BRIEFING
1059 Excipient Performance. This proposal is based on the version of the chapter official as of May 1,
2018. It is proposed to revise the chapter as follows based on the Excipient Performance 〈1059〉 Expert
Panel's recommendations:
1. Change the chapter layout. Because one functional category can be used in multiple dosage forms,
remove the dosage form titles under which the functional categories were grouped. Under each
functional category create a section titled Dosage Forms that contains a list of dosage forms in which
the functional category is generally used.
2. Align types of dosage forms listed in the Dosage Forms sections with those described in Pharmaceutical
Dosage Forms 〈1151〉.
3. Divide the pH Modifier (Acidifying/Alkalizing/Buffering Agent) functional category into two functional
categories, Acidifying and Alkalizing Agent and Buffering Agent, respectively.
4. Revise the category title Adhesive to Adhesive (Pressure Sensitive).
5. Combine the Capsule Shell and DPI Capsule Shell categories under Capsule Shell.
6. Add 29 new NF functional categories: Air Displacement, Alcohol Denaturant, Antifoaming or Defoaming
Agent, Antitack Agent, Biodegradable Polymer, Cationic Dendrimer, Crystallization Inhibitor, Desiccant,
Drag-Reducing Agent, Emulsifying Agent, Filtering Aid, Gelling Agent, Humectant, Liposome-Forming
Agent, Muco-adhesive, Opacifier, Permeation Enhancer, Physical Form Stabilizer, Physical-Chemical
Identifier, Polymeric Membrane, Printing Ink Component, Solvent, Sorbent, Stabilizer, Sugar-Coating
Agent, Surfactant, Vehicle, Viscosity-Lowering Agent, and Water-Repelling Agent.
7. Revise the existing functional categories to update any outdated or missing information.
Additionally, it is proposed to revise the USP and NF Excipients, Listed by Functional Category reference
table , in conjunction with this chapter to reflect the proposed changes to the chapter and to provide a list of
excipients grouped on the basis of their functional categories. In addition to updating the current list of
excipients under existing functional categories and adding excipients under new functional categories, it is
proposed to rearrange the reference table to remove references to the dosage forms in which these excipients
are commonly used. The reference table is an extension of this chapter and is a useful tool for the reader to
navigate through the list of functional categories and dosage forms in search of a suitable excipient. The
revision of the reference table has been conducted in parallel with the revision of the chapter and will appear
in PF for public comment. See the Briefing for USP and NF Excipients, Listed by Functional Category and for
Description and Relative Solubility published elsewhere in this PF. Interested parties are encouraged to
comment. The comment period for this revision ends March 31, 2020.
(EXC1: G. Holloway.)
Correspondence Number—C231815
USP-NF DocID: GUID-3BF78364-5934-428D-9FFC-CC3E9AA26AD1_3_en-US
1059 EXCIPIENT PERFORMANCE
Change to read:
INTRODUCTION
Excipients are used in virtually all drug products and are essential for product manufacturing and
performance. Thus, the successful manufacture of a robust product requires the use of well-defined
excipients and manufacturing processes that consistently yield a quality product. Excipients used in drug
products typically are manufactured and supplied in compliance with compendial standards. However, the
effects of excipient properties on the critical quality attributes (CQAs) of a drug product are unique for each
formulation and process and may depend on properties of excipients that are not evaluated in USP or NF
monographs. The effects of variations in excipient material attributes depend on the role of an excipient in a
formulation and the CQAs of the drug product. This general chapter provides a framework for applying
Quality by Design (QBD) principles to excipient quality and performance.
An excipient may be used in different ways or for different purposes in a formulation and may therefore
require different material attributes to achieve the desired performance. Excipient functional categories are
broad, qualitative, and descriptive terms for the purpose an excipient serves in a formulation. A list of
excipients grouped by functional category is included in NF under Front Matter, Excipients, which
summarizes some of the more common purposes that excipients serve in drug products. Also important are
the material attributes of the ingredients that must be identified and controlled to ensure the excipient
performs its intended function in a drug product. A critical material attribute (CMA) is a physical, chemical,
biological, or microbiological property of a material that must be within an appropriate limit, range, or
distribution to ensure that drug product CQAs are maintained throughout the product life cycle. Most, but
not all, CMAs become tests in a compendial monograph. In some applications, excipient suppliers and users
will need to identify and control material attributes in addition to monograph specifications. Identification of
CMAs requires a thorough understanding of drug product CQAs; the manufacturing process(es); and the
physical, chemical, biological, or microbiological properties of each ingredient. Manufacturers should
anticipate lot-to-lot and supplier-to-supplier variability in excipient properties and should have in place
appropriate control measures to ensure that CMAs are maintained within the required limits. Prior
knowledge, experimental designs, and risk-assessment tools can be used to prioritize and identify CMAs of
excipients as well as critical process parameters. A CMA of an excipient may not be related to the major
component of the excipient because, for example, the presence of minor components (e.g., peroxides,
elemental impurities, or microbiological content) may affect product stability or quality. Good product
development practices, which at times are termed QBD principles, require understanding excipient CMAs
that contribute to consistent performance and are the foundation of a control strategy that accommodates
excipient variability, consistently achieving final product CQAs.
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
In this chapter, the functional categories have been organized by their most typical use in common
pharmaceutical dosage forms. However, functional categories can apply to multiple dosage forms. The
association of a functional category with a particular dosage form does not limit the use of an excipient to a
single type of dosage form or delivery system. Each functional category includes a general description; the
mechanisms by which excipients achieve their function; physical properties common to these excipients;
chemical properties; and a list of USP general chapters that can be useful in the development of specific
tests, procedures, and acceptance criteria to ensure that CMAs are adequately monitored and controlled.
Because of the complex nature and interplay of formulation ingredients, processing, and dosage form
performance requirements, the information provided in this chapter should not be viewed as either
restrictive or completely comprehensive.
Change to read:
TABLETS AND CAPSULES
Functional Category: Diluent
Diluents are components that are incorporated into tablet or capsule dosage forms to increase dosage
form volume or weight. Sometimes referred to as fillers, diluents often compose a large portion of the
dosage form, and the quantity and type of diluent selected often depend on its physical and chemical
properties. Thus, successful and robust manufacturing and dosage form performance depend on the
measurement and control of the CMAs.
Among the most important functional roles diluents play is their ability to impart desirable
manufacturing properties (e.g., powder flow, tablet compaction strength, wet or dry granule formation, or
homogeneity) and performance (e.g., content uniformity, disintegration, dissolution, tablet integrity,
friability, or physical and chemical stability). Some diluents (e.g., microcrystalline cellulose) occasionally
are referred to as “dry binders” because of the high degree of tablet strength they impart to the final
compressed tablet.
The primary physical properties relevant to tablet/capsule diluents are those that can have a direct effect
on diluent and formulation performance. These include: 1) particle size and size distribution, 2) particle
shape, 3) bulk/tapped/true density, 4) specific surface area, 5) crystallinity, 6) moisture content, 7)
powder flow, 8) solubility, 9) crystal form, and 10) compaction properties for tablet dosage forms.
Tablet diluents comprise a large and diverse group of materials that include inorganics (e.g., dibasic
calcium phosphate or calcium carbonate), single-component organic materials (e.g., lactose monohydrate
or mannitol), and multicomponent (e.g., silicified microcrystalline cellulose or sugar spheres), or complex
organics (e.g., microcrystalline cellulose or starch). They may be soluble or insoluble in water, and they
may be neutral, acidic, or alkaline in nature. These chemical properties can have a positive or negative
effect on the drug substance physical or chemical stability and on performance. Appropriate selection of
excipients with desirable physical and chemical properties can enhance the physical and chemical stability
as well as the performance of the drug substance and dosage form. The detailed composition of an
excipient may be important because excipient function could be influenced by the presence of minor
concomitant components that are essential for proper performance. Pharmaceutical scientists may find it
necessary to control the presence of undesirable components (e.g., elemental impurities or peroxides) to
ensure adequate dosage form stability and performance.
The following general chapters may be useful in ensuring consistency in diluent functions: Light
Diffraction Measurement of Particle Size 〈429〉, Bulk Density and Tapped Density of Powders 〈616〉,
Crystallinity 〈695〉, Characterization of Crystalline Solids by Microcalorimetry and Solution Calorimetry
〈696〉, Density of Solids 〈699〉, Loss on Drying 〈731〉, Optical Microscopy 〈776〉, Particle Size Distribution
Estimation by Analytical Sieving 〈786〉, Powder Fineness 〈811〉, Specific Surface Area 〈846〉, Water
Determination 〈921〉, and Powder Flow 〈1174〉.
Functional Category: Wet Binder
Tablet and capsule binders are incorporated into formulations to facilitate the agglomeration of powder
into granules during mixing with a granulating fluid such as water, hydroalcoholic mixtures, or other
solvents. The binder may be either dissolved or dispersed in the granulation liquid or blended in a dry
state, and other components and the granulation liquid may be added separately during agitation.
Following evaporation of the granulation liquid, binders typically produce dry granules that achieve the
desired properties such as granule size, size distribution, shape, content, mass, and active content. Wet
granulation facilitates the further processing of the granules by improving one or more of the granule
properties such as flow, handling, strength, resistance to segregation, dustiness, appearance, solubility,
compaction, or drug release.
Binders are soluble or partially soluble in the granulating solvent or, as in the case of native starches,
can be made soluble. Concentrated binder solutions also have adhesive properties. Upon addition of liquid,
binders typically facilitate the production of moist granules (agglomerates) by altering interparticle
adhesion. They also may modify interfacial properties, viscosity, or other properties. During drying they
may produce solid bridges that yield improved residual dry granule strength.
Dispersion or dissolution of a binder in the granulation liquid depends on its physical properties:
depending on the application, then surface tension, particle size, size distribution, solubility, and viscosity
are among the important properties. Homogeneous incorporation of a binder into a dry blend also depends
on its physical properties such as particle size, shape, and size distribution. Viscosity often is an important
property to consider for binders: for polymers, viscosity is influenced by the nature of the polymer
structure, molecular weight, and molecular weight distribution. Polymeric binders may form gels.
Tablet and capsule binders can be categorized as: 1) natural polymers, 2) synthetic polymers, or 3)
sugars. The chemical nature of polymers—including polymeric structure, monomer properties and
sequence, functional groups, degree of substitution, and cross-linking—influences the complex interactions
that can occur during granulation. Natural polymers in particular may exhibit greater variation in their
properties because of variations in their sources and therefore their composition.
The following general chapters may be useful in ensuring consistency in binder functions: Bulk Density
and Tapped Density of Powders 〈616〉, Chromatography 〈621〉, Crystallinity 〈695〉, Density of Solids 〈699〉,
Loss on Drying 〈731〉, Particle Size Distribution Estimation by Analytical Sieving 〈786〉, Specific Surface
Area 〈846〉, Viscosity—Capillary Methods 〈911〉, and Powder Flow 〈1174〉.
Functional Category: Disintegrant
Disintegrants are functional components that are added to formulations to promote rapid disintegration
into smaller units and to allow a drug substance to dissolve more rapidly. Disintegrants are natural,
synthetic, or chemically modified natural polymeric substances. When disintegrants come in contact with
water or stomach or intestinal fluid, they function by absorbing liquid and start to swell, dissolve, or form
gels. This causes the tablet structure to rupture and disintegrate, producing increased surfaces for
enhanced dissolution of the drug substance.
()
The ability to interact strongly with water is essential to the disintegrant function. Three major
mechanisms describe the function of the various disintegrants: volume increase by swelling, deformation,
and capillary action (wicking). In tablet formulations, the function of disintegrants is best described as a
combination of two or more of these effects. The onset and degree of the locally achieved actions depend
on various parameters of a disintegrant, such as its chemical nature and its particle size distribution and
particle shape, as well as some important tablet parameters such as hardness and porosity.
The primary physical properties relevant to a disintegrant are those that describe the product's particle
structure as a dry powder or its structure when in contact with water. These properties may include: 1)
particle size distribution; 2) water absorption rate; 3) swelling ratio or swelling index; and 4) the
characterization of the resulting product, whether it is still a particulate or a gel is formed.
Polymers used as disintegrants are either nonionic or anionic with counterions such as sodium, calcium,
or potassium. Nonionic polymers are natural or physically modified polysaccharides such as starches,
celluloses, pullulan, or cross-linked polyvinylpyrrolidone. The anionic polymers mainly are chemically
modified starches, cellulose products, or low-cross-linked polyacrylates. These chemical properties should
be considered in the case of ionic polymers. Disintegration performance is affected by pH changes in the
gastrointestinal tract or by complex formation with ionic drug substances.
The following general chapters may be useful in ensuring consistency in disintegrant functions: Light
Diffraction Measurement of Particle Size 〈429〉, Optical Microscopy 〈776〉, Particle Size Distribution
Estimation by Analytical Sieving 〈786〉, and Powder Flow 〈1174〉.
Functional Category: Lubricant
Lubricants typically are used to reduce the frictional forces between particles and between particles and
metal-contact surfaces of manufacturing equipment such as tablet punches and dies used in the
manufacture of solid dosage forms. Liquid lubricants may be absorbed into the granule matrix before
compaction. Liquid lubricants also can be used to reduce metal–metal friction on manufacturing
equipment.
Boundary lubricants function by adhering to solid surfaces (granules and machine parts) and by reducing
the particle–particle friction or the particle–metal friction. The orientation of the adherent lubricant
particles is influenced by the properties of the substrate surface. For optimal performance, the boundary
lubricant particles should be composed of small, plate-like crystals or stacks of plate-like crystals. Fluid
film lubricants melt under pressure and thereby create a thin fluid film around particles and on the surface
of punches and dies in tablet presses, which helps to reduce friction. Fluid film lubricants resolidify after
the pressure is removed. Liquid lubricants are released from the granules under pressure and create a
fluid film. They do not resolidify when the pressure is removed but are reabsorbed or redistributed through
the tablet matrix over the course of time.
The physical properties that are important for the function of boundary lubricants include particle size,
surface area, hydration state, and polymorphic form. Purity (e.g., stearate:palmitate ratio) and moisture
content also may be important. The physical properties of possible importance for fluid film lubricants are
particle size and solid state/thermal behavior. Purity also may be important.
Lubricants can be classified as boundary lubricants, fluid film lubricants, or liquid lubricants. Boundary
lubricants are salts of long-chain fatty acids (e.g., magnesium stearate) or fatty acid esters (e.g., sodium
stearyl fumarate) with a polar head and fatty acid tail. Fluid film lubricants are solid fats (e.g.,
hydrogenated vegetable oil, type 1), glycerides (glyceryl behenate and distearate), or fatty acids (e.g.,
stearic acid) that melt when subjected to pressure. Liquid lubricants are liquid materials that are released
from granules under pressure.
The following general chapters may be useful in ensuring consistency in lubricant functions: Light
Diffraction Measurement of Particle Size 〈429〉, Crystallinity 〈695〉, Characterization of Crystalline Solids by
Microcalorimetry and Solution Calorimetry 〈696〉, Loss on Drying 〈731〉, Optical Microscopy 〈776〉, Particle
Size Distribution Estimation by Analytical Sieving 〈786〉, Specific Surface Area 〈846〉, Thermal Analysis
〈891〉, Water Determination 〈921〉, and Characterization of Crystalline and Partially Crystalline Solids by X-
Ray Powder Diffraction (XRPD) 〈941〉.
Certain lubricants, particularly those used in effervescent dosage forms, do not fall into the chemical
categories defined above. These materials are used in special situations, and they are not suitable for
universal application. Talc is an inorganic material that may have some lubricant properties. It is generally
used in combination with fluid film lubricants to reduce sticking to punches and dies.
Functional Category: Glidant and/or Anticaking Agent
Glidants and anticaking agents are used to promote powder flow and to reduce the caking or clumping
that can occur when powders are stored in bulk. In addition, glidants and anticaking agents reduce the
incidence of bridging during the emptying of powder hoppers and during powder processing.
Glidants are thought to work by a combination of adsorption onto the surface of larger particles and
reduction of particle–particle adhesive and cohesive forces, thus allowing particles to move more easily
relative to one another. In addition, glidants may be dispersed among larger particles and thus may reduce
friction between these particles. Anticaking agents may absorb free moisture that otherwise would allow
the development of particle–particle bridges that are implicated in caking phenomena.
Primary physical properties of potential importance for glidants and anticaking agents are particle size,
particle size distribution, and surface area. They may be slightly hygroscopic.
Glidants and anticaking agents typically are finely divided inorganic materials. Typically they are
insoluble in water. Some of these materials are complex.
The following general chapters may be useful in ensuring consistency in glidant or anticaking agent
functions: Light Diffraction Measurement of Particle Size 〈429〉, Loss on Drying 〈731〉, Particle Size
Distribution Estimation by Analytical Sieving 〈786〉, Specific Surface Area 〈846〉, and Water Determination
〈921〉.
Functional Category: Coloring Agent
Coloring agents are incorporated into dosage forms to produce a distinctive appearance that may serve
to differentiate a product from others that have a similar physical appearance or, in some instances, to
protect photolabile components of the dosage form. These substances are subdivided into dyes (water-
soluble substances), lakes (insoluble forms of a dye that result from its irreversible adsorption onto a
hydrous metal oxide), inorganic pigments (substances such as titanium dioxide or iron oxides), and
natural colorants (colored compounds not considered dyes per se, such as riboflavin). Coloring agents are
subject to federal regulations, and consequently the current regulatory status of a given substance must
be determined before its use.
The Federal Food, Drug, and Cosmetic Act defines three categories of coloring agents:
FD&C colors: those certifiable for use in coloring foods, drugs, and cosmetics
D&C colors: dyes and pigments considered safe in drugs and cosmetics when in contact with mucous
membranes or when ingested
Ext. D&C colors: colorants that, because of their oral toxicity, are not certifiable for use in ingestible
products but are considered safe for use in externally applied products.
Water-soluble dyes usually are dissolved in a granulating fluid for use, although they also may be
adsorbed onto carriers such as starch, lactose, or sugar from aqueous or alcoholic solutions. These latter
products often are dried and used as formulation ingredients. Because of their insoluble character, lakes
almost always are blended with other dry excipients during formulation. For this reason, direct-
compression tablets often are colored with lakes.
Particle size and size distribution of dyes and lakes can influence product processing times (blending and
dissolution), color intensity, and uniformity of appearance. A coloring agent should be physically
nonreactive with other excipients and the drug substances.
The most important properties of a coloring agent are its depth of color and resistance to fading over
time. Substances can be graded on their efficiency in reflecting desired colors of visible light, as well as on
their molar absorptivities at characteristic wavelengths. A coloring agent should be chemically nonreactive
with other excipients and the drug substances. The quality of a coloring agent ordinarily is measured by a
determination of its strength, performance, or assay. The impurity profile is established by measurements
of insoluble matter, inorganic salt content, metal content, and organic impurities.
The following general chapters may be useful in ensuring consistency in selected coloring agent
functions: Light Diffraction Measurement of Particle Size 〈429〉 and Color—Instrumental Measurement
〈1061〉. Instrumental methods should be used to determine the absolute color of a coloring agent.
Coloring agents are subject to federal regulations, and consequently the current regulatory status of a
given substance must be determined before it is used.
Functional Category: Capsule Shell
The word “capsule” is derived from the Latin capsula, which means a small container. Among other
benefits, capsules enable pharmaceutical powders and liquids to be formulated for dosing accuracy, as well
as ease of transportation. The capsule material should be compatible with all other ingredients in the drug
product. Hard capsules typically consist of two parts: both are cylindrical, and one part is slightly longer
than the other and is called the body. The cap fits closely on the body to enclose the capsule. In contrast,
the soft capsule is a one-piece unit that may be seamed along an axis or may be seamless. The capsule
material may be derived from hydrolysis of collagen that originates from porcine, bovine, or fish sources,
or it can be of nonanimal origin, e.g., cellulosic or polysaccharide chemical entities. The capsule shell also
contains other additives such as plasticizers, colorants, and preservatives. In some cases, capsule shells
are sterilized to prevent microbial growth. The capsule shell is an integral part of the formulation, and
therefore robust manufacturing and formulation performance depends on the measurement and control of
CMAs. Capsules can be used to administer drugs by oral, rectal, vaginal, or inhalation routes.
Capsules can enclose solid, semisolid, or liquid formulations. Capsules have a variety of benefits:
masking unpleasant taste, facilitating blinding in clinical studies, promoting ease of swallowing, and
presenting a unique appearance. Conventional capsule shells should dissolve rapidly at 37° in biological
fluids such as gastric and intestinal media. However, the solubility properties of the shell can be modified
(e.g., with enteric and controlled-release polymers) to control the release of the capsule contents.
The primary physical properties relevant to the capsule shell are those that can have a direct effect on
product performance: 1) moisture content, 2) gas permeability, 3) stability on storage, 4) disintegration,
5) compactness, and 6) brittleness. The moisture content varies with the type of capsule. Hard gelatin
capsules typically contain 13%–16% water compared to hypromellose (hydroxypropyl methylcellulose or
HPMC) capsules that typically contain 4%–7% water content. Moisture content has an important effect on
capsule brittleness. Soft gelatin capsules contain 5%–15% water. Equilibrium water content also may be
crucial to dosage form stability because water migration can take place between the shell and capsule
contents. Gas permeability may be important and generally is greater for HPMC capsules than for gelatin
capsules because of the presence of open structures in the former. Unlike HPMC capsules, which do not
cross-link, gelatin capsules have the potential to cross-link due to environmental and chemical exposure.
Gelatin capsules may undergo cross-linking upon storage at elevated temperature and humidity [e.g.,
40°(75% RH)]. Gelatin shell material is also well known to cross-link due to exposure to aldehydes,
ketones, and certain dyes in shell formulations. Thus, presence of these materials in excipients should be
considered for gelatin encapsulated products. Cross-linking slows in vitro dissolution and often
necessitates introduction of enzymes in the test medium. Gelatin capsules should disintegrate within 15
min when exposed to 0.5% hydrochloric acid at 36°–38° but not below 30°. HPMC capsules can
disintegrate below 30°.
Gelatin is a commercial protein derived from the native protein, collagen. The product is obtained by
partial hydrolysis of collagen derived from skin, white connective tissue, and bones of animals. Type A
gelatin is derived by acid treatment, and Type B gelatin is derived from base treatment. The common
sources of commercial gelatin are pigskin, cattle hide, cattle bone, cod skin, and tilapia skin. The gelatin
capsule shell also typically contains coloring agents, plasticizers such as polyhydric alcohols, natural gums
and sugars, and preservatives such as sodium metabisulfite and esters of p-hydroxybenzoic acid. The
more commonly used nongelatin capsules today are made from HPMC. Different capsule types contain
different moisture levels and may thus influence drug product stability. The detailed composition of an
excipient may be important because the shell function can be influenced by small amounts of impurities in
the excipients (e.g., peroxides in oils or aldehydes in lactose and starches) that can cause capsule cross-
linking. The presence in capsule shells of undesirable materials, such as metals, odorants, water-insoluble
substances, and sulfur dioxide, should be evaluated to ensure stability and performance.
The following general chapters may be useful in ensuring consistency in selected capsule shell functions:
Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests 〈61〉, Microbiological
Examination of Nonsterile Products: Tests for Specified Microorganisms 〈62〉, Arsenic 〈211〉, Elemental
Impurities—Limits 〈232〉 and Elemental Impurities—Procedures 〈233〉, Residue on Ignition 〈281〉,
Disintegration 〈701〉, Dissolution 〈711〉, Water Determination 〈921〉, and Color—Instrumental Measurement
〈1061〉.
In addition to the general chapters listed above, useful information for ensuring consistency in selected
capsule shell functions may be found in Gelatin, Gel Strength (Bloom Value).
Functional Category: Coating Agent
Oral tablets may be coated using compression coating, sugar coating, or film coating. Compression
coating (effectively making a tablet within a tablet) typically uses the same ingredients as a conventional
tablet and thus is outside the scope of this section. The term “sugar coating” refers to a process and does
not require that sucrose be part of the formulation. Oral capsules can be coated using film-coating
procedures. Reasons for coating pharmaceutical dosage forms include masking unpleasant tastes or odors,
improving ingestion and appearance, protecting active ingredients from the environment, and modifying
the release of the active ingredient (e.g., controlled-release or gastrointestinal targeting). Materials used
as coating agents differ depending on the coating process used. Sugar coating was the original coating
process. However, today for technical and economic reasons, sugar coating largely has been replaced by
film coating. Sugar coating is a complex process that typically involves the application of several different
coats including a seal coat, key coat, subcoat, smoothing coat, color coat, and polishing coat. The coating
solutions or suspensions are slowly poured or otherwise applied in aliquots onto a bed of tablets in a
slowly rotating pan. The coating process typically takes an extended period (potentially several days) and
results in a substantial increase in tablet weight. In contrast, film coating generally is a simpler process in
which coating solution or suspension is sprayed onto tablets either in a rotating pan or in a fluid-bed
apparatus and results in only a modest increase in capsule or tablet weight. The materials used in both
sugar coating and film coating include natural, semisynthetic, and synthetic materials. These may be
solutions, suspensions, or colloidal dispersions (latexes or pseudolatexes) that can be applied as either
aqueous or nonaqueous systems. In addition, waxes and lipids can be applied as coatings in the molten
state without the use of solvents. They also can be applied in the solid state as a polishing coat on top of
sugar coating or film coating.
—
The seal coat is used to seal the surface of the tablet cores to prevent water in the coating solutions or
suspensions from causing the tablet cores to disintegrate during coating. The seal coat typically is a
polymer (e.g., shellac) that is insoluble in water and is applied as a thin coat from a solution in a
nonaqueous solvent. The key component of the majority of sugar-coating solutions or suspensions is a
solute, typically sucrose, that is highly soluble in water and forms a sticky, viscous solution (a syrup) at
very high concentration. Other materials can be dissolved or suspended in the solution, depending on the
stage during the coating process. As the coating dries, the dissolved coating material adheres to the
surface of the tablets. The coating solution or suspension typically is applied in incremental steps, followed
by drying, until the requisite coating has been achieved. The key coat is composed of another thin coat
that is designed to adhere to the seal-coated cores to provide a base for the subcoat so the latter can
adhere to the tablet surface. The subcoat typically contains a high concentration of suspended solids and is
designed to increase the weight of the tablets comparatively quickly. The smoothing coat is designed to
provide a smooth surface, and the color coat provides the final color if required. Finally, the tablets may be
transferred to a polishing pan and polished using a mixture of waxes to provide a high-gloss finish.
—
Film-coating agents are composed of film-forming materials (see Functional Category: Film-Forming
Agent) that impart desirable pharmaceutical properties such as appearance and patient acceptance (e.g.,
taste masking and ease of swallowing). Film-coating agents also can serve other functional purposes such
as providing a barrier against undesirable chemical reactions or untimely release of a drug from its
components. After ingestion, the film coating may dissolve by processes such as hydration, solubilization,
or disintegration, depending on the nature of the material used. Enteric coatings are insoluble in acidic
(low pH) media but dissolve readily in neutral pH conditions. However, most common film-coating
polymers do not have pH-specific solubility. The thickness of the film may vary by application and the
nature of the coating agents. In the coating process, the polymer chains spread out on the core surface
and coalesce into a continuous film as the solvent evaporates. Polymer solutions or dispersions with a low
viscosity and high pigment-binding capacity reduce the coating time and facilitate relatively simple and
cost-effective manufacturing. Plastic polymers, waxes, and lipid-based coatings can be applied without
solvents by melting and atomization. When molten fluid droplets strike the surface of the fluidized drug
particles, they spread and resolidify to form film layers. Therefore, film coating materials generally have
the ability to form a complete and stable film around the substrate. The film coating typically is applied
uniformly and is carefully dried to ensure that a consistent product is produced. Suitable plasticizers may
be required to lower the minimum film-forming temperature of the polymer, and formulators should
consider their potential effect on drug release.
Sugar coating is a lengthy, complex process. The physical properties of the seal-coating polymer and
solution are important. The physical properties of the syrup component in the subsequent layers and any
dissolved or suspended solids also are important, and coating agents must be sufficiently stable during
use.
Film coating is a complex process, and the characteristics of the film-forming polymer are important.
The particle size of colloidal dispersions varies with their composition and manufacture (latex, pseudolatex,
or redispersed powder) and can have an effect on film formation. The surface tension of coating
preparations can influence the spray pattern in the manufacturing process. The film should possess
sufficient elasticity and mechanical strength to withstand the stresses during coating and packaging
operations. For coatings that are applied in a molten state without solvents (plastic polymers, waxes, and
lipid-based coatings), melting range and melt viscosity are the primary properties that formulators must
consider.
Coating components can be of natural, semisynthetic, or synthetic origin and also can be available in
different chemical grades. They comprise a diverse variety of different chemical materials. Formulators
must consider the nature of the material and its intended use when they identify and quantitate chemical
CMAs to ensure consistent performance.
The following general chapters may be useful in ensuring consistency in selected coating agent
functions: Fats and Fixed Oils 〈401〉, Light Diffraction Measurement of Particle Size 〈429〉, Dissolution
〈711〉, Tensile Strength 〈881〉, Thermal Analysis 〈891〉, Viscosity—Capillary Methods 〈911〉, Viscosity—
Rotational Methods 〈912〉, and Viscosity—Rolling Ball Method 〈913〉. In addition, the general chapters listed
under Functional Category: Film-Forming Agent (below) also may be appropriate for the evaluation of film-
coating polymers.
Additives often are included in a coating formulation. Fillers (e.g., sugar alcohols, microcrystalline
cellulose, calcium carbonate, and kaolin) may be added to increase the solids content of the coating agent
without increasing viscosity. Stearic acid can be used to improve the protective function/moisture barrier
of a coating. Coloring agents (e.g., titanium dioxide and iron oxides) may be added to modify appearance.
Functional Category: Plasticizer
A plasticizer is a low molecular weight substance that, when added to another material—usually a
polymer—makes the latter flexible, resilient, and easier to handle. Plasticizers are key components that
determine the physical properties of polymeric pharmaceutical systems such as tablet film coatings and
capsule shells.
Plasticizers function by increasing the intermolecular and intramolecular mobility of the macromolecules
that comprise polymeric materials. They achieve this by interfering with the normal intermolecular and
intramolecular bonding mechanisms in such systems. The most effective plasticizers exert their effect at
low concentrations, typically less than 5% w/w. Plasticizers commonly are added to film coatings (aqueous
and nonaqueous systems) and capsule shells (hard and soft varieties) to improve their workability and
mechanical ruggedness. Without the addition of plasticizers, such materials can split or fracture
prematurely. Plasticizers also are added to semisolid pharmaceutical preparations, such as creams and
ointments, to enhance their rheological properties.
The most common plasticizers are low molecular weight (<500 Da) solids or liquids. They typically have
low melting points (<100°) and can be volatile (i.e., exert an appreciable vapor pressure) at ambient
temperature. Plasticizers can reduce the glass transition temperature (T ) of the system to which they are
added.
Many modern plasticizers are synthetic esters such as citrates and phthalates. Traditional pharmaceutical
plasticizers include oils, sugars, and their derivatives.
The following general chapters may be useful in ensuring consistency in selected excipient functions:
Residual Solvents 〈467〉, Melting Range or Temperature 〈741〉, Refractive Index 〈831〉, Specific Gravity
〈841〉, Thermal Analysis 〈891〉, and Water Determination 〈921〉.
The choice of an appropriate plasticizer often is guided by reference to its solubility parameter, which is
related to its cohesive energy density. Solubility parameter values for many common materials are
tabulated in standard reference texts. To ensure maximum effectiveness, the solubility parameter of the
plasticizer and the polymeric system being plasticized should be matched as closely as possible.
Functional Category: Film-Forming Agent
Film-forming agents typically are polymers that can be used to prepare polymer films to coat tablets or
capsules for oral administration, to modify appearance, to modify drug release, or to serve other purposes
such as melt-in-the-mouth formulations. Polymeric materials used as film-forming agents can be derived
from natural, semisynthetic, or synthetic sources, and they can be supplied as powders, granules, pre-
prepared solutions, or colloidal dispersions. Colloidal dispersions may contain other components such as
plasticizers, surface-active agents, preservatives, or stabilizers. Film-forming agents can be applied as
colloidal dispersions (latexes or pseudolatexes) or as aqueous, hydroalcoholic, or nonaqueous polymeric
solutions.
Film-forming agents typically are composed of polymeric materials that possess the ability to form films
after solvent evaporation from a solution of the polymer or from the continuous phase of a colloidal
dispersion. Thus, the polymer alone must be a solid at ambient temperature and humidity. Some polymers
can form films without the inclusion of added components, but other polymers may require the use of
additional components such as plasticizers.
Many polymeric film-forming agents are available in a variety of physical grades that typically are based
on the nominal viscosity of the particular grade. The physical properties of the polymer usually are those
of a solid, and many polymers are available as powders and granules. In addition to the normal properties
of bulk powders and granules, other important physical properties of a polymeric film-forming agent are
the molecular weight distribution, which is linked to the nominal viscosity of the grade, and the glass
transition temperature (T ). If the film-forming agent is provided as a pre-prepared solution or dispersion,
the viscosity of the solution or dispersion can affect performance and should be monitored.
Film-forming agents comprise a diverse group of materials, including natural, semisynthetic, and
synthetic materials as discussed above. They may have ionizable functional groups that impart pH-
dependent properties and also can be available in different chemical grades (e.g., with different degrees of
chemical substitution). Pharmacopeial monographs often describe classes of polymeric materials that allow
g
g
a considerable range of composition. Formulators should consider these factors when they identify critical
material attributes and establish specifications to ensure consistent performance.
The following general chapters may be useful in ensuring consistency in selected film-forming agent
functions: Fats and Fixed Oils 〈401〉, Light Diffraction Measurement of Particle Size 〈429〉, Bulk Density and
Tapped Density of Powders 〈616〉, Chromatography 〈621〉, Density of Solids 〈699〉, Dissolution 〈711〉,
Optical Microscopy 〈776〉, pH 〈791〉, Tensile Strength 〈881〉, Thermal Analysis 〈891〉, Viscosity—Capillary
Methods 〈911〉, Viscosity—Rotational Methods 〈912〉, Viscosity—Rolling Ball Method 〈913〉, Bulk Powder
Sampling Procedures 〈1097〉,
▲
Near-Infrared Spectroscopy—Theory and Practice 〈1856〉
▲ (CN 1-May-2020)
,
Raman Spectroscopy 〈1120〉, Pharmaceutical Dosage Forms 〈1151〉Powder Flow 〈1174〉, and Scanning
Electron Microscopy 〈1181〉.
Functional Category: Flavor and Fragrance
A flavor is a single chemical entity or a blend of chemicals of natural or synthetic origin that has the
ability to elicit a taste or aroma (i.e., fragrance) response when orally consumed or smelled. The primary
purpose of flavor that is added to a pharmaceutical preparation is to provide all or part of the taste and
aroma of the product taken into the mouth. Flavors commonly are used in pharmaceutical oral
disintegrating tablets, oral solutions, and oral suspensions to mask objectionable drug taste and to make
the formulation more palatable, thus promoting patient compliance.
Chemicals dissolved in saliva excite chemoreceptors on taste buds that reside primarily on the tongue
and thus arouse taste perception. Dissolution also releases volatile chemicals that reach the olfactory
receptors, triggering aroma perception. The total of taste and odor responses constitutes flavor. Humans
can distinguish among five components of taste: sourness, saltiness, sweetness, bitterness, umami
(savory), and a wide range of specific odors. Flavor enhancers and taste modifiers can be used to modify
the sweetness profile of a sweetening agent or to mask off-flavors. For example, organic acids, such as
aspartic and glutamic acids, are known to reduce bitterness.
Taste perception depends on physicochemical, physiological, and psychological factors. Physical
properties such as particle size, solubility, humectancy, texture, and color all influence the senses. In
addition to flavor, the sensory attributes of sight (e.g., appealing color), sound (e.g., crunch of a chewable
tablet), and mouth feel (e.g., viscous, slimy, chalky, cloying, or watery) also contribute to and influence
the overall sensory experience.
Chemicals that provide one of the five basic tastes possess a wide variety of structures, functional
groups, and molecular weights. Chemicals used to flavor pharmaceuticals by providing both odor and taste
tend to have low molecular weights (<250 Da) and polar functional groups such as esters, ketones,
aldehydes, amines, or alcohols. To increase the stability of the flavor(s) in a solid dosage form and to
minimize flavor–drug interactions, formulators can add flavors in an encapsulated or spray-dried form.
The following general chapters may be useful in ensuring consistency in flavor functions: Light
Diffraction Measurement of Particle Size 〈429〉, Chromatography 〈621〉, Congealing Temperature 〈651〉,
Loss on Drying 〈731〉, Melting Range or Temperature 〈741〉, Optical Rotation 〈781〉, Particle Size
Distribution Estimation by Analytical Sieving 〈786〉, Refractive Index 〈831〉, and Specific Gravity 〈841〉.
Functional Category: Release-Modifying Agents
Release-modifying agents are used to control drug release in extended-release formulations (also referred
to as prolonged-release or controlled-release formulations). Sustained-release and enteric coating agents
are included under Functional Category: Coating Agent.
Release-modifying agents change a medicinal product's drug-release pattern to achieve the desired drug
plasma profile for a given time. The majority of release-modifying agents are polymers that differ in
solubility, ease of erosion, rate of swelling, or sensitivity to the biological environment in which they are
placed. These polymers have been used to fabricate matrix- or membrane-based drug delivery systems for
oral, parenteral, transdermal, and other routes of administration. Matrix controlled-release drug delivery
systems can be classified as hydrophilic eroding matrices, hydrophilic noneroding matrices, or hydrophobic
matrices. In membrane controlled-release drug delivery systems, the drug reservoir is coated by a rate-
controlling polymeric membrane that may consist of a blend of polymers to control release. Such devices
may take the form of tablets, capsules, microspheres, vesicles, fibers, patches, and others. In addition to
polymers, certain lipid-based excipients also can be used as release-modifying agents in hydrophobic
matrix devices and other types of modified-release systems. Typically, these lipid-based materials are fats
and waxes or related materials with melting ranges above 45°.
Upon contact with a biological fluid, release-controlling polymers may undergo a variety of physical
changes such as swelling, gelling, dissolution, or erosion, each of which can be triggered by simple
aqueous exposure or can be modulated by pH, osmotic stress, or interactions with bile or other intestinal
contents. In addition to physical changes, polymers may undergo chemical degradation by acids, bases,
enzymes, water, heat, and others. Any or all of these mechanisms may act in concert to control the rate at
which the drug is released from the delivery system.
For hydrophilic matrices in which drug diffusion dominates release rate, the rate of drug release depends
on the properties of the polymer gel and the nature of the continuous phase in the interstices of the gel
influences the dissolution and diffusion rates of the drug. In the case of eroding matrices, the gel erodes
because of the mechanical action of the gastrointestinal tract as the water uptake increases, and the gel
becomes more dilute, thus reducing the diffusion distance or releasing drug particles that subsequently
dissolve. Hydrophobic matrix-forming materials are not soluble. Drug release from such systems is
governed by drug diffusion through the tortuous pores that remain as soluble components dissolve.
Membrane-based drug delivery systems include polymer-coated tablets, capsules, and microspheres.
Drug-release mechanisms from such systems are complex and depend on physicochemical characteristics
of the drug and polymers or lipids used as well as biological factors in the case of biocompatible and
biodegradable systems. Most commonly, drug release from such systems is governed by drug diffusion
through the hydrated rate-controlling membrane.
Other modified-release systems for parenteral use include solid lipid nanoparticles and liposomes. The
release mechanisms for these systems often involve a complicated interplay with biological processes such
as potential clearance through the reticulo-endothelial system, targeted delivery, and cellular uptake.
Osmotic pump devices are a special case of membrane delivery systems. The rate-controlling polymer is
insoluble and semipermeable—i.e., it will allow water but not drug molecules—to diffuse through the
membrane. Release is controlled by the osmotic pressure of the core components and the viscosity of the
resulting solution or suspension. The drug, either in solution or as a suspension, is forced out of a hole in
the membrane, which is typically drilled by a laser during product manufacture.
The physical properties of the release-controlling excipient depend on the chemical type: hydrophilic
polymer, hydrophobic polymer, semipermeable polymer blends, or lipid, wax, or biodegradable polymer
(which can be hydrophilic or hydrophobic).
Hydrophilic polymers gel in contact with water or aqueous media. Because they should provide
resistance to the mechanical action of the gastrointestinal tract during passage, they typically are higher
molecular weight grades of the polymers. At the concentrations typically used during in vivo release, these
high molecular weight polymers often do not exhibit Newtonian properties except in very dilute solution (if
they are soluble). Formulators should monitor the kinetic and viscoelastic properties of the gels formed in
the release medium.
Hydrophobic polymers are insoluble in water, and their solution properties are determined in nonaqueous
solutions. The polymers used in the preparation of semipermeable membranes in osmotic pump devices
also are insoluble in water, and similarly their solution properties are determined in nonaqueous solutions.
Similarly, hydrophobic lipid-based materials are insoluble in water.
Release-controlling agents have many different types and origins and are available in a range of grades
that reflect the considerable variation in their chemical structures and properties. Formulators must
consider these variables during any chemical investigation and when they consider the effects of chemical
structure on excipient performance. Properties of interest may include chemical composition for
copolymers and cellulosic derivatives, degree of ionization, molecular weight, degree of cross-linking, or,
for lipids, fatty acid composition. Residual impurities from the manufacturing process, e.g., monomers,
initiators, quenching agents, peroxides, and aldehydes, may affect drug substance stability and should be
monitored.
The following general chapters may be useful in ensuring consistency in selected functions of release-
modifying agents: Fats and Fixed Oils 〈401〉, Light Diffraction Measurement of Particle Size 〈429〉,
Crystallinity 〈695〉, Characterization of Crystalline Solids by Microcalorimetry and Solution Calorimetry
〈696〉, Dissolution 〈711〉, Loss on Drying 〈731〉, Melting Range or Temperature 〈741〉, Nuclear Magnetic
Resonance Spectroscopy 〈761〉, Optical Microscopy 〈776〉, Particle Size Distribution Estimation by Analytical
Sieving 〈786〉, Specific Surface Area 〈846〉, Mid-Infrared Spectroscopy 〈854〉 and Ultraviolet-Visible
Spectroscopy 〈857〉, Tensile Strength 〈881〉, Thermal Analysis 〈891〉, Viscosity—Capillary Methods 〈911〉,
Viscosity—Rotational Methods 〈912〉, Viscosity—Rolling Ball Method 〈913〉, Water Determination 〈921〉,
Characterization of Crystalline and Partially Crystalline Solids by X-Ray Powder Diffraction (XRPD) 〈941〉,
Powder Flow 〈1174〉, and Scanning Electron Microscopy 〈1181〉.
Some release-modifying agents may include additives such as an antioxidant or an anticaking agent.
Change to read:
ORAL LIQUIDS
Functional Category: pH Modifier (Acidifying/Alkalizing/Buffering Agent)
The hydrogen ion concentration, [H
+
], in an aqueous solution is expressed as pH = −log(H
+
). The pH of
pure water is 7 at 25°. An aqueous solution is acidic at pH <7 and alkaline at pH >7. An acid can be added
to acidify a solution. Similarly, a base can be used to alkalize a solution. A buffer is a weak acid (or base)
and its salt. When a buffer is present in a solution, the addition of small quantities of strong acid or base
leads to only a small change in solution pH. Buffer capacity is influenced by salt/acid (or base/salt) ratio
and total concentration of acid (or base) and salt. The pH of pharmaceutical solutions typically is controlled
using acidifying/alkalizing and buffering agents to: 1) maintain a pH close to that of relevant body fluid to
avoid irritation, 2) improve drug stability where it is found to be pH dependent, 3) control equilibrium
solubility of weak acids or bases, and 4) maintain a consistent ionization state of molecules during
chemical analysis, e.g., high-performance liquid chromatography.
The ionization equilibria of weak bases, weak acids, and water are the key to the functions of acidifying,
alkalizing, and buffering agents. The autoprotolytic reaction of water can be expressed as:
H O + H O ↔ H O
+
+ OH
−
The autoprotolysis constant (or ion product) of water is K = 1 × 10
−14
at 25° and varies significantly
with temperature. Because the concentrations of hydrogen and hydroxyl ions in pure water are equal, each
has the value of approximately 1 × 10
−7
mol/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 ionization equilibrium of water is shifted so that [H
+
][OH
−
]
remains constant, thus resulting in a solution pH that is different from 7.
pH modifiers typically are dissolved in liquid dosage forms. Physical properties may be important and
should be considered because they may influence processing requirements (e.g., particle size may
influence mixing time required to dissolve a pH modifier).
Buffers and pH modifiers influence solution pH, buffer capacity, osmolality, osmolarity, and water
conductivity. When used in chemical analysis, buffers must be chemically compatible with the reagents
and test substance. Buffers used in physiological systems should not interfere with the pharmacological
activity of the medicament or the normal function of the organism.
The following general chapters may be useful in ensuring consistency in selected pH-modifier or
buffering-agent functions: Water Conductivity 〈645〉, Osmolality and Osmolarity 〈785〉, and pH 〈791〉.
Functional Category: Wetting and/or Solubilizing Agent
Solubilizers can be used to dissolve otherwise insoluble molecules. They function by facilitating
spontaneous phase transfer to yield a thermodynamically stable solution. A number of solubilizers are
available commercially. Acceptable solubilizers for pharmaceutical applications have been fully evaluated in
animals for safety and toxicology. Wetting agents increase the spreading and penetrating properties of a
liquid by lowering its surface tension.
Wetting and solubilizing agents comprise a variety of different chemical structures or classes. Some
solubilizers have unique chemical structures. For example, a hydrophilic moiety may be tethered with a
hydrophobic moiety to yield distinct micelle shapes and morphologies in water, thus facilitating
solubilization. The mechanism of solubilization often is associated with a favorable interaction of the
insoluble agent and the interior core of the solubilizer assembly (e.g., micelles). In other cases, unique
hydrophobic sites that are capable of forming inclusion complexes are present. Other types of solubilizers
use a range of polymeric chains that interact with hydrophobic molecules to increase solubility by
dissolving the insoluble agent into the polymeric chains.
Wetting and solubilizing agents are typically solid, liquid, or waxy materials. Their physical properties
depend on their chemical structures. The physical properties and performance of the wetting agents and
solubilizers, however, depend on the surface-active properties of the solubilizers and on the hydrophilic–
lipophilic balance (HLB). Materials with lower HLB values behave as emulsifiers, whereas those with higher
HLB values typically behave as solubilizing agents. For example, the commonly used wetting and
solubilizing agent sodium lauryl sulfate (HLB 40) is hydrophilic and highly water soluble and, upon
2 2 3
w
dispersion in water, spontaneously reduces surface tension and forms micelles that function to solubilize
lipophilic materials.
The unique hydrophilicity and hydrophobicity properties of solubilizers can be characterized by their
chemical structures, aggregate numbers, or critical micelle concentrations (CMCs). The CMC value is
unique to an individual solubilizer that bears hydrophilic, lipophilic, and/or hydrophobic chains. CMC is a
measure of the concentration at which the surface-active molecules aggregate. These molecular
aggregates can solubilize the solute by incorporating part into the hydrophobic interior. Such interactions
with the insoluble molecule further stabilize the molecules in the entire assemblies without precipitation.
The chemical and surface-active properties depend on the structures of the solubilizers. Because of the
complex nature of solute–solvent–solubilizer interactions, pharmaceutical scientists must carefully
consider, identify, and control the CMAs of solubilizers.
The following general chapters may be useful in ensuring consistency in selected solubilizing agent
functions: Fats and Fixed Oils 〈401〉, Light Diffraction Measurement of Particle Size 〈429〉, pH 〈791〉,
Specific Gravity 〈841〉, Specific Surface Area 〈846〉, Mid-Infrared Spectroscopy 〈854〉 and Ultraviolet-Visible
Spectroscopy 〈857〉, Thermal Analysis 〈891〉, Viscosity—Capillary Methods 〈911〉, Viscosity—Rotational
Methods 〈912〉, Viscosity—Rolling Ball Method 〈913〉, and Scanning Electron Microscopy 〈1181〉.
Functional Category: Antimicrobial Preservative
Antimicrobial preservatives are used to kill or prevent growth of bacteria, yeast, and mold in the dosage
form.
Preservatives work by a variety of mechanisms to control microbes. Most work at the cell membrane,
causing membrane damage and cell leakage. Other modes of action include transport inhibition, protein
precipitation, and proton-conducting uncoupling. Some preservatives are bactericidal (kill bacteria or yeast
and mold); some are bacteriostatic (inhibit growth of microorganisms); and others are sporicidal (kill
spores). Several of the preservatives can act synergistically (e.g., combinations of parabens).
Antimicrobials generally are soluble in water at concentration ranges at which they are effective. The
vapor pressure of these agents is important, especially if the dosage form is intended for lyophilization or
spray drying. Several of these agents are flammable. Understanding an excipient's partition coefficient is
important because partitioning of a preservative into an oil phase can diminish the preservative's
concentration in the aqueous phase, which in turn can reduce its value as a preservative.
Phenolic preservatives can undergo oxidation and color formation. Incompatibilities of preservatives
(cationic and anionic mixtures, adsorption to tubes or filters, or binding to surfactants and proteins) should
be taken into account during product development.
The following general chapters may be useful in ensuring consistency in selected antimicrobial functions:
Injections and Implanted Drug Products 〈1〉, Antimicrobial Effectiveness Testing 〈51〉, Microbiological
Examination of Nonsterile Products: Microbial Enumeration Tests 〈61〉, Microbiological Examination of
Nonsterile Products: Tests for Specified Microorganisms 〈62〉, and Antimicrobial Agents—Content 〈341〉.
Safety and labeling requirements regarding the use of antimicrobial preservatives should be considered.
Functional Category: Chelating and/or Complexing Agents
Chelating agents form soluble complex molecules with certain metal ions (e.g., copper, iron, manganese,
lead, and calcium) and essentially remove the ions from solution to minimize or eliminate their ability to
react with other elements and/or to precipitate. The agents are used in pharmaceuticals (oral, parenteral,
and topical formulations), cosmetics, and foods to sequester ions from solution and to form stable
complexes. Chelating agents also are referred to as chelants, chelators, or sequestering agents.
Complexing agents form soluble complex molecules (e.g., inclusion complexes) with other solutes (e.g.,
drug substances) and can influence physical and chemical properties such as solubility and stability.
Chelating agents are used to sequester undesirable metal ions from solution. The chemical structure of
chelating agents allows them to act as a “claw” to associate with the metal atom by forming a heterocyclic
ring structure. Complexing agents function similarly but mechanistically and do not (by definition) require
a two-point claw structure because they can associate via one or more binding sites. All chelating agents
are complexing agents, but not all complexing agents are chelating agents. Chelating agents are used as
antioxidant synergists, antimicrobial synergists, and water softeners. By sequestering metal ions from
solution, chelating agents reduce the propensity for oxidative reactions. Chelating agents also have the
ability to enhance antimicrobial effectiveness by forming a metal-ion–deficient environment that otherwise
could feed microbial growth.
Complexing agents generally form soluble complex molecules with solutes (e.g., drug molecules) that
can influence physical, chemical, and drug delivery properties. Complexing agents that form inclusion
complexes typically contain a hydrophobic cavity into which a drug substance can enter and an outer,
more hydrophilic region.
Chelating and complexing agents generally are soluble in water and typically are dissolved in liquid
dosage forms. Physical properties may be important and should be considered because they may influence
processing requirements (e.g., particle size may influence mixing time required to dissolve). Chelating and
complexing agents exhibit different degrees of hygroscopicity. Because chelating agents are used in low
levels, particle size distribution can be important to enable acceptable dosage form content uniformity.
Chelating agents complex with metal ions via any combination of ionic and covalent bonds. Dilute
aqueous solutions may be neutral, acidic, or alkaline. Edetic acid and its salts are incompatible with strong
oxidizers, strong bases, and polyvalent metal ions (e.g., copper and nickel). Specific agents are selected
for a formulation based on their solubility, affinity for the target metal ion, and stability. Edetate salts are
more soluble than the free acid. Unlike other edetate salts and the free acid, edetate calcium disodium
does not sequester calcium and therefore is preferred to prevent hypocalcemia. It is also preferred to
chelate metals with the release of calcium ions. Alternatively, disodium edetate can be used to treat
hypercalcemia. Edetic acid will decarboxylate if heated above 150°.
Complexing agents generally form molecular complexes with drug substances that are dependent on
complexing agent physical and chemical properties. The ability of a solute to form an inclusion complex is
dependent on complexing agent molecular weight, chemical structure, and the dimensions of the
hydrophobic cavity.
The following general chapters may be useful in ensuring consistency in selected chelating and
complexing functions: Antimicrobial Effectiveness Testing 〈51〉, Microbiological Examination of Nonsterile
Products: Microbial Enumeration Tests 〈61〉, Elemental Impurities—Limits 〈232〉 and Elemental Impurities—
Procedures 〈233〉, Iron 〈241〉, Lead 〈251〉, Antimicrobial Agents—Content 〈341〉, Light Diffraction
Measurement of Particle Size 〈429〉, Loss on Drying 〈731〉, pH 〈791〉, Water Determination 〈921〉, and
▲
Cell-based Advanced Therapies and Tissue-Based Products 〈1046〉
▲ (CN 1-May-2020)
.
Functional Category: Antioxidant
This category applies to antioxidants used as in vitro stabilizers of pharmaceutical preparations to
mitigate oxidative processes. Antioxidants used for their biological activity in vivo may be regarded as
active ingredients with therapeutic effects and are not discussed. Antioxidants delay the onset of and/or
significantly reduce the rate of complex oxidative reactions that could otherwise have a detrimental effect
on the drug substance. Antioxidants also can be considered for protecting nonactive components such as
unsaturated oils, pegylated lipids, flavors, and essential oils. Thus, antioxidants preserve the overall
integrity of the dosage form against oxidative stress. Antioxidants are most effective when incorporated in
the formula to prevent or delay the onset of chain reactions and to inhibit free radicals and hydroperoxides
from engaging in the cascading processes described above. Effective application of antioxidants and
evaluation of their efficacy necessitate an understanding of oxidative mechanisms and the nature of the
byproducts they generate. Autoxidation is initiated when oxygen reacts with a substrate to form highly
reactive species known as free radicals (RH → R · ). After “initiation” the free radicals in the presence of
oxygen can trigger chain reactions (R · + O → ROO · and ROO · + RH → R · + ROOH) to form peroxy
radicals, hydroperoxides, and new alkyl radicals that can initiate and then propagate their own chain
reactions. The cascading reactions during the propagation phase can be accelerated by heat, light, and
metal catalysts. In the presence of trace amounts of metal catalysts (Cu
+
, Cu
2+
, Fe
2+
, and Fe
3+
),
hydroperoxides (ROOH) readily decompose to RO · and ROO · and subsequently can trigger reactions with
the API and/or the excipients (e.g., hydrocarbons) to form hydroxyl acids, keto acids, and aldehydes that
can have further undesirable effects. Note that hydroperoxides are not solely the reaction products of
oxidative mechanisms within a formulation. Residual amounts of hydroperoxides also can be found in
commonly used excipients like polyethylene glycols, polyvinylpyrrolidone, and polysorbates. The initiation
phase generally is slow and has a limited effect on the quality of the finished product. The propagation
phase, in contrast, involves rapid, irreversible degradation of chemical species.
Antioxidants can be grouped by their mode of action. Phenolic antioxidants that block free radical chain
reactions also are known as true or primary antioxidants. This group consists of monohydroxy or
polyhydroxy phenol compounds with ring substitutions. They have very low activation energy to donate
hydrogen atom(s) in exchange for the radical electrons that are rapidly delocalized by free radicals. By
accepting the radical electrons, they stabilize free radicals. The reaction yields antioxidant free radicals
that also can react with lipid free radicals to form other stable compounds. Thus, they can block oxidative
chain reactions both in the initiation and propagation stages. Because of their solubility behavior, phenolic
antioxidants are most effective in protecting oils and oil-soluble actives against oxidative stress. Reducing
agents generally are water-soluble antioxidants (e.g., -ascorbic acid) with lower redox potential than the
drug or the excipient they are protecting. They delay the onset and the rate of oxidative reactions by
sacrificially reacting with oxygen and other reactive species. The oxygen-scavenging potential of the
reducing agents may be sensitive to pH and also can be negatively affected in the presence of trace
elements. Chelating agents bind with free metals (Cu
+
, Cu
2+
, Fe
2+
, and Fe
3+
) that may be present in
trace amounts in the formulation. The newly formed complex ions are nonreactive. Chelating agents
therefore remove the capacity of the metal catalysts to participate in oxidative reactions that occur during
the propagation stage.
The utility of antioxidants can be maximized by synergistic use of one or two primary antioxidants along
with reducing and chelating agents. The combined effect often is greater than the sum of the individual
effects of each antioxidant (synergistic effect).
2
Solubility of the antioxidant should be greatest in the formulation phase (oily, aqueous, or emulsion
interface), where the drug substance is most soluble. The temperature at which the antioxidant
decomposes is critical for autoclaved preparations, where loss of antioxidant activity may occur. Stability of
the antioxidant also must be considered and may be a function of pH and processing conditions. Metal ions
may react with propyl gallate to form colored complexes. At alkaline pH, certain proteins and sodium salts
may bring about discoloration of tert-butylhydroquinone.
Activation energy, oxidation–reduction potential, and stability at different formulation (e.g., pH) and
processing (e.g., heat) conditions are important chemical properties. If the dosage form's expected shelf
life depends on the antioxidant's function, the concentration must be factored in and periodically assessed
to ensure that a sufficient amount of antioxidant remains throughout the product shelf life.
The following general chapters may be useful for assessing selected excipient antioxidant functions: Iron
〈241〉, Chromatography 〈621〉, Crystallinity 〈695〉, Melting Range or Temperature 〈741〉, Specific Surface
Area 〈846〉, and Water Determination 〈921〉.
Functional Category: Sweetening Agent
Sweetening agents are used to sweeten oral dosage forms and to mask unpleasant flavors. See
Functional Category: Flavor and Fragrance for more details.
Sweetening agents bind to receptors on the tongue that are responsible for the sensation of sweetness.
The longer the sweetener molecule remains attached to the receptor, the sweeter the substance is
perceived to be. The standard for sweetness is sucrose.
The primary physical properties relevant to sweeteners relate to their compatibility with the other
ingredients in the formulation (e.g., acidic ingredients), processing conditions (e.g., heating), particle size
and distribution, moisture content, isomerism, sweetness, and taste-masking capability. These properties
may be formulation dependent.
Sweeteners can be divided into three main groups: sugars (which have a ring structure), sugar alcohols
(sugars that do not have a ring structure), and artificial sweeteners. All sweeteners are water soluble. The
stability of many sweeteners is affected by pH and other ingredients in the formulation. Some sweeteners
may catalyze the degradation of some active ingredients, especially in liquids and in cases in which the
manufacturing processes involve heating.
The following general chapters may be useful in ensuring consistency in selected sweetening functions:
Light Diffraction Measurement of Particle Size 〈429〉, Loss on Drying 〈731〉, Melting Range or Temperature
〈741〉, Optical Rotation 〈781〉, and Water Determination 〈921〉.
Products that contain aspartame must include a warning on the label stating that the product contains
phenylalanine. Sugar alcohols have a glycemic index well below that of glucose. However, sorbitol is slowly
metabolized to fructose and glucose, which raises blood sugar levels. Sugar alcohols in quantities generally
greater than 20 g/day act as an osmotic laxative, especially when they are contained in a liquid
formulation. Preservative systems should be carefully chosen to avoid incompatibility with the sweetener,
and some sweeteners are incompatible with certain preservatives.
SEMISOLIDS, TOPICALS, AND SUPPOSITORIES
Functional Category: Suppository Base
Suppository bases are used in the manufacture of suppositories (for rectal administration) and pessaries
(for vaginal administration). They can be hydrophobic or hydrophilic.
Suppositories should melt at just below body temperature (37°), thereby allowing the drug to be
released either by erosion and partition if the drug is dissolved in the base or by erosion and dissolution if
the drug is suspended in the base. Hard fat suppository bases melt at approximately body temperature.
Hydrophilic suppository bases also melt at body temperature and typically also dissolve or disperse in
aqueous media. Thus, release takes place via a combination of erosion and dissolution.
The important physical characteristic of suppository bases is melting range. In general, suppository
bases melt between 27° and 45°. However, individual bases usually have a much narrower melting range
within these temperature boundaries, typically 2°–3°. The choice of a particular melting range is dictated
by the influence of the other formulation components on the melting range of the final product.
Hard fat suppository bases are mixtures of semisynthetic triglyceride esters of longer-chain fatty acids.
They may contain varying proportions of mono- and diglycerides and also may contain ethoxylated fatty
acids. They are available in many different grades that are differentiated by melting range, hydroxyl
number, acid value, iodine value, solidification range, and saponification number.
Hydrophilic suppository bases are mixtures of hydrophilic semisolid materials that in combination are
solid at room temperature and yet release the drug by melting, erosion, and dissolution when
administered to the patient. Hydrophilic suppository bases have much higher levels of hydroxyl groups or
other hydrophilic groups than do hard fat suppository bases. Polyethylene glycols that show appropriate
melting behavior are examples of hydrophilic suppository bases.
The following general chapters may be useful in ensuring consistency in selected suppository base
functions: Fats and Fixed Oils 〈401〉, Congealing Temperature 〈651〉, Melting Range or Temperature 〈741〉,
and Pharmaceutical Dosage Forms 〈1151〉.
Some materials included in suppositories based on hard fats have much higher melting ranges. These
materials typically are microcrystalline waxes that help stabilize molten suspension formulations.
Suppositories also can be manufactured from glycerinated gelatin.
Functional Category: Suspending and/or Viscosity-Increasing Agents
Suspending and viscosity-increasing agents are used in pharmaceutical formulations to stabilize
dispersal systems (e.g., suspensions or emulsions), to reduce the rate of solute or particulate transport, or
to decrease the fluidity of liquid formulations.
A number of mechanisms contribute to the dispersion stabilization or viscosity-increasing effect of these
agents. The most common is the increase in viscosity—because of the entrapment of solvent by
macromolecular chains or clay platelets—and the disruption of laminar flow. Other mechanisms include gel
formation via a three-dimensional network of excipient molecules or particles throughout the solvent
continuum and steric stabilization wherein the macromolecular or mineral component in the dispersion
medium adsorbs to the surfaces of particles or droplets of the dispersed phase. The latter two mechanisms
increase formulation stability by immobilizing the dispersed phase.
Each of the mechanisms—increased viscosity, gel formation, or steric stabilization—is a manifestation of
the rheological character of the excipient. Because of the molecular weights and sizes of these excipients,
the rheological profiles of their dispersions are non-Newtonian. Dispersions of these excipients display
viscoelastic properties. The molecular weight distribution and polydispersity of the macromolecular
excipients in this category are important criteria for their characterization.
The majority of the suspending and viscosity-increasing agents are: 1) hydrophilic carbohydrate
macromolecules (acacia, agar, alginic acid, carboxymethylcellulose, carrageenans, dextrin, gellan gum,
guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, maltodextrin, methylcellulose,
pectin, propylene glycol alginate, sodium alginate, starch, tragacanth, and xanthan gum); and 2)
noncarbohydrate hydrophilic macromolecules, including gelatin, povidone carbomers, polyethylene oxide,
and polyvinyl alcohol. Minerals (e.g., attapulgite, bentonite, magnesium aluminum silicate, and silicon
dioxide) comprise the second-largest group of suspending and viscosity-increasing agents. Aluminum
monostearate is the one non-macromolecular, nonmineral excipient in this functional category. It consists
chiefly of variable proportions of aluminum monostearate and aluminum monopalmitate.
The following general chapters may be useful in ensuring consistency in selected viscosity-increasing
functions: Viscosity—Capillary Methods 〈911〉, Viscosity—Rotational Methods 〈912〉, and Viscosity—Rolling
Ball Method 〈913〉.
Functional Category: Ointment Base
An ointment is a viscous semisolid preparation used topically on a variety of body surfaces. An ointment
base is the major component of an ointment and controls its physical properties.
Ointment bases serve as vehicles for topical application of medicinal substances and also as emollients
and protective agents for skin.
Ointment bases are liquids with a relatively high viscosity so that solids can be suspended as a stable
mixture.
Ointment bases are classified as: 1) oleaginous ointment bases that are anhydrous, do not absorb water
readily, are insoluble in water, and are not removable by water (e.g., petrolatum); 2) absorption ointment
bases that are anhydrous and absorb some water but are insoluble in water and are not water removable
(e.g., lanolin); 3) emulsion ointment bases that are water-in-oil or oil-in-water emulsions and are hydrous,
absorb water, and are insoluble in water (e.g., creams of water, oils, waxes, or paraffins); and 4) water-
soluble ointment bases that are anhydrous and absorb water and are soluble in water and are water
removable (e.g., polyethylene glycol).
Ointment bases are selected to be inert and chemically stable.
The following general chapters may be useful in ensuring consistency in selected ointment base
functions: Congealing Temperature 〈651〉, Viscosity—Capillary Methods 〈911〉, Viscosity—Rotational
Methods 〈912〉, and Viscosity—Rolling Ball Method 〈913〉.
Functional Category: Stiffening Agent
A stiffening agent is an agent or a mixture of agents that increases the viscosity or hardness of a
preparation, especially in ointments and creams.
In general, stiffening agents are high melting point solids that increase the melting point of ointments or
increase the consistency or body of creams. Stiffening agents can be either hydrophobic (e.g., hard fat or
paraffin) or hydrophilic (e.g., polyethylene glycol, high molecular weight).
The primary physical property relevant to stiffening agents is their high melting point or melting range.
Typical melting ranges for stiffening agents range from 43° to 47° (cetyl esters wax), 53° to 57° (glyceryl
distearate), 69° to 74° (glyceryl behenate), and 85° to 88° (castor oil, hydrogenated).
Stiffening agents comprise a diverse group of materials that include glycerides of saturated fatty acids,
solid aliphatic alcohols, esters of saturated fatty alcohols and saturated fatty acids, saturated
hydrocarbons, blends of fatty alcohols and a polyoxyethylene derivative of a fatty acid ester of sorbitan,
and higher ethylene glycol polymers.
The following general chapters may be useful in ensuring consistency in selected stiffening-agent
functions: Congealing Temperature 〈651〉, Melting Range or Temperature 〈741〉, Viscosity—Capillary
Methods 〈911〉, Viscosity—Rotational Methods 〈912〉, and Viscosity—Rolling Ball Method 〈913〉.
Some of the materials included as stiffening agents increase the water-holding capacity of ointments
(e.g., petrolatum) or function as co-emulsifiers in creams. Examples include stearyl alcohol and cetyl
alcohol.
Functional Category: Emollient
Emollients are excipients used in topical preparations to impart lubrication, spreading ease, texture, and
softening of the skin and to counter the potentially drying/irritating effect of surfactants on the skin.
Emollients help form a protective film and maintain the barrier function of the epidermis. Their efficacy
may be described by three mechanisms of action: protection against the delipidizing and drying effects of
surfactants, humectancy due to occlusion (by providing a layer of oil on the surface of the skin, emollients
slow water loss and thus increase the moisture-retention capacity of the stratum corneum), and lubricity,
adding slip or glide to the preparation.
Emollients impart one or more of the following attributes to a pharmaceutical preparation: spreading
capacity, pleasant feel to the touch, softness of the skin, and indirect moisturization of the skin by
preventing transepidermal water loss.
Emollients are either oils or are derived from components of oils as esters of fatty acids. Depending on
the nature of its fatty acid ester, an emollient may be liquid, semisolid, or solid at room temperature.
Generally, the higher the molecular weight of the fatty acid moiety (carbon chain length) the richer the
feel and softness of the touch. Fluidity generally is imparted by shorter chain length and higher degree of
unsaturation in the fatty acid moiety. The degree of branching of ester bonds also influences the emollient
properties.
The following general chapter may be useful in ensuring consistency in selected emollient functions: Fats
and Fixed Oils 〈401〉.
PARENTERALS
Functional Category: Pharmaceutical Water
Water is used as a solvent, vehicle, diluent, or filler for many drug products, especially those supplied in
liquid form. These may include injectable drugs, ophthalmic drugs, inhalation solutions, and others. Water
also is a vehicle for buffers and antimicrobial agents and is a volume expander for infusion solutions.
USP includes monographs for eight grades of pharmaceutical waters. Water for Injection is intended for
use in the preparation of parenteral solutions. Where used for the preparation of parenteral solutions
subject to final sterilization, use suitable means to minimize microbial growth, or first render the Sterile
Water for Injection and, thereafter, protect it from microbial contamination. For parenteral solutions that
are prepared under aseptic conditions and are not sterilized by appropriate filtration or in the final
container, first render the Sterile Water for Injection and, thereafter, protect it from microbial
contamination. Do not use Purified Water in preparations intended for parenteral administration. Where
used for sterile dosage forms other than for parenteral administration, process the article to meet the
requirements under Sterility Tests 〈71〉, or first render the Sterile Purified Water and, thereafter, protect it
from microbial contamination. USP also contains references to other types of water, such as distilled water,
deionized water, and others according to specific use as summarized in general information chapter Water
for Pharmaceutical Purposes 〈1231〉.
A solvent is able to dissolve materials because it is able to disrupt the intermolecular attractive forces
and to allow the individual molecules to become dispersed throughout the bulk solvent. Water is a favored
solvent and vehicle in the majority of applications because it is easy to handle, safe, and inexpensive.
Water is liquid at normal temperature and pressure. It forms ice at the freezing temperatures of 0° or
lower, and it vaporizes at a normal boiling temperature of 100°, depending on atmospheric pressure.
Vaporized water in the form of steam is used for sterilization purposes because the latent heat of steam is
significantly higher than that of boiling water.
Water in its pure form is neutral in pH and has very low conductivity and total organic carbon (TOC).
However, pH, conductivity, and TOC are affected by storage conditions and exposure to gases in the air.
Exposure to atmospheric carbon dioxide lowers water's pH. Storage in plastic containers may increase the
TOC content of water over time. Water stored in glass containers may result in an increase in pH and
conductivity over time.
The following general chapters may be useful in ensuring consistency in selected pharmaceutical water
functions: Injections and Implanted Drug Products 〈1〉, Bacterial Endotoxins Test 〈85〉, Total Organic
Carbon 〈643〉, Water Conductivity 〈645〉, Water for Hemodialysis Applications 〈1230〉, and Water for
Pharmaceutical Purposes 〈1231〉.
Functional Category: Bulking Agent
Bulking agents used in lyophilized pharmaceuticals, also referred to as freeze-dried products, include
various saccharides, sugar alcohols, amino acids, and polymers. The primary function of bulking agents is
to provide a pharmaceutically elegant freeze-dried cake with noncollapsible structural integrity that will
reconstitute rapidly before administration. In addition, bulking agents are selected to prevent product loss
caused by blow-out during freeze drying, to facilitate efficient drying, and to provide a physically and
chemically stable formulation matrix. Complementary combinations of bulking agents, e.g., mannitol and a
polymer, frequently are used to improve performance.
A bulking agent that readily crystallizes during lyophilization helps maintain the structural integrity of the
cake formed during primary drying, thereby preventing macroscopic collapse and maintaining
pharmaceutical elegance. Microscopic collapse of amorphous components in the formulation can still occur
(with some potentially undesirable results) but does not result in macroscopic collapse or “meltback” if the
bulking agent's properties and concentration are adequate. The bulking agent also should possess a high
eutectic melting temperature with ice to permit relatively high primary drying temperatures with
commensurate rapid and efficient drying and subsequent rapid reconstitution upon usage. Functional cake-
forming excipients, such as mannitol, frequently are used because they crystallize during freezing, thereby
allowing efficient drying and the formation of a structurally robust and stable cake. Amino acids and
cosolvents also have been used to achieve this effect. Most biopolymer active ingredients remain
amorphous upon freeze-drying, and bulking agents such as disaccharides can function as lyoprotectants
by helping to maintain a stable amorphous phase during freezing and drying to prevent denaturation.
Solubility enhancement of an insoluble crystalline active ingredient sometimes is achieved with the use of
a biopolymer that enhances solubility or prevents crystallization during lyophilization or subsequent
reconstitution. Bulking agents also are selected on the basis of biocompatibility, buffering capability, and
tonicity-modifying properties.
Lyoprotectant properties of bulking agents (i.e., those that protect the drug substance during
lyophilization) typically are achieved by the formation of a highly viscous glassy phase that includes the
biopolymer drug substance in combination with low molecular weight amorphous saccharides such as
sucrose, trehalose, or certain amino acids. A typical approach for protein pharmaceutical formulation is to
combine a sugar alcohol that readily crystallizes and an amorphous diluent. This mixture acts as a
lyoprotectant.
Bulking agents are dissolved in aqueous solution before lyophilization. Therefore, chemical purity and
the absence of bioburden and pyrogenic materials are essential properties of the excipient. However, the
physical form and particle properties of the excipient generally are not relevant to the final properties of
the lyophilized formulation. The solubilization process and the drying process can be facilitated by the use
of volatile cosolvents such as ethanol or tertiary butyl alcohol.
The physical properties that are essential to product performance during and after lyophilization include
the glass transition temperature (T ) of the amorphous frozen concentrate before drying, the glass
transition temperature of the final dried formulation cake, and the eutectic melting temperature of the
crystalline bulking agent with ice. The glass transition temperature (T ) of the formulation depends on the
glass transition temperatures of the individual components, concentrations, and interactions. Although
approximations can be made based on reported transition temperatures for individual components, current
practice includes the measurement of formulation glass transition temperatures by thermal analysis or
freeze-drying microscopy.
The physical states of the bulking agent during and after lyophilization are important physical properties.
Both formulation composition and processing parameters play roles in determining whether the bulking
agent is amorphous or takes a specific crystalline form. Rate of freezing, drying temperatures, and
g
g
annealing are among the important process parameters used to control the physical state of the
formulation and its components. Moisture retention and adsorption after lyophilization also can contribute
to formulation instability and poor reconstitution.
Reactivity of the bulking agent with other formulation components, especially the active ingredient, may
be critical. Reducing sugars are well known to react with aromatic and aliphatic amines. Glycols may
contain trace peroxide levels that can initiate oxidative degradation. The ability of saccharides and
polyhydric alcohols to form hydrogen bonds to biopolymers may play a role in their lyoprotection effects.
The following general chapters may be useful in ensuring consistency in selecting bulking agent
functions: Injections and Implanted Drug Products 〈1〉, Crystallinity 〈695〉, Characterization of Crystalline
Solids by Microcalorimetry and Solution Calorimetry 〈696〉, Thermal Analysis 〈891〉, Pharmaceutical Dosage
Forms 〈1151〉, and Water–Solid Interactions in Pharmaceutical Systems 〈1241〉.
Functional Category: Tonicity Agent
To avoid crenation or hemolysis of red blood cells and to mitigate pain and discomfort if solutions are
injected or introduced into the eyes and nose, solutions should be made isotonic. This requires that the
effective osmotic pressure of solutions for injection must be approximately the same as that of blood.
When drug products are prepared for administration to membranes, such as eyes or nasal or vaginal
tissues, solutions should be made isotonic with respect to these tissues.
Tonicity is equal to the sum of the concentrations of the solutes that have the capacity to exert an
osmotic force across a membrane and thus reflects overall osmolality. Tonicity applies to the impermeant
solutes within a solvent—in contrast to osmolarity, which takes into account both permeant and
impermeant solutes. For example, urea is a permeant solute, meaning that it can pass through the cell
membrane freely and is not factored when determining the tonicity of a solution. In contrast, sodium
chloride is impermeant and cannot pass through a membrane without the help of a concentration gradient
and, therefore, contributes to a solution's tonicity.
Solutions of sodium chloride, dextrose, and Lactated Ringer's are common examples of pharmaceutical
preparations that contain tonicity agents. Not all solutes contribute to the tonicity, which in general
depends only on the number of solute particles present in a solution, not the kinds of solute particles. For
example, mole for mole, sodium chloride solutions display a higher osmotic pressure than glucose
solutions of the same molar concentration. This is because when glucose dissolves, it remains one particle,
but when sodium chloride dissolves, it becomes two particles: Na
+
and Cl
−
. Several methods are available
to calculate tonicity.
Tonicity agents may be present as ionic or nonionic types. Examples of ionic tonicity agents are alkali
metal or earth metal halides such as calcium chloride (CaCl ), potassium bromide (KBr), potassium
chloride (KCl), lithium chloride (LiCl), sodium iodide (NaI), sodium bromide (NaBr) or sodium chloride
(NaCl), sodium sulfate (Na SO ), or boric acid. Nonionic tonicity agents include glycerol, sorbitol,
mannitol, propylene glycol, or dextrose. Sodium or potassium chloride and dextrose commonly are added
to adjust tonicity.
2
2 4
The following general chapters may be useful in ensuring consistency in selected tonicity agent
functions: Injections and Implanted Drug Products 〈1〉, Osmolality and Osmolarity 〈785〉, and
Pharmaceutical Calculations in Pharmacy Practice 〈1160〉.
AEROSOLS
Functional Category: Propellant
Propellants are compounds that are gaseous under ambient conditions. They are used in
pharmaceuticals (nasal sprays and respiratory and topical formulations), cosmetics, and foods to provide
force to expel contents from a container.
Propellant substances are low boiling point liquids or compressed gases that are relatively inert toward
active ingredients and excipients. They can be characterized by three properties: whether they form a
liquid phase at ambient temperatures and useful pressures, their solubility and/or miscibility in the rest of
the formulation, and their flammability. Their performance is judged by their ability to provide adequate
and predictable pressure throughout the usage life of the product.
Propellants that have both a liquid and gas phase in the product provide consistent pressures as long as
there is a liquid phase present—the pressure in the headspace is maintained by the equilibrium between
the two phases. In contrast, the pressure provided by propellants that have no liquid phase may change
relatively rapidly as the contents of the container are expelled. As the headspace becomes larger, the
pressure within the container falls proportionately. Propellants that have no liquid phase but have
significant pressure-dependent solubility in the rest of the formulation have performance characteristics
between those of the other two systems. In such cases, as the headspace increases the propellant comes
out of solution to help to maintain the pressure of the system.
In metered-dose inhalers, the propellant has a liquid phase that is an integral part of the dispensed
pharmaceutical product. Actuating the metering valve dispenses a defined volume of the liquid contents.
The propellant spontaneously boils and provides atomizing and propulsive force. A predictable change in
active concentration occurs from the beginning to the end of the container life cycle as the liquid phase of
the propellant vaporizes to reestablish the equilibrium pressure of the system as the headspace increases.
Propellants have boiling points well below ambient temperatures. A propellant's density for disperse
systems and its solubility properties may be significant considerations when one selects a propellant.
Apaflurane and norflurane have liquid-phase densities that are greater than that of water. Hydrocarbon
propellants (butane, isobutane, and propane) and dimethyl ether have liquid-phase densities that are less
than that of water.
Propellants typically are stable materials. The hydrocarbon propellants (butane, isobutene, and propane)
and dimethyl ether are all flammable materials. Apaflurane, carbon dioxide, nitrogen, and norflurane are
nonflammable. Nitrous oxide is not flammable but supports combustion. Chlorofluorocarbon propellants
are considered to be ozone-depleting substances. Their use in foods, drugs, devices, or cosmetics is
regulated by 21 CFR 2.125. Albuterol metered-dose inhalers formulated with chlorofluorocarbon
propellants have not been available in the United States since January 1, 2009.
The following general chapters may be useful in ensuring consistency in selected propellant functions:
Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders—Performance Quality Tests 〈601〉,
Chromatography 〈621〉, and Water Determination 〈921〉.
DRY POWDER INHALERS
Dry powder inhalers (DPIs) commonly contain few functional excipients. For example, DPIs may contain a
carrier and may use a capsule shell. Other useful excipients include glidants to improve flow during
manufacture of the active carrier mix. A discussion of the use of a lubricant can be found in the tablet or
capsule sections above in addition to the carrier properties discussed below.
Functional Category: Carrier
Carriers are used to help deposit the active ingredient in the lung and may have a secondary role in
diluting the active to ensure that dosages can be properly metered.
The carriers are used to promote drug deposition into the lungs for better penetration or absorption in
the appropriate lung location. In addition, the carrier is used to decrease the concentration of the active so
the latter is adequately dosed in a uniform manner.
The physical properties of carriers include appropriate morphology, hydration state, flowability, surface
energy, and particle size distribution.
Carriers must have suitable purity, including low microbial content and no extraneous proteins or
impurities, to avoid interactions with the patient's immune system.
The following general chapters may be useful in ensuring consistency in selected carrier functions:
Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests 〈61〉, Microbiological
Examination of Nonsterile Products: Tests for Specified Microorganisms 〈62〉, Elemental Impurities—Limits
〈232〉 and Elemental Impurities—Procedures 〈233〉, Light Diffraction Measurement of Particle Size 〈429〉,
Nitrogen Determination 〈461〉, Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders—
Performance Quality Tests 〈601〉, Bulk Density and Tapped Density of Powders 〈616〉, Crystallinity 〈695〉,
Characterization of Crystalline Solids by Microcalorimetry and Solution Calorimetry 〈696〉, Density of Solids
〈699〉, Loss on Drying 〈731〉, Optical Microscopy 〈776〉, Particle Size Distribution Estimation by Analytical
Sieving 〈786〉, Powder Fineness 〈811〉, Mid-Infrared Spectroscopy 〈854〉 and Ultraviolet-Visible
Spectroscopy 〈857〉, Water Determination 〈921〉, Characterization of Crystalline and Partially Crystalline
Solids by X-Ray Powder Diffraction (XRPD) 〈941〉, and Powder Flow 〈1174〉.
Functional Category: DPI Capsule Shells
Capsule shells sometimes are used in DPIs. The capsule shell is used to contain the dosage amount and
safeguard the inhalable powder in a DPI.
The use of capsule shell may speed pharmaceutical development because it does not require a complex
device and can use premeasured drug substance or formulation. A capsule shell must not fragment into
inhalable portions and should remain intact after the shell breaks to expose the powder for inhalation.
Capsule shell composition generally is dictated by the drug substance's moisture content, brittleness,
and electrostatic interactions with the inhalable powder.
The following general chapters may be useful in ensuring consistency in selected DPI capsule shell
functions: Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests 〈61〉,
Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms 〈62〉, Arsenic 〈211〉,
Elemental Impurities—Limits 〈232〉 and Elemental Impurities—Procedures 〈233〉, Residue on Ignition 〈281〉,
Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders—Performance Quality Tests 〈601〉,
Disintegration 〈701〉, Dissolution 〈711〉, Loss on Drying 〈731〉, Optical Microscopy 〈776〉, Particle Size
Distribution Estimation by Analytical Sieving 〈786〉, Uniformity of Dosage Units 〈905〉, Water Determination
〈921〉, Color—Instrumental Measurement 〈1061〉, and Water–Solid Interactions in Pharmaceutical Systems
〈1241〉.
additional information
In addition to the general chapters listed above, useful information for ensuring consistency in selected
capsule shell functions may be found in Gelatin, Gel Strength (Bloom Value).
OPHTHALMIC PREPARATIONS
Functional Category: Antimicrobial Preservatives
The preservative system acts as a safeguard to kill or inhibit the growth of microorganisms that may be
inadvertently introduced in the product after the manufacturing process either during storage or use.
Antimicrobial preservatives work by a number of mechanisms. Quaternary ammonium compounds affect
microbial cell membranes via charge interactions with phospholipids, leading to disruption of the cell
membrane. Parabens also disrupt cell membrane integrity. Alcohols such as chlorbutanol and benzyl
alcohol work via lipid (membrane) solvation and protein denaturation. N-[3-
(Dimethylamino)propyl]tetradecanamide has greater antimicrobial effectiveness toward fungi and protozoa
than do quaternary ammonium compounds. Similar to quaternary ammonium compounds, it disrupts
plasma membrane integrity. Sorbic acid works by reduction of the sulfhydryl groups of proteins.
Hypochlorite is a strong oxidizing agent. Reactions of chloramines with the amine groups of proteins can
cause changes in conformation and thus loss of protein activity. Chlorine released by these reactions can
react with cellular constituents, such as proteins and lipid. Polyaminopropyl biguanide accumulates in the
cell membrane, blocking the entry of nutrients.
To serve as an ophthalmic antimicrobial preservative, a compound should be at least sparingly soluble in
water, thus providing an appreciable range of usable concentrations.
A preservative must be compatible with the active and inactive ingredients of the finished product. For
example, quaternary ammonium compounds are incompatible with anionic surfactants. Benzyl alcohol is
incompatible with oxidizing agents. Chlorbutanol is incompatible with some nonionic surfactants.
Compatibility between compounds varies with the pH of the formula. The preservative should be stable in
solution at the formulation pH, usually from 5 to 8. Formulation pH can affect preservative activity by
influencing how the preservative partitions between the formulation and microbes and how the
preservative interacts with the target sites of the microbial cell. For example, preservatives that must pass
through cell membranes before exerting activity should be formulated at a pH at which the preservative is
mainly in its un-ionized state.
The following general chapters may be useful in ensuring consistent functions of selected antimicrobial
preservatives: Antimicrobial Effectiveness Testing 〈51〉, Sterility Tests 〈71〉, Bulk Density and Tapped
Density of Powders 〈616〉, Chromatography 〈621〉, Density of Solids 〈699〉, Loss on Drying 〈731〉,
Pharmaceutical Dosage Forms 〈1151〉, Powder Flow 〈1174〉, Sterility Assurance 〈1211〉, and Validation of
Microbial Recovery from Pharmacopeial Articles 〈1227〉.
Functional Category: Polymers for Ophthalmic Use
Polymers are used in ophthalmic preparations to enhance the retention of active ingredients by reducing
the amount of product that is lost from the eye when the patient blinks. In addition, polymers also can be
components of artificial tears. Most water-soluble polymers commonly used as film-forming agents in
ophthalmic preparations can be categorized as follows: 1) cellulose-based substances, 2) biologically
produced gums, and 3) synthetically produced substances.
Film-forming agents for ophthalmic preparations can enhance the retention of active ingredients in the
eye by a number of mechanisms. They can be used as simple viscosity-modifying agents to reduce the
flow of the product, thereby slowing the rate of product loss after administration. They also can be used to
form films on the surface of the eye so the drug remains deposited on the eye after the liquid portion of
the product has been expelled or has evaporated. These agents can be formulated to produce a film or a
gel when the product warms to body temperature (upon contacting the surface of the eye), mixing with
the tear film, and/or evaporating. Some polymers have shown bio-adhesive properties on the cornea and
can increase drug retention.
To serve as an ophthalmic film-forming agent, a polymer typically must be at least slightly soluble in
water, thus providing an appreciable range of usable concentrations. Such polymers often increase
viscosity or exhibit film- or gel-forming properties when warmed to body temperature, when exposed to
the pH or solute composition and ionic strength of the tear film, or when the product evaporates.
The finished product viscosity range that can be obtained with a film-forming agent is related to its
chemical structure and molecular weight. Functional groups such as the pyruvate and acetate groups of
xanthan gum can affect the relationship between viscosity and solution pH and ionic strength and also can
determine film- and gel-forming properties. Polymer charge can influence interactions with the mucous
layer of the eye. Molecular conformation, chain mobility, and degree of cross-linking also can affect the
degree of swelling and thus performance.
The following general chapters may be useful in ensuring consistent functions of polymers for ophthalmic
use: Bulk Density and Tapped Density of Powders 〈616〉, Chromatography 〈621〉, Density of Solids 〈699〉,
Loss on Drying 〈731〉, Particulate Matter in Ophthalmic Solutions 〈789〉, Viscosity—Capillary Methods 〈911〉,
Viscosity—Rotational Methods 〈912〉, Viscosity—Rolling Ball Method 〈913〉, Pharmaceutical Dosage Forms
〈1151〉, and Powder Flow 〈1174〉. In addition, the general chapters listed under Functional Category: Film-
Forming Agents also may be appropriate for the evaluation of polymers for ophthalmic use.
TRANSDERMALS AND PATCHES
Functional Category: Adhesive
Topical drug delivery systems (e.g., transdermals or skin patches) require the use of adhesives to
maintain contact between the applied drug delivery system and the skin. Adhesives can be intercalated as
a separate layer between the formulation matrix and the skin surface, incorporated as a part of the
formulation matrix itself, or applied to the periphery of the topical delivery system.
Adhesion is the tendency of dissimilar surfaces to adhere to one another as a result of one or more types
of interactions. For topical drug delivery systems, these adhesive interactions generally are chemical
(primarily electrostatic) or dispersive (van der Waals and/or hydrogen bonding) in nature, although there
is the possibility of mechanical interaction via the interlocking of microscopic asperities.
In general, the adhesives used in transdermals or skin patches are pressure-sensitive materials whose
performance is best characterized by physical test methods for tackiness and viscoelasticity of the
adhesive per se and viscosity of a solution of the adhesive.
In transdermals, the most widely used pressure-sensitive adhesives are acrylic, rubber, and silicone
polymers. Acrylic polymer adhesives include various esters of acrylic or methacrylic acid, acrylamide,
methacrylamide, N-alkoxyalkyl, or N-alkyl-acrylamides. Polyisobutylenes and polysiloxanes are among the
most common rubber-based and silicone-based adhesives, respectively. The molecular weight and
compositional distribution of the polymers are critical to the replication of the adhesive's efficacy from
batch to batch.
The following general chapters may be useful in evaluating the suitability of adhesives used in
transdermals: Tensile Strength 〈881〉 and Viscosity—Capillary Methods 〈911〉.
Functional Category: Film-Forming Agent
Film-forming agents used as the formulation matrix of topical drug delivery systems (e.g., transdermals
or skin patches) or in conjunction with such systems comprise a flexible, nontacky but adherent film, in
whole or in part, applied to the skin surface.
Film formation results from the progressive loss of solvent (or dispersion medium) from a solution (or
dispersion) of a film-forming agent, whether in particulate or molecularly dispersed form. Solvent (or
dispersion medium) loss leads to closer molecular or particulate packing and increased interaction among
the film-forming agent molecules or particles. Ultimately, a continuous film is formed as a result of
increased molecular entanglement or particulate sintering.
Properties critical to successful film formation include the film-forming agent's glass transition
temperature (T ), the viscosity of the solution or dispersion, and the surface characteristics of the
substrate. Viscoelastic properties such as elastic modulus, viscous modulus, and intrinsic or complex
viscosity describe functional characteristics, such as adhesion, for a pressure-sensitive adhesive
component. Adhesion to a substrate and tack and shear tests can be used for batch release.
Typical film-forming agents are thermoplastic or thermosetting high molecular weight polymers or
copolymers, often in the form of aqueous dispersions or latex compositions. Cellulosic polymers, vinyl
polymers and copolymers, and acrylic and methacrylic acid polymers and copolymers frequently are used
in topical delivery systems as film-forming agents.
The following general chapters may be useful in evaluating the suitability of film-forming agents used in
transdermals and patches: Thermal Analysis 〈891〉, Viscosity—Capillary Methods 〈911〉, Viscosity—
Rotational Methods 〈912〉, and Viscosity—Rolling Ball Method 〈913〉.
RADIOPHARMACEUTICALS
Radiopharmaceuticals commonly contain categories of excipients that also are used in conventional drugs.
For example, radiopharmaceutical capsules may contain diluents and necessarily use a capsule shell, and
parenteral radiopharmaceuticals may contain pharmaceutical water, diluents, tonicity agents, pH modifiers,
antimicrobial preservatives, chelating and/or complexing agents, and antioxidants. Many
g
radiopharmaceuticals differ from conventional drugs, however, because their preparation (reconstitution)
involves one or more chemical reactions that require unusual excipients. Furthermore, the self-absorption of
emitted radiation may result in the radiolytic decomposition of many radiopharmaceuticals. Hence, several
excipients are used predominately in radiopharmaceutical formulations, although they occasionally may be
used for other drugs.
Functional Category: Reducing Agent
Reducing agents generally are required for technetium Tc 99m radiopharmaceuticals. Technetium Tc
99m, in the chemical form of sodium pertechnetate (+7 oxidation state), must be reduced to a lower
oxidation state so that it can be chelated or otherwise complexed by the intended ligand to form the final
Tc 99m radiopharmaceutical. The reducing agent, typically a stannous salt, generally is formulated in the
kit for the preparation of the technetium Tc 99m radiopharmaceutical.
The reducing agent (e.g., stannous ion) must be present in sufficient quantity to reduce all of the
technetium atoms to the intended oxidation state but must not produce undesired reduction products or
other impurities (e.g., stannous hydroxide precipitates).
Reducing agents (e.g., stannous salts) must be readily soluble in water.
Reducing agents (e.g., stannous salts) are sensitive to oxidation by atmospheric oxygen and oxidizing
species in solution. Hence, lyophilized contents of kit vials must be filled with a nonoxidative gas such as
nitrogen or argon. The reducing agent also must be stable at the intended pH of the formulated product.
The following general chapters may be useful in ensuring consistency in selected reducing agent
functions: Chromatography 〈621〉 and Radioactivity 〈821〉.
Functional Category: Transfer Ligand
In the preparation of certain radiopharmaceuticals, the radiometal (e.g., stannous-reduced technetium
Tc 99m) is first chelated by a relatively weak chelating ligand and then is transferred to the principal
chelating ligand or complexing moiety. Examples of such transfer ligands include citrate, gluconate, and
tartrate.
Transfer ligands typically undergo rapid reactions with reduced technetium to form weak chelates, thus
keeping the reduced technetium in a soluble form until it is transferred to the principal ligand. This
procedure is especially useful when the kinetics of complexation with the principal ligand is slow or when a
heating step is necessary to expose chelating groups on the principal ligand.
Transfer ligands must be readily soluble in water.
Transfer ligands must have rapid complexation kinetics and must form relatively weak chelates
compared to complexation with the principal ligand.
The following general chapters may be useful in ensuring consistency in selected transfer ligand
functions: Chromatography 〈621〉 and Radioactivity 〈821〉.
Functional Category: Colloid Stabilizing Agent
Lyophobic colloids tend to clump together and form large aggregates to minimize their surface-area-to-
volume ratio. Colloid stabilizing agents are relatively large lyophilic molecules that coat the surface of each
individual colloid particle and prevent or inhibit clumping. Examples of colloid stabilizing agents include
gelatin and dextran.
The colloid stabilizing agent coats the surface of the lyophobic colloid particles, making them appear
lyophilic. Additionally, the colloid stabilizing agent may be charged, thus causing the coated colloid
particles to repel one another.
Colloid stabilizing agents must be readily soluble in water.
Colloid stabilizing agents must be capable of coating the lyophobic colloid particles, e.g., by electrostatic
attraction of an opposite charge.
The following general chapters may be useful in ensuring consistency in selected colloid stabilizing agent
functions: Chromatography 〈621〉 and Radioactivity 〈821〉.
Functional Category: Free Radical Scavenger
Radiation interactions with water and other molecules frequently produce free radicals. Free radical
scavengers preferentially interact with oxidative or reductive free radicals that otherwise would result in
degradation of formulation components. In the case of radiopharmaceuticals, free radical scavengers can
be used to enhance radiochemical purity. Examples of free radical scavengers include methylene blue and
aminobenzoic acid.
Free radical scavengers preferentially interact with radiolytically produced free radicals before these free
radicals can interact with the radiopharmaceutical and produce radiochemical impurities.
Free radical scavengers must be readily soluble in water.
Free radical scavengers must be capable of preferentially interacting with free radicals without causing
other effects.
▲
INTRODUCTION
The purpose of this chapter is to explain how excipients may be used in formulations and how they relate
to compendial specifications, performance-related properties (PRPs), critical material attributes (CMAs), and
quality by design (QbD) principles that aid in their selection and control. Excipients are used in virtually all
drug products and are essential for drug product manufacturing and performance. To ensure robust drug
products with consistent quality, the excipients must be well characterized, qualified, and appropriately
specified. Excipients used in drug products typically are manufactured and supplied in compliance with
compendial standards. However, the effects of excipient properties on the quality and performance of a
drug product may be unique for each formulation and process, and could depend on properties of excipients
that are not evaluated in USP or NF monographs, and which may vary from supplier to supplier and batch
to batch (see General Notices, 4.10 Monographs). The impact of excipient properties and their variability
depends on the role of an excipient in a formulation and the critical quality attributes (CQAs) of the drug
product.
An excipient may be used in different ways or for different purposes in a formulation and may therefore
require different material properties to achieve the desired performance. Excipient functional categories are
broad, qualitative, and descriptive terms for the purpose an excipient serves in a formulation. There may be
specific limitations related to dosage forms and patient populations (pediatric, geriatric, etc.). A list of
excipients grouped by functional category is included in USP and NF Excipients, Listed by Functional
Category.
Minimum quality requirements for an excipient are specified in an excipient monograph. Additional
performance-related properties (PRPs) described in this chapter may also be identified as critical material
attributes (CMAs).
A PRP is a physical, chemical, biological, or microbiological property of an excipient anticipated to
potentially impact finished product quality and performance, dependent on the application. For example,
excipient particle size distribution would be a PRP for oral solid dose forms as this property can impact flow,
compactability, and active pharmaceutical ingredient (API) content uniformity. In contrast, if the excipient is
dissolved in a liquid dosage form, the particle size distribution may not be a PRP. PRPs are typically
assessed during development and when critical to product quality, acceptance criteria should be
established. Those properties determined to be CMAs may be adequately controlled through excipient
supplier specifications and by grade selection in consultation with the excipient suppliers. PRPs are often the
properties that differentiate multiple grades of an excipient.
A CMA is a product-specific physical, chemical, biological, or microbiological property of an excipient
intended to control finished product quality and performance. CMAs are properties not necessarily specified
by either the supplier or the excipient monograph. Good product development practices, which at times are
termed QbD principles, require understanding of how excipient properties contribute to consistent finished
drug product performance and are the foundation of a control strategy.
CMAs must be within appropriate limits or used to control the process and/or composition to ensure that
the CQAs are consistently met for a particular drug product and maintained throughout the product life
cycle. CMAs may be identified during development, scale-up, and life cycle management and require a
thorough understanding of drug product CQAs; the manufacturing process(es); the formula; the physical,
chemical, biological, or microbiological properties of the excipient; and the interaction between them. Prior
knowledge, experiments, and risk assessment tools can also be used to identify potential CMAs. Drug
product manufacturers should anticipate batch-to-batch and supplier-to-supplier variability in excipient
properties. CMAs should be agreed upon with suppliers to ensure the limits are within the excipient process
capability and to ensure alignment on methods for characterization. CMAs are not always related to the
major component. The presence of minor components (e.g., peroxides, elemental impurities, or
microbiological content) may affect finished product manufacturability, stability, or quality.
Excipient specifications should be based on the monograph requirements and the identified CMAs. In
cases where there are no functionality related concerns, tests without acceptance criteria in the monograph
may be monitored without imposing limits. In such cases, the drug product manufacturer may employ
additional methods to monitor supplier consistency, compare multiple suppliers, and provide further
application-specific insight but need not impose their own limits especially if multiple methods are employed
across the supplier base.
Functional categories can apply to multiple dosage forms. Each functional category includes a general
description; physical properties common to these excipients; chemical properties; the mechanisms by
which excipients achieve their function; dosage forms; performance-related properties; and a list of USP
chapters that can be useful in conducting specific tests and procedures, and in establishing acceptance
criteria to ensure that material properties are adequately monitored and controlled. Because of the complex
nature and interplay of formulation ingredients, processing, and dosage form performance requirements,
the information provided in this chapter should not be viewed as restrictive or comprehensive.
ACIDIFYING OR ALKALIZING AGENT
Description
Acidifying and alkalizing agents may be liquid or solid. They are used to adjust the pH of pharmaceutical
drug products to a desired value or range. Acidifying agents lower the pH and alkalizing agents increase the
pH. Examples of acidifying agents include hydrochloric acid, phosphoric acid, acetic acid, and citric acid.
Examples of alkalizing agents include ammonia solution, sodium hydroxide, potassium hydroxide, and
sodium bicarbonate. Measurement of pH is described in pH 〈791〉. A related functional category is Buffering
Agent.
Physical Properties
Particle size may be important if it affects dissolution during the preparation, manufacture, or finished
product performance.
Chemical Properties
Acidifying and alkalizing agents influence the pH of the drug product but may not have adequate buffer
capacity (See Buffering Agent). Acidifying and alkalizing agents used in physiological systems should not
interfere with the pharmacological activity of the active ingredient. Multifunctional acidifying or alkalizing
agents may have multiple ionization equilibria (pKa), which influence pH titration.
Functional Mechanism
The pKa of acidifying and alkalizing agents in aqueous media are key to pH modification. Their strength is
a function of the pKa. Strong acids have a lower pKa and strong alkali have a higher pKa. The properties of
acidifying and alkalizing agents may vary significantly with temperature.
Dosage Forms
Acidifying and alkalizing agents are typically added to or dissolved in liquid dosage forms, including
solutions, injections, irrigations, shampoos, soaps, suspensions, sprays, and liquids to adjust solution pH.
These agents may also be incorporated into solid or semisolid dosage forms in the undissolved state for the
same purpose upon exposure to aqueous media.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include particle size and
solubility. Particle size may be important where dissolution of an acidifying and alkalizing agent may be
critical to assuring consistent properties and performance. The presence of insoluble particulates may
present problems in the preparation of sterile products. Particle size may influence content uniformity and
powder flow properties when incorporated as a solid form.
General Chapters
The following general chapters may be useful in ensuring consistency in selected acidifying functions:
〈791〉, Elemental Impurities 〈232〉, Particle Size Distribution by Analytical Sieving 〈786〉, and Light Diffraction
Measurement of Particle Size 〈429〉.
ADHESIVE (PRESSURE SENSITIVE)
Description
Pressure sensitive adhesives are excipients designed to maintain contact between the applied drug
delivery system and biological membranes. Some adhesives may be available as solutions in organic
solvents or water. In these instances, the properties and tests described below refer to the dry adhesive
after any cross-linking and removal of the solvent and/or water. Adhesives can be intercalated as a separate
layer between the formulation matrix and the skin surface (adhesive used in reservoir patches),
incorporated as a part of the formulation matrix itself (adhesive used in matrix patches), or applied to the
periphery of the topical delivery system (rim adhesive). Adhesives in systems must permit easy removal of
the release liner before use, adhere properly to human skin upon application, maintain adhesion to the skin
during the prescribed period of use, and permit easy removal of the dosage form at the end of use without
leaving a residue or causing damage to the skin or other undesirable effect(s). Additionally, adhesives must
be able to maintain the performance of the dosage form throughout the shelf life of the drug product. A
related functional category is Muco-Adhesive.
Physical Properties
In general, pressure sensitive adhesives are viscoelastic materials that can adhere to various surfaces
such as skin upon application of light contact pressure and leave no residue upon removal.
Chemical Properties
The most commonly used pressure sensitive adhesives are composed of acrylic, rubber, or silicone
polymers. Acrylic polymer adhesives include various esters of acrylic or methacrylic acid, acrylamide,
methacrylamide, N-alkoxyalkyl, or N-alkyl-acrylamides. Polyisobutylenes and polysiloxanes are among the
most common rubber- and silicone-based adhesives, respectively.
Functional Mechanism
Adhesion is the tendency of dissimilar surfaces to adhere to one another as a result of one or more types
of interactions.
For topical drug delivery systems, adhesive interactions generally are chemical (primarily electrostatic) or
dispersive (van der Waals and/or hydrogen bonding) in nature, although there is the possibility of
mechanical interaction via the interlocking of microscopic asperities.
Dosage Forms
Pressure sensitive adhesives are typically used in transdermal systems to maintain contact between the
applied drug delivery system and the skin. They are also used in adhesive dressings and bandages.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include peel adhesion,
release liner peel, tack (quick stick), cold flow, and shear (cohesive strength). The peel adhesion, release
liner peel, and tack tests measure the adhesion properties of the dosage form. Each of these tests
measures the force required to separate the dosage form from another surface. The cold flow and shear
tests measure the cohesive properties of the dosage form. These latter tests measure the resistance to flow
of the adhesive matrix.
However, direct peel adhesion, tack, and shear measurements may not be true material properties of the
adhesive because they depend on substrate, backing material, and test parameters; therefore, measures of
adhesive viscoelastic properties should be considered.
In addition, viscosity of an adhesive solution (if available as a solvent solution) can often be used as a
critical material attribute in the processing of the dosage form.
Other potential performance-related properties may include adhesive molecular weight, molecular weight
distribution, and cross-link density.
General Chapters
The following general chapters may be useful in evaluating the suitability of adhesives used in
transdermals: Topical and Transdermal Drug Products—Product Quality Tests 〈3〉, Tensile Strength 〈881〉,
Viscosity—Capillary Methods 〈911〉, and Viscosity—Rotational Methods 〈912〉.
Additional Information
The following references are provided for additional information on this topic.
Wokovich AM, Shen M, Doub WH, Machado SG, Buhse LF. Release liner removal method for
transdermal drug delivery systems (TDDS). J Pharm Sci. 2010;99(7)3177–3187.
Prodduturi S, Sadrieh N, Wokovich AM, Doub WH, Westenberger BJ, Buhse L. Transdermal delivery of
fentanyl from matrix and reservoir systems: effect of heat and compromised skin. J Pharm Sci.
2010;99(5)2357–2366.
Wokovich AM, Brown SA, Shen M, Doub WH, Cai B, Sadrieh N, Chen ML, Machado SG, Buhse LF.
Evaluation of substrates for 90 degrees peel adhesion-A collaborative study. II. Transdermal drug
delivery systems. J Biomed Mater Res B Appl Biomater. 2009;88(1)61–65.
Wokovich AM, Brown SA, McMaster F, Doub WH, Cai B, Sadrieh N, Chen ML, Machado SG, Shen M,
Buhse LF. Evaluation of substrates for 90 degrees peel adhesion-A collaborative study. I. Medical
tapes. J Biomed Mater Res B Appl Biomater. 2008;87(1)105–113.
Wokovich AM, Prodduturi S, Doub WH, Hussain AS, Buhse LF. Transdermal drug delivery system
(TDDS) adhesion as a critical safety, efficacy and quality attribute. Eur J Pharm
Biopharm.2006;64(1)1–8.
Minghetti P, Cilurzo F, Montanari L. Evaluation of adhesive properties of patches based on acrylic
matrices. Drug Dev. Ind. Pharm. 1999;25(1)1–6.
Ulman K, Thomas X. Silicone pressure sensitive adhesives for healthcare applications. In: Satas D,
ed. Handbook of Pressure Sensitive Adhesive Technology. 3rd ed. Warwick, Rhode Island: Satas &
Associates; 1999:724–747.
Steven-Fountain A, Atkins A, Jeronimidis G, Vincent J, Farrar D, Chivers R. The effect of flexible
substrates on pressure-sensitive adhesive performance. Int J Adhes. 2002;(22)423–430.
Pressure Sensitive Tape Council. PSTC 101 test method: peel adhesion of pressure sensitive tape. In:
Test Methods for Pressure Sensitive Tapes. 14th ed. Northbrook, IL: Pressure Sensitive Tape Council;
2004:101.1–101.10.
Van Buskirk GA, Arsulowicz D, Basu P, Block L, Cai B, Cleary GW, et al. Passive transdermal systems
whitepaper incorporating current chemistry, manufacturing and controls (CMC) development
principles. AAPS PharmSciTech. 2012;13(1)218–230.
AIR DISPLACEMENT
Description
Air displacement excipients are inert gases (e.g., nitrogen and argon) used to replace atmospheric air in
dosage forms that are liable to interact with gases commonly present in such an environment.
Physical Properties
Air displacement excipients are gaseous, colorless, odorless, and tasteless materials. Their physical
properties depend on their chemical structures. Moisture content of the air displacement agents should be
considered.
Chemical Properties
Air displacement excipients are inert substances.
Functional Mechanism
Oxygen present in atmospheric air may react with materials that are highly prone or sensitive to
oxidation. Air displacement excipients will simply replace atmospheric air in the contents of containers or
the container headspace. These oxidation sensitive materials may be drug substances or excipients that
may directly or indirectly oxidize and lead to further degradation of the drug substance or excipient. For
instance, polysorbates may oxidize upon relatively long exposures to atmospheric air and generate reactive
oxygen species, which, in turn, may destabilize drug substances or excipients. For this reason, nitrogen is
commonly used to displace atmospheric air in the headspace of packages of polysorbates intended to be
used as excipients. In other cases, air displacement may be required to protect the dosage form itself.
Dosage Forms
Oxidation-sensitive materials in solid state are usually less reactive. Therefore, air displacement
excipients are more likely to be used in solution dosage forms, including injections and solutions. Because
certain packaging materials may be permeable to gases (i.e. certain rubber types), appropriate selection of
packaging material and packaging processes are necessary to ensure drug product stability during shelf life.
Minimizing container headspace may also further support the control strategy for the drug product.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include attributes related to
impurities (i.e. presence of other gases and/or water). In particular, presence of water may lead to
degradation (i.e. hydrolysis) of moisture sensitive drug substances.
General Chapters
The following general chapters may be useful in ensuring consistency in selected air displacement
functions: Impurities Testing in Medical Gases 〈413〉, Medical Gases Assay 〈415〉, Elastomeric Closures for
Injections 〈381〉, Packaging and Storage Requirements 〈659〉, Package Integrity Evaluation—Sterile Products
〈1207〉, Package Integrity Testing in the Product Life Cycle—Test Method Selection and Validation 〈1207.1〉,
Package Integrity Leak Test Technologies 〈1207.2〉, and Package Seal Quality Test Technologies 〈1207.3〉.
ALCOHOL DENATURANT
Description
Alcohol denaturants are typically very bitter substances that are added to alcohol (e.g., ethanol,
methanol, and isopropyl alcohol) or other personal care products such as nail polish remover to deter
accidental or intentional consumption. The legally permitted alcohol denaturants may vary from country to
country. In some countries, but not the United States, denatured alcohol may be required to be colored
(e.g., aniline dye).
Physical Properties
Alcohol denaturants are sufficiently soluble in both alcohol and water to provide a bitter taste when
ingested. They may be solids or liquids.
Chemical Properties
Alcohol denaturants are a very diverse group of chemical substances. Examples of alcohol denaturants
include denatonium benzoate, methyl isobutyl ketone, and sucrose octaacetate. Additional denaturants also
may also include ethyl acetate, brucine, denatonium saccharide, and quassin (the bitter component from
quassia tincture). The addition of pyridine or methanol makes alcohol poisonous.
Functional Mechanism
Alcohol denaturants interact with the "bitter" taste buds in the mouth to produce a very unpleasant taste.
Denaturants are typically incorporated at low concentrations.
Dosage Forms
Denatured alcohol may be useful in topical dosage forms such as creams, lotions, rinses, shampoos,
solutions for topical use, sprays for topical use, ointments, or cosmetics depending upon its application, but
such products would not be suitable for ingestion or injection. Sucrose octaacetate is also used in
preparations to prevent nail biting.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include producing a very
bitter taste at a sufficiently low concentration.
General Chapters
None
Additional Information
Refer to 27 CFR §21 for additional details regarding denaturants.
ANTIFOAMING OR DEFOAMING AGENT
Description
Additives that prevent or eliminate liquid foams. Defoaming implies breaking, rapid knockdown, and
control of preexisting foam. Antifoaming or foam inhibition indicates preventing the foam from forming in
the first place. Applications may require both the prevention and control of foam. The same types of
materials are often used for both antifoaming and defoaming.
Physical Properties
In general, ideal antifoaming agents are insoluble in the foaming medium and have as low a surface and
interfacial tension as possible in order to promote spreading of the foam films or foam-stabilizing
properties. Typically, they have low viscosity, surface active properties, and spread rapidly on foamy
surfaces. Antifoaming agents have an affinity to the air-liquid surface where they destabilize foam lamella.
Chemical Properties
Commonly used antifoaming agents include: silicone derivatives (e.g., poly(dimethylsiloxane),
simethicone, and simethicone emulsions) and saturated fatty acids (e.g., lauric acid and myristic acid).
Functional Mechanism
Antifoaming agents function at the air-liquid surface to destabilize foam lamellas, rupture bubbles, break
down surface foam, and/or compete at surface with foam-generating moieties.
Dosage Forms
Antifoaming agents are typically added at low levels to liquid formulations, including solutions, liquids and
suspensions to prevent or eliminate foaming. As most antifoaming agents are insoluble oils or silicone
derivatives, the miscibility of the additive can be improved by emulsification or addition of surfactant. In
addition, they are used for foam suppression during bottle-filling operations where foaming is a problem.
Antifoaming agents also have a clinical use (atypical active) in certain antacid preparations.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include viscosity, molecular
weight, specific gravity, melting temperature, acid value, water content, and iodine and peroxide values.
General Chapters
The following general chapters may be useful in ensuring consistency in performance of antifoaming
agents: Fats and Fixed Oils 〈401〉, Procedures, Acid Value, Fats and Fixed Oils 〈401〉, Procedures, Iodine
Value, Fats and Fixed Oils 〈401〉, Procedures, Peroxide Value, Congealing Temperature 〈651〉, Refractive
Index 〈831〉, Specific Gravity 〈841〉, 〈911〉, 〈912〉, and Water Determination 〈921〉.
ANTIMICROBIAL PRESERVATIVE
Description
Antimicrobial preservatives are used to kill or prevent growth of bacteria, yeast, and mold in the dosage
form. They can show limited protection against viral contamination. Use of preservatives to counter
microorganisms that may be inadvertently introduced during manufacture does not reduce the need to
minimize bioburden in accordance with current good manufacturing practice regulations. Preservatives are
also mandatory for multidose liquid products with potential for in-use contamination.
Physical Properties
Antimicrobials generally must be present in the aqueous phase at an effective concentration.
Understanding an excipient's partition coefficient is important because partitioning and/or adsorption of a
preservative into an oil phase, processing equipment, or packaging can diminish the preservative's effective
concentration in the aqueous phase, which, in turn, can reduce its value as a preservative. Volatile
preservatives such as alcohols may not be suitable for lyophilization or spray drying processes, for which
solid antimicrobials should be added.
Chemical Properties
A preservative must be compatible with the active and inactive ingredients of the finished product. For
example, benzyl alcohol is incompatible with oxidizing agents. Chlorobutanol is incompatible with some
nonionic surfactants. Others may interact with peptides and proteins. Compatibility among compounds may
vary with the pH of the formula. The preservative should be stable in solution at the pH of the formulation.
Individual preservative efficacies may be pH-dependent.
Functional Mechanism
Preservatives work by a variety of mechanisms. Most work at the cell wall or cytoplasmic membrane,
causing membrane damage and cell leakage. Other modes of action include transport inhibition, protein
precipitation, and proton-conducting uncoupling. Some preservatives are bactericidal (kill bacteria or yeast
and mold); some are bacteriostatic (inhibit growth of microorganisms); and others are sporicidal (kill
spores). Several of the preservatives can act synergistically (e.g., combinations of parabens). Quaternary
ammonium compounds affect microbial cell membranes via charge interactions with phospholipids, leading
to disruption of the cell membrane. Parabens also disrupt cell membrane integrity. Alcohols such as
chlorobutanol and benzyl alcohol work via lipid (membrane) solvation and protein denaturation. Sorbic acid
works by reduction of the sulfhydryl groups of proteins. Although not preservatives per se, sugars such as
sucrose or sorbitol at high concentrations may inhibit growth due to high osmotic pressure. When using
high concentrations of sucrose as a preservative, the increased risk of dental caries should be considered.
Dosage Forms
Preservatives may be used in aqueous liquid dosage forms, including solutions, liquids, irrigations,
shampoos, soaps, suspensions, sprays, and multiuse injections. Other dosage forms in which antimicrobial
preservatives are often included are creams, lotions, and solid formulations intended for reconstitution as
liquids. Choice of preservatives may be dictated by the route of administration, and there may be specific
requirements such as a potential for ocular irritancy.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include aqueous solubility,
partitioning, organoleptic properties, and particle size where speed of dissolution is critical in a powder or
tablet presentation for reconstitution.
General Chapters
The following general chapters may be useful in ensuring consistent functions of selected antimicrobial
preservatives: Antimicrobial Effectiveness Testing 〈51〉, Sterility Tests 〈71〉, Bulk Density and Tapped
Density of Powders 〈616〉, Chromatography 〈621〉, Density of Solids 〈699〉, Loss on Drying 〈731〉,
Pharmaceutical Dosage Forms 〈1151〉, Powder Flow 〈1174〉, Sterility Assurance 〈1211〉, and Validation of
Microbial Recovery from Pharmacopeial Articles 〈1227〉.
ANTIOXIDANT
Description
Antioxidants are used to mitigate oxidative processes and to stabilize drug product formulations.
Antioxidants such as butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, methionine, and
tryptophan delay the onset of and/or significantly reduce the rate of complex oxidative reactions that could
otherwise have a detrimental effect on the drug substance. Antioxidants also can be considered for
protecting the sensitive components of a formulation such as unsaturated oils, pegylated lipids, flavors, and
essential oils. Thus, antioxidants preserve the overall integrity of the dosage form against oxidative stress.
Physical Properties
Solubility of the antioxidant should be greatest in the formulation phase (oily, aqueous, or emulsion
interface), where the drug substance or sensitive formulation components are most soluble. The
temperature at which the antioxidant decomposes is critical for autoclaved preparations, where loss of
antioxidant activity may occur. Stability of the antioxidant also must be considered and may be a function of
pH and processing conditions. Metal ions may react with propyl gallate to form colored complexes. At
alkaline pH, certain proteins and sodium salts may bring about discoloration of tert-butylhydroquinone.
Chemical Properties
Activation energy, oxidation–reduction potential, and stability at different formulation (e.g., pH) and
processing (e.g., heat) conditions are important chemical properties. If the dosage form's expected shelf life
depends on the function of the antioxidant, the concentration must be considered and periodically assessed
to ensure that a sufficient amount of antioxidant remains throughout the product shelf life.
Functional Mechanism
Autoxidation is initiated when oxygen reacts with a substrate to form highly reactive species known as
free radicals (RH → R · ). After “initiation” the free radicals in the presence of oxygen can trigger chain
reactions (R · + O → ROO · and ROO · + RH → R · + ROOH) to form peroxy radicals, hydroperoxides, and
new alkyl radicals that can initiate and then propagate their own chain reactions. The cascading reactions
during the propagation phase can be accelerated by heat, light, and metal catalysts. In the presence of
trace amounts of metal catalysts (Cu
+
, Cu
2+
, Fe
2+
, and Fe
3+
), hydroperoxides (ROOH) readily decompose
to RO · and ROO · and subsequently can trigger reactions with the API and/or the excipients (e.g.,
hydrocarbons) to form hydroxyl acids, keto acids, and aldehydes that can have further undesirable effects.
Antioxidants can be grouped by their mode of action. Phenolic antioxidants that block free radical chain
reactions also are known as true or primary antioxidants. This group consists of monohydroxy or
polyhydroxy phenolic compounds with ring substitutions. They have very low activation energy to donate
hydrogen atom(s) in exchange for the radical electrons that are rapidly delocalized by free radicals. By
accepting the radical electrons, they stabilize free radicals. The reaction yields antioxidant free radicals that
also can react with lipid free radicals to form other stable compounds. Thus, they can block oxidative chain
reactions both in the initiation and propagation stages. Because of their solubility behavior, phenolic
antioxidants are most effective in protecting oils and oil-soluble actives against oxidative stress. Reducing
agents generally are water-soluble antioxidants (e.g., -ascorbic acid) with lower redox potential than the
drug or the excipient they are protecting and delay the onset and rate of oxidative reactions by sacrificially
reacting with oxygen and other reactive species. The oxygen-scavenging potential of the reducing agents
may be sensitive to pH and also can be negatively affected in the presence of trace elements. Chelating
agents bind with free metals (Cu
+
, Cu
2+
, Fe
2+
, and Fe
3+
) that may be present in trace amounts in the
formulation. The newly formed complex ions are nonreactive. Chelating agents therefore remove the
capacity of the metal catalysts to participate in oxidative reactions that occur during the propagation stage.
The utility of antioxidants can be maximized by synergistic use of one or two primary antioxidants along
with reducing and chelating agents. The combined effect often is greater than the sum of the individual
effects of each antioxidant (synergistic effect).
Dosage Forms
Antioxidants have been used in a wide range of medicinal products for various administration routes
including oral, topical, and injectable. Typical dosage forms containing antioxidants are injections, creams,
lotions, foams, and liquids. They can also be used in tablets and in other solid dosage forms.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include purity, aeration,
heat, and moisture content. These vary with the type of antioxidant, its physico-chemical nature, the effect
it exerts on the active, excipient(s), formulation as a whole, and/or the drug container. The CQA-impacting
antioxidant activities are purity and mode of action, which determine how, where, and when the antioxidant
may be added in the manufacturing process to ensure content uniformity in the formulation. Process
2
conditions such as aeration, heat, and moisture that stand to exhaust antioxidant efficacy must be
identified and measured for impact on the final outcome, in part for stability. Further stability testing to
ensure that a sufficient amount of antioxidant remains to protect the medicinal product throughout its
entire shelf life and during the proposed in-use conditions should be undertaken.
General Chapters
The following general chapters may be useful for assessing selected excipient antioxidant functions: Iron
〈241〉, 〈621〉, Crystallinity 〈695〉, Melting Range or Temperature 〈741〉, Specific Surface Area 〈846〉, and
〈921〉.
Additional Information
Unless necessary and justified, the inclusion of antioxidants in medicinal products, notably in pediatrics, is
to be avoided. When justified, antioxidants should be used at the lowest feasible concentration levels,
sufficient for exerting the intended function. Taking into consideration the safety and allowable intake limits,
the usage levels should be carefully considered and justifiable. Antioxidants are most effective when
incorporated in the formula to prevent or delay the onset of chain reactions and to inhibit free radicals and
hydroperoxides from engaging in the cascading processes described above. Effective application of
antioxidants and evaluation of their efficacy necessitate an understanding of oxidative mechanisms and the
nature of the byproducts they generate. Note that hydroperoxides are not solely the reaction products of
oxidative mechanisms within a formulation. Residual amounts of hydroperoxides also can be found in
commonly used excipients such as polyethylene glycols, polyvinylpyrrolidone, and polysorbates. The
initiation phase generally is slow and has a limited effect on the quality of the finished product. The
propagation phase, in contrast, involves rapid, irreversible degradation of chemical species.
ANTITACK AGENT
Description
Antitack agents are used to reduce surface tackiness and the incidence of tablets sticking together during
coating and consequently improve process efficiency, coating uniformity, and appearance, particularly for
coatings such as enteric coatings, which often have a low glass transition temperature (T ). These materials
can be incorporated into the coating dispersion or loaded directly into the coating pan during or following
the coating process. A related functional category: Glidant and/or Anticaking Agent.
Physical Properties
Primary physical properties of potential importance for antitack agents are particle size distribution,
particle morphology, and surface area. For waxes, glass transition temperature is important.
Chemical Properties
The chemical nature of antitack agents is varied. Examples include talc, glyceryl monostearate, mono-
and diglycerides, carnuba wax, beeswax, and polyvinyl alcohol. Agents such as talc are finely divided
inorganic materials and are insoluble in water.
Functional Mechanism
Agents such as talc and waxes function primarily by adsorption onto the surface of tablets and reduction
of tackiness. Alternatively, waxes and surfactants may be incorporated into the coating dispersion to
increase the slip factor, thereby reducing tablet adhesion during coating and downstream processing.
Dosage Forms
Antitack agents are used mainly in coated tablets, capsules, and multiparticulate beads and granules.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include primarily particle
size distribution, particle morphology, surface area, andT of the antitacking agent.
g
g
General Chapters
The following general chapters may be useful in ensuring consistency in antitack agent functions: 〈429〉,
Particle Size Distribution Estimation by Analytical Sieving 〈786〉, 〈846〉, Thermal Analysis 〈891〉, 〈921〉, and
Scanning Electron Microscopy 〈1181〉.
BIODEGRADABLE POLYMER
Description
Biodegradable polymers are used to control and sustain drug release from injected particles (generally
described as microspheres or microcapsules) or implants. They are used as carriers for small molecules,
peptides, and proteins. Commonly used biodegradable polymers include synthetic polymers such as
poly(,-lactide-co-glycolide) (PLGA), poly(,-lactic acid) (PLA), derivatives of PLGA, and polyanhydride.
Natural polymers such as collagen, gelatin, alginate, cyclodextrins, chitosan, dextran, agarose, and
hyaluronic acid may be used in the formulation of sustained release products.
Physical Properties
The physical properties of biodegradable polymers depend mainly on the nature of monomers, type of
linkage, and molecular weight of the polymer. The polymer molecular weight is an important physical
property. The other important physical properties include crystallinity, T , melting point, and solubility. PLGA
particles and implants are generally amorphous. The morphology (amorphous or crystalline) affects the rate
of degradation and the mechanical properties of PLGA particles or implants. PLA and PLGA polymers
containing less than 50% glycolic acid units are soluble in common organic solvents, whereas PLGA
polymers containing more than 50% glycolic acid units are insoluble in common organic solvent. In the case
of natural polymers, the main physical properties may include molecular weight and viscosity. Mechanical
properties (strength, toughness, and elasticity) of biodegradable polymers may be important for the
manufacturing of drug products.
Chemical Properties
Biodegradable polymers are generally polyesters of lactic and glycolic acids.
Functional Mechanism
The performance of a biodegradable polymer such as PLGA is mainly linked to the rate of biodegradation,
which can be controlled by properties such as chemical composition (lactide/glycolide ratio) and
stereochemistry (composition of - or -lactide). Although PLGA polymers are generally hydrophobic
polymers, the PLGA polymer with higher content of lactic acid units is less hydrophilic with lower water
absorption property, resulting in slower degradation. The hydrophilicity of the polymer depends on type of
linkage, monomers, and chemical composition. PLGA derivatives, PLGA-glucose, or polyethylene glycol
(PEG)-PLGA have hydrophobic chains and hydrophilic groups (glucose or PEG). The end structure of
polymer can also affect its degradation.
Drugs are loaded into carrier particles or implants during or after formation in a manufacturing process
and are distributed throughout the polymer matrix or encapsulated as a core inside the particles. The drug
release profile depends on the nature of biodegradable polymers, the nature of drug, and the structure of
the carrier. Drug release may be due to a combination of mechanisms such as erosion or degradation of the
polymer, diffusion through water-filled pores, diffusion through the polymer, or osmotic pumping. Factors
affecting drug release profile other than the physical and chemical properties of biodegradable polymers
include the interaction of functional groups between drug and polymers, the shape and size of particles, and
other excipients.
Dosage Forms
Biodegradable polymers are used as carriers for small molecules, peptides, and large molecules. The
dosage forms of biodegradable polymer-based formulations are mainly lyophilized injections. Solid particles
or implants may be generally administered by intramuscular or subcutaneous injections.
g
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include viscosity, solubility,
molecular weight distribution, T , crystallinity, composition ratio (in the case of PLGA), loss on drying,
elemental impurities, and identity.
General Chapters
The following general chapters may be useful in ensuring consistency in selected biodegradable polymers:
Injections and Implanted Drug Products 〈1〉, 〈71〉, Bacterial Endotoxins Test 〈85〉, 〈621〉, 〈695〉, 〈731〉, 〈891〉,
〈911〉, 〈912〉, Viscosity—Rolling Ball Method 〈913〉, 〈1151〉, Water–Solid Interactions in Pharmaceutical
Systems 〈1241〉, and Rheology 〈1911〉.
BUFFERING AGENT
Description
A buffering agent is a weak acid or weak base and a conjugate protonated species, typically a salt.
Examples of conjugate acid-base pairs include acetic acid and sodium acetate or ammonia solution and
ammonium phosphate. When a buffer is present in a solution, the addition of small quantities of acid or
base leads to only a small change in solution pH. Buffer capacity is the ability of the buffering agent to
minimize pH change and is determined by the ratio of conjugate base to conjugate acid and total
concentration of buffering agent.
The pH of pharmaceutical solutions typically is controlled using buffering agents to: 1) improve drug
stability where it is found to be pH-dependent, 2) control equilibrium solubility of weak acids or bases, or 3)
maintain a pH close to that of relevant physiological pH to avoid irritation. Measurement of pH is described
in 〈791〉, and Pharmaceutical Calculations in Pharmacy Practice 〈1160〉 provides background information on
pH, pH buffers, buffer solutions, and buffer capacity calculations. A related functional category is Acidifying
or Alkalizing Agent .
Physical Properties
Physical properties such as particle size of the buffering agent may be important in preparing
pharmaceutical solutions as it may influence processing requirements such as the mixing time required to
dissolve a buffering agent.
Chemical Properties
Buffers influence solution pH, buffer capacity, osmolality, osmolality, and water conductivity. When used in
chemical analysis, buffers must be chemically compatible with the reagents and test substance. Buffers
used in physiological systems should not interfere with the pharmacological activity of the medicament. The
relationship between solution pH, the buffering agent pKa, and the ratio of ionized to nonionized buffer
species is given by the Henderson–Hasselbach equation:
Buffer capacity is at its maximum when solution pH is equal to the pKa of the buffering species and
decreases as pH deviates from the pKa. Buffer capacity is also dependent upon total buffering agent
concentration (C). Buffer capacity, β, may be estimated by the Van Slyke equation:
g
Functional Mechanism
The ionization equilibria of weak bases, weak acids, and water are key to the function of buffering agents.
The pKa of buffers may vary significantly with temperature.
Dosage Forms
Buffering agents are typically dissolved in liquid dosage forms to control the pH of a solution. Buffering
agents may be incorporated into solid or semisolid dosage forms in the undissolved state for the same
purpose upon exposure to aqueous media. Typical dosage forms include injections, suspensions, sprays,
liquids, emulsions, and ointments.
For injectable products the range of acceptable buffers is limited. Certain buffers may cause pain upon
injection or are sensitive to light; thus, the selection of the buffer should be carefully considered. Where
freezing may be a step in the process, pH shifts with certain buffers can occur and should be evaluated
(e.g., crystallization of phosphate salts). In the case of biological formulations, the buffer species may also
play a role in the physical or chemical stability of the protein.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include purity and particle
size where dissolution of the buffering agent may be critical to assuring consistent product properties and
performance. The presence of insoluble particulates may present problems in the preparation of sterile
products. Particle size may influence content uniformity and powder flow properties when incorporated as a
solid form.
General Chapters
The following general chapters may be useful in ensuring consistency in buffering agent functions:
Osmolality and Osmolarity 〈785〉, 〈791〉, 〈232〉, 〈786〉, and 〈429〉.
BULKING AGENT
Description
Bulking agents are excipients that provide body and structure to lyophilized (freeze-dried) formulations
and include various saccharides, sugar alcohols, amino acids, and polymers.
Physical Properties
Bulking agents are dissolved in aqueous solution before lyophilization. Hence, the physical form and
particle properties of the bulking agent are generally not relevant to the final properties of the lyophilized
formulation.
The physical properties that are essential to product performance during and after lyophilization include
the glass transition temperature (T ) of the amorphous frozen concentrate before drying, the glass
transition temperature of the final dried formulation cake, and the eutectic melting temperature of the
crystalline bulking agent with ice. The T of the formulation depends on the glass transition temperatures of
the individual components, concentrations, and molecular interactions. Although approximations can be
made based on reported transition temperatures for individual components, current practice includes the
measurement of glass transition temperature of formulation by thermal analysis or freeze-drying
microscopy.
The physical states of the bulking agent during and after lyophilization are important physical properties.
Both formulation composition and lyophilization processing parameters play roles in determining whether
the bulking agent is amorphous or takes a specific crystalline form. Rate of freezing, drying temperatures,
and annealing are among the important process parameters used to control the physical state of the
formulation and its components.
For protein formulations, the selection of bulking agents requires careful consideration as proteins
generally present complex biophysical stability problems. The bulking agent should effectively inhibit
g
g
protein unfolding and protect the protein during the lyophilization cycle while also providing a strong cake
structure. Disaccharides (i.e. sucrose and trehalose) that remain amorphous in the lyophilization process
have been found to be effective stabilizers for protein formulations, by immobilizing the protein in an
amorphous glassy sugar matrix inhibiting protein unfolding. In the selection of bulking agents for protein
formulations, the T of the bulking agent should be considered. Above T , the molecular mobility in the
system increases, allowing for increased reactivity that can potentially impact storage stability of the
protein. Sugars with glass transition temperature significantly above room temperature (i.e. sucrose and
trehalose) can provide for good storage stability for protein formulations by restricting molecular mobility in
the system during shelf storage of the product. The residual moisture in a lyophilized product can reduce
the T and thus needs careful evaluation during product development to maximize shelf stability. For some
proteins and peptides, bulking agents that can crystallize (i.e. mannitol and glycine) generally do not
protect the protein during the lyophilization process, but when mixed in the appropriate ratio with a sugar
that stays amorphous (i.e. sucrose) can provide for a stable lyophilized formulation. A potential advantage
of such mixed crystalline/amorphous systems is that the primary drying can be conducted at higher
temperatures, reducing lyophilization cycle times. The design of such mixed systems can pose challenges
and needs careful evaluation during development of the lyophilized product.
Chemical Properties
The control of the chemical purity of the bulking agent is especially critical as any reactive impurities may
potentially lead to chemical degradation in small molecules and proteins or aggregation/inactivation of
proteins.
A group of sugars that should be avoided as bulking agents for proteins and small molecules are reducing
sugars (glucose, lactose, maltose) as they may lead to a Maillard reaction between the carbonyls of the
sugar and free amino group on the active ingredient. Low levels of reducing sugars can also be present as
an impurity in some sugars that can lead to stability issues. In addition, the presence of trace metals such
as Cu
2+
and Fe
2+
in bulking agents can cause metal catalyzed oxidation of proteins and small molecules.
Functional Mechanism
A bulking agent that readily crystallizes during lyophilization helps maintain the structural integrity of the
cake formed during primary drying, thereby preventing macroscopic collapse and maintaining
pharmaceutical elegance. Microscopic collapse of amorphous components in the formulation can still occur
(with some potentially undesirable results) but does not result in macroscopic collapse or “meltback” if the
properties and concentration of the bulking agent are adequate. The bulking agent also should possess a
high eutectic melting temperature with ice to permit relatively high primary drying temperatures with
commensurate rapid and efficient drying and subsequent rapid reconstitution upon usage. Functional cake-
forming excipients such as mannitol are frequently used because they crystallize during freezing, thereby
allowing efficient drying and the formation of a structurally robust and stable cake.
Proteins and many of the biopolymer active ingredients such as nucleic acids remain amorphous upon
lyophilization. Bulking agents such as disaccharides can function as lyoprotectants by helping to maintain a
stable amorphous phase during freezing and drying that immobilizes the protein in the amorphous glassy
sugar matrix. Bulking agents also are selected based on synergistic functionality for biocompatibility,
buffering capability, and tonicity-modifying properties.
Dosage Forms
Bulking agents are used in lyophilized formulations for use in injections.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include the T of the bulking
agent and impurities (reducing sugars, reactive impurities that can interact with proteins, peroxides, and
trace metals).
g g
g
g
General Chapters
The following general chapters may be useful in ensuring consistency in selecting bulking agent functions:
〈1〉, 〈695〉, Characterization of Crystalline Solids by Microcalorimetry and Solution Calorimetry 〈696〉, 〈785〉,
〈891〉, 〈1151〉, and 〈 1241〉.
Additional Information
Bulking agents are used in lyophilized formulations of both small molecules and proteins. Bulking agents
are included in lyophilized drug products to provide various functions. A lyophilized drug product can
contain a single bulking agent or a complementary combination of bulking agents to improve performance.
In general, the primary function of the bulking agent is to provide a pharmaceutically elegant cake with
noncollapsible structural integrity that will reconstitute rapidly for administration. In addition, bulking
agents are selected to prevent product loss caused by blow out during lyophilization, to facilitate rapid and
efficient drying, and to provide a stable formulation matrix. In the case of protein drug products that are
lyophilized, the bulking agent selected should effectively inhibit protein unfolding and protect the protein
and its activity during the lyophilization process. The selected agent should also provide a good cake
structure while maintaining chemical and physical stability of the protein, both during lyophilization and on
reconstitution.
CAPSULE SHELL
Description
Capsules enable pharmaceutical powders and nonaqueous liquids to be formulated via encapsulation for
dosing accuracy as well as ease of transportation. The capsule material should be compatible with all other
ingredients in the drug product.
Hard capsules typically consist of two parts: both are cylindrical, the capsule body, which is slightly
longer, and the cap, which fits closely over the body to close the capsule. Hard capsule shells may also be
used in dry powder inhalers (DPIs). The capsule shell is used to contain the dosage amount and protect the
inhalable powder while in the DPI. Traditionally, hard capsules have been manufactured from gelatin derived
from the hydrolysis of bovine, porcine, or fish collagen. Type A gelatin is derived by acid treatment, and
Type B gelatin is derived from alkali treatment. The common sources of commercial gelatin are pigskin,
cattle hide, cattle bone, cod skin, and tilapia skin. In recent years, hard capsules also have been
manufactured from substituted celluloses and other polysaccharides, alone or in combination.
In contrast, the soft capsule is a one-piece unit that may be seamed along an axis or may be seamless.
Traditionally, soft capsules have been manufactured using a combination of gelatin and a plasticizer,
typically, glycerin or sorbitol. Nongelatin soft capsules are now available.
Physical Properties
The primary physical properties relevant to the capsule shell are those that can have a direct effect on
product performance: 1) moisture content, 2) gas permeability, 3) physical stability on storage (e.g.,
increase in brittleness and propensity for cross-linking), 4) disintegration, 5) compactness, and 6)
brittleness. The moisture content varies with the type of capsule. Hard gelatin capsules typically contain
13%–16% water compared to hypromellose (hydroxypropyl methylcellulose or HPMC) capsules that
typically contain 4%–7% water content. Soft gelatin capsules contain 5%–15% water. Moisture content has
an important effect on capsule brittleness. Equilibrium water content also may be crucial to dosage form
stability and filling performance because water migration can take place between the shell and capsule
contents, and if the capsules are in a brittle state during filling they can break. Gas permeability may be
important and generally is greater for HPMC capsules than for gelatin capsules because of the presence of
open structures in the former. Unlike HPMC capsules, which do not cross-link, gelatin capsules have the
potential to cross-link in an autocatalytic reaction due to environmental and chemical exposure. Gelatin
capsules may undergo cross-linking upon storage at elevated temperature and humidity (e.g., 40° 75%
RH). Cross-linking slows in vitro dissolution and often necessitates introduction of enzymes in the test
medium, see Dissolution 〈711〉 and Disintegration and Dissolution of Dietary Supplements 〈2040〉. Gelatin
capsules should disintegrate within 15 min when exposed to 0.5% hydrochloric acid at 36°–38° but not
below 30°. HPMC capsules can disintegrate below 30°. Gelatin capsules are easier to close after filling than
capsules manufactured from other materials.
Chemical Properties
Gelatin is a protein and has all of the characteristic chemical reactions of protein. Gelatin shell material is
also known to cross-link due to exposure to aldehydes, ketones, and certain dyes in shell formulations.
Thus, presence of these materials in excipients should be considered for gelatin encapsulated products.
Cross-linking may also be induced by exposure to high relative humidity, which can be affected by the
viscosity of the gelatins used to manufacture the capsule shell.
The capsule material may be derived from processing of collagen that originates from porcine, bovine, or
fish sources, or it can be of nonanimal origin, e.g., cellulosic or polysaccharide chemical entities. Gelatin is a
commercial protein derived from the native protein, collagen. The product is obtained by partial hydrolysis
processing of collagen derived from skin, white connective tissue, and bones of animals. See the Gelatin
monograph for further details. The gelatin capsule shell also typically contains coloring agents, plasticizers
such as polyhydric alcohols, natural gums and sugars, and preservatives such as sodium metabisulfite and
esters of p-hydroxybenzoic acid.
The more commonly used nongelatin capsules are made from hypromellose. In addition to hypromellose
“veggie” alternative capsule shells have been developed from pullulan, starch and starch derivatives, iota
and kappa carrageenan, and polyvinyl alcohols. To date, gelatin and hypromellose have had the most
commercial success. Different capsule types contain different moisture levels and may thus influence drug
product stability. The detailed composition of capsule shell may be important because the shell function can
be influenced by small amounts of impurities in the excipients (e.g., peroxides in oils or aldehydes in lactose
and starches) that can cause capsule cross-linking. The presence in capsule shells of undesirable materials
such as metals, odorants, water-insoluble substances, and sulfur dioxide should be evaluated to ensure
stability and performance. In some cases, capsule shells are sterilized to prevent microbial growth such as
for DPIs.
Functional Mechanism
Capsules function in several ways: containing the dose of the active ingredient, masking unpleasant taste,
facilitating blinding in clinical studies, promoting ease of swallowing, and aiding in identification of the drug
product. Conventional capsule shells should dissolve rapidly at 37° in biological fluids such as gastric and
intestinal media. Traditionally, modified release was achieved by coating the capsule shell with either a
disintegration delaying polymer or a rate controlling polymer; however, there are capsule shells available in
which the release-modifying polymer is incorporated into the capsule shell (e.g., with enteric and
controlled-release polymers) to modify the release of the capsule contents.
Hard capsule shells are also used as unit dose containers in some DPI devices. In addition, the capsule
may be opened, and the contents may be added to food or liquid.
Dosage Forms
Capsules are primarily used in oral dosage forms that can enclose solid, semisolid, or nonaqueous liquid
formulations. However, capsules can also be used to administer drugs by rectal, vaginal, or inhalation
routes.
Performance-Related Properties
Potential performance-related properties include: moisture content, gelling temperature, melt viscosity,
mechanical properties, gas permeability, potential to cross-link (gelatin capsules), stability, disintegration,
and brittleness.
General Chapters
The following general chapters may be useful in ensuring consistency in selected capsule shell functions:
Microbial Enumeration Tests 〈61〉, Tests for Specified Microorganisms 〈62〉, Arsenic 〈211〉, Residue on
Ignition 〈281〉, Disintegration 〈701〉, 〈711〉, 〈921〉, Color—Instrumental Measurement 〈1061〉, Capsules—
Dissolution Testing and Related Quality Attributes 〈1094〉, 〈2040〉, 〈911〉, 〈912〉, 〈913〉, Viscosity—Pressure
Driven Methods 〈914〉, 〈1911〉, and 〈 891〉.
CARRIER
Description
Carriers are used to help deposit the active ingredient in the lung and may have a secondary role in
diluting the active to ensure that dosages can be accurately metered.
Physical Properties
The physical properties of carriers include appropriate morphology, hydration state, flowability, surface
energy, and particle size distribution. Carriers must have low microbial content.
Chemical Properties
Carriers must have suitable purity and impurity profiles and no extraneous proteins or impurities to avoid
interactions with the patient's immune system.
Functional Mechanism
Carriers may be used to promote drug deposition into the lungs for better penetration or absorption in the
appropriate lung location. The carrier may be used to decrease the concentration of the active ingredient so
the latter is adequately dosed in a uniform manner. An appropriate balance of adhesive and cohesive forces
between the carrier and active ingredient is necessary to produce a stable formulation that permits release
of active ingredient at the desired site, improve powder flow, facilitate manufacturing, and improve dosing
accuracy.
Dosage Forms
Carriers are used in aerosols dosage forms as a mechanism to transport the drug product into the lung.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include: particle size
distribution, flowability, surface energy, particle morphology, amorphous content, impurity profile, water
content, microbial load, etc.
General Chapters
The following general chapters may be useful in ensuring consistency in selected carrier functions: 〈61〉,
〈62〉, 〈232〉, Elemental Impurities—Procedures 〈233〉, 〈429〉, Inhalation and Nasal Drug Products: Aerosols,
Sprays, and Powders—Performance Quality Tests 〈601〉, 〈616〉, 〈695〉, 〈696〉, 〈699〉, 〈731〉, Optical
Microscopy 〈776〉, 〈786〉, Powder Fineness 〈811〉, Mid-Infrared Spectroscopy 〈854〉, Ultraviolet-Visible
Spectroscopy 〈857〉, 〈921〉, Characterization of Crystalline and Partially Crystalline Solids by X-Ray Powder
Diffraction (XRPD) 〈941〉, and 〈1174〉.
CATIONIC DENDRIMER
Description
Cationic dendrimers are a type of well defined globular macromolecule with multibranched three-
dimensional structure. They are generally synthesized by precise stepwise introduction of branching points
onto a core molecule by either a convergent approach or divergent approach. Cationic dendrimers mainly
consist of an internal core, layers of branches, and a multivalent peripheral shell. They are commonly used
as nucleic acid carriers, which form stable complexes with nucleic acid and protect them from degradation
before reaching the action site. Commonly used dendrimers include polyamidoamine (PAMAM) dendrimers,
poly(propylenimine) (PPI) dendrimers, poly(-lysine) dendrimers, and their derivatives.
Physical Properties
Because of their well defined, highly branched molecular architecture, cationic dendrimers demonstrate
some unique physical properties such as their solubility and viscosity. Dendrimers usually present a tightly
packed state in solutions that greatly influence their rheological properties. Generally, dendrimer solutions
have lower viscosity than linear polymers. The dendrimer generation, branches, and the molecular weight
have important influence on their viscosity. The solubility of dendrimers is strongly influenced by the surface
groups. Dendrimers terminated in hydrophilic groups are commonly soluble in polar solvents, whereas
dendrimers terminated in hydrophobic end groups are generally soluble in nonpolar solvents. The dendrimer
generation and branches significantly influence the flexibility, the charge density, and buffer capacity of the
dendrimers, thus influencing the zeta potential, size distribution, stability, and endosome escape ability of
formed nucleic acid complexes.
Chemical Properties
Cationic dendrimers can provide high density and a precise number of multivalent functional groups. They
generally possess different types of amines, which can be protonated under different pH conditions and
given a positive charge formulation. For example, PAMAM dendrimers and PPI dendrimers both contain
primary amine groups that can be protonated at a pH of 7.4 to facilitate nucleic acid complexation and
tertiary amine that can be protonated in the endosomal pH range to mediate endosome escape.
Functional Mechanism
Under neutral pH conditions, cationic dendrimers are positively charged, whereas nucleic acids are
normally negatively charged. Thus, cationic dendrimers such as PAMAM dendrimers, PPI dendrimers, and
poly(-lysine) dendrimers all can form complexes with nucleic acids through electrostatic interaction.
Moreover, some of these cationic dendrimers such as PAMAM and PPI, which have a large number of
secondary and tertiary amines in the interior, are protonatable under endosomal pH conditions and can
mediate efficient endosome escape. Because the preparation of the nucleic acid-dendrimer complex cannot
withstand terminal sterilization, dendrimers should be prepared sterile and with low endotoxin.
Dosage Forms
Cationic dendrimers are used together with nucleic acid in injections to form stable complexes, thereby
eliminating nucleic acid degradation in blood circulation.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include properties related to
identity, viscosity, solubility, buffer capacity, molecular weight distribution, loss on drying, and elemental
impurities.
General Chapters
The following general chapters may be useful in ensuring consistency in selected cationic dendrimer
functions: 〈1〉, 〈71〉, 〈85〉, 〈621〉, 〈695〉, 〈731〉, 〈 891〉, 〈911〉, 〈912〉, 〈913〉, 〈 1151〉, 〈1241〉, and 〈1911〉.
COLLOID-STABILIZING AGENT
Description
Colloid-stabilizing agents, or protecting agents, are used in lyophobic particulate radiopharmaceuticals to
coat the surface of individual colloid particles and prevent or inhibit clumping.
Physical Properties
Colloid-stabilizing agents must be readily soluble in aqueous solution.
Chemical Properties
Colloid-stabilizing agents must be lyophilic and capable of coating the lyophobic colloid particles, e.g., by
electrostatic attraction of an opposite charge. Examples of colloid-stabilizing agents include gelatin and
dextran.
Functional Mechanism
Lyophobic colloid particles can form aggregates to minimize their surface area-to-volume ratio. Colloid-
stabilizing agents are lyophilic molecules that coat the surface of individual colloid particles, making them
appear lyophilic. Additionally, the colloid-stabilizing agent may be charged, thus causing the coated colloid
particles to repel one another. The net result is the prevention or inhibition of aggregation of colloid
particles.
Dosage Forms
Colloid-stabilizing agents are used primarily in radiopharmaceutical suspension dosage forms intended for
injection.
Performance-Related Properties
The potential performance-related properties for colloid-stabilizing agents are: solubility, lyophilicity,
molecular size or mass, and electrostatic charge at the intended pH.
General Chapters
The following general chapters may be useful in ensuring consistency in selected colloid stabilizing agent
functions: 〈621〉, Radioactivity 〈821〉, Capillary Electrophoresis 〈1053〉, and Solubility Measurements 〈1236〉.
COLORING AGENT
Description
A coloring agent is any dye, pigment, or substance that when added to a drug or to the human body will
impart a color. Coloring agents are incorporated into dosage forms to produce a distinctive appearance that
may serve to differentiate a product from others that have a similar physical appearance or, in some
instances, to protect photolabile components of the dosage form. These substances are subdivided into
soluble dyes, lakes (insoluble forms of a dye that result from its irreversible adsorption onto a hydrous
metal oxide), inorganic pigments (substances such as titanium dioxide or iron oxides), and natural colorants
(colored compounds not considered dyes per se, such as riboflavin).
Physical Properties
Particle size distribution of dyes and lakes can influence product processing times (blending and
dissolution), color intensity, and uniformity of appearance. For lakes and pigments, the color intensity and
uniformity of appearance can be influenced by their particle morphology. The color intensity may vary from
lot to lot and can influence the consistency of the color of the product. The most important properties of a
coloring agent are its depth of color and resistance to fading over time. Substances can be graded on their
efficiency in reflecting desired colors of visible light as well as on their molar absorptivities at characteristic
wavelengths.
Chemical Properties
This is a very broad group of substances with no apparent common chemical properties. Examples of
coloring agents include talc, titanium dioxide, β-carotene, calcium carbonate, ferric ferrocyanide, caramel,
iron oxide, triarylmethane dye, and others.
Functional Mechanism
Pigment is an insoluble fine powder that creates colors by its own spectral absorption and its reflection to
specific spectral light. Dye is a chemical substance dissolved in the solution that alters colors through the
ion or chemical reactions.
Dosage Forms
Coloring agents are used mainly for oral (solid and liquid) dosage forms such as tablets, capsules, gums,
pills, solutions, and suspensions to enhance patient compliance and aid in product identity. For tablets, an
opaque coating may protect photolabile active ingredients.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include particle size, color
intensity, and color uniformity.
General Chapters
The following general chapters may be useful in ensuring consistency in selected coloring agent functions:
〈429〉 and 〈1061〉. Instrumental methods should be used to determine the color of a coloring agent that is
typically compared with a reference standard for the desired color.
Additional Information
Coloring agents are subject to federal regulations, and consequently the current regulatory status of a
given substance must be determined before its use.
The Federal Food, Drug, and Cosmetic Act defines three categories of coloring agents:
FD&C colors: those certifiable for use in coloring foods, drugs, and cosmetics
D&C colors: dyes and pigments considered safe in drugs and cosmetics when in contact with mucous
membranes or when ingested
External D&C colors: colorants that, because of their oral toxicity, are not certifiable for use in
ingestible products but are considered safe for use in externally applied products
Federal regulations state the maximum daily intake allowed.
Patients may be allergic to certain dyes and lakes [such as tartarazine (FD&C Yellow 5), FD&C Red 40]
and should be considered in formulating products.
For tablets where the color is desired to be distributed throughout the tablet, water-soluble dyes usually
are dissolved in a granulating fluid for use, although they also may be adsorbed onto carriers such as
starch, lactose, or sugar from aqueous or alcoholic solutions. These latter products often are dried and used
as formulation ingredients. Because of their insoluble character, lakes and pigments almost always are
blended with other dry excipients during formulation. For this reason, direct compression tablets are colored
with lakes and pigments when the color is desired to be present throughout the dosage form.
Most tablets today are colored by the coating applied to the tablet. Dyes, lakes, and pigments are
combined with a polymer and typically a plasticizer, even though in rare cases, water can be used as a
plasticizer.
COMPLEXING AGENT
Description
A complexing agent is a compound that associates with metal ions or another compound in solution to
form an adduct. The degree of association is less than covalent and greater than that of counterions and is
mediated via charge transfer or hydrophobic interactions.
The term ligand is used for a compound that forms one or more coordinate bonds with a metal atom.
Chelating agents are multidentate ligands that form soluble complex molecules with certain metal ions
(e.g., copper, iron, manganese, lead, and calcium). If the complexing agent reduces the ability of the ion or
other compound to react or precipitate, then it is known as a sequestering agent.
Hydrophobic interactions predominate with associations between larger organic molecules, for example,
cyclodextrin-drug inclusion complexes.
Physical Properties
Complexing agents generally are soluble in water and typically are dissolved in liquid dosage forms.
Physical properties such as particle size of the chelating agent are not normally critical in solution
applications but may influence processing requirements such as the mixing time required to dissolve.
Chemical Properties
Complexing agents generally associate with metal ions via charge transfer and with larger organic
molecules via hydrophobic interactions.
The hexadentate edetic acid and its salts are representative of agents that complex with and sequester
metal ions. Polydentate ligands are key to the functionality of chelating agents that form stronger
complexes than with the corresponding number of monodentate ligands. Edetate calcium disodium does not
sequester calcium and therefore is preferred to prevent hypocalcemia. Sequestration may be pH-
dependent.
Cyclodextrins are representative of complexing agents that function by hydrophobic interaction. Their
hydrophobic cavities can accommodate a hydrophobic portion of a drug molecule. Steric effects can
interfere as illustrated by β-cyclodextrin, which has the optimum cavity size to house aromatic groups.
Polymeric excipients in general, including carbohydrates and proteins, may form complexes with ions and
organic molecules due to their polydentate nature and/or regions of hydrophobicity.
Complexing agents should be chemically compatible with the active ingredient and other formulation
components. When used in chemical analysis, they must be chemically compatible with the reagents and
test substance.
Functional Mechanism
In addition to ionic interactions, charge transfer can result from lone pair electrons, hydrogen bonding,
and aromaticity (π-delocalization) resulting in a degree of association between the complexing agent and
target greater than the interaction with simple counterions in solution. Association is greater for
multidentate ligands that statistically are less likely to simultaneously dissociate. For example,
ethylenediamine binds metals more strongly than methylamine.
Hydrophobic complexes in aqueous solution result from the energetically favored tendency for
hydrophobes to associate and exclude water. The greater the number of hydrophobic groups and the better
the steric fit, the greater the degree of association.
Dosage Forms
Complexing agents are typically dissolved in liquid dosage forms, including suspensions, liquids, and
solutions, or incorporated into solid dosage forms such as powders, tablets, capsules, and pills to deliver
the same benefits on subsequent dissolution such as reduced water hardness, reduced catalysis of drug
degradation, synergistic antioxidant/antimicrobial effects, and/or increased drug solubility or stability.
Specific complexing agents are selected for a formulation based on their functionality (benefit and affinity
for target), solubility, and stability.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include particle size, where
dissolution of the chelating agent is critical, or to assure content uniformity or flow properties when
incorporated in powder mixes.
General Chapters
The following general chapters may be useful: Water Conductivity 〈645〉, 〈785〉, 〈791〉, 〈786〉, 〈429〉, and
Particulate Matter in Injections 〈788〉.
CRYSTALLIZATION INHIBITOR
Description
Crystallization inhibitors are those molecules that prevent the nucleation and crystal growth of APIs in any
dosage form. It applies to all drug classes and formulation dosages where there is risk of solvent mediated
phase transition or need for stabilization of an amorphous form. These molecules are primarily polymers, or
solubilizers that inhibit crystallization or crystal growth (e.g., Ostwald ripening) of APIs in the desired
dosages by maintaining them in original suspensions, solutions, or amorphous solid dispersions.
Nucleation, if not prevented, can lead to a decrease in dissolution and bioavailability of drugs, which may
lead to recall of marketed drugs. This is more challenging with amorphous solid dispersions.
Physical Properties
Excipients that behave as crystallization inhibitors are selected based upon the nature of the interaction
between the drug and inhibitor molecules. Physical properties that can influence the inhibition of
crystallization in liquid dispersions include surface activity and adsorption (for polymeric excipients, folding,
unfolding, or re-arrangement of the polymeric chains). For solid dispersions, the ability to increase the glass
transition temperature of the dispersion is most important.
Chemical Properties
This is a very broad group of substances with no apparent common chemical properties. Examples of
polymeric crystallization inhibitors include povidone, copovidone, hypromellose acetate succinate,
polysorbates and polycaprolactam/polyvinyl acetate/polyethylene glycol copolymers. Examples of non-
polymeric crystallization inhibitors include sorbitol.
Functional Mechanism
Nucleation inhibitors interact with drug molecules to prevent the formation of crystals from aqueous
solution. Crystal growth inhibitors occupy suspended drug crystal surfaces and discourage further crystal
growth by hindering the deposition of additional drug molecules from solution. The ability of the excipients
to increase the glass transition temperature (T ) of solid dispersions provides increased stability in addition
to inhibition of nucleation and crystal growth. The stronger the intermolecular interactions between the drug
and excipients, the stronger the inhibitory effects.
Dosage Forms
Crystallization inhibitors may be used in many dosage forms, including tablets, capsules, other oral solid
dosage forms, and suspensions.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include polymeric chain
lengths, surface adsorption, and critical micelle concentration (CMC), if applicable.
General Chapters
〈1911〉, Viscosity 〈911〉, 〈741〉, 〈695〉, and 〈891〉.
DESICCANT
Description
Desiccants are hygroscopic substances that are used in packaging of pharmaceutical products to reduce
and maintain a low level of moisture in the product and humidity inside the container. Examples of most
popular desiccants include silica gel, molecular sieve, and calcium oxide.
Physical Properties
Desiccants are typically available in solid form with a high surface area and porosity to increase
adsorption. Desiccants may be packaged in a semipermeable package, most commonly packets or canisters
to minimize contact with packaging and pharmaceutical product, or they may be incorporated into the
container–closure system such as in the cap for a bottle of tablets.
Chemical Properties
Desiccants contain functional groups that interact favorably with water. The properties of desiccants vary
with temperature and relative humidity. Desiccants may be coated with or contain a moisture-sensitive
indicator. Cobalt dichloride should be avoided as a moisture-sensitive indicator due to contact allergies in
some individuals. Desiccants must be compatible with packaging and pharmaceutical products.
Functional Mechanism
g
Desiccants typically function by physical adsorption rather than chemical absorption of water. However,
some desiccants such as calcium oxide chemically react with water.
Dosage Forms
Desiccants may be used in pharmaceutical packaging of solid dosage forms (tablets, capsules, gums,
granules, pellets, and pills) to adsorb moisture and maintain a low relative humidity. However, caution must
be exercised when using desiccants with gelatin capsules as it may lead to brittleness and cross-linking of
the gelatin capsule shells.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include moisture content,
specific surface area, adsorption capacity, and particle size for desiccants used in solid form. Adsorption
capacity is the mass of water adsorbed per mass of desiccant and depends on time, relative humidity,
temperature, and physical and chemical properties of the desiccant.
General Chapters
The following general chapters may be useful in ensuring consistency in selected desiccant functions:
〈429〉, 〈731〉, 〈 786〉, 〈811〉, 〈921〉, 〈1241〉, and 〈891〉.
Additional Information
In addition to compatibility of the desiccant with the drug product, the packaging material of the
desiccant unit must also be taken into consideration. The methods found in 〈891〉 can be used to measure
dehydration.
DILUENT
Description
Diluents are components that are used to increase solid dosage form volume or weight. Sometimes
referred to as fillers or bulking agents, diluents often comprise a large portion of the dosage form, and the
quantity and type of diluent selected often depend on its physical and chemical properties.
Physical Properties
The primary physical properties relevant to diluents are those that can have a direct effect on diluent and
formulation performance. These include particle size and size distribution, particle shape, bulk/tapped/true
density, specific surface area, crystallinity, moisture content, powder flow, solubility, crystal form, and
compaction properties for tablets.
Chemical Properties
Tablet diluents comprise a large and diverse group of materials that include inorganics (e.g., dibasic
calcium phosphate or calcium carbonate), single-component organic materials (e.g., lactose monohydrate
or mannitol), and excipient blends and coprocessed excipients such silicified microcrystalline cellulose or
sugar spheres, or complex organics (e.g., microcrystalline cellulose or starch). They may be soluble or
insoluble in water, and they may be neutral, acidic, or alkaline in nature. These chemical properties can
have a positive or negative effect on the drug substance physical or chemical stability and on performance.
Appropriate selection of excipients with desirable physical and chemical properties can enhance the physical
and chemical stability as well as the performance of the drug substance and dosage form. The detailed
composition of an excipient may be important because excipient function could be influenced by the
presence of minor concomitant components that are essential for proper performance. Pharmaceutical
scientists may find it necessary to control the presence of impurities (e.g., elemental impurities or
peroxides) to ensure adequate dosage form stability and performance.
Functional Mechanism
Among the most important functional roles diluents play is their ability to impart desirable manufacturing
properties (e.g., powder flow, tablet compaction strength, wet or dry granule formation, or homogeneity),
performance (e.g., content uniformity, disintegration, dissolution, tablet integrity, friability, or physical and
chemical stability), and adjust the overall dosage form weight. Some diluents (e.g., microcrystalline
cellulose) occasionally are referred to as “dry binders” because of the high degree of tablet strength they
impart to the final compressed tablet.
Dosage Forms
Diluents are used in every type of solid dosage form such as tablets, capsules, granules, pellets, pills,
ointments, creams, and gels.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include particle size and size
distribution, particle shape, bulk/tapped/true density, specific surface area, crystallinity, moisture content,
powder flow, solubility, crystal form, and compaction properties for tablet dosage forms.
General Chapters
The following general chapters may be useful in ensuring consistency in diluent functions: 〈429〉, 〈616〉,
〈695〉, 〈696〉, 〈 699〉, 〈731〉, 〈776〉, 〈786〉, 〈811〉, 〈 846〉, 〈921〉, 〈941〉, Tablet Compression Characterization
〈1062〉, 〈1174〉, and 〈 1181〉.
DISINTEGRANT
Description
Disintegrants are functional components that are added to solid formulations to promote rapid
disintegration into smaller units and to allow a drug substance to dissolve more rapidly. Disintegrants are
natural, synthetic, or chemically modified natural polymeric substances. When disintegrants come in contact
with water or gastric or intestinal fluid, they function by absorbing liquid and start to swell, dissolve, or
form gels. This causes the dosage form structure to rupture and disintegrate, producing increased surfaces
for enhanced dissolution of the drug substance. Potent disintegrants, commonly called superdisintegrants,
are effective at lower levels in the final formulation, typically less than 10% (w/w).
Physical Properties
The primary physical properties relevant to a disintegrant are those that describe the product's particle
structure as a dry powder or its structure when in contact with water. These properties may include particle
size distribution, water absorption rate, porosity, swelling ratio or swelling index, and whether a gel is
formed.
Chemical Properties
Polymers used as disintegrants are either nonionic or anionic with counterions such as sodium, calcium,
or potassium. Nonionic polymers are natural or physically modified polysaccharides such as starches,
celluloses, pullulan, or nonpolysaccharides such as crospovidone. The anionic polymers mainly are
chemically modified starches, cellulose products, or low cross-linked polyacrylates. The chemical properties
of the drug or other ingredients should be considered in the case of ionic polymers where interactions may
occur. Disintegration performance is affected by pH changes in the gastrointestinal tract or by complex
formation with ionic drug substances. Depending on the manufacturing process, cellulose derived
disintegrants may retain residual acid, resulting in instability for acid-labile drugs.
Functional Mechanism(s)
The ability to interact strongly with water is essential to the disintegrant function. Three major
mechanisms describe the function of the various disintegrants: volume increase by swelling, deformation,
and capillary action (wicking). The function of disintegrants is best described as a combination of two or
more of these effects. The onset and degree of the locally achieved actions depend on various parameters
of a disintegrant such as its chemical nature and its particle size distribution and particle shape as well as
some important tablet parameters such as hardness and porosity. For disintegrants that gel, excessive
levels in the formulation may actually slow disintegration, particularly for capsules, as gelling may hinder
dispersion of the capsule contents in the stomach or intestinal fluid.
Dosage Forms
Disintegrants are used in solid dosage forms such as tablets, capsules, granules, pellets, and pills to
promote rapid disintegration.
Performance-Related Properties
The potential performance-related properties are particle size distribution, water content, and swelling
ratio or swelling index.
General Chapters
The following general chapters may be useful in ensuring consistency in disintegrant functions: 〈429〉,
〈731〉, 〈776〉, 〈 786〉, 〈921〉, and 〈1174〉.
DRAG-REDUCING AGENT
Description
Drag-reducing agents are excipients that increase the fluidity and/or decrease the turbulence of
pharmaceutical liquids (i.e. solutions and dispersions) flowing through narrow channels (in nasal sprays,
aerosol-metering valves, etc.), thereby enhancing spray patterns and improving the uniformity of
formulation delivery.
Physical Properties
The primary physical property exhibited by drag-reducing agents is high extensional (elongational)
viscosity at low solution concentrations. Surfactants that form worm-like micelles have also demonstrated
drag-reducing functionality.
Chemical Properties
This is a very broad group of substances, thereby precluding a description of chemical properties. Typical
drag-reducing agents are high molecular weight polymers such as polyethylene oxides, PEGs, and
polyacrylamides. Worm-like micelle formation and concomitant drag reduction or increased fluidity has also
been demonstrated with cationic, anionic, and nonionic surfactants.
Functional Mechanism
Drag reduction by polymers is a boundary layer effect resulting in a significant reduction in turbulent
energy losses during flow. The mechanism entails the uncoiling and stretching of polymer molecules under
the stress that the fluid exerts on them in flow. Surfactants that form worm-like micelles or shear-induced
gels increase wall slippage as the micelles or gels break when deformed too much at too large of a shear.
Dosage Forms
Drag-reducing agents have been incorporated in formulations of aerosols, sprays, and injections.
Performance-Related Properties
The rheological properties of solutions of drag-reducing agents, particularly at low concentrations, are
essential to the functioning of these agents. Accordingly, rheological methods that are applicable to dilute
solution measurements—particularly, the measurement of extensional (elongational) viscosity—would be
especially helpful in formulating dosage forms with these components. Given the polydispersity of polymeric
excipients in commerce and the multicomponent nature of most surfactants, size exclusion or gel phase
chromatography would help to ensure manufacturing replicability.
General Chapters
The following general chapters may be useful in ensuring consistency in selected drag reduction
functions: 〈912〉, 〈1911〉, and 〈621〉.
Additional Information
Even though USP does not currently provide for the measurement of elongational or extensional viscosity,
this is the most relevant physical parameter. As such, a formulator would be advised to seek out
instrumentation that would enable this property to be measured.
EMOLLIENT
Description
Emollients are excipients used to impart lubrication, spreading ease, texture, pleasant feel, indirect
moisturization of the skin by preventing transepidermal water loss, softening of the skin, and to counter the
potentially drying/irritating effect of surfactants on the skin.
Physical Properties
Emollients may be liquid, semisolid, or solid at room temperature and which can be spread on the skin
using light to moderate pressure.
Chemical Properties
Emollients are either oils or are derived from components of oils as esters of fatty acids, fatty alcohols, or
liquid hydrocarbons of requisite molecular weight.
Functional Mechanism
Emollients help form a protective film and maintain the barrier function of the epidermis. Their efficacy
may be described by three mechanisms of action: protection against the delipidizing and drying effects of
surfactants, humectancy due to occlusion (by providing a layer of oil on the surface of the skin, emollients
slow water loss and thus increase the moisture-retention capacity of the stratum corneum), and lubricity,
adding slip or glide to the preparation.
Generally, the higher the molecular weight of the fatty acid or fatty alcohol moiety (carbon chain length),
the richer the feel and softness of the touch. Fluidity generally is imparted by shorter chain length and a
higher degree of unsaturation in the fatty acid moiety.
Dosage Forms
Emollients are typically used in topical formulations such as creams, emulsions, gels, soaps, ointments,
lotions, and foams to impart lubrication, spreading ease, texture, and to counter the potentially
drying/irritating effect of surfactants on the skin. Emollients can also be included in suppository
formulations.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include carbon chain length,
rheology, coefficient of friction, dropping point, film forming, melting point, melting range, and sensorial
aspects such as slip, tackiness, etc.
General Chapters
The following general chapters may be useful in ensuring consistency in selected emollient functions:
〈401〉, 〈741〉, 〈 891〉, 〈911〉, 〈912〉, 〈913〉, 〈914〉, and 〈 1911〉.
EMULSIFYING AGENT
Description
Emulsifying agents are excipients generally used to stabilize two or more immiscible liquid phases that
would not normally mix, such as oil and water. Emulsifying agents help stabilize an emulsion to prevent
coalescence of the globules of the dispersed phase. Emulsions may be water-in-oil or oil-in-water and both
will require emulsifying agents.
Physical Properties
Emulsifying agents are amphiphilic molecules having both lipophilic and hydrophilic properties in the same
molecule. On the other hand, finely divided solid particles that stabilize emulsions tend not to be
amphiphilic.
Chemical Properties
The chemical properties of emulsifying agents vary considerably as these excipients may be anionic,
cationic, amophoteric, or nonionic in nature. Nonionic emulsifying agents are often classified according to
their hydrophilic/lipophilic balance (HLB), although strictly speaking, the HLB approach to surfactant
classification and utilization was developed for nonionic ethoxylated surfactants. Furthermore, emulsifying
agents may be synthetic, semisynthetic, or natural in origin. Regardless of their classification, all
emulsifying agents must be chemically stable in the system as well as nontoxic and nonirritant.
Functional Mechanism
Emulsifying agents act by reducing the interfacial tension between two phases and forming a stable
interfacial film. Soluble emulsifying agents tend to concentrate at the oil-water interface to provide a
protective film around the dispersed droplets. In addition to this protective layer, such emulsifying agents
stabilize the emulsion by reducing the interfacial tension of the system. Some emulsifying agents enhance
emulsion stability by imparting a charge to the droplet surface, thus reducing the physical contact between
adjacent droplets and thereby decreasing the potential for coalescence. Finely divided solids do not lead to
appreciable changes in interfacial tension nor is their emulsion stabilization necessarily affected by the
extent of droplet surface coverage.
Dosage Forms
Potential dosage forms include creams, emulsions, injections, foams, solutions, and suspensions.
Emulsifying agents may be used in the following routes of administration: oral, parenteral, and topical.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include the ratio of the HLB
of the molecule.
General Chapters
The following general chapters may be useful in ensuring consistency in selected emulsification functions:
〈3〉, 〈401〉, 〈741〉, 〈 791〉, and 〈1151〉.
FILM-FORMING AGENT
Description
Film-forming agents are polymeric materials that form a film when spray coated, solvent cast, or hot melt
extruded (HME). They have two categories of use: 1) a film coating on a dosage form such as a tablet and
capsule and 2) as a structural matrix in film products. Note that sugar coating is addressed separately.
Film coating can serve multiple purposes, including masking unpleasant tastes or odors, improving
ingestion and appearance, protecting active ingredients from the environment, providing a distinguishing
appearance, and modifying the release of the active ingredient (e.g., controlled-release or gastrointestinal
targeting). Materials used as coating agents differ depending on the purpose of the coating. Protective
coatings tend to be hydrophilic, whereas controlled release coatings tend to be more hydrophobic.
Hypromellose and polyvinyl alcohol are commonly used in film coating.
Film-forming agents may be added to a film formulation to form a structural matrix, allowing the film to
be placed or inserted at the administration site, typically a mucosal tissue such as in the mouth, eye, or
vagina. Film-forming agents are natural, semisynthetic, or synthetic polymers and are usually the main
component of a film. Hydroxypropyl cellulose is a popular choice for films.
Physical Properties
The primary physical properties that affect the performance of a film-forming agent are its mechanical
strength, solution viscosity, thermal properties such as T , melt viscosity (particularly for HME), water
absorption, and drug permeation properties. For mucosal films, bioadhesion is a critical property.
g
Film coating is a complex process and the characteristics of the film-forming polymer are critical. The
resulting film should possess sufficient elasticity and mechanical strength to withstand the stresses during
coating and downstream packaging operations. The particle size of colloidal polymer dispersions varies with
composition and manufacture (latex, pseudolatex, or redispersed powder) and significantly impacts the
coating dispersion and influences the spray pattern during the manufacturing process. For coatings applied
in a molten state without solvents (plastic polymers, waxes, and lipid-based coatings), melting range and
melt viscosity are the primary properties to consider, as well as water uptake, permeability, and drug
diffusion rate through the coating. For drugs prone to oxidation, oxygen permeability is important. The
diffuse reflectance properties of the coating may be important if the coating is designed to hide the
substrate, although this is primarily accomplished through the addition of an opacifier.
Chemical Properties
Coatings comprise a wide variety of different chemical materials. Coating components can be of natural,
semisynthetic, or synthetic origin and may be available in different chemical grades. Polymers used as film-
forming agents may be ionic or noniconic or, for those with bioadhesive properties, are typically anionic or
neutral charge, with anionic polymers generally having stronger adhesion to mucosal membranes. Common
film-forming agents include hypromellose, carboxymethylcellulose, hydroxypropyl cellulose, povidone,
polyvinyl alcohol, polyethylene oxide, pullulan, pectin, chitosan, sodium alginate, carrageenan,
polyacrylates, and gelatin.
Functional Mechanism
The mechanisms of film-forming agents can be divided into two categories: 1) those that affect
performance in the patient and 2) those that affect the manufacturing process. Patient performance
mechanisms include mechanical strength, which is necessary for handling and administration and affects
tactile response (e.g., mouth feel). Water interaction is critical for controlled-release coatings as a key
mechanism of release is the absorption of water and subsequent swelling of the matrix and drug diffusion.
Sometimes the release mechanism is the erosion of the polymer from the surface of the film, allowing the
release of drug from the core.
Film-coating systems are comprised primarily of film-forming agents that impart desirable pharmaceutical
properties such as appearance and patient acceptance (e.g., taste masking and ease of swallowing). Film
coating also can serve other functional purposes such as providing a barrier against undesirable chemical
reactions or untimely release of a drug from its components. After ingestion, the film coating may dissolve
by processes such as hydration, solubilization, or disintegration, depending on the nature of the material
used. Enteric coatings are insoluble in acidic (low pH) media but dissolve readily in the neutral pH
conditions of the intestines. Some film coatings are insoluble in aqueous solution but permeable to APIs
upon contact with water due to the existence of pore forms in the coating. The pore formers could be small
molecules or water-soluble polymers. The film-coating process may be applied with or without organic
solvents. In the solvent-coating process, the polymer chains spread out on the core surface and coalesce
into a continuous film as the solvent evaporates. Polymer solutions or dispersions with a low viscosity and
high pigment-binding capacity reduce the coating time and facilitate relatively simple and cost-effective
manufacturing. The thickness of the film may vary by application and the nature of the coating agents.
Plastic polymers, waxes, and lipid-based coatings can be applied without solvents by melting and
atomization. When molten fluid droplets strike the surface of the fluidized drug particles, they spread and
congeal to form film layers. Thus, film-coating materials generally have the ability to form a complete and
stable film around the substrate. The film coating is applied uniformly and carefully dried to ensure that a
consistent product is produced. Suitable plasticizers may be required to lower the minimum film-forming
temperature of the polymer, and formulators should consider their potential effect on drug release.
In addition, solution viscosity is a key attribute when solvent casting or spraying onto a surface. In
addition, films can also be made by hot melt extrusion, and melting temperature and melt viscosity are
critical to film formation. In addition, because solvent casting is commonly used, water is often the solvent
of choice so water interactions are important as it must be removed during drying, and some materials such
as HPMCs tightly bind water, so this affects drying and packaging needs.
Dosage Forms
Film-forming agents are used to coat tablets and capsules or to provide a structural matrix in sublingual,
buccal, vaginal, and other films. They are also used in ocular, topical, and vaginal delivery systems.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include solution viscosity,
water absorption rate, water content, mechanical film strength, bioadhesive properties, plasticizer
compatibility, polymer-dissolving rate, T or melting point, and residual solvents.
General Chapters
The following general chapters may be useful in ensuring consistency of film-forming agents: 〈401〉,
〈429〉, Residual Solvents 〈467〉, 〈711〉, 〈731〉, 〈881〉, 〈891〉, 〈911〉, 〈 912〉, 〈913〉,〈921〉, and 〈1911〉.
Additional Information
Additives often are included in a coating formulation. Fillers (e.g., sugar alcohols, microcrystalline
cellulose, calcium carbonate, and kaolin) may be added to increase the solids content of the coating agent
without increasing viscosity. Stearic acid can be used to improve the protective or moisture barrier function
of a coating. Opacifiers and coloring agents may be added to modify appearance. Additionally, products
manufactured using solvents for film formation should meet the requirements for that solvent as listed in
the Code of Federal Regulations.
Karki S, Kim H, Na SJ, Shin D, Jo K, Lee J. Thin films as an emerging platform for drug delivery. Asian
J. Pharm. Sci. 2016;11(5):559–574. doi: https://doi.org/10.1016/j.ajps.2016.05.004.
FILTERING AID
Description
Filtering aids are finely divided purified siliceous earth or powdered cellulose. Purified siliceous earth is a
finely divided powder consisting of the skeletons of diatoms that have been purified by calcining. Powdered
cellulose is mechanically abraded cellulose pulp. The filtering aid should be compatible with the materials
being filtered.
Physical Properties
Filtering aids are generally insoluble, particularly in the solvent being filtered.
Chemical Properties
Purified siliceous earth has the general properties of silica. Powdered cellulose has the properties of
cellulose. They are generally inert.
Functional Mechanism
Filtering aids are used to aid in the filtration of solutions and liquors containing small amounts of
undesirable solid particles. The filtering aid improves filtering efficiency by acting as a depth filter and
allows the entrapment of any suspended particles above a certain size with reduced risk of filter blockage
compared with a membrane filter.
Dosage Forms
Filtering aids may be used in the nonsterile processing of liquid dosage forms such as solutions,
suspensions, and liquids. They also may be used in the production of drug substances. The filtering aid
should not be present in the final drug dosage form.
Performance-Related Properties
g
Potential performance-related properties for filtering aids include particle size, particle size distribution,
specific surface area, and filtering characteristics.
General Chapters
The following general chapters may be useful in ensuring consistency in filtering aid function: 〈429〉,
〈616〉, 〈786〉, 〈 811〉, and 〈846〉.
FLAVOR AND FRAGRANCE
Description
A flavor or fragrance is a single chemical entity or a blend of chemicals of natural or synthetic origin,
which has the ability to elicit a taste or aroma response when orally consumed or smelled. These materials
often come in constellations of ingredients: for example, the perception of a flavor and its match to the
flavor name by a patient is a function of the color, taste, and aroma that make up a flavor system. The
primary purpose of a flavor system is to improve patient compliance especially in pediatric patients. The
flavors and fragrances do this by providing all or part of the taste and aroma of the product taken into the
mouth.
Physical Properties
Taste perception depends on physicochemical, physiological, and psychological factors. Physical properties
such as particle size, solubility, humectancy, texture, and color all influence the senses. In addition to flavor,
the sensory attributes of sight (e.g., appealing color), sound (e.g., crunch of a chewable tablet), and mouth
feel (e.g., viscous, slimy, chalky, or watery) also contribute to and influence the overall sensory experience.
In addition, the volatility affects retention in the dosage form. Flavor solubility in saliva fluids can affect
aftertaste; for example, some artificial sweeteners have an unpleasant aftertaste due to precipitation on the
tongue.
Chemical Properties
Chemicals that provide one of the five basic tastes possess a wide variety of structures, functional groups,
and molecular weights. Chemicals used to flavor pharmaceuticals by providing both odor and taste tend to
have low molecular weights (<250 Da) and polar functional groups such as esters, ketones, aldehydes,
amines, or alcohols. To increase the stability of the flavor(s) in a solid dosage form and to minimize flavor–
drug interactions, formulators can add flavors in an encapsulated or spray-dried form.
Functional Mechanism
After being released from the dosage form, chemicals dissolved in saliva excite chemoreceptors on taste
buds that reside primarily on the tongue and thus arouse taste perception and the perception of aroma in
the nasal cavity. Dissolution also releases volatile chemicals that reach the olfactory receptors, triggering
aroma perception. The total of taste and odor responses constitutes flavor. Humans can distinguish among
five components of taste: sourness, saltiness, sweetness, bitterness, umami (savory), and a wide range of
specific odors; however, for drugs, sweetness and bitterness are most important. Flavor enhancers and
taste modifiers can be used to modify the sweetness profile of a sweetening agent or to mask off-flavors.
For example, organic acids such as aspartic and glutamic acids are known to reduce bitterness.
Dosage Forms
Flavors commonly are used in pharmaceutical oral dosage forms such as chewable tablets, orally
disintegrating tablets, oral solutions, and oral suspensions to mask objectionable drug tastes and to make
the formulation more palatable, thus promoting patient compliance. One example is that of a peppermint or
cherry flavor to mask bitter tastes in oral dosage forms.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include molecular weight,
particle size, solubility, mouth feel, flavor, and color.
General Chapters
The following general chapters may be useful in ensuring consistency in flavor functions: 〈429〉, 〈621〉,
〈651〉, 〈731〉, 〈 741〉, Optical Rotation 〈781〉, 〈786〉, 〈831〉, and 〈841〉.
Additional Information
Products that contain aspartame must include a warning on the label stating that the product contains
phenylalanine. Sugar alcohols have a glycemic index well below that of glucose. However, sorbitol is slowly
metabolized to fructose and glucose, which raises blood sugar levels. Sugar alcohols in quantities generally
greater than 20 g/day (adults) act as an osmotic laxative, especially when they are contained in a liquid
formulation. Preservative systems should be carefully chosen to avoid incompatibility with the sweetener,
and some sweeteners are incompatible with certain preservatives.
FREE RADICAL SCAVENGER
Description
Free radical scavengers are used in radiopharmaceuticals to preferentially interact with radiation-
produced oxidative or reductive free radicals that otherwise would result in degradation of formulation
components. Free radical scavengers are also used to maintain radiochemical purity over a longer period of
time.
Physical Properties
Free radical scavengers must be readily soluble in aqueous solution.
Chemical Properties
Free radical scavengers must be capable of preferentially interacting with free radicals without causing
other undesirable effects on the radiopharmaceutical. Examples of free radical scavengers include ascorbic
acid, methylene blue, cobaltous chloride, and aminobenzoic acid.
Functional Mechanism
Radiation emitted from radiopharmaceuticals interact with water and other molecules to produce free
radicals. Free radical scavengers preferentially interact with these free radicals minimizing deleterious
interactions with the radiopharmaceutical that would result in radiochemical impurities.
Dosage Forms
Free radical scavengers are used primarily in liquid radiopharmaceutical dosage forms intended for
injection.
Performance-Related Properties
Potential performance-related properties for free radical scavengers are solubility, appropriate
oxidizing/reducing properties and ability to scavenge radiation-produced free radicals.
General Chapters
The following general chapters may be useful in ensuring consistent functions of selected free radical
scavengers: 〈621〉 and 〈821〉.
GELLING AGENT
Description
Gelling agents are excipients used to turn a liquid phase into a semisolid. Some gelling agents form a
cross-linked network, whereas others achieve gelation by physical entanglement of macromolecular chains.
Physical Properties
Gelling agents are ingredients that undergo a high degree of cross-linking or association when dissolved
or dispersed in the appropriate media. Structural properties based on differences in composition, linkage
types/and patterns, chain shapes, and degree of polymerization can dictate such physical properties as
solubility, flow behavior (thixotropic), gelling potential, and/or surface and interfacial properties.
Typical physical properties imparted by gelation may include thermal sensitivity and rheological behavior
such as thixotropy and/or viscoelasticity.
Other factors that can influence gelling agent properties include: temperature, pH, polymer concentration,
cross-linker concentration, and the presence of metal cations.
Chemical Properties
Some of the most common gelling agents used in pharmaceutical formulations include the following: 1)
hydrophilic polymers such as cellulose derivatives, alginates, acacia, tragacanth, xanthan gums, carbomers,
poloxamers, polysorbates, and polyvinyl alcohol; and 2) clays and other inorganic materials such as
colloidal silicon dioxide.
Polymer type, functionality, degree of substitution, degree of polymerization, pH, and metal cations can
all have an influence on replication of the gelation properties from batch to batch.
Functional Mechanism
The cross-linking or association of gelling agents, when dissolved or dispersed in the appropriate media,
result in an increase in viscosity and gelation as a function of structure, temperature, and concentration.
Dosage Forms
Gelling agents are used in formulations for oral administration such as suspensions and pastes to improve
handling and use and to modify drug release from solid oral dosage forms. Gelling agents are also used in
topical and transdermal formulations such as creams, lotions, gels, and ointments to increase their
viscosity.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include degree of
polymerization, degree of substitution, functionality, metal cations, loss on drying, and viscosity.
General Chapters
The following general chapters may be useful in ensuring consistency in selected gelation functions: 〈3〉,
Spectroscopic Identification Tests 〈197〉, 〈731〉, 〈791〉, 〈 911〉, 〈912〉, and 〈1911〉.
GLIDANT AND/OR ANTICAKING AGENT
Description
Glidants are used to promote powder flow, whereas anticaking agents are used to reduce the caking or
clumping that can occur when powders are stored in bulk. Often, these excipients can serve both purposes.
In addition, glidants and anticaking agents reduce the incidence of bridging during the emptying of powder
hoppers and during powder processing. Examples include talc and colloidal silicon dioxide.
Physical Properties
Primary physical properties of importance for glidants and anticaking agents are particle size distribution,
particle morphology, and surface area. They may be slightly hygroscopic. Although these agents typically
comprise a small portion of the formulation, due to their large surface area, the release of the drug may be
affected due to adsorption.
Chemical Properties
Glidants and anticaking agents typically are finely divided inorganic materials and are insoluble in water.
Functional Mechanism
Glidants are thought to work by a combination of adsorption onto the surface of larger particles and
reduction of particle–particle adhesive and cohesive forces, thus allowing particles to move more easily
relative to one another. In addition, glidants may be dispersed among larger particles and reduce friction
between these particles. Anticaking agents absorb free moisture that otherwise would allow the
development of particle–particle bridges that are implicated in caking.
Dosage Forms
Glidants and anticaking agents are used in all types of solid dosage forms as tablets, capsules, granules,
and pellets to promote particle flow and reduce caking or clumping that can occur during processing or
storage of the bulk materials.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include primarily particle
size distribution, moisture content, and surface area.
General Chapters
The following general chapters may be useful in ensuring consistency in glidant or anticaking agent
functions: 〈429〉, 〈731〉, 〈786〉, 〈846〉, 〈 921〉, and 〈1181〉.
HUMECTANT
Description
Humectants are hygroscopic substances that function to retain water or prevent moisture loss in a
product or application site (e.g., skin or hair).
Physical Properties
Humectants may be in liquid or solid form.
Chemical Properties
Humectants may be of natural or synthetic origin. They typically contain hydrophilic groups such as
hydroxyl, carboxyl or esterified groups, or amines that interact favorably with water through hydrogen
bonding. Examples of humectants include propylene glycol, glycerin, polyethylene glycol, and hyaluronic
acid.
Functional Mechanism
Humectants attract and retain moisture due to interactions between water, polar functional groups, and
hydrogen bonding. Moisture retention is typically by absorption. Humectants are typically hygroscopic.
Humectants may have emollient properties.
Dosage Forms
Humectants may be used in topical dosage forms such as ointments, creams, and emulsions to facilitate
the incorporation and retention of moisture into the dosage form. Humectants can increase skin hydration
in topical preparations and may be used in shampoos with ingredients that otherwise may have a drying
effect.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include particle size in solid
form, moisture content, water activity, and hygroscopicity.
General Chapters
The following general chapters may be useful in ensuring consistency in selected humectant functions
depending on physical state (solid or liquid form): 〈731〉, 〈921〉, and Application of Water Activity
Determination to Nonsterile Pharmaceutical Products 〈1112〉.
LIPOSOME-FORMING AGENT
Description
Liposomes are closed spherical vesicles consisting of an aqueous core surrounded by one or more bilayer
membranes consisted of liposome-forming agents. They can be used as a carrier for drugs. These bilayer
membranes are composed of lipid molecules (e.g., phospholipid or egg lecithin), cholesterol, and other
additives that modify the lamellarity and release of drug.
Physical Properties
Phospholipids are amphiphilic, surface-active molecules with a high tendency to aggregate both in the dry
state and when fully hydrated. Egg lecithins, which also contain phospholipids, are soluble in aliphatic and
aromatic hydrocarbons, halogenated hydrocarbons, mineral oil, and fatty acids. They are practically
insoluble in cold vegetable and animal oils, polar solvents, and water. When mixed with water, however,
phospholipids and lecithins hydrate to form emulsions.
Cholesterol and its derivatives have the function to build and maintain membranes and modulate the
membrane fluidity of liposomes. The hydroxyl group on cholesterol interacts with the polar heads of the
membrane phospholipids, whereas the bulky steroid rings and the hydrocarbon chain are embedded in the
membrane, alongside the nonpolar fatty acid chains of other lipids. Through the interaction with the
phospholipid fatty acid chains, cholesterol increases membrane packing, which both alters membrane
fluidity and maintains membrane integrity of liposomes. The physical properties of cholesterol and
derivatives include density, dielectric constant, viscosity, melting point, solubility, and specific rotation.
Chemical Properties
Phospholipid molecules comprise a polar head group coupled to fatty acid tails. The head group, in turn
comprises either a base such as choline, a sugar molecule such as inositol, or an amino acid such as serine
linked via a phosphate group to glycerol. The two fatty acid tails are also linked to the glycerol residue. The
chemical properties will be governed by the nature of the fatty acid substituents (saturated or unsaturated)
and the type of polar head group.
Cholesterol, as the name suggests has a steroid four-ring structure with a hydroxy substituent on the A-
ring, two methyl substituents, and a methylheptanyl substituent on the D-ring.
Other saturated or unsaturated lipid materials may also be incorporated into the liposomal membrane.
The lipid composition information includes the percentage of each lipid and fatty acid, positional specificity
of acyl side chains, and degree of fatty acid unsaturation. In the case of naturally sourced lipid mixtures
(e.g. egg lecithin), the lipid composition as a range of percentages for each stated lipid present in the
mixture and its fatty acid composition should be determined.
Additional chemical properties of liposome-forming agents include molecular weight, elemental impurities,
trans fatty acids, etc.
Functional Mechanism
Liposome-forming agents form liposomes by self-arrangement into bilayer vesicles when they are
exposed to an aqueous environment at the appropriate lipid-to-water ratio and temperature. The tetracyclic
ring structure of cholesterol contributes to the fluidity of the liposome membrane, as the molecule is in a
trans conformation, making all but the side chain of cholesterol rigid and planar.
Dosage Forms
Liposome-forming agents may be used in injections, topical creams, tablets, and capsules.
Performance-Related Properties
Solubility, viscosity, isoelectric point, saponification value, melting point, CMC, and temperature of
transition (Tm) are important properties for phospholipids. CMC is used to indicate the tendency of micelle
formation. Tm is the temperature of transition from crystalline to mesomorphic (liquid crystalline) state.
Other properties that may be important for excipient performance in a dosage form include properties
related to identity, HLB value, molecular weight distribution, loss on drying, and elemental impurities.
General Chapters
The following general chapters may be useful in ensuring consistency in selected liposome-forming agent
functions: 〈1〉, 〈71〉, 〈85〉, 〈621〉, 〈695〉, 〈731〉, 〈 891〉, 〈911〉, 〈912〉, 〈913〉, 〈 1151〉, 〈1241〉, and 〈1911〉.
LUBRICANT
Description
Lubricants typically are used to reduce the frictional forces between particles, particles and metal contact
surfaces, and metal-to-metal contact surfaces of manufacturing equipment. In solid dosage forms,
lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule-
filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction
between the solid and die wall. Common minerals such as talc or silica, fatty acid esters, and fats (e.g.,
vegetable stearin, magnesium stearate, or stearic acid) are the most frequently used lubricants in tablets or
hard gelatin capsules.
There are two main types of lubricants: boundary and fluid film. Boundary (solid) lubricants are agents
added in small quantities to tablet and capsule formulations to improve certain processing characteristics
and do not melt under pressure. Fluid film lubricants may be solids that melt under pressure (e.g., stearic
acid or hydrogenated vegetable oil) or liquid (e.g., vegetable oils, light mineral oil, or glycerin). Fluid film
lubricants are used in a variety of other applications including equipment lubrication.
Physical Properties
The physical properties that are important for the function of boundary lubricants include particle size,
surface area, hydration state, polymorphic form, and solid state/thermal behavior for solid lubricants. For
metal stearates, the stearate:palmitate ratio, polymorph, hydrate state, and moisture content may be
important. Boundary lubricants are salts of long-chain fatty acids (e.g., magnesium stearate) or fatty acid
esters (e.g., sodium stearyl fumarate) with a polar head and fatty acid tail. Fluid film lubricants are solid
fats (e.g., hydrogenated vegetable oil, type 1), glycerides (glyceryl dibehenate and distearate), or fatty
acids (e.g., stearic acid) that melt when subjected to pressure.
Chemical Properties
Boundary lubricants are metal salts, and the properties of the counterion, e.g., magnesium or sodium,
may impact drug substance stability. Fluid film lubricants, either solid or liquid, are typically saturated fatty
acids or fatty acid esters. However, they may contain trace levels of unsaturated fatty acids that are prone
to oxidation (rancidity). Hydrocarbon lubricants, e.g., light mineral oil, are chemically inert, provided that no
unsaturated bonds exist.
Functional Mechanism
Boundary lubricants function by adhering to solid surfaces (granules and machine parts) and by reducing
the particle–particle friction or the particle–metal friction. The orientation of the adherent lubricant particles
is influenced by the properties of the substrate surface. For optimal performance, the boundary lubricant
particles should be composed of small, plate-like particles or stacks of plate-like particles. Fluid film
lubricants melt under pressure and thereby create a thin fluid film around particles and on the surface of
punches and dies in tablet presses, which helps to reduce friction. Fluid film lubricants resolidify after the
pressure is removed. Liquid lubricants are released from the granules under pressure and create a fluid
film. They do not resolidify when the pressure is removed but are reabsorbed or redistributed through the
tablet matrix over the course of time.
Dosage Forms
Lubricants are typically used in solid dosage forms such as tablets, capsules, granules, and pellets to
reduce friction between the particles and the metal-contact surface such as the contact that can occur
between the punch/die and the formulation during tableting. Liquid lubricants may be used on
manufacturing equipment (e.g., light mineral oil) to reduce metal-to-metal friction.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include particle size, surface
area, hydration state, polymorphic form, purity, and moisture content. Viscosity may be an important
property of liquid lubricants.
General Chapters
The following general chapters may be useful in ensuring consistency in lubricant functions: 〈429〉, 〈695〉,
〈696〉, 〈731〉, 〈 776〉, 〈786〉, 〈846〉, 〈891〉, 〈911〉, 〈 912〉, 〈913〉, 〈914〉, 〈921〉, and 〈 941〉.
Additional Information
Certain lubricants, particularly those used in effervescent dosage forms, do not fall into the chemical
categories defined above. These materials are used in special situations, and they are not suitable for
universal application. Talc is an inorganic material that may have some lubricant properties. It is generally
used in combination with fluid film lubricants to reduce sticking to punches and dies.
MUCO-ADHESIVE
Description
Muco-adhesives are temporary adhesives designed to maintain contact between the applied drug delivery
system and a mucosal surface. A related functional category is Adhesive (Pressure Sensitive).
Physical Properties
Muco-adhesives are hydrophilic, viscoelastic materials that adhere to mucosal membranes upon
application of light contact pressure.
Chemical Properties
Muco-adhesive polymers often have numerous hydrophilic groups, such as hydroxyl, carboxyl, amide, and
sulfate. Common muco-adhesives include PEG, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid,
polyhydroxyethyl methacrylate, and chitosan.
Functional Mechanism
Muco-adhesives attach to mucus or the cell membrane by various interactions such as the following:
Nonspecific, noncovalent interactions that are primarily electrostatic in nature
Hydrogen bonding with similar groups on a biological surface
Binding to specific receptor sites on the cell or mucus surface (lectins and thiolated polymers)
Muco-adhesive polymers often swell in water and thus expose the maximum number of adhesive sites
and allow for polymer chain flexibility, thereby facilitating adhesiveness. Other mechanisms may be involved
depending on the polymer.
Dosage Forms
Muco-adhesives are primarily used in tablets, ointments, gels, and systems and are often delivered via
buccal, oral, nasal, ocular, vaginal, and rectal routes. The buccal and sublingual routes are considered as
the most commonly used routes.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include tensile strength and
resistance to shear, which can be affected by a number of factors, including hydrophilicity, amphiphilicity,
molecular weight, cross-linking, swelling, pH, and concentration of active polymer.
General Chapters
The following general chapters may be useful in evaluating the suitability of muco-adhesive: 〈3〉, Mucosal
Drug Products—Product Quality Tests 〈4〉, 〈881〉, 〈912〉, 〈1911〉, and 〈791〉.
Additional Information
Shaikh R, Singh TRR, Garland MJ, Woolfson AD, Donnelly RF. Mucoadhesive drug delivery systems. J.
Pharm. Bioallied Sci. 2011;3(1):89–100
OINTMENT BASE
Description
Ointment bases are viscous semisolids comprising the major component of a final ointment product,
thereby controlling the physical properties of the ointment. Ointment bases are classified as: 1) oleaginous
ointment bases [that are anhydrous, do not absorb water readily, are insoluble in water, and are not
removable by water (e.g., petrolatum)]; 2) absorption ointment bases [that are anhydrous and absorb
some water but are insoluble in water and are not water removable (e.g., lanolin)]; 3) emulsion ointment
bases [that are water-in-oil or oil-in-water emulsions and are hydrous, absorb water, and are insoluble in
water (e.g., creams of water, oils, waxes, or paraffins)]; and 4) water-soluble ointment bases [that are
anhydrous and absorb water and are soluble in water and are water removable (e.g., PEG)].
Physical Properties
Ointment bases have relatively high viscosities because of the amount of solid or semisolid material
dispersed throughout the product/preparation.
Chemical Properties
Ointment bases, in some cases, are selected for their inert properties, the improved stability of active
ingredients dispersed in them, ability to repel water, decrease transepidermal water loss, and increase skin
hydration. As described above, ointment bases may comprise oleaginous mixtures, water-soluble anhydrous
polymers, or high viscosity relatively hydrophobic emulsions that contain surfactants to facilitate their
formation and stability.
Functional Mechanism
Ointment bases serve as vehicles for topical application of medicinal substances. They are also used as
emollients and cutaneous protectives.
Dosage Forms
Ointment bases are heavily utilized, primarily in topical formulations. Ointment bases may also be used in
a variety of other dosage forms such as suppositories, medicated sticks, and formulations that are
administered to the eye, ear, rectum, and nose.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include hydrocarbon chain
length, rheology, fatty acid or fatty alcohol composition, hydrophilicity, and hydrophobicity.
General Chapters
The following general chapters may be useful in ensuring consistency in selected ointment base functions:
〈651〉, 〈911〉, 〈 912〉, 〈913〉, and 〈401〉.
Additional Information
The type of ointment base utilized in a formulation has a major impact on the delivery of a drug
substance. Some bases produce a local drug substance effect on or in the tissue to which it is applied.
Examples of local therapeutic treatment might be minor topical infections, itching, burns, diaper rash, insect
bites, athlete’s foot, corns, dandruff, hemorrhoids, and psoriasis. Other bases may deliver a drug substance
such that it has a systemic effect as a result of percutaneous absorption. Examples of systemic therapeutic
treatments are be found in pain relief, cardiology, hormone replacement, smoking cessation, and
hypertension.
OPACIFIER
Description
Opacifiers are excipients that are added to film-forming agents, hard capsule shells, and tablet matrices.
Opacifiers may also be added to soft shell capsules, but this is less common, and opacifiers are also
commonly used in sunscreens and cosmetics. In the case of capsule shells and coatings, the goal is to make
the film opaque to hide or protect the internal contents from light. Opacifiers can make the product more
stable in the case of drugs prone to photodegradation or improve the product appearance: for example, to
hide spots or improve a mottled appearance. The key property is a high refractive index, which increases
light scattering and makes the coating opaque to the eye. Opacifiers such as titanium dioxide are typically
used in the 10%–30% dry weight range and in the 5%–25% range in the coating dispersion.
Physical Properties
Key physical properties that are relevant to opacifier performance are the factors that affect light
scattering and distribution in the film or coating. These include particle size, refractive index, reflectiveness,
water content, pH (changes in pH can affect physical form of some opacifiers), and density. For some
opacifiers such as titanium dioxide, the index of refraction depends upon physical form; for example, the
anatase form has a different refractive index from the rutile form of titanium dioxide, which can affect the
light scattering properties and hence appearance of a coating or dosage form. Because of differences in
whiteness, the anatase form is more commonly used even though the rutile form is the most stable.
Examples of opacifiers include titanium dioxide, zinc oxide, zinc acetate, and sometimes calcium carbonate.
Most opacifiers are inorganic material that have a high refractive index. Oxidation state and ferric oxides
can change color as their oxidation state changes from yellow to red to black.
Chemical Properties
Opacifiers are substances that have a high refractive index. Typically, opacifiers have a particle size that is
in the nanometer range. Many opacifiers do not change color or structure when exposed to light for long
periods of time or intense light over a short period of time (e.g., light chamber testing).
Functional Mechanism
Opacifiers are materials with high refractive index and thus scatter light and make the film opaque, i.e.
light cannot pass through the film without scattering, thus, making the film opaque to light.
Dosage Forms
Opacifiers are used in film coatings, so dosage forms that are coated often use opacifiers, including
tablets and both hard and soft capsule shells. They can sometimes be used in tablet matrices and in some
liquid preparations (e.g., suspensions) but this is not typical.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include particle size, particle
morphology, specific surface area, refractive index, opacity, polymorphic form, color, and color stability.
Other factors such as pH sensitivity can be important, for example, sometimes opacifiers such as aluminum
oxide are used to make lakes that reduce the solubility of dyes, but at extreme pH, the dye and carrier can
dissociate and cause problems with coating stability.
General Chapters
The following general chapters may be useful in ensuring consistency in opacifier function: 〈429〉, 〈786〉,
〈776〉, Color and Achromicity 〈631〉, and 〈831〉.
PERMEATION ENHANCER
Description
Permeation enhancers play a vital role in drug absorption, thus increasing the bioavailability of poorly
absorbed drugs. Permeation enhancers are used especially for transdermal drug delivery by facilitating drug
penetration into and through the skin.
Physical Properties
Some physical properties that are desired in a permeation enhancer include good solvent properties for
the drug, skin permeation enhancement, and cosolvency.
Chemical Properties
Some chemical properties that are desired in a permeation enhancer include compatibility with drugs and
excipients and chemical stability.
Examples of common skin permeation enhancers include alcohols, amides, esters, glycols, fatty acids and
fatty alcohols, pyrrolidones, sulfoxides, surfactants (cationic, anionic and non-ionic), ureas, and
phospholipids.
Functional Mechanism
Penetration enhancers facilitate drug permeation through the skin by decreasing the impermeability of the
skin. In principle, an enhancer may act on skin so that drug diffusivity or drug solubility in the skin—or a
combination of both—is modified, leading to an increase in transport of the drug. They may act by one or
more of three main mechanisms: 1) disruption of the highly ordered structure of stratum corneum lipid; 2)
interaction with intercellular protein; and 3) improved partitioning of the drug, co-enhancer, or solvent into
the stratum corneum.
Dosage Forms
Permeation enhancers are most generally used in topical and transdermal systems.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include solubility, partition
coefficient, and rheological behavior.
General Chapters
The following general chapter may be useful in ensuring consistency in selected permeation enhancer
functions: 〈3〉, 〈197〉, and 〈1911〉.
Additional Information
Pfister WR, Dean S, Hsieh DS. Permeation enhancers compatible with transdermal drug delivery
systems. Parts I (Selection and formulation considerations) and II (System design consideration).
Pharm Tech. 1990;8,132.
Pathan IB, Setty CM. Chemical penetration enhancers for transdermal drug delivery systems. Trop J
Pharm Res.. 2009;8(2):173–179.
Shakeel F, Baboota S, Ahuja A, Ali J, Aqil M, Shafiq S. Nanoemulsions as vehicles for transdermal
delivery of aceclofenac. AAPS PharmSciTech. 2007;8(4):191.
Lane ME. Skin penetration enhancers. Int J Pharm. 2013;447(1-2):12–21.
Dragicevic N, Maibach HI. Percutaneous Penetration Enhancers Chemical Methods in Penetration
Enhancement. Berlin Heidelberg, Germany: Springer-Verlag GmbH; 2015.
Zhu H, Jung EC, Hui X, Maibach H. Proposed human stratum corneum water domain in chemical
absorption. J Appl Toxicol. 2016;36(8):991–996.
Osborne DW. Diethylene glycol monoethyl ether: an emerging solvent in topical dermatology
products. J Cosmet Dermatol. 2011;10(4):324–329.
PHARMACEUTICAL WATER
Description
Water is used as a solvent, vehicle, diluent, or filler for many drug products, especially those supplied in
liquid form.
Physical Properties
Water is liquid at normal temperature and pressure. It forms ice at freezing temperatures of 0° or lower,
and it vaporizes at a normal boiling temperature of 100°, depending on atmospheric pressure. Vaporized
water in the form of steam is used for sterilization purposes because the latent heat of steam is significantly
higher than that of boiling water.
Chemical Properties
Water in its pure form is neutral in pH and has very low conductivity and total organic carbon (TOC).
However, pH, conductivity, and TOC are affected by storage conditions and exposure to gases in the air.
Exposure to atmospheric carbon dioxide lowers the pH of water. Storage in plastic containers may increase
the TOC content of water over time. Water stored in glass containers may result in an increase in pH and
conductivity over time.
Functional Mechanism
A solvent is able to dissolve materials because it is able to disrupt the intermolecular attractive forces and
to allow the individual molecules to become dispersed throughout the bulk solvent. Water is a favored
solvent and vehicle in the majority of applications because it is easy to handle, safe, and inexpensive.
Dosage Forms
Pharmaceutical water is typically used in creams, emulsions, films, foams, gels, injections, irrigations,
liquids, lotions, ointments, rinses, shampoos, solutions, sprays, and suspensions for parenteral, oral, topical
and transdermal, mucosal, and radiopharmaceutical drug products in various manners. It is primarily used
as a solvent, vehicle, diluent, or filler in the formulations. Pharmaceutical water is also frequently used as a
processing aid, e.g., during wet granulation of solid dosage forms. USP includes monographs for multiple
grades of pharmaceutical water.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include pH, conductivity,
and TOC.
General Chapters
The following general chapters may be useful in ensuring consistency in selected pharmaceutical water
functions: 〈1〉, 〈85〉, Total Organic Carbon 〈643〉, 〈645〉, 〈791〉, Water for Hemodialysis Applications 〈1230〉,
and Water for Pharmaceutical Purposes 〈1231〉.
PHYSICAL-CHEMICAL IDENTIFIER
Description
Physical-chemical identifiers are added to pharmaceutical products to unambiguously identify the product
for the purposes of anticounterfeiting. Although typically used with solid oral dosage forms, physical-
chemical identifiers can be used in other dosage forms such as oral liquids or topical preparations. The
amount used in the product is usually very small so as to not affect the performance of the product.
Physical-chemical identifiers are typically used with products that are of high value and have a high
susceptibility to counterfeiting. This group does not include radioactive compounds or physical devices such
as miniature tracking devices but rather includes items that can be incorporated into the formulation of the
product. As a best practice, the inclusion of physical-chemical identifiers should be part of a complete
program to readily identify the product as genuine.
Physical-chemical identifiers can be incorporated into the product in many ways. For solid and liquid oral
dosage forms, they may be a part of the formulation. Coating or printing onto solid dosage forms are
possible as well with the introduction of high definition printing and alternative coating systems.
There are many substances that can be used as physical-chemical identifiers. One group consists of
simple stable inert compounds typically referred to as taggants or tracers that are incorporated into the
product, which are not visible or detectable without the use of analytical technology. These would be
substances that would be added in small quantities and uniquely identifiable or substances that are a part
of the formulation that has a unique property only known to the manufacturer such as differences in
isotopic distribution of an element in the substance or differences in physical forms of the substance.
Unique identifiers may also include inert molecular taggants.
Another group would be physical-chemical identifiers that form a visible but unrecognizable or unknown
pattern that can be printed on the tablet or capsule such as a Quick Response (QR) code. Other visible
physical-chemical identifiers would include coatings that are unique colors not readily replicated such as
pearlescent coatings.
Physical Properties
Due to the large number of physical-chemical identifiers and their unique properties, there is no specific
physical property common to all physical-chemical identifiers. However, the physical properties of the
physical-chemical identifiers should be compatible with the dosage form such as adequate solubility in an
oral liquid where precipitation or “salting out” of one or more ingredients or change in color could occur
during storage. As it is possible that a physical property is the key to the uniqueness of the physical-
chemical identifier, it is important to maintain the consistency of the unique physical property from batch to
batch.
Chemical Properties
Due to the large number of physical-chemical identifiers and their unique properties, there is no specific
chemical property common to all physical-chemical identifiers. However, the chemical properties of the
physical-chemical identifiers should be compatible with the dosage form. As it is possible that a chemical
property is key to the uniqueness of the physical-chemical identifier, it is important to maintain the
consistency of the unique chemical property from batch to batch.
Functional Mechanism
The functional mechanism of physical-chemical identifiers is based on the ability to be detected for
authentication purposes but not detectable to the patient or others who do not possess the expertise to
determine the physical-chemical identifier and/or its identifiable characteristic that makes it unique.
Examples include vanilla, titanium dioxide, ferric oxide, and magnesium aluminum silicates, but a multitude
of other examples exist.
Dosage Forms
Physical-chemical identifiers are used primarily in solid oral or liquid oral dosage forms.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include the physical or
chemical property that imparts the uniqueness to the product. Physical-chemical identifiers function in a
diverse number of ways that uniquely identify the product. Therefore, an important CMA would be that the
physical-chemical identifier functions as expected for the shelf life of the product. The physical-chemical
identifier should be generally accepted as safe or listed in the Inactive Ingredient Database.
General Chapters
None
Additional Information
General chapters related to how the physical-chemical identifier functions in the dosage form may be
useful in ensuring consistency. It should be noted that the excipients can impart the unique characteristic
for each product in a diverse number of ways, and therefore the appropriate chapter should reflect the
specific attributes or properties important for this functionality. Other sources of information may include
the CFR and the document FDA Guidance for Industry "Incorporation of Physical-Chemical Identifiers into
Solid Oral Dosage Form Drug Products for Anticounterfeiting”.
PHYSICAL FORM STABILIZER
Description
Physical form stabilizers are used to keep an ingredient in a dosage form in the desired physical state,
typically the amorphous state. There are a number of excipients that can work as a physical form stabilizer
such as povidones, povidone derivatives, polyoxylglycerides, polyethylene glycols, tocopherols, surfactants,
plasticizers, hypromellose, hypromellose derivatives, water-soluble cellulose esters, polyhydric alcohols
(e.g., sorbitol), hydrophilic synthetic polymers, and a combination of the excipients. See Stabilizer for a
related functional category.
Physical Properties
The key physical property of physical form stabilizers is the ability to keep the target ingredient in the
desired physical state during the manufacturing and shelf life of the product. This can be assessed by
measuring the T or melting point or amorphousness/crystallinity of the excipient(s) used as a physical
form stabilizer. Other excipients may require tests to show that the excipient will function as expected, e.g.,
determination of CMC for surfactants and hydroxypropyl and methoxy content for hypromellose using
nuclear magnetic resonance.
Other physical properties include being a solid at room temperature, solubility in aqueous media,
compatibility with pharmaceutical processing such as solvent spray drying or the hot melt extrusion
process, and compatibility with the bulk drug to form an amorphous drug excipient dispersion.
Chemical Properties
The physical form stabilizer must be compatible with the other ingredients, including the active ingredient
in the product.
Physical form stabilizers typically are rich in hydroxyl groups. As such they may form esters with organic
acids or amides with primary or secondary amines. They may also contain groups that provide for
differences in solubility at different pHs.
Functional Mechanism
Physical form stabilizers typically work by one or more of the following mechanisms: elevation of T ,
reduction in molecular mobility, favorable intermolecular interactions with the drug, and establishment of
phase equilibrium with the drug (minimization of free energy). Some stabilizers may work by solubilizing
the drug and prevent the formation of hydrates.
Additionally, amorphous bulk drugs or intermediates are frequently used to advantage in the oral delivery
of poorly water-soluble drug products. As high energy forms of the bulk drug, amorphous forms of a drug
are often prone to crystallization to a more stable, but less soluble form, particularly in the presence of free
moisture. Conversion to a crystalline (lower energy) form will result in a consequent loss of dissolution and
bioavailability. Physical form stabilizers are able to combine with the amorphous drug at a molecular level
and prevent or retard conversion to a crystalline form. Nevertheless, conversion to a crystalline form is
possible, particularly in the presence of free moisture and/or higher relative humidity, and the use of
moisture vapor-impervious packaging and desiccants may be required.
Dosage Forms
Physical form stabilizers are used primarily in tablets (e.g., hot melt extrusion, spray-dried dispersions),
but can be used in pellets, capsules, suspensions, and granules.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include melting point, glass
transition temperature (T ), free moisture content, molecular weight, and molecular weight distribution.
General Chapters
The following general chapters may be useful in ensuring consistency in selected physical stabilizer
functions: 〈695〉, 〈741〉, Nuclear Magnetic Resonance Spectroscopy 〈761〉, 〈854〉, 〈891〉, 〈 941〉, 〈921〉, 〈1112〉,
Near-Infrared Spectroscopy 〈1119〉, and Raman Spectroscopy 〈1120〉.
g
g
g
PLASTICIZER
Description
A plasticizer is a low molecular weight substance that, when added to another material (usually a
polymer) imparts flexibility, resilience, and ease of handling. Plasticizers are key components that
determine the physical properties of polymeric pharmaceutical systems.
Physical Properties
The most common plasticizers are low molecular weight (<500 Da) solids or liquids. They typically have
low melting points (<100°) and can be volatile (i.e., exert an appreciable vapor pressure) at ambient
temperature. Plasticizers can reduce the T of the system to which they are added.
Chemical Properties
Many modern plasticizers are synthetic esters such as citrates and phthalates. Traditional pharmaceutical
plasticizers include oils, polyethylene glycols, sugars, and their derivatives. Other commonly used
plasticizers include water and triacetin. Plasticizers typically do not react with other components of drug
dosage forms.
Functional Mechanism
Plasticizers function by increasing the intermolecular and intramolecular mobility of the macromolecules
that comprise polymeric materials. They achieve this by affecting the normal intermolecular and
intramolecular interactions and bonding mechanisms in such systems. The most effective plasticizers exert
their effect at low concentrations, typically less than 5% (w/w).
Dosage Forms
Plasticizers are used in solid drug products (tablets, capsules, pills, granules, and pellets), creams,
ointments, films, systems, and mucosal drug products to enhance the flexibility and resilience of the
formulation and improve handling. Plasticizers commonly are added to film coatings (aqueous and
nonaqueous systems) and capsule shells (hard and soft varieties) to improve their workability and
mechanical ruggedness. Without the addition of plasticizers, such materials can split or fracture
prematurely or hinder dissolution. Plasticizers also are added to semisolid pharmaceutical preparations such
as creams and ointments to enhance their rheological properties. The use of phthalates should be
considered carefully as the use of certain phthalates as excipients in Center for Drug Evaluation and
Research (CDER)-regulated products is limited.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include composition,
rheology, molecular weight, melting points, compatibility with the excipients, drug substance, and method
of manufacture.
General Chapters
The following general chapters may be useful in ensuring consistency in selected excipient functions:
〈401〉, 〈467〉, 〈 741〉, 〈831〉, 〈841〉, 〈891〉, 〈921〉, 〈 911〉, 〈912〉, 〈913〉, and 〈914〉.
Additional Information
The choice of an appropriate plasticizer often is guided by reference to its solubility parameter, which is
related to its cohesive energy density. Solubility parameter values for many common materials are
tabulated in standard reference texts. To ensure maximum effectiveness, the solubility parameter of the
plasticizer and the polymeric system being plasticized should be matched as closely as possible.
POLYMERIC MEMBRANE
Description
g
Polymeric membranes may be used to control the rate of diffusion of the drug out of a dosage form or
delivery system to the absorption site.
Physical Properties
Examples of physical properties of a polymer membrane include: hydrophilic-hydrophobic character,
polymer composition, molecular weight, molecular weight distribution, and membrane thickness.
Chemical Properties
Polymer membrane excipients are a very diverse group of materials and can have a range of different
chemical properties, including polymer backbone and functional chemical groups. Examples of common
polymer membranes use in transdermal delivery systems include ethylene vinyl acetate copolymers,
microporous polypropylene, n-vinyl pyrrolidone copolymers, microporous polyethylene, polyurethanes, and
silicone elastomers.
Functional Mechanism
Reservoir-type drug delivery systems contain an inert membrane enclosing an active agent that diffuses
through the membrane at a finite, controllable rate. The release rate-controlling membrane can be
nonporous so that the drug is released by diffusing directly through the material, or the material may
contain fluid-filled micropores—in which case the drug may additionally diffuse through the fluid, thus filling
the pores. In the case of nonporous membranes, the rate of passage of drug molecules depends on the
solubility of the drug in the membrane and the membrane thickness. By varying the composition and
thickness of the membrane, the dosage rate per area of the device can be controlled.
Dosage Forms
Polymeric membranes are most generally used in tablets, capsules, transdermal systems, and ophthalmic
ointments and solutions.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include polymer type,
permeability, membrane porosity, and membrane thickness.
General Chapters
The following general chapters may be useful in ensuring consistency in selected permeation enhancer
functions: 〈3〉 and 〈881〉.
Additional Information
For capsule dosage forms, the capsule shell can function as a polymeric membrane. A distinct difference
from the polymeric membranes or coatings covered by this functional category, however, is that the capsule
shell typically dissolves or disperses at the administration site (e.g., the gut) so that its effect on drug
release is short-lived. On the other hand, if the capsule shell is enteric-coated, it can persist in the gut and
continue to affect drug release.
Tetrahertz (THz) spectroscopy can be used to determine membrane or coating thickness. Permeability of
a membrane can be determined using a diffusion cell. However, dissolution testing is often used to evaluate
membrane permeability and drug release from controlled release formulations.
The following reference is provided for additional information on this topic.
Kandavilli S, Nair V, Panchagnula R. Polymers in transdermal drug delivery systems. Pharm Tech.
2002;26(5)62–81.
POLYMER FOR OPHTHALMIC USE
Description
Polymers are used in topical ophthalmic preparations to enhance the retention of active ingredients on the
surface of the eye. In addition, polymers also can be components of artificial tears. Most water-soluble
polymers commonly used as film-forming agents in ophthalmic preparations can be categorized as follows:
cellulose-based polymers, natural or biologically produced gums, and other synthetic polymers.
Physical Properties
To serve as an ophthalmic film-forming agent, a polymer typically must be at least slightly soluble in
water, thus providing an appreciable range of usable concentrations. Such polymers often increase viscosity
or exhibit film- or gel-forming properties when warmed to body temperature, when exposed to the pH or
solute composition and ionic strength of the tear film, or when the product evaporates.
Chemical Properties
The finished product viscosity range that can be obtained with a film-forming agent is related to its
chemical structure and molecular weight. Functional groups such as the pyruvate and acetate groups of
xanthan gum can affect the relationship between viscosity and solution pH and ionic strength and also can
determine film- and gel-forming properties. Polymer charge can influence interactions with the mucous
layer of the eye. Molecular conformation, chain mobility, and degree of cross-linking also can affect the
degree of swelling and thus performance.
Functional Mechanism
Film-forming agents for ophthalmic preparations can enhance the retention of active ingredients in the
eye by a number of mechanisms. They can be used as simple viscosity-modifying agents to reduce the flow
of the product, thereby slowing the rate of product loss after administration. They also can be used to form
films on the surface of the eye so the drug remains deposited on the eye after the liquid portion of the
product has been expelled or has evaporated. These agents can be formulated to produce a film or a gel
when the product warms to body temperature (upon contacting the surface of the eye), mixing with the
tear film, and/or evaporating. Some polymers have shown bioadhesive properties on the cornea and can
increase drug retention. These polymers may also aid in reducing eye irritation by forming a lubricating
layer on the surface of the cornea.
Dosage Forms
These polymers are typically used in ophthalmic ointments and solutions.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include solubility, rheology,
degree of cross-linking, polymer molecular weight, and degree of substitution.
General Chapters
The following general chapters may be useful in ensuring consistent functions of polymers for ophthalmic
use: 〈731〉, Particulate Matter in Ophthalmic Solutions 〈789〉, 〈911〉, 〈912〉, 〈913〉, 〈1151〉, 〈1911〉, 〈401〉,
〈429〉, 〈467〉, 〈 711〉, 〈881〉, 〈891〉, and 〈921〉.
PRINTING INK COMPONENT
Description
Printing inks are mixtures of colorants and volatile solvents that are used to print various characters,
shapes, and logos on tablets and capsule shells with various colors. Printing inks are used as a method of
uniquely identifying a product where other means of identification may not be acceptable or workable. For
example, tablets that have many coating layers or a coating layer containing an active ingredient would be
a candidate for printing. Capsule shells, if marked, are printed with a unique printing to identify the
product. Printing inks may be used to uniquely identify products for different markets even though the
remainder of the formulation is the same.
Physical Properties
Printing inks are a mixture of colors and a solvent system to suspend the pigments where the solvent
system quickly dries after application to prevent smudging or running. The properties of the mixture must
be compatible with the substrate to which the ink is being applied and must allow the colorants to remain
on the dosage form from the printing unit process to the end user. Printing inks are usually suspensions and
must be agitated to ensure uniform coloring and intensity from unit to unit and batch to batch. The
ingredients in the printing ink must be combined in such a manner that the color meets the acceptance
criteria from batch to batch. This would be dependent on the particle size, particle shape, color intensity,
color, viscosity, and particle morphology. Printing inks when dry should contain low levels of organic
solvents.
Although evaporation is a desired attribute of the printing ink formulation, the evaporation of the solvent
during the printing process will cause the density and viscosity of the printing ink system to increase,
leading to smearing and other undesired effects. A compatible solvent system diluent that can be added to
decrease the viscosity and density to allow the printing ink application and drying to occur more
consistently throughout the printing process should be formulated for use during the printing process.
Chemical Properties
Typically, inks contain solvents or solvent system to suspend the ink components and allow the solvents
to evaporate quickly upon application along with the ink (coloring components). These ingredients must be
compatible with each other and the ingredients of the surface onto which the ink is applied.
Functional Mechanism
Printing inks contain ingredients that during drying do not smear or run but can deposit the ink in place
upon printing with the liquid components evaporating during drying leaving an imprint that is resilient. The
suspending agents in printing inks should be compatible with the substrate (e.g., hypromellose for aqueous
film-coated tablets) as this will assure maximum interaction with the substrate.
Dosage Forms
Printing inks are used primarily in tablets and capsule dosage forms.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include solubility, color,
particle size of insoluble ingredients, viscosity, and dispersibility of insoluble ingredients.
General Chapters
The following general chapters may be useful in ensuring consistency in selected printing ink component
functions: 〈911〉, 〈912〉, 〈913〉, and 〈914〉, 〈61〉, 〈 62〉, 〈631〉, 〈429〉, 〈232〉, 〈233〉, and 〈 841〉.
Additional Information
Ingredients in the printing ink should comply with 21 CFR §206, Imprinting of Solid Oral Dosage Form
Drug Products for Human Use, even though some ingredients comply with the USP and NF monographs.
Further assurance for ingredients not listed in the USP-NF can be obtained by demonstrating compliance
with the Food Chemical Codex and/or relevant European Union directives.
PROPELLANT
Description
Propellants are compounds that are gaseous under ambient conditions. They provide force to expel
contents from a container.
Physical Properties
Propellants have boiling points well below ambient temperatures. A propellant's density for disperse
systems and its solubility properties may be significant considerations when one selects a propellant.
Apaflurane and norflurane have liquid phase densities that are greater than that of water. Hydrocarbon
propellants (butane, isobutane, and propane) and dimethyl ether have liquid phase densities that are less
than that of water.
Chemical Properties
Propellants typically are stable materials. The hydrocarbon propellants (butane, isobutane, and propane)
and dimethyl ether are all flammable materials. Apaflurane, carbon dioxide, nitrogen, and norflurane are
nonflammable. Nitrous oxide is not flammable but supports combustion. Hydrofluoroalkanes, which are not
ozone-depleting substances (ODS), have replaced chlorofluorocarbon propellants, that are ODS and no
longer permitted in foods, drugs, devices, or cosmetics by 21 CFR §2.125, Use of Ozone-Depleting
Substances in Foods, Drugs, Devices, or Cosmetics.
Functional Mechanism
Propellant substances are low boiling point liquids or compressed gases that are relatively inert toward
active ingredients and excipients. They can be characterized by four properties: existence in a liquid phase
at ambient temperatures and useful pressures; solubility and/or miscibility in the rest of the formulation;
density; and flammability. Their performance is judged by their ability to provide adequate and predictable
pressure throughout the shelf life of the product.
Propellants that have both a liquid and gas phase in the product provide consistent pressures as long as
there is a liquid phase present—the pressure in the headspace is maintained by the equilibrium between the
two phases. In contrast, the pressure provided by propellants that have no liquid phase may change
relatively rapidly as the contents of the container are expelled. As the headspace becomes larger, the
pressure within the container falls proportionately. Propellants that have no liquid phase but have significant
pressure-dependent solubility in the rest of the formulation have performance characteristics between those
of the other two systems. In such cases, as the headspace increases the propellant comes out of solution to
help to maintain the pressure of the system.
In metered-dose inhalers, the propellant has a liquid phase that is an integral part of the dispensed
pharmaceutical product. Actuating the metering valve dispenses a defined volume of the liquid contents.
The propellant spontaneously boils and provides atomizing and propulsive force. A predictable change in
active concentration occurs from the beginning to the end of the container shelf life, as the liquid phase of
the propellant vaporizes to reestablish the equilibrium pressure of the system as the headspace increases.
Dosage Forms
Propellants are used in pharmaceuticals (inhalation aerosols, nasal aerosols, and topical aerosols) to
provide force to expel contents from a container.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include solubility, water
content, density, boiling point, purity, impurity profile (related and unrelated), and high-boiling residues.
General Chapters
The following general chapters may be useful in ensuring consistency in selected propellant functions:
〈601〉, 〈621〉, 〈 921〉, and Propellants 〈602〉.
REDUCING AGENT
Description
Reducing agents, or reductants, are used in the preparation of some radiopharmaceuticals to reduce the
oxidation state of certain radiometals such as sodium pertechnetate (+7 oxidation state) to a lower
oxidation state, so that they can be chelated or otherwise complexed by the intended ligand to form the
final radiopharmaceutical.
Physical Properties
Reducing agents must be readily soluble in aqueous solution.
Chemical Properties
Reducing agents are sensitive to oxidation by atmospheric oxygen and oxidizing species in solution.
Hence, lyophilized contents of kit vials must be filled with a nonoxidative gas such as nitrogen or argon. The
reducing agent also must be stable at the intended pH of the formulated product. A common example of a
reducing agent is stannous ion in the form of salts (e.g., chloride, fluoride, and tartrate).
Functional Mechanism
The reducing agent must be present in sufficient quantity to reduce all of the radiometal atoms to the
intended oxidation state but must not produce undesired reduction products or other impurities (e.g.,
stannous hydroxide precipitates).
Dosage Forms
Reducing agents are used primarily in liquid radiopharmaceutical dosage forms intended for injections.
Performance-Related Properties
Potential performance-related properties for reducing agents are water solubility and stability in the
formulated environment.
General Chapters
The following general chapters may be useful in ensuring consistency in selected reducing agent
functions: 〈621〉 and 〈821〉.
RELEASE-MODIFYING AGENT
Description
Release-modifying agents are used to alter the rate and/or time of release of the drug substance
compared with that observed or anticipated for an immediate-release product. There are two types of
modified release formulations, i.e. delayed-release formulations (also referred to as enteric-coated or
gastroresistant formulations) and extended-release formulations (also referred to as prolonged-release,
controlled-release, or sustained-release formulations).
For delayed-release, commonly used enteric polymers include methacrylic acid copolymers and cellulose
acetate phthalate. For extended-release, hydrophilic polymers such as cellulose derivatives, hypromellose,
and hydroxyl propyl cellulose are widely used in hydrophilic matrix drug delivery systems. Hydrophobic
polymers such as ethyl cellulose can be used to achieve extended-release along with water-soluble pore
formers. Other ingredients commonly combined with release-modifying ingredients, such as plasticizers,
surfactants, colorants, fillers, and buffers are discussed in corresponding functional categories.
Physical Properties
The majority of release-modifying agents are polymers that differ in solubility, ease of erosion, rate of
swelling, or sensitivity to the biological environment in which they are placed. An understanding of the
functional mechanism of the release-modifying agent is necessary to identify potential important physical
and chemical properties. The physical properties of the release-controlling excipient depend on the chemical
type: hydrophilic polymer, hydrophobic polymer, semipermeable polymer blends, or lipid, wax, or
biodegradable polymer (which can be hydrophilic or hydrophobic).
Hydrophilic polymers gel in contact with water or aqueous media. Because they should provide resistance
to the mechanical action of the gastrointestinal tract during passage, they typically are higher molecular
weight grades of the polymers. At the concentrations typically used during in vivo release, these high
molecular weight polymers often do not exhibit Newtonian properties except in very dilute solution (if they
are soluble). Formulators should monitor the kinetic and viscoelastic properties of the gels formed in the
release medium.
Hydrophobic polymers are insoluble in water, and their solution properties are determined in nonaqueous
solutions. The polymers used in the preparation of semipermeable membranes in osmotic pump devices
also are insoluble in water, and similarly their solution properties are determined in nonaqueous solutions.
Similarly, hydrophobic lipid-based materials are insoluble in water.
Chemical Properties
Release-modifying agents are composed of many different types and origins and are available in a range
of grades that reflect considerable variation in their chemical structures and properties. Many of those
agents are cellulose derivatives, such as water-soluble hypromellose and hydroxyl propyl cellulose, water-
insoluble ethylcellulose, and the pH-sensitive polymer cellulose acetate phthalate. Synthetic polymers
include methacrylate ester polymers, polyethylene oxide, etc.
Formulators must consider these variables during any investigation and consider the effects of chemical
structure on excipient performance. Properties of interest may include chemical composition for copolymers
and cellulosic derivatives, degree of ionization, molecular weight, degree of cross-linking, or, for lipids, fatty
acid composition. Residual impurities from the manufacturing process, e.g., monomers, initiators,
quenching agents, peroxides, and aldehydes, may affect drug substance stability and should be monitored.
Functional Mechanism
Upon contact with a biological fluid, release-modifying polymers may undergo a variety of physical
changes such as swelling, gelling, dissolution, or erosion, each of which can be triggered by simple aqueous
exposure or can be modulated by pH, osmotic stress, or interactions with bile or other intestinal contents.
In addition to physical changes, polymers may undergo chemical degradation from the influence of acids,
bases, enzymes, water, heat, and other factors. Any or all of these mechanisms may act in concert to
control the rate at which the drug is released from the delivery system.
For hydrophilic matrices in which drug diffusion dominates release rate, the rate of drug release depends
on the properties of the polymer gel and the nature of the continuous phase in the interstices of the gel that
influences the dissolution and diffusion rates of the drug. In the case of eroding matrices, the gel erodes
because of the mechanical action of the gastrointestinal tract as the water uptake increases, and the gel
becomes more dilute, thus reducing the diffusion distance or releasing drug particles that subsequently
dissolve. Hydrophobic matrix-forming materials are not soluble. Drug release from such systems is
governed by drug diffusion through the tortuous pores that remain as soluble components dissolve.
Membrane-based drug delivery systems include polymer-coated tablets, capsules, and microspheres.
Drug-release mechanisms from such systems are complex and depend on physicochemical characteristics of
the drug and polymers or lipids used as well as biological factors in the case of biocompatible and
biodegradable systems. Most commonly, drug release from such systems is governed by drug diffusion
through the hydrated rate-controlling membrane. The drug release rate can often be modulated by
plasticizer, surfactants, or water-soluble pore formers.
Delayed-release can be achieved via enteric coatings, which are insoluble in acidic (low pH) media but
dissolve readily in neutral pH conditions. Those pH-sensitive polymers usually have acidic groups that can
be ionized at neutral pH, resulting in the breakdown of coating and the release of drug substance. The
triggering pH value could be fine-tuned by the variation of acidic groups and hydrophobic groups such as
acetate groups.
Other modified-release systems for parenteral use include solid lipid nanoparticles and liposomes. The
release mechanisms for these systems often involve a complicated interplay with biological processes such
as potential clearance through the reticuloendothelial system, targeted delivery, and cellular uptake.
Osmotic pump devices are a special case of membrane delivery systems. The rate-controlling polymer is
insoluble and semipermeable—i.e. it will allow water but not drug molecules—to diffuse through the
membrane. Release is controlled by the osmotic pressure of the core components and the viscosity of the
resulting solution or suspension. The drug, either in solution or as a suspension, is forced out of a hole in
the membrane, which is typically drilled by a laser during product manufacture.
Dosage Forms
Polymers have been used to fabricate matrix-based or membrane-based drug delivery systems for oral,
parenteral, transdermal, and other routes of administration. Such devices may take the form of tablets,
capsules, systems, and others.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage for release-modifying agents are
dependent upon the release-modifying mechanism and include: viscosity, substitution, solubility, particle
size, elasticity and plasticity, kinetic and viscoelastic properties of gel, and mechanical strength.
General Chapters
The following general chapters may be useful in ensuring consistency in selected functions of release-
modifying agents: 〈401〉, 〈429〉, 〈695〉, 〈696〉, 〈711〉, 〈731〉, 〈741〉, 〈761〉, 〈776〉, 〈786〉, 〈846〉, 〈854〉, 〈857〉,
〈881〉, 〈891〉, 〈 911〉, 〈912〉, 〈913〉, 〈921〉, 〈941〉, 〈 1174〉, and 〈1181〉.
Additional Information
Some release-modifying agents may include additives such as an antioxidant or an anticaking agent.
SOLVENT
Description
Solvents and cosolvents are used to dissolve the active ingredient(s) and excipients in liquid, semisolid,
and solid drug products. The most common solvent is water. This section of the chapter will focus on
organic solvents. Frequently, the hydrophobicity of active ingredients precludes their simple dissolution in a
volume of water appropriate for the intended dosage form. Amphiphilic solvents and cosolvents can be used
to improve the solubility or stability of lipophilic or insoluble active ingredients.
Physical Properties
Solvents or cosolvents need be in the appropriate state (liquid, semisolid, or solid) at the intended
storage temperature of the drug product. The solvents’ and cosolvents’ dielectric constant and solubility
parameters must ensure complete dissolution of the active ingredient and, if applicable, miscibility with
water.
Chemical Properties
Solvents and cosolvents can be categorized into the following three classes: nonpolar solvents such as
oils of plant origin; polar protic solvents such as ethanol, propylene glycol, or polyethylene glycols; and
polar aprotic organic solvents such as dimethyl sulfoxide, benzyl benzoate, N,N-dimethylacetamide, 2-
pyrrolidone, and N-methyl-2-pyrrolidone.
Functional Mechanism
The intermolecular interactions between solute-solute, solvent-solvent, and solute-solvent control the
solubility of the active ingredient(s) in a solvent system. Dissolution is most appropriately viewed as an
entropically driven process rather than an enthalpically driven one as solute molecules in solution are more
randomly distributed than in the pure solid or liquid bulk phase. Solubility of the solute in a solvent or
solvent system depends on the solvation ability of the solvent and the intrinsic ability of a solute molecule
to interact with the solvent and thereby separate from the solute phase and transfer into the solvent phase.
Dosage Forms
Typical dosage forms that use solvents are aerosols, creams, films, foams, gels, irrigations, liquids,
lotions, ointments, rinses, shampoos, soaps, solutions, sprays, and suspensions.
The parenteral use of solvents and cosolvents entails more restrictions than their use in oral drug
products. In addition to the high standards of purity and sterility required, the formulator has to consider
safety and tolerability of the (co-)solvent, as well as potential hypertonicity if the cosolvent is present at a
high enough concentration.
For topical or mucosal routes of administration, the (co-)solvent might affect the structure or integrity of
the epithelium, influencing permeation and release kinetics. Special care should be exercised if the drug
product is intended to be applied to a diseased or compromised epithelium.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include attributes related to
identity and impurities. The performance-related properties of the raw materials must enable the final drug
product to comply with the relevant monographs (e.g., 〈1〉). Solvents and cosolvents can interact with
primary packaging and influence the level of leachables present in the drug product.
General Chapters
The following general chapters may be useful in ensuring consistency in selected solvents and cosolvents:
〈1〉, Oral Drug Products 〈2〉, 〈4〉, 〈5〉, Ophthalmic Products—Quality Tests 〈771〉, 〈1094〉, 〈1231〉, Assessment
of Extractables Associated with Pharmaceutical Packaging/Delivery Systems 〈1663〉, Assessment of Drug
Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems 〈1664〉, and Orally Inhaled
and Nasal Drug Products 〈1664.1〉.
SORBENT
Description
Sorbents are materials that function to attract and hold other molecules. Sorbents are classified into two
categories: absorbents and adsorbents. Absorbents are used to take up liquids or gases and are
characterized by the volume of the substance being absorbed. Adsorbents take up liquids or gases by
interacting with the surface of the adsorbing material and forming surface layers. Adsorbents are
characterized by the surface interactions that occur.
Sorbents can be used as a rapid-release or modified-release or sustained-release agent for an active
ingredient or to adsorb/absorb undesirable compounds like water, solvent molecules, or gas molecules (e.g.,
oxygen). Additional uses include adsorption of active ingredients to assist the manufacturing process (e.g.,
content uniformity, stability, minimization of the effects of the deleterious physical properties of the active
ingredient on the manufacturing unit processes).
Examples of absorbents include cellulosic compounds, gums, fibers (e.g., cotton, rayon, and polyester),
and sugars. Examples of adsorbents include activated charcoal, silica gel, zeolite, crospovidone, titanium
dioxide, sodium carbonate, sodium chloride, and ascorbic acid.
Physical Properties
One property of sorbents is high surface area. High surface area is more important for adsorbents than
absorbents in their function. It should be noted that the surface area should be controlled especially for
adsorbents where effects on the performance of the product may occur (e.g., hindering the rate and extent
of dissolution).
Chemical Properties
For adsorbents, the chemistry and consistency of the surface with respect to the molecular structures
predominating at the surface is a key property. Adsorbents with highly active surfaces may interact with
other parts of the dosage form including the active ingredient or even substances in the environment (e.g.,
water or gases) and not function as expected. In some cases, the adsorbent/absorbent may undergo a
chemical reaction on interacting with a gas or liquid such as iron to ferrous/ferric oxide, ascorbate to
dehydroascorbic acid, and calcium oxide to calcium hydroxide.
Functional Mechanism
Sorbents function via one of two mechanisms: absorption or adsorption. The absorption mechanism is
one related to the volume of the absorbent where the substance interacts with the mass of the absorbent.
Absorption involves the processes of dissolution or diffusion.
In contrast, the mechanism of adsorption involves the interaction of a gas or liquid or solid with the
surface of the adsorbent particles with the substance-forming layers on the surface.
Dosage Forms
Sorbents are used in solid dosage forms (tablets, capsules, gums, pills, pellets, and granules) and
transdermal products (creams, lotions, and ointments).
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include surface area,
particle size, morphology, density, potential interactions with other ingredients in formulation, specificity in
adsorption/absorption, and absorptive/adsorptive capability. Adsorption/desorption kinetics may be
important.
General Chapters
The following general chapters may be useful in ensuring consistency in selected sorbent functions: 〈921〉,
〈846〉, 〈429〉, 〈 776〉, Loss on Ignition 〈733〉, 〈232〉, 〈233〉, 〈786〉, 〈776〉, 〈811〉, 〈699〉, and 〈1241〉.
STABILIZER
Description
Stabilizers are used to prevent or retard a change in a system or individual component in a dosage form.
The stabilization of pharmaceutical products may occur via numerous mechanisms including: sequestration,
antioxidants, neutralizing agents, viscosity modifying agents, the presence or absence of a particular ion or
functional group, or charge-modifying agents (e.g., flocculants). Examples of types of stabilizers include
antioxidants (e.g., alkylated phenols, butylated hydroxytoluene, metabisulfites, gallates), sequestrants
(e.g., edetates, disodium ethylenediaminetetraacetate), light stabilizers (e.g., ferric oxide and titanium
dioxide), emulsion stabilizers [e.g., proteins, polysaccharides, cellulosics, starches, surfactants, charged
inorganic, and organic compounds (flocculants)]. See Physical Form Stabilizer for a related functional
category.
Physical Properties
A stabilizer must be compatible with the state of the system in which it is being used (e.g., liquids are
typically not a good fit for tablets). Further considerations include other aspects of physical stability such as
solubility, precipitation (“salting out”), discoloration, organoleptic properties, flow properties, processing,
microbial activity, amorphous or crystalline form stabilization, suspendibility, emulsion stabilization
(breaking or inversion), viscosity, or micelle breakdown/formation.
Chemical Properties
A stabilizer should be chemically compatible with the system intended for use. Knowledge of the
mechanism of stabilization is key to understanding the important chemical properties. Other considerations
include compatibility with the active ingredient and other ingredients, stability of stabilizer function, and
initiation of other unintended chemical reactions.
Functional Mechanism
The functional mechanisms of stabilizers are numerous and are dependent on both the stabilizer and the
product. Stabilizers may have a direct effect on the stability of the product or an indirect effect (e.g., use of
a chelating agent to reduce microbial activity). Mechanisms include, but are not limited to, viscosity change,
zeta potential change (charge modification), sequestration, electron scavenging, photon energy dissipation,
chemical reaction, neutralization, and absence or dilution of an offending ion or functional group.
Dosage Forms
Stabilizers are used in tablets, capsules, liquids, gels, ointments, creams, injections, emulsions,
suspensions, lotions, pastes, solutions, and granules.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include solubility and
physical and chemical compatibility. Performance-related properties are unique to each application and can
be wide and varied in important attributes.
General Chapters
The following general chapters may be useful in ensuring consistency in selected stabilizer functions:
〈232〉, 〈233〉, 〈 776〉, 〈695〉, 〈1181〉, 〈846〉, Porosimetry by Nitrogen Adsorption-Desorption 〈268〉, Porosimetry
by Mercury Intrusion 〈267〉, 〈1174〉, 〈61〉, 〈62〉, 〈 51〉, 〈71〉, Globule Size Distribution in Lipid Injectable
Emulsions 〈729〉, 〈429〉, and 〈891〉.
STIFFENING AGENT
Description
A stiffening agent is an agent or a mixture of agents that increases the consistency of a nonaqueous or
biphasic preparation. Stiffening agents can be either hydrophobic (e.g., hard fat or paraffin) or hydrophilic
(e.g., polyethylene glycol, high molecular weight).
Physical Properties
The primary physical property relevant to stiffening agents is their high melting point or melting range,
thus their ability to raise the melting point of the dosage form. Typical melting ranges for stiffening agents
range from 43° to 47° (cetyl esters wax), 53° to 57° (glyceryl distearate), 69° to 74° (glyceryl behenate),
and 85° to 88° (castor oil, hydrogenated).
Chemical Properties
Stiffening agents comprise a diverse group of materials that include glycerides of saturated long-chain
fatty acids, solid aliphatic alcohols, esters of saturated fatty alcohols and saturated fatty acids, saturated
hydrocarbons, blends of fatty alcohols and a polyoxyethylene derivative of a fatty acid ester of sorbitan,
waxes, and higher ethylene glycol polymers.
Functional Mechanism
In general, stiffening agents are high melting point solids that increase the melting point of ointments or
increase the consistency or body of creams. They may also modify the microstructure of the ointment
cream or suppository and thus change its rheological properties.
Dosage Forms
Stiffening agents are used for mucosal, topical, and dermal dosage forms as a means to increase the
viscosity of hardness of a preparation. Stiffening agents are especially useful in ointments and creams.
They are also used in the formulation of suppositories.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include melting
point/melting range and viscosity.
General Chapters
The following general chapters may be useful in ensuring consistency in selected stiffening-agent
functions: 〈651〉, 〈741〉, 〈911〉, 〈912〉, 〈 1911〉, and 〈913〉.
Additional Information
Some of the materials included as stiffening agents increase the water-holding capacity of ointments
(e.g., petrolatum) or function as co-emulsifiers in creams. Examples include stearyl alcohol and cetyl
alcohol. Some stiffening agents may act as auxillary suspending agents in the formulation of suppositories.
SUGAR-COATING AGENT
Description
Three methods for coating are compression coating, sugar coating, or film coating. Compression coating
(effectively making a tablet within a tablet) typically uses the same ingredients as a conventional tablet and
thus is outside the scope of this section. The term “sugar coating” refers to a process and does not require
that sucrose be part of the formulation. Sugar coating was the original coating process. However, today for
technical and economic reasons, sugar coating largely has been replaced by film coating. The reasons for
sugar coating pharmaceutical dosage forms include masking unpleasant tastes or odors, improving patient
acceptance (especially in pediatric patients) and appearance, and protecting active ingredients from the
environment. Materials used as sugar-coating agents differ depending on the coating stages (i.e. seal
coating, key coating, subcoating, smoothing coat, color coating, and polishing coat). For the sealing step,
polymers such as shellac and zein are used to water-proof and harden the tablet core to prevent damage
during subcoating. Subcoating is the main step to gain weight (30%–50% of the weight of tablet core), and
typical materials used are bulking agents such as calcium carbonate or talc in combination with sucrose
solution. The smoothing step is usually completed by applications of plain 70% (w/w) syrup. The color-
coating step originally used water-soluble dyes, but water-insoluble pigments including aluminum lakes
have gained popularity in the past decades. Finally, waxes, such as carnauba and beeswax in organic
solvent or dispersion with aid of surfactants, are applied to the tablet as a final polishing step.
Physical Properties
The viscosity, spreadability, and adherence to substrate of each coating layer are important physical
properties. The solids content of the coating suspensions is important because it influences the quality of
finished tablets and the speed of processing.
Chemical Properties
Sugar coating comprises a diverse variety of different excipients depending on coating stages. Coating
components can be of natural, semisynthetic, or synthetic origin. Typical coating agents are shellac, zein, or
other proteins for seal coating; minerals such as talc or calcium carbonate for subcoating; sucrose for
smoothing coat; pigments/dyes for color coating; and natural wax for polishing coat.
Functional Mechanism
The coating layers and their functions are as follows, in order of application:
Seal coat: harden and water-proof the core
Key coat: adhesion of the subcoat to the seal coat, if required
Sub coat: bulking, rounding, and shaping
Smoothing coat: create smooth appearance
Color coat: provides final color
Polishing coat: provides surface gloss
Dosage Forms
Sugar-coating agents are used on tablets to enhance the visual appearance, mask bad taste, increase the
hardness of the formulation, and provide a unique product identity.
Performance-Related Properties
Because sugar coating is a multicomponent system, properties that may be important for excipient
performance for each component will depend on its function in the coating.
General Chapters
The following general chapters may be useful in ensuring consistency in selected coating agent functions:
〈401〉, 〈429〉, 〈 891〉, 〈911〉, 〈912〉, and 〈913〉.
Additional Information
Refer to other functional categories within this chapter, such as Film-Forming Agent and Coloring Agent.
Other tests that may be useful in ensuring consistency in the coating agent functions are: tackiness,
dynamic mechanical analysis, and glossimetry.
SUPPOSITORY BASE
Description
Suppository bases are hydrophobic or hydrophilic semisolid materials that are solid at room temperature
but release the drug product by melting, erosion, and/or dissolution when administered to the patient.
Physical Properties
The important physical characteristic of suppository bases is melting range. In general, suppository bases
melt between 27° and 45°. However, individual bases usually have a much narrower melting range within
these temperature boundaries, typically 2°–3°. The choice of a particular melting range is dictated by the
influence of the other formulation components on the melting range of the final product.
Chemical Properties
Hard fat suppository bases are mixtures of semisynthetic triglyceride esters of longer chain fatty acids.
They may contain varying proportions of mono- and diglycerides as well as additives. They are available in
different grades that are differentiated by melting range, hydroxyl number, acid value, iodine value,
solidification range, and saponification number.
Hydrophilic suppository bases are mixtures of hydrophilic semisolid materials that in combination are solid
at room temperature and yet release the drug by melting, erosion, and/or dissolution when administered to
the patient. Hydrophilic suppository bases have much higher levels of hydroxyl groups or other hydrophilic
groups than do hard fat suppository bases. Polyethylene glycols that show appropriate melting behavior are
examples of hydrophilic suppository bases.
Functional Mechanism
Suppositories should melt at just below body temperature (37°), thereby allowing the drug to be released
either by erosion and partition if the drug is dissolved in the base or by erosion and dissolution if the drug is
suspended in the base. Hard fat suppository bases melt at approximately body temperature. Hydrophilic
suppository bases also melt at body temperature and typically dissolve or disperse in aqueous media. Thus,
release takes place via a combination of erosion and dissolution.
Dosage Forms
Suppository bases are used in the manufacture of suppositories (for rectal administration) and inserts
(pessaries for vaginal administration).
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include melting range,
hydrocarbon chain length, hydroxyl value, and iodine value.
General Chapters
The following general chapters may be useful in ensuring consistency in selected suppository base
functions: 〈401〉, 〈651〉, 〈741〉, and 〈1151〉.
Additional Information
Some materials included in suppositories based on hard fats have much higher melting ranges. These
materials typically are microcrystalline waxes that help stabilize molten suspension formulations.
Suppositories also can be manufactured from glycerinated gelatin.
SURFACTANT
Description
Surfactants are amphiphilic molecules that lower the surface (or interfacial) tension at solid-liquid, liquid-
liquid, and/or gas-liquid interfaces. As such, they comprise both hydrophilic moieties and lipophilic moieties
in the same molecule. Surfactants play a significant role in stabilizing proteins from aggregation and/or
particulate formation upon interfacial and shear stresses. The most commonly used surfactants in protein
solutions are polysorbates 80 and 20. Poloxamer 188 is also used in a few cases. Given the
multifunctionality of surfactants, see also the functional category Wetting and/or Solubilizing Agent for more
details in their use with small molecules.
Physical Properties
Surfactants are typically solid, liquid, or waxy materials. Their physical properties depend on their
chemical structures. Surfactants are usually used in concentrations above their CMCs. CMC is a measure of
the concentration at which the surfactant molecules aggregate. By using concentrations above CMC,
surfactant levels are believed to be at a sufficient level to saturate interfaces.
Chemical Properties
The chemical properties depend on the structures of the surfactants. As a critical excipient to mitigate
particulate formation upon interfacial stress in protein solutions, it is important to understand surfactant
stability for each drug product. For example, polysorbates are known to be hydrolyzed by residual enzymes
(i.e. lipases) co-concentrated during the protein purification process. The ester hydrolysis leads to
separation of the lipophilic and hydrophilic portions of the surfactant molecules, leading to loss of surface
active properties and yielding poorly soluble degradation products (e.g., fatty acids). The extent of
degradation will likely depend on the capability of the drug substance purification process to remove
residual enzymes. Also, some surfactants, e.g., polysorbates, can generate reactive oxygen species, which
can in turn react with methionine and tryptophan residues in proteins, leading to oxidation and, potentially,
biophysical destabilization (i.e. aggregate and/or particulate formation). Therefore, the levels of peroxides
in such surfactants should be monitored and controlled and the handling of solutions should be carefully
controlled.
Functional Mechanism
In protein therapeutics, the hydrophilic moiety will strongly interact with the aqueous media, whereas the
hydrophobic portion may interact with either air at the air-water interface, or with hydrophobic regions in
the protein structure, or with hydrophobic surfaces (e.g., on the primary container).
Dosage Forms
Surfactants are commonly used to stabilize protein therapeutics. Proteins are most commonly delivered
by intravenous, subcutaneous, or intramuscular injections. Surfactants are added to both ready-to-use
solutions and to lyophilized drug products. For lyophilized powders, surfactants can mitigate protein
degradation also during reconstitution prior to administration. When protein therapeutics are developed to
be delivered with prefilled syringes (PFS), surfactants play a critical stabilizing role as the internal barrels of
PFS are commonly lubricated with silicone oil. Interacting with hydrophobic patches in protein structures,
the presence of silicone can trigger protein destabilization (aggregation and/or particulate formation).
Surfactants also protect protein therapeutics during manufacturing operations (e.g., mixing and filling) and
during administration (e.g., after dilution in an intravenous bag).
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include attributes related to
identity and impurities (i.e. elemental impurities, peroxides, etc.). In particular, the level of endotoxin may
be relevant for parenteral dosage forms.
General Chapters
The following general chapters may be useful in ensuring consistency in selected surfactant functions: 〈1〉,
〈85〉, 〈232〉, Subvisible Particulate Matter in Therapeutic Protein Injections 〈787〉, 〈788〉, Visible Particulates
in Injections 〈790〉, Measurement of Subvisible Particulate Matter in Therapeutic Protein Injections 〈1787〉,
Methods for the Determination of Particulate Matter in Injections and Ophthalmic Solutions 〈1788〉, and
Visual Inspection of Injections 〈1790〉.
SUSPENDING AND/OR VISCOSITY-INCREASING AGENT
Description
Viscosity-increasing and suspending agents are used in pharmaceutical formulations to stabilize dispersed
systems (e.g., to inhibit sedimentation of the dispersed phase of suspensions or emulsions), to reduce the
rate of solute or particulate transport, or to decrease the fluidity of liquid formulations.
Physical Properties
Each of the mechanisms—increased viscosity, gel formation, or steric stabilization—is a manifestation of
the rheological character of the excipient. Because of the molecular weights and sizes of these excipients,
the rheological profiles of their dispersions are non-Newtonian. Dispersions of these excipients display
viscoelastic properties. The molecular weight distribution and polydispersity of the macromolecular
excipients in this category are important criteria for their characterization.
Chemical Properties
The majority of the suspending and viscosity-increasing agents are:
Hydrophilic carbohydrate macromolecules (acacia, agar, alginic acid, carboxymethylcellulose,
carrageenans, dextrin, gellan gum, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose,
hypromellose, maltodextrin, methylcellulose, pectin, propylene glycol alginate, sodium alginate,
starch, tragacanth, and xanthan gum)
Noncarbohydrate hydrophilic macromolecules, including gelatin, povidone carbomers, polyethylene
oxide, and polyvinyl alcohol
Minerals (e.g., attapulgite, bentonite, magnesium aluminum silicate, and silicon dioxide) comprise the
second largest group of suspending and viscosity-increasing agents
Aluminum monostearate is the one nonmacromolecular, nonmineral excipient in this functional
category. It consists chiefly of variable proportions of aluminum monostearate and aluminum
monopalmitate
Functional Mechanism
A number of mechanisms contribute to the dispersion stabilization or viscosity-increasing effect of these
agents. The most common is the increase in viscosity due to the entrapment of solvent by macromolecular
or insoluble particle networks that disrupt laminar flow. Other mechanisms include gel formation via a
three-dimensional network of excipient molecules or particles throughout the solvent continuum and steric
stabilization wherein the macromolecular or mineral component in the dispersion medium adsorbs to the
surfaces of particles or droplets of the dispersed phase. The latter two mechanisms increase formulation
stability by immobilizing the dispersed phase.
Dosage Forms
Viscosity-increasing or suspending agents are typically used in creams, emulsions, gels, lotions,
ointments, pastes, shampoos, and suspensions as noted above. They may also be employed in solid dosage
forms to retard drug release at the site of administration.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include molecular weight,
molecular weight distribution, polydispersity, particle size, and zeta potential.
General Chapters
The following general chapters may be useful in ensuring consistency in selected viscosity-increasing
functions: 〈429〉, 〈776〉, 〈786〉, 〈846〉, 〈 911〉, 〈912〉, 〈913〉, 〈914〉, and 〈1911〉.
SWEETENING AGENT
Description
Sweetening agents are compounds or blends of compounds of natural or synthetic origin that have the
ability to elicit a sweet taste to the drug product formulation. They are normally used to mask undesirable
tastes and to promote patient compliance. A related functional category is Flavor and Fragrance.
Physical Properties
Sweeteners can be broadly grouped into nutritive and non-nutritive. Nutritive sweeteners deliver calories.
The primary physical properties relevant to sweeteners relate to their compatibility with the other
ingredients in the formulation (e.g., acidic ingredients), processing conditions (e.g., heating), particle size
and distribution, moisture content, isomerism, sweetness, and taste-masking capability. These properties
may be formulation-dependent.
Chemical Properties
Sweeteners can be divided into three main groups: sugars (which have a ring structure), sugar alcohols
(sugars that do not have a ring structure), and artificial sweeteners. All sweeteners are water-soluble. The
stability of many sweeteners is affected by pH and other ingredients in the formulation. Some sweeteners
may catalyze the degradation of some active ingredients, especially in liquids and in cases in which the
manufacturing processes involve heating.
Functional Mechanism
Sweetening agents bind to specific G-protein coupled receptors located on the taste cell membrane on the
tongue that are responsible for the sensation of sweetness. The better the fitting of a chemical structure of
the sweetener is to a corresponding receptor, the longer the sweetener molecule remains attached to the
receptor and the sweeter the substance is perceived to be. The standard for sweetness is sucrose.
Dosage Forms
Sweeteners are used to sweeten oral (solid and liquid) dosage forms to mask unpleasant taste or make
the pharmaceutical product more palatable. Typical dosage forms that use sweeteners include tablets,
lozenges, liquids, and pastes.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include particle size, particle
distribution, moisture content, sweetness, and solubility.
General Chapters
The following general chapters may be useful in ensuring consistency in selected sweetening functions:
〈429〉, 〈731〉, 〈 781〉, and 〈921〉.
Additional Information
Products that contain aspartame must include a warning on the label stating that the product contains
phenylalanine. Sugar alcohols have a glycemic index well below that of glucose. However, sorbitol is slowly
metabolized to fructose and glucose, which raises blood sugar levels. Sugar alcohols in quantities generally
greater than 20 g/day act as an osmotic laxative, especially when they are contained in a liquid formulation.
Preservative systems should be carefully chosen to avoid incompatibility with the sweetener, and some
sweeteners are incompatible with certain preservatives.
TONICITY AGENT
Description
The tonicity agents are solutes such as salts, sugars, and amino acids that contribute to solution
osmolality. The tonicity agents are included in formulations to avoid crenation or hemolysis of red blood
cells and/or to mitigate pain and discomfort if solutions are injected or introduced into the eyes and nose.
This requires that the tonicity of solutions for injection must be approximately the same as that of blood.
When drug products are prepared for administration to membranes, such as eyes, nasal or vaginal tissues,
solutions should be made isotonic with respect to these tissues.
Physical Properties
All solutes do not contribute equally to tonicity, which in general depends only on the number of solute
particles present in a solution, not the kinds of solute particles. For example, mole for mole, sodium
chloride solutions display a higher tonicity than glucose solutions of the same molar concentration. This is
because when glucose dissolves, it remains one particle, but when sodium chloride dissolves, it becomes
two particles: Na
+
and Cl
–
.
Chemical Properties
Tonicity agents can be ionic or nonionic in nature. Examples of ionic tonicity agents are alkali metal or
earth metal halides such as sodium chloride (NaCl), sodium sulfate (Na SO ), or boric acid. Nonionic
tonicity agents include glycerol, sorbitol, mannitol, propylene glycol, or dextrose. Sodium chloride and
dextrose are commonly added to adjust tonicity.
Functional Mechanism
Tonicity is a medical term that relates to the osmotic pressure difference between the internal and
external sides of a cell membrane. In many cases, tonicity and osmolality are not the same because some
solutes are able to rapidly pass through the cell membrane. Tonicity applies to the impermeant solutes
within a solvent, in contrast to osmolality, which takes into account both permeant and impermeant solutes.
For example, urea is a permeant solute, meaning that it can pass through the erythrocyte membrane freely
and does not contribute to tonicity of a solution with respect to blood. In contrast, sodium chloride is
impermeant and cannot pass through the erythrocyte membrane without the help of a concentration
gradient and, therefore, contributes to a solution's tonicity. Different biological membranes may show
different permeability to a given solute.
Dosage Forms
Tonicity agents may be used in liquid and semisolid dosage forms, including injections, creams, lotions,
solutions, and sprays, intended for parenteral, topical, mucosal, ophthalmic, and inhalation use. The tonicity
should be assessed with respect to the biological membrane relevant to the dosage form (e.g., erythrocyte
for parenteral formulations and conjunctiva for ophthalmic solutions). Solutions of sodium chloride,
dextrose, and Lactated Ringer's are common examples of pharmaceutical preparations that contain tonicity
agents.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include attributes related to
impurities.
General Chapters
The following general chapters may be useful in ensuring consistency in selected tonicity agent functions:
〈1〉, 〈4〉, 〈5〉, 〈771〉, 〈 785〉, Excipient Biological Safety Evaluation Guidelines 〈1074〉, 〈1160〉, and Vaccines for
Human Use—Polysaccharide and Glycoconjugate Vaccines 〈1234〉.
TRANSFER LIGAND
Description
Transfer ligands, also known as auxiliary ligands, auxiliary chelating ligands, and exchange ligands, are
used as a step in the preparation of some radiopharmaceuticals whereby a radiometal (e.g., stannous-
reduced technetium Tc 99m) is first chelated by a relatively weak chelating ligand (transfer ligand) and is
subsequently transferred to the principal chelating ligand or complexing moiety to form the final
radiopharmaceutical.
Physical Properties
Transfer ligands must be readily soluble in aqueous solution.
Chemical Properties
2 4
Transfer ligands must have rapid complexation kinetics and must form relatively weak chelates compared
to complexation with the principal ligand. Examples of such transfer ligands include citrate, gluconate, and
tartrate.
Functional Mechanism
Transfer ligands typically undergo rapid reactions to form weak chelates. This procedure is especially
useful when the kinetics of complexation with the principal ligand is slow or when a heating step is
necessary to expose chelating groups on the principal ligand.
Dosage Forms
Transfer ligands are used primarily in liquid radiopharmaceutical dosage forms intended for injection.
Performance-Related Properties
Performance-related properties for transfer ligands are: solubility, rapid complexation kinetics with the
desired radiometal, and relatively weak chelation of the radiometal compared with the principal ligand.
General Chapters
The following general chapters may be useful in ensuring consistency in selected transfer ligand
functions: 〈621〉 and 〈821〉.
VEHICLE
Description
Vehicles have typically been considered as carriers or inert media used as a diluent in which the active
ingredient is formulated or administered. Vehicles are often liquid solvents but the term may be applied to
solid carriers and diluents. Vehicles may be considered to be drug carriers that are compatible with the drug
or formulation and facilitate the formulation and administration of the drug. Vehicles may be used to
directly manufacture liquid dose forms or be copresented with powder or tablets for reconstitution by the
pharmacist or patient.
Physical Properties
Liquid vehicles may be aqueous (e.g., sodium chloride injection, bacteriostatic), nonaqueous (e.g., oils),
with appropriate viscosity, solubilizing, or suspending properties or solid (e.g., sugar spheres).
Chemical Properties
Vehicle components should be compatible with the active ingredient and may include buffers,
preservatives, tonicity agents, and flavor. Vehicle composition is dependent on formulation objectives.
Functional Mechanism
Functional mechanism is dependent on composition and formulation objectives. Examples include
solvency, suspension, stability, or taste-masking.
Dosage Forms
Liquid vehicles enable manufacture of liquids and suspensions dosage forms or may be a component of
the dose form when copresented for reconstitution in injections dosage forms. Hard fats are the common
carrier for suppository dosage forms, and sugar spheres may be a vehicle for solid dosage form
preparation. Related functional categories are: Wetting and/or Solubilizing Agent, Solvent, Diluent, and
Pharmaceutical Water.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include viscosity, tonicity,
pH, or particle size.
General Chapters
The following general chapters may be useful in ensuring consistency in vehicle functionality: 〈51〉, 〈71〉,
〈616〉, 〈699〉, 〈 731〉, 〈1174〉, 〈1227〉, and 〈786〉.
Additional Information
Vehicles may facilitate the formation of a stable drug suspension and cover a wide range of excipients
including but not limited to inert powders (e.g., talc); polymers; liquid solvents; suspending agents; sugars;
oils; and semisolid or solid pegylated lipids. Glycerides including oils are often suitable vehicles for delivery
of liposoluble compounds. Liquid to solid surfactants help the formation of a stable suspension in aqueous
media. Cosolvents such as ethanol, glycerol, or propylene glycol may be included to solubilize the active
ingredient.
VISCOSITY-LOWERING AGENT
Description
Proteins such as monoclonal antibodies can display high viscosities in highly concentrated solutions. This
buildup of viscosity can pose issues in the successful development of high concentration monoclonal
antibody formulations, especially for subcutaneous administration. Viscosity-lowering agents are used to
reduce the viscosity of high concentration protein formulations. A number of agents including amino acids,
salts, polar solvents, etc. may be used to reduce the viscosity of monoclonal antibody formulations.
Physical Properties
The viscosity-lowering agents such as amino acids, salts, and other excipients are dissolved in aqueous
solution for preparation of formulation. Hence, the physical form and particle properties of the viscosity-
lowering agent are generally not relevant to the final properties of the solution or lyophilized protein
formulation. However, bioburden and endotoxin levels need to be controlled as for any excipient to be used
in the formulation of an injectable drug product.
Chemical Properties
The control of the chemical purity of viscosity-lowering agents is critical for protein formulations as with
any other excipient as presence of reactive impurities can potentially lead to protein aggregation or
inactivation of the protein. Because these agents can be included at significant levels in the formulation,
they should be also be monitored for impurities such as trace metals that can cause oxidation and/or
aggregation of proteins.
Functional Mechanism
The build-up of viscosity at high protein concentrations (e.g. ,>100 mg/mL) is related to increased
protein-protein interactions in solution. The intermolecular interactions between protein molecules can be
due to both electrostatic and hydrophobic interactions that can result in increased noncovalent protein
association at high concentrations resulting in buildup of viscosity.
Amino acids such as arginine, histidine, proline, and lysine have been used to reduce the viscosity of
monoclonal antibody solutions. These amino acids reduce viscosity by a combination of mechanisms
including screening of electrostatic charge and/or binding to specific residues on the protein molecule to
reduce interaction between protein molecules. As an example, the amino acid arginine, which is commonly
used to reduce viscosity, is known to interact with the aromatic residues on the protein leading to reduced
protein-protein interaction and lowering of viscosity. Inorganic salts such as sodium chloride can screen
charges on the protein surface, modulating electrostatic attractive or repulsive forces leading to an impact
on viscosity. It has been shown that depending on the nature of the protein-protein interaction, salts can
either reduce or increase viscosity for a given molecule and need to be evaluated for viscosity reduction. In
addition to amino acids and salts, organic cosolvents can also reduce viscosity but their use needs to be
carefully evaluated from a biocompatibility perspective.
The viscosity of a monoclonal antibody can be dependent on the solution pH. A change in solution pH can
alter the charge on the protein surface and the interaction between protein molecules, resulting in viscosity
changes. The use of formulation pH can be a viable approach to reduce viscosity but needs to be carefully
balanced with any impact of pH changes on stability and other formulation properties. A number of novel
excipients have also been evaluated for viscosity lowering of monoclonal antibody formulations, but the
suitability of their use for parenteral administration needs to be established.
Dosage Forms
The viscosity-lowering agents are generally used as excipients in injections especially formulations to be
used for administration by the subcutaneous route. Because the injection volume that can be administered
by subcutaneous route is small, the delivery of higher protein doses requires development of higher
concentration formulations that can exhibit high viscosities. The selection of the viscosity decreasing agent
should be carefully studied during formulation development to ensure that its inclusion does not impact
protein stability, loss in potency, or other issues with delivery systems to be used for administration.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include purity of the
viscosity-lowering agents and control of any impurities that can impact protein stability.
General Chapters
The following general chapters may be useful in ensuring consistency in selecting bulking agent functions:
〈1〉, 〈695〉, 〈696〉, 〈 891〉, 〈1151〉, 〈1911〉, and 〈1241〉.
WATER-REPELLING AGENT
Description
A water-repelling agent is a hydrophobic excipient that is resistant to but not impervious to penetration
by water.
Physical Properties
A water repellant surface can be characterized by the nonspreading of water droplets. Topical water-
repelling agent coatings are resistant to wash off when immersed in water.
Chemical Properties
The majority of water-repelling agents are silicone polymers with a high degree of backbone flexibility and
hydrophobic surface characteristics. They have the typical chemical properties of silicones.
Functional Mechanism
Water-repelling agents repel water due to the presence of hydrophobic functional groups on the silicone
molecule. Another important property is their ability to spread easily and cover the skin. An advantage of
silicones is their chemical and thermal stability and their resistance to photodegradation, especially
ultraviolet radiation.
Dosage Forms
Water-repelling agents are used in topical skin care products such as creams, lotions, ointments, and
sunscreens.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include hydrophobicity as
measured by water contact angle.
General Chapters
The following general chapters may be useful in ensuring consistency in selected gelation functions: 〈3〉,
〈731〉, 〈911〉, and 〈912〉.
WET BINDER
Description
Wet binders are incorporated into formulations to agglomerate powder to form granules using a
granulating fluid such as water, hydroalcoholic mixtures, or other solvents. Wet binders include natural
materials such as sugars and starch and semisynthetic and synthetic polymers such as modified cellulose
and povidone. The typical use level of wet binder is between 2% and 20%, depending on wet binder
physicochemical properties, formulation components, and composition. The wet binder may be incorporated
either dissolved in the granulating fluid or dry blended with the other powders to be wet granulated.
Physical Properties
Important physical properties include solubility in the granulating fluid, spreadability on the powder
substrate, the ability to cause the powders to adhere and agglomerate, and the ability to provide plasticity
to the granules. Homogeneous incorporation of a binder into a dry blend also depends on particle size
distribution and morphology. High viscosity may reduce spreadability. Viscosity is dependent on polymer
structure and molecular weight. Excessive levels of binder, especially high viscosity grades, may form gels
and retard drug dissolution.
Chemical Properties
Wet binders are a diverse range of materials usually polymeric. The chemical nature of polymers,
including monomer sequence, functional groups, degree of substitution, and branching, can influence the
complex interactions during granulation.
Functional Mechanism
The adhesive properties of binder solutions facilitate agglomeration of powders into granules. The binder
may modify interfacial properties of poorly water-soluble drug substances, improving wettability, and
facilitating subsequent dissolution from the tablet. During drying, binders produce solid bridges between the
powder particles, yielding granules with improved properties such as flow, handling, mechanical strength,
resistance to segregation, reduced dustiness, and compatibility.
Dosage Forms
Wet binders are used to manufacture solid oral dosage forms including tablets, capsules, granules, pills,
and pellets.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include viscosity. Particle
size distribution may be important when incorporating the binder by dry blending.
General Chapters
The following general chapters may be useful in ensuring consistency in binder functions: 〈786〉, 〈911〉,
〈912〉, Viscosity—Rolling Ball Methods 〈913〉, and 〈1911〉.
WETTING AND/OR SOLUBILIZING AGENT
Description
Solubilizers can be used to dissolve otherwise insoluble molecules. They function by facilitating
spontaneous phase transfer to yield a thermodynamically stable solution. Solubilizers may be classified into
four main groups: hydroalcoholic solvents such as alcohol and propylene glycol; lipophilic or oily solvents
such as glycerides; surfactants, also referred to as wetting agents; and polymeric solvents (e.g.,
polyethylene glycols). Related functional categories are Surfactant, Complexing Agent, and Solvent.
Physical Properties
The physical properties of solubilizers vary with their chemical structures. Hydroalcoholic solvents
classically are low viscosity liquids with good miscibility or solubility in aqueous media. They typically are
low molecular weight molecules (<300 Da) appropriate for highly aqueous delivery systems. Oils and their
derivatives are slightly more viscous, immiscible with aqueous media, and serve as solubilizers for lipophilic
drug actives (e.g., emulsions). Polyethylene glycol (polymeric) solubilizers vary in molecular size and solid
state properties (liquid to solid). Another category is surfactants that are amphiphilic in nature due to their
dual molecular structure (i.e. presence of both a lipophilic and a hydrophilic moiety in their molecular
construct). The solubilization capacity and the melt characteristics of the surfactant are dictated by the type
and size of the molecular moieties.
Chemical Properties
The key chemical properties of solubilizers relate to their HLB value and miscibility with the intended
solvent. HLB may be measured experimentally (practical HLB) or mathematically (theoretical HLB). The HLB
value is a useful tool in relative ranking of the solubilizer for its function against other excipients. On a scale
of 1–20, oily solvents are identified with an HLB of 1–3; water insoluble surfactants/cosurfactants fall in the
HLB range of 3–6; water-dispersible surfactants have HLB values of 6–11; and water-soluble surfactants
are known to possess HLB of 12 or higher. Another surfactant characteristic is the CMC, which is the lowest
concentration at which the surfactant molecules begin to aggregate, forming a micellar solution. Solubilizers
come in a wide range of chemical structures affecting their physical and surface-active properties.
Functional Mechanism
The functional mechanism depends upon the nature of the solubilizing agent. Surfactants typically reduce
surface tension and form micelles within the solvent system for the solute to dissolve or disperse. The
mechanism of solubilization with surfactants often is associated with a favorable interaction of the insoluble
agent and the interior core of the solubilizer assembly (e.g., micelles). Hydroalcoholic solvents such as
propylene glycol enable solubilization based on changes in the dielectric constant of the medium. In other
cases, unique hydrophobic sites that are capable of forming inclusion complexes are present. Other types of
solubilizers use a range of polymeric chains that interact with hydrophobic molecules to increase solubility
by dissolving the insoluble agent into the polymeric chains. Surface active agents facilitate solubilization,
micellization, or wetting of the solute by enhancing the spreading and penetrating properties of a liquid by
lowering its surface tension.
Dosage Forms
Wetting and/or solubilizing agents are mainly used in injections and oral dosage forms (including liquids,
suspensions, solutions, tablets, and capsules) to improve the solubility and/or wettability of otherwise
insoluble, hydrophobic molecules.
Performance-Related Properties
Properties that may be important for excipient performance in a dosage form include fluidity (viscosity),
molecular weight distribution, visual appearance (clarity and color), purity, presence of peroxides, and CMC.
General Chapters
The following general chapters may be useful in ensuring consistency in selected solubilizing agent
functions: 〈401〉, 〈429〉, 〈791〉, 〈841〉, 〈 846〉, 〈854〉 and 〈857〉, 〈891〉, 〈911〉, 〈912〉, and 〈913〉.
Additional Information
The physical and chemical properties of the solute (active drug) and the route of administration dictate
the type and combination of solubilizers that are appropriate. Because of the complex nature of solute–
solvent–solubilizer interactions, careful consideration, identification, and control of the CMAs of solubilizers
is required. To achieve the desired drug concentration in the formulation, it may be necessary to use two or
more types of solubilizers. Combinations of solvents and surfactants can create a variety of systems
including: aqueous or oily solutions; micellar solutions; self-emulsifying drug delivery systems;
micro/nanoemulsions; and colloidal dispersions. Whereas solutions are dispersions of the solute at the
molecular level, micellar solutions consist of a surfactant forming an aggregate that envelopes the solute in
the solvent system. Nanomicroemulsions typically are much larger or complex aggregates and may consist
of at least four types of solubilizers: hydroalcoholic solvent (water, alcohol, etc.), oil (e.g., glycerides), and
primary and secondary surfactant (e.g., cosurfactant). Generally, these molecular aggregates can solubilize
the solute by incorporating the drug into the hydrophobic regions of the formulation.
▲ (USP 1-May-2021)
1
This general information chapter provides nonmandatory information that 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.
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