Uy, Alyssa V.

2BPh
Chapter 7 – CAPSULES  made of gelatin, sugar & water
 clear, colorless & essentially tasteless
 colored with various FD&C and D&C dyes and made opaque by
CAPSULES
adding agents such as TITANIUM DIOXIDE
- solid dosage forms in which one or more medicinal &/or inert  combination of colorants & opaquants to make them distinctive,
substances are enclosed within a small shell or container many with caps & bodies of different colors
generally prepared from a suitable form of gelatin
- Depending upon their formulation, the gelatin capsule shells GELATIN
may be hard or soft.
 is obtained by the partial hydrolysis of collagen obtained from skin,
Characteristics: white connective tissue & bones of animals
 available in the form of a fine powder, a coarse powder, shreds,
1. May be swallowed whole by the patient flakes, or sheets
2. May be inserted into the rectum for drug release & absorption from  Stable in air when dry but when become moist - subject to microbial
the site decomposition
3. The contents may be removed from the gelatin shell & employed as  HGC contain 13-16% of moisture
a pre measured medicinal powder, the capsule shell being use to  extreme dryness - capsules may become brittle & crumble
contain a dose of the medicinal subs. (e.g. Theo-dur Sprinkle)  capsules absorbed moisture - a small packet of a dessicant material -
4. Elegance to protect against moisture
5. Ease of use  dessicant use = DRIED SILICA, GEL, CLAY, ACTIVATED CHARCOAL
6. Portability  prolong exposure to high humidity can affect in vitro capsules
7. Tasteless shell to mask the unpleasant taste/odor of the drug dissolution - changes have been observed in capsules containing
8. Permits physician to prescribe the exact medication TETRACYCLINE, CHLORAMPHENICOL, NITROFURANTOIN

9. Conveniently carried  gelatin is insoluble in cold water & soluble in hot water and in warm
10. Readily identified gastric fluid
11. Easily taken  gelatin being a protein, is digested by PROTEOLYTIC ENZYMES and
12. Tasteless when swallowed absorbed
13. Commonly embossed or imprinted on their surface the
manufacturer’s name and product code readily identified Method used to track the passage of capsules and tablets through GIT to map
14. Available in variety of dosage strength their transit time and drug release patterns
15. Provide flexibility to the prescriber & accurate individualized dosage
1. Scintigraphy - a noninvasive procedure that entails use of gamma
for the patient
ray- emitting radiotracer incorporated into the formulation with
16. Packaged & shipped by manufacturers at lower cost less breakage
gamma camera coupled to a data recording system
than liquid forms
2. When Scintigraphy is combined with pharmacokinetic studies, the
17. More stable & longer shelf life
resultant pharmacoscintographic evaluation provides information
Components of Capsules 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.
1. Gelatin
2. FD&C and D&C colorant Uses of Pharmacoscintographic
3. Sugar
1. Determining whether a correlation exists between in vitro and in vivo
4. Water  12-16% but may vary depending on the storage condition
bioavailability for immediate-release products
5. Sulfur dioxide (.15%) - prevent decomposition during manufacture
2. Assessing the integrity and transit time of enteric coated tablets
6. Opaquants/Opacifying agent - titanium dioxide
through the stomach en route to intestines
HARD GELATIN CAPSULES 3. Drug and dosage form evaluation in new product development
4. A separate technique using a pH-sensitive nondigestible
- Also referred to as “DFC” (Dry Filled Capsule) radiotelemetric device termed the Heidelberg capsule, the
- Manufactured into 2 sections, the capsule body and a shorter approximate size of a No. 0 gelatin capsule, has been used as a
cap nonradioactive means
- A recent innovation in capsule shell design is the Snap-Fit, Coni- o To measure gastric pH
Snap, and Coni Snap Supro hard gelatin capsules. o Gastric residence time
o Gastric emptying time of solid dosage forms in fasting &
Capsule size nonfasting human objects

For human use, empty capsules ranging in size from 000 the largest Drug absorption depends on a number of FACTORS
to 5 the smallest. Generally, hard gelatin capsule are used to encapsulate
between 65 mg to 1 gram 1. Solubility of the drug
2. Type of product formulation ( immediate release, modified,enteric)
HARD GELATIN CAPSULES 3. Gastrointestinal contents
4. Physiologic character & response
 usually use in the extemporaneous compounding of Rx

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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 Lubricants/glidants Talc, colloidal silicon dioxide
wetting by the Gastrointestinal fluids to overcome the problem Wetting agent Sodium lauryl sulfate
- inserting tablets or small capsules into capsules are possible Capsule opaquant Titanium dioxide

Examples:

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

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
- 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

Tetracycline Capsules
Vibration-Assisted Filling
Active Ingredient Tetracycline hydrochloride 250 mg
Filler Lactose
 Capsules are placed under the powder bowl
Lubricant/glidant Magnesium stearate
 Powders or granules pass through the bowl’s mesh flow with help of
Capsule colorants FD & C Yellow No.6, D & C Yellow no.10, D & C
vibration
Red No.28, FD & C Blue No.1
 Bodies are filled to maximum plus more on top
Capsule opaquant Titanium dioxide
 Spring-loaded plunger compresses the powder inside the capsule
Acetaminophen With Codeine Capsules
body to make a firm plug
Active ingredients Acetaminophen 325 mg,  A scraper removes the powder outside the turn table bores
Codeine phosphate 30 mg  Capsule bodies are pushed upwards to be closed
Disintegrant Sodium starch glycolate
Lubricant/glidants Magnesium stearate, stearic acid
Filling of Pellets
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)
1. Double Slide Method
Diphenhydramine Hydrochloride Capsules
 Pellets flow from pellet machine to dosing chambers
Active ingredient Diphenhydramine HCl 25 mg  Dosing slide is closed to separate dosing chamber and
Filler Confectioner’s sugar 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.
 9. Moisture Permeation Test
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
 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 Advantages Of Coni-Snap
8. Packaging
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

Empty Hard Gelatin Capsule Physical Specifications

Typical Fill Weights 1. Tapered rim

Outer Diameter Height or Locked Actual Volume
Size (mg) 0.70 Powder
(mm) Length (mm) (mL)
Density 2. Grooves

000 9.91 26.14 1.37 960 3. Indentations

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

Preparation Of Filled Hard Gelatin Capsules

3 5.82 15.90 0.30 210
1. Developing & preparing the formulation & selecting the size of
capsule
4 5.31 14.30 0.21 145
2. Filling the capsule shell
3. Cleaning and polishing the filled capsules
5 4.91 11.10 0.13 90

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  Two ribbons can be sealed and cut along the slightly raised rims
completely automatically by leading two films of gelatin between a of the dies for filling
set of vertical dies. These dies as they close, open, and close, are in  The capsule is washed with organic solvent and pre-dried
effect a continual vertical plate forming row after row of pockets  Advantages:
across the gelatin film. These are filled with medicament and as they - capsules can have all kinds of shapes & sizes
progress through the dies, are sealed, shaped, and cut out of the film - different colors for both sides
as capsules which drop into a cooled solvent bath. - wide variety of fills
4. Accogel Capsule Machine. Or Stern machine, uses a system of rotary  Disadvantages:
dies but is unique in that it is the only machine that can successfully - high amount of shell waste material
fill dry powder into a soft gelatin capsule. - longer drying time compared to Globex Method

Application Of Soft Gelatin Capsule Check-weighing Based on Gravity Flow

 The capsules are fed from the hopper by means of a drive
Liquid which may be encapsulated into soft gelatin capsules include:
mechanism and size-dependent guiding plate onto the weighing cell.
1. Water immiscible, volatile & nonvolatile liquids such as
 After check weighing, the capsules are classified into correctly and
vegetable & aromatic oils, aromatic and aliphatic
incorrectly filled ones
hydrocarbons, chlorinated hydrocarbons, ethers, esters,
alcohol & organic acids.
2. Water miscible, nonvolatile liquids such as polyethylene
Cleaning and Polishing
glycols, and nonionic surface active agents as polysorbate 80
 On a small scale, capsules maybe cleaned individually or in
3. Water miscible and relatively nonvolatile compounds, as
small numbers by rubbing them with a clean gauze or cloth.
propylene glycol and isopropyl alcohol, depending upon factors
 On a large scale, many capsule-filling machines are affixed with
as concentration used and packaging conditions.
a cleaning vacuum that removes any extraneous material from
the capsules as they exit the equipment. Or using Accela-Cota
Drugs commercially prepared in Soft Gelatin capsules:
apparatus.
1. Ethychlorvynol (Placidyl)
Inspecting, Counting, Packaging, and Storing Capsule
2. Demeclocycline HCl ( Declomycin )
3. Chlortrianisene (TACE)
1. Using Sanitary Counting Tray
4. Digoxin (Lanoxicaps)
(a) placing units from stock package onto tray,
5. Docusate calcium (Surfak)
(b) counting and transferring units to trough,
6. Vitamin E
(c) returning excess units to stock container,
(d) placing counted units into prescription container.
Manufacturing Soft Gel Capsules
2. Using Mini-Counter II
1. Globex Method
- Small automatic tablet and capsule counting and filling
 Filling is pumped through the inner capillary of a concentric
apparatus.
double capillary
3. Using Versacount Model
 Shell forming solution is pumped through the outer capillary of
- Automatic tablet and capsule counting and filling apparatus.
the concentric double capillary
4. Using large Merill filling machine
 The soft capsules are then immersed in a cooling bath of about - fills 16 bottles with 200 tablets each at one time, a flipper gate in the
4oC (usually liquid paraffin) upper manifold directs the tablets into one row of bottles while the
 Cooling bath ensures immediate sol-gel transformation, hence other filled row is evacuated and a new row of bottles moves into place.
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

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