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 Empty capsule contain a significant amount of water that acts as
plasticizer for the gelatin film and is essential for their function.
 manufactured into 2 sections, the capsule body and the shorter cap
 the 2 parts overlap when joined, with the cap fitting snugly over the The standard moisture content specification of HGC is between 13-16% w/w.
open end of the capsule body
 shells are produced by chemical dipping of pins or pegs of the MANUFACTURING OF SOFT GELATIN CAPSULES
desired shape & diameter into a temperature-controlled reservoir of 1. Preparation of the fill material
melted gelatin mixture - This process is specific to each product
 the pegs made of manganese bronze, are affixed to plates, each 2. Shell-film formation
capable of holding up to about 500 pegs - The shell mass is heated and melted as required. The
 each plate is mechanically lowered to the gelatin bath, the peg molten material is pressure-fed to extrusion dies via a
submerge to the desired depth & maintained for the desired period metering pump, producing a film as the mass is extruded
to achieve the proper length & thickness of coating onto a casting drum. The film thickness is precisely
 the plate and the pegs are slowly lifted from the bath and the gelatin controlled using electronic positioning of the extrusion
dried by a gentle flow of temperature-and humidity-controlled air dies.
3. Encapsulation
 when dried, each capsule part is trimmed mechanically to the proper
- The resulting films are peeled from the casting drums and
length and removed from the pegs, the capsule bodies and caps are
fed between a pair of rotating dies. A “FORM, FILL, SEAL”
joined together
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
1. Once raw materials have been received & released by Quality Control, the soft gels are then transferred to drying device.
gelatin & hot demineralized water are mixed under vacuum in Stainless Steel 4. Drying
Gelatin Melting System. - The first stage – a tumble drier –removes a significant
2. After aging in stainless steel receiving tanks, the gelatin solution is transferred
portion of the water present in the shell. The semi-dried
to stainless steel feed tanks.
capsules are spread onto trays and kept under controlled
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 temperature and humidity to complete the drying
used to gravity-feed gelatin into the Capsule Machine activity.
4. From the feed tank, the gelatin is gravity fed to Dipper section. Here, the 5. Inspection & Sorting
capsules are molded onto stainless steel Pin Bars which are dipped into the - The dried capsules are inspected and sorted to ensure
gelatin solution. uniformity in weight, size and shape.
5. Once dipped, the Pin Bars rise to the upper deck allowing the cap and body to
set on the Pins.
Developing the Formulation and Selection of Capsule Size
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,
 The goal is to prepare a capsule with accurate dosage, good
temperature, and humidity, removes the exact amount of moisture from the
capsule halves. bioavailability, ease of filling& production, stability and elegance
7. Once drying is complete, the Pin Bars enter the Table section which positions  The active and inactive components must be blended thoroughly to
the capsule halves for stripping from the Pins in the Automatic section. ensure a uniform powder mix for the fill
8. In the Automatic section, capsule halves are individually stripped from the  Preformulation studies are performed to determine whether all of
Pins.
the formulation’s bulk powders may be effectively blended together.
9. The cap and body lengths are precisely trimmed to a ±0.15 mm tolerance.
 Diluent or filler may be added to produce the proper capsule fill
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 volume - ex. LACTOSE, MICROCRYSTALLINE CELLULOSE and STARCH
container.  Disintegrants are frequently included in a capsule formulation - to
12. Capsule quality is monitored throughout the production process including size, assist the breakup and distribution of the capsule’s contents in the
moisture content, single wall thickness, and color. stomach - ex. PREGELATINIZED STARCH, CROSCARMELLOSE, SODIUM
13. Capsules are sorted and visually inspected on specially designed R&J STARCH GLYCOLATE
Inspection Stations.
 When necessary, particle size may be reduced by milling to produce
14. Perfect capsules are imprinted with the client logo on high-speed
particles ranging from 50 to 1000 µm
 Drugs of lower dose or smaller particles are required, micronization
Empty capsule property
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
- with empty capsule in the loader tray, the tray placed on top of the
 Gelatin capsules are unsuitable for aqueous liquids because water
filler unit
softens gelatin and distorts the capsules, resulting leakage of the
- the loader inserts the capsules into the filling unit and is removed,
content
and the top plate is lifted to separate the caps from the bodies
 Some liquids or volatile oil do not interfere with the stability of the - the powder is placed on the unit and the capsule bodies filled
gelatin shells - may be placed in locking gelatin capsules to ensure - the top plate is returned to the unit and the caps placed on filled
retention of the liquid capsule bodies
 Eutectic mixtures of drugs - tends to liquefy - may be mixed with a
diluent or absorbent such as magnesium carbonate, kaolin or light ProFill 100 - The ProFill 100 Capsule Filling Machine utilizes an advanced design
magnesium oxide to separate the interacting agents and to absorb for fool-proof manual filling of two-piece capsules. With the ProFill 100
any liquefied material that may form machine, there is no need for expensive capsule filling equipment and
 Liquids are placed in soft gelatin capsules that are sealed during electrical/vacuum connections.
filling and manufacturing
Auger-Filling Principle
Selection of capsule size is done during product development
 Powder or granules are contained in mass flow hoppers with rotating
The choice is determined by requirements of formulation, including the dose of augers
the active ingredient and the density and compaction characteristics of the  Powder is fed continuously out of the hopper outlet due to the
drugs. rotation of the auger.
 Amount of powder fed into the body depends on the time capsule
Hard gelatin capsules are used to encapsulate about 65 mg to 1 g of powdered
body spends underneath the hopper outlet and auger speed
material
- 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 4. Dissolution Test for capsules
5. Weight Variation
2. Vacuum-assisted Method  Hard Capsules - 10 capsules are individually weighed & the content
 Dosing tube enters pellet bed removed. Empty shells are individually weighed & the net weight of
 With the help of vacuum, the pellets are sucked into the the contents calculated by subtraction
dosing tube  Soft Gelatin - the gross weight of 10 intact capsules is determined
 Excess pellet are scraped off the end of the dosing tube individually. Then each capsule is cut open & the contents removed
 Dosing tube is lowered and pellets released into capsule by washing with suitable solvent. The solvent is allowed to evaporate
body at room temperature over about 30 minutes. The individual shells
are weighed and net contents calculated.
6. Content Uniformity
Filling of Tablets  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
 Dosing slide, which can accommodate exactly 1 tablet, moves
underneath tablet feeder 7. Content Labeling Requirement
 Slider moves over the capsule body where tablet simply drops into it
 all official capsules must be labeled to express the quality of each
 If properly filled, the pin dropped into the capsule body will have
limited movements, the horizontal bar connected to the pin touches active ingredient in each dosage unit
the sensor 8. Stability Testing
 If not properly filled, horizontal bar will switch the sensor indicating  to determine the appropriate conditions for storage and the
incorrect filling. Empty capsules can be detected and eliminated
from the product. product’s anticipated shelf life
 9. Moisture Permeation Test
Capsule Sealing  determined by packaging the dosage unit together with a color-
revealing dessicant pellet, exposing the packaged unit to known
1. Tamper evident capsules by sealing the joint between the 2 capsule relative humidity over a specified time, observing the dessicant
parts pellet for color change (indicating absorption of moisture) &
2. Distinctive looking capsules by sealing them with colored band of comparing the pretest & posttest weight of the package unit
gelatin (KAPSEALS). If removed, the band cannot be restored w/o
expert sealing with gelatin Inspecting, Counting, Packaging, and Storing Capsules
3. Through a heat welding process that fuses the capsule cap to the  should have a uniform in appearance
body through the double wall thickness at their juncture - distinctive  defective capsules should be rejected
ring around the capsule where heat welded  capsules may be counted manually or automated equipment
Ex.: Weld’s gelatin seal  containers are then mechanically capped, inspected visually or
4. Liquid wetting agent that lowers the melting point in the contact electronically, labeled, and inspected once more.
areas of the capsule’s cap and the body using low temperatures (40-  packaged in glass or in plastic containers
450C)
5. Lightly coating the inner surface of the cap with a warm gelatin Oral Administration of Solid Dosage Forms
solution immediately prior to placement on the filled capsule body.
 placing the dose upon tongue & swallowing it w/ a glassful of water
The capsule sealing process of banding ( Kapseals, Quali-caps) has been utilized or beverages
for a number of years. In this process, two capsule parts are sealed with  without water is dangerous because of the possibility that will lodge
gelatin or polymer band at the seam of the cap and body. in the esophagus. Esophageal ulceration can occur with dry ingestion
Recently, a tamper resistant seal on hard gelatin capsules was developed in of tablets and capsules, particularly taken just before bedtime
which the contact areas of the cap and body are wetted with a mixture of  example of drugs of greatest concern are: ALENDRONATE SODIUM,
ASPIRIN, FERROUS SULFATE, NSAID, POTASSIUM CHLORIDE, & TETRACYCLINE
water and ethanol and then thermally bonded at 1040 to 1130F.
 the proper administration of alendronate sodium tablets (FOSAMAX)
calls for tablets to be taken with full 6 or 8 ounce glass of plain water
Compendial Requirements for Capsules upon rising in the morning or half an hour before taking any food –
1. Added Substances to prevent local irritation of esophagus
a. Harmless in the quantities used
b. Do not exceed the minimum amounts required to provide their Some Medications Commercially Prepared Into Soft Gelatin Capsule
intended effect 1. Acetazolamide - Diamox = Carbonic anhydrase inhbitor
c. Do not impair the product’s bioavailability, therapeutic efficacy or 2. Cyclosporine - Sandimmune = Immunosuppressive
safety 3. Cyclosporine - Neoral =Immunosuppressive
d. Do not interfere with requisite compendial assays & test 4. Digoxin - Lanoxicaps = Cardiac glycoside
2. Containers for dispensing 5. Ethosuximide - Zarontin = Anticonvulsant
 tight, well closed & light resistant containers depending on the item 6. Ranitidine HCl - Zantac GELdose = Histamine H2 receptor inhibitor
3. Disintegration Test for Capsules
 the capsules are placed in the basket rack assembly, which is Process Capsule Filling
immersed 30 times per minutes into a thermostatically controlled 1. Milling /Sieving of all Ingredients
fluid at 37 0C and observed over the time described in the individual 2. Blending
monograph 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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