CAPSULE

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 Outline
 Introduction
 Empty hard gelatin capsules
 Raw materials
 Manufacturing
 Filled hard gelatin capsules
 Formulation
 Filling and equipment and QC
 Soft gelatin capsules
 Description of the soft gel
 Formulation, manufacturing

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 Introduction
 Capsules are solid dosage forms in which medicinal agents and/or

inert substances are enclosed in a small shell of gelatin.

 Gelatin capsule shells may be hard or soft, depending on their

composition.
 The shells may be composed of two pieces, a body and a cap, or

they may be composed of a single piece.

 Two-piece capsules are commonly referred to as

 hard-shell capsules, and

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 Cont,…
 One-piece capsules are often referred to as

 soft-shell capsules.

 Most filled capsules are intended to be swallowed whole.

 However, it is fairly common in hospitals and extended care

facilities for a caregiver to open capsules or crush tablets to

mix with food or drink, especially for children or other
patients unable to swallow solid dosage forms.

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 Advantages of capsule
 The use of capsules avoids many unit operations

 Rapid drug release possible

 Flexibility of formulation

 The stability of therapeutic agents may be improved in a

capsule formulation
 Elegant appearance and shape, easy to swallow

 Minimum excipients are required

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 Disadvantages of capsule
 Very bulky materials are a problem.

 Filling equipment slower than tableting.

 Concern over maintaining proper shell moisture content.

 Shell should have moisture content of 13-16%.

 Not suitable for highly soluble substances like potassium

chloride.
 Not suitable for highly deliquescent materials.

 Special conditions are required for storage.

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 Raw materials
 Gelatin

 Water

 Colourants

 Optional materials

 Preservatives

 Wetting agent

 Recent years hard capsules have been manufactured also

from hydroxypropyl methylcellulose (HPMC).

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 Cont,…
 Gelatin

 Gelatin was the first material used for the manufacture of

capsules because of its unique properties.

 Is obtained by the partial hydrolysis of collagen, a natural

protein, obtained from the skin, white connective tissue, and

bones of animals.
 It is insoluble in water

 Commercially, it is available in the form of a fine powder, a

coarse powder.
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 Gelatin is stable in air when dry but is subject to microbial

decomposition when it becomes moist.

 if stored in an environment of high humidity, additional

moisture is absorbed by the capsules.

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 Cont,…

Skins collagen Type A gelatin

Acid hydrolysis

Bovine bones Type B gelatin

Basic hydrolysis

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 Cont,…
extracted from the
 After hydrolysis
treated material
using hot water
Extraction
The resulting weak solution of
gelatin is concentrated in a
Evaporation series of evaporators

Cooling Then chilled to form

a gel

Drying The gel is then dried in a

fluidized-bed system
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 Cont,…
 Limitation of gelatin

 There are certain religious or dietary restrictions on its use.

 Bovine spongi form encephalopathy

 Gelatin Alternative Materials

 hydroxypropyl methylcellulose (HPMC )

 Moisture content is much lower

 Colorants

 Commonly, various soluble synthetic dyes (“coal tar dyes”)

and insoluble pigments are used.

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 Cont,…
 Opaquing Agents

 Titanium dioxide may be included to render the shell opaque

 Preservatives

 When preservatives are employed, parabens are often

selected
 Process aids

 Sodium lauryl sulphate as a wetting agent and to ensure

uniformly covering moulds by gelatin.

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 Capsule shell manufacture

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 Cont,…

Gelatin Solution Dipping Rotation

Drying

Joining Trimming Stripping

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 Cont,…

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Gelatin Solution
Raw gelatin and water are mixed
in the ratio of 1 : 2 and processed
at precise temperature

Dipping

Pairs of stainless steel pins are dipped

into the dipping solution to
simultaneously form the caps and
bodies.
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 Cont,…

While raising, they are rotated

Rotation for required distribution of
gelatin on the pins.

Drying
Drying is done mainly be dehumidification by
passing large volumes of dry air over the pins.
Only a temperature elevation a few degrees is
permissible to prevent film melting
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 Cont,…

strippers remove the dried halves of

Stripping
capsules from the pins and place them
into the collets for further operations

Caps and body halves are trimmed to

Trimming narrow tolerance as per standards .The
cutting are vacuumed away and
collected in separate drums
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 Cont,…

Joining The capsule halves move to the

centre of the machine and enter the
joiner blocks. Joined capsules are
then pushed on to the conveyor belt

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 Cont,…
Capsule quality is monitored
throughout the production
process including size, moisture
content, single wall thickness,
and color.

Capsules are sorted and visually

inspected on specially designed
Inspection Stations
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 Cont,…

Perfect capsules are imprinted with the client logo on high-

speed.
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 Empty capsule properties
 Empty capsule contain a significant amount of water that acts

as plasticizer for the gelatin film and is essential for their

function.
 The standard moisture content specification of HGC is
between 13% to 16% w/w.
 Gelatin capsules are readily soluble in water at 37 °C.

 Capsules made from hypromellose have a different solubility

profile, being soluble at temperatures as low as 10 °C.

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 Formulation of Capsules
 The development of a capsule formulation follows the same

principles as that of tablet.

 Excipients are similar to those required for formulation of

tablets
 include diluents, disintegrants, surfactants, glidants, lubricants,

and dyes or colorants.

 The capsule fill can comprise simple blends of powders, or

granules/pellets/tablets.

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 Cont,…
 A diluent or filler may be added to the formulation to produce

the proper capsule fill volume.

 E.g. Lactose, microcrystalline cellulose, and starch are
commonly used for this purpose.
 Disintegrants are frequently included in a capsule formulation

to assist the breakup and distribution of the capsule’s contents

in the stomach.
 Among the disintegrants used are pregelatinized starch,

croscarmellose, and sodium starch glycolate.

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 Cont,…
 In preparing capsules on an industrial scale using high-speed

automated equipment, the powder mix or granules must be

free-flowing to allow steady passage of the capsule fill from
the hopper into the capsule shells.
 Thus, the addition of a lubricant or glidant such as Silicon

dioxide, Magnesium stearate, or talc (about 0.25% to 1%) to

the powder mix is important in order to enhance flow
properties.

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 Capsule filling
 Capsule filling capacity

Size Volume Fill weight(g)

(ml)
000 1.37 1.096
00 0.95 0.760
0 0.68 0.544
1 0.50 0.400
2 0.37 0.296
3 0.30 0.240 5 4 3 2 1 0 00
4 0.21 0.168

5 0.13 0.104

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 Cont,…

 The fill capacity of a hard capsule is dependent on

 physical size of the capsule,

 type of formulation,

 dosing mechanism on the filling device

 Fill weight = Body volume x Tapped bulk density

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 Cont,…
 Types of material for filling in to hard gelatin capsules

Dry solids Semisolids Liquids

Powders Thermo softening Oily liquids

Pellet mixtures Non- aqueous
Granules Thixotropic mixtures liquids
Tablets Pastes

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 Cont,…

Ingredient A Ingredient B Ingredient c

Packaging
Powder
blend
Empty Mixing
capsules

Capsule filler Capsule capsule inspection

Machine cleaner/deduster screen

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 Cont,…
Rectification

Capsule separation

Filling

Closure of the capsule

Ejection of the filled and closed

capsule from the machine

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 Filling principles/methods:

 Auger Principles: semi-automatic operation

 Filling based on volume

 Need good powder flow properties

 Dosator: filling based on weight

 Continuous operation

 Dosing disc: filled based on weight

 Continuous operation

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 Capsule filling machines
 The same set of basic operations is performed whether

capsules are being filled on the bench for extemporaneous

dispensing or on high-speed automatic machines for industrial
products.
 The major difference between the many methods available is

 the way in which the dose of material is measured into the

capsule body.
 Empty capsules are fed into the holes, either manually or with a

simple loading device.

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 Filling of capsules with solid formulations
 Bench-scale filling

 There is a requirement for filling small quantities of capsules,

from 50 to 10000, in hospital pharmacies or in industry for

special prescriptions or trials.
 There are several simple pieces of equipment available, e.g. the

Feton filling machine,

 which consists of sets of plastic plates with predrilled holes to

take either 30 or 100 capsules of a specific size.

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 Industrial-scale filling

 The machines for the industrial-scale filling of hard capsules come

 in great variety of shapes and sizes, ranging from semiautomatic

to fully automatic and ranging in output from 3000 to 150 000 per
hour.
 Automatic machines can be either continuous in motion, like a

rotary tablet press, or intermittent in motion,

 where the machine stops to perform a function and then indexes

round to the next position to repeat the operation on a further set of

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 Cont,…

Filling machine

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 Filling of capsules with semisolids and liquids
 Liquids can easily be dosed into capsules by volumetric

pumps.
 The problem after filling is to stop leakage from the closed

capsule.
 This can be done in one of two ways, either by formulation or

by sealing of the capsule.

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 Cont,…

 Semisolid mixtures are formulations that are solid at ambient

temperatures and can be liquefied for filling by either heating

(thermosoftening mixtures) or stirring (thixotropic mixtures).

 After filling, they cool and solidify or revert to their resting state in

the capsule to form a solid plug.

 Capsules are filled with both types of formulations as liquids with

use of volumetric pumps.

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 Cleaning and polishing capsules
 Powder may adhere to the outside of capsules after filling.

 Removing powder from the capsules that may be bitter or

unpalatable before packaging

 On small scale, cleaned by rubbing them with a clean gauze or

cloth using small amount of paraffin

 On large scale, a cleaning vacuum affixed with filling

machines removes any powder from the capsules

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 Inspecting, counting and packaging capsules
 Visual or electronic inspection should be undertaken to

detect any defects in the integrity and appearance of the

capsules.
 Defective capsules should be rejected.

 After inspection blistered or placed into containers.

 Blisters: appearance, sealing, and leak test should be

considered.

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 Soft gelatin capsules
 Soft gelatin capsules' is commonly abbreviated to 'softgels’.

 It is becoming more difficult to formulate poorly water-soluble

drugs into products from which the drug is fully released and
well absorbed.
 One of the best methods to overcome this problem is to make a

liquid formulation containing the drug.

 In order to convert this liquid formula into a solid dosage form,

it may be encapsulated into soft gelatin capsules.

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 Cont,…
 Soft capsules are a single-unit solid dosage form consisting of a

liquid or semi-solid fill enveloped by a one-piece hermetically

sealed elastic outer shell.
 The drug compound itself may be either in solution or in

suspension in the capsule-fill matrix.

 The characteristics of the fill matrix may be hydrophilic (for

example polyethylene glycols) or lipophilic (such as

triglyceride vegetable oils).

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 Cont,…

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 Soft capsules formulation

 The softgel capsule shell consists of :

 Gelatin, Water and Plasticizer

 It may be transparent and can be coloured and flavoured if

desired.
 Preservatives are not required owing to the low water activity

in the finished product.

 The softgel can be coated with gastric-resistant or delayed-

release material.

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 Soft capsules manufacture
 There are two sub processes that are often carried out

simultaneously, yielding the two components of a softgel.

 These are:

 gel mass which will provide the softgel shell

 fill matrix for the contents

 Typical softgel shells are made up of gelatin, a plasticizer

and (colourants and/or opacifiers) and sometimes flavours.

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 Plasticizers

 Used to make the softgel shell elastic and pliable.

 Account for 20-30% of the wet gel formulation.

 The most common plasticizer used in softgels is 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.

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 Cont,…

 Colourants/opacifiers

 Used at low concentrations in the wet gel formulation.

 An opacifier, usually titanium dioxide, may be added to

produce an opaque shell when the fill formulation is a

suspension, or
 to prevent photodegradation of light-sensitive fill ingredients.

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 Formulation of softgel fill materials
 The choice of components is made according to one or more of

a number of criteria, including the following:

 Capacity to dissolve the drug

 Rate of dispersion in the gastrointestinal tract after the softgel

shell ruptures and releases the fill matrix

 Capacity to retain the drug in solution in the gastrointestinal

fluid
 Compatibility with the softgel shell

 Ability to optimize the rate, extent and consistency of drug

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absorbed.
 Types of softgel fill matrices

 Lipophilic liquids/oils

 Hydrophilic liquids

 Self-emulsifying oils

 Microemulsion and nanoemulsion systems

 Suspensions

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 Soft capsule manufacturing
 Soft capsule manufactured by four methods:

 Plate process

 Rotary die process

 Reciprocating die

 Accogel machine

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 Cont,..
 Plate process

 Place the gelatin sheet over a die plate containing numerous die

pockets (a set of molds).

 Application of vacuum to draw the sheet into 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.
 The capsules are removed and washed with a solvent harmless

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 Cont,..
 Rotary Die Process

 The material to be encapsulated flows by gravity

 Uses rolls containing small orifice lined up with the die pocket (set

of molds)
 Two plasticized gelatin ribbons are simultaneously fed with liquid or

paste fill between the rollers of the rotary die where the capsules 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 - 40°C) of the ribbons by the wedge.
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Rotary die process

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 Reciprocating die process

 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 the capsules are cut from the ribbons, they fall into

refrigerated tanks that prevent the capsules from adhering to

one another.

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 Cont,..
 Accogel process

 The process involves a measuring roll that holds the fill

formulation in its cavities under the vacuum.

 The ribbon is drawn into the capsule cavities of the

capsule die roll by vacuum.

 The measuring rolls empty the fill material into the capsule-shaped gelatin

cavities on the die roll.

 The die roll then converges with the rotating sealing roll covered with

another sheet of elasticized gelatin and creates pressure to seal and cut the

formed capsules.
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 Hard gelatin vs soft gelatin capsules

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 Quality control of soft gelatin capsules
 Similar to hard gelatin capsules, soft gelatin capsules
subjected to following tests:
 Shape and size
 Color
 Thickness of capsule shell
 Leaking test for semi-solid and liquid ingredients from
soft capsules
 Disintegration
 Weight variation

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 Reading Assignments
 Quality evaluation of capsules

 Bloom strength of gelatin

 general appearance,

 thickness, hardness

 Moisture permeation

 weight variation, content uniformity.

 disintegration time, dissolution test

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 Quiz
1. What are the advantages of soft gelatin capsules that hard
gelatin capsules do not have ?

2. Explain the method of manufacturing of soft gelatin capsule by

plate process ?

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 Quiz
1. What are the advantages of soft gelatin capsules that hard
gelatin capsules do not have ?

2. Explain the method of manufacturing of soft gelatin

capsule by rotary die process ?

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