A

PROJECT REPORT

FOR ELECTIVE SUBJECT

SUBMITTED TO THE

HEMCHANDRACHARYA NORTH GUJARAT UNIVERSITY, PATAN

IN PARTIAL FULFILLMENT OF

THE REQUIREMENT FOR THE DEGREE OF

BACHELOR OF PHARMACY

SUBMITTED BY

SACHIN K. PETHANI

TO

DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY

S.K. PATEL COLLEGE OF

PHARMACEUTICAL EDUCATION AND RSEARCH.

GANPAT VIDYANAGAR

KHERVA, NORTH GUJARAT

2005-2006

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This is certify that the project work for elective subject entitled “CAPSUEL” AS A

SOLID DOSAGE FORM represents the bonafide work of Sachin K. Pethani which

is carried out under my guidance and supervision in the department of pharmaceutics

of Shree S. K. Patel college of pharmaceutical education and research institute,

Ganpat vidhyanagar, during the academic year 2005-2006. He has collected the

literature very sincerely and methodically. This work is up to my satisfaction.

GUIDED BY :

Mr. R. P. PATEL

(M.PHARM, LECTURER)

Dept. Of Pharmaceutics,

Shree S. K. Patel College Of

Pharmaceutical Education And

Research.

Ganpat Vidhyanagar, Kherva.

H. O. D :

Prof. Dr. P. D. BHARADIA

(M. PHARM., Ph.D.)

Dept. Of Pharmaceutics,

Shree S. K. Patel College Of

Pharmaceutical Education And

Research.

Ganpat Vidhyanagar, Kherva

I/C PRINCIPAL

Prof. DR. N. J. PATEL

(M.PHARM., Ph.D.)

Head of Department,

Department of Pharmacology,

Shree S. K. Patel College of

Pharmaceutical education and research,

Ganpat vidhyanagar

DATE:

PLACE:

SHREE S. K. PATEL COLLEGE OF PHARMACEUTICAL

EDUCATION AND RESEARCH, GANPAT VIDHYANAGAR

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ACKNOWLEDGEMENT

“IF U WANTS TO SUCCEED IN LIFE

YOU SHOULD SRTIKE OUT ON NEW PATHS

RATHER THAN TRAVEL ON THE

WORN OUT PATHS OF THE ACCEPTED SUCCESS.”

This is my pleasure to submit the project report giving a brief studies on

“CAPSUEL” AS A SOLID DOSAGE FORM which was undertaken for the partial

fulfillment of degree course of pharmaceutical sciences.

First of all, by heart, I wish to thank my guide Mr. R. P. PATEL for their

encouraging guidance and support for the successful completion of this project and of

course without their moral support and knowledge this will not be possible.

“THE POWERS OF MIND ARE

LIKE THE RAYS OF SUN,

WHEN THEY ARE CONCENTRATE,

THEY ILLUMINE.”

I am very thankful to my respected teachers Dr. P. D. Bharadia, Dr. J. K. Patel, Mr.

R. M. Patel, Mr. B. G. Prajapati, Mr. V. M. Patel and all the teachers of the

college, who let me to do what I believe and who help me to dissipate those power

rays of my mind and illumine my future. I also thank them for providing me guidance

and inspiring me throughout the year.

I am also thankful to our honorable Principal Dr. N. J. Patel for providing

infrastructure and research facilities at the college.

“A PRAYER IS NOT A ‘SPARE WHEEL’ THAT YOU PULL OUT WHEN YOU ARE IN TROUBLE ,

BUT A PRAYER ISA ‘STEERING WHEEL’ DIRECTING THE RIGHT PATH THROUGHTOUT OUR LIFE.”

So, how can I forget to thank God, who gave me such a beautiful life and the

opportunities so that I can run ahead in my field and cover my knowledge to reach the

top in every aspects of my life. God’s best gift to us is not the things but the opportunities.

“INDEED WE DO NOT REALLY LIVE UNLESS WE HAVE FRIENDS

SURROUNDING US LIKE A FIRM WALL

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AGAINST THE WINDS OF THE WORLD.”

I especially thank to my friends, BHAVIN, KAMAL, NISARG, ALPESH

LAKKAD, DIPU, ANDY, HEMANT, BHARAT, ANI who touched my life with

tenderness and help me out in every phase of my life.

“EXPERIENCE IS THE LEARNING MOMENT

ON THE ROAD OF SUCCESS.”

So, I am grateful to my lovely college for providing me a platform where I can learn,

achieve, and made my dreams come true.

“BELIEVE THAT BY WORKING, LEARNING AND ACHIEVING,

YOU CAN REACH YOUR GOALS

AND BE SUCCESSFUL.

BELIEVE IN YOUR OWN CREATIVITY,

AS A MEANS OF EXPRESSING

YOUR TRUE FEELINGS.”

At last but not the least I am thankful to all members of my family for their moral

support and constant encouragement for successful completion of this project work.

I owe my success to my father Mr. K. J. Pethani and my mother Mrs. Manjulaben

K. Pethani and also the encouragement by my brother Mr. Rajesh H. Pethani and

my bhabhi Mrs. Shital R. Pethani.

“SUCCESS IS A CONSTANT JOURNEY

AND NOT A DESTINATION.”

So, I will continue on the road of success to become best in my field and will make

everyone to be proud on me.

SACHIN K. PETHANI

FINAL B. PHARM

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INDEX Sr. No. Topics Page No..

1. HISTORY AND INTRODUCTION OF CAPSULE 1

2. DEFINATION OF CAPSULE 3

3. ADVANTAGES 4

4. DISADVANTAGES 5

5. TYPES OF CAPSULES 6

5.1 HARD GELATIN CAPSULE 6

5.1.1 SHELL COMPOSITION 6

5.1.2 SHELL MANUFACTURING 8

5.1.3 SELECTING THE CAPSULE SIZE AND SHAPE 10

5.1.4 SEALING AND SELF-LOCKING CLOSURES 11

5.1.5 DESIGN OF HARD GELATIN CAPSULE POWDER

FORMULATION AND CHOICE OF EXCIPIENTS

12

5.1.6 HARD GELATIN CAPSULE FILLING PROCESS 16

5.1.6.1 POWDER FILLING 16

5.1.6.2 NON POWDER FILLING 20

5.1.7 METHODS FOR FILLIG OF CAPSULE SHELL 20

5.1.8 STORAGE AND STABILITY 22

5.2 SOFT GELATIN CAPSULES 23

5.2.1 INTRODUCTION 23

5.2.2 ADVANTAGES 23

5.2.3 DISADVANTAGES 24

5.2.4 COMPOSITION OF THE SHELL 24

5.2.5 FORMULATION OF SOFT GELATIN CAPSULE 24

5.2.6 APPLICATION 27

5.3 MICROENCAPSULATION 27

5.3.1 INTRODUCTION 27

5.3.2 MATERIALS 29

5.3.3 METHODS OF MICROENCAPSULATION 29

5.3.3.1 TYPE A ENCAPSULATION PROCESSES 30

5.3.3.2 TYPE B ENCAPSULATION PROCESSES 31

6. EVALUATION OF CAPSULES 34

6.1 STANDARDS 34

6.2 EVALUATION OF MICROCAPSULES 38

7. SPECIAL APPLICATIONS OF CAPSULES 40

8. SUMMARY 41

9. REFERENCES 42

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DDEEDDIICCAATTEEDD

TTOO GGOODD,,

MMYY BBEELLOOVVEEDD PPAARREENNTTSS

AANNDD MMYY FFRRIIEENNDDSS

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INDEX

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1

1. HISTORY AND INTRODUCTION OF CAPSULE( 1 )

The word capsule is derived from the Latin word capsula, meaning a small box.

Mothers and dublanc two Frenchmen are generally credited with the invention of the

gelatin capsule. They discover a method for producing single-piece, olive shaped,

gelatin capsules. Their patents granted in March and December of 1834.

The two pieces telescoping capsules invented by james Murdock of London was

patented in England in 1865. Hard gelatin capsules are the type used by pharmaceutical

manufacturers in the preparation of the majority of their capsule product and by the

community pharmacist in the extemporaneous compounding of prescription.

The basic empty capsule shells are made from a mixture of gelatin, sugar, water and

are cleaned colorless and essentially tasteless. Gelatin is the product obtained by the

partial hydrolysis of collagen obtained from the skin, white connective tissue and bones

of animals.

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

flakes or sheets. Gelatin is stable in air when dry but is subject to microbial

decomposition when it becomes moist or when it is maintained in aqueous solution.

For this reason soft gelatin capsule, which contain more moisture than the hard

gelatin capsules may be prepared with a preservative agent added to prevent the growth

of fungi in capsules shell.

Normally hard gelatin capsules contain between 13 to 16% of moisture.

However if stored in an environment of high humidity additional moisture is absorbed

by the capsules and they may become distorted and lose their rigid shape.On the other

hand in an environment of extreme dryness, some of the moisture normally present in

the gelatin capsules may be lost and the capsule may become brittle and may crumble

when handled.

Although gelatin is insoluble in cold water it does soften through the absorption

up to ten times its weight of the water. Some patients prefer to swallow a capsule

wetted with water or saliva because the capsule softens and slides down the throat more

readily than does dry capsule.

Gelatin is soluble in hot water and in warm gastric fluid a gelatin capsule

rapidly releases its contents. Gelatin, being a protein is digested and absorbed.

Colorants may be used to prepare capsule bodies and caps having the same or different

colors.

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By combining the various capsules parts, beautiful, transparent and distinctive

capsules may be prepared. Opaque capsule may also be prepared to make a

pharmaceutical product distinctive. These capsules are formed by adding an insoluble

substance; such as titanium dioxide to the gelatin mixture.

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2. DEFINATION OF CAPSULE( 2 )

“Capsules are solid dosage forms in which the drug substance is enclosed in

either a hard or soft soluble container or shell of a suitable form of gelatin.”

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3. ADVANTAGES( 3-6 )

Elegance, ease of use and portability also having smooth, slippery, easily

swallowed and tasteless shell for drugs.

Economically produced in large quantities and in wide range of colors.

It masks the unpleasant taste and odor of the medicament.

Colored to protect content from light and improve the acceptability.

Requires less excipients than tablets.

Shells are physiologically innert and easily digested.

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4. DISADVANTAGES( 7-12 )

Not useful for extremely soluble material such as potassium chloride since the

sudden release of such compound in the stomach could result in irritating

concentration.

Not used for highly efflorescent or deliquescent material. As efflorescent

material may cause the capsule to soften and deliquescent powders may dry the

capsules shell to excessive brittleness.

Aqueous or hydro alcoholic liquid can not be enclosed in capsule because they

dissolve gelatin.

Bulk dosage can not be dispensed in capsule.

Require proper storage condition.

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5. TYPES OF CAPSULES :

5.1 HARD GELATIN CAPSULE( 13-17 )

Hard gelatin capsules are thin shells of gelatin. Shell consists of two parts, the

longer being Known, as base or body and the shorter as the cap. One part slipping over

the other, thus completely surrounding the drug formulation.

5.1.1 SHELL COMPOSITION

GELATIN

Although development work has been done on the preparation of capsules from

methyl cellulose and calcium alginate, gelatin because of its unique properties

remain the primary composition material for manufacture of capsule shell.

Gelatin is prepared by the hydrolysis of collagen obtained from animal

connective tissue, bone, skin and sinew. This long polypeptide chain yields on

hydrolysis 18 amino acids the most prevalent of which are glycine and alanine.

Gelatin can vary in its chemical and physical properties depending on the source of

the collagen and the manner of extraction. There are two basic types of gelatin.

Type A

Type B

Type A, which is produced by an acid hydrolysis, is manufactured mainly from

pork skin.

Type B gelatin produced by alkaline hydrolysis is manufactured mainly from

animal bones.

Their iso-electric points, 4.8 to 5.0 for type B and 7.0 to 9.0 can differentiate the

two types for type A and by their viscosity building and film forming

characteristics. Either type of gelatin may be used, but combinations of pork skin

and bone gelatin are often used to optimize shell characteristic.

Bone gelatin contributes firmness and pork skin gelatin contributes plasticity

and clarity. The physicochemical properties of gelatin of most interest to shell

manufacturers are the bloom strength and viscosity.

Bloom strength is an empirical gel strength measure, which gives an indication

of the firmness of the gel. It is measured in a bloom geometer which determines the

weight in grams required to depress a standard plunger a fixed distance into which gn

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are produced from the first extraction of the raw materials have the highest bloom

strength. Bloom strength in range of 150 to 280 is used for capsules.

The viscosity of gelatin solution is vital to the control of thickness of the cast

film. Viscosity is measured on a standard 6-2/3% w/w solution at 60o c in a

capillary pipette, and is generally in the range of 30-60 milli poise-(mP).

COLORANTS

There are mainly two types of colorants are used.

1. Various soluble synthetic dye (coal tar dyes)

2. Insoluble pigments

Commonly used pigments are the iron oxides. Colorants not only play a role in

identifying the product but may also play a role in improving patient compliance.

Thus the color of a drug product may be selected in consideration of the disease

state for which it is intended.

Aluminium lakes are used to retard the movement of release of color from one

side to other. Lakes are derived from dyes by precipitation with carriers. E.g.

aluminium or talc. Lakes may consist of 10 to 30% of dye concentration.

PRESERVATIVE

Gelatin more prone to microbial attack during and after manufacturing.

Preservative include parabens or sulfur dioxide in the form of sodium metabisulfite or

sodium sulfite. Generally antifungal agents are used in soft gelatin capsules.

PLASTICIZER

They are used to provide flexibility to the capsule shell. Most frequently used

plasticizer is glycerol, sorbitol, propylene glycerol, sucrose, and acacia. Usually 5 to 10

% concentration is used for hard gelatin capsule while 10 to 15 % for soft gelatin

capsule. Plasticizer can be expressed as part of dry plasticizer to one part of dry gelatin.

OPAQUING AGENT

Titenium dioxide may be included to render the shell opaque. Opaque capsule

may be employed to provide protection against light or to conceal the content.

WATER

Usually de-mineralized water is used in the preparation of the dipping solution.

Initially 30 to 40 % w/w solution of gelatin is prepared in large stainless steel tanks

using hot de-mineralized water. Vacuum may be applied to assist in the removal of

entrapped air from this viscous preparation. Portion of this stock solution are removed

and mixed with any other ingredient as required to prepare the dipping solution. At this

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point the viscosity of the dipping solution is measured and adjusted. The viscosity of

this solution is critical to control of the thickness of the capsule walls.

5.1.2 SHELL MANUFACTURING( 18-23)

For the production of capsule shell completely automatic machine most

commonly used. The process consist of complete automatically dipping, spinning,

drying, stripping, trimming and joining of capsules.

1. DIPPING

Pairs of stainless steel pins are dipped into the dipping solution to form the caps

and bodies simultaneously. The pins are lubricated with a proprietary mold-release

agent. The pins are at ambient temperature about 22°c. whereas the dipping solution is

maintained at a temperature of about 50°c. in a heated, jacketed dipping pan. The

length of time to cast the film has been reported to be about 12 seconds, with larger

capsules requiring longer dipping times.

Other matters critical to the final dimensions are mold pin dimensions and

machine control relating to cut lengths. Also require to maintain a dipping solution at a

50oc in a heated and jacketed dipping pan.

The process controls include periodic monitoring and adjustment when

required, of film thickness, cut lengths of both cap and body, colour and moisture

content.

2. ROTATION

After dipping the pins are withdrawn from the dipping solution and as this is

done, they are elevated and rotated until they are facing upward. Rotation helps to

distribute the gelatin over the pins uniformly and to avoid the formation of a bead at the

capsule ends. After rotation they are given a blast of cool air to set the film.

3. DRYING

The racks of film-coated pins then pass into a series of four drying ovens.

Drying is done mainly by dehumidification on by passing large volumes of dry air over

the pins. Only a temperature elevation of few degrees is permissible to prevent film

melting. Drying also must not be too rapid to prevent “case hardening.” Over-drying

must be avoided as this could cause films to split on the pins due to shrinkage or at least

make them too brittle for the later trimming operation. Under drying will leave the

films too pliable or sticky for subsequent operations. Proper drying is necessary for the

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require thickness of the capsule shell and also essential to the ultimate quality of the

cast film.

4. STRIPPING

A series of bronze jaws strip the cap and body portions of the capsules from the pins.

5. TRIMMING

The stripped cap and body portions are delivered to collets, in which they are

firmly held. As the collets rotate, knives are brought against the shells to trim them to

the length required.

6. JOINING

The cap and body portions are aligned concentrically in channels and the two

portions are slowly pushed together. The entire cycle takes about 45 minutes however,

about two thirds of this time is required for the drying step alone.

7. SORTING

The moisture content of the capsules as they are ejected from the machine will

be the range 15 to 18 % w/v. Additional adjustment of moisture content toward the

final desired specification will occur during the sorting step. In this capsule passing on

a lighted moving conveyor are examined visually by inspector. Any defective capsules

are removed manually. Defects are generally classified according to their nature and

potential to cause problems in usage. E.g. imperfect cuts, capsules with holes, grease

inside etc.

8. PRINTING

In general capsules are printed prior to filling because it can faster than filled

capsules and if any damage to the capsules no active ingredients would be involved.

Printing is usually done on offset rotary presses having capacity of 3 to 4 million

capsules/hour. It prints either axially or radially.

9. FINISHING AND POLISHING

Finished capsules from all filling equipment require some sort of dusting and

polishing operation before the remaining operation of inspection. Dusting or polishing

operation vary according to the type of filling equipment used, the type of powder used

for filling and the individual desires for the finished appearance of the completed

capsules. There are various methods for finishing and polishing.

A. PAN POLISHING B. BRUSHING C. CLOTH DUSTING

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A. PAN POLISHING

Because of its unique design the Accelacota tablet coating pan may be used to

polish capsules. A polyurethane or cheesecloth liner is placed in the pan and the liner is

used to trap the removed dust as well as to impart a gloss to the capsules. In this

method, the bulk filled capsules are rubbed with a cloth that may or may not be

impregnated with inert oil. This procedure is a hand operation, but one that can handle

reasonable volumes and that results in a positive method for removal of resistant

materials. It also imparts improve gloss to the capsules.

B. BRUSHING

In this procedure capsules are fed under rotating soft brushes, which serve to

remove the dust from the capsule shell. This operation must be accompanied by a

vacuuming for dust removal. Some materials are extremely difficult to remove by

brushing, event to the point of impregnating the brushes and causing scratches or

deformation of the capsules

5.1.3 SELECTING THE CAPSULE SIZE AND SHAPE

SIZE(25)

For human use empty gelatin capsules are manufactured in eight sizes ranging

from 000 (the largest) to 5 (the smallest). The capsule of various size and capacity are

listed below:

Table 1 ( 24 )

SIZE VOLUME (ml) WEIGHT OF

POWDER (gm)

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

4 0.21 0.168

5 0.13 0.104

Most commonly used capsule is a no. 0 Large sizes are available for veterinary

use. Their capacities vary with the density of the drug and pressure applied during

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filling. The capsule is selected during the development of the formulation because the

amount of any inert materials to be employed is dependent upon the size of the capsule

to be selected.

If the formulation does not require diluents to increase the bulk, the capsule size

may be selected after the preparation of formulation. The capsule size is selected on the

basis of the amount of formulation to be filled in the capsule or sometimes it is selected

on the basis of the dose.

In instances, in which there are a specific need for a small capsule the capsule

size may be selected first and the formulation is based on that capsule size. Depending

upon the particular situation and requirements of the intended patient the capsule size

may be determine by the formulation or the formulation may be altered by the capsule

size.

Determination of the capsule size according to weight to be filled. To determine

capsule size required; to fill weight for a formulation following partial relationship is

used.

Capsule fill wt. = tapped bulk density of formulation X capsule volume.

e.g. a formulation has theoretical fill wt. of 350 mg. and a tapped bulk density

of 0.75 gm/lit. then volume occupied,= 0.35 / 0.75 = 0.47 ml. So size no. 1 capsule

shell is used.

But if the value obtained does not coincide with the standard value then,

diluents are added . e.g. fill wt. = 500 mg. Density = 0.8 gm/lit. Therefore, volume =

0.5 / 0.8 = 0.3 ml. But volume of size no. 0 capsule is 0.67 ml. So, 0.04 ml is

unoccupied volume in capsule. Therefore, diluent added = 0.04 x 0.8 = 32 mg.

SHAPE(26)

The standard shape of capsule is the traditional and symmetrical bullet shape

some manufacturers have employed distinctive proprietary shapes. Smith Kline capsule

for merely exhibited a characteristic taper at both the cap and body ends.

5.1.4 SEALING AND SELF-LOCKING CLOSURES(18-20)

Today usually capsules are locked or sealed by self-locking system e.g.

conisnap capsule. In this grooves are made on inside of the cap and body portion. Thus

when they are fully engaged a positive interlock is created between the cap and body

portion. Grooves formed further down on the cap provide a pre-lock preventing

accidental separation of the empty capsules. In locking system now there are also

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capsule available with two grooves in capsules so, if one groove opens then second

keeps cap and body align.

1. SPOT WELDING

In this method, two hot rods are brought near the end of the cap where it

overlaps the body and touched to form bead. This is done to melting of gelatin and

capsule is sealed. Tablets are used in cap to provide modified release pattern and to

separate incompatible ingredients. For filling tablet should be smooth i.e. preferable

film coated which also reduce diameter and shape that will easily fit, into capsule body.

2. THERMAL SEALING METHOD

This process involves immersion of the capsule for fraction of seconds in hydro

alcoholic solvent followed by rapid removal. Excess of solvent then drained off leaving

the traces in the over lapping area of the cap and body which is held by capillary forces

and finally dried under warm air. Here seal is formed because hydroalcolic solution will

dissolve gelatin and on drying this dissolved gelatin forms welding or sealing. E.g.

Capsugel used this type of sealing for capillstarch capsule.

3. BANDING

In this method there is a layering of gelatin film around the seam of cap and

body which may distinctively colored. This is single most commonly used current

sealing technique. e.g. Parke Davis, Qualicaps.

5.1.5 DESIGN OF HARD GELATIN CAPSULE POWDER

FORMULATION AND CHOICE OF EXCIPIENTS

1. ACTIVE INGREDIENT(27-29)

The amount and type of active ingredient influence capsule size and the nature and

amount of excipients to be used in the formulation. If the amount of active ingredient is

small i.e. approximate 10 mg. then it is rarely formulated as capsule. So active

ingredient makes up high percentage of the contents of a capsule. There are many

factors, which affect the dissolution of the drug.

Solubility of the active ingredients: -

The absorption of the drug occurs after its dissolution. So there are fewer problems

in absorption if water solubility of drug is high. If drug is less soluble then absorption

rate is governed by dissolution rate means absorption occurs to slowly.

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Particle size: -

Particle size is the most important factor that governs the dissolution of the drugs.

For the drug of low water solubility are micronized to increase the dissolution rate.Here

decrease in particle size increases the surface area from when dissolution can occur.

e.g. Fincher studied different particle size of sulfathiazole administered in capsules to

dogs and found that the smallest size gave the highest blood level.

But; this approach of reducing particle size have some limitations. Micronized

particles with high surface to mass ratio may tend to aggregate because of surface

cohesive interaction and so reducing the surface area and so decreasing dissolution rate.

But from manufacturing point of view small particles having poor flow property than

larger particles. This happens because of surface cohesive and frictional interaction and

having larger surface area. To reduce the aggregation and to enhance flow property of

smaller particles granulation is done which also enhances dissolution than micronized

powder.

2. DILUENTS OR FILLERS(30-32)

Diluents are used to increase the bulk of the formulation. This medication

improves flow and compressibility while maintaining the basic properties of the

original material. The smallest capsule, a no.5, capsule is capable of holding 1.065gm.

powder. So to fill a capsule completely even of smallest size min. 65mg. of powder is

required. If the amount of drug is inadequate to fill the capsule volume then diluent is

added or necessary to produce proper fill. If the amount of drug is enough to fill the

capsule then diluent is not require.

Lactose, microcrystalline cellulose and pre-gelatinized starch are commonly

used as diluents. Effect of fillers on dissolution of drug is depending upon its

concentration. e.g. dissolution if poorly soluble drug from capsule is improves greatly

When concentration of lactose in the formulation was about 50%. But much more

concentration affect adversely or with soluble drug it also affects adversely. With the

soluble drug chloramphenicol 50% of lactose dose not affect the dissolution of the drug

but when the concentration increased up to 80% in formulation it severely retards drug

dissolution from capsules because lactose dissolution occurs more rapidly than

chloramphenicol end lactose concentration is also high.

The filler also affects the bioavailability. When any manufacturer using lactose

instead of calcium sulfate as filler in sodium phenytoin there is an increase in the

number of patients exhibiting phenytoin toxicity. Here increase in the bioavailability

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when lactose is the filler. This is not only due to greater solubility of lactose but

dissolution of phenytoin was not complete in the presence of the calcium sulfate and

lactose increases the solubility of sodium phenytoin so bioavailability is also increased.

Cornstarch at 50% slowed the dissolution of sodium Phenobarbital. This effect

is depends upon the moisture content of the starch. The t50 for 50:50 sodium

Phenobarbital / cornstarch is decreased with the increase in the moisture.

3. GLIDANT(33-35)

Glidants are used to improve the fluidity of powders because the mixture must be

free flowing to allow steady passage of the capsule fill from the hopper through the

encapsulating equipment and into capsule shell. They appear to coat the particles of the

bulk powder and works by several mechanisms.

1. Reducing roughness by filling surface irregularities.

2. Reducing attractive forces by physically separating host particles.

3. Modifying electrostatic charges.

4. Acting as moisture scavengers.

5. Serving as ball bearings between host particles.

The optimum concentration is less than 1% and particularly 0.25 to 50%. This

concentration is related to the conclusion needed to coat the particles. More than

this concentration either results in no change or even a worsening of flow.

Commonly used glidants are talc, magnesium stearate, silica and cornstarch.

4. LUBRICANT(30,36-40)

Lubricant are generally used during the encapsulation of powder because it

facilitates flow of powder when automatic capsule filling machine is used. It eases the

ejection of plugs. Reduce filming on piston and adhesion of powder to metal surface.

Reduce friction between sliding surfaces in contact with powder. Increasing the

concentration of hydrophobic lubricant such as magnesium stearate retard drug release

because of water proofing characteristics, which create problem to penetrate the drug

by gastrointestinal fluid intended to dissolve it, and so dissolution and absorption is also

delayed. But the effect of magnesium stearate on dissolution of drug is also depending

upon the type of filler.

Soluble filler increases time with increasing lubricant level. Lubricant also

decreases the strength of plug and this could have a beneficial effect on drug

dissolution. Insoluble filler decreases dissolution time as compared to soluble filler. gn

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Drug with two fillers lubricated, with 0.05-0.75% magnesium stearate and

compressed at the same 22 kg compression force. With microcrystalline cellulose

insoluble filler T60 decreased from 55minutes to 12 minutes and plug hardness

decreases from 84gm to 2.0gm. Whereas with lactose a soluble filler T60 is increased

with the lubricant level from 12 minutes to 18 minutes while plug hardness is decreased

slightly from 18gm to 13gm. For the microcrystalline cellulose, increase in

hydrophobicity due to increased lubricant concentration reduced plug hardness; which

enhances moisture penetration and promotes de-aggregation in the dissolution medium.

5. DISINTEGRANT(41-47)

Disintegrates were used in capsule formulation, which enhances disintegration

and finally dissolution of the drug from capsule. Now a day’s newer disintegrate has

been developed which has a superior swelling or moisture absorbing property. These

new disintegrate called “super disintegrate” like croscormellose sodium, sodium starch

glycolate etc. The effect of disintegrate is concentration dependent. The usual

concentration used is 2-4% but for fast dissolution requires 4-6%.

6. SURFACTANT(28,30,37,43,48)

Surfactant may be used in capsule formulation to increase the wetting of the

powder mass and enhance drug dissolution. The “waterproofing” effect of hydrophobic

lubricant may be offset by the use of surfactant. There are beneficial effects of

surfactant on disintegration and de-aggregation and dissolution of drug. Surfactant

enhances liquid uptake into capsule plugs. Most commonly used surfactants are sodium

lauryl sulfate and sodium docusate. The usual concentration is about 0.1-0.5%.

7. HYDROPHILLIZATION(49-51)

It is another approach of improving, the wet ability of poorly soluble drug. In

this method a solution of hydrophilic polymer like methyl cellulose or hydroxymethyl

cellulose was spread onto the drug in a high-shear mixer and the resultant mixture dried

and screened. The method improved both wet ability as well as the rate of dissolution

of the drug.The drug, which is treated with hydrophylization is dissolved and absorbed

faster than the untreated drug.

e.g. Phenytoin after hydrophillization with methylcellulose was compressed into

plugs and the plugs were filled manually into hard gelatin capsule. Then this treated

phenytoin is compared with untreated phenytoin. The treated phenytoin was dissolved

and absorbed faster than the untreated drugs through, no lubricant; fillers etc. were

included in these capsules as actually required.

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5.1.6. HARD GELATIN CAPSULE FILLING PROCESS(52)

5.1.6.1. POWDER FILLING

There are mainly four steps of this process

1. RECTIFICATION

2. SEPARATION OF CAP FROM BODY

3. DOSING OF FILL MATERIAL

4. REPLACEMENT OF CAPS AND EJECTION OF FILLED CAPSULES

1. RECTIFICATION

The empty capsules are oriented so that all point the same direction body end

downward. In general the capsule pass one at a time through a channel just wide

enough to provide a frictional grip at the cap end. A specially designed blade pushes

against the capsule and causes it to rotate about its cap end as a fulcrum. After two

pushes the capsule will always be aligned body end down ward regardless of which end

entered the channel first.

2. SEPARATION OF CAP FROM BODY

Like rectification this process depends on the difference in diameters between

cap and body portions. Here the rectified capsules are delivered body end first into the

upper portion of split bushings of split filling rings. A vacuum applied from below pulls

the bodies down into the lower portion of the split bushing. The diameter of the caps is

too large to allow them to follow the bodies into the lower bushing portion. The spilt

bushings are then separated to expose the bodies for filling.

3. DOSING OF FILL MATERIAL

Various methods are employed for this and they are described later.

4. REPLACEMENT OF CAPS AND EJECTION OF FILLED

CAPSULES

The cap and body-bushing portion are rejoined. Pins are used to push the filled

bodies up into the caps for closure and to push the closed capsule out of the bushings.

Compressed air may also be used to eject the capsules.

VARIOUS FILLING PRINCIPLES FOR POWDER FILLING(52-57)

For filling purpose semiautomatic or automatic machines are used. The semi

automatic machine such as parkedavis no. 8 require an operator to give attendance at all

time and it give about 120,000-160,000 capsules in 8 hr shift while automatic machine

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gives that amount capsules in 1 hr. the main difference between the capsule filling

machine is the mean by which the formulation is dosed into the capsule. There are

mainly four dosing methods.

1. AUGER FILL PRINCIPLE(58-59)

In earlier days all capsules were filled by means of semiautomatic equipment

were in the powder is driven into the capsule bodies by means of a rotating auger. The

empty capsule bodies are held in a filling ring; which rotates on a turntable under the

powder hopper. The fill of the capsules is primarily volumetric. Because the auger

mounted in the hopper rotates at a constant rate, the delivery of powder to the capsules

tends to be at a constant rate. Consequently the major control over fill weight is the rate

of rotation of the filling ring under the hopper. Faster rates produce lighter fill weights

because bodies have a shorter dwell time under the hopper. The mean fill weight was

dependent on machine speed, capsule size, and on the formulation specific volume in

that order. Weight variation was found to be a function of machine speed, specific

volume, flow ability and the presence of glidant but independent of capsule size.

Lubricant, such as magnesium as magnesium stearate and stearic acid, are also

required. These facilitate the passage of the filling ring under the foot of the powder

hopper and help prevent the adherence of certain materials to the auger.

2. VACUUM FILL PRINCIPLE(53-54)

The vacuum fill principle is represented by, the Perry Accofil machine. This

dosing unit is a cylinder containing a porous piston. The position of the piston in the

cylinder can be adjusted to define a volume; which provides the desired dosage of the

formulation. The cylinder is dipped into the powder and vacuum is applied through the

piston, thus causing powder to fill the cylinder up to the piston. The other end of the

powder plug thus formed is scraped off level with the edge of the cylinder. The cylinder

is then moved to the open capsule body by means of pressurized air. There is no

formulation requirement of this machine. However the method does not rely on any

cohesiveness of the formulation and thus may be suited to powders difficult to fill by

other methods.

3. VIBRATORY FILL PRINCIPLE(60-61)

The Osaka machines utilize a vibratory feed mechanism. In this machine, the

capsule body passes under a feed frame; which holds the powder in the filling section.

In the powder a perforated resin plate is positioned which is connected to a vibrator.

The powder bed tends to be fluidized by the vibration and this assists the powder to

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flow into the bodies through holes in the resin plate. The fill weight is controlled by the

vibrators and by setting the position of the body under the feed frame. Much like the fill

mechanism of a tablet press there is overfill and then adjustment with scrape off excess

material as the capsule bodies pass under the feed frame.

The capsule bodies are supported on pins in holes bored through a plate. While they

pass under the feed area, the pins may be set to the bodies to below the level of the

disk, there by causing “overfill”. However, before their passage is completed under the

feed frame, the capsules are eventuality pushed up so that their upper edges become

level with the surface of the disk plate.

When this occurs the excess powder is forced out and eventually scraped off by the

trailing edge of the feed frame. This process affords some light compression of the

powder against the resin plate and offers the opportunity to modify the fill weight.

4. PISTON-TAMP PRINCIPLE

Piston-tamp machines are fully automatic fillers in which pistons tamp the

individual doses of powders into plugs, which often resemble soft tablets in

consistency, and eject the plugs into the empty, capsule bodies. There are two types of

piston-tamp fillers.

1. DOSING DISK MACHINE

2. DOSATOR MACHINE

1. DOSING DISK MACHINE(54,60,62,63)

This type of machine is exemplified by the Hofliger-Karg. GKF models and the

Harro-Hofliger KFM models. The dosing disk, which forms the base of the dosing or

filling chamber, has a number of holes bored through it. A solid brass “stop” plate

slides along the bottom of the dosing disk to close off these holes, thus forming

openings similar to the die cavities of a tablet press.

The powder is maintained at a relatively constant level over the dosing disk.

Five sets of pistons (Hofliger-Karg) compress the powder into the cavities to form

plugs. The cavities are indexed under each of the five sets of pistons so that each plug is

compressed five times per cycle. After the five tamps, any excess powder is scraped off

as the dosing disk indexes to position the plug over empty capsule bodies, where they

are ejected by transfer pistons. The dose is controlled by the thickness of the dosing

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The flow of powder from the hopper to the disk is auger assisted. A capacitance

probe senses the powder level and activates an auger feed if the level falls to below the

preset level. The powder is distributed over the dosing disk by the centrifugal action of

the indexing rotation of the disk. Baffles are provided to help maintain a uniform

powder level. The Harro-Hofliger is similar to Hofliger-Karg except it employs only

three tamping stations. However at each station the powder in the dosing cavities is

tamped twice before rotating a quarter-turn to the next station.The other difference is

that the powder in the filling chamber is constantly agitated. These machines generally

require that formulation be adequately lubricated for efficient plug ejection, to prevent

filming on piston and to reduce friction between any sliding components with which

powder may come into contact. Some degree of compressibility is important; as

coherent plugs appear to be desirable for clean, efficient transfer at ejection.

2. DOSATOR MACHINE(64-66)

The dosator machine is exemplified by the Zanasi, MG2, Macofar etc. The

dosator consists of a cylindrical dosing tube fitted with a movable piston. The end of

the tube is open and the position of the piston is preset to particular height to define a

volume that would contain the desired dose of powder. In operation the dosator is

planged down into a powder bed maintained at a constant level by agitators and

scrapers. The powder bed height is generally greater than piston height. Powder enters

the open end and is slightly compressed against the piston. The piston then gives a

tamping blow, thus forming the plug.

The dosator, bearing the plug is withdrawn from the powder hopper and is

moved over to the empty capsules body, where the piston is pushed downward to eject

the plug. In certain machines the body bushing is rotated into position under the dosator

to receive the ejected plug. e.g. Macofar machine. For dosator the primary control over

fill wt. is the initial piston height in the dosing tube. A secondary control is the height

of the powder bed into, which the dosator dips. For dosator filling machine the

formulation should have following characteristic.

1. Fluidity – for powder feed from reservoir to the dipping bed.

2. Compressibility – to prevent loss of material.

3. Lubricity – for easy and efficient plug ejection.

4. Moderate bulk density – for efficient capping.

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5.1.6.2 NON POWDER FILLING

Dry solids- Powders, pellets, granules, tablets.

Semisolids – Thermosoftening paste, mixture, thixotropic mixture.

Along with active ingredients some times diluents, glidants, lubricants,

surfactants etc. are added.

This material should fulfill following requirements.

They must be able to accurately close into capsule shell.

Release their active ingredients in the form, which is acceptable to patient.

1. GRANULES AND PELLETS

Both should posses near spherical shapes as, possible granules are produced by

using a coating or micro-encapsulation technique. Both of these are used in capsule to

produce modified release pattern. Uniform filling depends on shape and size of

particles.

2.TABLETS

Tablets are used in cap to provide modified release pattern and to separate

incompatible ingredients. For filling tablet should be smooth i.e. preferable film coated

which also reduce diameter and shape that will easily fit, into capsule body.

3. SEMISOLID

Filling a semisolid into the capsule shell cause a probability of product leaking

out from capsule. But this difficulty has been overcome by use of self-locking capsule

and by new formulation technique. In this technique, mixing remains in liquid state

during filling but in the capsule it become solid. This is achieved by using materials

which are either thermo softening or thixotropic in nature. They are liquidified for

filling either by heat or shearing process and converted to solid state within capsule

shell when these are withdrawn.

5.1.7 METHODS FOR FILLING OF CAPSULE SHELL

PUNCHED METHOD(69-71)

When filling a small number of capsules in the pharmacy the pharmacist

generally uses the “punch” method. In this method the pharmacist takes the precise

number of empty capsules to be filled from his stock container. By counting out the

capsules as the initial step rather than taking a capsule from stock as each one is filled

the pharmacist guards against filling an erroneous number of capsules and avoids

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contaminating the stock container of empty capsules with drug particles that may cling

to his finger tips. The powder to be encapsulated is placed on a sheet of clean paper of a

glass of porcelain plate and with a spatula is formed into a cake having a depth of

approximately one fourth to one third the length of the capsule body.

Then the empty capsule body is held between the thumb and forefinger and

“punched” vertically into the powder cake repeatedly until filled. Some pharmacists

wear surgical gloves to avoid handling the capsule with bare fingers. Because the

amount of powder into a capsule depends upon the degree of compression; the

pharmacist should punch each capsule in the same manner and after capping weight to

ensure equal and accurate filling. When non potent materials are being placed in

capsules the first filled capsule should be weighed to assist in the determination of the

proper capsule size and degree of compression to be used in filling and then. The cap

should fit completely down on the body.

HAND OPERATED MACHINE(72-74)

Pharmacist use hand operated capsule machines. These machines are available

in capacities of 24, 96, 100 capsules. When efficiently operated they can produce from

about 2 for smallest machine and up to 2000 capsules / hour for machine. Machines

developed for industrial use can automatically caps from empty capsules, fill the

capsules, replace the caps outside of the capsules at a rate of up to 1,65,000 capsules at

greater / hour.

USING AUTOMATIC CAPSULE FILLING MACHINE(75-79)

1. Capsule manufacturing.

Elanco Qualicaps.

Eli lilly

Indianapolis

Rotosort.

2. Capsule Filling.

Parke-davis.

Formatic.

Hofliger and Karg.

Hacofar.

MG2

Csaka

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Zanasi.

Rotoweigh – Capsule weighing machine.

Vericap – Capsule weighing machine.

Ermeka KEA – Capsle de-dusting and polishing machine.

Seidenader – Capsule polishing machine.

Hartnell (B) – Capsule imprinting machine.

Markem model 280A – Capsule imprinting machine.

5.1.8 STORAGE AND STABILITY(80-91)

Empty capsules are subject to size variation as a result of moisture content

variation. This can be caused by exposure to extreme variation in absolute humidity or

elevated temperature. Unopened shipping containers are usually adequate protection

against these changes, but storage in unopened containers should not be subjected to

temperature condition of over 100 °F.

Open storage under either high or low humidity condition, should be

minimized. Finished capsule normally contains 13-16% of moisture. If low moisture

content (<12%) shell become brittle and if higher (>18%) shell becomes too soft. So,

during storage and handling maintain relative humidity of 40-60% and avoid extreme

temperature capsule should be stored in airtight close vessel.

A. STORAGE OF CAPSULES

Capsule are stored in cool place having moderate humidity, since they tend to

lose water and become brittle if kept in a warm place for long time. Conversely, if kept

in excess humidity, they tend to soften causing problems in the separation of the cap

from the body of the capsule during filling of the capsules. Therefore the correct

method of storing empty of filled capsules is – It should be stored in tightly closed

containers at temperature not exceeding 30°c. The container should provide maximum

protection from moisture and other untoward external factors. Usually amber colored

glass or plastic bottles should be used.

Recently, blister packing of filled capsules has become very popular since it is

considered to be one of the best pilferage proof packaging. Blister packing of capsules

provides complete operator safety and requirements of GMP. Strip packed capsules are

also equally popular but they are not liked by manufacturers as much because of the

high cost of the aluminium foil.

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B. STABILITY

Avoid deliquescent material for filling because it may cause shell splitting or

cracking. Avoid exposure to traces of aldehydes because it decreases water stability of

shells and fails to meet the USP requirements for drug dissolution.

5.2 SOFT GELATIN CAPSULES

5.2.1 INTRODUCTION(92)

Soft gelatin capsule have been available since the middle of the nineteenth

century. Soft gelatin capsule is a “glob” of molten gelatin that is filled by medicine

dropper and sealed by hand. Because of their special properties and advantages soft

gelatin capsules are used in a wide variety of industries. Production of tablets, liquid

and hard shell capsules but they usually depend upon custom manufacturer for

production because of economic, patent and technologic factors.

5.2.2 ADVANTAGES(93,94,96)

Compression stage is not include during filling just like in hard gelatin capsule.

The dose content uniformity is optimized because the drug is dissolved or dispersed

in a liquid is then closed volumetrically into capsule.

Rapid release of the content with potential enhanced bio-availability. The proper

choice of vehicle may promote rapid dispersion of capsule content and drug

dissolution on breakage of capsule.

The areas under the 14-hour plasma concentration curves were also greater for the

soft gelatin capsule compared to the solution or tablets.

Soft gelatin is hermetically sealed as a natural consequence of the manufacturing

process. Thus this dosage form is uniquely suited for liquids and volatile drugs.

Drug sensitive to oxidation or hydrolysis on long-term storage can be protected

from the environment by solution of dispersion in oil and encapsulated by gelatin.

Content uniformity is high because higher degree of homogenicity is possible in

liquid system.

Soft gelatin capsule shell can be an effective barrier to oxygen.

Soft gelatin are available in a wide variety of sizes and shapes.

They permit liquid medication to become easily portable.

Soft gelatin capsule had a reduced ulcerogenic potential when compared to the

tablet formulation.

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5.2.3 DISADVANTAGES(97)

Material used for production has to be carried to place of firm having necessary

filling equipment and expertise and then again shipped to pharmaceutical

manufacturer for final packaging and distribution.

If there is more intimate contact between shell and its liquid contents then exists in

dry filled hard gelatin capsule, which increases possibility of interaction.

There are chances of drug migration from oily vehicle into the shell.

5.2.4 COMPOSITION OF THE SHELL(92,98)

The basic component of soft gelatin shell is gelatin however the shell has been

plasticized by the addition of glycerin, sorbitol or propylene glycol. Other component

may include dyes, opacifiers, preservatives, flavors, acids, sugars, colors etc. The ratio

of dry plasticizer to dry gelatin determines the “hardness” of the shell and can vary

from 0.3 to 1.0 for a very hard shell and 1.0 to 1.8 for a very soft shell. Up to 5% sugar

may be included to give a “chewable” quality to the shell. The basic gelatin formulation

from which the plasticized films are cast usually consists of one part gelatin, one part

water and 0.4 to 0.6 part plasticizer. The residual shell moisture content of finished

capsules will be in the range of 6 to 10 %.

5.2.5 FORMULATION OF SOFT GELATIN CAPSULE(99)

The formulation for soft gelatin capsule involves liquid rather than powder

technology. Materials are generally formulated to produce the smallest possible capsule

consistent with maximum stability, therapeutic effectiveness, and manufacture

efficiency. Soft gelatin capsules contain a single liquid, a combination of miscible

liquids a solution of a drug in a liquid of a suspension of drug in a liquid. The liquids

are limited to those, which don’t have an adverse effect on the gelatin walls.

The pH of the liquid can be between 2.5-7.5. Liquid with more acid pH values

would tend to cause leakage by hydrolysis of the gelatin. Liquid with more alkaline pH

value decreases shell solubility by tanning the gelatin. Emulsion cannot be filled

because inevitably, water will be released which will affect the shell.

The types of vehicles used in soft gelatin capsules fall into two main groups.

Water-immiscible: volatile, or more likely nonvolatile, liquids such as vegetable oils, gnu.i

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aromatic and aliphatic hydrocarbons, medium-chain triglycerides and acetylated

glycerides.

Water-miscible : non-volatile liquids such as low molecular weight poly

ethylene glycol that have come into use more recently because of their ability to mix

readily with water and accelerate dissolution of dissolved or suspended drugs. All

liquids used for filling must flow by gravity at a temperance of 35 c or less. The sealing

temperature of gelatin film is 37-40 C. Liquids that cannot be encapsulated include

water, low molecular weight alcohol such as ethanol, emulsion is and aldehydes.

METHODS FOR MANUFACTURING OF SOFT GELATIN

CAPSULE(92,100)

There are mainly four methods.

(1) PLATE PROCESS

(2) ROTARY DIE PROCESS

(3) ACCOGELL PROCESS

(4) BUBBLE METHOD

1. PLATE PROCESS

The oldest commercial process, the plate process, a semiautomatic batch

process, has been supplanted by more modern, continuous process, by more modern,

continuous processes. In general the process involved placing the upper half of a

plasticized gelatin over a die plate containing numerous die pockets. Application of

vacuum to draw the sheet into the die pockets. Filling the pockets with liquid or paste.

Folding the lower half of the gelatin sheet back over the filled pockets. Inserting the

“sandwich” under a die press where the capsules are formed and cut out.

2. ROTARY DIE PROCESS

For soft gelatin capsule manufacturing first require gelatin preparation which

requires air-conditioned areas for the proper conditioning of the gelatin films, for

proper drying of the capsules.

The temperature is between 20 to 22 c. and humidity is maximum of 40% in

operating areas and 30% in drying areas. For gelatin preparation first gelatin is weighed

in metered scale and mixed with chilled liquid constituent in pony mixer. The resultant

fluffy mass is transferred to melting tanks and melted at 93°c, which requires 3 hours.

This mass is then maintained at temperature 57 to 60°c. before and during capsulation.

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For the preparation of the materials, which is to be capsulated, the department should

require suitable and proper equipment with metered scale for exact measurement,

stainless steel jacketed tank for handling of 10 to 450 gallon mixtures and mixers such

as cowls for the initial blending of solids with the liquid base.

After that mixture is put through milling using equipment such as stone mill to

break up agglomerates of solids and to “wet” all solid with the liquid carrier for smooth

and homogeneous mixture. After that all mixtures are subjected to de-aeration which

requires the attachment of positive displacement pump. De-aeration is necessary to

achieve uniform capsule fill weights and to avoid loss of potency through oxidation.

After de aeration the mixture is ready to be capsulated.

Now the gelatin mass is fed by gravity to a spreader box which controls the

flow of mass on to air cooled rotating drums. So gelatin ribbon; of controlled thickness

are formed. The ribbons are fed through a mineral oil lubricating bath, over guide rolls

and then down between the wedge and the die rolls. The materials to be capsulated

flows by gravity in to a positive displacement pump which meets the material through

the leads and wedge a into the gelatin ribbon between the die rolls.

The bottom of the wedge contains small orifice lined up with the die pockets of

the die rolls. The capsule is about half sealed when the pressure of the pumped material

forces the gelatin into die pockets. So the capsules are simultaneously filled, shaped,

hermetically sealed and cut from the gelatin ribbon.

3. ACCOGEL PROCESS

This is a continuous process for the manufacture of soft gelatin capsule filled

powders or granules. In general, in this process, involves a measuring roll. A die roll

and the other a sealing roll. The measuring roll rotates directly over the die roll and the

pockets in the two rolls are aligned with each other. The powder or granular fill

material is held in the pockets of the measuring roll under vacuum.

A plasticized sheet is drawn into the die pockets of the die roll under vacuum.

As the measuring roll and die roll rotates, the measured doses are transferred to the

gelatin-lined pockets of the die roll. The continued rotation of the filled die converges

with the rotating sealing roll, where a second gelatin sheet is applied to form the other

half of the capsule. Pressure develops between the die roll and sealing roll seals and

cuts out the capsules.

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4. BUBBLE METHOD

A “Bubble Method” produces a truly seamless, one-piece soft gelatin capsule. A

concentric tube dispenser simultaneously discharges the molten gelatin from the outer

annulus and the liquid content from the inner tube. By means of a pulsating pump

mechanism, the liquids are discharged from the concentric tube orifice into a chilled oil

column as droplets, which consist of a liquid medicament core within molten gelatin,

envelop. The droplets assume a spherical shape under surface tension forces and the

gelatin congeals on cooling. The finished capsules must then be degreased and dried.

5.2.6 APPLICATION(98,99)

As an oral dosage form of ethical product for human or veterinary use.

As a suppository dosage form for rectal use of vaginal use.

As a special package in tube form for single dose application of topical, ophthalmic

and rectal ointment.

In cosmetic industry these capsule may be used as a speciality package for

breathlessness perfumes, bath oils and various skin creams.

Water immiscible, volatile non volatile liquids such as vegetable and aromatic oils,

aromatic and aliphatic hydrocarbons, chlorinated hydrocarbons, ethers, esters,

alcohols and organic acids may be encapsulated in soft gelatin capsule.

Water miscible, non-volatile liquids such as polyethylene glycols and non-ionic

surface-active agent as polysorbate 80 and propylene glycol and isopropyl alcohol

may be encapsulated in soft gelatin capsule.

Solids may be encapsulated into soft gelatin as solutions in one of the suitable

liquid solvents, as suspension or as dry powders, palletized material.

5.3 MICROENCAPSULATION

5.3.1 INTRODUCTION(101)

Definition: Microencapsulation is a process by which tiny particles of a gas,

liquid, or solid active ingredient are packed within a second material for the purpose of

shielding the active ingredient from the surrounding environment.

These capsules, which range in size from one micron seven mm, release their

contents at a later time by means appropriate to the application. Microencapsulaton is gn

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the process of creating small particles consisting of a core containing One or more

materials surrounded by a barrier layer.

PROPERTIES(102)

Microencapsulate hydrophilic and hydrophobic materials as well as solid or

liquid materials. Provide capsule pay loads as low as 20% or as high as 99% Provide

capsule in the size range of 41 micron up to 1,800 microns in size. Besides obtaining

the above size ranges, we have also developed nano particle encapsulations as well as

specialized techniques to provide uerosol delivery. We can mask an active taste and

odors well as isolate and protect the active from reactive materials and its environment.

Capsules can be released by bursting, fracturing, constant and slows release as well as

by diffusion, abrasion and dissolution.

REASONS FOR MICROENCAPSULATION(103,104)

Isolation of active ingredient.

Protection of internal phase.

Controlled releasing system.

Presentation under solid or liquid form.

Visual effect.

ADVANTAGE(105)

Colored microcapsules can create “eye appeal” in a wide range of personal care

products.

The size and hardness of the microcapsules can be customized to provide a special

feel.

Microcapsules can protect material that are incompatible in a formation.

Providing a controlled delivery of active ingredients.

DISADVANTAGE(106)

Micro capsular coat may be incomplete.

Every technique has its own limitation, e.g. pan coating can be used only for solids.

Solvents used are inflammable, toxic and noxious.

Accumulation of electric charges in the manufacturing areas.

RELEASE MECHANISM(107)

There are four typical mechanisms by which the core material is released from a

microcapsule.

Mechanical rupture of the capsule wall.

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Dissolution of the walls.

Melting of the wall.

Diffusion through the wall.

Abrasion and degradation are less common.

5.3.2 MATERIALS(103,108,109)

CORE MATERIALS.

Acetaminophen

Activated charcoal

Aspirin

Islets of langerhans

Isosorbide dinitrate

Menthol

Progesterone

Potassium chloride.

COATING MATERIALS

Gums-sugar, sodium alginate.

Carbohydrates-starch, sucrose.

Cellulose-methyl cellulose,

ethyl

Lipids-wax, paraffin cellulose

Inorganic materials-calcium

sulfate, silicates.

Profeins-gelatin, alluminium.

5.3.3 METHODS OF MICROENCAPSULATION

Type A (chemical) processes Type B (mechanical) processes

Complex coacervation Spray drying

Polymer-polymer incompatibility Spray chilling

Interfacial polymerization in liquid media Fluidized bed

In situ polymerization Electrostatic deposition

In liquid drying Centrifugal extrusion

Thermal and ionic gelation in liquid media Spinning disk or rotational suspension

separation

Thermal and inonic gelation in liquid

media

Polymerization at liquid-gas or solid-gas

interface

Desolvation in liquid media Pressure extrusion or spraying into solvent

extraction bath

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5.3.3.1 TYPE A ENCAPSULATION PROCESSES

A. COMPLEX COACERVATION(110,111)

Because of its original use in carbonless paper, the first type A process

considered is complex coacervation. It is based on the ability of cationic and anionic

water-soluble polymers to interact in water to form a liquid, polymer-rich phase called

a complex coacervate. Gelatin is normally the cationic polymer used. A variety of

natural and synthetic anionic water-soluble polymers interact with gelatin to form

complex coacervate forms, it is in equilibrium with a dilute solution called the

supernatant. In this two-phase system, the supernatant acts as the continuous phase,

whereas the complex coacervate acts as the dispersed phase. If a water-insoluble core

material is dispersed in the system and the complex coacervate wets this core material,

each droplet or particle of dispersed core material is spontaneously coated with a thin

film of coacervate. When this liquid film is solidified, capsules are formed.

This technology routinely produces single capsules of 20-800 um diameter that

contain 80-90 wt. percent core materials. Most coacervate capsules have a continuous

core/shell structure, although the shell is not of uniform thickness. The mechanical and

barrier properties of dry capsules formed by complex coacervation generally are

sensitive to moisture.

B. POLYMER- POLYMER INCOMPATIBILITY(112-115)

This technology utilizes a second type A process that has been commercialized.

This technology utilizes a polymer phase-separation phenomenon quit different from

complex coacervation. In complex coaservation, two oppositely charged polymers,

gelatin and apolyanion, join together to form the complex coaservate and both

polymers become part of the final capsule shell. In contrast, polymer-polymer

incompatibility occurs because two chemically different polymers dissolved in a

common solvent are incompatible and do not mix in solution.

C. IN SITU POLYMERISATION(116)

In situ polymerization is a type A encapsulation technology closely related to

IFP. Like IFP, capsule shell formation occurs because of polymerization of monomers

added to the encapsulation reactor.

D.INTERFACIAL POLYMERIZATION(117-119)

Interfacial polymerization (IFP) is a third type A encapsulation process that has

been commercialized. A unique feature of this technology is that the capsule shell is gnu.i

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formed at or on the surface of a droplet or particle by polymerization of reactive

monomers.

5.3.3.2 TYPE B ENCAPSULATION PROCESSES(120-122)

Centrifugal force, extrusion, co extrusion, and formation of sprays are the

principal means by which type B capsule are made. Type B methods of encapsulation

predate type A encapsulation processes, since spray drying, a type B process, was

developed in the 1930s. Because spray drying is the oldest type B encapsulation

process, it is appropriate to discuss it first.

A. SPRAY DRYING

The first step in a spray-dry encapsulation processes is to emulsify or disperse

the core material in a concentrated (40-60 wt. Percent solids) solution of shell material.

The core material generally is water-immiscible oil such as a fragrance, flavor, or

vitamin. It is emulsified in a solution of shell material until 1-to 3-um oil droplets are

obtained.

The shell material normally is a water-soluble polymer like gum Arabic or a

modified starch. Mixtures of these shell materials with hydrolyzed starches

(maltodextrins) or hydrolyzed gelatins have been used. Water is the preferred solvent or

most spray-drying encapsulations. Once a suitable dispersion of core material in a

solution of shell material has been prepared, the resulting emulsion is fed as droplets

into the heated chamber of a spray drier.

The droplets may be sprayed into this chamber or spun off a rotating disk. In

either case, they are rapidly dehydrated in a heated chamber, thereby producing dry

capsules. The capsules fall to the bottom of the spray-drying chamber where they are

harvested. Capsules produced in this manner typically fall between 10 and 300 um-in

diameters. They tend to have an irregular geometry and may be aggregates of a number

of small particles. Each spray-dried capsule has a number of small droplets of core

material dispersed throughout it.

Spray-dry encapsulation has a number of advantages. It is a well-established

technology, involves readily available equipment, and is able to produce large amounts

of capsules. Many shell materials preferred for spray drying are approved for food use.

Furthermore, these materials are water-soluble and not chemically cross linked. Thus,

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leaving any capsule shell debris. To date, spray drying has primarily been used to

encapsulate fragrances and flavors.

B. FLUIDIZED BED COATERS

Fluidized bad coaters are another type B encapsulation technology. They are

limited to encapsulating solid particles or porous particles into which a liquid has been

absorbed. Nevertheless, they are used extensively to encapsulate many different solids.

Fluidized bed coaters function by suspending a bed or column of solid particles in a

moving gas stream, usually air. A liquid coating formulation is sprayed onto the

individual particles, and the freshly coated particles are cycled into a zone where the

coating formulation is dried either by solvent evaporation or cooling.

This coating and drying sequence is repeated until a desired coating thickness

has been applied. They represent a major capital investment, but are widely used to

produce encapsulated solids, especially for the pharmaceutical industry.

A major advantage of fluidized bed coaters is their ability to handle an

extremely wide range of coating formulations. They have been used to apply hot melts,

aqueous latex dispersions, organic solvent solutions of shell material, and aqueous

solutions of shell material. Enteric polymer solutions have been of particular interest,

since they are used by the pharmaceutical industry to produce drug-dosage

formulations that survive passage through the stomach.

Three types of fluidized beds are available: top-spray, tangential-spray, and

bottom-spray. These units differ in location of the nozzle or nozzles used to apply the

coating formulation. In the top-spray unit, the coating formulation is sprayed into the

fluidized bed. The droplets of spray leaving the nozzle move countercurrent to the gas

stream until they impact the particles being coated.

If the spray formulation contains a volatile solvent, evaporation of this solvent

from the spray droplets occurs, thereby increasing the solids content, perhaps to such a

degree that the spray droplets cannot spread on the particles being coated. This spray-

drying effect has been used to explain why aolvent-based coating formulations applied

in top-spray fluidized bed coaters often yield coated particles with a degree of internal

void volume and porous coatings.

In tangential-spray and bottom-spray units, the droplets of coating formulation

move in the same direction as the particles being coated. The droplets of coating

formulation travel a shorter distance before they impact the particles being coated.

Solvent evaporation is minimized, and a more uniform film of coating material is

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deposited. The bottom-spray, or Wurster coater, has become a standard unit used to

produce encapsulated solids, especially solid pharmaceuticals.

The partition and gas-distribution plates of such units are important

components, because they direct the particles being coated in a cyclic path past the

nozzle that supplies the coating formulation. Particles move past this nozzle, receive a

spray of coating material, and move up into the upper section of the unit.

Here the coating is solidified either by solvent evaporation or cooling of a hot

melt. The coated particles then fall back down to the bottom of the unit where a fresh

coating is applied. This cyclic process as repeated until the desired weight of shell

material has been applied.

C. CENTRIFUGAL EXTRUSION

The core and shell material, two mutually immiscible liquids, are pumped

through a spinning two-fluid nozzle. This produces a continuous two-fluid column or

rod of liquid that spontaneously breaks up into a stream of spherical droplets

immediately after it emerges from the nozzle. Each droplet contains a continuous core

region surrounded by a liquid shell.

How these droplets are converted into capsules is determined by the nature of

the shell material. If the shell material is a relatively low-viscosity hot melt that

crystallizes rapidly on cooling (e.g., a wax or wax toughened with a polymer), the

droplets are converted into solid particles as they fall away from the muzzle. Suitable

core materials typically are polar liquids like water or aqueous solutions, since they are

immiscible with a range of hot melt shell materials like waxes.

Alternatively, droplets emerging from the nozzle may have a shell that is an

aqueous polymer solution able to be gelled rapidly. In this case, the droplets fall into a

gelling bath where they are converted into gel beads. The gel beads produced can be

dried to give capsules with a solid shell. Core materials suitable for this type of

capsules shell are water-immiscible oils.

D. ROTATIONAL SUSPENSION SEPARATION

In this process, core material dispersed in a liquid shell formulation is fed onto a

rotating disk. When the shell formulation is solidified, e.g. by cooling, discrete micro-

encapsules are produced. This technology is claimed to be a fast, low-cost, high-

volume method of encapsulating a variety of materials that act like solids on the

rotating disk, including particles below 150 μm in diameter.

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6. EVALUATION OF CAPSULE

6.1 STANDARDS(123)

A. Content of active ingredients :

Determine the amount of active ingredient(s) by the method described in the

Assay and calculate the amount of active ingredient(s) in each capsule. The result lies

within the range for the content of active ingredient(s) stated in the monograph. This

range is based on the requirement the 20 capsules, or such other number as may be

indicated in the monograph, are used in the Assay. Where 20 capsules cannot be

obtained, a smaller number which must not be less than 5, may be used, but to allow for

sampling errors the tolerance are widened in accordance with Table 1. The

requirements of Table 1 apply when the stated limits are between 90 and 110%,

proportionately smaller or larger allowances should be made.

TABLE 1

Weight of active

Ingredients in

each capsule

Subtract from the lower limit

for samples of

Add to the upper limit for samples

of

0.12 g or less

More than 0.12 g

and less than 0.3 g

0.3 or more

15

0.2

0.2

0.1

10

0.7

0.5

0.2

5

1.5

1.2

0.8

15

0.3

0.3

0.2

10

0.8

0.6

0.4

5

1.8

1.5

1.0

B. Uniformity of weight :

This test is not applicable to capsules that are required to comply with the test

for Uniformity of content for all active ingredients. Weigh an intact capsule. Open the

capsule without losing any part of the shell remove the contents as completely as

possible. To remove the contents of a soft capsule the shell may be washed with ether

or other suitable solvent and the shell allowed to stand until the odour of the solvent is

no longer detectable. Weigh the shell. The weight of the contents is the difference

between the weighing. Repeat the procedure with a further 19 capsules. Determine the

average weight.

Not more than two of the individual weights deviate from the average weight by

more than the percentage deviation shown in Table 2 and none deviates by more than

twice that percentage. gn

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TABLE 2

Average weight of capsule contents Percentage deviation

Less than 300 mg

300 mg or more

10

7.5

C. Uniformity of content :

This test is applicable to capsule that contain less than 10 mg or less than 10%

w/w of active ingredient. For capsules containing more than one active ingredient carry

out the test for each active ingredient that corresponds to the afore-mentioned

conditions.

The test should be carried out only after the content of active ingredient(s) in a

pooled sample of the capsules has been shown to be within accepted limits of the stated

content. NOTE – The test is not applicable for capsules containing multivitamins and

trace elements.

Determine the content of active ingredient in each of 10 capsules taken at

random using the method given in the monograph or by any other suitable analytical

method of equivalent accuracy and precision. The capsules comply with the test if not

more than one of the individual values thus obtained is outside the limits 85 to 115% of

the average value and none are outside the limits 75 to 125%. If two or three individual

values are outside the limits 85 to 115% of the average value repeat the determination

using another 20 capsules. The capsules comply with the test if in the total sample of 30

capsules not more than three individual values are outside the limits 85 to 115% and

none is outside the limits 758 to 125% of the average value.

D. Disintegration :

The disintegration test is not applicable to Modified-release Capsules. For those

Hard Capsules and Soft Capsules for which the dissolution test for tablets and capsules,

Appendix 7.3, is included in the individual monograph, the test for Disintegration is not

required.

Hard Capsules :

comply with the disintegration test for tablets and capsules, Appendix 7.1.

Unless otherwise directed in the individual monograph use water as the medium. If the

capsules float on the surface of the medium, a disc may be added. If the capsules adhere

the discs, attach a removable piece of stainless steel woven gauze with mesh aperture of gnu.i

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2.00 mm to the upper plate of the basket rack assembly and carry out the test omitting

the discs. Operate the apparatus for 30 minutes unless otherwise directed.

Soft Capsules :

Comply with the disintegration test for tablets and capsules, Appendix 7.1.

Unless otherwise directed in the individual monograph use water as the medium and

add a disc to each tube. Operate the apparatus for 60 minutes unless otherwise directed.

Enteric Capsules :

Use the apparatus described under disintegration test for tablets and capsules,

Appendix 7.1, using one capsule in each tube. Operate the apparatus for 2 hours

without the discs in 0.1M hydrochloric acid. No capsule shows signs of disintegration

or of rupture permitting the escape of the contents. Replace the medium in the vessel

with mixed phosphate buffer pH 6.8, add a disc to each tube and operate the apparatus

for a further 60 minutes. Remove the apparatus from the medium and examine the

capsules. They pass the test if no residue remains on the screen or on the underside of

the discs, or, if a residue remains, it consists of fragments of shell or of a soft mass with

no palpable, unmoistened core.

E. Dissolution Test for Capsules(124)

The choice of the Apparatus to be used depends on the physico-chemical

characteristics of the dosage form. When this Appendix is invoked in an individual

capsule monograph of the British Pharmacopoeia, use Apparatus I unless otherwise

directed.

Method

Introduce the stated volume of the dissolution medium, free from dissolved air,

into the vessel of the apparatus. Warm the dissolution medium between 36.5 and 37.5.

unless otherwise stated use one capsule.

When Apparatus I is used, place the capsule in a dry basket at the beginning of

each test. lower the basket into position before rotation. When Apparatus 2 is used,

allow the capsule to sink to the bottom of the vessel prior to the rotation of the paddle.

A suitable device such as a wire or glass helix is used to keep capsule that would

otherwise float horizontal at the bottom of the vessel.

Care should be taken to ensure that air bubbles are excluded from the surface of

the capsule. Operate the apparatus immediately at the speed of rotation specified in the

individual monograph. when Apparatus 3 is used, place glass beads of a suitable size,

preferably 0.9 to 1.1 mm in diameter at the bottom of the cone to protect the fluid entry

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of the tube and introduce the capsule in the cell on or within the layer of glass

beads or by means of a holder. Assemble the filter head and fix the parts together by

means of a suitable clamping device. warm the dissolution medium to between 36.50

and 37.50

and introduce it through the bottom of the cell using the suitable pump to

obtain a suitable continuous flow at the specified rate (+/-5%)

Take sample at 45 minutes or at the prescribed intervals or continuously.

Withdraw the samples from a point half way between the surface of the dissolution

medium and the top of the rotating basket or blade, NLT 10mm from the wall of the

vessel, or from the continuously flowing medium of the flow through cell. Except in the

cases of continuous flow with the paddle or basket method, where the liquid removed is

returned to the dissolution vessel, and single sampling, add a volume of dissolution

medium equal to the volume of sample withdrawn or compensate by calculation. Filter

the samples at 36.50 to 37.5

0 and determine the amount of active ingredient present by

the method prescribed in the individual monograph. The filter used is inert, causes no

significant absorption of the active ingredient from the solution, contains no materials

extractable by the dissolution medium that would interfere with the prescribed

analytical procedures and has an appropriate pore size.

Repeat the complete operation five times. Where 1 capsule is directed to be

placed in the apparatus, for each of the six capsules tested the amount of active

ingredient in solution is NLT 70% of the prescribed or stated amount, unless otherwise

specified in the monograph, except that if one fails this requirement a further six may

be tested individually and all must comply. Where two or more capsules are directed to

be placed together in the apparatus, a total of six replicates tests are carried out. In each

test the amount of active ingredient in solution per capsule is NLT 70% of the

prescribed or stated amount, unless otherwise specified in the monograph. No retesting

is permitted.

Where capsule shells interfere with the analysis, remove the content of no fewer

than six capsules as completely as possible and dissolve the empty capsule shells in the

specified volume of the dissolution medium. Carry out the test as directed in the

individual monograph and make any necessary correction. Correction factors should

not be greater than 25% of the labeled content.

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6.2 EVALUATION PARAMETERS OF MICROCAPSULES(125)

A. Surface Morphology :

Microcapsules prepared by the interfacial polymerization method have spherical

geometry with a continuous core; wall structure. The interior surface of these

microcapsules is generally irregular, where as the exterior surface is uniform and

smooth. Spherical microcapsules have a rough porous surface with deep splits

penetrating to the centre of the capsules.

B. Size and Size Distribution :

In general, the interfacial polymerization method can be used to produce large

microcapsules of around 20-30 μm diameter. However, microcapsules of 3-6 μm can

also be produced by this method. The effect of variation in polymerization conditions

(such as variations in temperature and monomer concentration ) on the size of

microcapsules. Decrease in temperature and monomer concentration was found to

increase microcapsule size. Effect of process variable such as; nozzle size, flow rate of

disperse phase, interelectrode distance, and presence of and acid acceptor on the size

distribution. Increase in nozzle diameter and decrease in interelectrode distance was

found to decrease the microcapsule size, whereas addition of acid acceptor and

thickening agent resulted in an increase in average capsule size. The diameter of

microcapsules decreased and their distribution became narrower as the emulsifying

time was increased within the initial time period of 45s. As the agitation speed was

increased, particle size decreased. The addition of a co-surfactant significantly reduced

the mean droplet size of the initial emulsion leading to the formation of microcapsules

in the sub micrometer range.

C. Membrane Properties :

The thickness, permeability, and stability of the membranes are important

parameters of the microcapsules.

1. Membrane Thickness : The membrane thickness of microcapsules depends on

the method of preparation. Microcapsules prepared by interfacial

polymerization in the monometer range because the membrane thickening is

restricted by the limited solubility of the reactants in the phase to be

encapsulated.

2. Membrane Permeability: Membrane permeability characteristic of

microcapsules membranes is very important in the design of drug delivery and

artificial organs using microcapsules. This characteristic of the microcapsules

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provide us with useful information for sustained/ controlled release properties of the

encapsulated drugs. Membrane permeability is defined by the thickness, pore size,

and chemical composition of the polymer shell. Membrane permeability defines the

rate of substrate mass transfer from the surrounding solution into the microcapsules.

These difference in permeability coefficients between two different polymer walls

suggested the necessary to investigate the microcapsules permeability as a function

of capsule size, membrane thickness, temperature, molecular size of solute, and

concentration gradient. The penetration rate of electrolyte ions through

microcapsule size showed an abrupt increase.

3. Membrane Stability : The stability of microcapsule membranes by varying

the total ratio polymer, ratios of amines to acid chlorides, concentration of

surfactants, and stirring speed. They obtained stable capsule membrane by

increasing the ratio of amine to acid chlorides and with low concentration of

total polymer.

D. Potential :

Microcapsules prepared by the interfacial polymerization technique have a

microcapsule membrane that does not bear any electric charge. However, when

suspended in an aqueous medium, they migrate either to anode or cathode, depending

on the sign of electric charge on the encapsulated polyelectrolyte. The nobilities were

decreased with increasing ionic strength of the medium pH of the dispersing medium

also affected electrophoretic mobility. Microcapsules moved either to anode or cathode

depending on the pH of the medium showing the existence of an isoelectric point.

Addition of an emulsifier to the aqueous phase also rresulted in a decrease in the

potential of the microcapsules.

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7. SPECIAL APPLICATIONS OF CAPSULES(126)

Capsules are popular for some other applications like: Substitute for suppositories.

Packaging of ophthalmic ointments and packaging of inhalants.

Gelatin capsules for rectal or vaginal use replace oleaginous and water-soluble

suppositories.

There are many advantages of the soft gelatin capsules which have been used to

insert into body cavities after moistening them with water like:

Drug remains safe for long period.

Capsules can hold large doses as compared to suppositories.

Storage of soft gelatin capsules is easy compared to oleaginous suppositories and

Capsules take less time to disintegrate as compared to suppositories.

Soft gelatin capsules are now becoming very popular as “applicaps”, which are

single applications of eye ointments.

These are discarded after tubes are as under: They are hermetically sealed hence

sterility is maintained through out its shelf-life.

They are pricked at the time of application and applied with slight pressure to the

ophthalmic cavity.

This does not allow contamination from the microbes during frequent opening and

closing of the cap of conventional tube.

Applicaps are more economical as wastage of ointment is negligible.

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8. SUMMARY :

“Capsules are solid dosage forms in which the drug substance is enclosed in either a

hard or soft soluble container or shell of a suitable form of gelatin.”

In addition to having the advantages of elegance, ease of use, and portability,

capsules have become a popular dosage form because they provide a smooth, slippery,

easily swallowed, and tasteless shell for drugs; the last advantage is particularly

beneficial for drugs having an unpleasant taste or odor. Telescoping capsules are made

principally of gelatin blends and may contain small amounts of certified dyes, opaquing

agents, plasticizers, and preservatives. The main three types of capsules include the

following:

Hard Gelatin Capsule

Soft Gelatin Capsule

Microencapsulation

Capsules have been made with methylcellulose, polyvinyl alcohols, and

denatured gelatins to modify their solubility or produce and enteric effect. They are

formed by dipping cool stainless steel mold pins into a gelatin solution. Other methods,

such as centrifugal casting, have been used, but the pin method is the only one used in

large-scale commercial production.

Hard gelatin capsules are thin shells of gelatin. Shell consists of two parts, the

longer being Known, as base or body and the shorter as the cap. One part slipping over

the other, thus completely surrounding the drug formulation. These are not used for

administration of extremely soluble materials such as potassium bromide, potassium

chloride, or ammonium chloride since the sudden release of such compounds in the

stomach could result in irritating concentrations.

Soft Gelatin owing to their special properties and advantages are used in a wide

variety of industries but they are most widely used in the pharmaceutical industry.

Essentially these capsules are solid dosage forms containing liquid medication and they

permit the liquid medication to become easily portable.

Microencapsulation is a rapidly expanding technology and is a means of

applying thin coatings to small particles of solids or droplets of liquids and dispersions.

The applications of microencapsulation includes sustained-release or prolonged-action

medications, taste-masked chewable tablets, powders and suspensions, single-layer

tablets containing chemically incompatible ingredients, and new formulation concepts

for creams, ointments, aerosols, dressings, plasters, suppositories, and injectables.

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9. REFRENCES

1. L.Lachman et al, The Theory And Practice Of Industrial Pharmacy, 3rd

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additives on the release of drug from hard gelatin capsules, J.

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38. K.S.Murthy and J.C. Samyn, Effect of shear mixing on in vitro drug release of

capsule formulations containing lubricants, J.Pharm .Sci. 66, 1215(!977)

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