efficiency. The
maximum capsule size for convenient oral use in humans is 20
minim oblong, 16 minim oval, 9 minim round.
Liquids that are water miscible and volatile cannot be
formulated as a major constituent of the capsule content since they
can migrate into the hydrophilic shell and volatalize from its surface.
Eg. water, ethyl alcohol etc. but they can be used as co – solvents in
the preparation of solutions.
 Liquids like aromatic and aliphatic hydrocarbons, chlorinated
hydrocarbons, esters, organic acids can be formulated as active
ingredient. The most widely used liquids for human use are oily
active ingredients, vegetable oils, mineral oils, no ionic surfactants
and polyethylene glycols.
All liquid solutions, suspensions, for capsulation should be
homogenous and air free, should flow by gravity at room
temperature. Preparations for encapsulation should have a pH
between 2.5 -7.5, since preparations that are more acidic can cause
hydrolysis, and leakage of gelatin shell, and preparations that are
more alkaline can tan the gelatin and thus affect the solubility of the
shell.
Combination of miscible liquids often are used to produce
desired physiological actions ( increased or more rapid absorption of
active ingredient) or physiochemical actions (improved solubility and
flow property).
 Except for Accogel process (where solids are formulated as dry
powders), solids are filled into soft gelatin capsules in the form of
solution or suspension. Solids should be 80 mesh size or finer
particles. A solution is more easily capsulated and exhibits better
uniformity, stability and biopharmaceutical properties than a
suspension.
In formulation of a suspension, minimum capsule size should
be determined. The final formulation also requires a suspending
agent to prevent the settling of solids and to maintain homogeneity.
Suspending agent used is melted in a suitable portion of the liquid
base, and the hot melt is added slowly with the stirring in to the bulk
portion of the liquid base.
Two important factors that affect the calculation of the
minimum capsule size are :-
• Base Adsorption Factor
• Minim / Gram Factor
 BASE ADSORPTION FACTOR (BA)

Base adsorption is defined as the number of grams of liquid

base required to produce the capsulated mixture when mixed with 1
gm of solid(s). BA of a solid is influenced by its particle size and
shape, its physical state ( fibrous, amorphous or crystalline), its
density, its moisture content, and its oleophilic or hyrophilic nature.
In determination of a BA factor, the solid must be wetted
thoroughly by the liquid base, and in case of solids that are not easily
done, a wetting agent is required.
Procedure :-
Two 150 ml beakers are taken. Weigh a definite amount of
solid (40gm) into one beaker, and 100g of the liquid base in the
other. Add small increments of the liquid base to the solid, and
using a spatula, stir the base into the solid, until the solid is
thoroughly wetted and uniformly coated with the base. This
produces a mixture that has a soft ointment like consistency.
Continue to add liquid and stir until the mixture flows steadily
from the spatula when held at a 45⁰ angle. As the mixture tends to
stop flowing, note down the weight of the added liquid base.
Formula of finding BA Factor :-
BA = weight of the liquid base added / weight of the solid
Lower the BA of the solid, higher the density of the mixture,
smaller the capsule size.
 MINIM / GRAM FACTOR (M/G)

BA factor is used to determine the minim/ gram factor of the solid.

M/G factor is the volume in minims that is occupied by one
gram of solid plus the weight of the liquid base required to make the
capsulated mixture.
M/G factor is calculated by the following formula,
M/G = {( BA + S ) x V } / W
S = gram of solid
W = weight of the mixture
V = minim
Problem :-
A soft gelatin capsule (4gm mixture ) of drug (1gm) by
using vegetable oil (liquid base) is to be prepared. If BA =
0.75 gm and M/G = 25, then find the volume to be
capsulated.
Solution :-
M/G = {( BA + S ) x V } / W

25 = {( 0.75 + 1 ) x V } / 4

V = 3.52 ml or 57.14 minims

( 1 minim = 0.062 ml)
 IN PROCESS AND FINAL PRODUCT
QUALITY CONTROL TESTS

During the process, capsules are taken periodically for

checking :-
• Seal thickness
• Fill weight check
• Capsule diameter sorter
• Capsule colour sorter
• Capsule counting
• Seal thickness :- is measured under a microscope and changes
in gelatin ribbon thickness, heat or pressure are made if
necessary. Acceptable seal thickness is ½ - 2/3 of the ribbon
thickness.
• Fill weight check :- are made by weighing the whole fresh
capsule, slitting it open, and the contents are removed. The
shell is then washed in a suitable solvent, and the empty shell is
reweighed. If there is weight variation, then necessary changes
are made in the pump that measure the weight of the material
to be filled.
• Capsule diameter sorter :- allows to sort and check the capsules
are within the range of ± 0.020 inch of the theoretical diameter
of the capsules. Overfills, underfills, or foreign capsules are
discarded.
• Capsule colour sorter :- capsules are fed into the colour sorter
automatically from the diameter sorter. Any capsule whose
colour does not conform to the standard for that particular
product is discarded, while other capsules that pass the test are
accepted.
• Capsule counting :- here the capsules are counted, and about
8000 capsules can be counted per minute. They are then,
moved to further quality control tests of the finished product.
 Appearance

Moisture Weight
permeation variation
tests Soft gelatin tests
capsules are
subjected for
following tests
during quality
control:-
Content
Disintegration
uniformity
tests tests

Dissolution
tests
 Weight variation testing conditions

Average net
Deviation (%) No. of Capsules
weight

±10 Min 18
Less than 300 mg
±20 Max 2

±7.5 Min 18
300mg and more
±15 Max 2
 Disintegration testing condition and interpretation
Disintegr
Type of
ation Temperature Limit
capsule
medium
Hard
Water/
gelatin 37 ℃ ± 2℃ 30 min
buffer
capsule
Soft
37 ℃ ± 2℃
gelatin Water 60 min
capsule
0.1 M HCl
2 hr in HCl – no
Enteric mixed
37 ℃ ± 2℃ disintegation
coated phosphate
1 hr in buffer -
capsule buffer pH
disintegrate
6.8
 Difference between Hard and Soft Gelatin Capsule
Hard gelatin capsules Soft gelatin capsules

Cylindrical in shape Round, oval and tube like shapes

Two piece :- body and cap One piece

Plasticizer to gelatin ratio :- 0.4:1 Plasticizer to gelatin ratio :- 0.8:1

Boundary wall firm and rigid Boundary wall soft and flexible

Volatile drug substance is not suitable Volatile drug substance is suitable for
for filling filling

Preservative less Preservative more than hard capsules

Amount of plasticizer is more than

Amount of plasticizer is less
hard capsules
 STABILITY TESTING
Stability testing of capsules is performed to determine the
physicochemical stability of the drug substance in the finished
drug product under specified package and recommended storage
conditions and the influence of environmental factors.
Unprotected capsules rapidly reach equilibrium with
atmospheric conditions under which they are stored. Due to this
property, effect of humidity and temperature, storage and packing
conditions, effect of capsule content on the gelatin shell should be
studied and the standards should be established.
Stability studies should be conducted by comparing test
capsules and control capsule (capsule with just mineral oil). The
capsules must be set to an equilibrium conditions with 20 – 30%
RH at 21 -24℃ before starting a stability study. The physical
stability of soft gelatin capsules is associated primarily with the
pick up or loss of water by the capsule shell.
 If the capsules have protected packaging, the capsules
should have satisfactory physical stability at temperatures
ranging from the freezing point to as high as 60℃.
For unprotected capsules, stability test should be
conducted as the following :-

Condition 1 Observation

The transient effects are

brittleness, susceptibility to
RH lower than 20%, temperature mechanical shock. The capsule
lower than 2℃ and greater than can return to normal when
38℃ . Such a condition has only optimum storage conditions are
transient effects. provided. On returning to
normal, capsule can become dull
or may stick together.
 Condition 2 Observation

RH greater than 45%, and

Capsule melts and fuse together
temperature greater than 24℃

Condition 3 Observation

Capsule shell picks up moisture.

The capsule becomes softer,
tackier, and bloated. The
RH greater than 60%, and a
capsules do not leak unless any
reasonable temperature 21-24℃
ingredient in the capsule attacks
the gelatin under the influence
of the moisture picked.
Manufacturer also conducts accelerated physical stability study. The
results of the study are then taken as a guide for reformulation of
capsule content or capsule shell or for selection of retail package.
The tests are done in the following conditions for two weeks :-

Tests conditions Observation

Condition 1 :- 80% RH at room

temperature in an open container The results show a change in :-
disintegration, leakage, unusual
brittleness or softening of the
Condition 2 :- 40℃ in an open
capsule shell, loss of volatile
container
ingredients from the capsule,
widening of the corners of the
Condition 3 :- 40℃ in a closed
capsule etc.
container (glass bottle with tight
screw cap)
• Such defects observed in the results can be further corrected by
changing the capsule content, gelatin content, colorants used,
or the machine speed or machine dies.
• The control capsule should not undergo any changes other
than Condition 1, as in such condition capsules have the effect
of high humidity, and undergo picking up of moisture in the
capsule shell.
• The stability studies and accelerated studies should be further
conducted with capsules in its retail package.
PACKAGING & STORAGE OF CAPSULES

When bulk shipments of capsules are made by the

manufacturer, they are temporarily protected from the
normal changes in humidity by a suitable barrier such as
0.003 inch polyethylene bag within a standard fibre board
carton. The bulk capsules should be stored in an air
conditioned area in which the humidity does not exceed
45% RH at 21-24℃.
 Retail packaging of capsules in the bulk
shipment should be done in the similar
conditions as soon as the shipments are
opened, for the maximum physical and
chemical stability of the product.
Capsules should be stored in glass or
plastic containers or maybe strip or blister
packaged, and stored at temperature not
exceeding 30℃.
If the content in the capsules in glass or
plastic container, are hygroscopic in nature, a
packet of dessicant (eg. silica gel) is added to
absorb any excess moisture present.
In strip packaging, capsules are tight
sealed in aluminum or plastic film. In blister
packaging, capsules are pushed out of the
package, by a force given on any blister in the
package.