Capsules are solid dosage forms in which one or

more medicinal and/or inert substances are

enclosed within a small shell or container

generally prepared from a suitable form of

gelatin.

Depending upon their formulation, the gelatin

capsule shells may be hard or soft.

Hard Gelatin CapsulesHard Gelatin CapsulesThe hard gelatin The hard gelatin

capsule consists of a capsule consists of a

base or body and a base or body and a

shorter cap, which fits shorter cap, which fits

firmly over the base of firmly over the base of

the capsulethe capsule. .

Hard Gelatin CapsulesHard Gelatin Capsules

1. Mask the unpleasant tastes of a drug. 1. Mask the unpleasant tastes of a drug.

2. Allow powders to be dispensed in an uncompressed 2. Allow powders to be dispensed in an uncompressed

form, thus allowing for quicker dissolution and form, thus allowing for quicker dissolution and

absorption of the drug following oral dosingabsorption of the drug following oral dosing

3. Have the flexibility which permit a wide prescribing 3. Have the flexibility which permit a wide prescribing

opportunity by the physician in that the pharmacist opportunity by the physician in that the pharmacist

may prepare capsules containing a single chemical may prepare capsules containing a single chemical

substance or a combination of drugs at the substance or a combination of drugs at the

accurate dosage level for the individual patient. accurate dosage level for the individual patient.

4. Be easier than tablets for some people to swallow.4. Be easier than tablets for some people to swallow.

5. Can alter the release rate of the drug. 5. Can alter the release rate of the drug.

Advantage of Hard gelatin capsulesAdvantage of Hard gelatin capsules

DisadvantagesDisadvantages or limitations include the or limitations include the

followingfollowing: :

1.1. They are subject to the effects of relative humidity They are subject to the effects of relative humidity

and to microbial contaminationand to microbial contamination. .

2. They may be difficult for some people to swallow2. They may be difficult for some people to swallow. .

3. More expensive (commercially)3. More expensive (commercially). .

Opaque capsules may be prepared by adding an Opaque capsules may be prepared by adding an

insoluble substance as titanium dioxide to the gelatin insoluble substance as titanium dioxide to the gelatin

mixture. Colored, opaque capsules may be prepared mixture. Colored, opaque capsules may be prepared

by using both a colorant and the opaque-producing by using both a colorant and the opaque-producing

substance.substance.

Gelatin, NF, is a product obtained by partial Gelatin, NF, is a product obtained by partial

hydrolysis of collagen obtained from the skin, white hydrolysis of collagen obtained from the skin, white

connective tissue, and bones of animals.connective tissue, and bones of animals.

It is found in commerce in the form of a fine powder, It is found in commerce in the form of a fine powder,

a coarse powder, shreds, flakes, or sheets a coarse powder, shreds, flakes, or sheets

The basic empty capsule The basic empty capsule

shells are made from a mixture of shells are made from a mixture of

gelatin, sugar, and water and are gelatin, sugar, and water and are

clear, colorless, and essentially clear, colorless, and essentially

tasteless.tasteless.

Colorants may be used to prepare Colorants may be used to prepare

distinctive capsules.distinctive capsules.

depending upon the environmental conditions, depending upon the environmental conditions,

in high humidity, capsules absorb moisture and in high humidity, capsules absorb moisture and

become distorted and lose their rigid shape. become distorted and lose their rigid shape.

but in extreme dryness, some of the moisture but in extreme dryness, some of the moisture

normally present in the gelatin capsules may be normally present in the gelatin capsules may be

lost, and the capsules become brittle and lost, and the capsules become brittle and

crumble.crumble.

Thus capsules should be stored in areas of low Thus capsules should be stored in areas of low

humidity.humidity.

Normally, hard gelatin capsules Normally, hard gelatin capsules

contain between 13 and 16% of contain between 13 and 16% of

moisture.moisture.

moisture may be absorbed or moisture may be absorbed or

released by gelatin capsules, released by gelatin capsules,

Gelatin is insoluble in cold water but soluble in Gelatin is insoluble in cold water but soluble in

hot water, and in gastric fluid where a gelatin hot water, and in gastric fluid where a gelatin

capsule rapidly releases its contents. capsule rapidly releases its contents.

Gelatin, being a protein, is digested and Gelatin, being a protein, is digested and

absorbed.absorbed.

Hard gelatin capsule shells are manufactured

mechanical dipping of manganese bronze pins of the

desired shape and diameter to the desired depth and

time into a reservoir of the melted gelatin mixture,

maintained at a constant temperature to achieve the

desired degree of fluidity.

Then the plate and the pins slowly lifted from the

gelatin bath and gently dried by a flow of

temperature and humidity controlled air

Capsule SizesCapsule SizesEmpty gelatin capsules are manufactured in Empty gelatin capsules are manufactured in

various sizes, varying in length, in diameter, and various sizes, varying in length, in diameter, and

capacity.capacity.

For human use, empty capsules ranging in size For human use, empty capsules ranging in size

from 000 the largest, to 5 the smallest are from 000 the largest, to 5 the smallest are

commercially available.commercially available.

Preparation of Filled Hard Gelatin Capsules Preparation of Filled Hard Gelatin Capsules

The preparation of filled hard gelatin capsules may be The preparation of filled hard gelatin capsules may be

divided into the following steps:divided into the following steps:

1.1. Preparing the formulation Preparing the formulation

2.2. Selecting the capsule size.Selecting the capsule size.

3. Filling the capsule shells.3. Filling the capsule shells.

4. Cleaning and polishing the filled capsules.4. Cleaning and polishing the filled capsules.

Preformulation studies are used to determine if the Preformulation studies are used to determine if the

bulk powders may be blended together as such, or if bulk powders may be blended together as such, or if

they require reduction of particle size or processing they require reduction of particle size or processing

into formed granules.into formed granules.

I. Preparing the formulationI. Preparing the formulation

MillingMilling

To achieve uniform drug distribution through out a To achieve uniform drug distribution through out a

powder mix, it is advantageous that the density and powder mix, it is advantageous that the density and

particle size of the drug and non-drug components particle size of the drug and non-drug components

are similar. This is achieved by particle size are similar. This is achieved by particle size

reduction (milling).reduction (milling).

Dry PowderDry Powder

DiluentDiluent

Generally, hard gelatin capsules are used to Generally, hard gelatin capsules are used to

encapsulate between about 65 mg and 1 g of encapsulate between about 65 mg and 1 g of

powdered material, including drug and any di luent powdered material, including drug and any di luent

required. required.

If the dose of the drug to be placed in a single If the dose of the drug to be placed in a single

capsule is smaller than 65 mg to produce the proper capsule is smaller than 65 mg to produce the proper

fill, lactose, microcrystalline cellulose, and fill, lactose, microcrystalline cellulose, and

pregelatinized starch are common diluents used in pregelatinized starch are common diluents used in

capsule filling. But when the amount of drug is large capsule filling. But when the amount of drug is large

enough to fill a capsule completely, a diluent may enough to fill a capsule completely, a diluent may

not be required.not be required.

LubricantLubricant

a lubricant as 1% Magnesium stearate is utilized to a lubricant as 1% Magnesium stearate is utilized to

prevent adhesion and facilitate the flow of the prevent adhesion and facilitate the flow of the

powder in capsule filling machine.powder in capsule filling machine.

GlidantGlidant

The powder mixture or granules must be free-The powder mixture or granules must be free-

flowing to allow passage from the hopper by the flowing to allow passage from the hopper by the

addition of a glidant such as 1% silicon dioxide.addition of a glidant such as 1% silicon dioxide.

Lubricant and Glidant are used to improve filling Lubricant and Glidant are used to improve filling

properties. properties.

Wetting agentWetting agent

Addition wetting agents, as sodium lauryl Addition wetting agents, as sodium lauryl

sulfate, in capsule facilitate the wetting sulfate, in capsule facilitate the wetting

of the drug substance by gastrointestinal fluids of the drug substance by gastrointestinal fluids

to enhance dissolution, and overcome the to enhance dissolution, and overcome the

problem associated with water-insoluble problem associated with water-insoluble

lubricant as magnesium stearate which can delay lubricant as magnesium stearate which can delay

the dissolution of the drug and its absorption.the dissolution of the drug and its absorption.

Eutectic mixtures Eutectic mixtures or mixtures that tend to liquefy, or mixtures that tend to liquefy,

may require a diluent or absorbant such as may require a diluent or absorbant such as

magnesium carbonate, kaolin, or light magnesium magnesium carbonate, kaolin, or light magnesium

oxide to separate physically the interacting agents oxide to separate physically the interacting agents

and to absorb any liquefied material. and to absorb any liquefied material.

Eutectic mixturesEutectic mixtures

However, some liquids such as fixed or volatile oils However, some liquids such as fixed or volatile oils

that do not interfere with the stability of the gelatin that do not interfere with the stability of the gelatin

shells may be placed in gelatin capsules which then shells may be placed in gelatin capsules which then

may be sealed to ensure the retention of the liquid may be sealed to ensure the retention of the liquid

((soft gelatin soft gelatin capsules)capsules)

Gelatin capsules are Gelatin capsules are

unsuitable for the unsuitable for the

encapsulation of encapsulation of

aqueous liquids, aqueous liquids,

because water softens because water softens

the gelatin to produce the gelatin to produce

distortion of the distortion of the

capsules. capsules.

LiquidsLiquids

SemisolidsSemisolidsThis system can be used for both This system can be used for both

liquid and solid active ingredients.liquid and solid active ingredients.

Mixtures for filling need only beMixtures for filling need only be

liquid when filled and should be liquid when filled and should be

semisolid after being inside the capsules.semisolid after being inside the capsules.

The materials to be filled must be either The materials to be filled must be either

thermosoftening or thixotropic in nature to be thermosoftening or thixotropic in nature to be

liquefied by heating or shearing forces using heated liquefied by heating or shearing forces using heated

hopper with a stirrer and revert to the solid state hopper with a stirrer and revert to the solid state

within the capsule shell. within the capsule shell.

Used for potent drugs to improve uniformity of Used for potent drugs to improve uniformity of

filling.filling.

Used for safely handling toxic drugs to reduce Used for safely handling toxic drugs to reduce

contamination with filling of powders. contamination with filling of powders.

Granules and PelletsGranules and Pellets

Granules are produced Granules are produced

by granulation and are by granulation and are

more irregular than more irregular than

pellets which are pellets which are

spherical and produced spherical and produced

by microencapsulation by microencapsulation

techniquetechnique

Granules and Pellets are Granules and Pellets are

packed in capsules instead packed in capsules instead

of powder to produce of powder to produce

modified release patterns.modified release patterns.

Capsules within capsules:Capsules within capsules:

Tablets within capsules:Tablets within capsules:

This small tablet can be placed inside the capsule This small tablet can be placed inside the capsule

following the addition of a small quantity of the powder following the addition of a small quantity of the powder

and the filling completed.and the filling completed.

Small tablets are filled into capsules to Small tablets are filled into capsules to

produce special release forms or to produce special release forms or to

separate incompatible ingredients.separate incompatible ingredients.

If one ingredient must be separated If one ingredient must be separated

from others in the formulation, a small from others in the formulation, a small

capsule, such as a No. 5, may be filled capsule, such as a No. 5, may be filled

with one powder and placed into a with one powder and placed into a

larger capsule with the remaining larger capsule with the remaining

ingredients in the formulation. ingredients in the formulation.

                                                                                                                                                            

                                            

PowdersPowders

                                                                                                                                                            

                                            

GranulesGranules

                                                                                                                                                            

                                            

BeadsBeads

                                                                                                                                                            

                                            TabletsTablets

                                                                                                                                                            

                                            CapsulesCapsules

                                                                                                                                                            

                                            PastesPastes

                                                                                                                                                               

                                            LiquidsLiquids

The selection of capsule size is best done during the The selection of capsule size is best done during the

development of the formulation, because the amount development of the formulation, because the amount

of inert materials to be employed is dependent upon of inert materials to be employed is dependent upon

the size or capacity of the capsule to be selected. the size or capacity of the capsule to be selected.

II. SELECTION OF CAPSULE SIZEII. SELECTION OF CAPSULE SIZE

The density and compressibility of a powder or a The density and compressibility of a powder or a

powder mixture will largely determine to what extent powder mixture will largely determine to what extent

it can be packed into a capsule shell.it can be packed into a capsule shell.

The amount may vary according to the degree of The amount may vary according to the degree of

pressure used in filling the capsules.pressure used in filling the capsules.

Determination of capsule fill weightDetermination of capsule fill weight

To determine the size of capsule to be used or To determine the size of capsule to be used or

the fill weight for a formulation the following the fill weight for a formulation the following

relationship is used:relationship is used:

Capsule fill weight =Capsule fill weight =

Tapped Bulk Density of Formulation X Capsule Tapped Bulk Density of Formulation X Capsule VolumeVolume

III. Filling the capsule shellsIII. Filling the capsule shells

1.1."Punch" Method "Punch" Method

2.2. Hand-Operated Capsule Filling MachinesHand-Operated Capsule Filling Machines

3.3. Automatic-Operated Capsule Filling Automatic-Operated Capsule Filling

Machines Machines

Used for filling a small number of capsules in the Used for filling a small number of capsules in the

pharmacy, at the prescription counter.pharmacy, at the prescription counter.

The ingredients are triturated to the same particle The ingredients are triturated to the same particle

size and then mixed by geometric dilution. size and then mixed by geometric dilution.

The powder is placed on a powder paper or The powder is placed on a powder paper or

ointment slab and smoothed with a spatula to a ointment slab and smoothed with a spatula to a

height approximately half the length of the capsule height approximately half the length of the capsule

body. body.

"Punch" Method "Punch" Method

The base of the capsule is held vertically and the The base of the capsule is held vertically and the

open end is repeatedly pushed or "punched" into open end is repeatedly pushed or "punched" into

the powder until the capsule is filled; the powder until the capsule is filled;

The cap is then replaced to close the capsule. Each The cap is then replaced to close the capsule. Each

filled capsule is weighed using an empty capsule as filled capsule is weighed using an empty capsule as

a counterweight. a counterweight.

Powder is added or removed until the correct Powder is added or removed until the correct

weight has been placed in the capsule. weight has been placed in the capsule.

The filled capsule is tapped so that no air spaces The filled capsule is tapped so that no air spaces

are visible within the contents. are visible within the contents.

Cappunch.rm

Pharmacists that prepare capsules on a regular or Pharmacists that prepare capsules on a regular or

extensive basis may use hand-operated capsule extensive basis may use hand-operated capsule

machines. machines.

These machines are available in capacities of 24, These machines are available in capacities of 24,

96, 100, and 144 capsules. 96, 100, and 144 capsules.

First, the plates are adjusted to hold the capsule First, the plates are adjusted to hold the capsule

bodies in place while the caps are removed all at bodies in place while the caps are removed all at

one time. one time.

The caps remain in place in the top of the machine The caps remain in place in the top of the machine

for later use. for later use.

hand-operated capsule machineshand-operated capsule machines

Then the plates are adjusted again so that the Then the plates are adjusted again so that the

capsule bodies will "drop" into place so that the capsule bodies will "drop" into place so that the

tops are flush with the working surface of the tops are flush with the working surface of the

plate. plate.

The formulation powder is poured onto the plate The formulation powder is poured onto the plate

and special spreaders are used to fill the individual and special spreaders are used to fill the individual

capsules. capsules.

The combs are used to tamp (compress) and pack The combs are used to tamp (compress) and pack

the powder into the capsules. the powder into the capsules.

All of the caps are then returned to the capsule All of the caps are then returned to the capsule

bodies, and the closed capsules are removed from bodies, and the closed capsules are removed from

the machine. the machine.

Automatic-Operated Capsule Filling MachinesAutomatic-Operated Capsule Filling Machines

Machines developed for industrial use can Machines developed for industrial use can

automatically remove the caps from empty capsules, automatically remove the caps from empty capsules,

fill the capsules, replace the caps, and clean the fill the capsules, replace the caps, and clean the

outside of the capsules at a rate of up to 165,000 outside of the capsules at a rate of up to 165,000

capsules and greater per hour.capsules and greater per hour.

In this process, the two capsule parts are sealed In this process, the two capsule parts are sealed

with a gelatin or polymer band at the joint of the cap with a gelatin or polymer band at the joint of the cap

and body. and body.

A tamper-resistant seal on hard gelatin capsules wasA tamper-resistant seal on hard gelatin capsules was

SEALING of Gelatin capsulesSEALING of Gelatin capsules

developed in which developed in which

the contact areas of the contact areas of

the cap and body are the cap and body are

wetted with a wetted with a

mixture of water and mixture of water and

ethanol to soften the ethanol to soften the

gelatin and then gelatin and then

thermally bonded at thermally bonded at

104° to 113104° to 113ooF to form F to form

the seal. the seal.

CONI-SNAP Hard gelatin capsuleCONI-SNAP Hard gelatin capsule

A recent innovation in capsule A recent innovation in capsule

shell shell

design, where the two halves design, where the two halves

of the of the

capsule shells are enable to be capsule shells are enable to be

positively joined through positively joined through

locking locking

grooves in the shell walls.grooves in the shell walls.

The two grooves fit into each The two grooves fit into each

other other

and ensure reliable closing of and ensure reliable closing of

the the

filled capsule.filled capsule.

Opening of such capsule is Opening of such capsule is

difficult difficult

with increasing security of the with increasing security of the

contents of the capsule.contents of the capsule.

IV. Cleaning and polishing the filled capsulesIV. Cleaning and polishing the filled capsules

Capsules prepared on a small scale or on a large scale Capsules prepared on a small scale or on a large scale

may have small amounts of the powder adhering to may have small amounts of the powder adhering to

the outside of the capsules. the outside of the capsules.

This powder should be removed before packaging or This powder should be removed before packaging or

dispensing to improve the appearance of the capsules dispensing to improve the appearance of the capsules

and to preserve their quality of being tasteless on and to preserve their quality of being tasteless on

administration. On a large scale, many capsule-filling administration. On a large scale, many capsule-filling

machines are affixed with a cleaning vacuum that machines are affixed with a cleaning vacuum that

removes any extraneous material from the capsules.removes any extraneous material from the capsules.

Another proposed cleaning method is to put the Another proposed cleaning method is to put the

capsules in a container filled with sodium capsules in a container filled with sodium

bicarbonate, sugar, or sodium chloride, and gently bicarbonate, sugar, or sodium chloride, and gently

roll the container. roll the container.

Then the container contents can be poured into a Then the container contents can be poured into a

ten-mesh sieve where the "cleaning salt" will pass ten-mesh sieve where the "cleaning salt" will pass

through the sieve. through the sieve.

Soft Gelatin CapsulesSoft Gelatin CapsulesSoft gelatin capsules (soft elastic gelatin capsules) or Soft gelatin capsules (soft elastic gelatin capsules) or

(softgels) are prepared from continuous gelatin shells to (softgels) are prepared from continuous gelatin shells to

which glycerin or a polyhydric alcohols such as sorbitol has which glycerin or a polyhydric alcohols such as sorbitol has

been added to render gelatin elastic or plastic-like. been added to render gelatin elastic or plastic-like.

Soft gelatin capsules may be oblong, elliptical (oval), or Soft gelatin capsules may be oblong, elliptical (oval), or

sphericalspherical round, oval, oblong, tube in shape., They may round, oval, oblong, tube in shape., They may

also be prepared of single or two-tone color, also be prepared of single or two-tone color,

Application of Soft Gelatin CapsulesApplication of Soft Gelatin Capsules1. Water immiscible, volatile and nonvolatile liquids 1. Water immiscible, volatile and nonvolatile liquids

such as vegetable and aromatic oils, aromatic and such as vegetable and aromatic oils, aromatic and

aliphatic hydrocarbons, chlorinated hydrocarbons, aliphatic hydrocarbons, chlorinated hydrocarbons,

ethers, esters, alcohols, and organic acids.ethers, esters, alcohols, and organic acids.

2. Water miscible, nonvolatile liquids such as 2. Water miscible, nonvolatile liquids such as

polyethylene glycols, and nonionic surface active polyethylene glycols, and nonionic surface active

agents as tween 80.agents as tween 80.

3. Solids may be encapsulated into soft gelatin 3. Solids may be encapsulated into soft gelatin

capsules as capsules as

solutions in one of the suitable liquid solvents, as solutions in one of the suitable liquid solvents, as

suspensions, or as dry powders, granules, or suspensions, or as dry powders, granules, or

pelletized pelletized

materials.materials.

Liquids which can easily migrate through the

capsule shell cannot be encapsulated into soft

gelatin capsules.

These materials include:

Water, above 5%, and low molecular weight

water soluble and volatile organic compounds

such as alcohols, ketones, acids, amines, and

esters.

1.1. They permit liquid medications to become easily They permit liquid medications to become easily

portable.portable.

2.2. Comparing the degree of irritation or ulcerogenic Comparing the degree of irritation or ulcerogenic

potential of soft gelatin capsule formulations potential of soft gelatin capsule formulations

with a tablet formulation, Capsule formulations with a tablet formulation, Capsule formulations

had a reduced ulcerogenic potential when had a reduced ulcerogenic potential when

compared to the tablet formulation.compared to the tablet formulation.

3. Dose uniformity is optimized, because the drug is 3. Dose uniformity is optimized, because the drug is

dissolved or dispersed in a liquid which is then dissolved or dispersed in a liquid which is then

dosed dosed

volumetrically into the capsule accurately.volumetrically into the capsule accurately.

Advantages of Soft Gelatin Capsules Advantages of Soft Gelatin Capsules

4. Improve drug stability by resist gaseous diffusion 4. Improve drug stability by resist gaseous diffusion

and contain no water, thus protect drugs sensitive and contain no water, thus protect drugs sensitive

to oxidation or hydrolysis on long term storage.to oxidation or hydrolysis on long term storage.

5. Good bioavailability of drugs than from the 5. Good bioavailability of drugs than from the

commercial tablets or capsules, that dissolved or commercial tablets or capsules, that dissolved or

dispersed in a water miscible or oily liquids, thus dispersed in a water miscible or oily liquids, thus

when the capsule ingested, the drug dispersed as when the capsule ingested, the drug dispersed as

solution or emulsion to give a drug dispersion of solution or emulsion to give a drug dispersion of

high surface area high surface area

Preparation of Soft Gelatin CapsulesPreparation of Soft Gelatin Capsules

In a soft gelatin capsule formulation the medicament In a soft gelatin capsule formulation the medicament

is in solution or is dispersed as a fine suspension in is in solution or is dispersed as a fine suspension in

either a hydrophilic vehicle or a hydrophobic base. either a hydrophilic vehicle or a hydrophobic base.

Formulation of soft gelatin capsulesFormulation of soft gelatin capsules

There are two main aspects to be considered during There are two main aspects to be considered during

the formulation of soft gelatin capsules:the formulation of soft gelatin capsules:

The composition of the gelatin shell and the The composition of the gelatin shell and the

composition of the fill material.composition of the fill material.

The composition of the soft capsule shell consists of The composition of the soft capsule shell consists of

two main ingredients: gelatin and a plasticize (e.g. two main ingredients: gelatin and a plasticize (e.g.

glycerol). Water is used to form the capsule and it glycerol). Water is used to form the capsule and it

may be desirable or even necessary to add other may be desirable or even necessary to add other

additives such as preservatives, dyes, opacifiers and, additives such as preservatives, dyes, opacifiers and,

rarely, flavours and drugs.rarely, flavours and drugs.

Formulation of the gelatin shellFormulation of the gelatin shell

To produce shells with a greater flexibility than hard To produce shells with a greater flexibility than hard

gelatin capsules it is necessary to control carefully the gelatin capsules it is necessary to control carefully the

viscosity and strength of the gelatin used in production.viscosity and strength of the gelatin used in production.

The mechanical properties of the gelatin shells are The mechanical properties of the gelatin shells are

controlled by choice of gelatin grade and by adjusting controlled by choice of gelatin grade and by adjusting

the concentration of plasticizer in the shell.the concentration of plasticizer in the shell.

GelatinGelatin

If the viscosity of aqueous gelatin solution is too low, a If the viscosity of aqueous gelatin solution is too low, a

thin, thin,

low strength shell is produced which has the low strength shell is produced which has the

disadvantage of disadvantage of

requiring prolonged drying. requiring prolonged drying.

If the viscosity of the gelatin solution is too high, a If the viscosity of the gelatin solution is too high, a

thick thick

film is produced which may be too hard and brittle. film is produced which may be too hard and brittle.

also also

require higher sealing temperatures during require higher sealing temperatures during

manufacture.manufacture.

The main plasticizer used for soft gelatin capsules is The main plasticizer used for soft gelatin capsules is

glycerol.glycerol.

Sorbitol and propylene glycol have also been used Sorbitol and propylene glycol have also been used

but they are normally added in combination with but they are normally added in combination with

glycerol. Plasticizers are added in relatively large glycerol. Plasticizers are added in relatively large

concentrations. The greater the plasticizer content concentrations. The greater the plasticizer content

the greater the flexibility of the shell. (0.3-1.0 parts the greater the flexibility of the shell. (0.3-1.0 parts

of dry plasticizer to 1 part of dry gelatin). of dry plasticizer to 1 part of dry gelatin).

Low ratios 0.3-0.5 are used for oily liquid fills, Low ratios 0.3-0.5 are used for oily liquid fills,

(0.4-0.6) for oily fills with added surfactant,(0.4-0.6) for oily fills with added surfactant,

(0.6-1.0) for water-miscible fills and chewable (0.6-1.0) for water-miscible fills and chewable

capsules.capsules.

PlasticizersPlasticizers

WaterWater

The demineralized water content of gelatin solution The demineralized water content of gelatin solution

used to produce a soft gelatin capsule shell depends used to produce a soft gelatin capsule shell depends

on the viscosity of gelatin used (0.7-1.3 parts of on the viscosity of gelatin used (0.7-1.3 parts of

water to each part of dry gelatin), 1: 1 ratio being water to each part of dry gelatin), 1: 1 ratio being

typical. typical.

PreservativesPreservatives

Preservatives are added to prevent mould growth in Preservatives are added to prevent mould growth in

the gelatin shell. Potassium sorbitate and methyl, the gelatin shell. Potassium sorbitate and methyl,

ethyl and propyl hydroxybenzoate (methyl-, ethyl- ethyl and propyl hydroxybenzoate (methyl-, ethyl-

and propylparaben) are common additives. and propylparaben) are common additives.

ColoursColoursA wide range of colours can be incorporated into A wide range of colours can be incorporated into

soft gelatin shells soft gelatin shells

Water-soluble dyes (synthetic and vegetable), Water-soluble dyes (synthetic and vegetable),

insoluble inorganic and organic pigments and lakes.insoluble inorganic and organic pigments and lakes.

OpacifiersOpacifiersTitanium dioxide is the most common. It is added in Titanium dioxide is the most common. It is added in

concentrations of about 0-0.5%.concentrations of about 0-0.5%.

Enteric treatmentEnteric treatmentEnteric properties can be imparted to soft gelatin Enteric properties can be imparted to soft gelatin

shells by coating with 4% cellulose acetate shells by coating with 4% cellulose acetate

phthalate.phthalate.

Any non-aqueous liquid or powdered solid in Any non-aqueous liquid or powdered solid in

suspension can be filled into soft gelatin capsules.suspension can be filled into soft gelatin capsules.

It is possible to fill soft gelatin capsules with a very It is possible to fill soft gelatin capsules with a very

wide range of materials. wide range of materials.

Suspensions, pastes, drugs in solution in either oils, Suspensions, pastes, drugs in solution in either oils,

self-emulsifying oils or water-miscible liquids. self-emulsifying oils or water-miscible liquids.

Formulation of the capsule contentsFormulation of the capsule contents

Limitations for fill materialsLimitations for fill materialsDrugs or excipients containing large amounts of water Drugs or excipients containing large amounts of water

or other gelatin solvents cannot be incorporated. or other gelatin solvents cannot be incorporated.

It is not recommended to fill emulsions (whether they It is not recommended to fill emulsions (whether they

be o/w or w/o) since they are unstable and will crack be o/w or w/o) since they are unstable and will crack

as the water is lost from the shell in the as the water is lost from the shell in the

manufacturing process. manufacturing process.

Surfactants may have a deleterious effect on the Surfactants may have a deleterious effect on the

capsule seal. capsule seal.

Extremes of pH must be avoided. pHs below about 2.5 Extremes of pH must be avoided. pHs below about 2.5

attack the gelatin leading to hydrolysis and leakage attack the gelatin leading to hydrolysis and leakage

and pHs above about 7.5 have a tanning effect on the and pHs above about 7.5 have a tanning effect on the

gelatin, and affecting the solubility of the shell.gelatin, and affecting the solubility of the shell.

Aldehydes must also be avoided since these have a Aldehydes must also be avoided since these have a

tanning action on the proteins of the gelatin shell.tanning action on the proteins of the gelatin shell.

Liquid vehiclesLiquid vehicles

Water-immiscible oils or water-miscible liquids.Water-immiscible oils or water-miscible liquids.

Water-immiscible oils:Water-immiscible oils:

Either volatile or non-volatile oils,Either volatile or non-volatile oils,

Fixed aromatic vegetable oils, Fixed aromatic vegetable oils,

Aliphatic, aromatic and chlorinated hydrocarbons, Aliphatic, aromatic and chlorinated hydrocarbons,

Liquid ethers and esters.Liquid ethers and esters.

Water-miscible liquids (hydrophilic)Water-miscible liquids (hydrophilic)

Polyols as Polyethylene glycols with low molecular Polyols as Polyethylene glycols with low molecular

weight (400-600) since they are liquid at ambient weight (400-600) since they are liquid at ambient

temperatures. Alcohols as isopropyl alcohol, temperatures. Alcohols as isopropyl alcohol,

polyglycerols, triacetin, glyceryl esters, sorbitan polyglycerols, triacetin, glyceryl esters, sorbitan

esters, sugar esters and polyglyceryl esters.esters, sugar esters and polyglyceryl esters.

Propylene glycol and glycerol can be used, but the Propylene glycol and glycerol can be used, but the

concentration must be low, (5-10%), in order to concentration must be low, (5-10%), in order to

prevent migration into the gelatin and softening of prevent migration into the gelatin and softening of

the shell.the shell.

SuspensionsSuspensions

The particle size of the solid should be reduced to The particle size of the solid should be reduced to

less than 180 µm to pass through the filling head. less than 180 µm to pass through the filling head.

Insoluble drugs can be dispersed (with suspending Insoluble drugs can be dispersed (with suspending

agents and surfactants) in the above vehicles or agents and surfactants) in the above vehicles or

combinations of vehicles. combinations of vehicles.

Suspending agentsSuspending agents are added to prevent settling are added to prevent settling

and maintain homogeneityand maintain homogeneity

• For oily bases (beeswax, paraffin wax, For oily bases (beeswax, paraffin wax,

ethylcellulose ethylcellulose

and hydrogenated vegetable oil)and hydrogenated vegetable oil)

• For non-oily bases (solid glycol esters as PEG For non-oily bases (solid glycol esters as PEG

4000 and 4000 and

PEG 6000).PEG 6000).

Surfactants Surfactants as polysorbate 80 (Tween 80) are often as polysorbate 80 (Tween 80) are often

added as wetting agent. added as wetting agent.

Caking of suspensions in soft gelatin capsules can Caking of suspensions in soft gelatin capsules can

be avoided by rheological control of the vehicle.be avoided by rheological control of the vehicle.

Preparation of Soft Gelatin CapsulesPreparation of Soft Gelatin Capsules

Preparation of Soft Gelatin CapsulesPreparation of Soft Gelatin CapsulesSoft gelatin capsules may be prepared by:Soft gelatin capsules may be prepared by:

The plate process, using a set of molds to form the The plate process, using a set of molds to form the

capsules.capsules.

The die processes (rotary or reciprocating The die processes (rotary or reciprocating

processes) processes)

more efficient and productive processes more efficient and productive processes

A warm sheet of gelatin (plain or colored) is A warm sheet of gelatin (plain or colored) is

placed on placed on

the bottom plate of the mold.the bottom plate of the mold.

The liquid medication is poured on it. The liquid medication is poured on it.

Then a second sheet of the prepared gelatin is Then a second sheet of the prepared gelatin is

carefully carefully

laid in place on top of the medication, and the top laid in place on top of the medication, and the top

plate plate

of the mold is put in place.of the mold is put in place.

The entire mold is then subjected to a press where The entire mold is then subjected to a press where

pressure is applied to form, fill, and seal the pressure is applied to form, fill, and seal the

capsules capsules

simultaneously. simultaneously.

The capsules are then removed and washed with a The capsules are then removed and washed with a

solvent harmless to the capsules. solvent harmless to the capsules.

the plate processthe plate process

Liquid gelatin flowing from an Liquid gelatin flowing from an

overhead tank is formed into overhead tank is formed into

two continuous ribbons by the two continuous ribbons by the

rotary die machine and rotary die machine and

brought together between brought together between

twin rotating dies.twin rotating dies.

the rotary die processthe rotary die process

At the same time, metered fill material is injected At the same time, metered fill material is injected

between the ribbons at the moment that the dies between the ribbons at the moment that the dies

form pockets of the gelatin ribbons.form pockets of the gelatin ribbons. These pockets of fill-containing gelatin are then These pockets of fill-containing gelatin are then

sealed by pressure and heat.sealed by pressure and heat. The soft gelatin capsules may be prepared of The soft gelatin capsules may be prepared of

single or two-tone color, the latter resulting from single or two-tone color, the latter resulting from

the employment of two different colored ribbons the employment of two different colored ribbons

of gelatin to form the sides of the capsule. of gelatin to form the sides of the capsule.

Manufacturing processManufacturing process

• The reciprocating die process is similar to the The reciprocating die process is similar to the

rotary rotary

process in that ribbons of gelatin are formed and process in that ribbons of gelatin are formed and

used to used to

encapsulate the fill,encapsulate the fill,

• But it differs in that the gelatin ribbons are fed But it differs in that the gelatin ribbons are fed

between a between a

set of vertical dies that continually open and close set of vertical dies that continually open and close

to form to form

rows of pockets in the gelatin ribbons. rows of pockets in the gelatin ribbons.

• These pockets are filled with the medication and These pockets are filled with the medication and

are are

sealed, shaped, and cut out of the film as they sealed, shaped, and cut out of the film as they

progressprogress

through the machinery.through the machinery.

• As the capsules are cut from the ribbons, they fall As the capsules are cut from the ribbons, they fall

into into

refrigerated tanks which prevent the capsules from refrigerated tanks which prevent the capsules from

adhering to one another. adhering to one another.

The reciprocating die processThe reciprocating die process

• Capsules are usually packaged in glass or in Capsules are usually packaged in glass or in

plastic plastic

containerscontainers

• Some containing packets of a desiccant to Some containing packets of a desiccant to

prevent the prevent the

absorption of excessive moisture by the absorption of excessive moisture by the

capsules. capsules.

• Soft capsules have a greater tendency than do Soft capsules have a greater tendency than do

hard hard

capsules to soften and adhere to one another, capsules to soften and adhere to one another,

and they and they

must be maintained in a cool, dry place. must be maintained in a cool, dry place.