PFR-PF2009 1051..1053

BRIEFING

h1151i Pharmaceutical Dosage Forms, USP 32 page

663. This general information chapter is being revised in its en-

tirety to represent current compendial thinking with respect to

ofﬁcial preparation s. The proposed revisio n incorpor ates con-

cepts outlined in a Stimuli to the Revision Process article, Devel-

opment of a Compendial Taxonomy and Glossary for

Pharmaceutical Dosage Forms, authored by an Ad Hoc Commit-

tee composed of the chairs of the Pharmace utical Dosage

Forms Expert Committee, Biopharmaceutics Expert Commit-

tee, Nomenclature and Labeling Expert Committee, and the

Council of Experts for the revision cycle, 2000—2005, and pub-

lished in PF 29(5). The Stimuli article proposed a tiered catego-

rization for pharmaceutica l dosage forms proceeding from

route of administration to physical form and ultimately release

pattern. This proposed general information chapter emphasizes

the second tier of the compendial taxonomy, the physical dos-

age form, rather than the route of administration, with the in-

tention of avoiding redundancy for dosage forms given by

multiple routes.

The proposed revision is organized into four sections provid-

ing discussion of general considerations, product quality tests,

dosage form monographs, and a glossary. General considera-

tions include dose uniformity, stability, bioavailability, manufac-

ture, and route of administration. T he discussi on of product

quality tests reﬂects the universally applied as well as dosag e

form speciﬁc testing that hel p assure safety and efﬁcacy from

manufacture through shelf life. The dosage form monographs

provide general descriptions, discussion of general principles of

their manufacturing or compounding, and recommendations

for proper use and storage. The glossary is intended to provide

guidance in selection of ofﬁcial names for ofﬁcial articles but

also as a resource to provide deﬁnitions beyond those used in

ofﬁcial names for dosage forms.Theglossaryclearlydistin-

guishes preferred from not preferred terminology.

The revised general information chapter presents current

concepts relating to the naming of dosage forms. Outdated

forms such as elixirs, spirits, tinctures, and syrups are herein re-

cognized as solutions. Lotions are deﬁned as emulsions typically

for topical use. While inserts are deﬁned as solid dosage forms

for placement within body cavities, suppositories are differenti-

ated as only for placement within the rectum.

This general informati on chapter is intended to be supple-

mented by more detailed discussion of characteristics, quality

tests, and other considerations based on route of administra-

tion. Early drafts of such concepts relating to topical and trans-

dermal dosage form s are presented in PF 35(3) [May–June

2009]. Proposed general test chapter h3i Topical and Transder-

mal Drug Products—Product Quality Tests, providing quality test-

ing procedures, complements the performance testing

proposed in h725i Topical and Transdermal Drug Products—

Product Performance Tests. Additional revision proposals of sim-

ilar standards for the oral (gastro-intestinal), mucosal, by inha-

lation, and by injection routes are planned.

(BPC: W. Brown.) RTS—C69686

Change to read:

h1151i PHARMACEUTICAL

DOSAGE FORMS

Dosage forms are pr ovided for most of the Pharmacopeial

drug substances, but the processes for the preparation of many

of them are, in general, beyond the scope of the Pharmacopeia.

In addition to deﬁning the dosage forms, this section presents

the general principles involved in the manufacture of some of

them, particularly on a small scale. Other information that is gi-

ven bears on the use of the Pharmacopeial substances in extem-

poraneous compounding of dosage forms.

BIOAVAILABILITY

Bioavailability, or the extent to which the therapeutic constit-

uent of a pharmaceutical dosage form intended for oral or top-

ical use is available for absorption, is inﬂuenced by a variety of

factors. Among the inherent factors known to affect absorption

are the method of manufacture or method of compounding;

the particle size and crystal form or polymorph of the drug sub-

stance; and the diluents and excipients used in formulating the

dosage form, including ﬁllers, binders, disintegrating agents,

lubricants, coatings, solvents, suspending agents, and dyes. Lu-

bricants and coatings are foremost among these. The mainte-

nance of a demonstrably high degree of bioavailability requires

particular attention to all aspects of production and quality con-

trol that may affect the nature of the ﬁnished dosage form.

TERMINOLOGY

Occasionally it is necessary to add solvent to the contents of a

container just prior to use, usually because of instability of some

drugs in the diluted form. Thus, a solid diluted to yield a suspen-

sion is called [DRUG] for Suspension; a solid dissolved and dilu-

ted to yield a solution is called [DRUG] fo r Solution; and a

solution or suspension diluted to yield a more dilute form of

the drug is called [DRUG] Oral Concentrate. After dilution, it is

important that the drug be homogeneously dispersed before

administration.

AEROSOLS

Pharmaceutical aerosols are products that are packaged un-

der pressure and contain therapeutically active ingredients that

are released upon activation of an appropriate valve system.

They are intended for topical application to the skin as well as

local application into the nose (nasal aerosols), mouth (lingual

aerosols), or lungs (inhalation aerosols). These products may be

ﬁtted with valves enabling either continuous or metered-dose

delivery; hence, the terms ‘‘[DRUG] Metered Topical Aerosols,’’

‘‘[DRUG] Metered Nasal Aerosols,’’ etc.

The term ‘‘aerosol’’ refers to the ﬁne mist of spray that results

from most pressurized systems. However, the term has been

broadly misapplied to all self-contained pressurized products,

some of which deliver foams or semisolid ﬂuids. In the case of

Inhalation Aerosols, the particle size of the delivered medication

must be carefully controlled, and the average size of the parti-

cles should be under 5 mm. These products are also known as

metered-dose inhalers (MDIs). Other aerosol sprays may con-

tain particles up to several hundred micrometers in diameter.

The basic components of an aerosol system are the container,

the propellant, the concentrate containing the active ingredi-

ent(s), the valve, and the actuator. The nature of these compo-

nents determines such characteristics as particle size

distribution, uniformity o f dose fo r meter ed v alves, del ivery

rate, wetness and temperature of the spray, spray pattern and

velocity or plume geometry, foam density, and ﬂuid viscosity.

Types of Aerosols

Aerosols consist of two-phase (gas and liquid) or three-phase

(gas, liquid, and solid or liquid) systems. The two-phase aerosol

consists of a solution of active ingred ients in liqueﬁed propel-

lant and the vaporized propellant. The solvent is composed of

the propellant or a mixture of the p ropellant and cosolvents

such as alcohol, p ropylene glycol, and polyethylene glycols,

which are often used to enhance the solubility of the active in-

gredients.

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Three-phase systems consist of a suspension or emulsion of

the active ingredient(s) in addition to the vaporized propel-

lants. A suspension consists of the active ingredient(s) that

may be dispersed in the propellant system with the aid of suit-

able excipients such as wetting agents and/or solid carriers such

as talc or colloidal silicas.

A foam aerosol is an emulsion containing one or more active

ingr edients, surfactants, aqueous or nonaqueous liquids, and

the propellants. If the propellant is in the internal (discontinu-

ous) phase (i.e., of the oil-in-water type), a stable foam is dis-

charged; and if the propellant is in the external (continuous)

phase (i.e., of the water-in-oil type), a spray or a quick-breaking

foam is discharged.

Propellants

The propellant supplies the necessary pressure within an aer-

osol system to expel material from the container and, in com-

bination with other components, to convert the material into

the desired physical form. Propellants may be broadly classiﬁed

as liqueﬁed or compressed gases having vapor pressures gener-

ally exceeding atmospheric pressure. Propellants w ithin this

deﬁnition include various hydrocarbons, especially halogenat-

ed derivatives of methane, ethane, and propane, low molecular

weight hydrocarbons such as the butanes and pentanes, and

compressed gases such as carbon dioxide, nitroge n, and ni-

trous oxide. Mixtures of propellants are frequently used to ob-

tain desirable pressure, delivery, and spray characteristics. A

good propellant system should have the proper vapor pressure

characteristics consistent with the other aerosol components.

Valves

The primary function of the valve is to regulate the ﬂow of the

therapeutic agent and propellant from the container. The spray

characteristics of the aerosol are inﬂu enced by oriﬁce dimen-

sion, number, and location. Most aerosol valves provide for

continuous spray operation and are used on most topical prod-

ucts. However, pharmaceutical products for oral or nasal inha-

lation often utilize metered-dose valves that must deliver a

uniform quantity of spray upon each valve activation. The accu-

racy and reproducibility of the doses delivered from metering

valves are generally good, comparing favorably to the uniformi-

ty of solid dosage forms such as tablets and capsules. However,

when aerosol packages are stored impr operly, or when they

have no t been used for long periods of time, valves must be

primed before use. Materials used for the manufacture of valves

should be inert to the formulations used. Plastic, rubber, alumi-

num, and stainless steel valve components are commonly used.

Metered-dose valves must deliver an accurate dose within spec-

iﬁed tolerances.

Actuators

An actuator is the ﬁtting attached to an aerosol valve stem,

which when depressed or moved, opens the valve, and directs

the spray containing the drug preparation to the desired area.

The actuator usually indicates the direction in which the prep-

aration is dispensed and protects the hand or ﬁnger from the

refrigerant effects of the propellant. Actuators incorporate an

oriﬁce that may vary widely in size and shape. The size of this

oriﬁce, the expansion chamber design, and the nature of the

propellant and formulation inﬂuence the delivered dose as well

as the physical characteristics of the spray, foam, or stream of

sol id particles d ispensed. For inhalation aerosols, an actuator

capable of delivering the medication in the proper particle size

range and with the appropriate spray pattern and plume geom-

etry is utilized.

Containers

Aerosol containers usually are made of glass, plastic, or metal,

or a combination of these materials. Glass containers must be

precisely engineered to provide the maximum in pressure safe-

ty and impact resistance. Plastics may be employed to coat

glass containers for improved safety characteristics, or to coat

metal containers to improve corrosion resistance and enhance

stability of the formulation. Suitable metals include stainless

steel, aluminum, and tin-plated steel. Extractables or leachables

(e.g ., drawing oils, cleaning agents, etc.) and particulates on

the internal surfaces of containers should be controlled.

Manufacture

Aerosols are usually prepared by one of two general proces-

ses. In the ‘‘cold-ﬁll’’ process, the concentrate (generally cooled

to a temperature below 08) and the refrigerated propellant are

measured into open containers (usually chilled). The valve-actu-

ator assembly is then crimped onto the container to form a

pressure-tight seal. During the interval between propellant ad-

diti on and crimping, sufﬁ cient volatilization of propellant oc-

curs to displace air from the container. In the ‘‘pressure-ﬁll’’

method, the concentrate is placed in the container, and either

the propellant is forced under pressure through the valve oriﬁce

after the valve is sealed, or the propellant is allowed to ﬂow un-

der the valve cap and then the valve assembly is sealed (‘‘under-

the-cap’’ ﬁlling). In both cases of the ‘‘pressure-ﬁll’’ method,

provision must be made for evacuation of air by means of vac-

uum or displacement with a small amount of propellant vapor.

Manufacturing process controls usually include monitoring of

proper formulation and propellant ﬁll weight and pressure test-

ing, leak testing, and valve function testing of the ﬁnished aer-

osol. Microbiological attributes should also be controlled.

Extractable Substances

Since pressurized inhalers and aerosols are normally formulat-

ed with organic solvents as the propellant or the vehicle, leach-

ing of extractables from the elastomeric and plastic

components into the formulation is a potentially serious prob-

lem. Thus, the composition and the quality of materials used in

the manufacture of the valve components (e.g., stem, gaskets,

housing, etc.) must be carefully selected and controlled. Their

compatibility with formulation components should be well es-

tablished so as to prevent distortion of the valve components

and to minimize changes in the medication delivery, leak rate,

and impurity proﬁle of the drug product over time. The extract-

able proﬁles of a representative sample of each of th e elasto-

meric and plastic components of the valve should be

established under speciﬁed conditions and should be correlated

to the extractable proﬁle of the aged drug product or placebo,

to ensure reproducible quality and purity of the drug product.

Extractables, which may include polynuclear aromatics, nitrosa-

mines, vulcanization accelerators, antioxidants, plasticizers,

monomers, etc., should be identiﬁed and minimized wherever

possible.

Speciﬁcations and limits for individual and total extractables

from different valve components may require the use of differ-

ent analytical methods. In addition, the standard USP biological

testing (see the general test chapters Biological Reactivity Tests,

In Vitro h87i and Biological Reactivity Tests, In Vivo h88i) as well as

other safety data may be needed.

Labeling

Medicinal aerosols should contain at least the following

warning information on the label as in accordance with appro-

priate regulations.

Warning—Avoid inh aling. Avoid s praying into eye s or onto

other mucous membranes.

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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

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

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also may be printed with a product code, strength, etc. In most

cases, soft-shell capsules are ﬁlled with liquid contents. Typical-

ly, active ingredients are dissolved or suspended in a liquid ve-

hicle. Classically, an oleaginous vehicle such as a vegetable oil

was used; however, nonaqueous, water-miscible liquid vehicles

such as the lower -molecular-weight polyethylene glycols are

more common today due to fewer bioavailability problems.

Available in a wide variety of sizes and shapes, soft-shell cap-

sules are both formed, ﬁlled, and sealed in the same machine;

typically, this is a rotary die process, although a plate process or

reciprocating die process also may be employed. Soft-shell cap-

sules also may be manufactured in a bubble process that forms

seamless spherical capsules. With suitable equipment, powders

and other dry solids also may be ﬁlled into soft-shell capsules.

Liquid-ﬁlled capsules of either type involve similar formula-

tion technology and offer similar advantages and limitations.

For instance, both may offer advantages over dry-ﬁlled capsules

and tablets in content uniformity and drug dissolution. Greater

homogeneity is possible in liquid systems, and liquids can be

metered more accurately. Drug d issolut ion may b eneﬁt be-

cause the drug may already be in solution or at least suspended

in a hydrophilic v ehicle. However, the contact between the

hard or soft shell and its liquid content is more intimate than

exists with dry-ﬁlled capsules, and this may enhance the chanc-

es for undesired interactions. The liquid nature of capsule con-

tents presents different technological problems than dry-ﬁlled

capsules in regard to disintegration and dissolution testing.

From formulation, technologi cal, and biopharmaceutical

points of view, liquid-ﬁlled capsules of either type hav e more

in common than liquid-ﬁlled and dry-ﬁlled capsules having

the same shell composit ion. Thus, for compendial purposes,

standards and methods should be established based on capsule

contents rath er th an on whether the contents ar e ﬁl led in to

hard- or soft-shell capsules.

DELAYED-RELEASE CAPSULES

Capsules may be coated, or, more commonly, encapsulated

granules may be coated to resist releasing the drug in the gas-

tric ﬂuid of the stomach where a delay is important to alleviate

potential problems of drug inactivation or gastric mucosal irri-

tation. The term ‘‘delayed-release’’ is used for Pharmacopeial

monographs on enteric coated capsules that are intended to

delay the release of medicament until the capsule has passed

through the stomach, and the individual monographs include

tests and speciﬁcations for Drug release (see Drug Release h724i)

or Disintegration (see Disintegration h701i).

EXTENDED-RELEASE CAPSULES

Extended-release capsules are formulated in such manner as

to make the contained medicament available over an extended

period of time following ing estion. Expressions such as ‘‘pro-

longed-action,’’ ‘‘repeat-action,’’ and ‘‘sustained-release’’ have

also been used to describe such dosage forms. However, the

ter m ‘‘extended-rel ease’’ is used for Pharmacopeial purposes

and requirements for Drug release (see Drug Release h724i) typ-

ically are speciﬁed in the individual monographs.

CONCENTRATE FOR DIP

Concentrate for Dip is a preparation containing one or more

active ingredients usually in the form of a paste or solution. It is

used to prepare a diluted suspension, emulsion, or solution of

the active ingredient(s) for the prevention and treatment of ec-

toparasitic infestations of animals. The diluted preparation

(Dip) is applied by complete immersion of the animal or, where

appropriate, by spraying. Concentrate for Dip may contain suit-

able antimicrobial preservatives.

CREAMS

Creams are semisolid dosage forms containing one or more

drug substances dissolved or dispersed in a suitable base. This

term has traditionally been applied to semisolids that possess a

relatively ﬂuid consistency formulated as either water-in-oil

(e.g., Cold Cream) or oil -in-water (e.g., Fluocinolone Acetonide

Cream) emulsions. However, more recently the term has been

restricted to products consisting of oil-in-water emulsions or

aqueous microcrystalline dispersions of long-chain fatty acids

or alcohols that are w ater washable and more cosmetically

and aesthetically acceptable. Creams can be used for adminis-

tering drugs via the vaginal route (e.g., Triple Sulfa Vaginal

Cream).

ELIXIRS

See Solutions.

EMULSIONS

Emulsions are two-phase systems in which one liquid is dis-

persed throughout another liquid in the form of small droplets.

Where oil is the dispersed phase and an aqueous solution is the

continuous phase, the system is designated as an oil-in-water

emulsion. Conversel y, where water or an aqueous solution is

the dispersed phase and oil or oleaginous material is the contin-

uous phase, the system is designated as a water-in-oil emulsion.

Emulsions are stabilized by emulsifying agents that prevent co-

alescence, the merging of small droplets into larger droplets

and, ultimately, into a single separated phase. Emulsifying

agents (surfactants) do this by concentrating in the interface

between the droplet and external phase and by providing a

physical barrier around the particle to coalescence. Surfactants

also reduce the interfacial tension between the phases, thus in-

creasing the ease of emulsiﬁcation upon mixing.

Natural, semisynthetic, and synthetic hydrophilic polymers

may be used in conjunction with surfactants in oil-in-water

emulsions as they accumulate at interfaces and also increase

the viscosity of the aqueous phase, thereby decreasing the rate

of formation of aggregates of droplets. Aggregation is generally

accompanied by a relatively rapid separation of an emulsion in-

to a droplet-rich and droplet-poor phase. Normally the density

of an oil is lower than that of water, in which case the oil drop-

lets and droplet aggregates rise, a process referred to as cream-

ing. The greater the rate of aggregation, the greater the droplet

size and the greater the rate of creaming. The water droplets in

a water-in-oil emulsion generally sediment because of their

greater density.

The consistency of emulsions varies widely, ranging from eas-

ily pourable liquids to semisolid creams. Generally oil-in-water

creams are prepared at high temperature, where they are ﬂuid,

and cooled to room temperature, whereupon they solidify as a

result of solidiﬁcation of the internal phase. When this is the

case, a high internal-phase volume to external-phase volume

ratio is not necessary for semisolid character, and, for example,

stear ic acid creams or v anishing creams are semisolid with as

little as 15% internal phase. Any semisolid character with wa-

ter-in-oil emulsions generally is attributable to a semisolid exter-

nal phase.

All emulsions require an antimicrobial agent because the

aqueous phase is favorable to the growth of microorganisms.

The presence of a preservative is particularly critical in oil-in-wa-

ter emulsions where contamination of the external phase oc-

curs readily. Since fungi and yeasts are found with greater

frequency than bacteria, fungistatic as well as bacteriostatic

properties are desirable. Bacteria have been shown to degrade

nonionic and anionic emulsifying agents, glycerin, and many

natural stabilizers such as tragacanth and guar gum.

Complications arise in preserving emulsion systems, as a re-

sult of partitioning of the antimicrobial agent out of the aque-

ous phase where it is most needed, or of complexation with

emulsion ingredients that reduce effectiveness. Therefore, the

effectiveness of the preservative system should always be tested

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in the ﬁnal product. Preservatives commonly used in emulsions

include me thyl-, ethyl-, propyl-, and butyl-parabens, benzoic

acid, and quaternary ammonium compounds.

See also Creams and Ointments.

EXTRACTS AND FLUIDEXTRACTS

Extra cts are concentrated preparations of vegetable or ani-

mal drugs obtained by removal of the active constituents of

the respective drugs with suitable menstr ua, by evaporation

of all or nearly all of the solvent, and by adjustment of the re-

sidual masses or powders to the prescribed standards.

In the manufacture of most extracts, the drugs are extracted

by percolation. The entire percolates are concentrated, gener-

ally by distillation under reduced pressure in order to subject

the drug principles to as little heat as possible.

Fluidextracts are liquid preparations of vegetable drugs, con-

taining alcohol as a solvent or as a preservative, or both, and so

made that, unless otherwise speciﬁed in an individ ual mono-

graph, each mL contains the therapeutic constituents of 1 g

of the standard drug that it represents.

A ﬂuidextract that tends to deposit sed iment may be aged

and ﬁltered or the clear portion decanted, provided the result-

ing clear liquid conforms to the Pharmacopeial standards.

Fluidextracts may be prepared from suitable extracts.

GELS

Gels (sometimes called Jellies) are semisolid systems consist-

ing of either suspensions made up of small inorganic particles or

large organic molecules interpenetrated by a liquid. Where the

gel mass consists of a network of small discrete particles, the gel

is classiﬁe d as a t wo-phase system (e.g., Aluminum Hydroxide

Gel). In a two-phase system, if the particle size of the dispersed

phase is relatively large, the gel mass is sometimes referred to as

a magma (e.g., Bentonite Magma). Both gels and magmas may

be thixotropic, forming semisolids on standing and becoming

liquid on agitation. They should be shaken before use to ensure

homogeneity and should be labeled to that effect. (See Suspen-

sions.)

Single-phase gels cons ist of org anic macromolecules uni-

formly distributed throughout a liquid in such a manner that

no apparent boundaries exist between the d ispersed macro-

molecules and the liquid. Single-phase gels may be made from

synthetic macromolecules (e.g., Carbomer) or fro m natur al

gums (e.g., Tragacanth). The latter preparations are also called

mucilages. Although these gels are comm only aqueous, alco-

hols and oils may be used as the continuous phase. For exam-

ple, mineral oil can be combined with a polyethylene resin to

form an oleaginous ointment base.

Gels can be used to administer drugs topically or into body

cavities (e.g., Phenylephrine Hydrochloride Nasal Jelly).

IMPLANTS (PELLETS)

Implants or pellets are small sterile solid masses consisting of

a highly puriﬁed drug (with or without excipients) mad e by

compression or molding. They are intend ed for implantation

in the body (usually subcutaneously) for the purpose of provid-

ing continuous release of the drug over long periods of time.

Implants are administered by means of a suitable special injec-

tor or surgical incision. This dosage form has been used to ad-

minister hormones such as testosterone or estradiol. They are

packaged individually in sterile vials or foil strips.

INFUSIONS, INTRAMAMMARY

Intramammary infusions are suspensions of drugs in suitable

oil vehicles. These preparations are intended for veterinary use

only, and are administered by instillation via the teat canals into

the udders of milk-producing animals.

INHALATIONS

Inhalations are drugs or solutions or suspensions of one or

more drug substances administered by the nasal or oral respi-

ratory route for local or systemic effect.

Solutions of drug substances in sterile water for inhalation or

in sodium chloride inhalation solution may be nebulized by use

of inert gases. Nebulizers are suitable for the administration of

inhalation solutions only if they give droplets sufﬁciently ﬁne

and uniform in size so that the mist reaches the bronchioles.

Nebulized solutions may be breathed directly from the nebuliz-

er or the nebulizer may be attached to a plastic face mask, tent,

or intermittent positive pressure breathing (IPPB) machine.

Another group of products, also known as metered-dose in-

halers (MDIs) are propellant-driven drug suspensions or solu-

tions in liquiﬁed gas propellant with or without a cosolvent

and are intended for deliveri ng metered doses of the drug to

the respiratory tract. An MDI contains multiple doses, often ex-

ceeding several hundred. The most common single-dose vol-

umes delivered are from 25 to 100 mL (also expressed as mg)

per actuation.

Examples of MDIs containing drug solutions and suspensions

in this pharmacopeia are Epinephrine Inhalation Aerosol and Iso-

proterenol Hydrochloride and Phenylephrine Bitartrate Inhalation

Aerosol, respectively.

Powders may also be ad minist ered by mechani cal dev ices

that require manually produced pressure or a deep inhalation

by the patient (e.g., Cromolyn Sodium for Inhalation ).

A special class of inhalations termed inhalants consists of

drugs or combination of drugs, that by virtue of their high va-

por pressure, can be carried by an air current into the nasal pas-

sage where they exert their effect. The container from which

the inhalant generally is administered is known as an inhaler.

INJECTIONS

An Injection is a preparation intended for parenteral admin-

istration or for constituting or diluting a parenteral article prior

to administration (see Injections h1i).

Each container of an Injection is ﬁlled with a volume in slight

excess of the labeled ‘‘size’’ or that volume that is to be with-

drawn. The excess volumes recommended in the accompany-

ing tabl e ar e us ually sufﬁcient to permit withdrawal and

administration of the labeled volumes.

Recommended Excess Volume

Labeled Size

For Mobile

Liquids

For Viscous

Liquids

0.5 mL 0.10 mL 0.12 mL

1.0 mL 0.10 mL 0.15 mL

2.0 mL 0.15 mL 0.25 mL

5.0 mL 0.30 mL 0.50 mL

10.0 mL 0.50 mL 0.70 mL

20.0 mL 0.60 mL 0.90 mL

30.0 mL 0.80 mL 1.20 mL

50.0 mL or more 2% 3%

IRRIGATIONS

Irrigations are sterile solutions intended to bathe or ﬂush o-

pen wounds or body cavities. They are used topically, never par-

enterally. They are labe led t o i ndicate that they are not

intended for injection.

LOTIONS

See Solutions or Suspensions.

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LOZENGES

Lozenges are solid preparations, that are intended to dissolve

or disintegrate slowly in the mouth. They contain one or more

medicaments, usually in a ﬂavored, sweetened base. They can

be prepared by molding (gelatin and/or fused sucrose or sorbi-

tol base) or by compression of sugar-based tablets. Molded loz-

enges are sometimes referred to as pastilles while compressed

lozenges are often referred to as troches. They are usually in-

tended for treatment of local irritation or infections of the

mouth or throat but may contain active ingredients intended

for systemic absorption after swallowing.

OINTMENTS

Ointments are semisolid preparations intended for external

application to the skin or mucous membranes.

Ointment bases recognized for use as vehicles fall into four

general classes: the hydrocarbon bases, the absorption bases,

the water-removable bases, and the water-soluble bases. Each

therapeutic ointment possesses as its base a representative of

one of these four general classes.

Hydrocarbon Bases

These bases, which are known also as ‘‘oleaginous ointment

bases,’’ are represented by White Petrolatum and White Oint-

ment. Only small amounts of an aqueous component can be

incorporated into them. They serve to keep medicaments in

prolonged contact with the skin and act as occlusive dressings.

Hydrocarbon bases are used chieﬂy for their emollient effects,

and are difﬁcult to wash off. They do not ‘‘dry out’’ or change

noticeably on aging.

Absorption Bases

This class of bases may be divided into two groups: the ﬁrst

group consisting of bases that permit the incorporation of

aqueous solutions with the formation of a water-in-oil emulsion

(Hydrophilic Petrolatum and Lanolin), and the second group con-

sisting of water-in-oil emulsions that permit the incorporation

of additional quantities of aqueous solutions (Lanolin). Absorp-

tion bases are useful also as emollients.

Water-Removable Bases

Such bases are oil-in-water emulsions, e.g., Hydrophilic Oint-

ment, and are more correctly called ‘‘creams.’’ (See Creams. )

They are also described as ‘‘water-washable, ’’ since they may

be readily washed from the skin or clothing with water, an at-

tribute that makes them more acceptable for cosmetic reasons.

Some medicaments may be more effective in these bases than

in hydrocarbon bases. Other advantages of the water-r emov-

able bases are that they may be diluted with water and that

they favor the absorption of serous discharges in dermatologi-

cal conditions.

Water-Soluble Bases

This group of so-called ‘‘greaseless ointment bases’’ compris-

es water-soluble constituents. Polyethylene Glycol Ointment is

the only Pharmacopeial preparation in this group. Bases of this

type offer many of the advantages of the water-removable ba-

ses and, in addition, contain no water-insoluble substances

such as petrolatum, anhydrous lanolin, or waxes. They are more

correctly called ‘‘Gels.’’ (See Gels.)

Choice of Base—The choice of an ointment base depends

upon many factors, such as the action desired, the nature of the

medicament to be incorporated and its bioavailability and sta-

bility, and the requisite shelf-life of the ﬁnished product. In some

cases, it is necessary to use a base that is less than ideal in order

to achieve the stability required. Drugs that hydrolyze rapidly,

for example, are more stable in hydrocarbon bases than in ba-

ses containing water, even though they may be more effective

in the latter.

OPHTHALMIC PREPARATIONS

Drugs are administered to the eyes in a wide variety of dos-

age forms, some of which require special con sideration. They

are discussed in the following paragraphs.

Ointments

Ophthalmic ointmen ts are ointments for application to the

eye. Special precautions must be taken in the preparation of

ophthalmic ointments. They are manufactured from sterilized

ingredients under rigidly aseptic con ditions and meet the re-

quirements under Sterility Tests h71i. If the speciﬁc ingredients

used in the formulation do not lend themselves to routine ster-

ilization techniques, ingredients that meet the sterility require-

ments described under Sterility Tests h71i, along with aseptic

manufacture, may be employed. Ophthalmic ointments must

contain a suitable su bstanc e or mixture of substances to p re-

vent growth of, or to destroy, microorganisms accidentally in-

troduced wh en t he cont ainer is opened during use, unless

otherwise directed in the individual monograph, or unless the

formula itself is bacteriostatic (see Added Substances under Oph-

thalmic Ointments h771i). The medicinal agent is added to the

ointment base either as a solution or as a micronized powder.

The ﬁnished ointment must be free from large particles and

must meet the requirements for Leakage and for Metal Particles

under Ophthalmic Ointments h771i. The immediate containers

for o phthalmic ointments shall be sterile at the time of ﬁl ling

and closing. It is mandatory that the immediate containers

for ophthalmic ointments be sealed and tamper-proof so that

sterility is assured at time of ﬁrst use.

The ointment base that is selected must be nonirritating to

the eye, permit diffusion of the drug throughout the secretions

bathing the eye, and retain the activity of the medicament for a

reasonable period under proper storage conditions.

Petrolatum is mainly used as a base for ophthalmic drugs.

Some absorption bases, water-removable bases, and water-sol-

uble bases may be desirable for water-soluble drugs. Such bases

allow for better dispersion of water-soluble medicaments, but

they must be nonirritating to the eye.

Solutions

Ophthalmic solutions are sterile solutions, essentially free

from foreign particles, suitably compounded and packaged

for instillation into the eye. Preparation of an ophthalmic solu-

tion requires careful consideration of such factors as the inher-

ent toxicity of the drug itse lf, isotonicity v alue, the need for

buffering agents, the need for a preservative (and, if needed,

its selection), sterilization, and proper packaging. Similar con-

siderations are also made for nasal and otic products.

ISOTONICITY VALUE

Lacrimal ﬂuid is isotonic with blood, having an isotonicity val-

ue corresponding to that of a 0.9% sodium chloride solution.

Ideally, an ophthalmic solution should have this isotonicity val-

ue; but the eye can tolerate isotonicity values as low as that of a

0.6% sodium chloride solutio n and as high as that of a 2.0%

sodium chloride solution without marked discomfort.

Some ophthalmic solutions are necessarily hypertonic in or-

der to enhance absorption and provide a concentration of the

active ingredient(s) strong enough to exert a prompt and effec-

tive action. Where the amount of such solutions used is small,

dilution with lacrimal ﬂuid takes place rapidly so that discomfort

from the hypertonicity is only temporary. However, any adjust-

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ment toward isotonicity by dil ution with tears is negligible

where large volumes of hypertonic solutions are used as collyria

to wash the eyes; it is, therefore, important that solutions used

for this purpose be approximately isotonic.

BUFFERING

Many drugs, notably alkaloidal salts, are most effective at pH

levels that favor the undissociated free bases. At such pH levels,

however, the drug may be unstable so that compromise levels

must be found and held by means of buffers. One purpose of

buffering some ophthalmic solutions is to prevent an increase in

pH caused by the slow release of hydroxyl ions by glass. Such a

rise in pH can affect both the solubility and the stability of the

drug. The decision whether or not buffering agents should be

added in preparing an ophthalmic solution must be based on

several considerations. Normal tears have a pH of about 7.4 and

possess some buffer capacity. The application of a solution to

the eye stimulates the ﬂow of tears and the rapid neutralization

of any excess hydrogen or hydroxyl ions within the buffer capa-

city of the tears. Many ophthalmic drugs, such as alkaloidal

salts, are weakly acidi c and have on ly weak buffer capacity.

Where only 1 or 2 drops of a solution containing them are add-

ed to the eye, the buffering action of the tears is usually ade-

quate to raise th e pH and pr event m arked discomfort. In

some cases pH may vary between 3.5 and 8.5. Some drugs, no-

tably pilocarpine hydrochloride and epinephrine bitartrate, are

more acid and overtax the buffer capacity of the lacrimal ﬂuid.

Ideally, an ophthalmic solution should have the same pH, as

well as the same isotonicity value, as lacrimal ﬂuid. This is not

usually possible since, at pH 7.4, many drugs are not apprecia-

bly soluble in water. Most alkaloidal salts precipitate as the free

alkaloid at this pH. Additionally, many drugs are chemically un-

stable at pH levels ap proaching 7.4. Thi s instability is more

marked at the high temperatures employed in heat sterilization.

For this reason, the b uffer system should be selected that is

nearest to the physiological pH of 7.4 and does not cause pre-

cipitation of the drug or its rapid deterioration.

An ophthalmic preparation with a buffer system approaching

the physiological pH can be obtained by mixing a sterile solu-

tion of the drug with a sterile buffer solution using aseptic tech-

nique. Even so, the possibility of a shorter shelf-life at the higher

pH must be taken into consideration, and attention must be di-

rected toward the attainment and maintenance of sterility

throughout the manipulations.

Many drugs, when buffered to a therapeutically acceptable

pH, would not be stable in solution for long periods of time.

These products are lyophilized and are intended for reconstitu-

tion immediately before use (e.g., Acetylcholine Chloride for Oph-

thalmic Solution).

STERILIZATION

The sterility of solutions applied to an injured eye is of the

greatest importance. Sterile preparations in special containers

for individual use on one patient sho uld be available in every

hospital, ofﬁce, or other installation where accidentally or sur-

gically traumatized eyes are treated. The method of attaining

sterility is determined primarily by the character of the particu-

lar product (see Ster ilization and Sterility Assurance of Compen-

dial Articles h1211i).

Whenever possible, sterile membrane ﬁltration under aseptic

conditions is the preferred method. If it can be shown that pro-

duct stability is not adversely affected, sterilization by autoclav-

ing in the ﬁnal container is also a preferred method.

Buffering certain drugs near the physiol ogical pH r ange

makes them quite unstable at high temperature.

Avoiding the use of heat by employing a bacteria-retaining

ﬁlter is a valuabl e technique, provided caution is exercised in

the selection, assembly, and use of the equipment. Single-ﬁltra-

tion, presterilized disposable units are available and should be

utilized wherever possible.

PRESERVATION

Ophthalmic solutions may be packaged in multiple-dose

containers when intended for the individual use of one patient

and where the ocular surfaces are intact. It is mandatory that

the immediate containers for ophthalmic solutions be sealed

and tamper-proof so that sterility is assured at time of ﬁrst

use. Each solution must contain a suitable substance or mixture

of substances to prevent the growth of, or to destroy, microor-

ganisms accidentally introduced when the container is opened

during use.

Where intended for use in surgical procedures, ophthalmic

solutions, although they must be sterile, should not contain an-

tibacterial agents, since they may be irritating to the ocular tis-

sues.

THICKENING AGENT

A pharmaceutical grade of methylcellulose (e.g., 1% if the

viscosity is 25 centipoises, or 0.25% if 4000 centipoises) or oth-

er suitable thickening agents such as hydroxypropyl methylcel-

lulose or polyvinyl alcohol occasionally are added to

ophthalmic solutions to increase the viscosity and prolong con-

tact of the drug with the tissue. The thickened ophthalmic so-

lution must be free from visible particles.

Suspensions

Ophthalmic suspensions are steril e liquid preparations con-

taining soli d parti cles dispersed in a liquid vehicle intended

for application to the eye (see Suspensions). It is imperative that

such suspensions contain the drug in a micronized form to pre-

vent irritation and/or scratching of the cornea. Ophthalmic sus-

pensions should never be dispensed if there is evidence of

caking or aggregation.

Strips

Fluorescein sodium solution should be dispensed in a sterile,

single-use container or in the form of a sterile, impregnated pa-

per strip. The strip releases a sufﬁcient amount of the drug for

diagnostic purposes when touched to the eye being examined

for a foreign body or a corneal abrasion. Contact of the paper

with the eye may be avoided by leaching the drug from the

strip onto the eye with the aid of sterile water or sterile sodium

chloride solution.

PASTES

Pastes are semisolid dosage forms that contain one or more

drug substances intended for topical application. One class is

made from a single-phase aqueous gel (e.g., Carboxymethylce-

llulose Sodium Paste). The other class, the fatty pastes (e.g., Zinc

Oxide Paste), consists of thick, stiff ointments that do not ordi-

narily ﬂow at body temperature, and therefore serve as protec-

tive coatings over the areas to which they are applied.

The fatty pastes appear less greasy and more absorptive than

ointments by reason of a high proportion of drug substance(s)

having an afﬁnity for water. These pastes tend to absorb serous

secretions, and are less penetrating and less maceratin g than

ointments, so that they are preferred for acute lesions that have

a tendency towards crusting, vesiculation, or oozing.

A dental paste is intended for adhesion to the mucous

membrane for local effect (e.g., Triamcinolone Acetonide Dental

Paste). Some paste preparations intended for administration to

animals are applied orally. The paste is squeezed into the mouth

of the animal, generally at the back of the tongue, or is spread

inside the mouth.

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PELLETS

See Implants.

POWDERS

Powders are intimate mixtures of dry, ﬁnely divided drugs

and/or chemicals that may be intended for internal (Oral Pow-

ders) or external (Topical Powders) use. Because of their greater

speciﬁc surface area, powders disperse and dissolve more read-

ily than compacted dosage forms. Child ren and those adults

who experi ence d ifﬁculty in swall owing tablets or capsules

may ﬁnd powders more acceptable. Drugs that are too bulky

to be formed into tablets or capsules of convenient size may

be administered as powders. Immediately prior to use, oral

powders are mixed in a beverage or apple sauce.

Often, stability problems encountered in liquid dosage forms

are avoided in powdered dosage forms. Drugs that are unstable

in aqueous suspensions or solutions may be prepared in the

form of granules or powders. These are intended to be consti-

tuted by the pharmacist by the addition of a speciﬁed quantity

of water just prior to dispensing. Because these constituted

products have limited stability, they are required to have a spec-

iﬁed expiration date after constitution and may require storage

in a refrigerator.

Oral powders may be dispensed in doses premeasured by the

pharmacist , i.e., divided powders, or in bulk. Traditionally, di-

vided powders have been wrapped in materials such as bond

paper and parchment. However, the pharmacist may provid e

greater protection from the environment by sealing individual

doses in small cellophane or polyethylene envelopes.

Granules for veterinar y use may be admini stered by sprin-

kling the dry powder on animal feed or by mixing it with animal

food.

Bulk oral powders are limite d to relatively nonpotent drugs

such as laxatives, antacids, dietary supplements, and certain an-

algesics that the patient may safely measure by the teaspoonful

or capful. Other bulky powders include douche powders, tooth

powders, and dusting powders. Bulk p owders are best dis-

pensed in tight, wide-mouth glass containers to afford maxi-

mum protection from the atmosphere and to prevent the loss

of volatile constituents.

Dusting powders are impalpable powders intended for topi-

cal application. They may be dispensed in sifter-top containers

to facilitate dusting onto the skin. In general, dusting powders

should be passed through at least a 100-mesh sieve to assure

freedom fr om gri t that could irritate tra umatized areas (see

Powder Fineness h811i).

PREMIXES

Premixes are mixtures of one or more drug substances with

suitable vehicles. Premixes are intended for admixture to animal

feedstuffs before administration. They are used to facilitate di-

lution of the active drug components with animal feed. Premix-

es should be as homogeneous as possi ble. It is essential that

materials of suitable ﬁneness be used and that thorough mixing

be achieved at all stages of premix preparation. Premixes may

be prep ared as p owder, pellets, or in granulat ed form. The

granulated form is free-ﬂowing and free from aggregates.

SOLUTIONS

Solutions are liquid preparations that contain on e or mor e

chemical substances dissolved, i.e., molecularly dispersed, in a

suitable solvent or mixture of mutually miscible solvents. Since

molecules in solutions are uniformly dispersed, the use of solu-

tions as dosage forms generally provides for the assurance of

uniform dosage upon administration, and good accuracy when

diluting or otherwise mixing solutions.

Substances in solutions, however, are more susceptible to

chemical instability than the solid state and dose for dose, gen-

erally require more bulk and weight in packaging relative to sol-

id dosage forms. For all solutions, but particularly t hose

containing volatile solvents, tight containers, stored away from

exces sive heat, should be used. Consideration should also be

given to the use of light-resistant containers when photolytic

chemical degradation is a potential stability problem. Dosage

forms categorized as ‘‘Solutions’’ are classiﬁed according to

route of administration, such as ‘‘Oral Solutions’’ and ‘‘Topical

Solutions,’’ or by their solute and solvent systems, such as ‘‘Spir-

its,’’ ‘‘Tinctures,’’ and ‘‘Waters.’’ Solutions intended for paren-

teral admini stration are ofﬁcially entitled ‘‘Injections’’ (see

Injections h1i).

Oral Solutions

Oral Solutions are liquid preparations, intended for oral ad-

ministration, that contain one or more substances with or with-

out ﬂavoring, sweetening, or coloring agents dissolved in water

or cosolvent-water mixtures. Oral Solutions may be formulated

for direct oral administration to the patient or they may be dis-

pensed in a more concentrated form that must be diluted prior

to administration. It is important to recognize that dilution with

water of Oral Solutions containing cosolvents, such as alcohol,

could lead to precipitation of some ingredients. Hence, great

care must be taken in diluting concentrated solutions when co-

solvents are present. Preparations dispensed as soluble solids or

soluble mixtures of solids, with the intent of dissolving them in a

solvent and administering them orally, are designated ‘‘for Oral

Solution’’ (e.g., Potassium Chloride for Oral Solution).

Oral Solutions containing high concentrations of sucrose or

other sugars traditionally have been designated as Syrups. A

near-saturated solution of sucrose in puriﬁed water, for exam-

ple, is known as Syrup or ‘‘Simple Syrup.’’ Through common

usage the term, syrup, also has been used to include any other

liquid dosage form prepared in a sweet and viscid vehicle, in-

cluding oral suspensions.

In addition to sucrose and other sugars, certain polyols such

as sorbitol or glycerin may be present in Oral Solutions to inhibit

crystallization and to modify solubility, taste, mouth-feel, and

other vehicle p roperties. Antimicrobial agent s to prevent the

gro wth of bacteria, yeasts, and molds a re generally also pre-

sent. Some sugarless Oral Solutions contain sweetening agents

such as sorbitol or aspartame, as well as thickening agents such

as the cellulose gums. Such viscid sweetened solutions, contain-

ing no sugars, are occasionally prepared as vehicles for admin-

istration of drugs to diabetic patients.

Many oral solutions, that contain alcohol as a cosolvent, have

been traditionally designated as Elixirs. However, many others

designated as Oral Solutions also contain signiﬁcant amounts of

alcohol. Since high concentr ations of alcohol can p roduce a

pharmacologic effect when administered orally, other cosol-

vents, such as glycerin and prop ylene glycol, should be used

to minimize the amount of alcohol required. To be designated

as an Elixir, however, the solution must contain alcohol.

Topical Solutions

Topical Solutions are solutions, usually aqueous but often

containing other solvents, such as alcohol and polyols, intend-

ed for topical application to the skin, or as in the case of Lido-

caine Oral Topical Solution, to the oral mucosal surface. The term

‘‘lotion’’ is applied to solutions or suspensions applied topically.

Otic Solutions

Otic Solutions, intended for instillation in the outer ear, are

aqueous, or they are solutions prepared with glycerin or other

solvents and dispersing agents (e.g., Antipyrine and Benzocaine

Otic Solution and Neomycin and Polymyxin B Sulfates and Hydro-

cortisone Otic Solution).

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Ophthalmic Solutions

See Ophthalmic Preparations.

Spirits

Spirits are alcoholic or hydroalcoholic solutions of volatile

substances prepared usually by simple solution or by admixture

of the ingredients. Some spirits serve as ﬂavoring agents while

others have medicinal valu e. Reduction of the high alcoholic

content of spirits by admixture with aqueous preparations often

causes turbidity.

Spirits require storage in tight, light-resistant containers to

prevent loss by evaporation and to limit oxidative changes.

Tinctures

Tinctures are alcoholic or hydroalcoholic solutions prepared

from vegetable materials or from chemical substances.

The proportion of drug represented in the different chemical

tinctures is not uniform but varies according to the established

standards for each. Traditionally, tinctures of potent vegetable

drugs essentially represent the activity of 10 g of the drug in

each 100 mL of tincture, the potency being adjusted following

assay. Most other vegetable tinctures represent 20 g of the re-

spective vegetable material in each 100 mL of tincture.

PROCESS P

Carefully mix the ground drug or mixture of drugs with a suf-

ﬁcient quantity of the prescribed solvent or solvent mixture to

render it evenly and distinctly damp, allow it to stand for 15

minutes, transfer it to a suitable percolator, and pack the drug

ﬁrmly. Pour on enough of the prescribed solvent or solvent mix-

ture to saturate the drug, cover the top of the percolator, and,

when the liquid is about to drip from the percolator, close the

lower oriﬁce and allow the drug to macerate for 24 hours or for

the time speciﬁed in the monograph. If no assay is directed, al-

low the percolation to proceed slowly, or at the speciﬁed rate,

gradually adding sufﬁcient solvent or solvent mixture to pro-

duce 1000 mL of tincture, and mix (for deﬁnitions of ﬂow rates,

see under Extracts and Fluidextracts). If an assay is directed, col-

lect only 950 mL of percolate, mix this, and assay a portion of it

as directed. Dilute the remainder with such quantity of the pre-

scribed solvent or solvent mixture as calculation from the assay

indicates is necessary to produce a tincture that conforms to the

prescribed standard, and mix.

PROCESS M

Macerate the drug with 750 mL of the prescribed solvent or

solvent mixture in a container that can be closed, and put in a

warm place. Agitate it frequently during 3 days or until the sol-

uble matter is dissolved. Transfer the mixture to a ﬁlte r, and

when most of the liquid has drained away, wash the residue

on the ﬁlter with a sufﬁcient quantity of the prescribed solvent

or solvent mixture, combining the ﬁltrates, to produce 1000 mL

of tincture, and mix.

Tinctures require storage in tight, light-resistant containers,

away from direct sunlight and excessive heat.

Waters, Aromatic

Aromatic waters are clear, saturated aqueous solutions (un-

less otherwise speciﬁed) of volatile oils or other aromatic or vol-

atile substances. Their odors and tastes are similar, respectively,

to those of the drugs or volatile substances from which they are

prepared, and they are free from empyreumatic and other for-

eign odors. Aromatic waters may be prepared by distillation or

solution of the aromatic substance, with or without the use of a

dispersing agent.

Aromatic waters require protection from intense light and ex-

cessive heat.

SUPPOSITORIES

Suppositories are solid bodies of various weights and shapes,

adapted for introduction into the rectal, vaginal, or urethral or-

iﬁce of the human body. They usually melt, soften, or dissolve at

body temperature. A suppository may a ct as a protectant or

palliative to the local tissues at the point of introduction or as

a carrier of therapeutic agents for systemic or local action. Sup-

pository bases usually employed are cocoa butter, glycerinated

gelatin, hydrogenated vegetable oils, mixtures of polyethylene

glycols of various molecula r weights, and fatty acid esters of

polyethylene glycol.

The sup pository base employed has a marked inﬂuence on

the release of the active ingredient incorporated in it. While co-

coa butter melts quickly at body temperature, it is immiscible

with body ﬂu ids and this inhibits the diffusion of fat-solu ble

drugs to the affected sites. Polyethylene glycol is a suitable base

for some antiseptics. In cases where systemic action is expected,

it is preferable to incorporate the ionized rather than the non-

ionized form of the drug, in order to maximize bioavailability.

Although nonionized drugs partition more readily out of water-

miscible bases such as glycerinated gelatin and polyethylene

glycol, the bases themselves tend to dissolve very s lowly and

thus retard release in this manner. Oleaginous vehicles such

as cocoa butter are seldom used in vaginal preparations be-

cause of the nonabsorbable residue formed, while glycerinated

gelatin is seldom used rectally because of its slow dissolution.

Cocoa butter and its substitutes (Hard Fat) are superior for allay-

ing irritation, as in preparations intended for treating internal

hemorrhoids.

Cocoa Butter Suppositories

Suppositories having cocoa butter as the base may be made

by means of incorporating the ﬁnely divided medicinal sub-

stance into the solid oil at room temperature and suitably shap-

ing the resulting mass, or by working with the oil in the melted

state and allowing the resulting suspension to cool in molds. A

suitable quantity of hardening agents may be added to coun-

teract the tendency of some medicaments such as chloral hy-

drate and phenol to soften the base. It is important that the

ﬁnished suppository melt at body temperature.

The approximate weights of suppositories prepared with co-

coa butter are given below. Suppositories prepared from other

bases var y in weight and generally are heavier than the weights

indicated here.

Rectal Suppositories for adults are tapered at one or both ends

and usually weigh about 2 g each.

Vaginal Suppositories are usually globular or oviform and

weigh about 5 g each. They are made from water-soluble or wa-

ter-miscible vehicles such as polyethylene glycol or glycerinated

gelatin.

Suppositories with cocoa butter base require storage in well-

closed containers, preferably at a temperature below 308 (con-

trolled room temperature).

Cocoa Butter Substitutes

Fat-type suppository bases can be produced from a variety of

vegetable oils, such as coconut or palm kernel, which are mod-

iﬁed by esteriﬁcation, hydrogenation, and fractionation to ob-

tain products of varying composition and melting temperatures

(e.g., Hydrogenated Vegetable Oil and Hard Fat). These products

can be so designed as to reduce rancidity. At the same time,

desired characteristics such as narrow inter vals between melt-

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ing and solidiﬁcation temperatures, and melting ranges to ac-

commodate v arious formulation and climatic conditions, can

be built in.

Glycerinated Gelatin Suppositories

Medicinal substances may be incorporated into glycerinated

gelatin bases by addition of the prescribed quantities to a vehi-

cle consisting of about 70 parts of glycerin, 20 parts of gelatin,

and 10 parts of water.

Glycerinated gelatin suppositories require storage in tight

containers, preferably at a temperature below 358.

Polyethylene Glycol–Base Suppositories

Several combinations of polyethylene glycols having melting

temperatures that are above body temperature have been used

as suppository bases. Inasmuch as release from these bases de-

pends on dissolution rather than on melting, there are signiﬁ-

cantly fewer problems in preparation and storage than exist

with melting-type vehicles. However, high concentrations of

higher-molecular-weight polyethylene glycols may lengthen

dissolution time, resulting in problems with retention. Labels

on polyethylene glycol suppositories should contain directions

that they be moistened with water before inserting. Although

they can be stored without refrigeration, they should be pack-

aged in tightly closed containers.

Surfactant Suppository Bases

Several nonionic surface-active agents closely related chemi-

cally to the polyethylene glycols can be used as suppository ve-

hicles. Examples of such sur factants are polyoxyethylene

sorbitan fatty acid esters and the polyoxyethylene stearates.

These surfactants are used alone or in combination with other

suppository vehicles to yield a wide range of melting tempera-

tures and consistencies. One of the major advantages of such

vehicles is their water-dispersibility. However, care must be tak-

en with the use of surfactants, because they may either increase

the rate of drug a bsorption o r interact with drug molecules,

causing a decrease in therapeutic activity.

Tableted Suppositories or Inserts

Vaginal suppositories occasionally are prepared by the com-

pression of powdered materials into a suitable shape. They are

prepared also by encapsulation in soft gelatin.

SUSPENSIONS

Suspensions are liquid preparations that consist of solid par-

ticles dispersed throughout a liquid phase in which the particles

are not soluble. Dosage forms ofﬁcially categorized as ‘‘Suspen-

sions’’ are designated as such if they are not included in other

more speciﬁc categories of suspensions, suc h as Oral Suspen-

sions, Topical Suspensions, etc. (see these other categories).

Some suspensions are prepared and ready for use, while others

are prepared as solid mixtures intended for constitution just be-

fore use with an appropriate vehicle. Such products are desig-

nated ‘‘for Oral Suspension’’, etc. The term ‘‘Milk’’ is sometimes

used for suspensions in aqueous vehicles intended for oral ad-

ministration (e.g., Milk of Magnesia). The term ‘‘Magma’’ is of-

ten used to describe suspensions of inorganic solids such as

clays in water, where there is a tendency for strong hydration

and aggregation of the solid, giving rise to gel-like consistency

and thixotropic rheological behavior (e.g., Bentonite Magma).

The term ‘‘Lotion’’ has been used to categorize many topical

suspensions and emulsions intended for application to the skin

(e.g., Calamine Lotion). Some suspensions are prepared in sterile

form and are used as Injectables, as well as for ophthalmic and

otic administration. These may be of two types, ready to use or

intended for constitution with a prescribed amount of Water for

Injection or other suitable diluent before use by the designated

route. Suspensions should not be injected intravenously or in-

trathecally.

Suspensions intended for any route of administration should

contain suitable antimicrobial agents to protect against bacte-

ria, yeast, and mold contamination (see Emulsions for some

consideration of antimicrobial preservative properties that ap-

ply also to Suspensions). By its very nature, the particular matter

in a suspension may settle or se diment t o the bottom of the

container upon standing. Such sedimen tation may also lead

to caking and solidiﬁcation of the sediment with a resulting dif-

ﬁculty in redispers ing the suspension upon agitation. To pre-

vent such problems, suitable ingredients that increase

viscosity and the gel state of the suspension, such as clays, sur-

factants, polyols, polymers, or sugars, should be added. It is im-

portant that suspensions always be shaken well before use to

ensure uniform distribution of the solid in the vehicle, thereby

ensuring uniform and proper dosage. Suspensions require stor-

age in tight containers.

Oral Suspensions

Oral Suspensions are liquid preparations containing solid par-

ticles dispersed in a liquid vehicle, wit h suit able ﬂavor ing

agents, intended for oral administration. Some suspensions la-

beled as ‘‘Milks’’ or ‘‘Magmas’’ fall into this category.

Topical Suspensions

Topical Suspensions are liquid preparations containing solid

particles dispersed in a liquid vehicle, intended for application

to the skin. Some suspensions labeled as ‘‘Lotions’’ fall into this

category.

Otic Suspensions

Otic Suspensions are liquid preparations containing micron-

ized particles intended for instillation in the outer ear.

Ophthalmic Suspensions

See Ophthalmic Preparations.

SYRUPS

See Oral Solutions.

SYSTEMS

In recent years, a number of dosage forms have been devel-

oped using modern technology that allows for the uniform re-

lease or targeting of drugs to the body. These products are

commonly ca lled delivery systems. The most widely use d of

these are Transdermal Systems.

Transdermal Systems

Transdermal drug delivery systems are self-contained, dis-

crete dosage fo rms that, when applied to intact skin, are de-

signed to deliver the drug(s) through the skin to the systemic

circulation. Systems typically comprise an outer covering (bar-

rier), a drug r eservoir, which ma y have a rate- controlling

membrane, a contact adhesive applied to some or all parts of

the system and the system/skin interface, and a protective liner

that is removed befor e applying the syst em. T he act ivity of

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these systems is deﬁned in term s of the r elease rate of the

drug(s) from the system. The total duration of drug release from

the system and the system surface area may also be stated.

Transdermal drug delivery systems work by diffusion: the

drug diffuses from the drug rese rvoir, directl y or through the

rate-controlling membrane and/or contact adhesive if present,

and then through the skin into the general circulation. Typical-

ly, modiﬁed-release systems are designed to provide drug deliv-

ery at a constant rate, such that a true steady-state blood

concentration is achieved and maintained until the system is re-

moved. At th at time, blood concentration declines a t a rate

consistent with the pharmacokinetics of the drug.

Transdermal drug delivery systems are applied to body areas

consistent with the labeling for the product(s). As long as drug

concentration at the system/skin interface remains constant,

the amount of drug in the dosage form does not inﬂuence plas-

ma concentrations. The functional lifetime of the system is de-

ﬁned by the initial amount of drug in t he r eservoir and the

release rate from the reservoir.

NOTE—Drugs for local rather than systemic effect are com-

monly applied to the skin embedded in glue on a cloth or plas-

tic backing. These products are deﬁned traditionally as plasters

or tapes.

Ocular System

Another type of system is the ocular system, which is intend-

ed for placement in the lower conju nctival fo rnix from which

the drug diffuses through a membrane at a constant rate

(e.g., Pilocarpine Ocular System).

Intrauterine System

An intrauterine system, based on a similar principle but in-

tended for release of drug over a much longer period of time,

e.g., one year, is als o available (e.g., Progesterone Intrauterine

Contraceptive System).

TABLETS

Tablets are solid dosage forms containing medicinal sub-

stances with or without suitable diluents. They may be classed,

according to the method of manufacture, as compressed tab-

lets or molded tablets.

The vast majority of all tablets manufactured are made by

compression, and compressed tablets are the most widely used

dosage form in this country. Compressed tablets are prepared

by the application of high pressures, utilizing steel punches and

dies, to powders or granulations. Tablets can be produced in a

wide variety of sizes, shapes, and surf ace markings, depending

upon the design of the punches and dies. Capsule-shaped tab-

lets are commonly referred to as caplets. Boluses are large tab-

lets intended for veterinary use, usually for large animals.

Molded tablets are prepared by forcing dampened powders

under low pressure into die cavities. Solidiﬁcation depends up-

on crystal bridges built up during the subsequent drying pro-

cess, and not upon the compaction force.

Tablet triturates are small, usually cylindrical, molded or com-

pressed tablets. Tablet triturates were traditionally used as dis-

pensing tablets in order to provide a convenient, measured

quantity of a potent drug f or compounding purposes. Such

tablets are rarely used today. Hypodermic tablets are molded

tablets mad e from comple tely a nd readily water-soluble in-

gredients and formerly were intended for use in making pre-

parations for hypodermic injection. They are employed orally,

or where rapid drug availability is required such as in the case

of Nitroglycerin Tablets, sublingually.

Buccal tabl ets ar e in tended t o be inser ted in the buccal

pouch, and sublingual tablets are intended to be inserted be-

neath the tongue, where the active ingredient is absorbed di-

rectly through the oral mucosa. Few drugs are readily absorbed

in this way, but for those that are (such as nitroglycerin and cer-

tain steroid hormones), a number of advantages may result.

Soluble, effervescent tablets are prepared by compression

and contain, in addition to active ingredients, mixtures of acids

(citric acid, tartaric acid) and sodium bicarbonate, which re-

lease carbon dioxide when dissolved in water. They are intend-

ed to be dissolved or dispersed in water before administration.

Effervescent tablets should b e st ored in tightly closed con-

tainers or moisture-proof packs and labeled to indicate that

they are not to be swallowed directly.

Chewable Tablets

Chewable tablets are formulated and manufactured so that

they may be chewed, producing a pleasant tastin g residue in

the oral cavity that is easily swallowed and does not leave a bit-

ter or unpleasant aftertaste. These tablets have been used in

tablet formulations for children, especially multivitamin formu-

lations, and for the administration of antacids and selected an-

tibiotics. Ch ewable tablets are prepared by compres sion,

usually utilizing mannitol, sorbitol, or sucrose as binders and ﬁl-

lers, and containing colors and ﬂavors to enhance their appear-

ance and taste.

Preparation of Molded Tablets

Molded tablets are prepared from mixtures of medicinal sub-

stances and a diluent usually consisting of lactose and pow-

dered sucrose in varying proportions. The powders are

dampened with solutions containing high percentages of alco-

hol. The concentration of alcohol depends upon the solubility

of the active ingredients and ﬁllers in the solvent system and the

desired degree of hardness of the ﬁnished tablets. The damp-

ened powders are pressed into molds, removed, and allowed

to dry. Molded tablets are quite friable and care must be taken

in packaging and dispensing.

Formulation of Compressed Tablets

Most compressed tablets consist of the active ingredient and

a diluent (ﬁller), binder, disintegrating agent, and lubricant. Ap-

proved FD&C and D&C dyes or lakes (dyes adsorbed onto in-

soluble aluminum hydroxide), ﬂavors, and sweetening agents

may also be present . D iluents are added where the quantity

of active ingredient is small or difﬁcult to compress. Common

tablet ﬁllers include lactose, starch, dibasic calcium phosphate,

and microcrystalline cellulose. Chewable tablets often contain

sucrose, mannitol, or sorbitol as a ﬁller. Where the amount of

active ingredien t is small, the overall tableting properties are

in large measure determined by the ﬁller. Because of problems

encountered with bioavailab ility of hydrophobic drugs of low

water-solubility, water-soluble diluents ar e used as ﬁllers for

these tablets.

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Binders give adhesiveness to the powder during the prelimi-

nary granulation and to the compressed tablet. They add to the

cohesive strength already available in the diluent. While binders

may be added dry, they are more effective when added out of

solution. Common binders include acacia, gelatin, sucrose, po-

vidone, methylcellulose, carboxymethylcellulose, and hydro-

lyzed starch pastes. The most effective dry binder is

microcrystalline cellulose, which is commonly used for this pur-

pose in tablets prepared by direct compression.

A disintegrating agent serves to assist in the fragmentation of

the tablet after administration. The most widely used tablet dis-

integrating agent is starch. Chemically modiﬁed starch es and

cellulose, alginic acid, microcrystalline cellulose, and cross-

linked povidone, are also used for this pu rpose. Effer v escent

mixtures are used in soluble tablet system s as disintegrating

agents. The concentration of the disintegrating agent, method

of addition, and degree of compaction play a role in effective-

ness.

Lubricants reduce friction during the compression and ejec-

tion cycle. In addition, they aid in preventing adherence of tab-

let material to the dies and punches. Metallic stearates, stearic

acid, hydrog enated vegetable oils, and talc are used as lubri-

cants. Because of the nature of this function, most lubricants

are hydrophobic, and as such tend to reduce the rates of tablet

disintegration and dissolution. Consequently, excessive con-

centrations of lubricant should be avoided. Polyethylene glycols

and some lauryl sulf ate salts have been used as soluble lubri-

cants, but such agents generally do not possess optimal lubri-

cating properties, and comparatively high concentrations are

usually required.

Glidants are agents that improve powder ﬂuidity, and they

are commonly employed in direct compression where no gran-

ulation step is involved. The most effective glidants are the col-

loidal pyrogenic silicas.

Colorants are often added to tablet formulations for esthetic

value or for product identiﬁcation. Both D&C and FD&C dyes

and lakes are used. Most dyes are photosensitive and they fade

when exposed to light. The federal Food and Drug Administra-

tion regulates the colorants employed in drugs.

Manufacturing Methods

Tablets are prepared by three general methods: wet granula-

tion, dry granulation (roll compaction or slugging), and direct

compression. The purpose of both wet and dry granulation is to

improve ﬂow of the mixture and/or to enhance its compressi-

bility.

Dry granulation (slugging) involves the compaction of pow-

ders at high pr essures into large, often poor ly formed t ablet

compacts. These compacts are then milled and screened to

form a granulation of the desired particle size. The advantage

of dry granulation is the elimination of both heat and moisture

in the processing. Dry granulations can be produced also by ex-

truding powders between hydraulically operated rollers to pro-

duce thin cakes which are subsequently screened or milled to

give the desired granule size.

Excipients are available that allow production of tablets at

high speeds without prior granulation steps. These directly

compressible excipients consist of special physical forms of sub-

stances such as lactose, sucrose, dextrose, or cellulose, whi ch

possess the desirable properties of ﬂuidity and compressibility.

The most widely used direct-compaction ﬁllers are microcrystal-

line cellulose, anhydrous lactose, spray-dried lactose, compress-

ible sucrose, and some forms of modiﬁed starches. Direct

compression avoids many of the problems associated with

wet and dry granulations. However, the inherent physical pro-

perti es of the individual ﬁller materials ar e highly critical, and

minor variations can alter ﬂow and compression characteristics

so as to make them unsuitable for direct compression.

Physical evidence of poor tablet quality is d iscussed under

Stability Considerations in Dispensing Practice h1191i.

WEIGHT VARIATION AND CONTENT UNIFORMITY

Tablets are required to meet a weight variation test (see Uni-

formity of Dosage Units h905i) where the active ingredient com-

prises a major portion of the tablet and where control of weight

may be presumed to be an adequate control of drug content

uniformity. Weight variation is not an adequate indic ation of

content uniformity where the drug substance comprises a rela-

tively minor portion of the tablet, or where the tablet is sugar-

coated. Thus, the Pharmacopeia generally requires that coated

tablets and tablets containing 50 mg or less of active ingredi-

ent, com prising less than 50% by weight of the dosage-form

unit, pass a c ontent uniform ity test (see Uniformity of Dosage

Units h905i), wherein indiv idual tablets are assayed for actual

drug content.

DISINTEGRATION AND DISSOLUTION

Disintegration is an essential attribute of tablets intended for

administration by mouth, except for those intended to be

chewed before being swallowed and for some types of extend-

ed-release tablets. A disintegration test is provided (see Disinte-

gration h701i), and limits on the times in which disintegration is

to take place, appropriate for the types of tablets concerned,

are given in the individual monographs.

For drugs of limited water-solubility, dissolution may be a

more meaningful quality attribute than disintegration. A disso-

lution test (see Dissolution h711 i) is requ ired in a numb er of

monographs on tablets. In many cases, it is possible to correlate

dissolution rates with biological availability of the active ingre-

dient. However, such tests are useful mainly as a means of

screening preliminary formulations and as a routine quality-

control procedure.

Coatings

Tablets may be coated for a variety of reasons, including pro-

tection of the ingredients from air, moisture, or light, masking

of unpleasant tastes and odors, improvement of appearance,

and control of the site of drug release in the gastrointestinal

tract.

PLAIN COATED TABLETS

Classically, tablets have been coated with sugar applied from

aqueous suspensions containing insoluble powders such as

starch, calcium carbonate, talc, or titanium dioxide, suspended

by means of acacia or gelatin. For purposes of identiﬁcation and

esthetic value, the outside coatings may be colored. The ﬁn -

ished coated tablets are polished by application of dilute solu-

tions of wax in solvents such as chloroform or powdered mix.

Water-protective coatings consisting of substances such as shel-

lac or cellulose acetate phthalate are often applied out of non-

aqueous solvents prior to application of sugar coats. Excessive

quantities should be avoided. Drawbacks of sugar coating in-

clude the lengthy time necessary for application, the need for

waterprooﬁng, which also adversely affects dissolution, and the

increased bulk of the ﬁnished tablet. These factors have resulted

in increased acceptance of ﬁlm coatings. Film coatings consist

of water-soluble or dispersible materials such as hydroxypropyl

methylcellulose, methylcellulose, hydroxypropylcellulose, car-

boxymethylcellulose sodium, and mixtures of cellulose acetate

phthalate and polyethylene glycols applied out of nonaqueous

or aqueous solvents. Evaporati on of the solvents leaves a thin

ﬁlm that adhe res directly to the tablet and allows it to retain

the original shape, including grooves or identiﬁcation codes.

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DELAYED-RELEASE TABLETS

Where the drug may be destroyed or inactivated by the gas-

tric juice or where it may irritate the gastric mucosa, the use of

‘‘enteric’’ coatings is indicated. Such coatings are intended to

delay the release of the medication until the tablet has passed

through the stomach. The term ‘‘delayed-release’’ is used for

Pharmacope ial purposes, and the individual monographs in-

clude tests and speciﬁcations for Drug release (see Drug Release

h724i)orDisintegration (see Disintegration h701i).

EXTENDED-RELEASE TABLETS

Extended-release tablets are formulated in such manner as to

make the con tained medicament available over an extended

period of time following ingestion. Expressions such as ‘‘pro-

longed-action,’’ ‘‘repeat-action,’’ and ‘‘sustained-release’’ have

also been used to describe such dosage forms. However, the

term ‘‘extended-release’’ is used for Pharmacopeial purposes,

and requirements for Drug release typically are speciﬁed in the

individual monographs.

GENERAL CONSIDERATIONS

This chapter provides general descriptions of and def-

initions for drug products, or dosage forms, commonly

used to administe r the drug substance [active pharma-

ceutical ingredient (API)]. It discusses general principles

involved in the manufacture or compo unding of these

dosage forms, and recom mendations for proper use

and storage. A glossary is provided as a resource on no-

menclature.

A dosage form is a combination of d rug s ubstances

and excipients to facilitate dosing, administration, and

delivery of the medicine to the patient. The design and

testing of all dosage forms target drug product quality.

A testing pro tocol must consider not only the physical,

chemical, and biological properties of the dosage form

as appropriate but also the administration route and de-

sireddosingregimen.Theinterrel ationship s of dosage

forms and routes of administration have been summa-

rized in the compendial taxonomy for pharmaceutical

dosage forms (Figure 1).

The organization of this general

information chapter is by the physical attributes of each

particular dosage form (Tier Two), generally without spe-

ciﬁc reference to route of administration. Information

speciﬁc to route of administration is given when needed.

Tests to ensure compliance with pharmacopeial stan-

dards for dos age form perf ormance fall into one of the

following areas.

In the United States, a drug with a name recognized in USP–

NF must comply with compendial identity standards or be

deemed a dulterated, misbranded, or both. To avoid being

deemed adulterated, such drugs also must comply with com-

pendial standards for strength, quality, or purity, unless labeled

to show all respects in which the drug differs. See the Federal

Food, Drug, and Cosmetic Act (FDCA), Sections 501(b) and

502(e)(3)(b), and Food and Drug Administration (FDA) regu-

lations at 21 CFR 299.5. In addition, to avoid being deemed

misbranded, drugs recognized in USP–NF also must comply

with compendial standards for packing and labeling, FDCA Sec-

tion 502(g). ‘‘Quality’’ is used herein as suitable shorthand for

all such compendial requirements. This approach also is consis-

tent with U.S. and FDA participation in the International Con-

ference on Harmonization (ICH). The ICH guideline on

speciﬁcations, Q6A, notes that ‘‘speciﬁcations are chosen to

conﬁrm the quality of the drug substance and drug product. . .’’

and deﬁne s ‘‘quality’’ as ‘‘The s uitability of either a drug sub-

stance or drug product for its intended use. This term includes

such attributes as identity, strength, and purity.’’

Marshall K, Foster TS, Carlin HS, Williams RL. Development of

a compendial taxonomy and glossary for pharmaceutical dos-

age forms. Pharm Forum. 2003;29(5):1742–1752.

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Dose Uniformity (see also Uniformity of Dosage Units

h905i)—Consistency in dosing for a patient or consu mer

requires that the variation in the drug substance content

of each dosage unit be accurately controlled throughout

the manufactured batch or compounded lot of drug pro-

duct. Uniformity of dosage units typically is demonstra-

ted by one of two procedures: content uniformity or

weight variation. The procedure for content uniformity

requires the assay of drug substance content of individual

units, and that for weight variation uses the weight of the

individual units to estimate their content. Weight varia-

tion may be used w here the underlying distribution of

drug substance in the blend is presumed to be uniform

and well-controlled, as in solutions. In such cases t he

content of drug substance may be adequately estim ated

by the net weight. Content uniformity does not rely on

the assumption of blend uniformity and can be applied in

all cases. Tablets and capsules are assigned a limit below

which the weight variation procedure is not applicable.

Successful development and manufacture of dosage

forms requires careful evaluation of drug substance par-

ticle or droplet size, inc orporation techniques, and excip-

ient properties.

Stability (see also Pharmaceutica l Stability h1150i)—

Drug product stability involves the evaluation of chemi-

cal stability, physical stability, and performance over

time. The chemical stability of the drug substance in

the dose form matrix must support the expiration dating

for the commercially prepared dosage forms and a be-

yond-use date for a compounded dosage form. Test pro-

cedures for potency must be stability indicating (see

Validation of Compendial Procedures h 12 25i). Degrada-

tion products should be quantiﬁed. In the case of dis-

persed or emulsiﬁed systems, consideration must be

given to the potential for settling or separation of the for-

mulation components. Any physical changes to the dos-

age form must be easily reversed (e.g., by shaking) prior

to dosing or administration. In vitro release test proce-

dures such as dissolu tion and disintegration provide a

measure of continuing consistency in performance over

time (see Dissolution h711i, Disintegration h701i,and

Drug Release h724i).

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Bioavailability (see also In Vitro and In Vivo Evaluation

of Dosage Forms h1088i, and Assessment of Drug Product

Performance—Bioavailability, Bioequ ivalence, and Dissolu-

tion h1090i)—Bioavailability is inﬂuenced by factors such

as the method of manufacture or compounding, particle

size, crystal form (polymorph) of the drug substance, the

properties of the excipients used to formulate the dosage

form, and physical changes as the drug product ages. As-

sura nce of consistency in b ioavailability over time (bio-

equivalence) requires close attention to all aspects of

the production (or compounding) and testing of the

dosage form. In vitro release (disintegration and dissolu-

tion) testing is commonly used as a surrogate to demon-

strate consistent availability of the API from the

formulated dosage.

Manufacture—Although detailed instructions about

the manufacture of any of t hese dosage forms are be-

yond the scope of this general information chapter, gen-

eral manufacturing principles have been included, as well

as suggested testing for proper use and storage. Further

information relative to extemporaneous compounding

of dosage forms can be found in Pharmaceutical Com-

pounding—Nonsterile Preparations h795i and Pharmaceu-

tical Compounding—Sterile Preparations h797i.

Route of Administration—The pri mary routes of

administration for pharmaceutical dosage forms can be

deﬁned as mucosal, oral, parenteral (by injection), inha-

lation, and top ical/derma l, and each has subcategories

as needed. Many tests employed to ensure quality gen-

erally are applied across all of the administration routes,

but some tests are speciﬁc for individual routes. For ex-

ample, products intended for injection must be evaluat-

ed for Sterility h71i and Pyrogen Test h151i,andthe

manufacturing process (and sterilization technique) em-

ployed for parenterals (by injection) should ensure com-

pliance with these tests. Tests for particulate matter may

be required for solution dosage forms depending on the

route of administration (e.g., by injection—Particulate

Matter in Injections h788i, or mucosal—Particulate Matter

in Ophthalmic Solutions h789i). Additionally, dosage

forms intended for the inhalation route of administration

must be monitored for particle size and spray pattern (for

a metered-dose inhaler or dry-powder inhaler) and drop-

let size (for nasa l sprays). Further information regarding

administration routes and suggested testing can be

found in the Guide to General Chapters, Charts 4–8 and

10–13.

An appropriate manufacturing process and testing re-

gimen help ensure that a dosage form can meet the ap-

propriate quality attributes for the intended route of

administration.

PRODUCT QUALITY TESTS, GE NERAL

ICH Guidance Q6A (available at www.ich.org) recom-

mends speciﬁcations (list of tests, references to analytical

procedures, and acceptance criteria) to ensure that com-

mercialized drug products are safe and effective at the

time of release and over their shelf life. Tests that are uni-

versally applied to ensure safety and efﬁcacy (and

strength, quality, and purity) include description, identi-

ﬁcation, assay, and impurities.

Description—Accor ding to the ICH guidance a qual-

itative description (size, shape, color, etc.) of the dosage

form should be provided. The acceptance criteria should

include the ﬁnal acceptable appearance. If any of these

characteristics change during manufacturing or storage,

a quantitative procedure may be appropriate. It speciﬁes

the content or the label claim of the article. This param-

eter is not part of the USP dosage form monograph be-

cause it is product speciﬁc. USP monographs deﬁne the

product by specifying the range of a cceptable assayed

content of the active substance(s) present in the dosage

form, together with any additional information about

the presence or absence of other components, excipi-

ents, or adjuvants.

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Identiﬁcation—Identiﬁcation tests are d iscussed in

the General Notices and Requirements. Identiﬁcation tests

should establish the identity of the drug or drug s present

in the drug product and should discriminate between

compounds of closely related structure that are likely to

be present. Identiﬁcation tests should be speciﬁc for the

drug substances. The most conclusive test for identity is

the infrared absorption spectrum (see Spectrophotometry

and Light-Scattering h851i and Spectrophotometric Identi-

ﬁcation Tests h197i). If no suitable infrared spectrum can

be obtained, other analytical methods can be used.

Near-infrared (NIR) or Raman spectrophotometric meth-

ods also could be acceptable as the sole identiﬁcation

method of the drug product formulation (see Near-

infrared Spectrophotometry h1119i and Raman Spectrosco-

py h1120i). Identiﬁcation by a chromatographic reten-

tion time from a single procedure is not regarded as

speciﬁc. The use of retention times from two chromato-

graphic procedures for which the separation is based on

different principles or a co mbination of tests in a single

procedure can be acceptable (see Chromatography

h621i and Thin-Layer Chromatographic Identiﬁcation Test

h201i).

Assay—A speciﬁc an d stability-indicating test should

be use d to determine the strength (API co ntent) of the

drug product. Some examples of these procedures a re

Antibiotics—Microbial Assays h81i, Chromatography

h621i,orAssay for Steroids h351i. In cases when the use

of a nonspeciﬁc assay is justiﬁed, e.g., Titrimetry h541i,

other supporting analytical procedures should be u sed

to achieve speciﬁcity. When evidence of excipient inter-

ference with a nonspeciﬁc assay exists, a procedure with

demonstrated speciﬁcity should be used.

Impurities—Process impurities, synthetic by-

products, and other inorganic and organic impurities

may be present in the API and excipients used in the

manufacture of the drug product. These impurities are

evaluated by tests in API and excipients monographs. Im-

purities arising from degradation of the drug substance

or from the drug -product manufacturing process should

be monitored. Residual S olvents h467i is applied to all

products where relevant.

In addition to the universal tests listed above, the fol-

lowing tests may be considered on a case-by-case basis.

Physicochemical Properties—Examples include pH

h791i, Viscosity h

911i, and Speciﬁc Gravity h841i .

Particle Size—Forsomedosageforms,particlesize

can have a signiﬁcant effect on dissolution rates, bioavail-

ability, therapeutic outcome, a nd stabil ity. Procedures

such as Aerosols, Nasal Sprays, Metered-Dose Inhalers,

and Dry Powder Inhalers h601i, and Particle Size Distribu-

tion Estimation by Analytical Sieving h786i could be used.

Uniformity of Dosage Units—See discussion of

dose uniformity above.

Water Content—A test for water content is included

when appropriate (see Water Determination h921i).

Microbial Limits—The type of microbial test(s) and

acceptance criteria are based on the nature of the drug

substance, method of manufacture, and the route of ad-

ministration (see Microbiological Exami nation of Nonsterile

Produc ts: Microbial Enumeration Tests h61i and Microbio-

logical Examination of Nonsterile Products: Tests for Speci-

ﬁed Microorganisms h62i).

Antimicrobial Preservative C ontent—Accep-

tance criteria for preservative content in multidose prod-

ucts should be established. They are based on the levels

of antimicrobial preservative necessary to maintain the

product’s microbiolo gical quality at all stages through-

out its proposed usage and shelf life (see Antimicrobial Ef-

fectiveness Testing h51i).

Antioxidant Preservative Content—If antioxida nt

preserv atives are pres ent in the dru g pr oduct, tests of

their content should be performed.

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Sterility—Depending on the route of administra-

tion—e.g., ophthalmic preparations, implants, and solu-

tions for injection—sterility of the product is

demonstrated as appropriate (see Sterility Tests h71i).

Dissolution—A test to measure release of the drug

substance(s) from the drug product normally is included

for dosage forms such as tablets, capsules, suspensions,

granules for suspensions, implants, transdermal delivery

systems, and medicated chewing gums. Single-point

measuremen ts typically are used for immediate-release

dosage forms. For mod iﬁed-release dosage forms, appr o-

priate test conditions and sampling pr ocedures a re es-

tablished as needed (see Dissolution h711i and Drug

Release h724i). In some cases, dissolution testing may

be replaced by disintegration testing (see Disintegration

h701i).

Hardness and Friability—These parameters are

evaluated as in-process controls. Acceptance criteria de-

pend on packaging, supply chain, and intended use (see

Tablet Friability h1216i and Tablet Breaking Force h1217i).

Extractables—When evidence exists that extracta-

bles from the container-closure systems (e.g., rubber

stopper, cap liner, o r plastic bott le) have an impact on

the safety or efﬁcacy of the drug product, a test is includ-

ed to evaluate the p resence o f extractables and leach-

ables.

Depending on the type and composition of the dosage

form, other tests such as alcohol content, redispersibility,

particle size distribution, rheological properties, reconsti-

tution time, endotoxins/pyrogens, particulate matter,

functionality testing of delivery systems, and osmolarity

may be necessary.

DOSAGE FORMS

Aerosols

Aerosols are preparations packaged under pressure

and contain therapeutic agent(s) and a propellant that

are released upon activation of an appropriate valve sys-

tem. Upon activation of the valve system, the drug sub-

stance is released as a plume of ﬁne particles or droplets.

Only one dose is released from the preparation upon ac-

tivation o f a metered valve. In the case of topical prod-

ucts, activation of the valve results in a continuous

release of the formulation.

In this chapter, the aerosol dosage form refers only to

those pr oducts pa ckaged un der p ressure that r elease a

ﬁne mist of partic les or droplets when activated (see Glos-

sary). Other products that produce dispersions of ﬁne

droplets or particles will be covered in subseque nt sec-

tions (e.g., Dry Powder Inhalers and Sprays).

TYPICAL COMPONENTS

Typical components of aerosols are the formulation

containing one or more drug substances and propellant,

the container, the valve, and the actuator. Each compo-

nent plays a role in determining various characteristics of

the emitted plume, such as droplet or particle size distri-

bution, uniformit y of delivery of the therapeutic agent,

delivery rate, and plume velocity and geometry. The me-

tering valve and actuator act in tandem to generate the

plume of droplets or particles. The metering valve allows

measure of an accurate volume of the liquid formulation

under pressure within the container. The activator directs

the metered volume to a small oriﬁce that is open to the

atmosphere. Upon activation, t he formulation is forced

through the opening, forming th e ﬁne mist of particles

that are directed to the site of administration.

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Aerosol preparations may consist of either a two-phase

(gas and liquid) or a three-phase (gas, liquid, and solid or

liquid) formulation. The two-phase formulation consists

of drug(s) dissolved in liqueﬁed propellant. Liquid co-

solvents, such as alcohol, propylene glycol, and polyeth-

ylene glycols often are added to enhance the solubility of

the drug substance(s). Three phase inhalation and nasal

aerosol systems consist of a suspension or emulsion of

the drug substance(s) [i.e., API(s)] in addition to the va-

porizable propellants. The suspension or emulsion of the

ﬁnely divided drug substance typically is dispersed in the

liquid propellant with the aid of suitable bi ocompatible

surfactants or other excipients.

Propellants for aerosol formulations are typically low

molecular weight hydroﬂuorocarbons or hydrocarbons

that are liquid when constrained in the container, exhibit

a suitable vapor pressure at room temperature, and are

biocompatible and nonirrita ting. Compressed gases do

not supply a co nstant pressure over use and typically

are not employed as propellants.

Metal containers can withstand the vapor pressure

produced by the propellant and reduce the opportunity

that leachable components will enter the formulation.

Excess form ulation may be added to the container to en-

sure that the full number of lab eled doses can be ac-

curately administered. The container and closure must

be able to withstand the pressures anticipated under nor-

mal use conditions as well as when the system is exposed

to elevated temperatures.

TYPES OF AEROSOL DOSAGE FORMS

Aerosol dosage forms can be delivered via various

routes. The design of the container and metering valve,

as well as the formulation, are designed to target the site

of administration.

Inhalation aerosols are intended to produce ﬁne parti-

cles or droplets for inhalation through the mouth and de-

position in the pulmonary tree. The design of the delivery

system releases one dose with each actuation. These

products are commonly known as metered-dose inhal-

ers.

Nasal aerosols produce ﬁne particles or droplets for in-

halation through the nasal vestibule and d eposition in

the nasal cavity. One dose is released with each activation

of the valve.

Lingual aerosols are intended to produce ﬁne particles

or droplets for deposition in the mouth. The design of

the delivery system r eleases one dose with ea ch actua-

tion.

Topical aerosols pr oduce ﬁ ne particles or droplets for

application to the skin. Formulations that are intended

for inhalation, nasal, or lingual administration are typical-

ly aqueous based, but topical aerosols may utilize nonaq-

ueous solvents to achieve rapid drying or disinfectant

action for abraded skin surfaces.

PACKAGING

The accuracy of a s ystem’s delivered dose is d emon-

strated at the range of pressures likely to be encountered

as a result of ambient temperature variations or storage

in a refrigerator. As an alternative, the system should in-

clude clear instructions for u se to ensure the container

and contents have been equilibrated to roo m tempera-

ture prior to use.

LABELING FOR PROPER USE

Typical warning statements include:

 Contents under pressure. Do not puncture or incin-

erate container.

 Do not expose to heat or store at temperatures

above 498.

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 Keep out of the reach of children unless other wise

prescribed.

 Use only as directed; intentional misuse by deliberate

concentration and inhaling of the contents can be

harmful or fatal.

Many experts recommend the addition of a statement

indicating that patients and/or consumers should seek

advice and instruction from a health care professional

about the proper use of the device.

Capsules

Capsules are solid dosage forms in which the API and

excipients are enclosed within a soluble container or

shell. The shells may be composed of two pieces, a body

and a cap, or they may be composed of a single piece.

Tw o-piece capsules are commonly refer red to as hard-

shell capsules, and one-piece capsules are often referred

to as soft-shell capsules. This distinction, although it is

imprecise, r eﬂects differing levels of plasticizers in the

two compositions and th e fact that one-piece capsules

typically are more pliable than two-piece capsules.

The shells of capsules usually are made from gelatin.

However, they also may be made from cellulose polymers

or other suitable mat erial. Most capsules are designed for

oral administration.

Tw o-Piece or Hard-Shell Capsules—Tw o- piec e

capsules consist of two telescoping cap and body pieces

in a range of standard sizes.

One-Piece or Soft-Shell Capsules—One-piece cap-

sules typically are used to deliver an API as a solut ion or

suspension. Liquid for mulations placed into one-piece

capsules may offer advantages by comparison with dry-

ﬁlled capsules and tablets in achi eving content uniformi-

ty of potent APIs or acc eptable dissolution of APIs with

poor aqueous solubility. Because the contact between

the shell wall and its liquid contents is more intimate than

in dry-ﬁlled capsules, undesired interactions may be

more likely to occur (including gelatin crosslinking and

pellicle formation).

Modiﬁed-Release Capsules—The release of APIs

from capsules can be mod iﬁed in several ways, includi ng

coating the ﬁlled capsule shel ls or the contents in the

case of dry-ﬁlled capsules.

Delayed-Release Capsules— Capsules sometimes

are formulated to include enteric-coated granules to pro-

tect acid-labile APIs from the gas tric environment or to

prevent adverse events such as irritation. Enteric-coated

multiparticulate capsule dosage forms may reduce vari-

ability in bioavailability associated with gastric emptying

times for larger particles (i.e., tablets) and to minimize

the likelihood of a therapeutic failure when coating de-

fects occur during manufacturing.

PREPARATION

Two-Piece Capsules—Two-piece gelatin capsules us-

ually are formed from blends of ge latins that have rela-

tively high gel strength in order to optimize shell clarity

and toughness or from hypromellose. They also may

contain colorants such as D&C and FD&C dyes

or vari-

ous iron oxides, opaquing agents such as titanium diox-

ide, dispersing agents, and preservatives. Gelatin capsule

shells normally contain between 12% and 16% water.

In 1960 Congress enacted the Color Additive Amendments,

requiring FDA to regulate dyes, pigments, or other coloring

agents in foods, drugs, and cosmetics separately from food ad-

ditives. Under the law, color additives are deemed unsafe unless

they are used in compliance with FDA regulations. The law pro-

vides a framework for the listing and certiﬁcation of color addi-

tives. See FDCA section 721; see FDA regulations at 21 CFR Part

70. Colors must also be listed in pertinent FDA regulations for

speciﬁc uses; the list of color additives for drugs that are exempt

from certiﬁcation is published at 21 CFR Part 73, Subpart B. FDA

also conducts a certiﬁcation program for batches of color addi-

tives that are required to be certiﬁed before sale; see 21 CFR Part

74 (Subpart B re: drugs). Regulations rega rding certiﬁcation

procedures, general speciﬁcations, an d the listing of certiﬁed

provisionally listed colors, are at 21 CFR Part 80. FDA maintains

a color additives website, with links to various legal and regula-

tory resources, at: http://www.cfsan .fda.gov/~dms/col-

toc.html

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The shells are manufactured in one set of operations

andlaterﬁlledinaseparatemanufacturingprocess.

Two-piece shell capsules are made by a process that in-

volves dipping shaped pins into gelatin or hypromellose

solutions, followed by drying, cutting, and joining steps.

Powder formulations for two-piece gelatin capsules

generally consist of the API and at least one excipient.

Both the formulation and the method of ﬁlling can affect

release of the API. In the ﬁlling operation, the body and

cap of the shell a re separated before ﬁlling. Following the

ﬁlling operation, the machinery rejoins the body and cap

and ensures satisfactory closure of the capsule by exert-

ing appropriate force on the two pieces. The joined cap-

sules can be sealed after ﬁlling by a band at the joint of

the body and cap or by other suitable means. In com-

pounding prescription practice, two-piece capsules

may be hand-ﬁlled. This permi ts the prescriber the

choice of selecting either a sin gle API or a combination

of APIs at the exact dose level considered best for an in-

dividual patient.

One-Piece Cap sules—On e-piece shell capsu les are

formed, ﬁlled, and sealed in a single process on the same

machine and are available in a wide variety of sizes,

shapes, and colors. The most common type of one-piece

capsule is that produced by a rotary die process that re-

sults in a capsule with a seam. The soft gelatin shell is

somewhat thicker t han that of two-piece capsules and

is plasticized by the addition of polyols such as glycerin,

sorbitol, or other suitable material. The ratio of the plas-

ticizer to the gelatin can be varied to change the ﬂexibil-

ity of the shell depending on the nature of the ﬁll

material, its intended usage, or environmental c ondi-

tions.

In most cases, one-piece capsules are ﬁlled with liquids.

Typically, APIs are dissolved or suspended in a liquid ve-

hicle. Classically, an oleaginous vehicle such as a vegeta-

ble oil was used. However, nonaqueous, water-miscible

liquid vehicles such as the lower molecular weight poly-

ethylene glycols now are m ore c ommon . The physico-

chemical properties of the vehicle can be chosen to

ensure stability of the API as well as to inﬂuence the re-

lease proﬁle from the capsule shell.

Dry Powder Inhalers

The dry powder in haler (DPI) consists of a mixture of

drug(s) and carrier, and all components exist in a ﬁnely

divided solid state packaged as a unit dose. The dose is

released from the packaging by an appropriate mec ha-

nism and is mobilized into a ﬁne mist only upon oral in-

halation by the patient.

TYPICAL COMPONENTS

The basic components of the DPI are the formulation

consisting of the drug(s) and carrier, both i n the dry

state; packaging that contains an amount equivalent to

a unit dose; and a mechanism designed to open the unit-

dose container and permit mobilization of the powders

by the patient inhaling through the built-in mouthpiece.

Ty pically, the unit-dose container is either a capsule

made of gelatin or other suitable non-animal-derived

material (e.g., hypromellose or starch), or the container

may consi st of a series of unit doses in foil-lined blisters

arranged in a strip. When the drug is contained in a cap-

sule, release of the medication takes place when the cap-

sule is pierced. As a consequence of this release

mechanism, the device is designed to minimize the gen-

eration of capsule fragments that might subsequently be

inhaled. When the drug is contained in a blister pack, the

mechanism is designe d to advance an unused blister to a

platform where the foil lining can be peeled back to ex-

pose the powder mixture to an air stream created when

the patient inhales. To facili tate d osing compliance,

some delivery devices incorporate dosing administration

information such as number of doses remaining.

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PACKAGING

For drug contained in blister-pack strips, the packs

must be designed to allow individual blister cavities to

be opened without compromising the seal of adjacent

cavities. Pack age components must pro vide acceptable

protection from humidity, light, and/or oxygen as appro-

priate. Containers for DPIs typically are made of plastic,

but metal may be suitable. Packaging for the encapsulat-

ed drug must provide protection from humidity ex-

tremes to ensure that capsule breakage will occur in

the desired fashion.

LABELING AND USE

Typical warning statements include:

 Keep out of the reach of children unless other wise

prescribed.

 Do not attempt to dissemble mechanism. Discard

the device after all doses have been administered.

 Keep the device level while in use.

 Do not breathe into the device.

Many experts recommend the addition of a statement

indicating that patients and/or consumers should seek

advice and instruction from a health care professional

about the proper use of the device.

Emulsions (Creams and Lotions)

Creams—Creams are semisolid emulsion dosage

forms. They often contain more than 20% water and vol-

atiles and typically contain less than 50% hydrocarbons,

waxes, or polyols as the vehicle for the API. Creams gen-

erally are intended for external application to the skin or

to the mucous membranes. Creams have a relatively soft,

spreadable consistency and can be formulated as either a

water-in-oil emulsion (e.g., Cold Cream or Fatty Cream as

in the European Pharmacopoeia)orasanoil-in-water

emulsion (e.g., Betamethasone Valerate Cream). Creams

generally are described as either nonwashable or wash-

able, reﬂecting the fact that an emulsion with an aqueous

external continuous phase is more e asily rem oved than

one with a nonaqueous ex ternal pha se (water-in-oil

emulsion). Where the term ‘‘cream’’ i s u sed w ithout

qualiﬁcation, a water-washable product is generally in-

ferred.

Lotions—Lotions are an emulsiﬁed liquid dosage form

generally intended for e xternal application to the skin.

Historically, some topical suspensions such as calamine

lotion have been called lotions but that nomenclature

is not currently preferred. Lotions share many character-

istics with creams. The distinguishing factor is that they

are more ﬂuid than semisolid and thus pourable. Due to

their ﬂuid character, lotions are more easily applied t o

large skin surfaces than semisolid prep arations. Lotions

may contain antimicrobial agents as preservatives.

PREPARATION

Pharmaceutical Compounding—Nonsterile Preparat ions

h795i provides general information regarding the prep-

aration of emulsions.

Creams—Creams may be formulated from a variety of

oils, both mineral and vegetable, and from fatty alcohols,

fatty acids, and fatty esters. The solid excipients are melt-

ed at the time of preparation. Emulsifying agents include

nonionic surfactants, detergents, and soaps. Soaps are

usually formed from a fatty acid in the oil phase hydro-

lyzed by a base dissolved in the aqueous phase in situ

during the preparation of creams.

Preparation usually involves separating the formula

components into two porti ons: lipid and aqueous. The

lipid portion contains all water-inso luble co mponents

and the aqueous portion the water-soluble components.

Both phases are heated to a temperature above the melt-

ing point of the highest melting component. The phases

then are mixed and the mixture is stirred until reaching

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ambient temperature or the mixture has congealed. Mix-

ing generally is continued during the cooling process to

prom ote uniformity. Tradi tionall y, the aqueous phase is

added to the lipid phase, b ut comparable results have

been obtained with the reverse procedure. High-shear

homogenation may be employed to reduce particle or

droplet size and improve the physical stability of the re-

sultant dosage form.

The API(s) can be add ed to the phase in which it is sol-

uble at the beginning of the manufacturing process, or it

can be added after th e cream is prepared by a suitable

dispersion process such as levigation or milling with a rol-

ler mill. Creams usually require the addition of a preser-

vative(s) unless they are compounded immediately prior

to use and intended to be consumed in a relatively short

period of time.

Lotions—Lotions usually are prepared by dissolving or

dispersing the API into the more appropriate phase (oil or

water), adding the appropriate emulsifying or suspend-

ing agents, and mixing the oil and water phases to form

a uniform ﬂuid emulsion.

LABELING AND PACKAGING

Some products may require labeling directions indicat-

ing to shake well prior to application and to avoid freez-

ing. Storage limits must b e sp eciﬁcally indicated to

prevent melting of semisolid components. Instructio ns

to ensure proper dosing and administration must accom-

pany the product. Tight containers are used for prepara-

tion and storage to prevent loss by evaporation.

Feed Additives

Feed additives are preparations u sed in veterinary

medicine to deliver the API(s) via the water or food given

to animals. The feed additive may be either a solid or liq-

uid and sometimes is called a premix. Feed additives are

further subdivided into three types.

TYPE A MEDICATED ARTICLES

Type A medicated articles are products containing one

or more animal APIs, and that are sold to licensed feed

mills or producers and are intended to be further diluted

by mixing into food or water prior to consumption by

the animals. Because these preparations are not actually

dosed to animals, they are not considered dosage forms.

TYPE B MEDICATED FEEDS

Type B m edicated feeds are produ cts that contain a

type A medicated article, or another type B medicated

feed, plus a substantial quantity of nutrients (not less

than 25% of the total weight). Like type A medicated ar-

ticles, typ e B medicated feeds ar e intended for mixture

with food or water and additional nutrients, are not to

be fed directly to the animals, and are not c onsidered

dosage forms.

TYPE C MEDICATED FEEDS

Type C medicat ed feeds are made from type A medi-

cated articles or type B medicated feeds and are prepared

at concentrations of the API appropriate for administ ra-

tion to animals by mixing in food or water. Administra-

tion of type C medicated feeds can be accomplished

by blending directly into the feed; top-dressing the prep-

aration onto the animal’s normal daily rations; or heat-

ing, steaming, and extruding into pellets that are

mixed or top-dressed onto the animal’s food. Another

form of type C medicated feeds is compressed or molded

blocks from which animals receive the API or nutrients via

licking the block.

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PREPARATION

Type A medicated articles that are liquids are produced

by mixing the API(s) with a suitable solvent (e.g., water or

propylene glycol). The API(s) is usually dissolved to pro-

duce a solution, but suspension products also could be

produced.

Type A medicated articles that are solids are produced

by blending the API with e xcipients to provide a uniform

dosage form when mixed with the animal’s feed. Often

the API is ﬁrst mixed with an excipient (e.g., starch or so-

dium aluminosilicate) that has a similar particle size and

can help distribute the API uniformly throu ghout the ﬁnal

drug product. This pre-blend is then mixed with bulking

excipients (e.g., calcium carbonate or soybean hulls).

Mineral oil may be added to aid uniform distr ibution,

to prevent particle segregation during shipping, and to

minimize formation of airborne API particles during pro-

duction of type B or C medicated feeds.

Type B or C medicated feeds are produced at licensed

feed mills or by farm producers. Type A medicated arti-

cles are added to the feeds (e.g., ground co rn or o ats)

during the milling process of making feeds. Liquid typ e

A medicated ar ticles often are sprayed in at set rates,

and solid type A medicated articles are added slowly to

aid in creating uniform distribution in the feeds. Liquid

type A medicated articles can also be mixed in with bulk

water sources at prescribed amounts.

LABELING AND PACKAGING

Type A medicated articles or type B medicated feeds

include special labeling to indicate that they should be

used in the manufacture of animal feeds or added to

the drinking water. The labels indicate that they are not

to be fed directly to animals. Also included is a statement

indicating ‘‘Not for Human Use’’. Type A medicated arti-

cles or type B medicated feeds are packaged either in pa-

per bags, often with polyethylene liners, for solids and in

plastic containers for liquids. Typical sizes are 50-lb bags

or several-gallon containers.

Foams

Medicated foams are emulsions containing a dispersed

phase of gas bubbles in a liquid continuous phase con-

taining the API. Medicated foams are packaged in pres-

surized containers or special dispensing devices and are

intended for application to the skin or mucous mem-

branes. The medicated foam is formed at the time of ap-

plication. Surfactants are used to ensure the dispersion of

the gas and the two phases. Medicated foams have a

ﬂuffy, semisolid consistency and can be formulated to

break to a liquid quickly or to remain as foam to ensure

prolonged contact.

Medicated foams intended to treat severely injured

skin or open wounds must be sterile.

PREPARATION

A foam may contain one or more APIs, sur factants,

aqueous or nonaqueous liquids, and the propellants. If

the propellant is in the internal (discontinuous) p hase

(i.e., is of the oil-in-water type), a stable foam is dis-

charged. If the propellant is in the external (continuous)

phase (i.e., is of the water-in-oil typ e), a spray or a quick-

breaking foam is discharged. Quick-breaking foams for-

mulated with alcohol create a cooling sensation when

applied to the skin and may have disinfectant properties.

LABELING AND USE

Foams formulated with ﬂammable components should

be appropriately labeled. Labeling indicates that prior to

dispensing, a foam drug product is shaken well to ensure

uniformity. The instructions for use must clear ly note spe-

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cial precautions that are necessary to preserve sterility. In

the absence of a metering valve, delivered volume may

be variable.

Medical Gases (Inhalation Materials)

Medical gases are products that are administered di-

rectly as a gas. A medical gas has a direct pharmacolog-

ical action or acts as a diluent for another medical gas.

Gases employed as excipients for administration of aero-

sol products, as an adjuvant in packaging, or prod uced

by other dosage forms, are not included in this deﬁnition.

Components—Medical gases may be single compo-

nents or deﬁned mixtures of components. Mixtures also

can be extemporaneously prepared at the point of use.

Administration—Medical gases may be adm inis-

tered to the patient via the pulmonary route or via extra-

corporeal methods. The dose of medical gas typicall y is

metered by a volume rate of ﬂow under ambient temper-

ature and pressure conditions. Administration of a highly

compressed gas generally requires a regulator to de-

crease the pressure, a variable-volume ﬂow controller,

and suitable tubing to conduct the g as to the patient.

For pulmonary administration, the gas ﬂow will be direct-

ed to the nose or mouth by a suitable device or into the

trachea through a mechanical ventilator. When medical

gases are administered chronically, provision for humid-

iﬁcation is common. Care sh ould be exercised to avoid

microbial contamination.

STORAGE

Medical gases are stored in a comp ressed state in cyl-

inders or other suitable containers. The containers must

be constructed of materials that can safely withstand the

expected pressure and must be impact resistant. In some

cases each container holds a single deﬁned dose (e.g.,

general anesthetics), but in other cases the container

holds sufﬁcient gas for extended adm inistration.

SPECIAL CONSIDERATIONS

The container and system ﬁttings should be appropri-

ate for the medical gas. Adaptors should not be used to

connect containers to pat ient-use suppl y system piping

or equipment. Large quantities of gases such as oxygen

or nitrogen can be stored in the liquid state in a cryogen-

ic container and converted into a gas, as needed, by

evaporation. Additional rules concerning the construc-

tion and u se of cryogenic containers are promulgated

by governmental agencies (e.g., U.S. Department of

Commerce).

Containers, tubing, and administration masks em-

ployed for gases containing oxygen are free of any com-

pound that would be sensitive to oxidation or that would

be irritating to the respiratory tract.

A signiﬁcant fraction of the dose of a medical gas may

be released into the general vicinity of the patient due to

incomplete absorption. Adequate ventilation may be

necessary to protect health care workers and others from

exposure to the gas (e.g., nitrous oxid e).

LABELING

Warning statements to be placed on pressurized co n-

tainers include:

 Contents under pressure.

 Do not puncture or incinerate container.

 Do not expose to heat or store at temperatures

above 498.

 Keep out of the reach of children unless other wise

prescribed.

 Use only as d irected; intentional misuse may be

harmful or fatal.

If required under the individual monograph, label to

indicate method of manufacture (such as oxygen via air

liquefaction). When piped directly from the storage con-

tainer to the point of use, the gas must be labeled for

content at each outlet.

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When oxygen is in use, a posted warning should indi-

cate the necessity of extinguishing smoking m aterials

and avoiding the use of open ﬂames or other potential

ignition sources.

Gels

Gels (sometimes called jellies) are semisolid systems

consisting either of suspensions of small inorganic parti-

cles or of organic molecules interpenetrated by a liquid.

Gels can be classed either as single-phase or two-phase

systems.

A two-phase gel consists of a network of small discrete

particles (e.g., Aluminum Hydroxide Gel or Psyllium Hemi-

cellulose). In a two-phase system the gel mass sometimes

is referred to as a magma (e.g., Bentonite Magma) if the

particle size of the suspended material is large. Both gels

and magmas may be thixotropic, forming semisolids on

standing and becoming liquid on agitation. They should

be shaken before use to ensure homogeneity and should

be so labeled (see Suspensions).

Single-phase gels consist of organic macromolecules

uniformly distributed throughout a liquid in such a man-

ner that no apparent boundaries exist between the dis-

persed macromolecules and the liquid. Single-phase

gels may be made from natural or synthetic macromole-

cules (e.g., Carbomer, Hydroxypropyl Methylcellulose,or

Starch) or natural gums (e.g., Tragacanth). The latter pre-

parations are also called mucilages. Although these gels

commonly are aqueous, alcohols and oils may be used as

the continuous phase. For example, mineral oil can be

combined with a polyethylene resin to form an oleagi-

nous ointment base.

Gels can be administere d b y the topical or mucosal

routes. Gels containing antibiotics a dministered by teat

infusion are often the dosage form used in vet erinary

medicine to treat mastitis.

PREPARATION

See Pharmaceutical Compounding—Nonsterile Prepara-

tions h795i for general procedures. Also see the informa-

tion contained under Dosage Forms, Suspensions for the

formulation and manufacture of gels containing inorgan-

ic components or APIs in the solid phase. See Pharmaceu-

tical Compoundi ng—Sterile Preparations h797i for general

procedures for the preparation of sterile gels such as Lido-

caine Hydrochloride Jelly.

Gels formed with large organic molecules may be

formed by dispersing the molecule in t he co ntinuous

phase (e.g., by heating starch), by cross-linking the dis-

persed molecules by chang ing the pH (as for Carbomer

Copolymer ), or by reducing the continuous phase (as

for jellies formed with sucrose).

Care should be taken to ensure uniformity of the APIs

by dispersing them by vigorous mi xing or milling or by

shaking if the preparation is less viscous.

PACKAGING AND STORAGE

Store in tight containers to prevent water loss. Avoid

freezing.

Granules

Granules are solid dosage forms that are composed of

agglomerations of smaller particles. These multicompo-

nent compos itions are pr epared for oral administration

and are used to facilitate ﬂexible dosing regimens, ad-

dress stability challenges, allow taste masking, or facil i-

tate ﬂexibility in administration (for instance, to

pediatric patients, geriatric patients, or animals). Granu-

lar dosage forms may be formulated for direct oral ad-

ministration and may facilitate compounding of

multiple APIs by allowing compound ing pharmacists to

blend various granular compositions in the retail or hos-

pital pharmacy. More co mmonly, granu les are reconsti-

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tuted to a suspension by the addition of water or a sup-

plied liquid di luent immediately prior to delivery to the

patient. Effervescent granules are formulated to liberate

gas (carbon dioxide) upon addition of water. Common

examples of effer vescent granules include antacid and

potassium supplementation preparations. Common

therapeutic classes formulated as granule dosage forms

include antibiotics, certain laxatives (such as senna ex-

tract products), electrolytes, and various cough and cold

remedies that contain multiple APIs.

Granular dosages also are employed in veter inary med-

icine when they are often placed on top of or mixed with

an animal’s food. They are frequently provided with a

measuring device to allow addition to feeds. The resul-

tant mix facilitates dosing.

PREPARATION

Granules often are the precursors used in tablet com-

pression or capsule ﬁlling. Although this application rep-

resents a pharmaceutical intermediate and not a ﬁnal

dosage form, numerous commercial products are based

on granules. In the typical manufacture of granules, the

API is blended with excipients (processing aids) and wet-

ted with an appropriate pharmaceutical solvent or blend

of solvents to promote agglomeration. This composition

is dried and sized to yield the desired material properties.

Frequently, granules are used because the API is unsta-

ble in aqueous environments and cannot be exposed to

water for periods sufﬁcient to accommodate manufac-

ture, storage, and distribution in a suspension. Prepara-

tion of the liquid dosage form from the granules

immediately prior to dispensing allows acceptable stabil-

ity for th e duration of use. Granules manufactured for this

purpose are packaged in quantities sufﬁcient for a limited

time period—usually one course of therapy that typically

does not exceed 2 weeks. In addi tion to the API, other

ingredients may be added to ensure acceptable stability

(e.g., buffers, antioxidants, or chelating agents) or to

provide color, sweetness, ﬂavor, and for suspensions, ac-

ceptable viscosity to ensure adequate suspension of the

particulate to enable uniform dosing.

Effervescent granules typically are formulated from so-

dium or potassium bicarbonate and an acid such as citric

or tartaric acid. To prevent untimely generation of car-

bon dioxide, manufacturers should take special precau-

tions to limit residual water in the product due to

manufacture and to select packaging that protects the

product from moisture. The manufacture of effervescent

granules can require specialized facilities designed to

maintain very low humidity (approximately 10% relative

humidity). Effervescent powder mixtures are purposely

formed into relatively course granules to reduce the rate

of dissolution and provide a more c ontrolled effer ves-

cence.

PACKAGING AND STORAGE

Granules for reconstitution may be packaged in unit-

of-use containers or in containers with sufﬁcient q uan-

tities to accommodate a typical course of therapy (fre-

quently 10 days to 2 weeks with antibiotic products).

Packaging should provi de suitable protection from mois-

ture. This is particularly true for effervescent granules.

Granules may be stored under controlled room temper-

ature conditions unless other conditions are speciﬁcally

noted.

Many granule products specify refrigerated storage fol-

lowing reconstitution and direct the patient to discard

unused co ntents after a speciﬁed date that is based on

the stability of the API in the reconstituted pr eparation.

LABELING AND USE

Effervescent granules (and tablets) are labeled to indi-

cate that they are not to be swallowed directly.

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Reconstitution of granules must ensure complete wet-

ting of all ingredients and sufﬁcient time and agitation to

allow the soluble components to dissolve. Speciﬁc in-

structions for reconstitution provided by the manufactur-

er should be carefully followed.

Reconstituted suspensions should be shaken before use

to re-suspend the dispersed particulates. This is especially

true of suspension preparations dosed from multiple-

dose containers. For particularly viscous suspensions

prone to air entrapment, instructions may advise the user

how to shake the preparation to re-suspend settled par-

ticulates while minimizing air entrapm ent.

SPECIAL CONSIDERATIONS

For granules reconstituted to form suspensions for oral

administration, acceptable suspension of the particulate

phase depends on the particle size of the dispersed phase

as well as the viscosity of the ve hicle. Temperature can

inﬂuence the viscosity, which inﬂuences suspension pro-

perties and the ease of removal of the dose from the bot-

tle. In addition, temperature cycling can lead to changes

in the particle size of the dispersed phase via Ostwald rip-

ening. Thus, clear instructions should be provided re-

garding the appropriate storage temperature for the

product.

Medicated Gums

Medicated gum is a semisolid confection that is de-

signed to be chewed rather than swallowed. Medicated

gums release the API(s) into the saliva. M edicated gums

can deliver therapeutic agents for local action in the

mouth (such as antibiotics to control gum d isease) or

for systemic absorption via the buccal or gastrointestinal

routes (e.g., nicotine or aspirin). Most medicated gums

are manufactured using the convention al melting pro-

cess derived from the confectionary industry or alterna-

tively may be direct ly comp ressed from gum p owder.

Medicated gums are formulated from insoluble synthetic

gum bases such as polyisoprene, polyisobutylene, isobu-

tyleneisoprene copolymer, styrene butadiene rubber,

polyvinyl acetate, polyethylene, ester gums, or polyt er-

penes. Plasticizers and softeners such as propylene gly-

col, glycerin, oleic acid, or processed vegetable oils are

added to keep the gum base pliable and to aid incorpo-

ration of the API(s), sweeteners, and ﬂavoring agents.

Sugars as well as artiﬁcial sweeteners and ﬂavorings are

incorporated to improve taste, and dyes may be used

to enhance appearance. Some medicated gums are coat-

ed with magnesium stearate to reduce tackiness and im-

prove handling during packaging. A preservative may be

added.

PREPARATION

Melted Gum—The gum base is melted at a tempera-

ture of about 1158 until it has the viscosity of thick syrup

and at that point is ﬁltered through a ﬁne-mesh screen.

This molten gum base is transferred to mixing tanks

where the sweeteners, plasticizers, and typically the API

are added and mixed. Colorings, ﬂavorings, and preser-

vatives are added and mixed while the melted gum is

cooling. The cooled mixture is shaped by extrusion or

rolling and cutting. Dosage unit s of the desi red shape

and potency are packaged individually. Additional coat-

ings such as powder coatings to reduce tackiness or ﬁlm

or sugar coatings may be added to improve taste or fa-

cilitate bulk packaging.

Directly Com pressed Gum—The gum base is sup-

plied in a free-ﬂowing granular powder form. The pow-

der gum base is then dr y blended with sweeteners,

ﬂavors, the API, and lubricant. The blend is then pro-

cessed through a conventional tablet press and tableted

into desired shapes. The resulting medicated gum tablets

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can be further coated with sugar or sugar-free excipients.

These tablets can be packaged in blisters or bottles as

needed.

SPECIAL CONSIDERATIONS

Medicated gums are typically dispensed in unit-dose

packag ing. The pati ent instructions also may include a

caution to avoid excessive heat.

Implants

Implants are long-acting dosage forms that provide

continuous release of the API for periods of months to

years. They are administered by the parenteral route.

For systemic delivery they may be placed subcutane-

ously, or for local delivery they can be placed in a speciﬁc

region in the body.

Several types of implants are availab le. Pellet implants

are small, sterile, solid masses composed of an API with or

without excipients. They are usually administered by

means of a suitable special injector (e.g., trocar) or by

surgical incision. Release of the API from pellets typically

is controlled by diffusion and dissolution kinetics. The size

of the pellets and rate of erosion will inﬂuence the release

rate, which typically follows ﬁrst-order kinetics. Drug re-

lease from pellets for periods of 6 months or more is pos-

sible. Pellet implants have been used to provide

extended delivery of hormones such as testosterone or

estradiol.

Resorbable micropartic les are a type of implants that

provide extended release of drug over periods var ying

from a few weeks to months. They can be administered

subcutaneously or intramuscularly for systemic delivery,

or they may be deposited in a desired location in the

body for site- speciﬁc de livery. Injectable resorbabl e mi-

croparticles (or microspheres) generally range from 20

to 100 mm in diameter. They are composed of a drug dis-

persed within a biocompatible, bioresorbable polymeric

excipient (matrix). Poly(lactide-co-glycolide) polymers

have been used frequently. These excipients typically re-

sorb by hydrolysis of ester linkages. The microparticles

are administered by suspension in an aqueous vehicle fol-

lowed by injection with a conventional syringe and nee-

dle. Release of the drug from the microparticles begins

after physiological ﬂuid enters the polymer matrix, dis-

solving some of the drug that then is released by a diffu-

sion-controlled process. Drug release also can occur as

the matrix erodes.

Polymer implants can be formed as a single shaped

mass such as a cyli nder. The polymer matrix must be bio-

compatible, but it can be eithe r biodegradable or non-bi-

odegradable. Shaped polymer implants are administered

by means of a suitable special injector. Release kinetics

typically are not zero-order, but zero-order kinetics are

possible. Drug release can be controlled by the diffusion

of the API from the bulk polymer matrix or by the proper-

ties of a rate-limiting polymeric membrane coating. Poly-

mer implants are used to deliver potent small molecules

like steroids (e.g., estradiol for cattle) and large molecules

like pepti des [e.g., luteinizing hormone-releasing hor-

mone (LHRH)]. Example durations of drug release are 2

and 3 months for biodegradable implants and 1 year

for non -biodegradable implants. An advantage of biode-

gradable implants is that they do not require removal af-

ter release of a ll d rug content. Non-biodegradable

polymer im plants can be removed before or after drug

release is complete or may be left in situ. An implant

can have a tab with a hole i n it to facilitate suturi ng it

in place, e.g., for an intravitreal implant for local ocular

delivery. Such implants may provide therapeutic release

for periods as long as 2.5 years.

Some implants are designed to form as a mass in situ.

These implants are i nitially prepared as liquid formula-

tions comprising polymer, API, and solvent for the poly-

mer. The polymer solvent can be water or an organic

solvent. Af ter administration of the liquid formulation

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to a patient by subcutaneous or intramuscular adminis-

tration, it forms a gel or a solid polymeric matrix that

traps th e API and extends the API release for days or

months. In situ-forming implants also are used for local

delivery of the API to treat periodontal disease. The im-

plant is formed within the periodontal pocket.

Another type of implant can be fabricated from a metal

such as titanium and plastic components. These implants

are administ ered b y means of a suitable injector or by

surgical installation. A solution of API inside the implant,

like an LHRH solution, is released via an osmotically dri-

ven pump inside the implant. Duration of release may

be as long as 1 year or more. Release kinetics are zero or-

der. After the drug is delivered, metal-based implants are

removed.

Drug-eluting stents combine the mechanical effect of

the stent to maintain arterial patency with the prolonged

pharmacologic effect of the incorporated API (to reduce

restenosis, inhibit clot formation, or combat infection).

As an example , a m etal stent can be coated with a

non-biodegradable or biodegradable polymer-

containing API. The resultant coating is a polymeric ma-

trix that controls the extended release of the API.

PREPARATION

Pellet implants are made by API compression or mold-

ing. Cylindrical polymeric implants typically are made by

melt extrusion of a blend of API and polymer, resulting in

a rod that is cut into shorter lengths. Polymer implants

also can be made by injection molding. Still other im-

plants are assembled from m etal tube s and injection-

molded plastic components.

Sterility can be achieved by terminal sterilization or by

employing aseptic manufacturing procedures.

PACKAGING AND STORAGE

All implants are individually packaged (typically in their

injector or for veterinary use in cartridges that are placed

in the injector guns), are sterile (except for some animal

health products), and conform to the appropriat e stan-

dards for injection. Biodegrad able implants are protected

from moisture so the polymer does not hydrolyze and al-

ter drug release kinetics before use.

Inserts

Inserts are solid dosage forms that are inserted into a

body cavity other than the rectum ( see Suppositories).

The API is delivered in inserts for local or systemic action.

Inserts applied to the eye, such as Pilocarpine Ocular Sys-

tem, typicall y are sterile. Vaginal inserts for humans are

usually globular or oviform and weigh about 5 g each.

Vaginal inserts for cattle are T-shaped, are formed of poly-

mer, ar e removable, and can be use d for u p to 8 days.

One veterinary application is for estrus synchronization.

Inserts intended to dissolve in vaginal secretions usually

are ma de from wa ter-soluble or water-miscible vehicles

such as polyethylen e glycol or glycerinated gelatin. Vagi-

nal inserts such as dinoprostone vaginal insert (e.g., see

USP monograph Dinoprost one Vaginal Suppositories)are

formulated to deliver medication to the cervix and to

be removed or recovered once the API has been released.

Intrauterine inserts such as Prog esterone Intrauterine Con-

traceptive System are used to deliver APIs locally to

achieve efﬁcacy while reducing side effects. Some intra-

uterine inserts are formulated to remain in the uterus for

extended periods of tim e. An intra-urethral insert of al-

prostadil is available for the tre atment of erectile dysfunc-

tion.

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PREPARATION

For general considerations see Pharmaceutical Com-

pounding—Nonsterile Preparations h795i. Inserts var y

considerably in their preparation. Inserts may be molded

(using technology similar tothatemployedtoprepare

lozenges, suppositories, or p lastics), compressed from

powders (as in tableting), or formulated as special appli-

cations of capsules (soft gelatin capsules and hard gelatin

capsules have been employed for extemporaneously

compounded preparations) . Inserts may be formulated

to melt at body temperature or disintegrate upon inser-

tion. Design of the dosage form should take into consid-

eration the ﬂuid volume available at the insertion site and

minimize the potential to cause local irritation. Most in-

serts are formulated to ensure retention at the site of ad-

ministration.

STORAGE AND LABELING

Appropriate storage conditions must be clearly indicat-

ed in the labeling for all inserts, especially for those that

are designed to melt at body temperature. Instructions

to ensure proper dosing and administration must accom-

pany the product.

Liquids

As a dosage form a liquid consists of a pure chemical in

its liquid state. Examples include mineral oil , isoﬂurane,

and ether. This dosage form term is not applied to solu-

tions. In veteri nary medicine liquids may be administered

topically or diluted via mixing wit h drinking water or

food.

STORAGE AND LABELING

Storage, packaging, and labeling consider the physical

properties of the material and are designed to maintain

potency and purity.

Lotions (see Emulsions)

Lozenges

Lozenges are solid oral dosage forms that are designed

to dissolve or disintegrate slowly in the mouth. They con-

tain one or more APIs that are slowly liberated from the

ﬂavored and sweetened base. They are frequently in-

tended to provide local action in the oral cavity or the

thro at but also include those intended for systemic ab-

sorption after dissolution. The typical therapeuti c cate-

gories of APIs delivered in lozenges a re antiseptics,

analgesics, decongestants, antitussives, and ant ibioti cs.

Molded lozenges are called cough drops or pastilles.

Molded lozenges mounte d on a stick are known as lolli-

pops. Lozenges prepared by compression or by stamp-

ing or cutting from a unif orm bed of paste sometimes

are known as troches. Troches are often produced in a

circular shape.

Lozenges can be made using sugars such as sucrose

and dextrose or can provide the beneﬁts of a sugar-free

formulation that is usually based on sorbitol or mannitol.

Polyethylene glycols and hypromellose sometimes are in-

cluded to slow the rate of dissolution .

MANUFACTURE

Excipients used in molded lozenge manufacture in-

clude gelatin, fused sucrose, sorbitol, or another carbo-

hydrate base.

Molded lozenges using a sucrose or sorbitol base con-

taining APIs such as phenol, dextromethorp han, fenta -

nyl, and dyclonine hydrochlo ride and menthol are

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prepared by cooking the sug ar (sucrose, corn syrup, and

sorbitol)andwateratabout1508 to reduce the w ater

content to less than 2 %. The molten sugar solution is

transferred to a cooling belt or cooling table, and medic-

aments, ﬂavorings, and colorings are added and thor-

oughly mixed while coo ling. Individual dosage units of

the desired shape are formed by ﬁlling the molten mass

into molds. These lozenges are quickly cooled in the

molds to trap the base in the glassy state. Once formed,

the lo zenges are removed from the molds and packaged.

Care is taken to avoid excessive moisture during storage

to prevent crystallization of the sugar base.

Compressed lozenges are made using excipients that

may include a ﬁller, binder, sweetening agent, ﬂavoring

agent, and lubricant. Sugars s uch as sucrose, sorbitol,

and mannitol often are included because they can act

as ﬁller and binder as well as ser ve as sweetening agents.

Approved FD&C and D&C dyes or lakes (dyes adsorbed

onto insoluble aluminum hydroxide) also may be pre-

sent.

The manufacturing of compressed lozenges is essen-

tially the same a s that for conventional tableting, with

the exception that a tablet press capable of making lar-

ger tablets and exerting greater force to produce harder

tablets may be required (see Tablets).

The paste used to produce lozenges manufactured by

stamping or cutting contains a moistening agent, su-

crose, and ﬂavoring and sweetening agents. The homog-

enous paste is spread as a bed of uniform thickness, and

the l ozenges are cut or stamped from the bed and are

allowed to dry. Some lozenges are prepared by forcing

dampened powders under low pressure into mold cavi-

ties and then ejecting them onto suitable trays for drying

at moderate temperatures.

PACKAGING AND STORAGE

Many lozenges are sensitive to moisture, and typically

a monograph indicates that the package or container

type is well closed and/or moisture resistant. Storage in-

structions may include protection from high humidity.

Ointments

Ointments are semisolid preparations intended for ex-

ternal application to the skin or mucous membranes.

APIs delivered in ointments are intended for local action

or for systemic absorption. Ointments usually contain

less than 20% water and volatiles and more than 50%

hydrocarbons, waxes, or polyols as the vehicle. Ointment

bases recognized for use as vehicles fall into four general

classes: hydrocarbon bases, absorption bases, water-re-

movable bases, and water-soluble bases.

Hydrocarbon Bases—Also known as ole aginous

ointment bases, they allow the incorporation of only

small amounts of an aqueous component. Ointments

prepared from hydrocarbon bases act as occlusive dress-

ings and provide prolonged contact of the API with the

skin. They are difﬁcult to remove and do not change

physical characteristics upo n aging.

Absorption Bases— Allow the incorporat ion of aque-

ous sol utions. Such bases include only anhydrous com-

ponents (e.g., Hydrophilic Petrolatum)orwater-in-oil

emulsions (e.g., Lanolin). Absorption bases are also useful

as emollients.

Water-Removable Bases—Oil-in-water emu lsions

(e.g., Hydrophilic Ointment) and are sometimes referred

to as creams (see Emulsions). They may be readily washed

from the skin or clothing with water, making them ac-

ceptable for cosmetic reasons. Other advantages of the

water-removable bases are that they can be diluted with

water and that they favor the absorption of serous dis-

charges in dermatological conditions.

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Wa ter-Soluble Bases—Also known as greaseless

ointment bases, they are formulated entirely from

water-soluble constituents. Polyethylene Glycol Ointment

is the only ofﬁcial preparation in this group. They offer

many of the advantages o f the water-r emovable bases

and, in addition, contain no water-insoluble substances

such as petrolatum, anhy drous lanolin, or waxes. They

are more correctly categorized as gels (see Gels).

The choice of an ointment base depends on the action

desired, the characteristics of the incorporated API, and

the latter’s bioavailability if systemic action is desired. The

product’s stability may require the use of a base that is

less than ideal in meeting other quality attributes. APIs

thathydrolyzerapidly,forexample,aremorestablein

hydrocarbon bases than in bases that contain water.

Ophthalmic ointmen ts are intended for application di-

rectly to the eye or eye-associated structures such as the

subconjunctival sac. They are manufactured from steri-

lized ingredients under aseptic conditions and meet the

requirements under Sterility Tests h71i. Ingredients meet-

ing the requirements described under Sterility Tests h71i

are used if they are not suitable for sterilization proce-

dures. Ophthalmic ointments in multiple-dose con-

tainers contain suitable antimicrobial agents to contro l

microorganisms that might be introduc ed during use un-

less otherwise directed in the individual monograph or

unless the formula itself is bacteriostatic (see Ophthalmic

Ointments h771i, Added Substances). The ﬁnished oint-

ment is free from large particles and must meet the re-

quirements for Leakage and for Metal Particles under

Ophthalmic Ointments h77 1i. T he immediate container

for ophthalmic ointments is ste rile at the time of ﬁlling

and closing. The immediate containers for ophthalmic

ointments are sealed and made tamper-proof so that ste-

rility is ensured at time of ﬁrst use.

A suitable ophthalmic ointment base is nonirritating to

the eye and permits diffusion of the API throughout the

secretions bathing the eye. Petrolatum is most common-

ly used as a base for ophthalmic drugs. Some absorption

bases, water-removable base s, and water-s oluble bases

may be desirable for water-soluble APIs if the bases are

nonirritating.

MANUFACTURE

Ointments typically are prepared by either direct incor-

poration into a previously prepared ointment base or by

fusion (heating during the preparation of the ointment).

A levigating agent is often added to facilitate the incor-

poration of the medicament into the ointment base by

the direc t incorporation procedure. In the fusion meth-

od, the ingredients are heated, often in the range of

608 to 808. Homogenization is often necessary. The rate

of cooling is an important manufacturing detail because

rapid cooling can impart increased structure to the pro-

duct of the fusion method.

PACKAGING AND STORAGE

Protect from moisture. For emulsiﬁed systems, temper-

ature extremes can lead t o physical instability of the

preparation. When this is the case products should be

clearly labeled to specify appropriate storage conditions.

Ointments typically are packaged either in ointment jars

or ointment tubes. Ointment jars are often used for more

viscous ointments that do not require sterility. Ointment

tubes typically are used for less viscous ointments and

those such as ophthalmic ointments that require the

maintenance of sterility. The package sizes for ophtha l-

mic preparations are controlled to minimize the likeli-

hood of contamination and loss of sterility.

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Pastes

Pastes are semisolid preparations of stiff consistency

and contain a high percentage of ﬁnely dispersed solids.

Pastes are intended for application to the skin, oral cavity,

or mucous membranes. In veterinary practice, pastes are

used for systemic deliver y of APIs.

Pastes ordinarily do not ﬂow at body temperature and

thus can serve as occlusive, protective coatings. As a con-

sequence, pastes are more often used for protective ac-

tion than are ointments.

Fatty pastes that have a high proportion of hydrophilic

solids appear less greasy and more absorptive than oint-

ments. They are used to absorb serous secretions and are

often preferred for acute lesions that have a tendency to-

ward crusting, vesiculation, or oozing.

Dental pastes may be applied to the teeth, or alterna-

tively they may be indicated for adhesion to the mucous

membrane for a local effect (e.g., Triamcinolone Acetonide

Dental Paste). Some paste preparations intended for ani-

mals are administered orally. The paste is squeezed into

the mouth of the animal, generally at the back of t he

tongue, or is spread inside the mouth.

PREPARATION

Pastes can be prepared by direct incorporation or by

fusion (the use of heat to soften the base). The solid in-

gredients often are incorporated following comminution

and sieving. If a levigating agent is needed, a portion of

the ointment base is often employed rather than a liquid.

LABELING AND STORAGE

Veterinary products should be labeled to ensure they

are not administered to humans. Labeling should indi-

cate the need for protection from heat.

Transdermal Systems (Patches)

Transdermal drug delivery systems (TDSs) are discrete

dosage forms that are designed to deliver the API(s)

through intact skin to the systemic circulation. Typically,

a TDS is composed of an outer covering (barrier), a drug

reservoir (possibly covered with a rate-controlling

membrane), a contact adhesive applied to some or all

parts of the system (to attach the TDS to the skin sur-

face), and a protective layer that is removed before the

patch is applied. The activity of a TDS is deﬁned in terms

of the release rate of the API(s) from the system. The total

duration of drug release from the system and the system

surface area also may be stated.

Most TDSs can be considered either matrix-type or

reservoir-type systems. Matrix-type patches are often fur-

ther divided into monolithic adhesive matrix or polymer

matrix types. Reservoir-type systems include liquid reser-

voir systems and solid-state reservoir systems. Solid-state

reservoir patches also include m ultilaminate adhesiv e

and multilaminate polymer matrix systems.

Drug delivery from some TDSs is controlled by diffu-

sion kinetics. The API diffuses from the drug reservoir di-

rectly or through the rate-controlling membrane and/or

contact adhesive and then through the skin into the gen-

eral circulation. Modiﬁed-release systems are generally

designe d to provide drug delivery at a constant rate so

that a true steady-state blood concentration is ach ieved

and maintained until the system is removed. Other TDSs

work by active transport of the API. For example, ionto-

phoretic transdermal delivery uses the current between

two electrodes to enhance the movement of ionized APIs

through the skin.

TDSs are applied to the body areas recommended by

the labeling. The API content of the system provides a

reservoir that, by design, maintains a constant API con-

centration at the system-skin interface. The dosing inter-

val of the system is a function of the amount of API in the

reservoir and the release rate. Some API concentration

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may remain in the reservoir at the end of the dosing in-

terval, in particular for diffusion-controlled deli very

mechanisms. [

NOTE—Where the API is intended for local

action, it may be embedded in adhesive on a cloth or

plastic backing. This type of product is more correctly

called a plaster or tape (see Plasters and Tapes).]

PREPARATION

TDSs require a backing, a means of storing the API for

delivery to the skin, an adhesive to attach the system to

the skin, and a removable release liner to protect the ad-

hesive, API, and excipients before application. The back-

ing has low moisture- and vapor-transmission rates to

support product stability. The adhesive layer may contain

the API and permeation enhancers in the case of matrix-

type systems or m ulti-laminate reser voir systems for

which a priming dose is desired. Adhesive may be ap-

plied to the entire patch release surface or merely to

the periphery. Liquid reservoir systems are often

formed–ﬁlled–sealed between the b acking and release-

controlling materials. For monolithic adhesive matrix sys-

tems, the API and excipients are applied as a solution or

suspension either to the backing or the release liner, and

the solvent is allowed to evaporate.

PACKAGING AND STORAGE

Storage conditions are clearly speciﬁed because ex-

treme temperature excursions can inﬂuence the perfor-

mance of some systems.

LABELING

The labeling should clearly indicate any performance

limitations of the system (e.g., inﬂuence o f application

site, hydration state, hair, or other variables).

Pellets

Pellets are dosage forms composed of small, solid par-

ticles of uniform shape sometimes called beads. Typically,

pellets are nearly spherical but this is not required. Pellets

may be administered by the oral (gastrointes tinal) or by

the injection route (see also Implants). Pellet formulations

may provide several advantages including physical sepa-

ration for chemically or physically incompatible mat e-

rials, extended release of the API, or delayed release to

protect an acid-labile API from degradation in the stom-

ach or to protect stomach tissues from irritation. Extend-

ed-release pellet formulations may be designed with the

API dispersed in a matrix, or the pellet may be coated

with an a ppropriate polymer coating that modiﬁes the

drug-release ch aracteristics. Alternatively, t he pellet de-

sign may combine these two approaches. In the case of

delayed-release formulations, the coating polymer is

chosen to resist dissolution at the lower pH of the gastric

environmen t but to dissolve in the higher pH intestinal

environment. Injected or surgically administered pellet

preparations (see Implants) are often used to provide

continuous therapy for periods of months or years.

Pellet dosage forms may be designed as single or mul-

tiple entities. Often implanted pellets will contain the de-

sired API content in one or several units. In veterinary

practice, 4 to 8 pellets may be implanted in the ears for

cattle, depending on animal size. Oral pellets typically are

contained within hard gelatin capsules for administra-

tion. Although there are no absolute requirements for

size, the useful size range of pellets is governed by the

practical constraints of the volume of co mmonly used

capsules and t he need to include sufﬁcient numbers of

pellets in each dose to ensure un iform dosing of the

API. As a result, many pellets used for oral administration

fall within a size range of 8 to 24 mesh. Pellet formula-

tions sometimes are used to minimize variability associat-

ed with larger dosage forms caused by gastric retention

upon stomach emptying.

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Enteric-coated (delayed-release) pellet formulations

and some e xtended-release formulations are prepared

by applying a coating to the formulated particles. The

coating must be applied as a continuous ﬁlm over the en-

tire surface of each particle. Because a small population

of imperfectly coated particles may be unavoidable, oral

pellets are designed to require the administration of a

larg e number in a single dose to minimize any adverse

inﬂuence of imperfectly coated pellets on drug delivery.

PREPARATION

The desired performance characteristics determine the

manufacturing method chosen. In general, pellet dosage

forms are manufactured by wet extrusion processes fol-

lowed by spheronization, by wet or dry coating proces-

ses, or by compression. M anufactu re of pellets b y wet

coating usually involves the application o f successive

coatings upon nonpareil seeds. This manufacturing pro-

cess frequently is conducted in ﬂuid-bed processing

equipment. Dry powder coating or layering processes of-

ten are performed in specialized rotor granulation equip-

ment. The extent of particle growth achievable in wet

coating p rocesses is generally more limited than the

growth that can be obtained with dry pow der layering

techniques, but either method allows the formulator to

develop and apply multiple layers of coatings to achieve

the desired release proﬁle. The manufacture of pellets by

compression is largely restricted to the production of ma-

terial fo r subcutaneous implantation. This method of

manufacture pr ovides the necessary control to ensure

dose uniformity and generally is better suited to aseptic

processing requirements.

Alternatively, microencapsulation techniques can be

used to manufacture pellets. Coacervation coating tech-

niques typically produce coated particles that are much

smaller than those made by other techniques.

PACKAGING AND STORAGE

Pellets for oral administration genera lly are ﬁlled into

hard gelatin capsules and are placed in bottles or blister

packages. The packaging provides suitable protection

from moisture to ensure the stability of the pellet formu-

lation as well as to preserve desirable moisture content of

the capsule shells. Pellets for implantation are sterile and

should be packaged in tight containers suitable for main-

taining steril e contents. Pellets may be stored under con-

trolled room temperature conditions unless other

conditions are speciﬁcally noted.

LABELING AND USE

Pellets for oral administration that are formulated to

provide delayed or controlled release must be swallowed

intact to ensure preservation of the desired release char-

acteristics. These products should be labeled accordingly

to ensure that the material is not crushed or chewed dur-

ing administration.

Pills

Pills are API-containing s mall round solid bod ies in-

tended for oral administration. At one time pills were

the most extensively used oral dosage form, but they

have been replaced by compressed tablets and capsules.

Pills are distinguished from tablets because pills are man-

ufactured by a wet massing and molding technique,

while tablets are formed by compression.

PREPARATION

Excipients are selected on the basis of their ability to

produce a mass that is ﬁrm and plastic. The API is triturat-

ed with powdered excipients in serial dil utions to attain a

uniform mixture. Liquid excipients that act to bind and

provide plasticity to the mass are subsequently added

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to the dry materials. The mass is f ormed by kneading.

The properties of ﬁrmness and plasticity are necessary

to permit the mass to be worked and retain the shape

produced. Cylindrical pill pipes are produced from por-

tions of the mass. The pill pipe is cut into individual

lengths corresp onding to the intended pill size, and the

pills are rolled to form the ﬁnal shape. Pill-making ma-

chines can automate the preparation of the mass, pro-

duction of pill piping, and the cutting and rolling of pills.

PACKAGING AND LABELING

Labeling and use instructions for p ills are similar to

those for tablets. Although many pills are resistant to

breakage, some pills are friable. Appropriate handling

guidelines should be provided in such cases in order to

avoid breakage.

Plasters

A plaster is a semisolid substance for external applica-

tion and usually is supplied on a support material. Plasters

are applied for prolonged per iods to provide protection,

support, or occlusion (maceration).

Plasters consist of an adhesive layer that may contain

active substances. This layer is spread uniformly on an ap-

propriate support that is usually made of a rub ber base or

synthetic resin. Unmedica ted plasters are designed t o

provide protection or mechanical support to the site of

application. These plasters are neither irritating nor sen-

sitizing to the skin.

Plasters are available in a range of sizes or cut to size to

effectively provide prolonged contact to the site of appli-

cation. They adhere ﬁrmly to the skin but can be peeled

off the skin without causing injury.

One example of a plaster currently in use is salicylic acid

plasters used for the removal of corns by the keratolytic

action of salicylic acid.

PACKAGING AND STORAGE

Plasters are preserved in well-closed containers, prefer-

ably at controlled room temperature.

Powders

Powders are deﬁned as a solid or a mixture of solids in a

ﬁnely divided state intended for inter nal or external use.

Powders used as pharmaceutical dosage forms may con-

tain one or more APIs and can be mixed with water for

oral administration or injection. Often pediatric antibiot-

ics utilize a powder dosage form for improved stability. In

some areas medicated powders are used for extempora-

neous compounding of preparations for simultaneous

administration of multiple APIs. Medicated powders also

can be i nhaled for pulmonary administration (see Dry

Powder Inhalers). Aeros olized powders for the lungs typ-

ically contain processing aids to improve ﬂow and ensure

uniformity (see Aerosols, Nasal Sprays, Metered-Dose In-

halers, and Dry Powder Inhalers h601i). Powders can also

be used topically as a dusting powder.

Externally applied powders should have a partic le size

of 150 mm or less (typically in the 50- to 100-mm range) in

order to prevent a gritty feel on the skin that could fur-

the r irritate traumatiz ed skin. Powders are grouped ac-

cording to the following terms: very coarse, coarse,

moderately coarse, ﬁne, and very ﬁne (see Powder Fine-

ness h811i). The performa nce of powder dosage fo rms

can be affected by the physical characteristics of the

powder. Particle size can inﬂuence the dissolution rate

of the particles and affect bioavailability. For dispersed

delivery systems, particle size can inﬂuence the mixing

and segregation behavior of the particle, which in turn

affects the uniformity of the dosage form.

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PREPARATION

Powder dosage forms can be produced by the combi-

nation of multiple components into a uniform blend.

This can also involve particle size reduction, a process re-

ferred to as comminution. Mills and pulverizers are used

to reduce the particle size of powders when necessary. As

the particle size is decreased, the number of particles and

the surface area increase, wh ich can increase the dissolu-

tion rate and bioavailability of the API.

Blending techniques for powders include those used in

compounding pharmacy such as spatulation and tritura-

tion (see Pharmaceutical Compounding Nonsterile Prepara-

tions h795i). Industrial processes ma y employ sifting or

tumbling the powders in a rotating container. O ne of

the most common tumble blenders is a V-blender, which

is available in a variety o f scales s uitable for small-scale

and large-scale compounding and industrial production.

Powder ﬂow can be inﬂuenced by both particle size

and shape. L arger particles generally ﬂow more freely

than do ﬁne particles. Powder ﬂow is an important attri-

bute that can affect the packaging or dispensing of a

medicated powder.

PACKAGING AND STORAGE

Powders for pharmaceutical use can be packaged in

multiple- or single-unit containers. Bulk containers have

been used for antac id powders and for laxative powders.

In these instances the patient dissolves the directed

amount in water prior to administration. This typ e of

multiple-unit packaging is acceptable for many APIs but

should not be utilized for powders that require exact dos-

ing. Multiple-unit powders for topical application often

are packaged in a container with a sifter top.

Potent APIs in a powder dosage form are dispensed in

unit-of-use allocations in folded papers, cellophane en-

velopes, or packets. Powder boxes are often used by

the dispensing pharmacist to hold multiple doses of indi-

vidual folded papers. Hygroscopic powders pose special

challenges and typically are dispensed in moisture-

resistant packaging.

LABELING

Typical warning statements include:

 External powders must indicate: ‘‘External Use

Only’’.

 Oral powders should indicate: ‘‘For Oral Use Only’’.

 Powders intended for veterinary use must indicate:

‘‘For Veterinary Use Only’’.

Individual monographs specify the labeling require-

ments for powder dosage forms that are listed in USP–

NF. Oral powders for reconstitution prior to dispensing

typically have a limited shelf life (for example, 2 weeks),

and the dispensed product should indicate a beyond-use

date based on the date of t he water addition. Pharma-

ceutical powders that are compounded indicate a be-

yond-u se date. Compounded preparations typically are

intended for immediate use and have short-term storage

durations.

Medicated Soaps And Shampoos

Medicated soaps and shampoos are solid or liquid pre-

parations intended for topical application to the skin or

scalp followed by sub sequent rinsing with water. Soaps

and shampoos are emulsions or surface-active composi-

tions that readily form emulsions or foams upon the ad-

dition of water followed by rubbing. Incorporation of

APIs in soaps and shampoos combines the cleansing/

degreasing abilities of the vehicle and facilitates the top-

ical application of the API to affected areas, even large ar-

eas, of the body. The surface-active properties of the

vehicle facilitate contact of the API with the skin or scalp.

Medicated soap and shampoo formulations frequently

contain suitable antimicrobial agents to protect against

bacteria, yeast, and mold contamination.

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PREPARATION

The preparation of medicated soaps and shampoos fol-

lows techniques frequently used for the preparation of

emulsiﬁed systems. To ensure uniformity, the API(s) must

be added to the vehicle prior to congealing (in the case

of soaps) followed by thorough mixing. If the medication

is present as a suspension, the particle size must be con-

trolled to promote u niform d istrib ution of the API and

possibly optimize performance. Because soap manufac-

ture frequently involves processing the ingredients at el-

evated temperature, care must be exercised t o av oid

excessive degradation of the API during processing.

PACKAGING AND STORAGE

Individual monographs specify the packaging and

storage requirements for medicated soaps and sham-

poos in USP–NF.

LABELING AND USE

Medicated soaps and shampoos are clearly labeled to

indicate ‘‘For External Use Only’’. The preparations also

clearly advise the patient to discontinue use and consult

a physician/veterinarian if skin irritation or inﬂammation

occurs or persists following application.

Solutions

A solution is a liquid preparation that contains one or

more dissolved chemical substances in a suitable solvent

or mixture of mutually miscible solvents. Bec ause mole-

cules of a drug substa nce in solution a re uniformly dis-

persed, the use of solutions as dosage forms generally

provides assurance of uniform dosage upon administra-

tion and good accuracy when the solution is diluted or

otherwise mixed.

Substances in solutions are more susceptible to chem-

ical instability than they are in the solid state and dose-

for-dose generally are heavier and more bulky than solid

dosage forms. These factors increase the cost of packag-

ing and shipping relative to that of solid dosage forms.

Solution dosage forms can be administered by injection;

inhalation; and the mucosal, topical/dermal, and gastro-

intestinal routes. Terminology for solutions in veterinary

practice includes spot-ons or pour-ons that refer to solu-

tions that are applied to an animal’s skin for systemic ab-

sorption, dips that refer to solutions that are used for

washing and disinfection (e.g., udders, eggs, and whole

animals), and drenches that include solutions that are

orally administered to livestock, usually with a dosing de-

vice. Solutions administered by injection are ofﬁcially ti-

tled injections (see Injections h1i).

Solutions intended for oral (gastrointestinal) adminis-

tration usually contain ﬂavorings and colorants to make

the medication more attractive and palatable for the pa-

tient or consumer. When needed, they also may contain

stabilizers to maintain chemical and physical stability and

preservatives to prevent microbial growth.

STORAGE AND USE

Light-resistant containers should be considered when

photolytic che mical degradation is a potent ial issue. To

prevent water or solvent loss, solutions are stored in tight

containers. Instructions to ensure proper dosing and ad-

ministration must accomp any the product

Sprays (Nasal, Pulmonary, or Solutions For

Nebulization)

A spray is a preparation that contains a therapeutic

agent(s) in either the liquid or solid state and is intended

for administration as a ﬁne mist of small aqueous drop-

lets. The droplets may be generated by means other than

the use of a volatile propellant (see Aerosols). The mech-

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anism for droplet generation and the intended use of the

preparation distinguish the various classes of sprays. A

spray is composed of a pump, container, valve, actuator,

and nozzle in addition to the formulation containing the

drug(s), solvents, and excipients. Each component plays

a role in determining the critical characteristics of the

mist of ﬁne droplets. Droplet size and size distribution,

uniformity of delivery of dose, plume geometry, and

droplet velocity are critical parameters that inﬂuence

the efﬁciency of dr ug delivery. When the preparation is

supplied as a multi-dose container, the addition of a suit-

able antimicrobial preservative may be necessary.

Spray formulations intended for nasal or pulmonary

administration have an aqueous base. Nasal preparations

may be solutions, suspensions, or emulsions intended for

local or systemic effect. Nasal delivery may be employed

for drugs with high hepatic extraction ratios. Pulmonary

prep arations typically are solutions, although appropri-

ately sized suspension formulations are permissible. Pre-

parations are usually isotonic and may contain excipients

to control pH and viscosity.

Metered-dose sprays typically r equire manually de-

pressing the top of the container to activate a metered

valve system. Depending on the design of the formula-

tion and the valve system, the droplets generated may

be intended for immediate inhalation through the

mouth and deposition in the pulmonary tree or for inha-

lation into the nose and d eposition in the nasal cavity.

These preparations are commonly known as metered-

dose sprays. The design of the pump, container, valve,

actuator, nozzle, and formulation are critical to the per-

formance of the product.

Alternatively, sprays can be generated by package de-

signs that do not accurately control the volume of formu-

lation delivered. These presentations release the

formulation as a ﬁne mist of droplets upon physical ma-

nipulation of the package by the patient. This generally

involves squeezing the sides of the container and expel-

ling the formulation throu gh the nozzle of the container.

Finally, liquid sprays may be generated from solutions

by nebulization. This is a method for continuous genera-

tion of a ﬁne mist of aqueous droplets from a drug-con-

taining s olution by application of the Venturi principle,

ultrasonic energy, or other suitable mechanical m eans.

The generated mist is directed to the patient for inhala-

tion , sometimes with the aid of an appropria te tube or

face mask. Although formulations for nebulization typi-

cally are solutions, they also may be ﬁne suspensions or

emulsions.

PACKAGING

Containers typically are made of a rigid plastic, but

metal or glass may be suitable.

The nasal spray pump is designed to allow convenient

one-handed operation. The nasal spray n ozzle is de-

signed so that it ﬁts comfortably into the vestibule of

the nasal cavity and allows the plume to be directed to-

ward the appropriate region of the cavity.

LABELING AND USE

Typical warning statements include:

 All inhalation sprays should indicate: ‘‘For Inhalation

Administration Only. Keep out of the reach of chil-

dren unless otherwise prescribed. Avoid spraying in-

to the eyes.’’

 All nasal sprays indicate: ‘‘For Intranasal Administra-

tion Only’’.

The device should conta in a statement that patients

should seek advice and instruction from a health care

professional about the proper use of the device. Guid-

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ance should be provided about the proper care and

cleaning of the device to prevent introduction of mi-

crobes into the pulmonary airways.

Suppositories

Suppositories are dosage forms adapted for applica-

tion into the rectum. They usually melt, soften, or dis-

solve at b ody temperature. A suppository may have a

local protectant or palliative effect or may deliver an

API for systemic or local action.

Suppository bases typically include cocoa butter, gly-

cerinated gelat in, hydrogenated vegetable oils, mixtures

of polyethylene glycols of various molecular weights, and

fatty acid esters of polyethylene glycol. The suppository

base can have a notable inﬂuence on the release of the

API(s). Although cocoa butter melts quic kly at body tem-

perature, it is immiscible with body ﬂuids and this inhibits

the diffusion of fat-soluble APIs to the affected sites. Poly-

ethylene glycol is a suitable base for some antiseptics. In

cases when systemic action is desired, incorporating the

ionized rather than the non-ionized form of the API may

help maximize bioavailability. Although non-ionized APIs

partition more readily out of water-miscible bases such as

glyc erinated gelatin and polyethyl ene gl ycol, the bases

themselves tend to dissolve ver y slowly, which slows

API release. Cocoa butter and its substitutes (e.g, Hard

Fat) perform better than other bases for allaying irritation

in preparations intended for treating internal hemor-

rhoids. Suppositori es for adults are t apered at one or

both ends and usually weigh about 2 g eac h.

PREPARATION

Cocoa butter suppositories have cocoa butter as the

base and can be made by incorporating the ﬁnely divid-

ed API into the solid oil at room temperature and suitably

shaping the resulting mass or by working with the oil in

the melted state and allowing the resulting suspension to

cool in molds. A suitable quantity of hardening agents

may be added to counteract the tendency of some APIs

(such as chloral hydrate and phenol) to soften the base.

The ﬁnished suppository melts at body temperature.

A variety of vegetable oils, such as coconut or palm ker-

nel, modiﬁed by esteriﬁcation, hydrogenation, or frac-

tionation, are used as cocoa butter substitutes to

obtain products that display vary ing compositions and

melting temperatu res (e.g., Hydrogenated Vegetable Oil

and Hard Fat). These products can be designed to reduce

rancidity while incorporating desired characteristics such

as narrow intervals between melting and solidiﬁcation

temperatures and melting ranges to accommodate for-

mulation and climatic conditions.

APIs can be incorporated into glycerinated gelatin ba-

ses by addition of the prescribed quantities to a vehicle

consisting of about 70 parts of glycerin, 20 parts of gel-

atin, and 10 parts of water.

Several combinations of polyethylene glycols that have

melting temperatures that are above body temperature

are used as suppository bases. Because release from these

bases depends on dissolutionratherthanonmelting,

there are signiﬁcantly fewer p roblems in preparation

and storage than is the case for melting-type vehicles.

However, high concentrations of higher molecular

weight polyethylene glycols may lengthen dissolution

time, resulting in problems with retention.

Several non-ionic surface-active agents closely related

chemically to the polyethylene g lycols can be used as

suppository vehicles. Examples include polyoxyethylene

sorbitan fatty acid esters and the polyoxye thylene stea-

rates. These surfactants are used alone or in combination

with other suppository vehicles to yield a wide range of

melting temperatures and consistencies. A notable ad-

vantage of such ve hicles is their water dispersibility. How-

ever, care must b e taken with the use of sur factants

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because they may either increase the rate of API absorp-

tion or interact with the API to reduce therapeutic activ-

ity.

Compounding suppositories using a suppository base

typically involves melting the suppository base and disso-

lution or dispersion of the API in the molten base (see

Pharmaceutical Compounding—Nonsterile Preparations

h795i). When compounding suppositories, the manufac-

turer or compounding professional prepares an excess

amount of total formulation to allow the prescribed

quantity to be accurately dispensed. In compounding

suppositories, avoid caustic or irritating ingredients, care-

fully select a base that will allow the API to provide the

intended effect, and in order to minimize abrasion of

the rectal membranes, reduce solid ingredients to the

small est reasonabl e particle size. A representative n um-

ber of the compounded suppositories should be

weighed to conﬁrm that none is less than 90% or more

than 110% of the average weight of all units in the batch.

STORAGE AND USE

Suppositories typically are provided in unit-dose pack-

aging with storage instructions to prevent melting of the

suppository base. Suppo sitories with cocoa butter base

require storage in well-closed c ontainers, preferably at

a temperature below 308(controlled room temperature).

Glycerinated gelatin suppositories require storage in

tight containe rs, prefera bly at a temperature below 28.

Although polyethylene glycol suppositories can be

stored without refrigeration, they should be p ackaged

in tightly closed containers.

Include instructions about insertion procedures to en-

sure ease of use and absorption. Labels on polyethyl ene

glycol suppositories should contain directions that they

be moistened with water before insertion.

Suspensions

A suspension is a biphasic preparation consisting of sol-

id particles dispersed throughout a liquid phase. Suspen-

sion dosage forms may be formulated for speciﬁc routes

of administration such as oral suspensions, topical sus-

pensions, or suspensions for aerosols (see Aerosols). Some

suspensions are prepared and ready for use, and others

are prepared as solid mixtures intended for reconstitu-

tion with an appropriate vehicle just before use. The term

‘‘milk’’ is sometimes used for suspensions in aqueous ve-

hicles intended for oral administration (e.g., Milk of Mag-

nesia). The term ‘‘magma’’ is often used to describe

suspensions of inorganic solids, such as clays in water,

that display a tendency toward strong hydration and ag-

gregation of the solid, giving rise to gel-like consistency

and thixotropic rheological behavior (e.g., Bentonite

Magma). The term ‘‘lotion’’ may refer to a suspension

dosage although the liquid phase in these preparations

is commonly an emulsion intended for application to

the s kin (e.g., Calamine Topical Suspension;seeEmul-

sions). Some suspensions are prepared in sterile form

and are used as injectables (see Injections h1i). Other ster-

ile suspensions are for ophthalmic or otic administratio n.

Suspensions generally are not injected intravenously, epi-

durally, or intrathecally unless the product labeling clear-

ly speciﬁes these routes of administration.

Limited aqueous solubility of the API(s) is the most

common rationale f or developing a suspension. Other

potential advantages of a suspension include taste mask-

ing and improved patient compliance because of the

more convenient dosage form. When comp ared to solu-

tions, susp ensions have improved chemical stability. Ide-

ally, a suspension should co ntain small uniform particles

that are readily suspended and easily re-disperse d follow-

ing settling. Unless the dispersed solid is colloidal, the

particulate matter in a suspension likely will settle to

the bottom of the container upon stand ing. Su ch sedi-

mentation m ay lead to caking and solidiﬁcation of the

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sediment and difﬁculty in re-dispersing the suspension

upon agitation. To prevent such problems, manufactur-

ers commonly add ingredients to increase viscosity and

the gel state of the suspension or ﬂocculation, including

clays, surfactants, polyols, polymers, or sugars. Frequent-

ly, thixotropic vehicles are employed to counter particle-

settling tendencies, but these vehicles must not interfere

with pouring or re-dispersal. Additionally, the density of

the dispersed phase and continuous phase may be mod-

iﬁed to further co ntrol settling rate. For topical suspen-

sions, rapid dryin g upon application is desirable.

The product is both chemically and physically stable

throughout its shelf life. Temp erature can inﬂuence the

viscosity (and thus s uspension propert ies and the ease

of removing the dose from the bottle), and temperature

cycling can lead to changes in the particle size of the dis-

persed phase via Ostwald ripening. When manufacturers

conduct stability studies to establish product shelf life

and storage conditions, they should cycle conditions

(freeze/thaw) to investigate temperature effects.

All suspensions contain suitable antimicrobial agents to

protect against bacterial, yeast, and mold contamination

(see Antimicrobial Effectiveness Testing h51i).

Suspensions for reconstitution are dry powder or gran-

ular mixtures that require the addition of water or a sup-

plied formulated diluent before adminis tration. This

formulation approach is frequently used when the chem-

ical or physical stability of the API or suspension does not

allow sufﬁcient shelf life for a preformulated suspension.

Typically, these suspensions are refrigerated after recon-

stitution to increase their shelf life. For this type of sus-

pension, the powder blend is uniform and the powder

readily disperses when reconstituted. Taste of the recon-

stituted suspension is also an important attribute because

many suspensions are used for pediatric populations.

Injectable suspensions generally are intended for either

subcutaneous or intramuscular routes of a dministration

and should have a controlled particle size, t ypically in

the range of 5 mm or smaller. The rationale for the devel-

opment of injectable suspensions includes poor API solu-

bility, improved chemical stability, prolonged duration of

action, and avoidance of ﬁrst-pass metabolism. Care is

needed in selecting the sterilization techniq ue because

it may affect product stability or alter the physical proper-

ties of the material.

PREPARATION

Suspensions are prepared by adding suspending

agents or other excipients and puriﬁed water or oil to sol-

id APIs and mixing to achieve uniformity. In the prepara-

tion of a suspension, the characteristics of both the

dispersed phase and the dispersion medium shou ld be

considered. Duri ng development manufacture rs should

deﬁne an appropriate particle si ze d istribution for the

suspended material to minimize the likelihood of particle

size changes during storage.

In some instances the dispersed phase has an afﬁnity

for the vehicle and is readily wetted upon its addition.

For some materials the displacement of air from the solid

surface is difﬁcult, and the solid particles may clump to-

gether or ﬂoat on top of the vehicle. In the latter case, a

wetting agent is used to facilitate displacement of air

from the powder surface. Surfactants, alcohol, glycerin,

and other hydrophilic liquids can be employed as wet-

ting a gents when an aqueous vehicle will be u sed as

the dispersion phase. These agents function by displac-

ing the air in the crevices of the particles and dispersing

the particles. In the large-scale preparation of suspen-

sions, wetting of the dispersed phase may be aided by

the use of high-energy mixing equipment such as colloid

mills or other rotor–stator mixing devices.

After the powder has been wetted, the dispersion me-

dium (containing t he soluble formulation components

such as colorants, ﬂavorings, and preservatives) is added

in portions to the powder, and the mixture is thoroughly

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blended before subsequent additions of the vehicle. A

portion of the vehicle is used to wash the mixing equip-

ment free of suspended material, and this portion is used

to bring the suspension to ﬁnal volume and ensure that

the suspension contains the desired concentration of sol-

id matter. The ﬁnal product may be passed through a col-

loid mill or other blender or mixing device to ensure

uniformity. When appropriate, preservatives are included

in the formulation of suspensions to protect against bac-

terial and mold contamination.

Suspensions are shaken before the dose is dispensed.

Because of the viscosity of many suspension vehicles,

air entrainment may occur duri ng dosing. The formula-

tion process allows evaluation of this possibility; adjust-

ments in vehicle viscosity or the incorporat ion of low

levels of antifoaming agents are common approaches

to minimize air entrainment. Alternatively, speciﬁc in-

structions for shaking the formulation may be provided

to mini mize air incorporation and ensu re accurate dos-

ing.

PACKAGING AND STORAGE

Individual monographs specify the packaging and

storage requirements for suspension products. Typically,

the monograph will indicate a container type such as

tight, well-closed, or light -resistant and may indic ate

storage conditions such as controlled room temperature.

For additional information about meeting packaging re-

quirements listed in the individual monographs, refer to

Containers—Glass h660i, Containers—P lastic h661i, Con-

tainers—Performance Testing h671i, Good Packaging Prac-

tices h1177i,andtheGeneral Notices for statements

about preservation, packaging, storage, and labeling.

Acceptable suspension of the particulate phase de-

pends on the particle size of th e dispersed phase as well

as the viscosity and density of the vehicle. Clear instruc-

tion is provided regarding the appropriate storage tem-

perature for the product because temperature can

inﬂuence the viscosity and density (that affect suspension

properties and the ease of removal of the dose from the

bottle), and temperat ure cycling can lead to changes in

particle size of the dispersed phase. Suspensions require

storage in tight containers. Avoid freezing.

LABELING AND USE

Instructions to ensure proper dosing and administra -

tion must accompany the product. When labeling a sus-

pension, consider any air that might be ent rained in the

preparation as a result of shaking, and avoid such en-

trainment. Compounded suspensions should indicate a

beyond-use date that is calculated from the time of com-

pounding. Suspensions are shaken well before use to en-

sure uniform distribution of the solid in the vehicles.

Tablets

Tablets are solid dosage forms in which the API is

blended with excipients and compressed into the ﬁnal

dosage. Tablets are the most widely used dosage form

in the U.S. Tabl et presses use steel punches and dies to

prepare compacted tablets by the application of high

pressures to powder blends or granulations. Tablets can

be produced in a wide variety of sizes, shapes, and sur-

face markings. Capsule-shaped tablets are commonly re-

ferred to as caplets. Specialized tablet presses may be

used to produce tablets with multiple layers or with spe-

cially formulated core tablets placed in the interior of the

ﬁnal dosage form. These specialized tablet presentations

can delay or extend the release of the API(s) or physically

separate incompatible APIs. Tablets may be coated by a

variety of techniques to provide taste masking, protec-

tion of photo-lab ile API(s), prolon ged or delayed release,

or unique appearance (colors). When no deliberate effort

has been made to modify the API release rate, tablets are

referred to as immediate-release.

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Tablet Triturates—Small, usually cylindrical, molded

or compacted tablets. Tablet triturates traditionally were

used as dispensing tablets in order to provide a conve-

nient, measured quantity of a potent API for compound-

ing purposes, but they are rarely used today.

Hypodermic Tablets—Molded tablets made f rom

completely and readily water-soluble ingredients; for-

merly intended for use in making preparations for hypo-

dermic injection. They may b e ad ministered orally or

sublingually when rapid API availability is required, as in

the case of Nitroglycerin Sublingual Tablets.

Bolus Tablets—Large, usually elongated, tablets in-

tended for administration to large animals. Conventional

tableting processes can be used to manufacture bolus

table ts, but due to their size higher compression forces

may be necessary.

Buccal Tablets—Intended to be inserted in the buc-

cal pouch, where the API is absorbed directly through the

oral mucosa. Few APIs are readily absorbed in this way

(examples are nitroglycerin and certain steroid hor-

mones).

Effervescent Tablets—Prepared by compaction and

contain, in addition to the API(s), mixtures of acids (e.g.,

citric acid or tartaric acid) and carbonates and/or hydro-

gen carbonates. Upon contact with water, these formu-

lations release carbon dioxide, producing the

characteristic effer vescent action.

Hard and Soft Chewable Tablets—Formulated and

manufactured to produce a p leasant-tasting residue in

the mouth and to facilitate swallowing. Hard chewable

tablets are prepared by compaction, usually utilizing

mannitol, sorbitol, or sucrose as binders and ﬁllers, and

contain colors and ﬂavors to enhance their appeara nce

and taste. Some c hewable tablets may be swallowed

without compromising delivery of the API. Chewable

tablets are c learly labeled to indicate whether chewing

is necessary to ensure reliable release of the API(s). Hard

chewable tablets in veterinary medicine often have ﬂavor

enhancers like brewe rs yeast or meat/ﬁsh-based ﬂavors.

Soft chewable tablets are made by a molding or extru-

sion p roc ess , fr eq uen tly with more than 10% water to

help maintain a pliable, soft product.

Orally Disinteg rating Tablets—Intended to disin-

tegrate rapidly within the mouth to provide a ﬁne disper-

sion before the patient swallows the resulting

suspension. Some of these dosage forms have been for-

mulated to facilitate rapid disintegration and are manu-

factured by conventional means or by using

lyophilization or molding processes.

Sublingual Tablets—Intended to be inserted be-

neath t he tongue, wher e th e API is absorbed directly

through the oral mucosa. As with buccal tablets, few APIs

are extensively absorbed in this way, and much of the API

is swallowed and is available for gastrointestinal absorp-

tion.

PREPARATION

Most compacted (compressed) tablets con sist o f the

API(s) and a number of excipients. These excipie nts

may include ﬁllers (diluents), binders, disintegrating

agents, lubricants, and glidants. Approved FD&C and

D&C dyes or lakes, ﬂavors , and sweetening agents also

may be present.

Fillers or diluents are added when the quantity of API(s)

is too small or the properties of the API do not allow sat-

isfactory compaction in the absence of other ingredients.

Binders impart adhesive ness to the powder blend and

promote tablet formation and maintenance of API uni-

formity in the tableting mixture. Disintegrating agents

facilitate reduction of the tablet into small particl es upon

contact with water or biological ﬂuids. Lubricants reduce

friction during the compaction and ejecti on cycles. Gli-

dants improve powder ﬂuidity, powder handling proper-

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ties, and tablet weight control. Colorants are often add-

ed to tablet formulations for esthetic value or for product

identiﬁcation.

Tablets are prepared from formulations that have been

processed by one of three general methods: wet granu-

lation, dr y granulation (roll comp action or slugging),

and direct compression.

Wet Granulation—Involves the mixing of dry pow-

ders with a granulating liquid to form a moist granular

mass that is dried and sized prior to compression. It is

particularly useful in achieving uniform blends of low-

dose APIs and facilitating the wetting and dissolution of

poorly soluble, hydrophobic APIs.

Dry Granulations—Can be produced by passing

powders between rollers a t elevated pressure (roll com-

paction). Alternatively, dry granulation also can be car-

ried out by the compaction of powders at high

pressures on tablet presses, a process also known as slug-

ging. In either case the compacts are sized before com-

pression. Dry granulation improves the ﬂow and

handling properties of th e powder formulation without

involving moisture in the processing.

Direct Compression—Tablet processing involves dry

blending of the API(s) and excipien ts followed by com-

pression. The simplest manufacturing technique, direct

compression is acceptable only when the API and excip-

ients possess acceptable ﬂow and compres sion proper-

ties without prior process steps.

Tablets may be coated to protect the ingredients from

air, moisture, or light; to mask unpleasant tastes and

odors; to improve tablet appearance; and to reduce dust-

iness. In addition, coating may be used to protect the API

from acidic pH values associated with gastric ﬂuid s or to

control the rate of drug release in the gastrointestinal

tract.

The most common coating in use today is a thin ﬁlm

coating composed of a polymer that is derived from cel-

lulose. Sugar coating is an alternative, less common ap-

proach. Sugar-coated ta blets have considerably thicker

coatings that are primarily sucrose with a number of in-

organic diluents. A variety of ﬁlm-coating polymers ar e

available and enable the development of specialized re-

lease proﬁles. These formulations are employed to pro-

tect acid-labile APIs from the acidic stomach

environment as well as to prolong the release of the

API to reduce dosing frequency (see Dissolution h711i

or Disintegration h701i).

PACKAGING, STORAGE, AND LABELING

Individual monographs s pecify t he packaging and

storage requirements for tablet products. Typically, the

monograph will indicate the container type such as tight,

well-closed, or light-resistant. For additional information

on meeting USP packaging requirements see

Containers—Glass h660i,Containers—Plastic h661i and

Containers—Performance Testing h671i . Effervescent tab-

lets are sto red in tightly closed containers or moisture-

proof packs and are labeled to indicate that they should

not be swallowed directly.

Tapes

A tape is a dosage form suitable for delivering APIs to

the skin. It co nsists of an API(s) impregnated into a dura-

ble yet ﬂexible woven fabric or extruded synthetic mate-

rial tha t is coated with an adhesive agent. Typically the

impregnated API is present in the dry state. The adhesive

layer is designed to hold the tape securely in place with-

out the aid of additional bandaging. Unlike transdermal

patches, tapes are not designed to control the release

rate of the API.

The API content of tapes is expressed as amount per

surfaceareawithrespecttothetapesurfaceexposed

to the skin. The use of an occlusive dressing with the tape

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enhances the rate and extent of delivery of the API to

deeper layers of the skin and m ay result i n greater sys-

temic absorption of the API.

LABELING, STORAGE, AND USE

Label to indicate ‘‘External Use Only’’. Tapes are stored

in tight containers protected from light and moisture. To

employ the tape, one cuts a patch slightly larger than the

area that will be treated. The backing paper is removed

from the adhesive side, and the tape is applied to the

skin. To ensure o ptimal adhesion, the tape should not

be applied to folds in the skin. To minimize systemic ab-

sorption and to ensure good adhesion, tapes should be

applied to dry skin.

GLOSSARY

This glossary provides deﬁnitions for terms in use in

medicine and serves as a source of ofﬁcial names for of-

ﬁcial articles. Examples of general nomenclature forms

for the more frequ ently encountered categories of dos-

age forms appear in Nomenclatur e h1121 i. In an attempt

to be comprehensive, this glossary was compiled without

the limits imposed by current preferred nomenclature

conventions. To clearly identify/distinguish preferred

from not pr eferred terms, entries indica te when a term

is not preferred and direct the user to the curr ent pre-

ferred term. When a term is described as an attribute of

a dosage form, it should not be used in the ofﬁcial name

for the dosage form.

AEROSOL: A dosage form consisting of a liquid or solid

preparation packaged under pressure and intended

for administration as a ﬁne mist. The descriptive term

aerosol also refers to the ﬁne mist of small droplets or

solid particles that are emitted from the product.

AROMATIC WATER (NOT PREFERRED; see Solution): A clear,

saturated, aqueous solution of volatile oils or other

aromatic or volatile sub stances.

AURAL (Auricular) (NOT PREFERRED; see Otic): For admin-

istration into, or by way of, the ear.

BEAD (NOT PREFERRED; see Pellets): A solid dosage form

in the shape of a small sphere. In most products a

unit dose consists of multiple beads.

BLOCKS: A large veterinary product intended to be

licked by animals and containing the API(s) and nu-

trients such as salts, vitamins, and minerals.

BOLUS (NOT PREFERRED ;seeTablet): A large tablet in-

tended for administration to large animals.

CAPLET (NOT PREFERRED; see Tablet): Tablet dosage form

in the shape of a capsule.

CAPSULE: A solid dosage form in which the API, with or

without other ingredients, is ﬁlled into eithe r a hard

or soft shell. Most capsule shells are composed main-

ly of gelatin.

CHEWABLE: Attribute of a solid dosage form that is in-

tended to be chewed before swallowing.

COATED: Attribute of a solid dosage form that is cov-

ered by deposition of an outer solid that is different

in composition from the core material.

COLLODION (NOT PREFERRED;seeSolution): A prepara-

tion that is a solution dosage form composed of pyr-

oxilin dissolved in a solvent mixture of alcohol and

ether and applied externally.

COLLODIAL DISPERSION: A system in which particl es of

colloidal dimension (i.e., typically between 1 nm

and 1 mm) are distributed uniformly throughout a

liquid.

CONCENTRATE: A liquid or soli d preparation of higher

concentration and smaller volume than the ﬁnal dos-

age form; usually intended to be diluted prior to ad-

ministration. The term continues to be used for

veterinary preparations but is being phased out of

USP–NF titles for human applications.

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CONVENTIONAL-RELEASE (NOT PREFERRED; see Immediate-

Release): Descriptive term for a dosage form in which

no deliberate effort has been made to modify the re-

lease rate of th e API. In the case of capsules and tab-

lets, the inclusion or exclusion of a disintegrating

agent is not interpreted as a modiﬁcation.

CREAM: An emulsion dosage form often containing

more than 20% water and volatiles or containing less

than 50% hydrocarbons, waxes, or polyols as the ve-

hicle for the API. Creams are generally intended for

external application to the skin or mucous mem-

branes.

DELAYED-RELEASE: A t ype of modiﬁed-release dosage

form. A descriptive term for a dosage form deliber-

ately modiﬁed to delay release o f the API for some

period of time after initial administration. Release of

the API is prevented in the gastric environment but

promoted in the intestinal environment; this term

is synonymous with Enteric-Coated or Gastro-

Resistant.

DENTAL: Descriptive term for a preparation that is ap-

plied to the teeth and/or gums for localized acti on.

DERMAL: Route of administration to the skin surface.

DOSAGE FORM: A formulation of the API(s) and excipi-

ents in quantities and physical form designed to al-

low the accurate and efﬁcient administration of the

API to the human or animal patient.

DRY POWDER INHALER: A dosage form consisting of a

mixture of the API(s) and carrier; all components ex-

ist in a ﬁnely divided solid state that is mobilized into

a ﬁne mist upon the oral inhalation by the patient.

EFFERVESCENT: Attri bute of an oral dosage for m, fre-

quently tablets or granules, containing ingredients

that, when in contact with water, rapidly release car-

bon dioxide. The dosage form is dissolved or dis-

persed in water to initiate the effervescence prior to

ingestion.

ELIXIR (NOT PREFERRED; see Solution): A preparation that

typically is a clear, ﬂavored, sweetened hydroalco-

holic solution intended for or al use. The term is no

longer used in USP–NF but is commonly encoun-

tered in compounding pharmacy practice.

EMOLLIENT: Attribute of a cream or ointment indicat-

ing an increase in the moisture content of the skin

following application of bland, f atty, or oleaginous

substances.

EMULSION: A dosage form consisting of a two-phase

system composed of at least two immiscible liquids,

one of which is dispersed as droplets (inter nal or dis-

persed phase) within the other liquid (external or

continuous phase), generally stabilized with one or

more emulsifying agents. Emulsion is not used as a

dosage form term if a more speciﬁ c term is applica-

ble (e.g., Cream, Lotion,orOintment).

ENTERIC-COATED (NOT PREFERRED;seeDelayed-Release):

Descriptive term for a solid dosage form in which a

polymer coating has been applied to prevent the re-

lease of the API in the gastric environment.

EXCIPIENT: An ingredient of a dosage form other than

an API.

EXTENDED-RELEASE: Descriptive term for a dosage form

that is deliberately modiﬁed to protract the release

rate of the API compared to that observed for an im-

mediate-release dosage form. The term is synony-

mous with prolonged- or sustained-release. Many

extended-release dosage form s have a pattern of re-

lease that begins with a ‘‘burst effect’’ that mimics an

immediate release followed by a slower release of the

remaining API in the dosage form.

FEED ADDITIVE: A preparation used in veterinary medi-

cine that is mixed with an animal’s food or water to

deliver the API. Three types exist: type A medicated

article, type B medicated feed, and type C medicated

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feed. Only type C medicated feed preparations con-

tain the API(s) in concentrations appropriate for ad-

ministration directly to animals.

FILM: A term used to describe a thin, ﬂexible sheet of

material, usually composed of a polymer in an amor-

phous state. Films are applied to solid dosages for

taste masking, product identiﬁcation, and aesthetic

purposes. Films also are employed as a means of oral

administration of material in a rapidly dissolving

form.

FOAM: An emulsion dosage form containing dis-

persed gas bubbles. When dispensed it has a ﬂuffy,

semisolid consistency.

GAS: One of the states of matter having no deﬁ nite

shape or volume and occupying the entire container

when conﬁned.

GASTRO-RESISTANT (NOT PREFERRED; see Delayed-Release):

Descriptive term for a solid dosage form in which a

polymer coating has been applied to prevent the re-

lease in the gastric environment.

GEL: A dosage form that is a semisolid dispersion of

small inorganic particles or a solution of large organ-

ic molecules containing a gelling agent to pr ovide

stiffness. A gel may contain suspended particles.

GRANULES (NOT PREFERRED): A dosage form composed

of dry aggregates of powder particles that may con-

tain one or more APIs, with or without other ingredi-

ents. They may be swallowed as such, dispersed in

food, or dissol ved in water. Granules are frequently

compacted into tablets or ﬁlled into capsules, with

or without additional ingredients.

GUM: A dosage form in which the base consists of a

pliable material that, when chewed, releases the API

into the oral cavity.

HARD-SHELL CAPSULE (NOT PREFERR ED;seeCapsules): A

type of capsule in whi ch one or more AP Is, wit h or

without other ingredients, are ﬁlled into a two-piece

shell. Most hard-shell capsules are composed mainly

of gelatin and are fabricated prior to the ﬁlling ope r-

ation.

IMMEDIATE-RELEASE: Descriptive term for a dosage form

in which no deliberate effort has been made to mod-

ify the API release rate. In the case of capsules and

tablets, the inclusion or exclusion of a disintegrating

agent is not interpreted as a modiﬁcation.

IMPLANT: A dosage form that is a solid or semisolid

material containing the API, that is inserted into the

body. The insertion process is invasive, and the ma-

terial is intended to reside at the site for a period con-

sistent with the design release kinetics or proﬁle of

the API(s).

INHALATION (BY INHALATION): A route of administration

for aerosols characterized by dispersion of the API in-

to the airways during inspiration.

BY INJECTION: A route of administration of a liq uid or

semisolid deposited into a body cavity, ﬂuid, or tissue

by use of a needle.

INSERT: A solid d osage form that is inserted into a

body cavity other than the rectum. A suppository is

an insert intended for application to the rectum (see

Suppository).

INTRAOCULAR: A route of administration (by injection)

for a sterile liquid within the eye.

IRRIGATI ON: A sterile solution or liquid intended to

bathe or ﬂush open wounds or body cavities.

JELLY (NOT PREFERRED;seeGel): A semisolid dispersion

of small inorganic particles or a solution of large or-

ganic molecules containing a gelling agent to pro-

mote stiffness.

LIQUID: A dosage form consisting of a pure chemical

in its liquid state. This dosage form term should not

be applied to solutio ns. The term is not used in article

names. When liquid is used as a descriptive term, it

indicates a material that is pourable and conforms to

its container at room temperature.

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LOTION: An emulsion liquid dosage form applied to

the outer surface of the body. Historically, this term

has also been applied to suspensions and solutions.

LOZENGE: A solid dosage form intended to disinte-

grate or dissolve slowly in the mouth.

MODIFIED-RELEASE: A descriptive term for a dosage

form with an API release pattern that has been deli-

berately changed from that observed for the imme-

diate-release dosage form of the same API.

MOLDED TABLET (NOT PREFERRED;seeTablet): A tablet

that has been formed by dampening the ingredients

and pressing into a mold, then removing and drying

the resulting solid mass.

MOUTHWASH (NOT PREFERRED;seeSolution): Term ap-

plied to a solution preparation used to rinse the oral

cavity.

NASAL: Route of administration (mucosal) character-

ized by deposition in the nasal cavit y for local or sys-

temic effect.

OCULAR (NOT PREFERRED; see Intraocular): Route of ad-

ministration (by injection) indicating deposition of

the API within the eye.

OINTMENT: A semisolid dosage form, usually contain-

ing less than 20% water and volatiles and more than

50% hydrocarbons, waxes, or polyols as the vehicle.

This dosage form generally is for external application

to the skin or mucous membranes.

OPHTHALMIC: A route of administration (mucosal)

characterized by application of sterile preparation

to the external parts of the eye.

ORAL: A route of administration (gastro-intestinal)

characterized by deposition of a preparation into

the mouth for absorption or action in the digestive

tract.

ORALLY DISINTEGRATING: A descriptive term for a solid

oral dosage form that disintegrates rapidly in the

mouth.

ORO-PHARYNGEAL: A route of admini stration character-

ized by deposition of a preparation into the buccal

cavity a nd/or pharyngeal region to exert a local or

systemic effect.

OTIC: A route of administration (mucosal) character-

ized by deposition of a preparation into, or by way

of, the ear. Sometimes referred to as Aural (Aural

NOT PREFERRED).

PASTE: A semisolid dosage form containing a high

percentage of ﬁnely dispersed solids with a stiff con-

sistency. This dosage form is intended for application

to the skin, oral cavity, or mucous membranes.

PELLET: A small solid dosage form of uniform, often

spherical, shape. Spherical pellets are sometimes re-

ferred to as Beads (Beads

NOT PREFERRED).

PILL (NOT PREFERRED but frequently incorrectly used to

describe a Tablet): A solid spheric al pha rmac eutical

dosage form, usually prepared by a wet massing

technique.

PLASTER: A semisolid dosage form supplied on a sup-

port material for external application. Plasters are ap-

plied for prolonged periods to provide protection,

support, or occlusion (for macerating action).

POWDER: A dos age form composed of a solid or mix-

ture of solids reduced to a ﬁnely divided state and in-

tended for internal or external use.

PROLONGED-RELEASE: NOT PRE FERRED;seeExtended-

Release.

RECTAL: A route of administration (mucosal) charac-

terized by deposition into the rectum to provide lo-

cal or systemic effect.

RINSE: A liquid preparation used to cleanse by ﬂush-

ing.

SEMISOLID: Attribute of a material characterized by a

reduced ability t o ﬂow or conform to its container

at room temperature. A semisolid does not ﬂ ow at

low shear stress and generally exhibits plastic ﬂow

behavior.

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SHAMPOO: A solution or suspension dosage form used

to clean the hair and scalp. May co ntain an API in-

tended for topical application to the scalp.

SOAP: The alkali salt(s) of a fatty acid or mixture of fat-

ty acids used to cleanse the skin. Soaps used as dos-

age forms may contain an API intended for topical

application to the skin. Soaps have also been used

as liniments and enemas.

SOFT GEL CAPSULE (NOT PREFERRED; see Capsule): A specif-

ic capsule type characterized b y increased levels of

plasticizers producing a more pliable and thicker-

walled material than hard gelatin capsules. Soft gel

capsules a re further distinguished because they are

single-piece sealed dosag es. Frequently used for de-

livering liquid compositions.

SOLUTION: A clear, homogeneous liquid dosage form

that contains one or more chemical substances dis-

solved in a solvent or mixture of mut ually miscible

solvents.

SPIRIT (NOT PREFERRED;seeSolution ): A liquid d osage

form composed of an alcoholic or hydroalcoholic so-

lution of volatile substances.

SPRAY: Attribute that describes the generation of

droplet s of a liquid or solution to facilitate applica-

tion to the intended area.

STENT, DRUG-ELUTING: A specialized form of implant

used for extended local delivery of the API to the im-

mediate location of stent placement.

STRIP (NOT PREFERRED; see Tape): A dosage form or de-

vice in the shape of a long, narrow, thin solid mate-

rial.

SUBLINGUAL: A route of administration (mucosal) char-

acterized by placement underneath the tongue and

for release of the API for absorption in that region.

SUPPOSITORY: A solid dosage form in which one or

more APIs are dispersed in a suitable base and mold-

ed or otherwise formed into a suitable shape for in-

sertion into the rectum to provide local or systemic

effect.

SUSPENSION: A liquid dosage form that consists of sol-

id particles dispersed throughout a liquid phase.

SYRUP (NOT PREFERRED;seeSolution): A solution con-

taining high concentrations of sucrose or other sug-

ars. This term is commonly used in compounding

pharmacy.

TABLET: A solid dosage form prepared from powders

or granules by compaction.

TAPE, MEDICATED: A dosage form or device composed

of a woven fabric or synthetic material onto which an

API is pla ced, usually with an adhe sive on o ne or

both sides to facilitate topical applicat ion.

TINCTURE (NOT PREFERRED; see Solution): An alcoholic or

hydroalcoholic solution prepared from vegetable

materials or from chemi cal substances.

TOPICAL: A route of administration characterized by

application to the outer sur face of the body.

TROCHE (NOT PREFERRED;seeLozenge): A solid dosage

form intended to disintegrate or dissolve slowly in

the mouth and usually prepared by compaction in

a manner similar to that used for tablets.

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URETHRAL: A route of administration (mucos al) char-

acterized by deposition into the urethra.

VAGINAL: A route of administration (mucosal) charac-

terized by deposition into the vagina.

VEHICLE: A term commonly encountered in com-

pounding pharmacy that refers to a component for

internal or external use that is used as a carrier or dil-

uent in which liquids, semisolids, or solids are dis-

solved or suspended. Examples include water,

syrups, elixirs, oleaginous liquids, solid and semisolid

carriers, and proprietary products (see Excipient).

VETERINARY: Descriptive term for dosage forms intend-

ed for nonhuman use.

&2S (USP33)

BRIEFING

h1231i Water for Pharmaceutical Purposes, USP 32

page 741. Although the majority of water used for production

is Puriﬁed Water and Water for Injection that is produced on site

(referred to as ‘‘bulk water’’), the Pharmaceutical Waters Expert

Committee recognizes the need for and the use of commercial-

ly available ‘‘packaged’’ Puriﬁed Water and Water for Injection in

some production environments. In addition, there are sterile

waters such as Sterile Puriﬁed Water and Sterile Water for Injection

(and Inhalation and Irrigation). As the tests and limits for these

various types of waters have been updated in recent years,

some of the terminology regarding ‘‘bulk’’, ‘‘sterile’’, and

‘‘packaged’’ needs to be updated and/or clariﬁed. The pro-

posed remedy is to distinguish between ‘‘bulk’’ water, ‘‘sterile’’

water, and ‘‘packaged bulk’’ water in the relevant monographs

and gene ral chapters. The term ‘‘packaged waters’’ has been

used as a substitute for ‘‘sterile waters’’ and as a term to de-

scribe commercially available package s of Puriﬁed Water and

Water for Injection. The Pharmaceutical Waters Expert Commit-

tee proposes that the term ‘‘packaged waters’’ be used for the

packaged form of bulk Puriﬁed Water and Water for Injection that

has been pr oduced elsewhere. Requir ements for pa ckaged

waters are contained in the Puriﬁed Water and Water for Injection

monographs. Sterile waters, although they are also packaged

articles, have their own unique monographs and uses. The Ex-

pert Committee is discouraging the use of the term ‘‘packaged

water’’ to mean ‘‘sterile water’’.

There are companion changes i n Water Conductivity h645i

and the monographs for Sterile Puriﬁed Water, Sterile Water for

Injection, Sterile Water for Inhalation, and Sterile Water for Irriga-

tion. All changes align the use of these terms.

(PW: A. Hernandez-Cardoso.) RTS—C76228

Change to read:

INTRODUCTION

Water is widely used as a raw material, ingredient, and sol-

vent in the processing, formulation, and manufacture of phar-

maceutical products, active pharmaceutical ingredients (APIs)

and intermediates, compendial articles, and analytical re-

agents. This general information chapter provides additional in-

formation about water, its quality attributes that are not

included within a water monograph, processing techniques

that can be used to improve water quality, and a description

of minimum water quality standards that should be considered

when selecting a water source.

This information chapter is not intended to replace existing

regulations or guides that already exist to cover USA and Inter-

national (ICH or WHO) GMP issues, engineering guides, or oth-

er regulator y ( FDA, E PA, or WHO) g uidances for wa ter. The

contents will he lp users to better understand pharmaceutical

water issues and some of the microbiological and chemical con-

cerns unique to water. This chapter is not an all-inclusive writing

on pharmaceutical waters. It contains points that are basic in-

formation to be considered, when appropriate, for the proces-

sing, holding, and use of water. It is the user’s responsibility to

assure that pharmaceutical water and its production meet ap-

plicable governmental regulations, guidances, and the com-

pendial speciﬁcations for the types of water used in

compendial articles.

Control of the chemical purity of these waters is important

and is the main purpose of the monographs in this compendi-

um. Unlike other ofﬁcial articles, the bulk wat er monographs

(Puriﬁed Water and Water for Injection ) also limit how the article

can be produced because of the belief that the nature and ro-

bustness of the puriﬁcation process is directly related to the re-

sulting purity. The chemical attributes listed in these

monographs should be considered as a set of minimum speci-

ﬁcations. More stringent speciﬁcations may b e needed for

some applications to ensure suitability for particular uses. Basic

guidance on the appropriate applications of these waters is

found in the monographs and is further explained in this chap-

ter.

Control of the microbiological quality of water is important

for many of its uses. All

Most

&2S (USP33)

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