NOTE—The statement ‘‘Avoid inhaling’’ is not necessary for
preparations specifically designed for use by inhal atio n. The
phrase ‘‘or other mucous membranes’’ is not necessary for pre-
parations specifically designed for use on mucous membranes.
Warning—Contents under pressure. Do not puncture or in-
cinerate container. Do not expose to heat or store at tempera-
tures above 1208 F (498 C). Keep out of reach of children.
In ad dition to the aforementioned warnings, the label of a
drug packaged in an aerosol container in which the propellant
consists in wh ole or in part of a hal ocarbon or hydrocarbon
shall, where required under regulations of the FDA, bear either
of the following warnings:
Warning—Do not inhale directly; deliberate inhalation of
contents can cause death.
Warning—Use only as directed; intentional misuse by deliber-
ately concentrating and inhaling the contents can be harmful
or fatal.
BOLUSES
Boluses are large elongated tablets intended for administra-
tion to animals (see Tablets).
CAPSULES
Capsules are solid dosage forms in which the drug is enclosed
within either a hard o r soft soluble container or ‘‘shell.’’ The
shells are usually formed from gelatin; however, they also may
be made from starch or other s uitable substances. Hard-shell
capsule sizes range from No. 5, the smallest, to No. 000, which
is the largest, except for veterinar y sizes. However, size No.
00 generally is the largest size accept able to pa tien ts. Size 0
hard gelatin capsules having an elongated body (known as size
OE) also are available, which provide greater fill capacity with-
outanincreaseindiameter.Hardgelatincapsulesconsistof
two, telescoping cap and body pieces. Generally, there are
unique grooves or indentations molded into the cap and body
portions to provide a positive closure when fully engaged,
which helps prevent the accidental separation of the filled cap-
sules during shipping and handling. Positive closure also may
be affected by spot fusion (‘‘welding’’) of the cap and body
pieces together through direct thermal means or by application
of ultrasonic energy. Factory-filled hard gelatin capsules may be
completely sealed by banding, a process in which one or more
layers of gelatin are applied over the seam of the cap and body,
or by a liquid fusion process wherein the filled capsules are wet-
ted with a hydroalcoholic solution that penetrates into the
space where the cap overlaps the body, and then dried.
Hard-shell capsules made from starch consist of two, fitted
cap and body pieces. Since the two pieces do not telescope
or interlock positively, they are sealed together at the time of
filling to prevent their separation. Starch capsules are sealed
by the application of a hydroalcoholic solution to the recessed
section of the cap immediately prior to its being placed onto
the body.
The banding of hard-shell gelatin capsules or the liquid seal-
ing of hard-shell starch capsules enhances consumer safety by
making the capsules difficult to open without causing visible,
obvious d amage, and may improve the stabilit y of contents
by limiting O
2
penetration. Industrially filled hard-shell capsules
also are often of distinctive color and shape or are otherwise
marked to identify them with the manufacturer. Additionally,
such capsules may be printed axially or radially with strengths,
product codes, etc. Pharmaceutical-grade printing inks are us-
ually based on shellac and employ FDA-approved pigments and
lake dyes.
In extemporaneous prescription practice, hard-shell capsules
may be h and-filled; this permits the prescr iber a latitude of
choice in selecting either a single dr ug or a combination of
drugs at the exact dosage level considered best for the individ-
ual patient. This flexibility gives hard-shell capsules an advan-
tage over compressed tablets and soft-shell capsules as a
dosage form. Hard-shell capsules are usually formed from gela-
tins having relatively high gel strength. Either type may be
used, but blends of pork skin and bone gelatin are often used
to optimize shell clarity and toughness. Hard-shell capsules also
may be formed from starch or other suitable substances. Hard-
shell capsules may also contain colorants, such as D&C and
FD&C dyes or the various iron oxides, opaquing agents such
as titanium dioxide, dispersing agents, hardening agents such
as sucrose, and preservatives. They normally contain between
10% and 15% water.
Hard gelatin capsules are made by a process that involves
dipping shaped pins into gelatin solutions, after which the gel-
atin films are dried, trimmed, and removed from the pins, and
the body and cap pieces are joined. Starch capsules are made
by injection molding a mixture of starch and water, after which
the capsules are dried. A separate mold is used for caps and bo-
dies, and the two parts are supplied separately. The empty cap-
sules should be stored in tight containers until they are filled.
Since gelatin is of animal origin and starch is of vegetable origin,
capsules made with these materials should be protected from
potential sources of microbial contamination.
Hard-shell capsules typically are filled with powder, beads, or
granules. Inert sugar beads (nonpareils) may be coated with ac-
tive ingredients and coating compositions that provide extend-
ed-release profiles or e nteric pr operties. Alter natively, larger -
dose active ingredients themselves may be suitably formed into
pellets and then coated. Semisolids or liquids also may be filled
into hard-shell capsules; however, when the latter are encapsu-
lated, one of the sealing techniques must be employed to pre-
vent leakage.
In hard gelatin capsule filling operations, the body and cap of
the shell are separated prior to dosing. In hard starch shell filling
operations, the bodies and caps are supplied separately and are
fed into separate hoppers of the filling machine. Machines em-
ploying various dosing principles may be employed to fill pow-
ders into hard-shel l ca psules ; howeve r, most fully automatic
machines form powder plugs by compression and eject them
into empty capsule bodies. Accessories to these machines gen-
erally are available for the other types of fills. Powder formula-
tions often require adding fillers, lubricants, and glidants to the
active ingredients to facilitate encapsulation. The formulation,
as well as the method of filling, particularly the degree of com-
paction, may influence the rate of drug release. The addition of
wetting agents to the powder mass is common where the ac-
tive in gred ient is hydrophobic. D isintegr ants also may be in-
cluded in powder formulations to facilitate d eaggregation
and dispersal of capsule plugs in the gut. Powder formulations
often may be produced by dry blending; however, bulky formu-
lations may require densification by ro ll compaction or other
suitable granulation techniques.
Powder mixtures that tend to liquefy may be dispensed in
hard-shell capsules if an absorbent such as magnesium carbo-
nate, colloidal silicon dioxide, or other suitable substance is
used. Potent drugs are often mixed with an inert diluent before
being filled into capsules. Where two mutually incompatible
drugs are prescribed together, it is sometimes possible to place
one in a small capsule and then enclose it with the second drug
in a larger capsule. Incompatible drugs also can be separated by
placing coated pellets or tablets , or soft-shell capsules of one
drug into the capsule shell before adding the second drug.
Thixotropic semisolids may be formed by gelling liquid drugs
or vehicles with colloidal silicas or powdered high m olecular
weight polyethylene glycols. Various waxy or fatty compounds
may be used to prepare semisolid matrices by fusion.
Soft-shell capsules made from gelatin (sometimes called soft-
gels) or other suitable material require large-scale production
methods. The soft gelatin shell is somewhat thicker th an that
of hard-shell capsules and ma y be plasticized by the addition
of a polyol such as sorbitol or glycerin. The ratio of dry plastici-
zer to dry gelatin determines the ‘‘hardness’’ of the shell and
may b e varied to accommodate environmental conditions as
well as the nature of th e contents. Like hard sh ells, t he shell
compo sition may include approved dye s and pigments, opa-
quing agents such as titanium dioxide, and preservatives. Fla-
vors may be added and up to 5% sucrose may be included
for its sweetness and to produce a chewable shell. Soft gelatin
shells normally contain 6% to 13% water. Soft-shell capsules
Pharmacopeial Forum
1262
IN-PROCESS REVISION Vol. 35(5) [Sept.–Oct. 2009]
# 2009 The United States Pharmacopeial Convention All Rights Reserved.
In-Process Revision