CAPSULES

Dr. Vishwajeet S. Ghorpade

(M. Pharm., Ph.D.)
 CAPSULES
• Definition: Capsules are solid dosage forms in
which the drug or a mixture of drugs with or
without excipients is enclosed in Hard or Soft
Gelatin Capsule Shells, or in hard or soft shells of
any other suitable material, of various shapes and
capacities.
 Capsules
Advantages:
• The drugs having unpleasant odour and taste can be
administered.
• They are smooth, become very slippery when moist
and can be easily swallowed.
• They are economical
• They are easy to handle and carry.
• The capsules release the medicament as and when
desired in gastro-intestinal tract.
 Capsules
Advantages:
• Capsules are made from gelatin and hence they are
therapeutically inert.
• Capsule have elegant appearance so that it enhance
patient acceptance.
• The drug in the form of solid, liquid & viscous form
can be encapsulated in capsule shell.
• Capsule formulation provide better stability of drug as
compare to uncoated tablet & liquid dosage form
 Capsules
Disadvantages:
• Capsule are not usually used for administration of extremely soluble
materials such as potassium chloride, potassium bromide etc. since there
is sudden release of such compound in stomach & causes irritation.
• Capsule should not used for highly efflorescent material as material may
cause the capsule to soften by losing water molecule to shell.
• Capsule should not used for highly deliquescent powder as powder have
tendency to absorb moisture from capsule shell & make it brittle.
• The capsule shells can absorb water from the environment and develop
problems with drug stability and capsule shell can become tacky
 Gelatin
• Gelatin is a heterogeneous product derived by
irreversible hydrolytic extraction of treated animal
collagen.
• Main source of collagen: Animal bones and frozen pork
skin.
• Types of gelatin:
– Type A Gelatin: It is derived from the acid treated precursor
and exhibit isoelectric point in region of pH 9.
– Type B Gelatin: It is derived from an alkali treated precursor
& exhibit isoelectric point in region of pH 4
Process of Manufacturing Gelatin
 Types of Capsules
• Hard gelatin capsule (HGC)
• Soft gelatin capsule (SGC)
 Hard Gelatin Capsules
• It consists of cap and body.
• Medicament, with or without excipients are
enclosed in it.
• All the enclosed components must be dry.
 Production of Hard Gelatin Capsule
Shells
• Preparation of gelatin solution
• Dipping
• Spinning
• Drying
• Stripping & Trimming
• Joining
 Production of Hard Gelatin Capsule
Shells
• Preparation of gelatin solution
– A concentrated solution of gelatin (35- 40%) is prepared
by dissolving the gelatin in demineralized water which
has been heated to 60–70°C in jacketed pressure
vessels.
– This is stirred until the gelatin has dissolved.
– Vacuum is applied to removed entrapped air bubbles.
– At this stage, other processing aids may be added like
plasticizer, colourant, opaquing agent etc.
 Production of Hard Gelatin Capsule
Shells
• Dipping
– Capsule shells are manufactured under strict climatic
conditions by dipping pairs (body and cap) of
standardized steel pins arranged in rows on metal bars
into an aqueous gelatin solution (25 – 30% w/w)
maintained at about 50 ° C in a jacketed heating pan.
 Production of Hard Gelatin Capsule
Shells
• Spinning
– After adsorption of the gelatin solution on to the surface of
the pins, the bar containing the pins is rotated more times
to evenly distribute the gelatin solution around the pins
• Drying
– Once the gelatin is evenly distributed on the mould, a
blast of cool air is used to set the gelatin on the mould. At
this point, the gelatin is dried, and the pins are then
passed through several drying stages to achieve the
target moisture content
 Production of Hard Gelatin Capsule
Shells
• Stripping & Trimming
– After the gelatin is dried, the capsule is stripped off the
mould and trimmed to the proper length
• Joining
– Once trimmed, the two halves (the cap and body) are
joined to the pre-closed position using a pre lock
mechanism. At this point, printing is done if needed
before packing in cartons for shipping

[Link]
Production of Hard Gelatin Capsule
Shells
Size of Hard Gelatin Capsule Shells
Size of Hard Gelatin Capsule Shells
 Filling of Hard Gelatin Capsule Shells
• Rectification
– The empty capsule are oriented so that all point the same
direction, i.e body end downward.
• Separation of cap from bodies
– A vacuum applied below pull the bodies down into the lower
portion
• Dosing of fill material
– Various method like Auger principle, vibratory fill principle,
piston- Tamp principle are employed
• Replacement of cap and ejection of filled capsule
[Link]
 Filling Principles
• Auger fill principle
Rotation of
Capsule
lower ring and
Rectifying unit filling with
auger drive
Filling rings
Joining of cap
Filling ring separation and body
(Upper ring-Cap,
Lower ring- Body
[Link]
 Filling Principles
• Auger fill principle
 Filling Principles
• Vibratory fill principle
– A perforated resin plate ( connected to vibrator) is
placed in feed hooper.
– Due to vibration of resin plate the powder flows freely
through the pores into the capsule bodies.
 Filling Principles
• Vibratory fill principle
 Filling Principles
• Piston-tamp principle
– Automatic capsule filling machines work on piston-Tamp
principle by using piston or Tamping pins.
– The piston tamps alter the shape of powder by compressing
the powder to form plugs (slugs).These plugs are transferred
into empty capsule shell with the application of little pressure.
– This piston pump principle can be explained by two type of
machine
i) Dosing-disc type machine
ii) Dosator type machine
 Filling Principles
• Piston-tamp principle

[Link]

Dosing-disc type machine

 Filling Principles
• Piston-tamp principle

Dosator type machine

 Filling Principles
• Vacuum fill principle
 Capsule filling methods
• Manual filling
• Hand filling machine
• Semi-automatic machine
• Fully automatic capsule filling machine
 Capsule filling methods
Hand filling machine
• Bed (200-300 holes)
• Loading tray
• Pin Plate
• Sealing plate
• Lever
• Cam

[Link]
 Capsule filling methods
Semi-automatic machine
3 stations
• Orientation of capsule
• Powder filling
• Capsule closing

[Link]
 Capsule filling methods
Fully automatic capsule filling machine
2 types of machines
• Dosing disc machine
• Dosator machine
-Compression force for plug formation: 50-150N
(less than tablet compression force)
 Finishing of capsule
• Cloth dusting
• Polishing (Pan lined with polyurethane cloth)
• Brushing (Soft rotating brushes)
 Special techniques of formulation of
HGCs
• Imprinting

• Decreasing solubility of gelatin capsule

– Formalin treatment
– Coating with salol,shellac,cellulose acetate phthalate
 Special techniques of formulation of
HGCs
• Separation of incompatible material

• Filling liquid or semi-solids

– Melting and filling
– Shear during filling causes melting followed by increase
in viscosity in absence of shear
Manufacturing defects in HGCs (Capsule shell
production)
Manufacturing defects in HGCs (Capsule shell
production)
Manufacturing defects in HGCs (Capsule shell
production)
Manufacturing defects in HGCs (Capsule shell
production)
Manufacturing defects in HGCs (Capsule filling)
Manufacturing defects in HGCs (Capsule filling)
Manufacturing defects in HGCs (Capsule filling)
 IPQC
• % purity of gelatin
• Viscosity of gelatin solution: 25-45 millipoise
• Bloom strength of gelatin solution: 150-250 gm
• Iron content: NMT 15 ppm
• Film Thickness
• Color, surface, appearance of empty shells
• Temperature of hot air, for drying of shells
• Length of Capsule & Body of the shell
• Moisture content: 12-15%
• Inspection of defects
 FPQC
• Appearance
– Uniform
– No defects
• Size and shape
• Unique identification marking
 FPQC
• Uniformity of weight

W1 –W2 = Wt. of content

 FPQC
• Uniformity of weight
– Repeat for 19 more capsules

• Uniformity of content
– Test is applicable to capsules that contain less than 10
mg or less than 10 per cent w/w of active ingredient
– Randomly select 10 capsules
 FPQC
• Uniformity of content
– Test is applicable to capsules that contain less than 10
mg or less than 10 per cent w/w of active ingredient
– Randomly select 10 capsules
– Determine content of API (Analytical techniques)
– The capsules comply with the test if:
• NMT one value is outside 85 - 115%
• None is outside 75 – 125%
 FPQC
• Uniformity of content
– The capsules comply with the test if:
• NMT one value is outside 85 - 115%
• None is outside 75 – 125%
– If 2 or 3 values are outside 85 - 115%, repeat the test
for another 20 capsules:
• NMT three values are outside 85 - 115%
• None is outside 75 – 125%
 FPQC
• Disintegration
– For those Hard Capsules and Soft Capsules for which the
dissolution test is included in the individual monograph, the
test for Disintegration test is not required.
– Unless otherwise directed in the individual monograph use
water as the medium and add a disc to each tube.
• HGC: 30 min
• SGC: 60 min
– For enteric coated capsules
• 2 hours without the discs in 0.1 M hydrochloric acid: No disintegration
• 1 hour with disc in mixed phosphate buffer pH 6.8
 FPQC
• Dissolution test

The quantity Q, is the specified amount of dissolved active

substance, expressed as a percentage of the labelled content.
 Soft Gelatin Capsules
• Soft gelatin capsules are one piece , hermetically
sealed, and are made up of gelatin in which
glycerin or polyhydric alcohol (sorbitol) are added,
containing liquid , suspension or semisolid
enclosed in it.
 Soft Gelatin Capsules
• Advantages
– Protect the inner fill from oxidation and degradation
– Protect the inner fill from UV radiation
– Enhance patient compliance
– Suitable for medicaments like semisolid, oils, liquid
forms
– Increase the bioavailability of API
 Soft Gelatin Capsules
• Disadvantages
– Few filling equipment are available
– Manufacturing is expensive
– Drugs from oily vehicle may pass into the shell
– Difficulties in dealing with water soluble materials.
– Highly sensitive to moisture.
– Difficulties in dealing with efflorescent materials.
– Difficulties in dealing with deliquescent material
 Soft Gelatin Capsules
• Shape of SGCs
 Soft Gelatin Capsules
• Chloramphenicol Eye Ointment
 Nature of Soft Gelatin Capsules
• Composition:
– Gelatin
– Plasticizer
– Water
– Preservative
– Colouring agent
– Opacifying agent,
– Flavor
– Sweetening agent
 Nature of Soft Gelatin Capsules
• Bloom strength:
– It is a measure of cohesive strength of cross linking that
occurs between gelatin molecule and is proportional to
the molecular weight of gelatin.
– Bloom is determined by measuring the weight in gram
required to move a plastic plunger that is 0.5 inches in
diameter 4mm into a 6.66 %w/v gelatin gel that has
been held at 10oC for 17 hours.
– Bloom may vary from 150-250g.
 Nature of Soft Gelatin Capsules
• Bloom strength:
 Nature of Soft Gelatin Capsules
• Viscosity:
– Viscosity of 6.66 %w/v gelatin solution in water: 25-45
mP.
• Iron content
– NMT 15 ppm
 Nature of Soft Gelatin Capsules
Typical shell Hardness ratios and their uses
 Capsule content
• Content may be liquid, or a combination of miscible
liquids, Solution of a solid(s) in a liquid(s) or
Suspension of a solid(s) in a liquid.
• It can be a liquid like a volatile oil composition E.g.
Vegetable oils like arachis oil or aromatic or aliphatic
hydrocarbons, ethers, esters, or alcohols.
• Solids that are not sufficiently soluble in liquids or in
combination of liquids are capsulated as Suspension.
Suspending agents used are Lecithin, Soyabean oil
 Capsule content
• Liquid that are both water miscible & volatile cannot be
included as major constituent.
• Gelatin plasticizer such as glycerin and propylene glycol
cannot be major constituent of capsule content owing to
their softening effect
• Preparation for encapsulation should have a pH between 2.5
and 7.5
– Acidic pH: Hydrolysis & leakage
– Alkaline pH: Tanning and affect solubility of gelatin
• The maximum capsule size and shape for convenient oral
use in human is the 20 minim oblong, the 16 minim oval, 9
minim round
 Formulation of filling material of SGC
• Filling materials are selected considering following
criteria:
– Compatibility with capsule shell
– Ability to dissolve the drug
– Rate of dispersion in the GI fluid after shell
disintegration in the GIT
– Ability to optimize the bioavailability of drug
 Formulation of filling material of SGC
• Types of filling material/bases:
– Hydrophilic Liquids: PEG 400 having high MW
– Lipophilic liquid: Soya bean oil (for steroid, vitamin D)
– Microemulsion system: Oil-surfactant-water system
– Emulsifying oil: Mixture of pharmaceutical oil & non
ionic surfactant like polyoxyethylene sorbitan mono-
oleate
– Suspension: Insoluble drugs.
 Formulation of filling material of SGC
• Base Adsorption
– Essential to determine minimum capsule size
– Expressed as the number of gram of liquid base
required to produce a capsulatable mixture when mixed
with one gram of solid
– The Base adsorption of solid influenced by
• Particle size & shape
• Its physical state (amorphous or crystalline)
• Density, moisture content, its oleophilic & hydrophilic nature
 Formulation of filling material of SGC
• Determination of Base adsorption
– Weigh a definite amount( 40 g is convenient) of solid into 150 ml
tared beaker. In a separate 150ml tared beaker , place about 100g
of the liquid base. Add small increment of base to the solid and
using the spatula ,stir the base into the solid after each addition
until the solid is completely wetted & uniformly coated with base.
– This should produce a mixture that has a soft ointment like
consistency.
– Continue to add liquid and stir until the mixture flows steadily from
the spatula blade when held at a 45o angle above the mixture.
Base adsorption = weight of base/weight of solid
 Formulation of filling material of SGC
• Minim per gram factor(M/g):
– The minim per gram factor is the volume in minims that is
occupied by one gram of the solid plus the weight of the liquid
base (BA) required to make capsulatable mixture.
– The minim per gram factor is calculated by dividing the
weight of the base plus the gram of solid base (BA+S) by the
weight of the mixture (W) per cubic centimeter or 16.23
minims (V).
(BA+S) x V/W = M/g
– Thus lower the base adsorption of the solids and higher the
density of the mixture, the smaller the capsule will be
 Manufacture of SGC
• Plate process
• Rotary die process
• Reciprocating die process
• Accogel capsule filling machine
 Plate process
• Place the gelatin sheet over a die plate containing
numerous die pockets.
• Apply 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.
Plate process
 Rotary die process

[Link] [Link]
 Reciprocating die process
• This machine produces capsule completely
automatically by leading two films of gelatin
between a set of vertical dies.
• Rows after rows of pockets are formed across the
gelatin film, filled with medicaments and as they
process through the dies, are sealed, shaped and
cut out of the film as capsules which drop into a
cooled solvent bath
 Accogel capsule filling machine
Three parts:
• Measuring roll
• Die roll
• Sealing roll
 In-process QC testing
• 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.
• For the determination of the fill weight each capsule
is weighed and the contents removed by cutting open
the capsule. The shell is then washed with petroleum
ether, and the empty shell is reweighed
 Finished Product QC testing
• Test parameter almost same as hard capsule.
 Special testing for SGCs
• Seal thickness: Measured under a microscope and it
should one half to two third of the ribbon thickness.
• Total or shell moisture test: Moisture content is
determined by the toluene distillation method.
Collecting the distillate over a period of one hour.
• Capsule fragility or rupture test: Force required to
rupture the capsule is determined.
• Determination of freezing and high temperature
effect: (>45oC for 30 days)
 Packaging & storage of SGCs
• 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.
• Now-a-days capsules are strip packaged which provide
sanitary handling of medicines, ease in counting and
identification
 Packaging & storage of SGCs
• Plastic bottle with screw cap (most popular package
in USA).
• Clam shell blister (one-piece plastic that folds over
and locks itself; no heating required.
• Blister pack (heat sealed blister on a cardboard).
• Plastic pail/bucket (economical bulk package).
• Plastic pouch zip locked (for sale via retail stores or
route trucks must be packed in outer case for
shipping).
Packaging & storage of SGCs
 Stability Testing of Soft Gelatin
Capsules
Moisture Permeation Test:
The degree and rate of moisture penetration are
determined by packaging the dosage unit together
with color-revealing desiccant pellet, exposing the
packaged unit to known relative humidity over a
specified time interval, observing the desiccant
pellet for colour change (indicating the absorption of
moisture), and comparing the pretest and posttest
weight of the packaged unit.
 Stability Testing of Soft Gelatin
Capsules
Physical Stability:
• The successful results are obtained by conducing at test conditions
like
(a) 80% RH at room temperature in an open container
(b) 400°C in open container
(c) 400°C in closed container.
• Prior to testing, the capsule should be equilibrated to known
humidity at many conditions, preferably 20 - 30% RH at 21 - 24°C.
• Evaluation of the results of the previously described heat test
should be made only after the capsules have returned to
equilibrium to room temperature.
 Stability Testing of Soft Gelatin
Capsules
Physical Stability:
 Applications of Soft Gelatin Capsules
Physical Stability:
• The successful results are obtained by conducing at test conditions
like
(a) 80% RH at room temperature in an open container
(b) 400°C in open container
(c) 400°C in closed container.
• Prior to testing, the capsule should be equilibrated to known
humidity at many conditions, preferably 20 - 30% RH at 21 - 24°C.
• Evaluation of the results of the previously described heat test
should be made only after the capsules have returned to
equilibrium to room temperature.