UNIT III

CAPSULES
Ms. TENY SARA THOMAS
MOUNT ZION COLLEGE OF PHARMACEUTICAL
SCIENCES AND RESEARCH, ADOOR, KERALA
ASSISTANT PROFESSOR
B.PHARM FIFTH SEMESTER
FORMULATIVE & INDUSTRIAL PHARMACY
 CONTENTS

• INTRODUCTION
• HARD GELATIN CAPSULES
• SOFT GELATIN CAPSULES
 INTRODUCTION

Capsules are solid dosage form in which the

drug substance is enclosed within a hard or soft
soluble shell made of gelatine or suitable material.
• The word capsule is derived from the latin word
“capsula” that means small box.
• Capsules are formulated for carrying fixed dose of
any active pharmaceutical ingredient.
• It is a unit solid dosage form meant for oral use in
which medicament and inert substances are enclosed.
 Advantages of Capsules
• Easy to manufacture because there are lesser step wise
operations.
• Liquids can be administered.
• Bioavailability of poorly soluble drugs can be improved
• Taste of bitter drugs can be masked
• Elegant in appearance
• Smooth and slippery surface facilitates swallowing
• Minimum excipients are only required.
• Rapid solubility of gelatine allows faster release of drugs.
• Pressure required during the manufacturer is lesser than
that required during tablet production.
• Easy to store and transport.
 Disadvantages of Capsules
• Capsules are not suitable for drugs that are highly
soluble like, potassium chloride, ammonium chloride
etc.
• Not a suitable dosage form for formulating drugs which
are highly efflorescent (that loses water to atmosphere)
or highly deliquescent (that absorbs water vapour).
• Efflorescence leads to a more softer capsule, while
deliquescence leads to forming a more dry capsule.
• Concentrated preparations that require dilution prior to
administration will not be possible to formulate as
capsules.
 GELATIN
Gelatin is a heterogeneous product derived by
irreversible hydrolytic extraction of collagen.
Common sources of collagen :- animal bones, skin of
ox and pigs etc. Gelatin’s chemical, physical, and
physiological properties make it an ideal substances
for the capsulation of pharmaceutical products.
Gelatin is available in mainly two forms :-
• Type A :- derived from acid catalysed hydrolysis and
exhibit an isoeletric point in the ph range 9.
• Type B :- derived from alkali catalysed hydrolysis
and exhibit an isoeletric point in the ph range 4.7.
 Preparation of Gelatine
• Inspection and Cutting :- animal parts are checked
for quality and the rotten parts are discarded. Bones,
tissues, and skins are cut into smaller pieces which are
about 12.7cm through chopping machines.
• Degreasing and Roasting :- The animal parts are
passed under high-pressure water sprays to wash away
debris. They are then degreased by soaking them in hot
water to reduce the fat content to about 2%. A conveyer
belt moves the degreased bones and skins to an
industrial dryer where they are roasted for
approximately 30 minutes at about 200° F (100° C).
• Acid and alkali treatment :- The animal parts are
soaked in vats of lime or some other type of acid or
akali for approximately five days. This process
removes most of the minerals and bacteria and
facilitates the release of collagen. The acid wash is
typically a 4% hydrochloric acid with a pH of less than
1.5. The alkaline wash is a potassium or sodium
carbonate with a pH above pH 7.
• Boiling :- The pieces of bone, tissue, and skin are
loaded into large aluminum extractors and boiled in
distilled water. A tube running from the extractor
allows workers to draw off the liquid that now contains
gelatin. The liquid is sterilized by flash-heating it to
about 375° F (140° C) for approximately 4 seconds.
• Evaporating and Grinding :- From the extractor, the
liquid is piped through filters to separate out bits of
bone, tissue or skin that are still attached. The liquid is
passed through evaporators. The gelatin is press into
sheets and passed through a grinder to get fine powder.
• Flavouring and colouring :- preset amount of
addictives are thoroughly mixed into the powdered
gelatin as required.
 Properties of Gelatine

The gelatin to be used in the pharmaceutical

manufacture should be of the USP Grade, along
with the further properties :-
• Bloom or Gel Strength of Gelatin
• Viscosity of Gelatin
• Iron Content in Gelatin
• Bloom or Gel Strength :- is the measure of the cohesive
strength of the cross linking that occurs between gelatin
molecules. This cohesive strength is directly proportional
to the molecular weight of the gelatin.
Bloom strength is measured using standard plunger
and this determines the weight in grams taken to penetrate
the gel surface by 4mm deep without breaking the gel at
10℃. The number of grams is called the bloom value.
Bloom value ranges from 150 - 250gm.
Higher the bloom strength of the gelatin, the more
physically stable is the resulting capsule shell. Cost of the
gelatin is directly proportional to the gel strength. Hence,
higher bloom value gelatin is majorly used when greater
physical stability is required or in the manufacture of
larger capsule shells.
• Viscosity of the Gelatin :- is the measure of the
molecular chain length and determines the
manufacturing characteristics of the gelatin film.
Viscosity is determined using a U – Tube
viscometer with a 6% gelatin solution at 60 ℃. The
viscosity varies from 25-45millipoise. Higher the
bloom value, greater the viscosity.
• Iron Content :- is always present in gelatin, and its
concentration usually depends on the large amount of
water required for washing during the manufacture of
gelatin. Therefore, the iron content in gelatine should
not exceed 15ppm.
HARD GELATIN
CAPSULES
 CONTENTS
• INTRODUCTION
• PRODUCTION OF HARD GELATIN CAPSULES
• SIZE OF HARD GELATIN CAPSULES
• FILLING OF CAPSULES
• FINISHING
• SPECIAL TECHNIQUES OF FORMULATION OF
HARD GELATIN CAPSULES
• QUALITY CONTROL TESTS OF HARD GELATIN
CAPSULES
 INTRODUCTION
Hard gelatin capsules consists of two pieces in
the form of cylinders closed at one end. The shorter
piece is called the cap. This cap fits over the open end
of longer piece called body. The drug substance is
placed in the body and the caps are slided over it,
hence enclosing the drug substance.
BODY

CAP
 PRODUCTION OF HARD GELATIN CAPSULE SHELL
All raw materials required for the
production of a capsule shell are collected
and weighed. A solution of gelatin with a
concentration of about 45-60% is prepared
by mixing of gelatin in demineralised hot
water at 60-70℃ in jacketed pressure
vessels. Vacuum can be applied to remove
entrapped air bubbles. Gelatin solution is
transferred to stainless steel feed tanks. Dyes,
opacifants, preservatives and any water
needed are added to the gelatin solution.
Finally the viscosity is adjusted
according to required thickness of the
capsule shell.
Stainless steel mold pins are those on
Steps in the Production of Hard Gelatin
Capsule Shell
• Dipping
• Spinning
• Drying
• Stripping
• Trimming
• Joining
• Polishing
• Dipping :- 150 pairs of stainless steel mold pins are
dipped in to the prepared gelatin solution of controlled
viscosity to form caps and bodies simultaneously. This
results in the formation of film on the surface of the
mold pins.
• Spinning :- The mold pins are rotated so as to provide
uniform distribution of gelatin.
• Drying :- The gelatin is dried at the blast of cool air to
form the hard shell. The pins are moved through a
series of air drying kilns which help in removing any
water content present.
• Stripping :- A series of bronze jaw strips the cap and
body portion of the capsules from the mold pins.
• Trimming :- the stripped cap and body portion of the
capsule are trimmed to the required length using
stationary knives.
• Joining :- After trimming, the cap and body sections
are joined and ejected from the machine.
• Polishing :- is done using Accela cota pans and then
rubbed with clothes.
The entire cycle of the machine lasts for
approximately 45 minutes. Inspection processes are
done finally to remove the imperfect capsules.
Capsules are then ready for sterilisation and
packaging.
 SIZE OF CAPSULES
For Human Use, empty capsule shells are
available in different sizes. Based on capacity of the
granules, capsule size are numbered and ranges
from 000 to 5. 000 being the largest and 5 being the
smallest size.
 SIZE VOLUME IN ml SIZE IN mm
000 (largest) 1.37 2.6
00 0.95 2.3
0 0.68 2.1
1 0.5 1.9
2 0.37 1.8
3 0.30 1.5
4 0.21 1.4
5 (smallest) 0.15 1.1
 CAPSULE FILLING
The hard two – piece capsule can be filled with
materials that have a wide range of physical
properties.
Types of dosage forms for filling into hard capsules :-
Solid Semi – Solid Liquid

• Paste
• Thermo
• Powders
softening • Non – aqueous
• Granules
mixtures solutions
• Pellets
• Thixo-tropic • Oily liquids
• Tablets
mixtures
• Powdered formulations often require excipients such as
fillers, lubricants, glidants, to facilitate their
encapsulation. This influences the rate of release.
Addition of wetting agents is needed in case of
hydrophobic drugs.
• In case of powders that have a chance to liquefy ,
adsorbents like colloidal silica, magnesium carbonate
must be used.
 Capsule Filling Machines
PUNCH
METHOD

HAND OPERATED AUTOMATIC

CAPSULE FILLING CAPSULE FILLING
MACHINE MACHINE

SEMI – AUTOMATIC
CAPSULE FILLING
MACHINE
 Hand Operated Capsule Filling Machine
The machine has the
Pharmacists following parts :-
that prepare • Capsule bed with 200-
capsules on a 300 holes
• Loading tray
regular or extensive
• Powder tray
basis may use hand
• Pin plate with 200-
operated capsule
300pins
machines. These
• Sealing plate with
machines are also rubber top
called Feton capsule • Lever
filling machine. • Cam handle
Working of Hand Operated Capsule Filling Machine
• Tighten the cam handle and placed lever in the
position. The machine is ready for capsule filling.
• Place the empty capsules onto the loading tray with the
body end of the capsules oriented downwards and the
cap oriented upwards.
• Placed the filled loading tray over the capsule bed.
• The cam handle is used to lock the body part of the
capsules at their place while of the cap of the capsule is
separated.
• Powder tray is placed in position, and the powder is
placed on to the surface. Using a spatula, spread the
powder uniformly to fill the bodies of the capsules.
Remove the excess powder.
• The pin plate is then lowered to press the filled powder.
Again raise the pin plate.
• Remove the powder tray after filling.
• The cap holding plate is then repositioned over the
body.
• The capsules are rejoined then by manual pressure.
• Remove the loading tray and collect the filled capsules.
 Semi Automatic Capsule Filling Machine

Semi automatic capsule filling machine are

employed when smaller batches sizes are
required. Production capacities can range from
6000 – 8000 capsules per hour. Semi automatic
capsule filling machines always require an
operator in attendance at all times of the
operation.
Semi automatic machines use the Auger
Filling Principle.
The machine has the
following parts :-
A. Capsule fill
B. Stirrer
C. Auger
D. Capsule body holder
E. Turn table
F. Capsule ring

• Peg ring
• Capsule hopper
• Turntables
• Rectifier
 Capsule ring

Auger

Peg Ring
Working of Semi Automatic Capsule Filling Machine
There are 3 stages of how the capsule filling
machine works :-
1. Orientation of capsule :- The capsule ring is
placed on a turntable under the Rectifier (they
orient the capsule in such a way that the body part
is oriented downwards and cap part is oriented
upwards). Empty capsule shells in the capsule
hopper are descended by the rectifier in to the
capsule ring. As the ring rotates on the turntable,
vacuum pulls the capsules bodies in to the lower
part of the capsule ring, leaving the caps behind in
the upper ring.
2. Powder filling of capsule :- After capsule
separation, the operator separates the rings of the
capsule ring and places the body ring on another
turntable that rotates beneath the foot of the powder
hopper. The auger in the hopper rotates to provide
constant downward flow of the formulation while
the filling ring rotates. The amount of formulation
delivered to the capsule bodies depends on the
dwell time of the bodies under the foot of the
hopper, i.e., the speed of rotation of the body ring.
3. Capsule Closing :- Upper and the lower holding
ring of the capsule ring is joined together and
positioned in front of the peg ring holding pins.
Pneumatic pressure is applied to the peg ring which
finally pushes the caps and the bodies together
inside the holes of the capsule ring. Filled capsules
are then removed from the capsule ring.
 Automatic Capsule Filling Machine
Automatic capsule filling machine are
designed and developed to fill hard gelatin
capsules with powders or pellets. It is an
extremely durable and reliable machine that fills
dosages to the highest accuracy. It can be
applicable to the widest range of capsules at all
sizes.
Automatic filling machines employ pistons,
or tamping pins that lightly compress the powder
into slugs, and eject the plugs into the empty
capsule bodies. Automatic machines use the
Dosing Disc Principle and Dosator Principle.
Working of a Automatic Capsule Filling Machine
Dosing disc Principle
• The dosing disc rotates continuously in a circular
manner. The stop plate closes the holes on the dosing
plate. The dosing disc rotates below the powder bed,
the material flows into each hole. The pins which are in
the station compress the powder to a controlled depth.
• The process of filling and compression continues till
reaching the last compressing pin, where the machine
ejects a compressed powder through the dosing plate
into the capsule.
• This is a continuous process and the production speed
will depend on the preset machine conditions.
Working of a Automatic Capsule Filling Machine
Dosator Principle

Diagram of a dosator or dosing tube system:

(A) compression force platen; (B) piston; (C) dosing tube; (D)
powder hopper; (E) plug ejection platen; (F) capsule body in
bush; and (G) powder plug
• A dosator machine has two segments :- powder bed on
one side while the empty capsule body on the opposite
side.
• As the dosing tube goes down, penetrates the powder
bed, powder enters the open end of the dosator.
• A plug is formed inside the dosing tube with a movable
piston that controls the dosing volume and applies a
force to form the plug.
• Dosage tube then moves up, takes a 180⁰ rotation, and
press powder plug into the capsule body to complete
capsule filling.
 Punch Method (Manual Filling)
To hand fill capsules, the pharmacist generally
uses the Punch Method.
• Ingredients are triturated an mixed. 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.
• The body of the capsule is held vertically and the open
end is pushed or punched into the powder until the capsule
is filled.
• The capsule is replaced to close the capsule.
• Each filled capsule is weighed after filling. Powder is
added and removed until the correct weight has been
placed in the capsule.
 All the capsule filling machines have the 4 steps
in common.
• Rectification of the empty capsule shell :- orientation of
the capsule – body oriented downwards and caps oriented
upwards.
• Separation of cap and body of empty capsule shell.
• Dosing of a fill material :- eg. Auger Principle, Dosing
disc Principle, Dosator fill principle, Punch Principle etc.
• Replacement of the caps over the body and Ejection of
the filled capsules.
 Famous companies manufacturing different
capsule filling machines :-
• Lilly and Parke – Davis
• Farmatic
• Hofliger and Karg
• Macofar
• mG2
• Osaka
• Perry
• Zanasi
 CAPSULE FINISHING

Filled capsules from the capsule equipment

require dusting or polishing operation before the
remaining operations of inspection, bottling, and
labeling are completed.
Dusting or polishing operations vary according
to the type of the filling equipment used, the type of
powder used for filling, and the individual
requirements for the finished appearance of the
completed capsules.
 Capsule Finishing Machines

PAN POLISHING
CLOTH DUSTING

BRUSHING
 Pan Polishing

Because of the unique design, especially

primary in the area of airflow, the Accela Cota
Tablet Coating Pan is used to dust and polish
capsules. A polyurethane or cheese cloth liner is
placed in the pan, and the liner is used to trap the
removed dust as well as impart a gloss to the
capsules.
 Cloth Dusting

In this method, the filled capsules are rubbed

with a cloth that may or may not be impregnated
with an inert oil. This procedure is a hand operation
and gives a shine to the capsules. Also it results in a
positive method for removal of resistant materials.
 Brushing

In this method, the filled capsules are fed

under rotating soft brushes, which serve to remove
the dust from the capsule shell. This operation must
be accomplished by application of vacuum for dust
removal.
Commercial Capsule Dust or Polish Equipments
There are mainly 3 commercial equipments :-
1. Rotosort :- is a mechanical sorting device that removes loose
powder, unfilled joined capsules, filled or unfilled capsule
bodies, and loose capsule caps. This machine can handle up
to 15000 capsules per hour
2. Erweka KEA :- is designed to handle the output from any
type of capsule filling machine. It moves the capsules
between soft plastic tassels against a perforated plastic sleeve,
under vacuum. Any residual powder is removed by the
vacuum.
3. PM60 :- the equipment has two units that may be used in the
finishing process of capsules, which may be used separately
or combined. A belt is available that presents capsules for
visual inspection, and it may include vacuum system that
removes the unfilled capsules. The machine has lamb wool
belts moving in opposite directions.
SPECIAL TECHNIQUES OF FORMULATION OF
HARD GELATIN CAPSULES

• Decreasing Solubility
• Formulating Incompatible Materials
• Filling of Semisolids
• Filling of Liquids
• HPMC Capsules
• Starch Capsules
• Cross Linked Dextran Capsules
 Decrease of Solubility
• Solubility is retarded in this technique of formulating a special
type capsule.
• Done in an attempt delay absorption of the active ingredient or to
provide enteric properties.
• Solubility is assured in two ways here:-
a) Water resistance – failure to dissolve in water in 15 mints at 20-
30℃.
b) Acid solubility – dissolve in less than 5 mints in 0.5% aq. HCl
at 36 - 80℃
• Two ways of formulating capsules with decreased solubility are :-
a) Formalin treatment :- exposure of the gelatin film to formalin
vapours decrease the solubility of gelatin due to the cross
linking of molecules in gelatin initiated by aldehyde.
b) Coating of the gelatin capsules with coating materials like
shellac, cellulose acetate phthallate etc., by usual pan coating
 Formulation of Incompatible Materials

• Formulation of Incompatible materials is carried out by the use of

a two phase fill in the capsule
• One phase :- consists of a soft capsule, or smaller hard capsule
or a pill that is filled into the capsule.
• Other phase :- powder fill is added in the usual manner.
• Changes should be made to the equipment for the machine
operation to allow the two filling.
 Filling of Semisolids
• Semisolids are melted to allow the filling of the
material in the capsules at ambient temperature.

Filling of Liquids
• Liquids in the form of thermosetting or thixotropic
mixture are filled in the capsule.
• Gelatin banding is required for the sealing of the
capsules to prevent leakage.
• Two bands of gelatin solution are applied around the
centre of the filled capsules and this then dried using
air ate ambient conditions.
 HPMC Capsules

• Developed as an alternative to hard gelatin capsules.

• Odourless and flexible, low moisture content, chemically
inert, stable under low moisture conditions.
• HPMC Capsules :- manufactured using 18-28% HPMC,
carrageenan (0.01 – 0,09% w/w) and potassium or calcium
ions (0.05-0.6% w/w)
• Carrageenan and potassium or calcium ions are used as co
gelling agents to facilitate the gelling of HPMC.
 Cross Linked Dextran Capsules

• Capsule shell are prepared by reacting dextran. Magnesium

chloride, glutaraldehyde, and polyethylene glycol 400 in
water.

Starch Capsules

• Capsule shell are prepared by starch obtained from potato.

• Dissolution is independent of pH.
• Usually used for manufacture of enteric coated capsules.
 QUALITY CONTROL TESTS OF HARD GELATIN
CAPSULE

• Weight variation test

• Content uniformity test
• Disintegration test
• Dissolution test
• Moisture permeation test
e.ta
l
h
g
il
rT
y
n
Weight Variation Test
eh
a
a
e9
t0
n
ed
%
ri
f-
tfi
h
e1n
a
r1d
n
e0
t
%
n
1ch
0
eo
%
f
a
b
o
etv
fth
e
er
w
tea
h
 If more than 2 but less than 6 of the individual
differences deviate from the requirements said before,
• Individual content weight, is determined for another 40
capsules.
• Average of 60 capsules content weight are taken.
• The difference of the individual content weight of the previous
20 capsules and the next 40 capsules are determined from the
new average content weight of 60 capsules.
• For the test to pass :-
a) Difference should not exceed 10% of the new average content
weight of 60 capsules for a minimum of 6 capsules.
b) when no capsule content weight is greater than 25%

• Rotoweigh and Vericap 1200 determines the

weight of individual capsules automatically and
also rejects the under filled or overfilled
capsules.
 Content Uniformity Test

• 30 capsules are selected, 10 of which are assayed as per

the procedure mentioned in the specific monograph.
• The requirements are met :-
a) If 9 out of 10 are in the range of 85 – 115% potency.
b) 10th capsule is not outside 75 – 125%.
• if more than 1 but less than 3 fall outside 85 – 115%,
then the rest of the 20 capsules are assayed.
• In that case, the test passes, when all the 30 capsules,
are within 75-125% potency, and not less than 27 of
the 30 capsules are within 85-115% potency.
 Disintegration Test
• Same apparatus as used in the evaluation of disintegration in
tablets.
• To test the disintegration time, one capsule is placed in each tube
of the basket assembly, and the basket rack is position in a
medium at 37℃. Perforated plastic discs are placed on top of the
capsules.
• The capsules complies with the test, if all the capsules
disintegrate, and all the particles pass through the mesh screen in
the specified time. If any residue remains, it must have only a soft
mass with no firm core.
• If 1 or 2 fails to disintegrate, the test is repeated with 12
additional tablets.
• According to the IP, hard shell capsules take only a maximum of
30 minutes to disintegrate.
 Dissolution Test
• Same apparatus as used in the evaluation of dissolution
in tablets.
• To test the dissolution or drug release from the capsule,
USP Apparatus II – the rotating paddle type is used
mainly.
• As the capsule comes in contact with the aqueous media
at 37℃, capsule shell absorb water and swell.
• The rate of water penetration is inversely proportional to
the thickness of the capsule shell. The shell ruptures at
the shoulder of the cap an the body part.
• Rate of gelatin solubility is dependent on the
temperature of the solution. As the temperature
decreases, the solubility of the gelatin decreases.
 Moisture Penetration Test

• Degree and rate of moisture penetration is determined

by packing the capsules together. Expose the packaged
unit to a known relative humidity over a specified time.
• The change in initial and final weight is determined.
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℃.
 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
 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
Disintegrati
uniformity
on 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

Type of Disintegrati
Temperature Limit
capsule on 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
Condition 2 :- 40℃ in an open
container
Condition 3 :- 40℃ in a closed
container (glass bottle with tight
screw cap)
The results show a change in :-
disintegration, leakage, unusual
brittleness or softening of the
capsule shell, loss of volatile
ingredients from the capsule,
widening of the corners of the
capsule etc.
• 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.