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Chapter 7 – CAPSULES

CAPSULES

- solid dosage forms in which one or more medicinal &/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.

Characteristics:

1. May be swallowed whole by the patient

2. May be inserted into the rectum for drug release & absorption from

the site

3. The contents may be removed from the gelatin shell & employed as

a pre measured medicinal powder, the capsule shell being use to

contain a dose of the medicinal subs. (e.g. Theo-dur Sprinkle)

4. Elegance

5. Ease of use

6. Portability

7. Tasteless shell to mask the unpleasant taste/odor of the drug

8. Permits physician to prescribe the exact medication

9. Conveniently carried

10. Readily identified

11. Easily taken

12. Tasteless when swallowed

13. Commonly embossed or imprinted on their surface the

manufacturer’s name and product code readily identified

14. Available in variety of dosage strength

15. Provide flexibility to the prescriber & accurate individualized dosage

for the patient

16. Packaged & shipped by manufacturers at lower cost less breakage

than liquid forms

17. More stable & longer shelf life

Components of Capsules

1. Gelatin

2. FD&C and D&C colorant

3. Sugar

4. Water 12-16% but may vary depending on the storage condition

5. Sulfur dioxide (.15%) - prevent decomposition during manufacture

6. Opaquants/Opacifying agent - titanium dioxide

HARD GELATIN CAPSULES

- Also referred to as “DFC” (Dry Filled Capsule)

- Manufactured into 2 sections, the capsule body and a shorter

cap

- A recent innovation in capsule shell design is the Snap-Fit, Coni-

Snap, and Coni Snap Supro hard gelatin capsules.

Capsule size

For human use, empty capsules ranging in size from 000 the largest

to 5 the smallest. Generally, hard gelatin capsule are used to encapsulate

between 65 mg to 1 gram

HARD GELATIN CAPSULES

usually use in the extemporaneous compounding of Rx

made of gelatin, sugar & water

clear, colorless & essentially tasteless

colored with various FD&C and D&C dyes and made opaque by

adding agents such as TITANIUM DIOXIDE

combination of colorants & opaquants to make them distinctive,

many with caps & bodies of different colors

GELATIN

is obtained by the partial hydrolysis of collagen obtained from skin,

white connective tissue & bones of animals

available in the form of a fine powder, a coarse powder, shreds,

flakes, or sheets

Stable in air when dry but when become moist - subject to microbial

decomposition

HGC contain 13-16% of moisture

extreme dryness - capsules may become brittle & crumble

capsules absorbed moisture - a small packet of a dessicant material -

to protect against moisture

dessicant use = DRIED SILICA, GEL, CLAY, ACTIVATED CHARCOAL

prolong exposure to high humidity can affect in vitro capsules

dissolution - changes have been observed in capsules containing

TETRACYCLINE, CHLORAMPHENICOL, NITROFURANTOIN

gelatin is insoluble in cold water & soluble in hot water and in warm

gastric fluid

gelatin being a protein, is digested by PROTEOLYTIC ENZYMES and

absorbed

Method used to track the passage of capsules and tablets through GIT to map

their transit time and drug release patterns

1. Scintigraphy - a noninvasive procedure that entails use of gamma

ray- emitting radiotracer incorporated into the formulation with

gamma camera coupled to a data recording system

2. When Scintigraphy is combined with pharmacokinetic studies, the

resultant pharmacoscintographic evaluation provides information

about the transit and drug release patterns of the dosage form as

well as the rate of drug absorption from the various regions of GT.

Uses of Pharmacoscintographic

1. Determining whether a correlation exists between in vitro and in vivo

bioavailability for immediate-release products

2. Assessing the integrity and transit time of enteric coated tablets

through the stomach en route to intestines

3. Drug and dosage form evaluation in new product development

4. A separate technique using a pH-sensitive nondigestible

radiotelemetric device termed the Heidelberg capsule, the

approximate size of a No. 0 gelatin capsule, has been used as a

nonradioactive means

o To measure gastric pH

o Gastric residence time

o Gastric emptying time of solid dosage forms in fasting &

nonfasting human objects

Drug absorption depends on a number of FACTORS

1. Solubility of the drug

2. Type of product formulation ( immediate release, modified,enteric)

3. Gastrointestinal contents

4. Physiologic character & response

Uy, Alyssa V.

2BPh

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Manufacture of Hard Gelatin Capsule

manufactured into 2 sections, the capsule body and the shorter cap

the 2 parts overlap when joined, with the cap fitting snugly over the

open end of the capsule body

shells are produced by chemical dipping of pins or pegs of the

desired shape & diameter into a temperature-controlled reservoir of

melted gelatin mixture

the pegs made of manganese bronze, are affixed to plates, each

capable of holding up to about 500 pegs

each plate is mechanically lowered to the gelatin bath, the peg

submerge to the desired depth & maintained for the desired period

to achieve the proper length & thickness of coating

the plate and the pegs are slowly lifted from the bath and the gelatin

dried by a gentle flow of temperature-and humidity-controlled air

when dried, each capsule part is trimmed mechanically to the proper

length and removed from the pegs, the capsule bodies and caps are

joined together

1. Once raw materials have been received & released by Quality Control, the

gelatin & hot demineralized water are mixed under vacuum in Stainless Steel

Gelatin Melting System.

2. After aging in stainless steel receiving tanks, the gelatin solution is transferred

to stainless steel feed tanks.

3. Dyes, opacifants, and any needed water are added to the gelatin in the feed

tanks to complete the gelatin preparation procedure. The feed tanks are then

used to gravity-feed gelatin into the Capsule Machine

4. From the feed tank, the gelatin is gravity fed to Dipper section. Here, the

capsules are molded onto stainless steel Pin Bars which are dipped into the

gelatin solution.

5. Once dipped, the Pin Bars rise to the upper deck allowing the cap and body to

set on the Pins.

6. The Pin Bars pass through the upper and lower kilns of Capsule Machine

Drying System. Here gently moving air which is precisely controlled for volume,

temperature, and humidity, removes the exact amount of moisture from the

capsule halves.

7. Once drying is complete, the Pin Bars enter the Table section which positions

the capsule halves for stripping from the Pins in the Automatic section.

8. In the Automatic section, capsule halves are individually stripped from the

Pins.

9. The cap and body lengths are precisely trimmed to a ±0.15 mm tolerance.

10. The capsule bodies and caps are joined automatically in the joiner blocks.

11. Finished capsules are pushed onto a conveyer belt which carries them out to a

container.

12. Capsule quality is monitored throughout the production process including size,

moisture content, single wall thickness, and color.

13. Capsules are sorted and visually inspected on specially designed R&J

Inspection Stations.

14. Perfect capsules are imprinted with the client logo on high-speed

Empty capsule property

Empty capsule contain a significant amount of water that acts as

plasticizer for the gelatin film and is essential for their function.

The standard moisture content specification of HGC is between 13-16% w/w.

MANUFACTURING OF SOFT GELATIN CAPSULES

1. Preparation of the fill material

- This process is specific to each product

2. Shell-film formation

- The shell mass is heated and melted as required. The

molten material is pressure-fed to extrusion dies via a

metering pump, producing a film as the mass is extruded

onto a casting drum. The film thickness is precisely

controlled using electronic positioning of the extrusion

dies.

3. Encapsulation

- The resulting films are peeled from the casting drums and

fed between a pair of rotating dies. A “FORM, FILL, SEAL”

process is used that is identical to the one used to

prepare traditional softgels. Capsule seals are formed by

a combination of heat and pressure. The freshly formed

soft gels are then transferred to drying device.

4. Drying

- The first stage – a tumble drier –removes a significant

portion of the water present in the shell. The semi-dried

capsules are spread onto trays and kept under controlled

temperature and humidity to complete the drying

activity.

5. Inspection & Sorting

- The dried capsules are inspected and sorted to ensure

uniformity in weight, size and shape.

Developing the Formulation and Selection of Capsule Size

The goal is to prepare a capsule with accurate dosage, good

bioavailability, ease of filling& production, stability and elegance

The active and inactive components must be blended thoroughly to

ensure a uniform powder mix for the fill

Preformulation studies are performed to determine whether all of

the formulation’s bulk powders may be effectively blended together.

Diluent or filler may be added to produce the proper capsule fill

volume - ex. LACTOSE, MICROCRYSTALLINE CELLULOSE and STARCH

Disintegrants are frequently included in a capsule formulation - to

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

stomach - ex. PREGELATINIZED STARCH, CROSCARMELLOSE, SODIUM

STARCH GLYCOLATE

When necessary, particle size may be reduced by milling to produce

particles ranging from 50 to 1000 µm

Drugs of lower dose or smaller particles are required, micronization

is employed - 1 to 20 um particle size

Industrial Scale

- The powder mix must be free-flowing to allow steady passage of the

capsule fill from hopper and into the capsule shell

- Addition of lubricant or glidant - FUMED SILICON DIOXIDE, MAGNESIUM

STEARATE, CALCIUM STEARATE, STEARIC ACID or TALC (about 0.25-1%) to

the powder mix enhances flow properties

- Magnesium stearate as lubricant, the water proofing characteristics

of this water-insoluble material can retard penetration by the

gastrointestinal fluids and delay drug dissolution and absorption

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- A surface active agent - sodium lauryl sulfate, is used to facilitate

wetting by the Gastrointestinal fluids to overcome the problem

- inserting tablets or small capsules into capsules are possible

Examples:

Developing the Formulation and Selection of Capsule Size

Gelatin capsules are unsuitable for aqueous liquids because water

softens gelatin and distorts the capsules, resulting leakage of the

content

Some liquids or volatile oil do not interfere with the stability of the

gelatin shells - may be placed in locking gelatin capsules to ensure

retention of the liquid

Eutectic mixtures of drugs - tends to liquefy - may be mixed with a

diluent or absorbent such as magnesium carbonate, kaolin or light

magnesium oxide to separate the interacting agents and to absorb

any liquefied material that may form

Liquids are placed in soft gelatin capsules that are sealed during

filling and manufacturing

Selection of capsule size is done during product development

The choice is determined by requirements of formulation, including the dose of

the active ingredient and the density and compaction characteristics of the

drugs.

Hard gelatin capsules are used to encapsulate about 65 mg to 1 g of powdered

material

Tetracycline Capsules

Active Ingredient Tetracycline hydrochloride 250 mg

Filler Lactose

Lubricant/glidant Magnesium stearate

Capsule colorants FD & C Yellow No.6, D & C Yellow no.10, D & C

Red No.28, FD & C Blue No.1

Capsule opaquant Titanium dioxide

Acetaminophen With Codeine Capsules

Active ingredients Acetaminophen 325 mg,

Codeine phosphate 30 mg

Disintegrant Sodium starch glycolate

Lubricant/glidants Magnesium stearate, stearic acid

Capsule colorants D & C Yellow No. 10, edible Ink, FD & C Blue No.1 (FD & C

Green No.3 and FD & C Red No. 40)

Diphenhydramine Hydrochloride Capsules

Active ingredient Diphenhydramine HCl 25 mg

Filler Confectioner’s sugar

Lubricants/glidants Talc, colloidal silicon dioxide

Wetting agent Sodium lauryl sulfate

Capsule opaquant Titanium dioxide

Filling Hard Capsules Shells

1. Use Punch Method

- powder is placed on a sheet of a clean paper or porcelain plate

- using spatula - formed into a cake having a depth of approximately

one-fourth to one-third the length of the capsule body

- then empty capsule body is held between the thumb and forefinger

and punched vertically into the powder cake repeatedly until filled

2. Feton capsule filling

- with empty capsule in the loader tray, the tray placed on top of the

filler unit

- the loader inserts the capsules into the filling unit and is removed,

and the top plate is lifted to separate the caps from the bodies

- the powder is placed on the unit and the capsule bodies filled

- the top plate is returned to the unit and the caps placed on filled

capsule bodies

ProFill 100 - The ProFill 100 Capsule Filling Machine utilizes an advanced design

for fool-proof manual filling of two-piece capsules. With the ProFill 100

machine, there is no need for expensive capsule filling equipment and

electrical/vacuum connections.

Auger-Filling Principle

Powder or granules are contained in mass flow hoppers with rotating

augers

Powder is fed continuously out of the hopper outlet due to the

rotation of the auger.

Amount of powder fed into the body depends on the time capsule

body spends underneath the hopper outlet and auger speed

- slower rotation increases the fill weight

Vibration-Assisted Filling

Capsules are placed under the powder bowl

Powders or granules pass through the bowl’s mesh flow with help of

vibration

Bodies are filled to maximum plus more on top

Spring-loaded plunger compresses the powder inside the capsule

body to make a firm plug

A scraper removes the powder outside the turn table bores

Capsule bodies are pushed upwards to be closed

Filling of Pellets

1. Double Slide Method

Pellets flow from pellet machine to dosing chambers

Dosing slide is closed to separate dosing chamber and

pellet magazine

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Outlet slides open

2. Vacuum-assisted Method

Dosing tube enters pellet bed

With the help of vacuum, the pellets are sucked into the

dosing tube

Excess pellet are scraped off the end of the dosing tube

Dosing tube is lowered and pellets released into capsule

body

Filling of Tablets

Dosing slide, which can accommodate exactly 1 tablet, moves underneath tablet feeder

Slider moves over the capsule body where tablet simply drops into it If properly filled, the pin dropped into the capsule body will have

limited movements, the horizontal bar connected to the pin touches the sensor

If not properly filled, horizontal bar will switch the sensor indicating incorrect filling. Empty capsules can be detected and eliminated from the product.

Capsule Sealing

1. Tamper evident capsules by sealing the joint between the 2 capsule

parts

2. Distinctive looking capsules by sealing them with colored band of

gelatin (KAPSEALS). If removed, the band cannot be restored w/o

expert sealing with gelatin

3. Through a heat welding process that fuses the capsule cap to the

body through the double wall thickness at their juncture - distinctive

ring around the capsule where heat welded

Ex.: Weld’s gelatin seal

4. Liquid wetting agent that lowers the melting point in the contact

areas of the capsule’s cap and the body using low temperatures (40-

450C)

5. Lightly coating the inner surface of the cap with a warm gelatin

solution immediately prior to placement on the filled capsule body.

The capsule sealing process of banding ( Kapseals, Quali-caps) has been utilized

for a number of years. In this process, two capsule parts are sealed with

gelatin or polymer band at the seam of the cap and body.

Recently, a tamper resistant seal on hard gelatin capsules was developed in

which the contact areas of the cap and body are wetted with a mixture of

water and ethanol and then thermally bonded at 1040 to 1130F.

Compendial Requirements for Capsules

1. Added Substances

a. Harmless in the quantities used

b. Do not exceed the minimum amounts required to provide their

intended effect

c. Do not impair the product’s bioavailability, therapeutic efficacy or

safety

d. Do not interfere with requisite compendial assays & test

2. Containers for dispensing

tight, well closed & light resistant containers depending on the item

3. Disintegration Test for Capsules

the capsules are placed in the basket rack assembly, which is

immersed 30 times per minutes into a thermostatically controlled

fluid at 37 0C and observed over the time described in the individual

monograph

4. Dissolution Test for capsules

5. Weight Variation

Hard Capsules - 10 capsules are individually weighed & the content

removed. Empty shells are individually weighed & the net weight of

the contents calculated by subtraction

Soft Gelatin - the gross weight of 10 intact capsules is determined

individually. Then each capsule is cut open & the contents removed

by washing with suitable solvent. The solvent is allowed to evaporate

at room temperature over about 30 minutes. The individual shells

are weighed and net contents calculated.

6. Content Uniformity

85-115% of the label claim for 9 of 10 dosage units assayed with no

unit outside the range of 70-125% of label claim

7. Content Labeling Requirement

all official capsules must be labeled to express the quality of each

active ingredient in each dosage unit

8. Stability Testing

to determine the appropriate conditions for storage and the

product’s anticipated shelf life

9. Moisture Permeation Test

determined by packaging the dosage unit together with a color-

revealing dessicant pellet, exposing the packaged unit to known

relative humidity over a specified time, observing the dessicant

pellet for color change (indicating absorption of moisture) &

comparing the pretest & posttest weight of the package unit

Inspecting, Counting, Packaging, and Storing Capsules

should have a uniform in appearance

defective capsules should be rejected

capsules may be counted manually or automated equipment

containers are then mechanically capped, inspected visually or

electronically, labeled, and inspected once more.

packaged in glass or in plastic containers

Oral Administration of Solid Dosage Forms

placing the dose upon tongue & swallowing it w/ a glassful of water

or beverages

without water is dangerous because of the possibility that will lodge

in the esophagus. Esophageal ulceration can occur with dry ingestion

of tablets and capsules, particularly taken just before bedtime

example of drugs of greatest concern are: ALENDRONATE SODIUM,

ASPIRIN, FERROUS SULFATE, NSAID, POTASSIUM CHLORIDE, & TETRACYCLINE

the proper administration of alendronate sodium tablets (FOSAMAX)

calls for tablets to be taken with full 6 or 8 ounce glass of plain water

upon rising in the morning or half an hour before taking any food –

to prevent local irritation of esophagus

Some Medications Commercially Prepared Into Soft Gelatin Capsule

1. Acetazolamide - Diamox = Carbonic anhydrase inhbitor

2. Cyclosporine - Sandimmune = Immunosuppressive

3. Cyclosporine - Neoral =Immunosuppressive

4. Digoxin - Lanoxicaps = Cardiac glycoside

5. Ethosuximide - Zarontin = Anticonvulsant

6. Ranitidine HCl - Zantac GELdose = Histamine H2 receptor inhibitor

Process Capsule Filling

1. Milling /Sieving of all Ingredients

2. Blending

3. Capsule Filler

4. Capsule cleaner/deduster

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5. Capsule injection screen

6. Capsule check-weighing system/reject

7. Finished capsules

8. Packaging

Empty Hard Gelatin Capsule Physical Specifications

Size Outer Diameter

(mm)

Height or Locked

Length (mm)

Actual Volume

(mL)

Typical Fill Weights

(mg) 0.70 Powder

Density

000 9.91 26.14 1.37 960

00 8.53 23.30 0.95 665

0 7.65 21.70 0.68 475

1 6.91 19.40 0.50 350

2 6.35 18.00 0.37 260

3 5.82 15.90 0.30 210

4 5.31 14.30 0.21 145

5 4.91 11.10 0.13 90

Advantages Of Coni-Snap

1. The tapered rim avoid telescoping

2. The indentations prevent premature opening

3. The grooves lock the two capsule parts together after the capsule has been

filled

1. Tapered rim

2. Grooves

3. Indentations

Preparation Of Filled Hard Gelatin Capsules

1. Developing & preparing the formulation & selecting the size of

capsule

2. Filling the capsule shell

3. Cleaning and polishing the filled capsules

SOFT GELATIN CAPSULES

- aka Soft Elastic Capsule

- prepared from shells of gelatin from w/c glycerin or a polyhydric

alcohol and as sorbitol has been added to render the gelatin elastic

or plastic like.

- The gelatin is plasticized by the addition of glycerin, sorbitol or

polyol. The shell may contain preservatives to prevent from fungi.

A soft gelatin capsule has a seam at the point of closure of the 2

halves, and the contents can be liquid, paste or powder

Methods For commercial Manufacture Of Soft Gelatin Capsule

1. Plate-Process. A warm sheet of prepared gelatin is laid over the

lower plate and the liquid is poured on it. A second sheet of gelatin

is carefully put in place and this is followed by the top plate of the

mold. The set is placed under the press where pressure is applied to

form the capsule which is washed off with a volatile solvent to

remove any trace of oil from exterior.

2. Rotary Die Process. The rotary die machine is a self-contained unit

capable of continuously & automatically producing finished capsules

from a supply of gelatin mass and filling material which may be any

liquid, semi- liquid, or paste that will not dissolve gelatin. Two

continuous gelatin ribbons, which the machine forms, are brought

into convergence between a pair of revolving dies and an ejection

wedge.

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3. Norton Capsule Machine. This machine produces capsule

completely automatically by leading two films of gelatin between a

set of vertical dies. These dies as they close, open, and close, are in

effect a continual vertical plate forming row after row of pockets

across the gelatin film. These are filled with medicament and as they

progress through the dies, are sealed, shaped, and cut out of the film

as capsules which drop into a cooled solvent bath.

4. Accogel Capsule Machine. Or Stern machine, uses a system of rotary

dies but is unique in that it is the only machine that can successfully

fill dry powder into a soft gelatin capsule.

Application Of Soft Gelatin Capsule

Liquid which may be encapsulated into soft gelatin capsules include:

1. Water immiscible, volatile & nonvolatile liquids such as

vegetable & aromatic oils, aromatic and aliphatic

hydrocarbons, chlorinated hydrocarbons, ethers, esters,

alcohol & organic acids.

2. Water miscible, nonvolatile liquids such as polyethylene

glycols, and nonionic surface active agents as polysorbate 80

3. Water miscible and relatively nonvolatile compounds, as

propylene glycol and isopropyl alcohol, depending upon factors

as concentration used and packaging conditions.

Drugs commercially prepared in Soft Gelatin capsules:

1. Ethychlorvynol (Placidyl)

2. Demeclocycline HCl ( Declomycin )

3. Chlortrianisene (TACE)

4. Digoxin (Lanoxicaps)

5. Docusate calcium (Surfak)

6. Vitamin E

Manufacturing Soft Gel Capsules

1. Globex Method

Filling is pumped through the inner capillary of a concentric

double capillary

Shell forming solution is pumped through the outer capillary of

the concentric double capillary

The soft capsules are then immersed in a cooling bath of about

4oC (usually liquid paraffin)

Cooling bath ensures immediate sol-gel transformation, hence

formation of flexible yet firm robust outer film.

Soft capsules are collected, washed with organic solvent to

remove residues of cooling liquid & gently dried at a relative

humidity of 20% in infrared tunnels.

Advantage: production of seamless capsules which are tamper-

evident and free of contamination or entrapped air.

2. Rotary Die Method

Shell materials are converted into liquid state.

Plasticizers and other additives are added to the liquid shell

materials.

Shell ribbons are formed and passed through cooling bath. This

transforms sol state to gel state.

After cooling bath, capsules are lubricated on either side with

liquid paraffin or vegetable oil.

The ribbons are guided to counter-rotating rolls containing

sharp- edged dies

Each die cavity has the size and shape of half of the capsule

Die rolls are pressed together with pressure

Two ribbons can be sealed and cut along the slightly raised rims

of the dies for filling

The capsule is washed with organic solvent and pre-dried

Advantages:

- capsules can have all kinds of shapes & sizes

- different colors for both sides

- wide variety of fills

Disadvantages:

- high amount of shell waste material

- longer drying time compared to Globex Method

Check-weighing Based on Gravity Flow

The capsules are fed from the hopper by means of a drive

mechanism and size-dependent guiding plate onto the weighing cell.

After check weighing, the capsules are classified into correctly and

incorrectly filled ones

Cleaning and Polishing

On a small scale, capsules maybe cleaned individually or in

small numbers by rubbing them with a clean gauze or cloth.

On a large scale, many capsule-filling machines are affixed with

a cleaning vacuum that removes any extraneous material from

the capsules as they exit the equipment. Or using Accela-Cota

apparatus.

Inspecting, Counting, Packaging, and Storing Capsule

1. Using Sanitary Counting Tray

(a) placing units from stock package onto tray,

(b) counting and transferring units to trough,

(c) returning excess units to stock container,

(d) placing counted units into prescription container.

2. Using Mini-Counter II

- Small automatic tablet and capsule counting and filling

apparatus.

3. Using Versacount Model

- Automatic tablet and capsule counting and filling apparatus.

4. Using large Merill filling machine

- fills 16 bottles with 200 tablets each at one time, a flipper gate in the

upper manifold directs the tablets into one row of bottles while the

other filled row is evacuated and a new row of bottles moves into place.

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