CHAPTER 7 CAPSULES

ADVANTAGES OF CAPS & TABS (SOLID FORMS)

Conveniently carried
Readily identified
Easily taken (TASTELESS)
Efficiently and productively manufactured
Packaged and shipped by manufacturers at
lower cost and w/ less breakage
More stable
Longer shelf life

DOSAGE FORMS THAT MUST BE LEFT INTACT
Enteric coated tablets
-designed to pass through the stomach for drug
release and absorption in the intestine
Extended-release
-prolonged release of medication
Sublingual/Buccal
-dissolves under the tongue or in mouth


CAPSULES
Solid dosage forms in w/c medicinal agents
and/or inert substances are enclose in a small
shell of gelatin

Gelatin capsule shells may be HARD or SOFT

HARD GELATIN CAPSULES
Used in most commercial medicated capsules
Used in the extemporaneous compounding of
prescriptions
13%-16% moisture

Empty capsule shells
Made of GELATIN, SUGAR, WATER
Clear, colorless, and essentially tasteless
May be colored w/ FD&C and D&C dyes
Made opaque by adding agents such as
TITANIUM OXIDE

Gelatin
Obtained by partial hydrolysis of collagen from
the skin, white connective tissue, and bones of
animals.
Available in the form of a fine powder, a coarse
powder, shreds, flakes, sheets.
Stable in air when dry but is subject to microbial
decomposition when it becomes moist
Insoluble
Soften in cold water through the absorption of
water up to 10 times its wt. of water
Soluble in hot water and in warm gastric fluid
Being a protein, digested by proteolytic
enzymes and absorbed

If stored in an environment of high humidity
-capsules absorbs more moisture
-they become distorted, and lose their rigid
shape

In an environment of extreme dryness
-some of the moisture of caps are lost
-capsules become brittle, and crumbled


DESSICANT MATERIALS
Protection against the absorption of
atmospheric moisture
DRIED SILICA GEL, CLAY, ACTIVATED CHARCOAL

METHODS TO TRACK THE PASSAGEOF CAPSULES AND
TABS THROUGH G.I.T. TO MAP THEIR TRANSIT TIME
AND DRUG-RELEASE PATTERNS

GAMMA SCINTIGRAPHY
-noninvasive procedure that entails the use of a
gamma ray-emitting radiotracer incorporated
into the formulation w/ a gamma camera
coupled to a data recording system

o Pharmacoscintographic Evaluation
-resultant when scintigraphy is combined w/
pharmacokinetic studies
-provides info about the transit and drug
release patterns of the dosage forms as well as
the rate of drug absorption from various GIT
-useful in:
a) Determining whether a correlation exist
bet. in vitro and in vivo bioavailability
for immediate-release products
b) Assessing the integrity & transit time of
enteric coated tabs thru the stomach
enroute to the intestines
c) Drug and dosage form evaluation in
new product devt.

HEIDELBURG CAPSULE
- a pH-sensitive nondigestible radiotelemetric
device
-approximate size of a No. 0 gelatin capsule has
been used as a NONRADIOACTIVE means to
measure gastric pH, gastric residence time, &
gastric emptying time

THE MANUFACTURE OF HARD GELATIN CAPSULE
SHELLS

2 SECTIONS:
1. Capsule body
2. Shorter Cap
o 2 parts overlap when joined, w/ the cap
fitting snugly over the open end of the
capsule body

SHELLS
-produced industrially by the mechanical dipping of
pins or pegs of the desired shape & diameter into a
temp.-controlled reservoir of melted gelatin mixture

PEGS
-made of manganese bronze, are affixed to PLATES,
each capable of holding up to about 500 pegs


Read pp. 205-206
INNOVATIONS MADE TO PRODUCE DISTINCT CAPS
By altering the usual rounded shape of the
capsule-making pegs
By tapering the end of the body-producing peg
while leaving the cap-making peg rounded
Pulvules (Eli Lilly) one manufacturer prepares
capsule differentiated from those of other
manufacturers
Spansules (SmithKline, Beecham) another
manufacturer uses capsules w/ the ends of both
the bodies and caps highly tapered

CAPSULE SHELL DESIGNS
Snap Fit
-enables the two halves of the capsule shells to
be positively joined thru locking grooves in the
shell walls
-the two grooves fit into each other and thus
ensure reliable closing of the filled capsule
Coni-Snap Capsule
-in which the rim of the capsule body is not
straight but tapered slightly
-reduces the risk of the capsule rims touching
on joining and essentially eliminates the
problem of splitting during large scale filling
operations.
Coni-Snap Supro
-upper capsule part extends so far over the
lower part that only the rounded edge of the
latter is visible.
-opening of such a filled capsule is difficult bec.
Lower surface offers less gripping surface to pull
the two halves apart

Capsules and tablets also may be imprinted
w/the names and monograms of the
manufacturer, the assigned national drug
code number, and other marking making the
product identifiable and distinguishable

CAPSULE SIZES
Determined by the amt of fill material to be
encapsulated
Determined by the density and compressibility
of the fill
For human use:
o 000 largest
o 5 smallest
Larger capsules are available for VETERINARY
USE

PREPARATION OF FILLED HARD GELATIN CAPSULES
General Steps
1. Developing and preparing the formulation and
selecting the capsule size
2. Filling the capsule shells
3. Capsule sealing (optional)
4. Cleaning and polishing the filled capsules


DEVELOPING THE FORMULATION &SELEECTING THE
CAPSULE SIZE
The goal is to prepare a capsule w/:
o accurate dosage,
o good bioavailability,
o ease of filling & production
o stability
o elegance

In dry formulations
-components must be blended thoroughly to
ensure a uniform powder mix for the fill
Care in blending is especially important for low-
dose drugs, since lack of homogeneity in
blending may result to therapeutic
consequences




Diluent/ Filler
-added to produce the proper capsule fill vol.
-provide cohesion to powders
o Lactose
o microcrystalline cellulose
o starch

Disintegrants
-to assist the breakup and distribution of the
capsules contents in the stomach
o pregelatinized starch
o croscarmellose
o sodium starch
When necessary , particle size may be reduced
by MILLING (50-1000um; drug dosage must be
10 mg and above)
MICRONIZATION (1-20um) for drugs of lower
dose or when smaller particles are desired
Lubricant/ glidant
-enhances flow properties
o Silicon dioxide
o Magnesium stearate
- waterproofing characteristics of this
water-insol. material can RETARD
penetration by gastrointestinal fluids
- delays drug dissolution and absorption
o Calcium stearate
o Stearic acid/ talc
Surface-active agent
o Sodium Lauryl Sulfate
-used to facilitate wetting by
gastrointestinal fluids
Disintegration Agents
-facilitate the breakup and distribution of the
capsules contents
Gelatin capsules are unsuitable for aqueous
liquids because water softens gelatin and
distorts the capsule resulting in leakage of
contents
Some liquids, such as fixed or volatile oils, that
do not interfere with the stability of the gelatin
shells may be placed in locking gelatin capsules
Eutectic mixtures
-have a propensity to liquefy when admixed
-may be mixed with a diluents or absorbent
such as magnesium carbonate, kaolin, or light
magnesium oxide to separate the interacting
agents and absorb liquefied materials
In large-scale capsule production, liq. are placed
in soft gelatin capsules
Hard gelatin caps are used to encapsulate 65
mg 1g of powdered material.

FILLING HARD CAPSULE SHELLS
PUNCH METHOD
-using the spatula, the powder mix is formed
into a cake, having a depth of approximately
one-fourth to one-third the length of the
capsule body.
-then an empty capsule body is held between
thumb and forefinger and punched vertically
into the powder cake

When NONPOTENT materials are placed in
capsules, the first filled capsule should be
weighed (using an empty capsule of the same
size on the opposite balance pan to counter the
weight of the shell)
When POTENT drugs are being used each
capsule should be weighed after filling to
ensure accuracy

CAPSULE SEALING
Colored band of gelatin
-if removed, the band cannot be restored w/out
expert resealing with gelatin
Heat-welding process
-fuses the capsule cap to the body through the
double wall thickness at their juncture
Process that uses Liquid wetting agent
-lowers melting pt. in the contact areas of caps
cap and body then thermally bonds the two
using low temp. (40-45C)
Industrial capsule-sealing machines
-capable of producing 60k-150k gelatin bonded,
heat welded, or thermally coupled capsules per
hour

CLEANING AND POLISHING CAPSULES
Rubbed w/ a clean gauze or cloth-small scale
Cleaning vacuum (Accela-Cotta Apparatus)-
large scale

SOFT GELATIN CAPSULES
- Made of gelatin w/c glycerin or a polyhydric
alcohol such as sorbitol has been added
- Contains more moisture than hard caps
- May have a preservative, such as methyparaben
and/or polyparaben, to retard microbial growth
- May be oblong, oval or round
- Maybe single-colored, or two-toned
- May be prepared with opaquants to reduce
transparency
- Used to encapsulate and hermetically seal
liquids, suspension, pasty materials, dry
powders and even preformed tablets

PREPARATION OF SOFT GELATIN CAPS
PLATE PROCESS
-a warm sheet of plain or colored gelatin is
placed on the bottom plate of the mold.

ROTARY DIE PROCESS
-method developed in 1933 by Robert p.
Scherer
-liq. gelatin flowing from an overhead tank is
formed into 2 continuous ribbons by the rotary
die machine and brought together bet. twin
rotating dies

RECIPROCATING DIE PROCESS
-ribbons of gelatin is formed and used to
encapsulate the fill, but it differs in the actual
encapsulating process

USE OF SOFT GEL CAPS
1. Water-immiscible volatile and nonvolatile
liquids
o Veg. and aromatic oils
o Aromatic and aliphatic hydrocarbons
o Chlorinated hydrocarbons
o Ethers
o Esters
o Alcohols
o And organic acids

2. Water-miscible nonvolatile liquids
o polyethylene glycol
o nonionic surface active ingredients-
polysorbate 80
3. Water-miscible and relatively nonvolatile
compounds
o Propylene glycol
o Isopropyl alcohol

**Liquids that can easily migrate through the capsule
shell are not suitable for soft gelatin capsules. These
materials include water above 5% and low-molecular-
weight water-soluble and volatile organic compds. Such
as alcohols, ketones, acids, amines, and esters.

COMPENDIAL REQUIREMENTS FOR CAPSULES
ADDED SUBSTANCES
-subs. added to preps includes to enchance
their stability, usefulness, or elegance or to
facilitate their manufacture may be used only if
they:
1. are harmless in qtys
2. do not exceed the minimum amts. Required
to provide their intended effect
3. do not impair the products bioavailability,
therapeutic efficacy, or safety
4. do not interfere with requisite compendia
assays and tests

CONTAINERS FOR DISPENSING CAPSULES
Tight
Well-closed
Light resistant

DISINTEGRATION TEST FOR CAPSULES
Caps are placed in BASKET RACK ASSEMBLY, w/c
is immersed 30 times per min. into a
thermostatically controlled fluid at 37C and
observed over the time described in the
individual monograph
To satisfy the test the capsules disintegrate
completely into a soft mass having no palpably
firm core and only some fragments of the
gelatin shell

DISSOLUTION TEST
The dissolution test uses the same apparatus,
dissolution medium, and test as that for
uncoated and plain-coated tablets
Apparatus I stainless steel basket on a stirrer
shaft
Apparatus II paddle as stirrer

WEIGHT VARIATION
Demonstrates Uniformity of dosage units
o HARD CAPSULES
-ten caps are weighed, contents removed
-emptied shells are weighed, net wt. is
calculated by subtraction
-from the results of an assay performed as
directed in the indiv. Monograph, the
content of the act. Ingredient in each cap is
determined
o SOFT CAPSULES
-gross wt. is determined individually
-each cap is cut and contents removed by
washing w/ solvent
-solvent evaporate at room temp. for 30
mins.
-indiv. Shells weighed, net content
calculated

CONTENT UNIFORMITY
85%-115% of the label claim for 9 of 10 dosage
units assayed, w/ no unit outside 75%-125%
CONTENT LABELLING REQUIREMENT
To express the qty or each act. ing. In each
dosage unit

STABILITY TESTING
To determine intrinsic stability of the active
drug and influenc of envt. factors such as temp,
humidity, light, formulative comp., container
and closure system
Battery of stress testing, long term stability,
and accelerated stability- help determine the
appropriate conditions for storage and
products anticipated shelf life.

MOISTURE PERMEATION TEST
To ensure suitability for packaging capsules
The degree and rate of moisture penetration
are determined by:
o Packaging the dosage unit together w/ a
color revealing desiccant pellet
o Exposing the packaged unit to known
relative humidity over specified time
o Observing the desiccant pellet for COLOR
CHANGE ( indicating absorption of moisture)
o Comparing the pretest and posttest wt. of
packaged unit
Read p. 218-220