Excipient Performance - General Chapter USP 38 PDF

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752 1059 Excipient Performance / General Information USP 37
1059 EXCIPIENT that accommodates excipient variability, consistently achiev-

ing final product CQAs.
PERFORMANCE This informational general chapter provides an overview
of the key functional categories of excipients and tests or
procedures that can be used to monitor and control CMAs.1
INTRODUCTION In this chapter the functional categories have been organ-
ized by their most typical use in common pharmaceutical
Excipients are used in virtually all drug products and are dosage forms. However, functional categories can apply to
essential for product manufacturing and performance. Thus, multiple dosage forms. The association of a functional cate-
the successful manufacture of a robust product requires the gory with a particular dosage form does not limit the use of
use of well-defined excipients and manufacturing processes an excipient to a single type of dosage form or delivery sys-
that consistently yield a quality product. Excipients used in tem. Each functional category includes a general descrip-
drug products typically are manufactured and supplied in tion; the mechanisms by which excipients achieve their
compliance with compendial standards. However, the ef- function; physical properties common to these excipients;
fects of excipient properties on the critical quality attributes chemical properties; and a list of USP general chapters that
(CQA) of a drug product are unique for each formulation can be useful in the development of specific tests, proce-
and process and may depend on properties of excipients dures, and acceptance criteria to ensure that CMAs are ade-
that are not evaluated in USP or NF monographs. The effects quately monitored and controlled. Because of the complex
of variations in excipient material attributes depend on the nature and interplay of formulation ingredients, processing,
role of an excipient in a formulation and the CQAs of the and dosage form performance requirements, the informa-
General Chapters
drug product. This general chapter provides a framework for tion provided in this chapter should not be viewed as either
applying Quality by Design (QBD) principles to excipient restrictive or completely comprehensive.
quality and performance.
An excipient may be used in different ways or for different TABLETS AND CAPSULES
purposes in a formulation and may therefore require differ-
ent material attributes to achieve the desired performance. Functional Category: Diluent
Excipient functional categories are broad, qualitative, and
descriptive terms for the purpose an excipient serves in a Description: Diluents are components that are incorpora-
formulation. A list of excipients grouped by functional cate- ted into tablet or capsule dosage forms to increase dosage
gory is included in NF under Front Matter, Excipients, which form volume or weight. Sometimes referred to as fillers, di-
summarizes some of the more common purposes that exci- luents often comprise a large portion of the dosage form,
pients serve in drug products. Also important are the materi- and the quantity and type of diluent selected often depend
al attributes of the ingredients that must be identified and on its physical and chemical properties. Thus, successful and
controlled to ensure the excipient performs its intended robust manufacturing and dosage form performance de-
function in a drug product. A critical material attribute pend on the measurement and control of the CMAs.
(CMA) is a physical, chemical, biological, or microbiological Functional Mechanism: Among the most important func-
property of a material that must be within an appropriate tional roles diluents play is their ability to impart desirable
limit, range, or distribution to ensure that drug product manufacturing properties (e.g., powder flow, tablet com-
CQAs are maintained throughout the product life cycle. paction strength, wet or dry granule formation, or homoge-
Most, but not all, CMAs become tests in a compendial mon- neity) and performance (e.g., content uniformity, disinte-
ograph. In some applications excipient suppliers and users gration, dissolution, tablet integrity, friability, or physical
will need to identify and control material attributes in addi- and chemical stability). Some diluents (e.g., microcrystalline
tion to monograph specifications. Identification of CMAs re- cellulose) occasionally are referred to as dry binders because
quires a thorough understanding of drug product CQAs, the of the high degree of tablet strength they impart to the final
manufacturing process(es), and the physical, chemical, bio- compressed tablet.
logical, or microbiological properties of each ingredient. Physical Properties: The primary physical properties rele-
Manufacturers should anticipate lot-to-lot and supplier-to- vant to tablet/capsule diluents are those that can have a di-
supplier variability in excipient properties and should have rect effect on diluent and formulation performance. These
in place appropriate control measures to ensure that CMAs include: (1) particle size and size distribution, (2) particle
are maintained within the required limits. Prior knowledge, shape, (3) bulk/tapped/true density, (4) specific surface
experimental designs, and risk-assessment tools can be used area, (5) crystallinity, (6) moisture content, (7) powder flow,
to prioritize and identify CMAs of excipients as well as criti- (8) solubility, (9) crystal form, and (10) compaction proper-
cal process parameters. A CMA of an excipient may not be ties for tablet dosage forms.
related to the major component of the excipient because, Chemical Properties: Tablet diluents comprise a large and
for example, the presence of minor components (e.g., per- diverse group of materials that include inorganics (e.g., di-
oxides, heavy metals, or microbiological content) may affect basic calcium phosphate or calcium carbonate), single-com-
product stability or quality. Good product development ponent organic materials (e.g., lactose monohydrate or
practices, which at times are termed QBD principles, require
understanding excipient CMAs that contribute to consistent 1 This general information chapter provides nonmandatory information that
performance and are the foundation of a control strategy does not create compendial requirements. For additional information about
nonmandatory general chapters and alternative methods and procedures, see
General Notices, 6.30 Alternative and Harmonized Methods and Procedures.
Official from August 1, 2014

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USP 37 General Information / 1059 Excipient Performance 753
mannitol), and multicomponent (e.g., silicified microcrystal- an important property to consider for binders and, for poly-
line cellulose or sugar spheres) or complex organics (e.g., mers, is influenced by the nature of the polymer structure,
microcrystalline cellulose or starch). They may be soluble or molecular weight, and molecular weight distribution. Poly-
insoluble in water, and they may be neutral, acidic, or alka- meric binders may form gels.
line in nature. These chemical properties can have a positive Chemical Properties: Tablet and capsule binders can be
or negative effect on the drug substance physical or chemi- categorized as (1) natural polymers, (2) synthetic polymers,
cal stability and on performance. Appropriate selection of or (3) sugars. The chemical nature of polymersincluding
excipients with desirable physical and chemical properties polymeric structure, monomer properties and sequence,
can enhance the physical and chemical stability as well as functional groups, degree of substitution, and cross-link-
the performance of the drug substance and dosage form. inginfluence the complex interactions that can occur dur-
The detailed composition of an excipient may be important ing granulation. Natural polymers in particular may exhibit
because excipient function could be influenced by the pres- greater variation in their properties because of variations in
ence of minor concomitant components that are essential their sources and therefore their composition.
for proper performance. Pharmaceutical scientists may find General Chapters: The following general chapters may
it necessary to control the presence of undesirable compo- be useful in ensuring consistency in binder functions: Bulk
nents (e.g., heavy metals or peroxides) to ensure adequate Density and Tapped Density of Powders 616, Chromatogra-
dosage form stability and performance. phy 621, Crystallinity 695, Density of Solids 699, Loss on
General Chapters: The following general chapters may Drying 731, Particle Size Distribution Estimation by Analytical
be useful in ensuring consistency in diluent functions: Light Sieving 786, Specific Surface Area 846, ViscosityCapillary
Diffraction Measurement of Particle Size 429, Bulk Density Viscometer Methods 911, and Powder Flow 1174.
General Chapters
and Tapped Density of Powders 616, Crystallinity 695,
Characterization of Crystalline Solids by Microcalorimetry and Functional Category: Disintegrant
Solution Calorimetry 696, Density of Solids 699, Loss on
Drying 731, Optical Microscopy 776, Particle Size Distribu- Description: Disintegrants are functional components
tion Estimation by Analytical Sieving 786, Powder Fineness that are added to formulations to promote rapid disintegra-
811, Specific Surface Area 846, Water Determination 921, tion into smaller units and to allow a drug substance to dis-
and Powder Flow 1174. solve more rapidly. Disintegrants are natural, synthetic, or
chemically modified natural polymeric substances. When
Functional Category: Wet Binder disintegrants come in contact with water or stomach or in-
testinal fluid they function by absorbing liquid and start to
Description: Tablet and capsule binders are incorporated swell, dissolve, or form gels. This causes the tablet structure
into formulations to facilitate the agglomeration of powder to rupture and disintegrate, producing increased surfaces for
into granules during mixing with a granulating fluid such as enhanced dissolution of the drug substance.
water, hydroalcoholic mixtures, or other solvents. The bind- Functional Mechanism(s): The ability to interact strongly
er may be either dissolved or dispersed in the granulation with water is essential to disintegrant function. Three major
liquid or blended in a dry state, and other components and mechanisms describe the function of the various disinte-
the granulation liquid may be added separately during agi- grants: volume increase by swelling, deformation, and capil-
tation. Following evaporation of the granulation liquid, lary action (wicking). In tablet formulations, the function of
binders typically produce dry granules that achieve the de- disintegrants is best described as a combination of two or
sired properties such as granule size, size distribution, shape, more of these effects. The onset and degree of the locally
content, mass, and active content. Wet granulation facili- achieved actions depend on various parameters of a disinte-
tates the further processing of the granules by improving grant, such as its chemical nature and its particle size distri-
one or more of the granule properties such as flow, han- bution and particle shape, as well as some important tablet
dling, strength, resistance to segregation, dustiness, appear- parameters such as hardness and porosity.
ance, solubility, compaction, or drug release. Physical Properties: The primary physical properties rele-
Functional Mechanism: Binders are soluble or partially vant to a disintegrant are those that describe the product's
soluble in the granulating solvent or, as in the case of native particle structure as a dry powder or its structure when in
starches, can be made soluble. Concentrated binder solu- contact with water. These properties may include (1) parti-
tions also have adhesive properties. Upon addition of liquid, cle size distribution, (2) water absorption rate, (3) swelling
binders typically facilitate the production of moist granules ratio or swelling index, and (4) the characterization of the
(agglomerates) by altering interparticle adhesion. They also resulting product whether it is still particulate or a gel is
may modify interfacial properties, viscosity, or other proper- formed.
ties. During drying they may produce solid bridges that Chemical Properties: Polymers used as disintegrants are
yield improved residual dry granule strength. either nonionic or anionic with counterions such as sodium,
Physical Properties: Dispersion or dissolution of a binder calcium, or potassium. Nonionic polymers are natural or
in the granulation liquid depends on its physical properties: physically modified polysaccharides such as starches, cellulo-
depending on the application, surface tension, particle size, ses, pullulan, or cross-linked polyvinylpyrrolidone. The
size distribution, solubility, and viscosity are among the im- anionic polymers mainly are chemically modified starches,
portant properties. Homogeneous incorporation of a binder cellulose products, or low-cross-linked polyacrylates. These
into a dry blend also depends on its physical properties such chemical properties should be considered in the case of ion-
as particle size, shape, and size distribution. Viscosity often is ic polymers. Disintegration performance is affected by pH

changes in the gastrointestinal tract or by complex forma- Characterization of Crystalline and Partially Crystalline Solids
tion with ionic drug substances. by X-ray Powder Diffraction (XRPD) 941.
General Chapters: The following general chapters may Other Information: Certain lubricants, particularly those
be useful in ensuring consistency in disintegrant functions: used in effervescent dosage forms, do not fall into the
Light Diffraction Measurement of Particle Size 429, Optical chemical categories defined above. These materials are used
Microscopy 776, Particle Size Distribution Estimation by Ana- in special situations, and they are not suitable for universal
lytical Sieving 786, and Powder Flow 1174. application. Talc is an inorganic material that may have
some lubricant properties. It is generally used in combina-
Functional Category: Lubricant tion with fluid film lubricants to reduce sticking to punches
and dies.
Description: Lubricants typically are used to reduce the
frictional forces between particles and between particles and Functional Category: Glidant and/or
metal-contact surfaces of manufacturing equipment such as Anticaking Agent
tablet punches and dies used in the manufacture of solid
dosage forms. Liquid lubricants may be absorbed into the Description: Glidants and anticaking agents are used to
granule matrix before compaction. Liquid lubricants also promote powder flow and to reduce the caking or clumping
can be used to reduce metalmetal friction on manufactur- that can occur when powders are stored in bulk. In addi-
ing equipment. tion, glidants and anticaking agents reduce the incidence of
Functional Mechanism: Boundary lubricants function by bridging during the emptying of powder hoppers and dur-
adhering to solid surfaces (granules and machine parts) and ing powder processing.
General Chapters
reducing the particleparticle friction or the particlemetal Functional Mechanism: Glidants are thought to work by a
friction. The orientation of the adherent lubricant particles is combination of adsorption onto the surface of larger parti-
influenced by the properties of the substrate surface. For op- cles and reduction of particleparticle adhesive and cohesive
timal performance the boundary lubricant particles should forces, thus allowing particles to move more easily relative
be composed of small, plate-like crystals or stacks of plate- to one another. In addition, glidants may be dispersed
like crystals. Fluid film lubricants melt under pressure and among larger particles and thus may reduce friction be-
thereby create a thin fluid film around particles and on the tween these particles. Anticaking agents may absorb free
surface of punches and dies in tablet presses, which helps to moisture that otherwise would allow the development of
reduce friction. Fluid film lubricants resolidify after the pres- particleparticle bridges that are implicated in caking phe-
sure is removed. Liquid lubricants are released from the nomena.
granules under pressure and create a fluid film. They do not Physical Properties: Primary physical properties of poten-
resolidify when the pressure is removed but are reabsorbed tial importance for glidants and anticaking agents are parti-
or redistributed through the tablet matrix over the course of cle size, particle size distribution, and surface area. They
time. may be slightly hygroscopic.
Physical Properties: The physical properties that are im- Chemical Properties: Glidants and anticaking agents typi-
portant for the function of boundary lubricants include par- cally are finely divided inorganic materials. Typically they are
ticle size, surface area, hydration state, and polymorphic insoluble in water. Some of these materials are complex.
form. Purity (e.g., stearate:palmitate ratio) and moisture General Chapters: The following general chapters may
content also may be important. The physical properties of be useful in ensuring consistency in glidant or anticaking
possible importance for fluid film lubricants are particle size agent functions: Light Diffraction Measurement of Particle Size
and solid state/thermal behavior. Purity also may be impor- 429, Loss on Drying 731, Particle Size Distribution Estima-
tant. tion by Analytical Sieving 786, Specific Surface Area 846,
Chemical Properties: Lubricants can be classified as boun- and Water Determination 921.
dary lubricants, fluid film lubricants, or liquid lubricants.
Boundary lubricants are salts of long-chain fatty acids (e.g., Functional Category: Coloring Agent
magnesium stearate) or fatty acid esters (e.g., sodium stear-
yl fumarate) with a polar head and fatty acid tail. Fluid film Description: Coloring agents are incorporated into dos-
lubricants are solid fats (e.g., hydrogenated vegetable oil, age forms in order to produce a distinctive appearance that
type 1), glycerides (glyceryl behenate and distearate), or fat- may serve to differentiate a product from others that have a
ty acids (e.g., stearic acid) that melt when subjected to pres- similar physical appearance or, in some instances, to protect
sure. Liquid lubricants are liquid materials that are released photolabile components of the dosage form. These substan-
from granules under pressure. ces are subdivided into dyes (water-soluble substances),
General Chapters: The following general chapters may lakes (insoluble forms of a dye that result from its irreversible
be useful in ensuring consistency in lubricant functions: adsorption onto a hydrous metal oxide), inorganic pigments
Light Diffraction Measurement of Particle Size 429, Crystallin- (substances such as titanium dioxide or iron oxides), and
ity 695, Characterization of Crystalline Solids by Microca- natural colorants (colored compounds not considered dyes
lorimetry and Solution Calorimetry 696, Loss on Drying per se, such as riboflavin). Coloring agents are subject to
731, Optical Microscopy 776, Particle Size Distribution Esti- federal regulations, and consequently the current regulatory
mation by Analytical Sieving 786, Specific Surface Area 846, status of a given substance must be determined before its
Thermal Analysis 891, Water Determination 921, and use.

The Federal Food, Drug, and Cosmetic Act defines three trast, the soft capsule is a one-piece unit that may be
categories of coloring agents: seamed along an axis or may be seamless. The capsule ma-
FD&C colors: those certifiable for use in coloring foods, terial may be derived from hydrolysis of collagen that origi-
drugs, and cosmetics nates from porcine, bovine, or fish sources, or it can be of
D&C colors: dyes and pigments considered safe in nonanimal origin, e.g., cellulosic or polysaccharide chemical
drugs and cosmetics when in contact with mucous entities. The capsule shell also contains other additives such
membranes or when ingested as plasticizers, colorants, and preservatives. In some cases,
Ext. D&C colors: colorants that, because of their oral capsule shells are sterilized to prevent microbial growth. The
toxicity, are not certifiable for use in ingestible products capsule shell is an integral part of the formulation, and
but are considered safe for use in externally applied therefore robust manufacturing and formulation perform-
products. ance depends on the measurement and control of CMAs.
Individual regulatory agencies may have different require- Capsules can be used to administer drugs by oral, rectal,
ments for acceptable coloring agents and quantities. Fur- vaginal, or inhalation routes.
ther, daily and cumulative intake of the colorants should be Functional Mechanism: Capsules can enclose solid, semi-
considered. solid, or liquid formulations. Capsules have a variety of ben-
Functional Mechanism: Water-soluble dyes usually are efits: masking unpleasant taste, facilitating blinding in clini-
dissolved in a granulating fluid for use, although they also cal studies, promoting ease of swallowing, and presenting a
may be adsorbed onto carriers such as starch, lactose, or unique appearance. Conventional capsule shells should dis-
sugar from aqueous or alcoholic solutions. These latter solve rapidly at 37 in biological fluids such as gastric and in-
products often are dried and used as formulation ingredi- testinal media. However, the solubility properties of the shell
General Chapters
ents. Because of their insoluble character, lakes almost al- can be modified (e.g., with enteric and controlled-release
ways are blended with other dry excipients during formula- polymers) to control the release of the capsule contents.
tion. For this reason direct-compression tablets often are Physical Properties: The primary physical properties rele-
colored with lakes. vant to the capsule shell are those that can have a direct ef-
Physical Properties: Particle size and size distribution of fect on product performance: (1) moisture content, (2) gas
dyes and lakes can influence product processing times permeability, (3) stability on storage, (4) disintegration, (5)
(blending and dissolution), color intensity, and uniformity of compactness, and (6) brittleness. The moisture content var-
appearance. A coloring agent should be physically nonreac- ies with the type of capsule. Hard gelatin capsules typically
tive with other excipients and the drug substances. contain 13%16% water compared to hypromellose (hy-
Chemical Properties: The most important properties of a droxypropyl methylcellulose or HPMC) capsules that typical-
coloring agent are its depth of color and resistance to fading ly contain 4%7% water content. Moisture content has an
over time. Substances can be graded on their efficiency in important effect on capsule brittleness. Soft gelatin capsules
reflecting desired colors of visible light, as well as on their contain 5%15% water. Equilibrium water content also may
molar absorptivities at characteristic wavelengths. A coloring be crucial to dosage form stability because water migration
agent should be chemically nonreactive with other exci- can take place between the shell and capsule contents. Gas
pients and the drug substances. The quality of a coloring permeability may be important and generally is greater for
agent ordinarily is measured by a determination of its HPMC capsules than for gelatin capsules because of the
strength, performance, or assay. The impurity profile is es- presence of open structures in the former. Unlike HPMC
tablished by measurements of insoluble matter, inorganic capsules, which do not cross-link, gelatin capsules have po-
salt content, metal content, and organic impurities. tential to cross-link due to environmental and chemical ex-
General Chapters: The following general chapters may posure. Gelatin capsules may undergo cross-linking upon
be useful in ensuring consistency in selected coloring agent storage at elevated temperature and humidity (e.g.,
functions: Light Diffraction Measurement of Particle Size 429 40/75% RH). Gelatin shell material is also well known to
and ColorInstrumental Measurement 1061. Instrumental cross-link due to exposure to aldehydes, ketones, and cer-
methods should be used to determine the absolute color of tain dyes in shell formulations. Thus, presence of these ma-
a coloring agent. terials in excipients should be considered for gelatin encap-
Other Information: Coloring agents are subject to federal sulated products. Cross-linking slows in vitro dissolution and
regulations, and consequently the current regulatory status often necessitates introduction of enzymes in the test medi-
of a given substance must be determined before it is used. um. Gelatin capsules should disintegrate within 15 min
when exposed to 0.5% hydrochloric acid at 3638 but not
Functional Category: Capsule Shell below 30. HPMC capsules can disintegrate below 30.
Chemical Properties: Gelatin is a commercial protein de-
Description: The word capsule is derived from the Latin rived from the native protein, collagen. The product is ob-
capsula, which means a small container. Among other bene- tained by partial hydrolysis of collagen derived from skin,
fits, capsules enable pharmaceutical powders and liquids to white connective tissue, and bones of animals. Type A gela-
be formulated for dosing accuracy as well as ease of trans- tin is derived by acid treatment, and Type B gelatin is de-
portation. The capsule material should be compatible with rived from base treatment. The common sources of com-
all other ingredients in the drug product. Hard capsules typ- mercial gelatin are pigskin, cattle hide, cattle bone, cod skin,
ically consist of two parts: both are cylindrical, and one part and tilapia skin. The gelatin capsule shell also typically con-
is slightly longer than the other and is called the body. The tains coloring agents, plasticizers such as polyhydric alco-
cap fits closely on the body to enclose the capsule. In con- hols, natural gums and sugars, and preservatives such as so-

dium metabisulfite and esters of p-hydroxybenzoic acid. The Functional MechanismSugar Coating: The seal coat is
more commonly used nongelatin capsules today are made used to seal the surface of the tablet cores to prevent water
from HPMC. Different capsule types contain different mois- in the coating solutions or suspensions from causing the
ture levels and may thus influence drug product stability. tablet cores to disintegrate during coating. The seal coat
The detailed composition of an excipient may be important typically is a polymer (e.g., shellac) that is insoluble in water
because the shell function can be influenced by small and is applied as a thin coat from a solution in a nonaqu-
amounts of impurities in the excipients (e.g., peroxides in eous solvent. The key component of the majority of sugar-
oils or aldehydes in lactose and starches) that can cause cap- coating solutions or suspensions is a solute, typically su-
sule cross-linking. The presence in capsule shells of undesira- crose, that is highly soluble in water and forms a sticky, vis-
ble materials such as metals, odorants, water-insoluble sub- cous solution (a syrup) at very high concentration. Other
stances, and sulfur dioxide should be evaluated to ensure materials can be dissolved or suspended in the solution de-
stability and performance. pending on the stage during the coating process. As the
General Chapters: The following general chapters may coating dries, the dissolved coating material adheres to the
be useful in ensuring consistency in selected capsule shell surface of the tablets. The coating solution or suspension
functions: Microbiological Examination of Nonsterile Products: typically is applied in incremental steps, followed by drying,
Microbial Enumeration Tests 61, Microbiological Examination until the requisite coating has been achieved. The key coat
of Nonsterile Products: Tests for Specified Microorganisms 62, is composed of another thin coat that is designed to adhere
Arsenic 211, Heavy Metals 231, Residue on Ignition 281, to the seal-coated cores in order to provide a base for the
Disintegration 701, Dissolution 711, Water Determination subcoat so the latter can adhere to the tablet surface. The
921, ColorInstrumental Method 1061, and Gel Strength subcoat typically contains a high concentration of suspen-
General Chapters
of Gelatin 1081. ded solids and is designed to increase the weight of the tab-
lets comparatively quickly. The smoothing coat is designed
Functional Category: Coating Agent to provide a smooth surface, and the color coat provides the
final color if required. Finally, the tablets may be transferred
Description: Oral tablets may be coated using compres- to a polishing pan and polished using a mixture of waxes to
sion coating, sugar coating, or film coating. Compression provide a high-gloss finish.
coating (effectively making a tablet within a tablet) typically Functional MechanismFilm Coating: Film-coating agents
uses the same ingredients as a conventional tablet and thus are composed of film-forming materials (see Functional Cate-
is outside the scope of this section. The term sugar coating gory: Film-forming Agent) that impart desirable pharmaceuti-
refers to a process and does not require that sucrose be part cal properties such as appearance and patient acceptance
of the formulation. Oral capsules can be coated using film- (e.g., taste masking and ease of swallowing). Film-coating
coating procedures. Reasons for coating pharmaceutical agents also can serve other functional purposes such as pro-
dosage forms include masking unpleasant tastes or odors, viding a barrier against undesirable chemical reactions or
improving ingestion and appearance, protecting active in- untimely release of a drug from its components. After inges-
gredients from the environment, and modifying the release tion, the film coating may dissolve by processes such as hy-
of the active ingredient (e.g., controlled-release or gastroin- dration, solubilization, or disintegration, depending on the
testinal targeting). Materials used as coating agents differ nature of the material used. Enteric coatings are insoluble in
depending on the coating process used. Sugar coating was acidic (low pH) media but dissolve readily in neutral pH con-
the original coating process. However, today for technical ditions. However, most common film-coating polymers do
and economic reasons sugar coating largely has been re- not have pH-specific solubility. The thickness of the film may
placed by film coating. Sugar coating is a complex process vary by application and the nature of the coating agents. In
that typically involves the application of several different the coating process, the polymer chains spread out on the
coats including a seal coat, key coat, subcoat, smoothing core surface and coalesce into a continuous film as the sol-
coat, color coat, and polishing coat. The coating solutions vent evaporates. Polymer solutions or dispersions with a low
or suspensions are slowly poured or otherwise applied in ali- viscosity and high pigment-binding capacity reduce the
quots onto a bed of tablets in a slowly rotating pan. The coating time and facilitate relatively simple and cost-effec-
coating process typically takes an extended period (poten- tive manufacturing. Plastic polymers, waxes, and lipid-based
tially several days) and results in a substantial increase in coatings can be applied without solvents by melting and
tablet weight. In contrast, film coating generally is a simpler atomization. When molten fluid droplets strike the surface of
process in which coating solution or suspension is sprayed the fluidized drug particles they spread and resolidify to
onto tablets either in a rotating pan or in a fluid-bed appara- form film layers. Therefore, film coating materials generally
tus and results in only a modest increase in capsule or tablet have the ability to form a complete and stable film around
weight. The materials used in both sugar coating and film the substrate. The film coating typically is applied uniformly
coating include natural, semisynthetic, and synthetic materi- and is carefully dried to ensure that a consistent product is
als. These may be solutions, suspensions, or colloidal disper- produced. Suitable plasticizers may be required to lower the
sions (latexes or pseudolatexes) that can be applied as either minimum film-forming temperature of the polymer, and for-
aqueous or nonaqueous systems. In addition, waxes and lip- mulators should consider their potential effect on drug re-
ids can be applied as coatings in the molten state without lease.
the use of solvents. They also can be applied in the solid Physical Properties: Sugar coating is a lengthy, complex
state as a polishing coat on top of sugar coating or film process. The physical properties of the seal-coating polymer
coating. and solution are important. The physical properties of the

syrup component in the subsequent layers and any dis- maturely. Plasticizers also are added to semisolid pharma-
solved or suspended solids also are important, and coating ceutical preparations such as creams and ointments to en-
agents must be sufficiently stable during use. hance their rheological properties.
Film coating is a complex process, and the characteristics Physical Properties: The most common plasticizers are
of the film-forming polymer are important. The particle size low molecular weight (< 500 Da) solids or liquids. They typi-
of colloidal dispersions varies with their composition and cally have low melting points (< 100) and can be volatile
manufacture (latex, pseudolatex, or redispersed powder) (i.e., exert an appreciable vapor pressure) at ambient tem-
and can have an effect on film formation. The surface ten- perature. Plasticizers can reduce the glass transition temper-
sion of coating preparations can influence the spray pattern ature (Tg) of the system to which they are added.
in the manufacturing process. The film should possess suffi- Chemical Properties: Many modern plasticizers are syn-
cient elasticity and mechanical strength to withstand the thetic esters such as citrates and phthalates. Traditional
stresses during coating and packaging operations. For coat- pharmaceutical plasticizers include oils, sugars, and their de-
ings that are applied in a molten state without solvents rivatives.
(plastic polymers, waxes, and lipid-based coatings), melting General Chapters: The following general chapters may
range and melt viscosity are the primary properties that for- be useful in ensuring consistency in selected excipient func-
mulators must consider. tions: Residual Solvents 467, Melting Range or Temperature
Chemical Properties: Coating components can be of nat- 741, Refractive Index 831, Specific Gravity 841, Thermal
ural, semisynthetic, or synthetic origin and also can be avail- Analysis 891, and Water Determination 921.
able in different chemical grades. They comprise a diverse Other Information: The choice of an appropriate plasticiz-
variety of different chemical materials. Formulators must er often is guided by reference to its solubility parameter,
General Chapters
consider the nature of the material and its intended use which is related to its cohesive energy density. Solubility pa-
when they identify and quantitate chemical CMAs to ensure rameter values for many common materials are tabulated in
consistent performance. standard reference texts. To ensure maximum effectiveness,
General Chapters: The following general chapters may the solubility parameter of the plasticizer and the polymeric
be useful in ensuring consistency in selected coating agent system being plasticized should be matched as closely as
functions: Fats and Fixed Oils 401, Light Diffraction Measure- possible.
ment of Particle Size 429, Dissolution 711, Tensile Strength
881, Thermal Analysis 891, ViscosityCapillary Viscometer Functional Category: Film-forming Agent
Methods 911, Rotational Rheometer Methods 912, and
Rolling Ball Viscometer Method 913. In addition, the general Description: Film-forming agents typically are polymers
chapters listed under Functional Category: Film-forming that can be used to prepare polymer films to coat tablets or
Agents (below) also may be appropriate for the evaluation of capsules for oral administration, to modify appearance, to
film-coating polymers. modify drug release, or to serve other purposes such as
Additional Information: Additives often are included in a melt-in-the-mouth formulations. Polymeric materials used as
coating formulation. Fillers (e.g., sugar alcohols, microcrys- film-forming agents can be derived from natural, semisyn-
talline cellulose, calcium carbonate, and kaolin) may be add- thetic, or synthetic sources, and they can be supplied as
ed to increase the solids content of the coating agent with- powders, granules, pre-prepared solutions, or colloidal dis-
out increasing viscosity. Stearic acid can be used to improve persions. Colloidal dispersions may contain other compo-
the protective function/moisture barrier of a coating. Color- nents such as plasticizers, surface-active agents, preserva-
ing agents (e.g., titanium dioxide and iron oxides) may be tives, or stabilizers. Film-forming agents can be applied as
added to modify appearance. colloidal dispersions (latexes or pseudolatexes) or as aque-
ous, hydroalcoholic, or nonaqueous polymeric solutions.
Functional Category: Plasticizer Functional Mechanism: Film-forming agents typically are
composed of polymeric materials that possess the ability to
Description: A plasticizer is a low molecular weight sub- form films after solvent evaporation from a solution of the
stance that, when added to another materialusually a pol- polymer or from the continuous phase of a colloidal disper-
ymermakes the latter flexible, resilient, and easier to han- sion. Thus the polymer alone must be a solid at ambient
dle. Plasticizers are key components that determine the temperature and humidity. Some polymers can form films
physical properties of polymeric pharmaceutical systems without the inclusion of added components, but other poly-
such as tablet film coatings and capsule shells. mers may require the use of additional components such as
Functional Mechanism: Plasticizers function by increasing plasticizers.
the intermolecular and intramolecular mobility of the mac- Physical Properties: Many polymeric film-forming agents
romolecules that comprise polymeric materials. They ach- are available in a variety of physical grades that typically are
ieve this by interfering with the normal intermolecular and based on the nominal viscosity of the particular grade. The
intramolecular bonding mechanisms in such systems. The physical properties of the polymer usually are those of a sol-
most effective plasticizers exert their effect at low concentra- id, and many polymers are available as powders and gran-
tions, typically less than 5% w/w. Plasticizers commonly are ules. In addition to the normal properties of bulk powders
added to film coatings (aqueous and nonaqueous systems) and granules, other important physical properties of a poly-
and capsule shells (hard and soft varieties) to improve their meric film-forming agent are the molecular weight distribu-
workability and mechanical ruggedness. Without the addition, which is linked to the nominal viscosity of the grade,
tion of plasticizers, such materials can split or fracture pre- and the glass transition temperature (Tg). If the film-forming

agent is provided as a pre-prepared solution or dispersion, Chemical Properties: Chemicals that provide one of the
the viscosity of the solution or dispersion can affect perform- five basic tastes possess a wide variety of structures, func-
ance and should be monitored. tional groups, and molecular weights. Chemicals used to fla-
Chemical Properties: Film-forming agents comprise a di- vor pharmaceuticals by providing both odor and taste tend
verse group of materials, including natural, semisynthetic, to have low molecular weights (< 250 Da) and polar func-
and synthetic materials as discussed above. They may have tional groups such as esters, ketones, aldehydes, amines, or
ionizable functional groups that impart pH-dependent prop- alcohols. To increase the stability of the flavor(s) in a solid
erties and also can be available in different chemical grades dosage form and to minimize flavordrug interactions, for-
(e.g., with different degrees of chemical substitution). Phar- mulators can add flavors in an encapsulated or spray-dried
macopeial monographs often describe classes of polymeric form.
materials that allow a considerable range of composition. General Chapters: The following general chapters may
Formulators should consider these factors when they identi- be useful in ensuring consistency in flavor functions: Light
fy critical material attributes and establish specifications to Diffraction Measurement of Particle Size 429, Chromatogra-
ensure consistent performance. phy 621, Congealing Temperature 651, Loss on Drying
General Chapters: The following general chapters may 731, Melting Range or Temperature 741, Optical Rotation
be useful in ensuring consistency in selected film-forming 781, Particle Size Distribution Estimation by Analytical Sieving
agent functions: Fats and Fixed Oils 401, Light Diffraction 786, Refractive Index 831, and Specific Gravity 841.
Measurement of Particle Size 429, Bulk Density and Tapped
Density of Powders 616, Chromatography 621, Density of Functional Category: Release-modifying
Solids 699, Dissolution 711, Optical Microscopy 776, pH Agents
General Chapters
791, Tensile Strength 881, Thermal Analysis 891, Viscosi-

tyCapillary Viscometer Methods 911, Rotational Rheometer Release-modifying agents are used to control drug release
Methods 912, Rolling Ball Viscometer Method 913, Bulk in extended-release formulations (also referred to as pro-
Powder Sampling Procedures 1097, Near-Infrared Spectrosco- longed-release or controlled-release formulations). Sus-
py 1119, Raman Spectroscopy 1120, Pharmaceutical Dos- tained-release and enteric coating agents are included un-
age Forms 1151, Powder Flow 1174, and Scanning Electron der Functional Category: Coating Agent.
Microscopy 1181. Description: Release-modifying agents change a medici-
nal product's drug-release pattern to achieve the desired
Functional Category: Flavor and Fragrance drug plasma profile for a given time. The majority of release-
modifying agents are polymers that differ in solubility, ease
Description: A flavor is a single chemical entity or a blend of erosion, rate of swelling, or sensitivity to the biological
of chemicals of natural or synthetic origin that has the abili- environment in which they are placed. These polymers have
ty to elicit a taste or aroma (i.e., fragrance) response when been used to fabricate matrix- or membrane-based drug de-
orally consumed or smelled. The primary purpose of flavor livery systems for oral, parenteral, transdermal, and other
that is added to a pharmaceutical preparation is to provide routes of administration. Matrix controlled-release drug de-
all or part of the taste and aroma of the product taken into livery systems can be classified as hydrophilic eroding matri-
the mouth. Flavors commonly are used in pharmaceutical ces, hydrophilic noneroding matrices, or hydrophobic matri-
oral disintegrating tablets, oral solutions, and oral suspen- ces. In membrane controlled-release drug delivery systems
sions to mask objectionable drug taste and to make the for- the drug reservoir is coated by a rate-controlling polymeric
mulation more palatable, thus promoting patient compli- membrane that may consist of a blend of polymers to con-
ance. trol release. Such devices may take the form of tablets, cap-
Functional Mechanism: Chemicals dissolved in saliva ex- sules, microspheres, vesicles, fibers, patches, etc. In addition
cite chemoreceptors on taste buds that reside primarily on to polymers, certain lipid-based excipients also can be used
the tongue and thus arouse taste perception. Dissolution al- as release-modifying agents in hydrophobic matrix devices
so releases volatile chemicals that reach the olfactory recep- and other types of modified-release systems. Typically these
tors, triggering aroma perception. The total of taste and lipid-based materials are fats and waxes or related materials
odor responses constitutes flavor. Humans can distinguish with melting ranges above 45.
among five components of taste: sourness, saltiness, sweet- Functional Mechanism: Upon contact with a biological
ness, bitterness, umami (savory), and a wide range of specif- fluid, release-controlling polymers may undergo a variety of
ic odors. Flavor enhancers and taste modifiers can be used physical changes such as swelling, gelling, dissolution, or
to modify the sweetness profile of a sweetening agent or to erosion, each of which can be triggered by simple aqueous
mask off-flavors. For example, organic acids such as aspartic exposure or can be modulated by pH, osmotic stress, or in-
and glutamic acids are known to reduce bitterness. teractions with bile or other intestinal contents. In addition
Physical Properties: Taste perception depends on physi- to physical changes, polymers may undergo chemical deg-
cochemical, physiological, and psychological factors. Physi- radation by acids, bases, enzymes, water, heat, etc. Any or
cal properties such as particle size, solubility, humectancy, all of these mechanisms may act in concert to control the
texture, and color all influence the senses. In addition to fla- rate at which the drug is released from the delivery system.
vor, the sensory attributes of sight (e.g., appealing color), For hydrophilic matrices in which drug diffusion domi-
sound (e.g., crunch of a chewable tablet), and mouth feel nates release rate, the rate of drug release depends on the
(e.g., viscous, slimy, chalky, cloying, or watery) also contrib- properties of the polymer gel, and the nature of the contin-
ute to and influence the overall sensory experience. uous phase in the interstices of the gel influences the disso-

lution and diffusion rates of the drug. In the case of eroding chemical composition for copolymers and cellulosic deriva-
matrices, the gel erodes because of the mechanical action of tives, degree of ionization, molecular weight, degree of
the gastrointestinal tract as the water uptake increases, and cross-linking, or, for lipids, fatty acid composition. Residual
the gel becomes more dilute, thus reducing the diffusion impurities from the manufacturing process, e.g., monomers,
distance or releasing drug particles that subsequently dis- initiators, quenching agents, peroxides, and aldehydes, may
solve. Hydrophobic matrix-forming materials are not solu- affect drug substance stability and should be monitored.
ble. Drug release from such systems is governed by drug dif- General Chapters: The following general chapters may
fusion through the tortuous pores that remain as soluble be useful in ensuring consistency in selected functions of re-
components dissolve. lease-modifying agents: Fats and Fixed Oils 401, Light Dif-
Membrane-based drug delivery systems include polymer- fraction Measurement of Particle Size 429, Crystallinity 695,
coated tablets, capsules, and microspheres. Drug-release Characterization of Crystalline Solids by Microcalorimetry and
mechanisms from such systems are complex and depend on Solution Calorimetry 696, Dissolution 711, Loss on Drying
physicochemical characteristics of the drug and polymers or 731, Melting Range or Temperature 741, Nuclear Magnetic
lipids used as well as biological factors in the case of bio- Resonance 761, Optical Microscopy 776, Particle Size Distri-
compatible and biodegradable systems. Most commonly, bution Estimation by Analytical Sieving 786, Specific Surface
drug release from such systems is governed by drug diffu- Area 846, Spectrophotometry and Light-Scattering 851,
sion through the hydrated rate-controlling membrane. Tensile Strength 881, Thermal Analysis 891, ViscosityCa-
Other modified-release systems for parenteral use include pillary Viscometer Methods 911, Rotational Rheometer Meth-
solid lipid nanoparticles and liposomes. The release mecha- ods 912, Rolling Ball Viscometer Method 913, Water Deter-
nisms for these systems often involve a complicated inter- mination 921, Characterization of Crystalline and Partially
General Chapters
play with biological processes such as potential clearance Crystalline Solids by X-ray Powder Diffraction (XRPD) 941,
through the reticulo-endothelial system, targeted delivery, Powder Flow 1174, and Scanning Electron Microscopy
and cellular uptake. 1181.
Osmotic pump devices are a special case of membrane Additional Information: Some release-modifying agents
delivery systems. The rate-controlling polymer is insoluble may include additives such as an antioxidant or an anticak-
and semipermeablei.e., it will allow waterbut not drug ing agent.
moleculesto diffuse through the membrane. Release is
controlled by the osmotic pressure of the core components ORAL LIQUIDS
and the viscosity of the resulting solution or suspension. The
drug, either in solution or as a suspension, is forced out of a Functional Category: pH Modifier (Acidifying/
hole in the membrane, which is typically drilled by a laser Alkalizing/Buffering Agent)
during product manufacture.
Physical Properties: The physical properties of the release- Description: The hydrogen ion concentration, [H+], in an
controlling excipient depend on the chemical type: hydro- aqueous solution is expressed as pH = log(H+). The pH of
philic polymer, hydrophobic polymer, semipermeable poly- pure water is 7 at 25. An aqueous solution is acidic at
mer blends, or lipid, wax, or biodegradable polymer (which pH < 7 and alkaline at pH > 7. An acid can be added to acidi-
can be hydrophilic or hydrophobic). fy a solution. Similarly, a base can be used to alkalize a solu-
Hydrophilic polymers gel in contact with water or aque- tion. A buffer is a weak acid (or base) and its salt. When a
ous media. Because they should provide resistance to the buffer is present in a solution the addition of small quantities
mechanical action of the gastrointestinal tract during pas- of strong acid or base leads to only a small change in solu-
sage, they typically are higher molecular weight grades of tion pH. Buffer capacity is influenced by salt/acid (or base/
the polymers. At the concentrations typically used during in salt) ratio and total concentration of acid (or base) and salt.
vivo release, these high molecular weight polymers often do The pH of pharmaceutical solutions typically is controlled
not exhibit Newtonian properties except in very dilute solu- using acidifying/alkalizing and buffering agents to (1) main-
tion (if they are soluble). Formulators should monitor the ki- tain a pH close to that of relevant body fluid to avoid irrita-
netic and viscoelastic properties of the gels formed in the re- tion; (2) improve drug stability where it is found to be pH-
lease medium. dependent; (3) control equilibrium solubility of weak acids
Hydrophobic polymers are insoluble in water, and their or bases; and (4) maintain a consistent ionization state of
solution properties are determined in nonaqueous solutions. molecules during chemical analysis, e.g., high-performance
The polymers used in the preparation of semipermeable liquid chromatography.
membranes in osmotic pump devices also are insoluble in Functional Mechanism: The ionization equilibria of weak
water, and similarly their solution properties are determined bases, weak acids, and water are the key to the functions of
in nonaqueous solutions. Similarly, hydrophobic lipid-based acidifying, alkalizing, and buffering agents. The autoproto-
materials are insoluble in water. lytic reaction of water can be expressed as
Chemical Properties: Release-controlling agents have
many different types and origins and are available in a range H2O + H2O H3O+ + OH
of grades that reflect the considerable variation in their
The autoprotolysis constant (or ion product) of water is Kw =
chemical structures and properties. Formulators must con-
1 1014 at 25 and varies significantly with temperature.
sider these variables during any chemical investigation and
Because the concentrations of hydrogen and hydroxyl ions
when they consider the effects of chemical structure on ex-
in pure water are equal, each has the value of approximately
cipient performance. Properties of interest may include
1 107 mole/L, leading to the neutral pH of 7 at 25. When

an acid, base, or salt of a weak acid (or base) is added, the tures, aggregate numbers, or critical micelle concentrations
ionization equilibrium of water is shifted so that [H+][OH] (CMC). The CMC value is unique to an individual solubilizer
remains constant, thus resulting in a solution pH that is dif- that bears hydrophilic, lipophilic, and/or hydrophobic
ferent from 7. chains. CMC is a measure of the concentration at which the
Physical Properties: pH modifiers typically are dissolved in surface-active molecules aggregate. These molecular aggre-
liquid dosage forms. Physical properties may be important gates can solubilize the solute by incorporating part into the
and should be considered because they may influence pro- hydrophobic interior. Such interactions with the insoluble
cessing requirements (e.g., particle size may influence mix- molecule further stabilize the molecules in the entire assem-
ing time required to dissolve a pH modifier). blies without precipitation.
Chemical Properties: Buffers and pH modifiers influence Chemical Properties: The chemical and surface-active
solution pH, buffer capacity, osmolality, osmolarity, and wa- properties depend on the structures of the solubilizers. Be-
ter conductivity. When used in chemical analysis, buffers cause of the complex nature of solutesolventsolubilizer in-
must be chemically compatible with the reagents and test teractions, pharmaceutical scientists must carefully consider,
substance. Buffers used in physiological systems should not identify, and control the CMAs of solubilizers.
interfere with the pharmacological activity of the medica- General Chapters: The following general chapters may
ment or the normal function of the organism. be useful in ensuring consistency in selected solubilizing
General Chapters: The following general chapters may agent functions: Fats and Fixed Oils 401, Light Diffraction
be useful in ensuring consistency in selected pH-modifier or Measurement of Particle Size 429, pH 791, Specific Gravity
buffering-agent functions: Water Conductivity 645, Osmo- 841, Specific Surface Area 846, Spectrophotometry and
lality and Osmolarity 785, and pH 791. Light-Scattering 851, Thermal Analysis 891, ViscosityCa-
General Chapters
pillary Viscometer Methods 911, Rotational Rheometer Meth-

Functional Category: Wetting and/or ods 912, Rolling Ball Viscometer Method 913, and Scanning
Solubilizing Agent Electron Microscopy 1181.
Description: Solubilizers can be used to dissolve other- Functional Category: Antimicrobial

wise insoluble molecules. They function by facilitating spon- Preservative
taneous phase transfer to yield a thermodynamically stable
solution. A number of solubilizers are available commercial- Description: Antimicrobial preservatives are used to kill or
ly. Acceptable solubilizers for pharmaceutical applications prevent growth of bacteria, yeast, and mold in the dosage
have been fully evaluated in animals for safety and toxicolo- form.
gy. Wetting agents increase the spreading and penetrating Functional Mechanism: Preservatives work by a variety of
properties of a liquid by lowering its surface tension. mechanisms to control microbes. Most work at the cell
Functional Mechanism: Wetting and solubilizing agents membrane, causing membrane damage and cell leakage.
comprise a variety of different chemical structures or classes. Other modes of action include transport inhibition, protein
Some solubilizers have unique chemical structures. For ex- precipitation, and proton-conducting uncoupling. Some
ample, a hydrophilic moiety may be tethered with a hydro- preservatives are bactericidal (kill bacteria or yeast and
phobic moiety to yield distinct micelle shapes and morphol- mold); some are bacteriostatic (inhibit growth of microor-
ogies in water, thus facilitating solubilization. The mecha- ganisms); and others are sporicidal (kill spores). Several of
nism of solubilization often is associated with a favorable in- the preservatives can act synergistically (e.g., combinations
teraction of the insoluble agent and the interior core of the of parabens).
solubilizer assembly (e.g., micelles). In other cases, unique Physical Properties: Antimicrobials generally are soluble in
hydrophobic sites that are capable of forming inclusion water at concentration ranges at which they are effective.
complexes are present. Other types of solubilizers use a The vapor pressure of these agents is important, especially if
range of polymeric chains that interact with hydrophobic the dosage form is intended for lyophilization or spray dry-
molecules to increase solubility by dissolving the insoluble ing. Several of these agents are flammable. Understanding
agent into the polymeric chains. an excipient's partition coefficient is important because par-
Physical Properties: Wetting and solubilizing agents are titioning of a preservative into an oil phase can diminish the
typically solid, liquid, or waxy materials. Their physical prop- preservative's concentration in the aqueous phase, which in
erties depend on their chemical structures. The physical turn can reduce its value as a preservative.
properties and performance of the wetting agents and solu- Chemical Properties: Phenolic preservatives can undergo
bilizers, however, depend on the surface-active properties of oxidation and color formation. Incompatibilities of preserva-
the solubilizers and on the hydrophiliclipophilic balance tives (cationic and anionic mixtures, adsorption to tubes or
(HLB). Materials with lower HLB values behave as emulsifiers filters, or binding to surfactants and proteins) should be tak-
while those with higher HLB values typically behave as solu- en into account during product development.
bilizing agents. For example, the commonly used wetting General Chapters: The following general chapters may
and solubilizing agent sodium lauryl sulfate (HLB 40) is hy- be useful in ensuring consistency in selected antimicrobial
drophilic and highly water soluble and, upon dispersion in functions: Injections 1, Antimicrobial Effectiveness Testing
water, spontaneously reduces surface tension and forms mi- 51, Microbiological Examination of Nonsterile Products: Mi-
celles that function to solubilize lipophilic materials. crobial Enumeration Tests 61, Microbiological Examination of
The unique hydrophilicity and hydrophobicity properties Nonsterile Products: Tests for Specified Microorganisms 62,
of solubilizers can be characterized by their chemical struc- and Antimicrobial AgentsContent 341.

Other Information: Safety and labeling requirements re- calcium disodium does not sequester calcium and therefore
garding the use of antimicrobial preservatives should be is preferred to prevent hypocalcemia. It is also preferred to
considered. chelate heavy metals with the release of calcium ions. Alter-
natively, disodium edetate can be used to treat hypercalce-
Functional Category: Chelating and/or mia. Edetic acid will decarboxylate if heated above 150.
Complexing Agents Complexing agents generally form molecular complexes
with drug substances that are dependent on complexing
Description: Chelating agents form soluble complex mol- agent physical and chemical properties. The ability of a sol-
ecules with certain metal ions (e.g., copper, iron, manga- ute to form an inclusion complex is dependent on complex-
nese, lead, and calcium) and essentially remove the ions ing agent molecular weight, chemical structure, and the di-
from solution to minimize or eliminate their ability to react mensions of the hydrophobic cavity.
with other elements and/or to precipitate. The agents are General Chapters: The following general chapters may
used in pharmaceuticals (oral, parenteral, and topical formu- be useful in ensuring consistency in selected chelating and
lations), cosmetics, and foods to sequester ions from solu- complexing functions: Antimicrobial Effectiveness Testing
tion and to form stable complexes. Chelating agents also 51, Microbiological Examination of Nonsterile Products: Mi-
are referred to as chelants, chelators, or sequestering agents. crobial Enumeration Tests 61, Heavy Metals 231, Iron
Complexing agents form soluble complex molecules 241, Lead 251, Antimicrobial AgentsContent 341, Light
(e.g., inclusion complexes) with other solutes (e.g., drug Diffraction Measurement of Particle Size 429, Loss on Drying
substances) and can influence physical and chemical proper- 731, pH 791, Water Determination 921, Biotechnology-
ties such as solubility and stability. Derived Articles 1045, and Cellular and Tissue-Based Products
General Chapters
Functional Mechanism: Chelating agents are used to se- 1046.
quester undesirable metal ions from solution. The chemical
structure of chelating agents allows them to act as a claw Functional Category: Antioxidant
to associate with the metal atom by forming a heterocyclic
ring structure. Complexing agents function similarly but Description: This category applies to antioxidants used as
mechanistically and do not (by definition) require a two- in vitro stabilizers of pharmaceutical preparations to miti-
point claw structure because they can associate via one or gate oxidative processes. Antioxidants used for their biologi-
more binding sites. All chelating agents are complexing cal activity in vivo may be regarded as active ingredients
agents but not all complexing agents are chelating agents. with therapeutic effects and are not discussed. Antioxidants
Chelating agents are used as antioxidant synergists, antimi- delay the onset of and/or significantly reduce the rate of
crobial synergists, and water softeners. By sequestering met- complex oxidative reactions that could otherwise have a
al ions from solution, chelating agents reduce the propensi- detrimental effect on the drug substance. Antioxidants also
ty for oxidative reactions. Chelating agents also have the can be considered for protecting nonactive components
ability to enhance antimicrobial effectiveness by forming a such as unsaturated oils, pegylated lipids, flavors, and essen-
metal-iondeficient environment that otherwise could feed tial oils. Thus antioxidants preserve the overall integrity of
microbial growth. the dosage form against oxidative stress. Antioxidants are
Complexing agents generally form soluble complex mole- most effective when incorporated in the formula to prevent
cules with solutes (e.g., drug molecules) that can influence or delay the onset of chain reactions and to inhibit free radi-
physical, chemical, and drug delivery properties. Complex- cals and hydroperoxides from engaging in the cascading
ing agents that form inclusion complexes typically contain a processes described above. Effective application of antioxi-
hydrophobic cavity into which a drug substance can enter dants and evaluation of their efficacy necessitate an under-
and an outer, more hydrophilic region. standing of oxidative mechanisms and the nature of the by-
Physical Properties: Chelating and complexing agents products they generate. Autoxidation is initiated when oxy-
generally are soluble in water and typically are dissolved in gen reacts with a substrate to form highly reactive species
liquid dosage forms. Physical properties may be important known as free radicals (RH R ). After initiation the free
and should be considered because they may influence pro- radicals in the presence of oxygen can trigger chain reac-
cessing requirements (e.g., particle size may influence mix- tions (R + O2 ROO and ROO + RH R + ROOH) to
ing time required to dissolve). Chelating and complexing form peroxy radicals, hydroperoxides, and new alkyl radicals
agents exhibit different degrees of hygroscopicity. Because that can initiate and then propagate their own chain reac-
chelating agents are used in low levels, particle size distribu- tions. The cascading reactions during the propagation phase
tion can be important to enable acceptable dosage form can be accelerated by heat, light, and metal catalysts. In the
content uniformity. presence of trace amounts of metal catalysts (Cu+, Cu2+,
Chemical Properties: Chelating agents complex with met- Fe2+, and Fe3+), hydroperoxides (ROOH) readily decompose
al ions via any combination of ionic and covalent bonds. Di- to RO and ROO and subsequently can trigger reactions
lute aqueous solutions may be neutral, acidic, or alkaline. with the API and/or the excipients (e.g., hydrocarbons) to
Edetic acid and its salts are incompatible with strong oxidiz- form hydroxyl acids, keto acids, and aldehydes that can
ers, strong bases, and polyvalent metal ions (e.g., copper have further undesirable effects. Note that hydroperoxides
and nickel). Specific agents are selected for a formulation are not solely the reaction products of oxidative mecha-
based on their solubility, affinity for the target metal ion, nisms within a formulation. Residual amounts of hydroper-
and stability. Edetate salts are more soluble than the free oxides also can be found in commonly used excipients like
acid. Unlike other edetate salts and the free acid, edetate polyethylene glycols, polyvinlypyrrolidone, and polysor-

bates. The initiation phase generally is slow and has a limi- Functional Category: Sweetening Agent
ted effect on the quality of the finished product. The propa-
gation phase, in contrast, involves rapid, irreversible degra- Description: Sweetening agents are used to sweeten oral
dation of chemical species. dosage forms and to mask unpleasant flavors. See Functional
Functional Mechanism: Antioxidants can be grouped by Category: Flavor and Fragrance for more details.
their mode of action. Phenolic antioxidants that block free Functional Mechanism: Sweetening agents bind to recep-
radical chain reactions also are known as true or primary an- tors on the tongue that are responsible for the sensation of
tioxidants. This group consists of monohydroxy or polyhy- sweetness. The longer the sweetener molecule remains at-
droxy phenol compounds with ring substitutions. They have tached to the receptor, the sweeter the substance is per-
very low activation energy to donate hydrogen atom(s) in ceived to be. The standard for sweetness is sucrose.
exchange for the radical electrons that are rapidly delocal- Physical Properties: The primary physical properties rele-
ized by free radicals. By accepting the radical electrons, they vant to sweeteners relate to their compatibility with the oth-
stabilize free radicals. The reaction yields antioxidant free er ingredients in the formulation (e.g., acidic ingredients),
radicals that also can react with lipid free radicals to form processing conditions (e.g., heating), particle size and distri-
other stable compounds. Thus they can block oxidative bution, moisture content, isomerism, sweetness, and taste-
chain reactions both in the initiation and propagation masking capability. These properties may be formulation de-
stages. Because of their solubility behavior, phenolic antioxi- pendent.
dants are most effective in protecting oils and oil-soluble ac- Chemical Properties: Sweeteners can be divided into
tives against oxidative stress. Reducing agents generally are three main groups: sugars (which have a ring structure),
water-soluble antioxidants (e.g., L-ascorbic acid) with lower sugar alcohols (sugars that do not have a ring structure),
General Chapters
redox potential than the drug or the excipient they are pro- and artificial sweeteners. All sweeteners are water soluble.
tecting. They delay the onset and the rate of oxidative reac- The stability of many sweeteners is affected by pH and other
tions by sacrificially reacting with oxygen and other reactive ingredients in the formulation. Some sweeteners may cata-
species. The oxygen-scavenging potential of the reducing lyze the degradation of some active ingredients, especially
agents may be sensitive to pH and also can be negatively af- in liquids and in cases in which the manufacturing processes
fected in the presence of trace metals. Chelating agents involve heating.
bind with free metals (Cu+, Cu2+, Fe2+, and Fe3+) that may be General Chapters: The following general chapters may
present in trace amounts in the formulation. The newly be useful in ensuring consistency in selected sweetening
formed complex ions are nonreactive. Chelating agents functions: Light Diffraction Measurement of Particle Size 429,
therefore remove the capacity of the metal catalysts to par- Loss on Drying 731, Melting Range or Temperature 741,
ticipate in oxidative reactions that occur during the propa- Optical Rotation 781, and Water Determination 921.
gation stage. Other Information: Products that contain aspartame must
The utility of antioxidants can be maximized by synergis- include a warning on the label stating that the product con-
tic use of one or two primary antioxidants along with reduc- tains phenylalanine. Sugar alcohols have a glycemic index
ing and chelating agents. The combined effect often is well below that of glucose. However, sorbitol is slowly me-
greater than the sum of the individual effects of each antiox- tabolized to fructose and glucose, which raises blood sugar
idant (synergistic effect). levels. Sugar alcohols in quantities generally greater than
Physical Properties: Solubility of the antioxidant should 20 g/day act as an osmotic laxative, especially when they
be greatest in the formulation phase (oily, aqueous, or are contained in a liquid formulation. Preservative systems
emulsion interface) where the drug substance is most solu- should be carefully chosen to avoid incompatibility with the
ble. The temperature at which the antioxidant decomposes sweetener, and some sweeteners are incompatible with cer-
is critical for autoclaved preparations where loss of antioxi- tain preservatives.
dant activity may occur. Stability of the antioxidant also
must be considered and may be a function of pH and pro- SEMISOLIDS, TOPICALS, AND
cessing conditions. Metal ions may react with propyl gallate SUPPOSITORIES
to form colored complexes. At alkaline pH, certain proteins
and sodium salts may bring about discoloration of tert-bu- Functional Category: Suppository Base
tylhydroquinone.
Chemical Properties: Activation energy, oxidationreduc- Description: Suppository bases are used in the manufac-
tion potential, and stability at different formulation (e.g., ture of suppositories (for rectal administration) and pessaries
pH) and processing (e.g., heat) conditions are important (for vaginal administration). They can be hydrophobic or
chemical properties. If the dosage form's expected shelf life hydrophilic.
depends on the antioxidant's function, the concentration Functional Mechanism: Suppositories should melt at just
must be factored in and periodically assessed to ensure that below body temperature (37), thereby allowing the drug
a sufficient amount of antioxidant remains throughout the to be released either by erosion and partition if the drug is
product shelf life. dissolved in the base or by erosion and dissolution if the
General Chapters: The following general chapters may drug is suspended in the base. Hard fat suppository bases
be useful for assessing selected excipient antioxidant func- melt at approximately body temperature. Hydrophilic sup-
tions: Iron 241, Chromatography 621, Crystallinity 695, pository bases also melt at body temperature and typically
Melting Range or Temperature 741, Specific Surface Area also dissolve or disperse in aqueous media. Thus release
846, and Water Determination 921. takes place via a combination of erosion and dissolution.

Physical Properties: The important physical characteristic rheological profiles of their dispersions are non-Newtonian.
of suppository bases is melting range. In general suppository Dispersions of these excipients display viscoelastic proper-
bases melt between 27 and 45. However, individual bases ties. The molecular weight distribution and polydispersity of
usually have a much narrower melting range within these the macromolecular excipients in this category are impor-
temperature boundaries, typically 23. The choice of a tant criteria for their characterization.
particular melting range is dictated by the influence of the Chemical Properties: The majority of the suspending and
other formulation components on the melting range of the viscosity-increasing agents are (1) hydrophilic carbohydrate
final product. macromolecules (acacia, agar, alginic acid, carboxymethyl-
Chemical Properties: Hard fat suppository bases are mix- cellulose, carrageenans, dextrin, gellan gum, guar gum, hy-
tures of semisynthetic triglyceride esters of longer-chain fat- droxyethyl cellulose, hydroxypropyl cellulose, hypromellose,
ty acids. They may contain varying proportions of mono- maltodextrin, methylcellulose, pectin, propylene glycol algi-
and diglycerides and also may contain ethoxylated fatty nate, sodium alginate, starch, tragacanth, and xanthan
acids. They are available in many different grades that are gum) and (2) noncarbohydrate hydrophilic macromole-
differentiated by melting range, hydroxyl number, acid val- cules, including gelatin, povidone carbomers, polyethylene
ue, iodine value, solidification range, and saponification oxide, and polyvinyl alcohol. Minerals (e.g., attapulgite,
number. bentonite, magnesium aluminum silicate, and silicon diox-
Hydrophilic suppository bases are mixtures of hydrophilic ide) comprise the second-largest group of suspending and
semisolid materials that in combination are solid at room viscosity-increasing agents. Aluminum monostearate is the
temperature and yet release the drug by melting, erosion, one non-macromolecular, nonmineral excipient in this func-
and dissolution when administered to the patient. Hydro- tional category. It consists chiefly of variable proportions of
General Chapters
philic suppository bases have much higher levels of hydroxyl aluminum monostearate and aluminum monopalmitate.
groups or other hydrophilic groups than do hard fat suppo- General Chapters: The following general chapters may
sitory bases. Polyethylene glycols that show appropriate be useful in ensuring consistency in selected viscosity-in-
melting behavior are examples of hydrophilic suppository creasing functions: ViscosityCapillary Viscometer Methods
bases. 911, Rotational Rheometer Methods 912, and Rolling Ball
General Chapters: The following general chapters may Viscometer Method 913.
be useful in ensuring consistency in selected suppository
base functions: Fats and Fixed Oils 401, Congealing Temper- Functional Category: Ointment Base
ature 651, Melting Range or Temperature 741, and Phar-
maceutical Dosage Forms 1151. Description: An ointment is a viscous semisolid prepara-
Other Information: Some materials included in supposito- tion used topically on a variety of body surfaces. An oint-
ries based on hard fats have much higher melting ranges. ment base is the major component of an ointment and con-
These materials typically are microcrystalline waxes that help trols its physical properties.
stabilize molten suspension formulations. Suppositories also Functional Mechanism: Ointment bases serve as vehicles
can be manufactured from glycerinated gelatin. for topical application of medicinal substances and also as
emollients and protective agents for skin.
Functional Category: Suspending and/or Physical Properties: Ointment bases are liquids with a rel-
Viscosity-increasing Agents atively high viscosity so that solids can be suspended as a
stable mixture.
Description: Suspending and viscosity-increasing agents Ointment bases are classified as (1) oleaginous ointment
are used in pharmaceutical formulations to stabilize disperse bases that are anhydrous, do not absorb water readily, are
systems (e.g., suspensions or emulsions), to reduce the rate insoluble in water, and are not removable by water (e.g.,
of solute or particulate transport, or to decrease the fluidity petrolatum); (2) absorption ointment bases that are anhy-
of liquid formulations. drous and absorb some water but are insoluble in water and
Functional Mechanism(s): A number of mechanisms con- are not water removable (e.g., lanolin); (3) emulsion oint-
tribute to the dispersion stabilization or viscosity-increasing ment bases that are water-in-oil or oil-in-water emulsions
effect of these agents. The most common is the increase in and are hydrous, absorb water, and are insoluble in water
viscositybecause of the entrapment of solvent by macro- (e.g., creams of water, oils, waxes, or paraffins); and (4) wa-
molecular chains or clay plateletsand the disruption of ter-soluble ointment bases that are anhydrous and absorb
laminar flow. Other mechanisms include gel formation via a water and are soluble in water and are water removable
three-dimensional network of excipient molecules or parti- (e.g., polyethylene glycol).
cles throughout the solvent continuum and steric stabiliza- Chemical Properties: Ointment bases are selected to be
tion wherein the macromolecular or mineral component in inert and chemically stable.
the dispersion medium adsorbs to the surfaces of particles General Chapters: The following general chapters may
or droplets of the dispersed phase. The latter two mecha- be useful in ensuring consistency in selected ointment base
nisms increase formulation stability by immobilizing the dis- functions: Congealing Temperature 651, ViscosityCapillary
persed phase. Viscometer Methods 911, Rotational Rheometer Methods
Physical Properties: Each of the mechanismsincreased 912, and Rolling Ball Viscometer Method 913.
viscosity, gel formation, or steric stabilizationis a manifes-
tation of the rheological character of the excipient. Because
of the molecular weights and sizes of these excipients, the

Functional Category: Stiffening Agent the touch. Fluidity generally is imparted by shorter chain
length and higher degree of unsaturation in the fatty acid
Description: A stiffening agent is an agent or a mixture of moiety. The degree of branching of ester bonds also influen-
agents that increases the viscosity or hardness of a prepara- ces the emollient properties.
tion, especially in ointments and creams. General Chapter: The following general chapter may be
Functional Mechanism: In general, stiffening agents are useful in ensuring consistency in selected emollient func-
high melting point solids that increase the melting point of tions: Fats and Fixed Oils 401.
ointments or increase the consistency or body of creams.
Stiffening agents can be either hydrophobic (e.g., hard fat PARENTERALS
or paraffin) or hydrophilic (e.g., polyethylene glycol, high
molecular weight). Functional Category: Pharmaceutical Water
Physical Properties: The primary physical property rele-
vant to stiffening agents is their high melting point or melt- Description: Water is used as a solvent, vehicle, diluent,
ing range. Typical melting ranges for stiffening agents range or filler for many drug products, especially those supplied in
from 43 to 47 (cetyl esters wax), 53 to 57 (glyceryl dis- liquid form. These may include injectable drugs, ophthalmic
tearate), 69 to 74 (glyceryl behenate), and 85 to 88 (cas- drugs, inhalation solutions, and others. Water also is a vehi-
tor oil, hydrogenated). cle for buffers and antimicrobial agents and is a volume ex-
Chemical Properties: Stiffening agents comprise a diverse pander for infusion solutions.
group of materials that include glycerides of saturated fatty USP includes monographs for eight grades of pharma-
acids, solid aliphatic alcohols, esters of saturated fatty alco- ceutical waters. Water for Injection is intended for use in the
General Chapters
hols and saturated fatty acids, saturated hydrocarbons, preparation of parenteral solutions. Where used for the
blends of fatty alcohols and a polyoxyethylene derivative of preparation of parenteral solutions subject to final steriliza-
a fatty acid ester of sorbitan, and higher ethylene glycol pol- tion, use suitable means to minimize microbial growth, or
ymers. first render the Sterile Water for Injection and, thereafter,
General Chapters: The following general chapters may protect it from microbial contamination. For parenteral solu-
be useful in ensuring consistency in selected stiffening agent tions that are prepared under aseptic conditions and are not
functions: Congealing Temperature 651, Melting Range or sterilized by appropriate filtration or in the final container,
Temperature 741, ViscosityCapillary Viscometer Methods first render the Sterile Water for Injection and, thereafter,
911, Rotational Rheometer Methods 912, and Rolling Ball protect it from microbial contamination. Do not use Purified
Viscometer Method 913. Water in preparations intended for parenteral administra-
Other Information: Some of the materials included as tion. Where used for sterile dosage forms other than for pa-
stiffening agents increase the water-holding capacity of oint- renteral administration, process the article to meet the re-
ments (e.g., petrolatum) or function as co-emulsifiers in quirements under Sterility Tests 71, or first render the Ster-
creams. Examples include stearyl alcohol and cetyl alcohol. ile Purified Water and, thereafter, protect it from microbial
contamination. USP also contains references to other types
Functional Category: Emollient of water, such as distilled water, deionized water, and others
according to specific use as summarized in general informa-
Description: Emollients are excipients used in topical tion chapter Water for Pharmaceutical Purposes 1231.
preparations to impart lubrication, spreading ease, texture, Functional Mechanism: A solvent is able to dissolve mate-
and softening of the skin and to counter the potentially dry- rials because it is able to disrupt the intermolecular attrac-
ing/irritating effect of surfactants on the skin. tive forces and to allow the individual molecules to become
Functional Mechanism: Emollients help form a protective dispersed throughout the bulk solvent. Water is a favored
film and maintain the barrier function of the epidermis. solvent and vehicle in the majority of applications because it
Their efficacy may be described by three mechanisms of ac- is easy to handle, safe, and inexpensive.
tion: protection against the delipidizing and drying effects Physical Properties: Water is liquid at normal temperature
of surfactants, humectancy due to occlusion (by providing a and pressure. It forms ice at the freezing temperatures of 0
layer of oil on the surface of the skin, emollients slow water or lower, and it vaporizes at a normal boiling temperature of
loss and thus increase the moisture-retention capacity of the 100, depending on atmospheric pressure. Vaporized water
stratum corneum), and lubricity, adding slip or glide to the in the form of steam is used for sterilization purposes be-
preparation. cause the latent heat of steam is significantly higher than
Physical Properties: Emollients impart one or more of the that of boiling water.
following attributes to a pharmaceutical preparation: Chemical Properties: Water in its pure form is neutral in
spreading capacity, pleasant feel to the touch, softness of pH and has very low conductivity and total organic carbon
the skin, and indirect moisturization of the skin by prevent- (TOC). However, pH, conductivity, and TOC are affected by
ing transepidermal water loss. storage conditions and exposure to gases in the air. Expo-
Chemical Properties: Emollients are either oils or are de- sure to atmospheric carbon dioxide lowers water's pH. Stor-
rived from components of oils as esters of fatty acids. De- age in plastic containers may increase the TOC content of
pending on the nature of its fatty acid ester, an emollient water over time. Water stored in glass containers may result
may be liquid, semisolid, or solid at room temperature. Gen- in an increase in pH and conductivity over time.
erally, the higher the molecular weight of the fatty acid moi- General Chapters: The following general chapters may
ety (carbon chain length) the richer the feel and softness of be useful in ensuring consistency in selected pharmaceutical

water functions: Injections 1, Bacterial Endotoxins Test 85, not relevant to the final properties of the lyophilized formu-
Total Organic Carbon 643, Water Conductivity 645, Water lation. The solubilization process and the drying process can
for Hemodialysis Applications 1230, and Water for Pharma- be facilitated by the use of volatile cosolvents such as etha-
ceutical Purposes 1231. nol or tertiary butyl alcohol.
The physical properties that are essential to product per-
Functional Category: Bulking Agent formance during and after lyophilization include the glass
transition temperature (Tg) of the amorphous frozen con-
Description: Bulking agents used in lyophilized pharma- centrate before drying, the glass transition temperature of
ceuticals, also referred to as freeze-dried products, include the final dried formulation cake, and the eutectic melting
various saccharides, sugar alcohols, amino acids, and poly- temperature of the crystalline bulking agent with ice. The
mers. The primary function of bulking agents is to provide a glass transition temperature (Tg) of the formulation depends
pharmaceutically elegant freeze-dried cake with noncollapsi- on the glass transition temperatures of the individual com-
ble structural integrity that will reconstitute rapidly before ponents, concentrations, and interactions. Although approx-
administration. In addition, bulking agents are selected to imations can be made based on reported transition temper-
prevent product loss caused by blow-out during freeze dry- atures for individual components, current practice includes
ing, to facilitate efficient drying, and to provide a physically the measurement of formulation glass transition tempera-
and chemically stable formulation matrix. Complementary tures by thermal analysis or freeze-drying microscopy.
combinations of bulking agents, e.g., mannitol and a poly- The physical states of the bulking agent during and after
mer, frequently are used to improve performance. lyophilization are important physical properties. Both formu-
Functional Mechanisms: A bulking agent that readily crys- lation composition and processing parameters play roles in
General Chapters
tallizes during lyophilization helps maintain the structural in- determining whether the bulking agent is amorphous or
tegrity of the cake formed during primary drying, thereby takes a specific crystalline form. Rate of freezing, drying
preventing macroscopic collapse and maintaining pharma- temperatures, and annealing are among the important
ceutical elegance. Microscopic collapse of amorphous com- process parameters used to control the physical state of the
ponents in the formulation can still occur (with some poten- formulation and its components. Moisture retention and ad-
tially undesirable results) but does not result in macroscopic sorption after lyophilization also can contribute to formula-
collapse or meltback if the bulking agent's properties and tion instability and poor reconstitution.
concentration are adequate. The bulking agent also should Chemical Properties: Reactivity of the bulking agent with
possess a high eutectic melting temperature with ice to per- other formulation components, especially the active ingredi-
mit relatively high primary drying temperatures with com- ent, may be critical. Reducing sugars are well known to re-
mensurate rapid and efficient drying and subsequent rapid act with aromatic and aliphatic amines. Glycols may contain
reconstitution upon usage. Functional cake-forming exci- trace peroxide levels that can initiate oxidative degradation.
pients such as mannitol frequently are used because they The ability of saccharides and polyhydric alcohols to form
crystallize during freezing, thereby allowing efficient drying hydrogen bonds to biopolymers may play a role in their lyo-
and the formation of a structurally robust and stable cake. protection effects.
Amino acids and cosolvents also have been used to achieve General Chapters: The following general chapters may
this effect. Most biopolymer active ingredients remain amor- be useful in ensuring consistency in selecting bulking agent
phous upon freeze-drying, and bulking agents such as disac- functions: Injections 1; Crystallinity 695; Characterization
charides can function as lyoprotectants by helping to main- of Crystalline Solids by Microcalorimetry and Solution Calorime-
tain a stable amorphous phase during freezing and drying try 696; Thermal Analysis 891; Biotechnology-Derived Arti-
to prevent denaturation. Solubility enhancement of an in- cles 1045, Product Formulation; Pharmaceutical Dosage
soluble crystalline active ingredient sometimes is achieved Forms 1151; and WaterSolid Interactions in Pharmaceutical
with the use of a biopolymer that enhances solubility or pre- Systems 1241.
vents crystallization during lyophilization or subsequent re-
constitution. Bulking agents also are selected on the basis of Functional Category: Tonicity Agent
biocompatibility, buffering capability, and tonicity-modify-
ing properties. Description: To avoid crenation or hemolysis of red blood
Lyoprotectant properties of bulking agents (i.e., those cells and to mitigate pain and discomfort if solutions are in-
that protect the drug substance during lyophilization) typi- jected or introduced into the eyes and nose, solutions
cally are achieved by the formation of a highly viscous glassy should be made isotonic. This requires that the effective os-
phase that includes the biopolymer drug substance in com- motic pressure of solutions for injection must be approxi-
bination with low molecular weight amorphous saccharides mately the same as that of blood. When drug products are
such as sucrose, trehalose, or certain amino acids. A typical prepared for administration to membranes such as eyes or
approach for protein pharmaceutical formulation is to com- nasal or vaginal tissues, solutions should be made isotonic
bine a sugar alcohol that readily crystallizes and an amor- with respect to these tissues.
phous diluent. This mixture acts as a lyoprotectant. Functional Mechanism: Tonicity is equal to the sum of
Physical Properties: Bulking agents are dissolved in aque- the concentrations of the solutes that have the capacity to
ous solution before lyophilization. Therefore chemical purity exert an osmotic force across a membrane and thus reflects
and the absence of bioburden and pyrogenic materials are overall osmolality. Tonicity applies to the impermeant sol-
essential properties of the excipient. However, the physical utes within a solventin contrast to osmolarity, which takes
form and particle properties of the excipient generally are into account both permeant and impermeant solutes. For

example, urea is a permeant solute, meaning that it can two systems. In such cases, as the headspace increases the
pass through the cell membrane freely and is not factored propellant comes out of solution to help to maintain the
when determining the tonicity of a solution. In contrast, so- pressure of the system.
dium chloride is impermeant and cannot pass through a In metered-dose inhalers the propellant has a liquid phase
membrane without the help of a concentration gradient that is an integral part of the dispensed pharmaceutical
and therefore contributes to a solution's tonicity. product. Actuating the metering valve dispenses a defined
Physical Properties: Solutions of sodium chloride, dex- volume of the liquid contents. The propellant spontaneously
trose, and Lactated Ringer's are common examples of phar- boils and provides atomizing and propulsive force. A pre-
maceutical preparations that contain tonicity agents. Not all dictable change in active concentration occurs from the be-
solutes contribute to the tonicity, which in general depends ginning to the end of the container life cycle as the liquid
only on the number of solute particles present in a solution, phase of the propellant vaporizes to reestablish the equilibri-
not the kinds of solute particles. For example, mole for um pressure of the system as the headspace increases.
mole, sodium chloride solutions display a higher osmotic Physical Properties: Propellants have boiling points well
pressure than glucose solutions of the same molar concen- below ambient temperatures. A propellant's density for dis-
tration. This is because when glucose dissolves it remains perse systems and its solubility properties may be significant
one particle, but when sodium chloride dissolves it becomes considerations when one selects a propellant. Apaflurane
two particles: Na+ and Cl. Several methods are available to and norflurane have liquid-phase densities that are greater
calculate tonicity. than that of water. Hydrocarbon propellants (butane, isobu-
Chemical Properties: Tonicity agents may be present as tane, and propane) and dimethyl ether have liquid-phase
ionic or nonionic types. Examples of ionic tonicity agents are densities that are less than that of water.
General Chapters
alkali metal or earth metal halides such as CaCl2, KBr, KCl, Chemical Properties: Propellants typically are stable mate-
LiCl, NaI, NaBr or NaCl, Na2SO4, or boric acid. Nonionic rials. The hydrocarbon propellants (butane, isobutene, and
tonicity agents include glycerol, sorbitol, mannitol, propy- propane) and dimethyl ether are all flammable materials.
lene glycol, or dextrose. Sodium or potassium chloride and Apaflurane, carbon dioxide, nitrogen, and norflurane are
dextrose commonly are added to adjust tonicity. nonflammable. Nitrous oxide is not flammable but supports
General Chapters: The following general chapters may combustion. Chlorofluorocarbon propellants are considered
be useful in ensuring consistency in selected tonicity agent to be ozone-depleting substances. Their use in foods, drugs,
functions: Injections 1; Osmolality and Osmolarity 785; Bio- devices, or cosmetics is regulated by 21 CFR 2.125. Albuter-
technology-Derived Articles 1045, Product Formulation; and ol metered-dose inhalers formulated with chlorofluorocar-
Pharmaceutical Calculations in Prescription Compounding bon propellants have not been available in the United States
1160. since January 1, 2009.
General Chapters: The following general chapters may
AEROSOLS be useful in ensuring consistency in selected propellant
functions: Aerosols, Nasal Sprays, Metered-Dose Inhalers, and
Functional Category: Propellant Dry Powder Inhalers 601, Chromatography 621, and Water
Determination 921.
Description: Propellants are compounds that are gaseous
under ambient conditions. They are used in pharmaceuticals DRY POWDER INHALERS
(nasal sprays and respiratory and topical formulations), cos-
metics, and foods to provide force to expel contents from a Dry powder inhalers (DPIs) commonly contain few func-
container. tional excipients. For example, DPIs may contain a carrier
Functional Mechanism: Propellant substances are low and may use a capsule shell. Other useful excipients include
boiling point liquids or compressed gases that are relatively glidants to improve flow during manufacture of the active
inert toward active ingredients and excipients. They can be carrier mix. A discussion of the use of a lubricant can be
characterized by three properties: whether they form a liq- found in the tablet or capsule sections above in addition to
uid phase at ambient temperatures and useful pressures, the carrier properties discussed below.
their solubility and/or miscibility in the rest of the formula-
tion, and their flammability. Their performance is judged by Functional Category: Carrier
their ability to provide adequate and predictable pressure
throughout the usage life of the product. Description: Carriers are used to help deposit the active
Propellants that have both a liquid and gas phase in the ingredient in the lung and may have a secondary role in di-
product provide consistent pressures as long as there is liq- luting the active to ensure that dosages can be properly me-
uid phase presentthe pressure in the headspace is main- tered.
tained by the equilibrium between the two phases. In con- Functional Mechanism: The carriers are used to promote
trast, the pressure provided by propellants that have no liq- drug deposition into the lungs for better penetration or ab-
uid phase may change relatively rapidly as the contents of sorption in the appropriate lung location. In addition, the
the container are expelled. As the headspace becomes larg- carrier is used to decrease the concentration of the active so
er, the pressure within the container falls proportionately. the latter is adequately dosed in a uniform manner.
Propellants that have no liquid phase but have significant Physical Properties: The physical properties of carriers in-
pressure-dependent solubility in the rest of the formulation clude appropriate morphology, hydration state, flowability,
have performance characteristics between those of the other surface energy, and particle size distribution.

Chemical Properties: Carriers must have suitable purity, Functional Mechanism: Antimicrobial preservatives work
including low microbial content and no extraneous proteins by a number of mechanisms. Quaternary ammonium com-
or impurities, in order to avoid interactions with the pa- pounds affect microbial cell membranes via charge interac-
tient's immune system. tions with phospholipids, leading to disruption of the cell
General Chapters: The following general chapters may membrane. Parabens also disrupt cell membrane integrity.
be useful in ensuring consistency in selected carrier func- Alcohols such as chlorbutanol and benzyl alcohol work via
tions: Microbiological Examination of Nonsterile Products: Mi- lipid (membrane) solvation and protein denaturation. N-[3-
crobial Enumeration Tests 61, Microbiological Examination of (dimethylamino)propyl]tetradecanamide has greater antimi-
Nonsterile Products: Tests for Specified Microorganisms 62, crobial effectiveness toward fungi and protozoa than do
Heavy Metals 231, Light Diffraction Measurement of Particle quaternary ammonium compounds. Like quaternary ammo-
Size 429, Nitrogen Determination 461, Aerosols, Nasal nium compounds, it disrupts plasma membrane integrity.
Sprays, Metered-Dose Inhalers, and Dry Powder Inhalers 601, Sorbic acid works by reduction of the sulfhydryl groups of
Bulk Density and Tapped Density of Powders 616, Crystallini- proteins. Hypochlorite is a strong oxidizing agent. Reactions
ty 695, Characterization of Crystalline Solids by Microcalorim- of chloramines with the amine groups of proteins can cause
etry and Solution Calorimetry 696, Density of Solids 699, changes in conformation and thus loss of protein activity.
Loss on Drying 731, Optical Microscopy 776, Particle Size Chlorine released by these reactions can react with cellular
Distribution Estimation by Analytical Sieving 786, Powder constituents such as proteins and lipid. Polyaminopropyl bi-
Fineness 811, Spectrophotometry and Light-Scattering 851, guanide accumulates in the cell membrane, blocking the
Water Determination 921, Characterization of Crystalline and entry of nutrients.
Partially Crystalline Solids by X-ray Powder Diffraction (XRPD) Physical Properties: To serve as an ophthalmic antimicro-
General Chapters
941, and Powder Flow 1174. bial preservative, a compound should be at least sparingly
soluble in water, thus providing an appreciable range of
Functional Category: DPI Capsule Shells usable concentrations.
Chemical Properties: A preservative must be compatible
Description: Capsule shells sometimes are used in DPIs. with the active and inactive ingredients of the finished prod-
The capsule shell is used to contain the dosage amount and uct. For example, quaternary ammonium compounds are
safeguard the inhalable powder in a DPI. incompatible with anionic surfactants. Benzyl alcohol is in-
Functional Mechanism: The use of capsule shell may compatible with oxidizing agents. Chlorbutanol is incom-
speed pharmaceutical development because it does not re- patible with some non-ionic surfactants. Compatibility be-
quire a complex device and can use premeasured drug sub- tween compounds varies with the pH of the formula. The
stance or formulation. A capsule shell must not fragment in- preservative should be stable in solution at the formulation
to inhalable portions and should remain intact after the shell pH, usually from 5 to 8. Formulation pH can affect preserva-
breaks to expose the powder for inhalation. tive activity by influencing how the preservative partitions
Physical Properties: Capsule shell composition generally is between the formulation and microbes and how the preser-
dictated by the drug substance's moisture content, brittle- vative interacts with the target sites of the microbial cell. For
ness, and electrostatic interactions with the inhalable pow- example, preservatives that must pass through cell mem-
der. branes before exerting activity should be formulated at a pH
General Chapters: The following general chapters may at which the preservative is mainly in its un-ionized state.
be useful in ensuring consistency in selected DPI capsule General Chapters: The following general chapters may
shell functions: Microbiological Examination of Nonsterile be useful in ensuring consistent functions of selected antimi-
Products: Microbial Enumeration Tests 61, Microbiological Ex- crobial preservatives: Antimicrobial Effectiveness Testing 51,
amination of Nonsterile Products: Tests for Specified Microor- Sterility Tests 71, Bulk Density and Tapped Density of Pow-
ganisms 62, Arsenic 211, Heavy Metals 231, Residue on ders 616, Chromatography 621, Density of Solids 699,
Ignition 281, Aerosols, Nasal Sprays, Metered-Dose Inhalers, Loss on Drying 731, Pharmaceutical Dosage Forms 1151,
and Dry Powder Inhalers 601, Disintegration 701, Dissolu- Powder Flow 1174, Sterilization and Sterility Assurance of
tion 711, Loss on Drying 731, Optical Microscopy 776, Compendial Articles 1211, and Validation of Microbial Recov-
Particle Size Distribution Estimation by Analytical Sieving 786, ery from Pharmacopeial Articles 1227.
Uniformity of Dosage Units 905, Water Determination 921,
ColorInstrumental Measurement 1061, Gel Strength of Gel- Functional Category: Polymers for Ophthalmic
atin 1081, and WaterSolid Interactions in Pharmaceutical Use
Systems 1241.
Description: Polymers are used in ophthalmic prepara-
OPHTHALMIC PREPARATIONS tions to enhance the retention of active ingredients by re-
ducing the amount of product that is lost from the eye
Functional Category: Antimicrobial when the patient blinks. In addition, polymers also can be
Preservatives components of artificial tears. Most water-soluble polymers
commonly used as film-forming agents in ophthalmic prep-
Description: The preservative system acts as a safeguard arations can be categorized as follows: (1) cellulose-based
to kill or inhibit the growth of microorganisms that may be substances, (2) biologically produced gums, and (3) syn-
inadvertently introduced in the product after the manufac- thetically produced substances.
turing process either during storage or use.

Functional Mechanism: Film-forming agents for ophthal- hydrogen bonding) in nature, although there is the possibil-
mic preparations can enhance the retention of active ingre- ity of mechanical interaction via the interlocking of micro-
dients in the eye by a number of mechanisms. They can be scopic asperities.
used as simple viscosity-modifying agents to reduce the flow Physical Properties: In general, the adhesives used in
of the product, thereby slowing the rate of product loss af- transdermals or skin patches are pressure-sensitive materials
ter administration. They also can be used to form films on whose performance is best characterized by physical test
the surface of the eye so the drug remains deposited on the methods for tackiness and viscoelasticity of the adhesive per
eye after the liquid portion of the product has been expelled se and viscosity of a solution of the adhesive.
or has evaporated. These agents can be formulated to pro- Chemical Properties: In transdermals, the most widely
duce a film or a gel when the product warms to body tem- used pressure-sensitive adhesives are acrylic, rubber, and sili-
perature (upon contacting the surface of the eye), mixing cone polymers. Acrylic polymer adhesives include various es-
with the tear film, and/or evaporating. Some polymers have ters of acrylic or methacrylic acid, acrylamide, methacryla-
shown bio-adhesive properties on the cornea and can in- mide, N-alkoxyalkyl, or N-alkyl-acrylamides. Polyisobutylenes
crease drug retention. and polysiloxanes are among the most common rubber-
Physical Properties: To serve as an ophthalmic film-form- based and silicone-based adhesives, respectively. The molec-
ing agent, a polymer typically must be at least slightly solu- ular weight and compositional distribution of the polymers
ble in water, thus providing an appreciable range of usable are critical to the replication of the adhesive's efficacy from
concentrations. Such polymers often increase viscosity or batch to batch.
exhibit film- or gel-forming properties when warmed to General Chapters: The following general chapters may
body temperature, when exposed to the pH or solute com- be useful in evaluating the suitability of adhesives employed
General Chapters
position and ionic strength of the tear film, or when the in transdermals: Tensile Strength 881 and ViscosityCapilla-
product evaporates. ry Viscometer Methods 911.
Chemical Properties: The finished product viscosity range
that can be obtained with a film-forming agent is related to Functional Category: Film-forming Agent
its chemical structure and molecular weight. Functional
groups such as the pyruvate and acetate groups of xanthan Description: Film-forming agents used as the formulation
gum can affect the relationship between viscosity and solu- matrix of topical drug delivery systems (e.g., transdermals or
tion pH and ionic strength and also can determine film- and skin patches) or in conjunction with such systems comprise
gel-forming properties. Polymer charge can influence inter- a flexible, nontacky but adherent film, in whole or in part,
actions with the mucous layer of the eye. Molecular confor- applied to the skin surface.
mation, chain mobility, and degree of cross-linking also can Functional Mechanism: Film formation results from the
affect the degree of swelling and thus performance. progressive loss of solvent (or dispersion medium) from a
General Chapters: The following general chapters may solution (or dispersion) of a film-forming agent, whether in
be useful in ensuring consistent functions of polymers for particulate or molecularly dispersed form. Solvent (or disper-
ophthalmic use: Bulk Density and Tapped Density of Powders sion medium) loss leads to closer molecular or particulate
616, Chromatography 621 (in particular see Size-exclusion packing and increased interaction among the film-forming
Chromatography), Density of Solids 699, Loss on Drying agent molecules or particles. Ultimately, a continuous film is
731, Particulate Matter in Ophthalmic Solutions 789, Vis- formed as a result of increased molecular entanglement or
cosityCapillary Viscometer Methods 911, Rotational Rhe- particulate sintering.
ometer Methods 912, Rolling Ball Viscometer Method 913, Physical Properties: Properties critical to successful film
Pharmaceutical Dosage Forms 1151, and Powder Flow formation include the film-forming agent's glass transition
1174. In addition, the general chapters listed under Func- temperature (Tg), the viscosity of the solution or dispersion,
tional Category: Film-forming Agents also may be appropriate and the surface characteristics of the substrate. Viscoelastic
for the evaluation of polymers for ophthalmic use. properties such as elastic modulus, viscous modulus, and in-
trinsic or complex viscosity describe functional characteris-
TRANSDERMALS AND PATCHES tics such as adhesion for a pressure-sensitive adhesive com-
ponent. Adhesion to a substrate and tack and shear tests
Functional Category: Adhesive can be used for batch release.
Chemical Properties: Typical film-forming agents are ther-
Description: Topical drug delivery systems (e.g., transder- moplastic or thermosetting high molecular weight polymers
mals or skin patches) require the use of adhesives to main- or copolymers, often in the form of aqueous dispersions or
tain contact between the applied drug delivery system and latex compositions. Cellulosic polymers, vinyl polymers and
the skin. Adhesives can be intercalated as a separate layer copolymers, and acrylic and methacrylic acid polymers and
between the formulation matrix and the skin surface, incor- copolymers frequently are employed in topical delivery sys-
porated as a part of the formulation matrix itself, or applied tems as film-forming agents.
to the periphery of the topical delivery system. General Chapters: The following general chapters may
Functional Mechanism: Adhesion is the tendency of dis- be useful in evaluating the suitability of film-forming agents
similar surfaces to adhere to one another as a result of one employed in transdermals and patches: Thermal Analysis
or more types of interactions. For topical drug delivery sys- 891, ViscosityCapillary Viscometer Methods 911, Rota-
tems, these adhesive interactions generally are chemical tional Rheometer Methods 912, and Rolling Ball Viscometer
(primarily electrostatic) or dispersive (van der Waals and/or Method 913.

RADIOPHARMACEUTICALS necessary to expose chelating groups on the principal li-

gand.
Radiopharmaceuticals commonly contain categories of Physical Properties: Transfer ligands must be readily solu-
excipients that also are used in conventional drugs. For ex- ble in water.
ample, radiopharmaceutical capsules may contain diluents Chemical Properties: Transfer ligands must have rapid
and necessarily use a capsule shell, and parenteral radio- complexation kinetics and must form relatively weak che-
pharmaceuticals may contain pharmaceutical water, di- lates compared to complexation with the principal ligand.
luents, tonicity agents, pH modifiers, antimicrobial preserva- General Chapters: The following general chapters may
tives, chelating and/or complexing agents, and antioxi- be useful in ensuring consistency in selected transfer ligand
dants. Many radiopharmaceuticals differ from conventional functions: Chromatography 621 and Radioactivity 821.
drugs, however, because their preparation (reconstitution)
involves one or more chemical reactions that require unusu- Functional Category: Colloid Stabilizing Agent
al excipients. Furthermore, the self-absorption of emitted ra-
diation may result in the radiolytic decomposition of many Description: Lyophobic colloids tend to clump together
radiopharmaceuticals. Hence, several excipients are used and form large aggregates in order to minimize their sur-
predominately in radiopharmaceutical formulations, al- face-area-to-volume ratio. Colloid stabilizing agents are rela-
though they occasionally may be used for other drugs. tively large lyophilic molecules that coat the surface of each
individual colloid particle and prevent or inhibit clumping.
Functional Category: Reducing Agent Examples of colloid stabilizing agents include gelatin and
dextran.
General Chapters
Description: Reducing agents generally are required for Functional Mechanism: The colloid stabilizing agent coats
technetium Tc 99m radiopharmaceuticals. Technetium Tc the surface of the lyophobic colloid particles, making them
99m, in the chemical form of sodium pertechnetate (+ 7 ox- appear lyophilic. Additionally, the colloid stabilizing agent
idation state), must be reduced to a lower oxidation state so may be charged, thus causing the coated colloid particles to
that it can be chelated or otherwise complexed by the in- repel one another.
tended ligand to form the final Tc 99m radiopharmaceuti- Physical Properties: Colloid stabilizing agents must be
cal. The reducing agent, typically a stannous salt, generally readily soluble in water.
is formulated in the kit for the preparation of the techneti- Chemical Properties: Colloid stabilizing agents must be
um Tc 99m radiopharmaceutical. capable of coating the lyophobic colloid particles, e.g., by
Functional Mechanism: The reducing agent (e.g., stan- electrostatic attraction of an opposite charge.
nous ion) must be present in sufficient quantity to reduce all General Chapters: The following general chapters may
of the technetium atoms to the intended oxidation state but be useful in ensuring consistency in selected colloid stabiliz-
must not produce undesired reduction products or other ing agent functions: Chromatography 621 and Radioactivity
impurities (e.g., stannous hydroxide precipitates). 821.
Physical Properties: Reducing agents (e.g., stannous salts)
must be readily soluble in water. Functional Category: Free Radical Scavenger
Chemical Properties: Reducing agents (e.g., stannous
salts) are sensitive to oxidation by atmospheric oxygen and Description: Radiation interactions with water and other
oxidizing species in solution. Hence, lyophilized contents of molecules frequently produce free radicals. Free radical scav-
kit vials must be filled with a nonoxidative gas such as nitro- engers preferentially interact with oxidative or reductive free
gen or argon. The reducing agent also must be stable at the radicals that otherwise would result in degradation of for-
intended pH of the formulated product. mulation components. In the case of radiopharmaceuticals,
General Chapters: The following general chapters may free radical scavengers can be used to enhance radiochemi-
be useful in ensuring consistency in selected reducing agent cal purity. Examples of free radical scavengers include meth-
functions: Chromatography 621 and Radioactivity 821. ylene blue and aminobenzoic acid.
Functional Mechanism: Free radical scavengers preferen-
Functional Category: Transfer Ligand tially interact with radiolytically produced free radicals be-
fore these free radicals can interact with the radiopharma-
Description: In the preparation of certain radiopharmaceutical and produce radiochemical impurities.
ceuticals, the radiometal (e.g., stannous-reduced techneti- Physical Properties: Free radical scavengers must be readi-
um Tc 99m) is first chelated by a relatively weak chelating ly soluble in water.
ligand and then is transferred to the principal chelating li- Chemical Properties: Free radical scavengers must be ca-
gand or complexing moiety. Examples of such transfer li- pable of preferentially interacting with free radicals without
gands include citrate, gluconate, and tartrate. causing other effects.
Functional Mechanism: Transfer ligands typically undergo General Chapters: The following general chapters may
rapid reactions with reduced technetium to form weak che- be useful in ensuring consistency in selected free radical
lates, thus keeping the reduced technetium in a soluble scavenger functions: Chromatography 621 and Radioactivity
form until it is transferred to the principal ligand. This proce- 821.
dure is especially useful when the kinetics of complexation
with the principal ligand is slow or when a heating step is

770 1061 ColorInstrumental Measurement / General Information USP 37
1061 COLORINSTRUMENTAL
MEASUREMENT
The observed color (see 631 Color and Achromicity) of an

object depends on the spectral energy of the illumination,
the absorbing characteristics of the object, and the visual
sensitivity of the observer over the visible range. Similarly, it
is essential that any instrumental method that is widely ap-
plicable take these same factors into account.
Instrumental methods for measurement of color provide
more objective data than the subjective viewing of colors by
a small number of individuals. With adequate maintenance
and calibration, instrumental methods can provide accurate
and precise measurements of color and color differences
that do not drift with time. The basis of any instrumental
measurement of color is that the human eye has been
shown to detect color via three receptors. Hence, all col-
ors can be broken down into a mixture of three radiant
General Chapters
stimuli that are suitably chosen to excite all three receptors

in the eye. Although no single set of real light sources can
be used to match all colors (i.e., for any three lights chosen,
some colors require a negative amount of one or more of
the lights), three arbitrary stimuli have been defined, with
which it is possible to define all real colors. Through exten-
sive color-matching experiments with human subjects hav- Distribution Coefficients from 400 to 700 nm
ing normal color vision, distributing coefficients have been Once the tristimulus values of a color have been deter-
measured for each visible wavelength (400 nm to 700 nm) mined, they may be used to calculate the coordinates of the
giving the relative amount of stimulation of each receptor color in an idealized three-dimensional color space referred
caused by light of that wavelength. These distribution coef- to as a visually uniform color space. Many sets of color equa-
ficients x, y, z, are shown below. Similarly, for any color the tions have been developed in an attempt to define such a
amount of stimulation of each receptor in the eye is defined space. The equations given in this chapter represent a com-
by the set of Tristimulus values (X, Y, and Z) for that color. promise between simplicity of calculation and conformance
The relationships between the distribution coefficient (see with ideality.
accompanying figure) and the tristimulus values are given in The coordinates of a color in a visually uniform color
the equations space may be used to calculate the deviation of a color from
a chosen reference point. Where the instrumental method is
used to determine the result of a test requiring color com-
parison of a test preparation with that of a standard or
matching fluid, the parameter to be compared is the differ-
ence, in visually uniform color space, between the color of
the blank and the color of the test specimen or standard.
in which
Procedure
The considerations discussed under Spectrophotometry and

is the spectral power of the illuminant, and fl is either the Light-Scattering 851 apply to instrumental color measure-
spectral reflectance (rl) or spectral transmittance (tl) of the ment as well. In the spectrophotometric method, reflec-
material. tance or transmittance values are obtained at discrete wave-
lengths throughout the visible spectrum, a band width of 10
nm or less being used. These values are then used to calcu-
late the tristimulus values through the use of weighting fac-
tors.1 In the colorimetric method, the weighting is per-
formed through the use of filters.
In the measurement of the spectral reflectance of opaque
solids, the angle of viewing is separated from the angle of il-
lumination in such a manner that only rays reflected diffuse-
1 Typical weighting factors are given by ASTM Z58.7.1-1951 as reported in

the Journal of the Optical Society of America, Vol. 41, 1951, pages 431-439.


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62 by ebsc0sa on Tue Sep 09 22:40:12 EDT 2014

1059 EXCIPIENT that accommodates excipient variability, consistently achiev-

Official from August 1, 2014

Official from August 1, 2014

Official from August 1, 2014

Official from August 1, 2014

Official from August 1, 2014

Official from August 1, 2014

791, Tensile Strength 881, Thermal Analysis 891, Viscosi-

Official from August 1, 2014

Official from August 1, 2014

pillary Viscometer Methods 911, Rotational Rheometer Meth-

Description: Solubilizers can be used to dissolve other- Functional Category: Antimicrobial

Official from August 1, 2014

Official from August 1, 2014

Official from August 1, 2014

Official from August 1, 2014

Official from August 1, 2014

Official from August 1, 2014

Official from August 1, 2014

Official from August 1, 2014

Official from August 1, 2014

RADIOPHARMACEUTICALS necessary to expose chelating groups on the principal li-

Official from August 1, 2014

The observed color (see 631 Color and Achromicity) of an

stimuli that are suitably chosen to excite all three receptors

The considerations discussed under Spectrophotometry and

1 Typical weighting factors are given by ASTM Z58.7.1-1951 as reported in

Official from August 1, 2014

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