PHARMACEUTICAL

EXCIPIENTS

Prof. Reza-ul Jalil

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page-
 ⇒ INTRODUCTION TO PHARMACEUTICAL EXCIPIENTS

⇒ MAJOR GROUPS OF EXCIPIENTS USED IN DOSAGE FORMS

⇒ COLORING AGENTS

⇒ FLAVORING AGENTS

⇒ ANTIOXIDANTS

⇒ ANTIMICROBIAL PRESERVATIVES

⇒ SOLVENT / VEHICLE

⇒ SURFACTANTS

⇒ BUFFERS

⇒ EXCIPIENTS IN TABLETS

⇒ POLYMERS

⇒ FLAVORS AND FLAVOR MODIFIERS

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 2
 INTRODUCTION TO PHARMACEUTICAL EXCIPIENTS
DEFINITION OF EXCIPIENT
The term comes from the Latin word
excipients, present participle of the verb
excipere which means to receive, to
gather, to take out. This refers to one of
the properties of an excipient, which is
to ensure that a medicinal product has
the weight, consistency and volume
necessary for the correct administration of
the active principle to the patient. In 1957,
excipients were defined as ‘the substance
used as a medium for giving a
medicament’, that is to say with simply the
functions of an inert support of the active
principle or principles. Again, in 1974 they
are described as ‘any more or less inert
substance added to a prescription in
order to confer a suitable consistency or
form to the drug: a vehicle.
This historically somewhat limiting
definition referred to those substances
employed in the preparation of pills, a now
obsolete pharmaceutical dosage form
later replaced by tablets and capsules.
Natural products, such as molasses and
honey, were long employed in the
preparation of pills up to 1940 and USP
10 also mentioned lactose, glucose,
lycopodium, glycerin and gelatin.
To the function of simple vehicle, galenic
science then added that of adjuvant in the
carrying and release of the active principle
of the formulation. Looking at the matter
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
from this angle, the United States’
National Formulary of 1994 states that
an excipient is any component other
than the active principle added
intentionally to the medicinal
formulation, or ‘everything in the
formulation except the active drug’.
The following general criteria are essential
for excipients:
• physiological inertness;
• physical and chemical stablility;
• conformance to regulatory agency
requirements;
• no interference with drug
bioavailability;
• absence of pathogenic microbial
organisms; and
• commercially available at low cost.
In reality, no single excipient would satisfy
all the criteria; therefore, a compromise of
the different requirements has to be made.
For example, although widely used in
pharmaceutical tablet and capsule
formulations as a diluent, lactose may not
be suitable for patients who lack the
intestinal enzyme lactase to break down
the sugar, thus leading to the
gastrointestinal tract symptoms such as
cramps and diarrhea. The role of
excipients varies substantially depending
on the individual dosage form.
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 ROLE OF EXCIPIENTS
Among these roles are to be remembered
those of guaranteeing the stability,
precision and accuracy of the dose,
improving the organoleptic characteristics
and the patient’s compliance. Modern
pharmaceutical technology also requires
verification of the physical state of the
excipient, which is so important both in the
manufacturing phase and to control the
release of the active principle, with the
object of improving the bioavailability and
consequently the efficacy and tolerability of
the medicinal drug.
Medicinal dosage forms, regardless of
composition or mode of use, must meet
the following requirements that underpin
efficacy, safety, and quality:
1. Contain an accurate dose.
2. Be convenient to take or administer.
3. Provide the drug in a form for
absorption or other delivery to the
target.
4. Retain quality throughout the shelf life
and usage period.
5. Be manufactured by a process that
does not compromise performance and
that is reproducible and economical.
Few if any active pharmaceutical
ingredients have properties that allow
incorporation in units that meet all these
criteria. Therefore, it is necessary to add
other materials to make good any
shortfalls. Consequently, virtually every
medicinal product is a combination of the
drug substance and excipients.
These are indispensable components of
medicinal products and, in most cases
comprise the greatest proportion of the
dosage unit. It goes without saying that
knowledge of the composition, function,
and behavior of excipients is a prerequisite
to the successful design, development and
manufacture of pharmaceutical dosage
forms.
The requirements listed above can be
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
considered the prime reasons for including
excipients in dosage forms since they
relate directly to product performance.
Issues such as regulatory acceptability,
environmental effects and impact on cost
of the product are also important selection
criteria.
Accuracy of dose
Where the active ingredient is very potent
(i.e., dose is low), it may be necessary to
disperse the drug in a ‘‘diluent’’ or bulking
agent. Otherwise, quantities being filled
into capsules or dies for tableting may be
so low that normal filling and other process
variations translate to excessive variation
in unit drug content. Likewise, low-dose
medications for inhalation as dry powders
may have the drug dispersed in or
otherwise associated with an inert ‘‘carrier’’
or flow aid. For a diluent to function in this
way it must form a homogenous blend with
the drug. Otherwise accuracy of dose
cannot be guaranteed.
Water may be considered a ‘‘diluent’’ in
liquid presentations as it provides the
required dose in a volume that can be
accurately dispensed or administered. It is
also invariably present in medications for
topical or transdermal application. Water
can be one of the most problematic
companion materials in a dosage form
because of its capability to promote
hydrolysis, act as a vehicle for other
molecular interactions, or simply be a
medium for microbial growth. Such
properties illustrate how a material that
resolves one problem may pose others
that in turn require the presence of
additional excipients.
Liquid or semisolid preparations may
require the presence of ancillary excipients
to effect solvation or dispersion of the
active ingredient. In particular, formulations
containing drugs in the suspended state
may require viscosity-enhancing agents or
other additives to ensure that the drug
remains homogenously dispersed.
Otherwise, the accuracy of the dose may
be compromised.
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User or patient convenience
Drugs that are bitter or otherwise
unpalatable, and administered as oral
liquids may be unacceptable, particularly
to younger patients. Compliance and
therefore efficacy may be compromised
unless the product can be made more
palatable. Thus, sweeteners, flavors, or
taste-masking agents may be present in
liquid oral products, in chewable dosage
forms, and in effervescent or dispersible
tablets that are constituted as liquids prior
to use.
Some drugs given by injection cause local
pain due to high volume, tonicity, pH, etc.
An additive that evinces a local anesthetic
effect may relieve such discomfort. Benzyl
alcohol is employed for this purpose.
Release of drug from the dosage
form
Once a medication is ingested, applied to
a target area, or otherwise administered,
the drug must leave the dosage form for
absorption or other delivery to the target.
This may involve the following:
⇒ Dissolution in the gastrointestinal (GI)
tract following oral dosage.
⇒ Partitioning to the skin in the case of
topical or transdermal preparations.
⇒ Passage to pulmonary or nasal
cavities (inhalation products).
Excipients can ensure that such delivery is
expeditious and consistent. Their presence
may be even more crucial with more
esoteric forms that must be delivered to a
tissue, organ, or even specific cells.
Researchers are developing excipients
that act as ‘‘homing devices’’ to guide
drugs to designated targets. Such
approaches will be discussed later in this
chapter. In its simplest form, designing
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
‘‘release’’ into a dosage form involves
adding a disintegrant to the tablet or
capsule formulation so that on ingestion
the compact breaks up and drug is
released for dissolution and absorption. In
the case of hydrophobic drugs, dissolution
may be aided by wetting agents. More
complex release patterns involve using
excipients to modify release from the
dosage form to delay onset of action or
otherwise modify the pharmacokinetics of
the drug, thereby maximizing efficacy or
minimizing side effects.
Excipients can influence delivery from
topical and transdermal medications. The
propensity of the drug to migrate from the
formulation to the application surface is
affected by factors such as lipophilicity of
the vehicle, drug solubility in the
formulation, and
effects of additives on the barrier
properties of the skin or mucosal surface.
Oral absorption enhancement
Oral absorption is indirectly aided by
excipients that promote release of drug
from the dosage form, or help dispersion
and dissolution prior to passage to the
systemic circulation. Excipients that
promote absorption per se are less widely
used. However, lipids have been used to
enhance absorption of hydrophobic active
ingredients. Dissolution or dispersion of
drug in such materials provides a substrate
for lipolysis, resulting in an emulsion of
drug and lipid that provides enhanced
surface area for dissolution and
absorption.
Excipients that are bioadhesive or that
swell on hydration can promote absorption
by increased contact with epithelial
surfaces, by prolonging residence time in
the stomach, or by delaying intestinal
transit. Cellulose ethers, gums of natural
origin, and synthetic
acrylic acid polymers have been evaluated
for such purposes. The range of materials
Page- 5
available and their differing viscoelastic
and rheological behaviors mean that it is
possible, by judicious admixture, to
develop delivery units with balanced
properties so that
adhesion, density, hydration, drug release
rate, etc. can be tailored to the drug in
question and the physiological
characteristics of the target delivery site.
Enhancers for Other Modes of
Absorption
Many physical and enzymatic barriers can
prevent successful delivery of active
pharmaceutical ingredients by non-
invasive, non-oral routes. It is not
surprising, therefore, that there is great
interest in excipients that can overcome
such obstacles. Transdermal delivery is a
case in point. The skin, particularly the
stratum corneum presents a formidable
barrier to diffusion. Materials used to
enhance its permeability have ranged from
simple solvents such as ethanol or
propylene glycol to aromatic chemicals
such as terpenoids. Such penetration
enhancers appear to work by disrupting
the lipid domains in the stratum corneum
that reduce permeability.
Entry via nasal or buccal mucosa allows
the delivery of peptides or other labile
drugs that are highly potent (low-dose
drugs) and that do not have steep
doseresponse relationships. Absorption
enhancement requires increased contact
time and reduced clearance rate (in the
case of nasal delivery), thereby optimizing
conditions for mucosal diffusion. Excipients
that enhance nasal absorption include
phospholipids to enhance mucosal
permeability and agents that imbibe water
and become mucoadhesive (e.g., glyceryl
mono oleate). In addition, the gelling
agents hydroxypropyl cellulose and
polyacrylic acid promote absorption of
insulin in dogs.
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
EXCIPIENTS AS STABILIZERS
Product quality can be compromised
during manufacture, transport, storage or
use. The causes of deterioration can be
manifold and product-specific. They
include microbial spoilage or chemical
transformation of the active or physical
changes that alter performance
in vivo. Deterioration can compromise
safety or make the medication less
attractive, which means it may not be
used. Excipients can contribute to or cause
such changes unless carefully screened
for possible interactions in preformulation
studies.
Stablization strategies include the
following:
• Formulation with an excipient whose
light absorption spectrum overlaps that
of the photolabile drug. This is the so-
called spectral overlay approach.
• Using an antioxidant in formulations that
are susceptible to degradation by
oxidation. This approach has been
particularly successful in vitamin-
containing products.
• Using an excipient that ‘‘hinders’’
association of groups in the same
molecule, in adjacent molecules, or in
the vehicle that can interact and cause
degradation. There are several reports
of cyclodextrins effecting such ‘‘steric
stabilizations.’’ Polyethylene glycol also
has been shown to stabilize an ointment
formulation by preventing formation of
inactive rearrangement products.
Equally important stabilizers include
preservatives in liquid products to
prevent microbial growth and buffers to
provide an environment conducive to
good stability where degradation is pH-
related. Chelating agents also are used
as stabilizers to prevent heavy metals
from catalyzing degradation.
EXCIPIENTS AS PROCESS AIDS
The vast majority of medicinal products are
manufactured by high-speed, largely
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automated processes for reasons that are
related as much to safety and quality as to
cost of goods. Excipients that aid in
processing include the following:
• The almost universal use of lubricants
such as stearates in tablets and
capsules to reduce friction between
moving parts during compression or
compaction.
• Excipients that aid powder flow in tablet
or capsule manufacture. Materials such
as colloidal silica improve flow from
hopper to die and aid packdown in the
die or capsule shell. Accuracy and
consistency of fill and associated dose is
thereby improved.
• Compression aids to help form a good
compact, whether on dry granulation
(slugging) prior to tableting or on tablet
compression. Most are derived from
plant, animal, or mineral origin
(microcrystalline cellulose, lactose, or
magnesium carbonate).
• Agents such as human or bovine serum
albumin that are used in the
manufacture of biotechnology- based
products. These avoid adsorption of the
protein to flexible tubing, filters, and
other process equipment.
• Stabilizers to protect the drug from
processing conditions that might
otherwise be deleterious. It is common
to use ‘‘cryoprotectants’’ such as sugars,
polyhydric alcohols or dextrans in
lyophilized parenteral biotechnology
products to prevent inactivation during
freezing.
• ‘‘Flow aids’’ also can help performance
in cases where the delivery device is an
integral part of the medication. Products
for pulmonary delivery are often
formulated as dry powders that are
inhaled via the oral cavity. The fine-
particle nature of the medicinal agent,
which may be vital for efficient delivery
to the bronchial target area, militates
against good flow. Materials such as
lactose or mannitol (of appropriate
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
particle size) can enhance flow or act as
a ‘‘carrier’’ from the dose unit (usually a
capsule) through the inhalation delivery
device to the oral cavity on inspiration.
They are widely used for these purposes
in inhalation formulations of anti-
asthmatic agents such as salbutamol
and budesonide.
ORIGINS AND SOURCES OF
EXCIPIENTS
Excipients are of various origin:
1. animal (e.g. lactose, gelatin, stearic
acid),
2. plant (e.g. starches, sugars, cellulose,
arginates),
3. mineral (e.g. calcium phosphate, silica)
and
4. synthesis (e.g. PEGs, polysorbates,
povidone, etc.)
Their origin and use do not often
guarantee the quality required by the
pharmaceutical industry, which must
therefore submit them to more thorough
-going analytical controls. In order to carry
out the numerous functions required, new
classes of excipients have now become
available, derived from old and new
materials, alone or in combination,
adapted to the manufacture of high-
performance pharmaceutical dosage
forms.
Looking at the matter from this angle,
excipients can no longer be considered
mere inert supports for the active
principles, but essential functional
components of a modern pharmaceutical
formulation.
It is also to be borne in mind that the
ratio of their weight to that of the active
principles is usually very high in a
formulation, and such as to cause possible
action due to their mass.
Like pharmaceutical drugs, they too
have their own thermo-dynamic activity
Page- 7
which, though generally low, can
contribute to reactions leading to
degradation or to interactions between the
drug and the excipient.
Today it is reckoned that over one
thousand different materials are used in
the pharmaceutical industry to fulfil its
various requirements such as diluents,
bulking agents, disintegrants, lubricants,
colouring agents, sweeteners, etc.
They are chemically heterogeneous
compounds that go from simple molecules
(water) to complex mixtures of natural,
semisynthetic or synthetic substances.
From the regulatory point of view, may
be subdivided into three categories.
1. In the first category (approved
excipients) we find the compounds
originating from the food industry
(generally recognised as safe: GRAS) or
that have been present in
pharmaceutical products for a very long
time.
2. The intermediate category (essentially
new excipients) covers compounds
obtained by means of the structural
modification of the excipients already
approved or those already used in the
food or cosmetic industries.
3. The third category covers new
compounds, never previously used in
the pharmaceutical field and it is
growing rapidly due to the present
interest in modified-release
formulations and the requirements of
the modern high productivity
compressing/tabletting machines.
PRINCIPAL REQUIREMENTS OF
EXCIPIENTS
Historically, the importance of excipients in
pharmaceutical formulations has
generally been underestimated, as they
were cheap ingredients viewed solely as
inert supports for medicaments. Today,
this view is out-dated and, on the basis of
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
what we have said above, we may say that
excipients are rather more than the sugar
in the pill.
At this point we may well ask ourselves
what the basic requirements of a modern
pharmaceutical excipient are. In Fig. 1 the
three essential requirements of active
principles are compared with those of
excipients. Fundamental for both are
quality and safety. The requirement of
therapeutic efficacy for drugs is replaced
by that of functionality for excipients,
defined as ‘the physical, physicochemical
and biopharmaceutical properties’ of the
same.
Safety has always been the most important
requirement and the most studied when
dealing with pharmaceutical drugs. Less
attention has been devoted to the safety of
excipients, because their inertia and
innocuity were taken for granted.
To this end, we shall examine three
issues that may compromise the safety of
pharmaceuticals:
(a) production, distribution and use;
(b) pharmaceutical-excipient interactions;
and
(c) toxicity, which may be the cause of
frequent and sometimes notable ‘adverse
effects’.
DRUG–EXCIPIENT INTERACTIONS
Excipients constitute the mass or greater
volume in the usual enteral or parenteral
formulations and, they often contain
reactive functional groups that may give
rise to chemical and physical
transformations. Interactions occur more
frequently between excipient and active
principle than between excipient and
excipient and these interactions can be of
two types. The physical type of interaction
can modify, for example, the speed of
dissolution or the uniformity of the dosage
of a solid formulation. Indeed, some
materials can adsorb drugs to their
Page- 8
surfaces, thus increasing the active
surface and consequently the wettability
and speed of dissolution. The contrary
effect may be encountered when the
forces of attraction are strong, in which
case the drug is released with difficulty and
assimilation is compromised. One example
is that of lipophilic lubricants (e.g.
magnesium stearate) which, when finely
dispersed on the particles of the active
principle, can slow down dissolution
and therefore bioavailability.
The chemical type of interaction, on the
other hand, can lead to the degradation
of the drug and/or the formation of the
so-called degradation impurities. The most
frequently encountered reaction is
hydrolisis, because water is the preferred
and prevalent solvent in liquid
formulations. In solid forms which
contain hygroscopic components, the
presence of humidity must be controlled
and reduced. Even the presence of
oxygen, when activated by traces of
catalysts (heavy metal ions, light, heat. .
.), may give rise to oxide-reduction and
the formation of free radicals (e.g. lipidic
peroxidation). Other, less frequent,
reactions are photolysis, isomerisation and
polymerisation, which are more likely to
occur with certain types of excipients,
lowering the title of the active principle and
generating dangerous impurities. One
example is the presence of polymeric
forms in beta-lactam drugs, such as
ampicillin, which are thought to be
responsible for dangerous allergic
reactions. Ionisable pharmaceuticals
may react with ionised soluble excipients
giving rise to the formation of insoluble
products due to charge interactions. In this
way, sodium alginate and neomycin cation
precipitate in an acqueous solution.
Another type of interaction may occur
between the carbonilic groups of a widely-
used excipient like poly-vinylpyrrolidone,
and pharmaceuticals containing donor
groups of hydrogen, like famotidine and
atenolol, thus causing problems of
incompatibility. Even silicon dioxide
(SiO2), in anhydrous conditions, behaves
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
like a Lewis acid, giving rise to reactions
such as hydrolisis, epimerisation, trans -
esterification, etc. One example is the
hydrolisis of the imino nitrogen link of
nitrazepam with consequent disactivation
of the drug.
However, when evaluating potential
pharmaceutical-excipient interactions, it
must however be considered that the
kinetics of chemical reactions involving
solutions are very high, whereas in the
case of solid formulations they are low, if
not negligible.
Despite the earlier account of excipients
acting as stabilizers, it is fair to state that
there are far more cases on record of
excipients adversely affecting quality.
Degradation may be caused by interaction
between functional groups in the excipient
and those associated with the drug. Many
small-molecule drugs contain primary,
secondary, or tertiary amino groups and
these have the propensity to interact with
aldehydic groups in sugars or volatile
aldehydes present as residues.
Chemical interaction can result in
degradation of the drug substance to
inactive moieties with loss of efficacy
where degradation is excessive. Even
when degradation is modest, it is possible
that the formed degradation products may
compromise safety.
Physical interactions between drug and
excipient also can compromise quality.
Adsorption of drug by microcrystalline
cellulose resulted in drug dissolution being
less than complete.
Interaction between chloramphenicol
stearate and colloidal silica during grinding
led to polymorphic transformation.
Excipients may contribute to degradation
even when not directly interacting with
active moieties. Soluble materials may
alter pH or ionic strength, thereby
accelerating hydrolytic reactions in liquid
presentations. Such effects may be
accentuated during processing.
Page- 9
For instance, sterilization by autoclaving,
while of short duration, may cause
significant degradation product formation
because of the high temperature involved.
Dextrose is widely used in parenteral
nutrition solutions or as a tonicity modifier
in other parenterals. Sterilization by
autoclaving can cause isomerization to
fructose and formation of 5-hydroxymethyl
furfulaldehyde in electrolyte-containing
solutions.
At the other extremes of processing,
succinate buffer was shown to crystallize
during the freezing stage of lyophilization,
with associated reduction of pH and
unfolding of gamma interferon.
It is important to identify and characterize
such ‘‘process stresses’’ during dosage-
form development and tailor processing
conditions accordingly.
Microcrystalline cellulose is a partially
depolymerized cellulose that is part-
crystalline/part non-crystalline and
hygroscopic. Adsorbed water is not held in
any ‘‘bound’’ state but will rapidly
equilibrate with the environment during
processing or storage. Thus, it is possible
that in a dosage form, water can be
sequestrated by a more hygroscopic active
ingredient. If the drug is moisture sensitive,
degradation may follow. Stabilization may
be possible by drying prior to use, but loss
of water may make it a less effective
compression aid.
TOXICITY OF EXCIPIENTS
A discussion of the toxicity of the
excipients employed in pharmaceutical
formulations is certainly a difficult and
extremely diversified task. To simplify
matters, the subject may be organised as
follows:
• toxic effects encountered in the whole
population;
• toxic effects encountered only in
specific populations.
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
Into the first category fall all the
adverse effects proper to chemical,
natural or synthetic substances when a
certain dose is exceeded. The second
category, however, has to do with
phenomena that are often independent
of, or only marginally dependent on, the
dose. That is to say, they are events linked
to specific characteristics of the subjects,
such as genetically-transmitted
pathologies (metabolic illnesses, among
which phenylketonuria and lactose
intolerance) or genetic predisposition
(among which diabetes and allergic
pathologies).
In principle, excipients ought to be
subjected to the same toxicity studies as
those requested for active principles, so
as to protect the population from
undesirable effects. This is assuredly
applicable to many compounds, especially
those that are used as food additives.
However, other substances, that have
been used for decades now, can be
considered ‘safe’, given that no adverse
effects have been encountered in man.
The excipients that have been authorised
to be used as food additives have been
evaluated as regards toxicology by the
JECFA (Joint Expert Committee on Food
Additives), which handles the evaluation
of the risk from consuming additives or
contaminants with food. In the case of
additives, their use is voluntary and has a
technological reason, exactly as in the
case of pharmaceutical excipients,
whereas contaminants are substances
that can be vehicled by the food chain,
given the ubiquitousness of the distribution
of pollutants in the environment. In this
article, our preferred source of toxicological
data has been the JECFA’s conclusions,
which take into particular consideration the
results of long-term toxicological studies.
The JECFA usually terminates its
toxicological evaluations with the
publication of an admissible daily intake
(ADI), which represents the dose that
does not carry risks to the population if
taken every day for a life-time. This dose is
expressed in mg (or microg) per kg of daily
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weight per day. To establish the total
daily dose, we should multiply this
number by the bodily weight (usually
reckoned as 60 kg). The value of the ADI
is extrapolated from studies conducted in
laboratory animals, dividing the highest
dose without toxic effects in the animal by
a safety factor (generally 100).
STABILITY OF EXCIPIENTS
Excipients can lose quality over time. Oils,
paraffins, and flavors oxidize; cellulose
gums may lose viscosity. Polymeric
materials used in film coating or to modify
release from the dosage form can age due
to changes in glass transition temperature.
This can lead to changes in elasticity,
permeability, and hydration rate and
associated changes in release properties
or appearance. Preservatives such as
benzoic acid or the para hydroxybenzoates
are volatile and can be lost during product
manufacture if the process involves
heating.
Loss during product storage is also
feasible if containers are permeable to
passage of organic vapors. Acetate buffer
is volatile at low pH and can be lost during
the drying stages of lyophilization. Such
behaviors reinforce the need to know the
behaviors of excipients as well as of the
active ingredient so that appropriate
processing, storage conditions, and ‘‘use
by’’ periods are stipulated where
necessary.
IMPURITIES IN EXCIPIENTS
Excipients, like drug substances contain
process residues, degradation products or
other structural deviants formed during
manufacture. Historically, it was not
unusual for adulterants to be added to
‘‘bulk up’’ the commodity. Thankfully, a
combination of better analytical
techniques, vendor certification programs,
and quality audit systems should mean
that adulteration is largely a thing of the
past. However, constant vigilance is
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
necessary. As recently as 1996, renal
failure in children in Haiti was ascribed to
use of glycerol contaminated with
diethylene glycol in a liquid paracetamol
product. Residues in excipients can affect
quality and performance by interacting with
the drug or other key components.
Reducing sugar impurities in mannitol were
responsible for the oxidative degradation
of a cyclic heptapeptide.
CONCLUSIONS
Medicinal products can be considered a
dosed combination of two types of
constituents: the active principles and the
excipients. The latter are the more
important as far as weight is concerned,
whether in solid forms, suspensions or
solutions. The ideal excipient should be
able to fill numerous and important
functions, first among which that of
guaranteeing the dose, stability and
release of the active principle, and the
patient’s ‘compliance’. Furthermore, it
should possess particular chemical,
physical and mechanical characteristics,
so as to optimise the formulation’s
‘performance’ both during the
manufacturing phase (manufacturability)
and when used by the patient. This
multiplicity of roles fits very ill with the
traditional galenic view, that saw these
‘non-medicinal ingredients’ as chemically
and pharmaco-toxicologically inert.
For a long time now, much attention has
been paid to the required quality, efficacy
and safety of active principles but only
recently has the necessity emerged of
examining not only the quality and
performance but also the safety of the
excipients. The problem is not simple if
one considers that in countries like the
United States, Japan and Europe there are
now in use over a thousand excipients of
varying origin, of more or less complex
structure and belonging to different
chemical classes. About one fifth of
them are present in the respective
Pharmacopoeiae, which list the
pharmaceutical quality requirements but
Page- 11
not physical chemistry requirements, active principle before it can be
much less do they embark on questions of accepted as an excipient.
safety. Some information on this aspect
may be gleaned from some texts. This
under-estimation of the safety aspect is
also a consequence of the fact that the first
excipients were taken from the food
industry and therefore considered ‘as
safe’, or else they were already used in
pharmaceutical products that had been
in therapeutic use for a very long time.
Today it is required that any chemically
new product whose effects on man are
not known must pass all the
toxicological tests envisaged for an

MAJOR GROUPS OF EXCIPIENTS USED IN DOSAGE FORMS

Acidifying agent Carriers for dry powder inhalers

Adhesive agent Solvents

Alkalizing agent Suppository bases

Adsorbent Surfactants

Aerosol propellants Suspending agents

Air displacement Sweetening agents

Anti foaming agents Tablet anti adherents

Antifungal preservatives Tablet binders

Antimicrobial preservatives Tablet/capsule diluents

Anti oxidants Tablet coating agents

Buffering agents Tablet disintegrants

Chelating agents Tablet glidants

Coating polymers Tablet lubricants

Coloring agents Tablet-coated, polishing agents

Emulsifying agents Tonicity agents

Flavoring agents Vehicles

Humectants Viscosity imparting agent

Ointment bases Wetting agent.

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 12

COLORING AGENTS
DEFINITION
A material that is a dye, pigment, or other substance
made by a process or similar artifice, or extracted,
isolated, or otherwise derived with or without
intermediate or final change of identity, from a vegetable,
animal, mineral or other source and when added or
applied to a food, drug, or cosmetic or to the human body
or any part thereof, is capable (alone or through reaction
with other substances) of imparting color.
According to the Code of Federal Regulation of USA,
color additives are: "Any substance, synthetic or
otherwise, that when added or applied to food, drug, or
cosmetic, or to the human body or any part thereof, is
capable of imparting a color thereto".
The use of coloring agents in pharmaceutical
preparations for purpose of esthetics, as sensory adjunct
to the flavors employed, and for purposes of product
distinctiveness is important.
The need to identify tablets in order to minimize the risk
of confusion to the patient is an important factor to be
considered in formulation. Color provides a relatively
simple and convenient solution to this problem, so is
widely used in tablet film coating.
Colorants commonly used can be divided into three
groups;
• the synthetic organic dyes and their respective lakes,
• inorganic pigments and
• miscellaneous natural colorants.
In this context the use of the world dye implies a pigment
implies a material that is insoluble but disperses in the
film-coating solution.
Definition of Terms
Dyes are substances which impart color to an object;
soluble dyes dissolve in specified liquids.
Pigments are solid dyestuffs or mineral colors which
unfold their color effect when finely dispersed. There are
colored and white pigments.
Colorants are preparations of dyestuffs meant for
coloring.
Color lakes are water-insoluble colorants obtained from
soluble, organic dyes by salt formation (e.g. with
aluminum or calcium) or surface fixation.
The importance of colorants and flavoring substances is
frequently undervalued, since they do not have a direct
influence on the therapeutic effect of a dosage form.
They do, however, enhance the acceptance of the
product and therefore contribute substantially to a reliable
therapy. Moreover, they are helpful in identifying
unpacked dosage forms. The coloring process for sugar-
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
coated products and film-coated tablets is essentially the
same.
• Aesthetic issues in dosage form design.
• Identification of the product by the manufacturer and
therefore act as an aid (not a replacement) for
existing GMP procedures. Colourants also aid in the
identification of individual products by patients,
particularly those taking multiple medication.
• They reinforce brand imaging by a manufacturer and
thereby decrease the risk of counterfeiting.
• Colourants for film-coated tablets have to a greater
or lesser extent opacifying properties which are
useful when it is desired to optimize the ability of the
coating to protect the active ingredient against the
action of light.
Synthetic organic dyes and lakes
If the water-soluble organic dye is precipitated as its
aluminum salt on to alumina by the addition of aluminum
chloride then the pigment so formed is known as an
aluminum salt by the addition of sodium hydroxide,
bicarbonate or carbonate. The calculated quantity of dye
necessary to achieve the required dye content is added
to the alumina slurry and aluminum chloride solution
added to effect lakeing. As soon as all the dye has been
absorbed the precipitate is washed and filtered before
being dry ground to the desired particle size. The
pigmentary properties and the shade of the aluminum
lakes depends a great deal on the preparation of the
alumina, the processing conditions during the deposition
of the dye and the extent of grinding. The amount of dye
precipitated on the alumina is generally in the region of
10-40% by weight. All lakes contain approximately 15-
23% by weight residual moisture, some of which is bound
as water of hydration and all are insoluble in most
solvents.
Chemistry of color:
Before the development of synthetic color additives, food
and cosmetic colorants were obtained form mineral,
animal and vegetable sources. Synthetic coloring agents,
which were extracted from coal tar, a by-product of coal
distillation, date back to the mid-19th century. By 1900,
nearly 700 colors had been synthesized from aniline, a
derivative of benzene produced from coal tar, and a
major industry developed in the field of coal-tar dyes.
Approximately 90% of color additives in prescription and
OTC drugs are synthesized from aniline that is currently
obtained from petroleum or petroleum products.
The cause of color is attributed to the presence of certain
chromophore groups within the color producing molecule.
These chromophores include the
-N = N- (AZO)
=C=S (THIO)
-N=O (NITROSO)
- N = N+ - O- (AZOXY)
- N+<OO (NITRIO)
Page- 13
- CH =N - (AZO METHINE)
=C=O (CARBONYL) a) certified colors - synthetic and mineral colors
=C=C (ETHENYL) approved by FDA.

Other substituent groups called AUXOCHROMES. They The Food, Drug and Cosmetic act of 1938 (US)
may be present in the molecule. This cause deepening of broadened the scope of certified colors, containing three
the color. categories:

The auxochromes include the F D & C, D & C and D & C for external use.

basic - N<RR - NH-R -NH2 It is again two types:

acidic -SO3H -COOH, -OH
The light of the visual spectrum which is not absorbed by
the compound is transmitted or reflected and the
compound assumes the color of the unabsorbed light.
Thus if a compound absorbs all light of the visible
spectrum except that viewed by the eye as red it will
appear to be that color.
Most of the dyes used in pharmacy, whether for their
therapeutic or coloring properties, are salts of acid or
basic dyes. The dye ion exhibits greater resonance than
the parent molecule. The auxochromes are
capable of forming ionizable salts. Any substance
causing a decrease in the ionization will reduce the
intensity of the color. This is the basis of many
incompatibilities.
-- Dyes
-- Lakes
-- Dyes are available in different form: Powder/ Granular/
Plating color/ Wet dry (blends)/ Diluted (cut blends)/
Liquid (aqueous)/ Liquid (non aqueous)/ Pests.
-- FD&C dyes are water soluble ( and insoluble in most
organic solvents). The dyes manifested their coloring
power by being dissolved in the water medium.
-- When anhydrous conditions are of important
considerations, glycerin and propylene glycol are used as
solvent.
-- dyes are made soluble in glycerin and then propylene
glycol.

DIFFERENT SOURCES OF COLORS: -- Only few dyes are soluble in alcohol.

Synthetic -- Good coloring technology recommends that the dyes

There are many synthetic dyes currently used solubilized before addition of colored product. However, it
(see below) is often possible when water is added in the process, to
add the dry color to the batch and depends upon the
Mineral added moisture and heat to dissolve the color in
Alumina (aluminum hydroxide) processing.
Red ferric oxide
Yellow ferric oxide FD&C lakes:
Titanium dioxide
Azurite The color regulations defined FD&C lake as "Extension
Carbon black on a substratum of alumina, or a salt prepared from one
Ultramarine blue (kaolin, sulfur, Na-carbonate, of the water soluble straight colors by combining such
carbon) color with the basic radical aluminum or calcium".
Mica
Pyrophylite The alumina hydrate or aluminum hydroxide substratum
Chromium oxide greens (chromic sesquioxide) is insoluble so what is produced is an insoluble form of
the dye - a pigment. Dye color by being dissolved in the
Vegetable solvent and the pigment (lake) by dispersion.
Canthaxanthin (natural beta carotene)
Saffron (Crocus sativis) b) uncertified colors - most natural colors.
Indigo (Indigo plant)
Chlorophyll (Green plant) Chemical classification of dyes:
Beet juice (beets)
Xanthantine (microalgae) 1. Acridine Dyes - Acriflavine
Tagetes (Aztec marigold petals)
Caramel (burnt sugar) 2. Azo dyes -Scarlet red, FD&C Red 1, Red 2,
Grape color extract (Concord grapes) Orange 2.
Alizarin (Madder plant)
Annatto extract (annatto seed) 3. Phthalein Dyes - FD&C red 3
Turmeric (Curcuma longat)
Logwood extract (leguminous trees) 4. Thiazine dyes - Methylene blue

Animal 5. Triphenylmethane - FD&C green 1, green 2

Guanine (from fish scales)
Tyrian purple (snails) 6. Nitro dyes - FD&C yellow 1, yellow 2
Cochineal (insect)
Carmine (lake of cochineal) 7. Indigo dyes - FD&C blue 2
Stability of dyes:
CLASSIFICATION

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 14
-- In general the certified colors can be said to be stable
for most uses. In the dye stage no degradation has been
noticed (other than loss in dye strength by absorbing
moisture) in storage for 15 years.
-- With the exception of FD&C Blue no-2 and FD&C red
no-3, the light stability of the dye in the finished product is
good.
-- Two areas, in which the majority of the certified FD&C
colors show instability are
i) in combination with reducing agent and
ii) retorted protein materials.
-- The azo triphenyl methane dyes are easily reduced to
colorless compounds. The ascorbic acid is a such
reducing agent.
-- Contact with metals, such as, zinc, copper, tin,
aluminum, etc. are the factors of color fading. The use of
EDTA serves as a protection of color fading.
Safety of dyes:
Some examples:
• Lash Lure, a coal-tar dye that was popular in 1930's for
eyebrows and eyelashes, in a few cases caused
devastating effects, such as, blindness and death.
• FD&C Red no 2 (amaranth) caused cancer in rats,
reported by Russians in 1970's. In 1976, amaranth as
well as FD&C Red no 4 and Carbon black were
delisted.
• FD&C yellow no 5 (Tartrazine) was suspected of
producing allergic-type reactions, including asthmatic
symptoms, urticaria, angioedema, or nasal symptoms,
especially in persons allergic to aspirin. Since 1980,
this color additive must be listed on the labels of food
and OTC drugs to alert consumers who may be
sensitive to it.
Coloring technology for pharmaceuticals:
-- in addition to esthetics and certification status of a
dye, a formulator must select the dyes to be used in a
particular formula on the basis of the physical and
chemical properties of the dyes available. These include:
solubility, pH & pKa values, pH stability, light stability
(photostable), thermal stability.
-- the dye must be chemically stable in the
environment of the other formulation ingredients and
must not interfere with the solubility
-- A colorant becomes an integral part of a
pharmaceutical formulation, and its exact quantitative
amount must be reproducible each time the formulation is
prepared,or else the preparation would have a different
appearance from batch to batch.
-- colorant generally added to liquid preparations
ranges between 0.0005 to 0.001% depending upon the
colorant and the depth of color desired.
-- in contrast, solid dosage forms such as tablets,
capsules, sugar coated tablets, film coated tablets and
chewable tablets contain approximately 0.1% dye.
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
-- whenever possible dyes are added to
pharmaceutical preparations in the form of dilute
solutions rather than as concentrated dry powders. This
permits greater accuracy in measurement and more
consistent color production.
-- in case of tablets, the color may be sprayed on the
formed tablet during the coating process,or the colorant
may be admixed as part of the dry powder mixture for
uncoated tablets.
ANTIOXIDANTS
ANTIOXIDANTS
Substances that reduces or inhibits oxidation of
chemicals and drugs in a formulation.
PROPERTIES:
1. Effective in low concentration.
2. adequately soluble in the product.
3. non-toxic and non-irritant at the effective
concentration.
4. odorless, tasteless and colorless.
5. decomposition products should be non-toxic and non
irritant.
6. stable and effective over a wide range of pH.
7. compatible with the drug and other formulation
ingredients.
8. non volatile.
Classification of Antioxidants:
A: Primary antioxidants:
act by interfering with the propagationstep of the
autoxidtion process.
AH + R* -----> RH + A*
AH + ROO* --------> ROOH + A*
Subsequently the antioxidant radical is annihilated by
combination with other antioxidant radical or some other
free radical.
A* + A* ------> AA
A* + R* ------> AR
It follwos that for effective stabilization against
autoxidation, the A-H chemical bond should be weaker
than the R-H bond of the oxidiziable substnce. However,
if the bond is too weak, then the anitoxidant will be
destroyed rapidly by reaction with atmospheric oxigen.
AH + O2 ----------> A* + HO2*
It is evident that a primary antioxidant is used up by
taking part in the chain process instead of the drug.
Page- 15
 Classification of Antioxidants

A. Primary antioxidants:

Quinol group
Hydroquinon
Tocopheorls
Hydroxychromans
Butylated hydroxy anisol
Butylated hydroxy toluene

Catechol group
Catechol
Pyrogallol
Nordihydroguaiaretic acid (NDGA)
Gallic acid
Ethyl gallate
Propyl gallate
Octyl gallate
Dodecyl gallate

Nitrogen containing substance

Diphenyl amines
Casein
Alkanolamine esters
Amino and hydroxy derivatives of p-phenyl amine diamine

Sulphur containing substances

Cysteine hydrochloride

B. Reducing agents

Potasium and sodium

metabilsulphiets-- for acidic solution
Bisulphites -- for solution of intermediate pH
Sulphites -- for unbuffered and alkaline pH

Other examples are:

Sulphurous acid
Hypophosphorous acid
Dextrose

C. Synergist

Water soluble
Citric acid
Tartaric acid
Phosphoric acid
Ascorbic acid
Water insoluble
Ascorbyl palmitate
Mono-isopropyl citrate
palmityl phosphate
Mono stearyl citrate

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 16

ANTIMICROBIAL
PRESERVATIVES
ANTIMICROBIAL PRESERVATIVES
DEFINITION OF TERMS
Disinfectants, antiseptics, and preservatives are
chemicals that have the ability to destroy or inhibit the
growth of microorganisms, and are used for this purpose.
These and other terms commonly employed are defined
as follows:
_ Disinfectants: Chemical agents or formulations that
are too irritant or toxic on body surfaces, but are used to
reduce the level of microorganisms from the surface of
inanimate objects to one that is safe for a defined
purpose.
_ Antiseptics: Chemical agents or formulations that can
be used as an antimicrobial agents on body surfaces.
_ Preservatives: Chemical agents or formulations that
are capable of reducing the number of viable
microorganisms within an object or field to a level that is
safe for its designated use and will maintain the numbers
of viable microorganisms at or below a level for the use/
shelf-life of the product.
_ Bacteriostasis: A state in which the growth of
microorganisms is halted or inhibited.
_ Bactericide: A chemical antimicrobial agent that
reduces the viability of a population of microorganisms
exposed to it. This term is meaningless without specifying
the concentration range over which this effect is
obtained; such concentration ranges will vary between
different species of microorganisms.
_ Bacteriostat: A chemical antimicrobial agent that can
prevent the growth of microorganisms within an
otherwise nutritious environment. This term is
meaningless without specifying the concentration at
which this effect is achieved. Bacteriostatic
concentrations do vary between different species of
microorganisms.
It should be noted that terms such as bactericide and
bacteriostat should be discouraged; in the USP and EP,
the term ‘‘antimicrobial agent’’ has replaced these terms.
Attributes desired for antimicrobial preservatives:
- broad spectrum and non specific
- continuing activity
- rapid action
- non-allergenic and non-sensitizing
- non toxic
- non irritant
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
- compatible with other ingredients
- stable against chemical degradation
- solubel in common pharmaceutical vehicles
- stable in sterilizing temperature
- capable of incativation or nutrilization for sterility testing
- non-volatile
Important points:
* inactivation of antimicribial agens can be accmplished
using polysorbate 80 (tween 80) or lecithin.
• Generally combinations of two gives better results
than using single preservative.
PRESERVATIVE IDEALS
At present there is no perfect preservative, and all
materials are a compromise of a number of often contrary
properties. The following are the properties of an ideal
preservative compound and need to be considered when
choosing a preservative.
1. Definable in chemical terms: Many of the existing
preservatives, such as the quaternary ammonium
compounds, are mixtures of various homologues. Often
the activity obtained is a function of the mixture
composition. Unless it is possible to define and control
mixture composition, the performance of the agents will
be variable, even if they conform to a pharmacopoeial
specification.
2. Broad spectrum of activity: The compounds must
possess a broad spectrum of antimicrobial activity
against all species of microorganisms and also toward
bacterial endospores. In practice, the only compounds
that meet this requirement are formaldehyde,
gluteraldehyde, hypochlorite, and ethylene oxide. All
these compounds are highly irritant at sterilizing
concentrations to be used in pharmaceutical products.
Formaldehyde is, however, used at low concentrations in
some shampoos; in these cases contact with the skin is
short-lived and irritancy minimal. Agents such as
quaternary ammonium compounds, phenolics, and the
parabens group possess good activity against gram-
positive bacteria but little or no activity toward spores.
Certain gram-negative organisms such a Pseudomonas
aeruginosa are virtually resistant to these agents.
Generally, antifungal activity is difficult to obtain.
Combinations of preservatives are sometimes employed
to widen the spectrum of activity to include molds,
bacteria, yeasts, and endospores.
3. Effectiveness: The compounds must be effective over
a wide range of pH in order to be effective in all
formulations. In practice, compounds are generally more
active at either acid or alkaline pH. Thus, the pH of a
formulation determines the types of preservative suitable
for inclusion.
4. Stablility: The compounds must be stable to light and
elevated temperatures for the expected shelf life of the
Page- 17
product. The effects of pH upon stability should be PRESERVATIVES FOR PHARMACEUTICAL
minimal. In this respect it is worth noting that the DOSAGEFORMS
preservative Bronopol is stable only in the dark and at an Preservative Con.(%)
acid pH. Under alkaline conditions or in the light it rapidly
decomposes to give formaldehyde at concentrations that
would be ineffective as a preservative.
For oral use:
5. Solubility: Preservatives should ideally be used at Benzoic acid 0.1
concentrations much lower than that of the main Sodium benzoate 0.1 - 0.2
constituents of the formulation. Their solubility ought to
be such that it is possible to add them as a concentrated Methyl Paraben and salts 0.1
solution and where there is no danger of creating a Propyl Paraben and salts 0.05
saturated solution. Butyl Paraben and salts 0.02
Alcohol 15 -20
6. Aesthetics: Preservatives should have no perceptible Glycerin 45
odor, color, or taste, which might affect the aesthetic
Sorbic acid and salts 0.1
qualities of the final product. This can be of crucial
importance for a cosmetic product but is less important Propionic acid and salts
for medical ones. Dehydroacetic acid

7. Volatility: Preservatives should be non-volatile. Thus, For parenteral and opthalmic prod-
chloroform is not an ideal preservative as it is lost from ucts:
the formulation each time it is exposed to air.
Benzalkonium chloride 0.01
8. Product incompatibility: Preservatives should not be Benzothonium chloride 0.01
incompatible with any of the likely excipients within the Benzyl alcohol 2
product formulation. This would include incompatibilities Chlorobutanol 0.5
with the container material and also the active
Phenyl ethyl alcohol 0.5
ingredients. In practice this is very difficult to achieve.
Cresol 0.3 - 0.5
9. Toxicity: At the concentrations employed, the Chlorocresol 0.1 - 0.2
preservative should be non-irritant, not cause Methyl paraben 0.1
hypersensitivity reactions, and be non-toxic. In this Propyl paraben 0.02
respect, the site of application is critical. Relatively few
Phenol 0.5
compounds are approved for use in opthalmic products
due to their high sensitivity towards xenobiotics. Also, Phenyl mercuric nitrate 0.002
compounds safe for use on intact skin might be Phenyl mercuric acetate 0.002
hazardous for inclusion in parenteral products. Thiomerosal 0.01
Polymyxin-B-Sulfate 1000 USP unit
10. Solubility in oil: Preservatives must not be too oil
soluble as this can produce problems in two and three-
phase systems where the preservative accumulates in For topical applications:
the oil and micellar phases and is unavailable for Benzoic acid
antimicrobial action in the biological (aqueous) phase. It Phenol
is worth noting that the oil : water partition coefficient can Sorbic acid
alter as a function of pH and also as a function of the Alcohols (ethyl and propyl)
nature of the oil.
Quarternary ammonium salts
Mercurals

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 18

SOLVENT / VEHICLE
SOLVENT / VEHICLE
Water:
The vast majority of injectable products and oral liquid
formulations are aqueous solutions because of the
physiological compatibility of water with body tissues.
Additionally, the high dielectric constant of water makes it
possible to dissolve ionizable electrolytes, and its
hydrogen-bonding potential facili-tates the solution of
alcohols, aldehydes, ketones, and amines.
The current USP has monographs for
1. Purified Water,
2. Water for Injec-tion (WFI),
3. Sterile WFI,
4. Bacteriostatic WFI, and
5. Sterile Water for Irrigation.
Water Miscible Vehicles: (Non-aqueous Solvents)
Cosolvents are defined as water-miscible organic
solvents that are used in liquid drug formulations to
• increase the solubility of poorly water-soluble
substances or to
• enhance the chemical stability of a drug.
Cosolvency, then, refers to the technique of using
cosolvents for the stated purposes; it is also commonly
referred to as solvent blending. Cosolvency has been
used as an approach for preparing liquid drug
preparations throughout the history of drug formulation.
Certain drugs of botanic origin were known to be poorly
soluble in water and required formulation in water–
ethanol mixtures in order to deliver an adequate dose of
drug in a small volume of preparation.
A common example of a class of formulation containing
cosolvents is the elixir, which by definition is a
sweetened, hydroalcoholic solution intended for oral use.
Tinctures, which generally contain even higher amounts
of alcohol, are another classic example of a liquid dosage
form containing a cosolvent. The need to employ
cosolvents in the formulation of new drugs as solutions
for oral, parenteral, and topical use remains high,
especially with the increasing structural complexity of
new therapeutic agents.
In many cases, cosolvency can increase the solubility of
a non-polar drug up to several orders of magnitude
above the aqueous solubility. This would be significant,
for example, in a formulation problem where it might be
necessary to increase the solubility of a drug 500-fold or
more. The use of cosolvents to prepare solution
formulations of non-polar drugs is a simple and
potentially effective way to achieve high concentrations of
drug.
The primary disadvantages of cosolvency include the
potential for biological effects and the potential for drugs
that have been solubilized using cosolvents to precipitate
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
upon dilution with aqueous fluids. The biological effects
of a cosolvent that may limit or eliminate its use in drug
formulations include their general toxicity, target organ
toxicity, tissue irritation, or tonicity with respect to biologic
membranes.
In addition, precipitation of drug upon dilution with
aqueous media or during injection or application to
mucous membranes must always be considered in
deciding if a co-solvent can be used as a vehicle for
poorly water-soluble drugs.
When used as a method for increasing the chemical
stability of a drug, cosolvents may be effective by one or
two mechanisms. If a drug is susceptible to hydrolytic
degradation, cosolvents may reduce the degradation of
the drug by substituting for some or all of the water in the
formulation. Alternatively, a cosolvent may enhance the
stability of a drug by providing a less suitable
environment for the transition state of the reactants,
provided the transition state is more polar than the
reactants themselves.
A non-aqueous solvent must be selected with great care
for it must not be irritating, toxic, or sensitizing, and it
must not exert an adverse effect on the ingredients of the
formulation.
Solvents that are miscible with water, and that are usually
used in combination with water as the vehicle, include
1. Dioxolanes,
2. Dimethylacetamide,
3. N-q3-hydroxyethyl)-lactamide,
4. Butylene glycol,
5. Polyethylene glycol 400 and 600,
6. Propylene glycol,
7. Glycerin, and
8. Ethyl alcohol.
The most frequently used nonaqueous solvents are
polyethylene glycol, propylene glycol, and fixed oils.
These solvents have been reviewed elsewhere and the
reader is referred to this review for further details.
Non-aqueous Vehicles:
Drugs that are insoluble in aqueous systems are often
incor-porated in metabolizable oils. Steroids, hormones,
and vitamins are incorporated in vegetable oils such as
peanut, sesame, corn, olive, and cottonseed. Oil
injections are only administered intramuscularly. There
are strict speci-fications for the vegetable oils used in
manufacturing intramuscular injections. Storage of these
preparations is important if stability is to be maintained.
For example, they should not be subjected to conditions
above room tempera-ture for extended periods of time.
Although the oils used for injections are of vegetable
origin, federal regulations require that the specific oil be
listed on the label of a product, because some patients
have exhibited allergic re-sponses to certain vegetable
oils.
Water-immiscible solvents include
1. Fixed oils,
2. Ethyl oleate,
3. Isopropyl myristate, and
4. Benzyl benzoate.
Page- 19

SURFACTANTS IN
PHARMACEUTICAL
PRODUCTS
Surfactants in Pharmaceutical Products
Surface-active agents (surfactants) are substances
which, at low concentrations, adsorb onto the surfaces or
interfaces of a system and alter the surface or interfacial
free energy and the surface or interfacial tension.
Surface-active agents have a characteristic structure,
possessing both polar (hydrophilic) and non-polar
(hydrophobic) regions in the same molecule. Thus
surfactants are said to be amphipathic in nature.
Surfactant classification
Surfactant molecules may be classified based on the
nature of the hydrophilic group within the molecule. The
four main groups of surfactants are defined as follows:
1. Anionic surfactants, where the hydrophilic group
carries a negative charge, such as carboxyl (RCOO_),
sulphonate (RSO3_) or sulphate (ROSO3_). Examples of
pharmaceutical importance include potassium laurate,
and sodium lauryl sulphate.
2. Cationic surfactants, where the hydrophilic group
carries a positive charge (e.g., quaternary ammonium
halide. Examples of pharmaceutical importance include
cetrimide, a mixture consisting mainly of tetradecyl,
dodecyl and hexa decyl trimethyl ammonium bromides,
as well as benzalkonium chloride, a mixture of
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
alkylbenzyl dimethyl ammonium Chlorides.
3. Ampholytic surfactants (also called zwitterionic
surfactants), where the molecule contains, or can
potentially contain, both a negative and a positive charge,
(e.g., the sulfobetaines). Examples of pharmaceutical
importance include N-Dodecyl-N,
N-Dimethylbetaine.
4. Nonionic surfactants, where the hydrophile carries
no charge but derives its water solubility from highly polar
groups such as hydroxyl or polyoxyethylene
(OCH2CH2O–) groups. Examples of pharmaceutical
importance include polyoxy ethylated glycolmonoethers
(e.g., cetomacrogol), sorbitan esters (Spans) and
polysorbates (Tweens).
Applicatons of surfactants
• Liquid dosage forms- solubilizers for poorly soluble
drugs-Miceller solubilization
• Suspensions- wettening agents for hydrophobic
drugs
• Emulsions- emulsifying agents, Micro-emulsions
• Topical ointment- as base, improve spreading.
• Solid dosage forms- solubility enhancement or
dissolution improvement of poorly soluble drugs
• Tablet coating- improvement of coating solution
spredability
• Drug delivery- Lyposome, Niosomes.
• Preservatives- some cationinc surfactants act as
preservative.
• Aerosols– wetting agents
Page- 20
 Buffers Concentration
range (%)
BUFFERS Acetic acid 0.22
Adipic acid 1.0
Buffers
Benzoic acid and sodium benzoate 5.0
It is well known that many drugs are unstable when ex-
posed to certain acidic or basic conditions, and such in- Citric acid 0.5
formation is routinely gathered during the preformulation
stage of development. When such instabilities are identi- Lactic acid 0.1
fied, one tool of the formulation sciences is to include a
buffering agent (or agents) in the dosage form with the
Maleic acid 1.6
hope that such excipients will impart sufficient stability to Potassium phosphate 0.1
enable the formulation. The properties that enable buffer-
ing agents to function as such is derived from their quali- Sodium phosphate monobasic 1.7
ties as weak acids or bases, and have their roots in their
respective ionic equilibria. Sodium phosphate dibasic 0.71
A buffer can be defined as a solution that maintains an Sodium acetate 0.8
approximately equal pH value even if small amounts of
acidic or basic substances are added. To function in this Sodium bicarbonate 0.005
manner, a buffer solution will necessarily contain either
an acid and its conjugate base, or a base and its conju- Sodium carbonate 0.06
gate acid. Sodium citrate 4.0
Sodium tartrate 1.2
Selection criteria for buffering agents:
Tartaric acid 0.65

1. The buffer must have adequate capacity in the desired

pH range.
2. The buffer must be biologically safe for the intended
use.
3. The buffer should have little or no deleterious effect on
the stability of the final product.
4. The buffer should permit acceptable flavoring and col-
oring of the product.

Buffers in pharmaceutical systems

It is well known that the stability of many active pharma-

ceutical substances can be strongly dependent on the
degree of acidity or basicity to which they are exposed,
and that a change in pH can cause significant changes in
the rate of degradation reactions. For such compounds,
formulators commonly include a buffer system to ensure
the stability of the drug substance either during the shelf
life of the product, or during the period associated with its
administration.

In addition, preformulation scientists routinely use buffer

systems to set the pH of a medium in which they intend
to perform experimentation. For instance, the pH stability
profile of a drug substance is routinely obtained through
the use of buffers, and the pH dependence of solubility is
frequently measured using buffered systems. However,
the possibility that the buffer system itself may influence
or alter the results must be considered in these studies.

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 21
 >1 function that may be similar (e.g., talc as lubricant and
glidant) or opposite (e.g., starch as binder and
EXCIPIENTS IN TABLETS disintegrant) to each other. Furthermore, the sequence of
adding the excipients during tablet production depends
AND CAPSULES on the function of the excipient. Whereas the diluents and
the binders are to be mixed with the active ingredient
early on for making granules, disintegrants may be added
For tablets and capsules, excipients are needed both for before granulation (i.e., inside the granules), and/or
the facilitation of the tableting and capsule-filling process during the lubrication step (i.e., outside the granules)
(e.g., glidants) and for the formulation (e.g., before tablet compression.
disintegrants). Except for diluents, which may be present
in large quantity, the level of excipient use is usually
limited to only a few percent and some lubricants will be
required at <1%. Details of the types, uses, and
mechanisms of action of various excipients for tablet and
capsule production have been discussed at length in
other articles in this encyclopedia. The types and
functions of excipients for tablet production are
summarized in Table 1. Although binders, lubricants, and
antiadherents are specific for making tablets, other
excipients in Table 1 are also used in capsule production
for reasons similar to those for tablets.

It is worth noting that some of these tableting excipients

may exert effects in opposition to each other. For
example, binders and lubricants, because of their
respective bonding and waterproofing properties, may
hinder the disintegration action of the disintegrants. In
addition, some of these tableting excipients may possess

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 22

POLYMERS
A monomer is a small molecule that combines with other
molecules of the same or different types to form a
polymer. Since drawing a complete structure of a
polymer is almost impossible, the structure of a polymer
is displayed by showing the repeating unit (the monomer
residue) and an “n” number that shows how many
monomers are participating in the reaction.
From the structural prospective, monomers are generally
classified as olefinic (containing double bond) and
functional (containing reactive functional groups) for
which different polymerization methods are utilized. If
two, three, four, or five monomers are attached to each
other, the product is known as a dimer, trimer, tetramer,
or pentamer, respectively. An oligomer contains from 30
to 100 monomeric units. Products containing more than
200 monomers are simply called a polymer (Fig. 20–1).
In a traditional pharmaceutics area, such as tablet
manufacturing, polymers are used as tablet binders to
bind the excipients of the tablet. Modern or advanced
pharmaceutical dosage forms utilize polymers for drug
protection, taste masking, controlled release of a given
drug, targeted delivery, increase drug bioavailability, and
so on and so forth.
Apart from solid dosage forms, polymers have found
application in liquid dosage forms as rheology modifiers.
They are used to control the viscosity of an aqueous
solution or to stabilize suspensions or even for the
granulation step in preparation of solid dosage forms.
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
Major application of polymers in current pharmaceutical
field is for controlled drug release, which will be
discussed in detail in the following sections. In the
biomedical area, polymers are generally used as
implants and are expected to perform longterm service.
This requires that the polymers have unique properties
that are not offered by polymers intended for general
applications. Table 20–3 provides a list of polymers with
their applications in pharmaceutical and biomedical
industries.
In general, the desirable polymer properties in
pharmaceutical applications are film forming (coating),
thickening (rheology modifier), gelling (controlled
release), adhesion (binding), pH-dependent solubility
(controlled release), solubility in organic solvents (taste
masking), and barrier properties (protection and
packaging).
From the solubility standpoint, pharmaceutical polymers
can be classified as water-soluble and water-insoluble
(oilsoluble or organic soluble). The cellulose ethers with
methyl and hydroxypropyl substitutions are water-soluble,
whereas ethyl cellulose and a group of cellulose esters
such as cellulose acetate butyrate or phthalate are
organic soluble. Hydrocolloid gums are also used when
solubility in water is desirable.
The synthetic water-soluble polymers have also found
extensive applications in pharmaceutical industries,
among them polyethylene glycol, polyethylene glycol
vinyl alcohol polymers, polyethylene oxide, polyvinyl
pyrrolidone, and polyacrylate or polymethacrylate esters
containing anionic and cationic functionalities are well-
established.
Page- 23
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 24
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 25

FLAVORS AND
FLAVOR MODIFIERS
Flavors and Flavor Modifiers
The use of flavors and flavor modifiers to improve the
taste and aroma of foods and pharmaceuticals is an art
that dates back several centuries. In large measure, the
practice is still the same today and, except for the advent
of new semi-synthetic flavoring agents with improved
stability, the field has remained relatively unchanged. In
the analytical arena, the story is different.
DEFINITION OF FLAVOR
The sensory perceptions are both qualitative as well as
quantitative and, therefore, can be measured. Webster’s
New Collegiate Dictionary defines flavor as the ‘‘ . . .
quality of something that affects the sense of taste, . . .
the blend of taste and smell sensations evoked by a
substance in the mouth.’’ This definition is correct, but
incomplete, and should be redefined to include feeling
factors.
1. “Flavor is the sensation produced by a material
taken in the mouth, perceived principally by the
senses of taste and smell, and also by the
general pain, tactile, and temperature receptors
in the mouth. Flavor also denotes the sum of the
characteristics of the material which produces
that sensation.”
2. Flavor is the complex effect of three
components: taste, odor, and feeling factors. It
is usually associated with the pleasure of
savoring food or beverages and has,
subsequently, suffered from considerable
imprecision in definition. Flavor is a sensation
with multidimensional components involving
subjective and objective perceptions.
3. “ Flavor is one of the three main sensory
properties which are decisive in the selection,
acceptance, and ingestion of a food.”
PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
CLASSIFICATION OF FLAVORING AGENTS
Natural flavouring substances: Natural flavouring
substances means flavouring substances obtained from
plant or animal raw materials, by physical, microbiological
or enzymatic processes. They can be either used in their
natural state or processed for human consumption, but
cannot contain any nature-identical or artificial flavouring
substances.
Nature-identical flavouring substances: Nature-
identical substances means flavouring substances that
are obtained by synthesis or isolated through chemical
processes, which are chemically identical to flavouring
substances naturally present in products intended for
human consumption. They cannot contain any artificial
flavouring substances.
Artificial flavouring substances: Artificial flavouring
substances means flavouring substances not identified in
a natural product intended for human consumption,
whether or not the product is processed.
TASTE
The four primary taste- Sweet, bitter, sour and saline-
appea4r to be the result of partly of physicochemical and
partly of psychological action.
Taste partly depends on the ions which are produced in
the mouth, but psychologists have demonstrated that
sight (color) and sound also play a definite role when
certain reflexes become conditioned through custom and
association of sense perceptions. Thus, in the classic
experiments of Pavlov demonstrating "conditiond
Page- 26
 head cold. There are many varieties of odorants, but a
Flavor types universally accepted structure–activity relationship of
Cherry Honey Cinnamon these has not been established. Yet, there is evidence
Pineapple Coconut Cardamon that odor may involve specific receptor interactions,
Peach Butter Clove suggesting that structural properties of odorants may be
apricot Cocoa Anise important in eliciting specific odor sensations.
Apple Milk Mint
Banana Pepermint Feeling Factors:
Strawberry Garlic
Raspberry Zinger ‘‘Mouth feel’’ factors are critical in flavor perception.
Grape Examples include astringency, pepper bite, menthol
cooling, and texture (e.g., softness or hardness as in
Plum
candy). Sensations, such as crunch after biting into a
Black currant
crisp stick of celery or an apple, contribute to the overall
Orange flavor of foods. These mouth feel factors are also
Vanilla important in improving the organoleptic qualities of
Mango pharmaceuticals.
Lemon
FLAVORING AGENTS
reflexs", the ringing of a bell or the showing circle of light
caused the gastric juices of a dog to follow although no Flavoring agents may be classified as natural, artificial, or
food was placed before it. natural and artificial (N&A) by combining the all natural
and synthetic flavors. Pharmaceutical flavors are
Taste consists of four primary sensations: sweet, sour, available as liquids (e.g., essential oils, fluid extracts,
bitter, and salty. Correspondingly, there are four different tinctures, and distillates), solids (e.g., spraydried,
kinds of taste buds. These sensations are elicited by the crystalline vanillin, freeze-dried cinnamon powders, and
tongue and interpreted by the brain. Certain areas of the dried lemon fluid extract), and pastes (e.g., soft extracts,
tongue respond more readily to specific tastes than resins, and so-called concretes, which are brittle on the
others. outside and soft on the inside). Liquid flavors are by far
the most widely used because they diffuse readily into
Sweet sensations are most easily detected at the tip of the substrate. They are available both as oily (e.g.,
the tongue, whereas bitter ones are most readily essential oils) or non-oily liquids.
detected at the back of the tongue.
Their texture is generally dependent on the solvent within
Sour sensations occur at the sides of the tongue, but which they are prepared. Fluid extracts may contain a
salty sensations are usually detected at both the tip and single ingredient or a variety of compounded ingredients.
at the sides of the tongue. Tinctures are obtained by maceration or percolation of
specific herbs and spices in alcohol. Essential oils boil at
During ingestion, taste buds react to soluble substances. elevated temperatures, but many cannot be directly
The resulting sensations are transmitted to the brain by distilled without decomposition.
the ninth cranial (glossopharyngeal) nerve. The tenth and
twelfth cranial nerves participate in this sensory reaction, Vacuum, steam, and fractional or molecular distillation
but their role is limited. are often used for their manufacture. Fractional
distillation removes traces of water, resinous materials,
Correlation of chemical structure with taste: colors, terpenes, and sesquiterpenes from the distillate.
This process improves solubility and enhances flavor
Sour taste- hydrogen ions. Characteristics of acids, intensity. Sesquiterpeneless oils are more soluble than
tannins, alum, phenol and lactons. terpeneless oils because of the removal of head and tail
fractions (e.g., waxy residues). Most common
Saltiness- simultaneos presence of anions and cations. sesquiterpeneless oils used in the pharmaceutical
e.g KBr, NaCl, etc. industry include oil of orange and oil of
lemon. Oils and juices are obtained from plant sources by
Bitterness- high molecular weight salts are bitter. Alkalis expression. Citrus essential oils are almost exclusively
both base and salt, many drugs, obtained by this method. Thoroughly washed unripe
citrus fruits are cold pressed manually, or mechanically,
Sweet- due to poly hydroxy compounds, poly to rupture oil cells in the rind. The oil is collected by
halogeneted aliphatic compounds, and "- draining and centrifuging. Manual operation is labor
amino acids. eg. glucose, sugars, glycerin, intensive and has been replaced by machines.
sorbitol,

Odor: FLAVOR SELECTION IN PHARMACEUTICAL

The odor component of flavor is due to conscious or
subconscious reactions to volatile substances, without
which most foods would be lacking in taste appeal. By
closing the nostrils while eating a mouthful of some
flavored substance and immediately following this with
another mouthful with the nostrils open, it may be shown
that food could be rendered tasteless, as is often
experienced by people suffering from the effects of a
PREPARATIONS
A number of criteria are used to select flavors during
formulation. Different flavor concentrations produce
highly subjective sensations. Specific requirements for
balance and fullness are dependent, in part, on the drug
substance and the physical form of the product.
For this reason, when selecting a flavor system, the

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 27
compounding pharmacist must take into account several
variables upon which a desired response would depend.
Some of these are product texture (e.g., viscosity of
formulation, solid or liquid), water content, base vehicle
or substrate, and taste of the subject drug. Notable
specific examples to consider are:
_ Immediate flavor identity from the formulation as it is
ingested.
_ Compatible mouth feel factors and rapid development
of a fully blended flavor in the mouth during ingestion of
the product.
_ Absence of ‘‘off’’ notes in the mouth and a mild
transient aftertaste during ingestion of the product.
The selection of a flavor system, thus, requires an
extensive evaluation of a number of organoleptic
qualities. Vehicle components within which the drug is
presented have a significant bearing on the performance
of the flavor system. Of these, the sweetener is perhaps
the most relevant.
Sweeteners
The most commonly used sweeteners are sucrose,
glucose, fructose, sorbitol, and glycerin. Using sucrose
(sugar) as a standard, with 100 units of sweetness, Table
6 lists the relative intensities of other sweeteners.
Glycerin, glucose, sorbitol, and sucrose have limited use
in solid dosage forms (e.g., tablets) because the
materials are hygroscopic. Mannitol is used more often in
tablet manufacture. Besides being less hygroscopic, it
has a negative heat of solution. For this reason,
chewable tablets containing mannitol have a pleasant
cooling sweet taste, which complements flavor quality.
The artificial sweetener saccharin is widely used in foods
and pharmaceuticals. It is approximately 350_ as sweet
as sugar. It is sweet at very low concentrations
(equivalent to about 5–10% sugar) but bitter at higher
concentrations.
Approximately 20% of the population are ‘‘saccharin
sensitive;’’ that is, they perceive saccharin to be bitter
even at low concentrations. Upon repeated tasting,
saccharin becomes less sweet and increasingly bitter. By
the third or fourth tasting, solutions of relatively low
concentrations are often no longer sweet to the saccharin
-sensitive person. The artificial sweeteners, cyclamate
and aspartame, are about 30_ as sweet as sugar, but like
saccharin, their sweet–bitter profiles are concentration
dependent. Aspartame does not have a significant bitter
aftertaste when compared to saccharin and has gained in
popularity. Cyclamates were
banned in the 1970s because of carcinogenic concerns,
which have, subsequently, been shown to be overstated.
countries xylitol, cyclamate and the herbal
sweetener stevia are used extensively.
Flavor Enhancers and Potentiators
Flavor enhancers are used universally in the food and
pharmaceutical industries. Sugar, carboxylic acids (e.g.,
citric, malic, and tartaric), common salt (NaCl), amino
acids, some amino acid derivatives (e.g., monosodium
glutamate—MSG), and spices (e.g., peppers) are most
often employed. Although extremely effective with
proteins and vegetables, MSG has limited use in
pharmaceuticals because it is not a sweetener. Citric acid
is most frequently used to enhance taste performance of
both liquid and solid pharmaceutical products, as well as
a variety of foods. Other acidic agents, such as malic and
tartaric acids, are also used for flavor enhancement. In
oral liquids, these acids contribute unique and complex
organoleptic effects, increasing overall flavor quality.
Common salt provides similar effects at its taste
threshold level in liquid pharmaceuticals. Vanilla, for
example, has a delicate bland flavor, which is effectively
enhanced by salt.
Taste-Masking Agents
The flavoring industry has many proprietary products
purported to have excellent taste-masking properties,
which have been used with some success. Yet, there are
a number of natural and artificial flavors that can be
generally described to possess similar taste-masking
effects. Of the many tastes that must be masked in
pharmaceuticals, bitterness is most often encountered; to
mask it completely is difficult. A tropical fruit has been
used for centuries in central Africa to mask the bitter
taste of native beers. This so-called ‘‘miracle berry’’
contains a glycoprotein that transiently and selectively
binds to bitter taste buds. Due to stability challenges,
attempts to isolate the compound for commercial
exploitation have been unsuccessful. Yet, many fruit
syrups are relatively stable in pharmaceuticals if
formulated with antimicrobial preservative agents. Syrups
of cinnamon, orange, citric acid, cherry, cocoa, wild

List of sugar substitutes

The three primary compounds used as sugar substitutes
in the United States are saccharin (e.g., Sweet'N
Low), aspartame (e.g., Equal, NutraSweet)
and sucralose (e.g., Splenda,Altern). Maltitol and sorbitol
are often used, frequently in toothpaste, mouth wash,
and in foods such as "no sugar added" ice
cream. Erythritol is gaining momentum as a replacement
for these other sugar alcohols in foods as it is much less
likely to produce gastrointestinal distress when
consumed in large amounts. In many other

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 28
cherry, raspberry, or glycyrrhiza elixir can be used to
effectively mask salty and bitter tastes in a number of
drug products. The extent to which taste-masking may be
achieved is not usually predictable due to complex
interactions of other flavor elements in these products.
The degree to which bitterness may be masked by these
agents ranks in a descending order: cocoa syrup is
most effective, followed by raspberry syrup, cherry,
cinnamon, compound sarsaparilla, citric acid, licorice,
aromatic elixir, orange, and wild cherry. Sour and metallic
tastes in pharmaceuticals also can be reasonably
masked. Sour substances containing hydrochloric acid
are most effectively neutralized with raspberry and other
fruit syrups. Metallic tastes in oral liquid products (e.g.,
iron) are usually masked by extracts of gurana, a tropical
fruit. Gurana flavor is used at concentrations ranging
from 0.001 to about 0.5% and may be useful in solid
products as well (e.g., chewable tablets and granules).

Natural sugar substitutes

SUCROSE
Sorbitol — 0.6× sweetness (by weight), 0.9× sweetness (by food energy), 0.65× energy density, E420

Glycerol — 0.6× sweetness (by weight), 0.55× sweetness (by food energy), 1.075× energy density, E422
Mannitol — 0.5× sweetness (by weight), 1.2× sweetness (by food energy), 0.4× energy density, E421
Erythritol — 0.7× sweetness (by weight), 14× sweetness of sucrose (by food energy), 0.05× energy density
of sucrose
Glycyrrhizin — 50× sweetness (by weight)
Hydrogenated — 0.4–0.9× sweetness (by weight), 0.5×–1.2× sweetness (by food energy), 0.75× energy density
starch hydrolys-
ates
Inulin
Isomalt — 0.45–0.65× sweetness (by weight), 0.9–1.3× sweetness (by food energy), 0.5× energy density,
E953
Lactitol — 0.4× sweetness (by weight), 0.8× sweetness (by food energy), 0.5× energy density, E966
Maltitol — 0.9× sweetness (by weight), 1.7× sweetness (by food energy), 0.525× energy density, E965
Tagatose — 0.92× sweetness (by weight), 2.4× sweetness (by food energy), 0.38× energy density
Xylitol — 1.0× sweetness (by weight), 1.7× sweetness (by food energy), 0.6× energy density, E967

Plant extracts
Monatin — naturally-occurring sweetener isolated from the plant Sclerochiton ilicifolius
Stevia — 250× sweetness (by weight) - extracts known as rebiana, Truvia, PureVia; mainly containing
rebaudioside A, a steviol glycoside

Monellin — protein, 3,000× sweetness (by weight); the sweetening ingredient in serendipity berries
Pentadin — protein, 500× sweetness (by weight)
Miraculin — protein, does not taste sweet by itself, but modifies taste receptors to make sour things taste
sweet temporarily
Thaumatin — protein, 2,000× sweetness (by weight), E957
Brazzein — protein, 800× sweetness of sucrose (by weight)
Curculin — protein, 550× sweetness (by weight)
Mabinlin — protein, 100× sweetness (by weight)

Artificial sugar substitutes

Sucralose — 600× sweetness (by weight), Kaltame, Splenda, Tate & Lyle, E955, FDA Ap-
proved 1998
Saccharin — 300× sweetness (by weight), E954, FDA Approved 1958
Aspartame — 160–200× sweetness (by weight), NutraSweet, E951, FDA Approved 1981
Neotame — 8,000× sweetness (by weight), NutraSweet, FDA Approved 2002
Salt of aspartame-acesulfame — 350× sweetness (by weight), Twinsweet, E962
Acesulfame potassium — 200× sweetness (by weight), Nutrinova, E950, FDA Approved 1988

Glucin — 300× sweetness (by weight)

Neohesperidin dihydrochalcone — 1,500× sweetness (by weight), E959

Alitame — 2,000× sweetness (by weight), Pfizer, Pending FDA Approval

Cyclamate — 30× sweetness (by weight), Abbott, E952, FDA Banned 1969
Dulcin — 250× sweetness (by weight), FDA Banned 1950

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 29
 EXCIPIENT-Classification
Citric Acid Monohydrate-Buffering Agent
Ammonium Chloride-Acidulant
Lactic Acid-Buffering Agent
Fumaric Acid-Acidulant
Maleic Acid-Buffering Agent
Hydrochloric Acid-Acidulant
Meglumine-Buffering Agent
Malic Acid-Acidulant
Monoethanolamine-Buffering Agent
Phosphoric Acid-Acidulant
Potassium Citrate-Buffering Agent
Sulfuric Acid-Acidulant
Potassium Hydroxide-Buffering Agent
Tartaric Acid-Acidulant
Sodium Carbonate-Buffering Agent
Aluminum Hydroxide Adjuvant-Adsorbant
Sodium Citrate Dihydrate-Buffering Agent
Aluminum Oxide-Adsorbant
Aluminum Phosphate Adjuvant-Adsorbant Sodium Lactate-Buffering Agent
Sodium Phosphate, Dibasic-Buffering Agent
Attapulgite-Adsorbant
Sodium Phosphate, Monobasic-Buffering Agent
Colloidal Silicon Dioxide-Adsorbant
Hydrophobic Colloidal Silica-Adsorbant Boric Acid-Buffering Agent
Diethanolamine-Buffering Agent
Magnesium Oxide-Adsorbant
Disodium Edetate-Chelating Agent
Dimethicone-Antifoaming Agent
Edetic Acid-Chelating Agent
Simethicone-Antifoaming Agent
Pentetic Acid-Chelating Agent
Alpha Tocopherol-Antioxidant
Shellac-Coating Agent
Ascorbic Acid-Antioxidant
Zein-Coating Agent
Ascorbyl Palmitate-Antioxidant
Iron Oxides-Color
Butylated Hydroxyanisole-Antioxidant
Titanium Dioxide-Color-Pigment
Butylated Hydroxytoluene-Antioxidant
Cyclodextrins-Complexing Agent
Butylparaben-Antioxidant
Hydroxypropyl Betadex-Complexing Agent
Erythorbic Acid-Antioxidant
Monothioglycerol-Antioxidant Sulfobutylether b-Cyclodextrin-Complexing Agent
Calcium Chloride-Desiccant
Potassium Metabisulfite-Antioxidant
Chloroxylenol-Disinfectants
Propyl Gallate-Antioxidant
Sodium Ascorbate-Antioxidant Lactose, Inhalation-Dpi-Diluent
Potassium Bicarbonate-Effervescent-Base
Sodium Formaldehyde Sulfoxylate-Antioxidant
Sodium Bicarbonate-Effervescent-Base
Sodium Metabisulfite-Antioxidant
Isopropyl Myristate-Emollient
Sodium Sulfite-Antioxidant
Isopropyl Palmitate-Emollient
Sodium Thiosulfate-Antioxidant
Mineral Oil-Emollient
Sulfur Dioxide-Antioxidant
Mineral Oil, Light-Emollient
Potassium Alum-Astringent
Lecithin-Emulsifier
Sodium Borate-Astringent
Cholesterol-Emulsifying Agent
Denatonium Benzoate-Bittering Agent
Mineral Oil and Lanolin Alcohols-Emulsifying Agent
Sucrose Octaacetate-Bittering Agent
Octyldodecanol-Emulsifying Agent
Acetic Acid, Glacial-Buffering Agent
Adipic Acid-Buffering Agent Polyoxylglycerides-Emulsifying Agent
Triethanolamine-Emulsifying Agent
Ammonia Solution-Buffering Agent
Vitamin E Polyethylene Glycol Succinate-Emulsifying Agent
Calcium Hydroxide-Buffering Agent
Wax, Anionic Emulsifying-Emulsifying Agent

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 30
Wax, Nonionic Emulsifying-Emulsifying Agent Sesame Oil-Oily Vehicle
Ethylene Glycol Stearates-Emulsion Stabilizer Soybean Oil-Oily Vehicle
Glyceryl Behenate-Emulsion Stabilizer Sunflower Oil-Oily Vehicle
Glyceryl Monooleate-Emulsion Stabilizer Castor Oil, Hydrogenated-Ointment Base
Glyceryl Monostearate-Emulsion Stabilizer Ceresin-Ointment Base
Glyceryl Palmitostearate-Emulsion Stabilizer Cetostearyl Alcohol-Ointment Base
Ethyl Maltol-Flavoring Agent Cetyl Alcohol-Ointment Base
Ethyl Vanillin-Flavoring Agent Lanolin-Ointment Base
Isomalt-Flavoring Agent Lanolin Alcohols-Ointment Base
Leucine-Flavoring Agent Lanolin, Hydrous-Ointment Base
Maltol-Flavoring Agent Paraffin-Ointment Base
Menthol-Flavoring Agent Petrolatum-Ointment Base
Methionine-Flavoring Agent Petrolatum and Lanolin Alcohols-Ointment Base
Monosodium Glutamate-Flavoring Agent Sodium Hydroxide-Ph ADJUSTMENT
Vanillin-Flavoring Agent Acetyltributyl Citrate-Plasticizer
Carbon Dioxide-Gas Acetyltriethyl Citrate-Plasticizer
Nitrogen-Gas Dibutyl Phthalate-Plasticizer
Acacia-Hydrocolloid Dibutyl Sebacate-Plasticizer
Alginic Acid-Hydrocolloid Diethyl Phthalate-Plasticizer
Ammonium Alginate-Hydrocolloid Dimethyl Phthalate-Plasticizer
Calcium Alginate-Hydrocolloid Triacetin-Plasticizer
Carrageenan-Hydrocolloid Tributyl Citrate-Plasticizer
Chitosan-Hydrocolloid Triethyl Citrate-Plasticizer
Guar Gum-Hydrocolloid Wax, Carnauba-Polishing Agent
Pectin-Hydrocolloid Wax, White-Polishing Agent
Potassium Alginate-Hydrocolloid Wax, Yellow-Polishing Agent
Sodium Acetate-Hydrocolloid Aliphatic Polyesters-Polymer
Sodium Alginate-Hydrocolloid Carbomer-Polymer
Tragacanth-Hydrocolloid Cellulose Acetate-Polymer
Xanthan Gum-Hydrocolloid Cellulose Acetate Phthalate-Polymer
Polacrilin Potassium-Ionexchange Resin Dextrin-Polymer
Almond Oil-Oily Vehicle Ethylcellulose-Polymer
Canola Oil-Oily Vehicle Ethylene Vinyl Acetate-Polymer
Castor Oil-Oily Vehicle Gelatin-Polymer
Coconut Oil-Oily Vehicle Hydroxyethyl Cellulose-Polymer
Corn Oil-Oily Vehicle Hydroxyethylmethyl Cellulose-Polymer
Cottonseed Oil-Oily Vehicle Hydroxypropyl Cellulose-Polymer
Ethyl Oleate-Oily Vehicle Hydroxypropyl Cellulose, Low-substituted-Polymer
Medium-chain Triglycerides-Oily Vehicle Hydroxypropyl Starch-Polymer
Oleyl Alcohol-Oily Vehicle Hypromellose-Polymer
Olive Oil-Oily Vehicle Hypromellose Acetate Succinate-Polymer
Palmitic Acid-Oily Vehicle Hypromellose Phthalate-Polymer
Peanut Oil-Oily Vehicle Methylcellulose-Polymer
Safflower Oil-Oily Vehicle Poloxamer-Polymer

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 31
Poly(DL-Lactic Acid)-Polymer Thymol-Preservative
Poly(methyl vinyl ether/maleic anhydride)-Polymer Chlorodifluoroethane (HCFC)-Propellant
Polycarbophil-Polymer Chlorofluorocarbons (CFC)-Propellant
Polydextrose-Polymer Difluoroethane (HFC)-Propellant
Polyethylene Glycol-Polymer Dimethyl Ether-Propellant
Polyethylene Oxide-Polymer Heptafluoropropane (HFC)-Propellant
Polymethacrylates-Polymer Hydrocarbons (HC)-Propellant
Polyvinyl Acetate Phthalate-Polymer Nitrous Oxide-Propellant
Polyvinyl Alcohol-Polymer Tetrafluoroethane (HFC)-Propellant
Povidone-Polymer Acetone-Solvent
Carboxymethylcellulose Sodium-Polymer Alcohol-Solvent
Carboxymethylcellulose Calcium-Polymer Butylene Glycol-Solvent
Copovidone-Polymer Cyclomethicone-Solvent
Potassium Sorbate-Preservative Dimethyl Sulfoxide-Solvent
Benzalkonium Chloride-Preservative Dimethylacetamide-Solvent
Benzethonium Chloride-Preservative Ethyl Acetate-Solvent
Benzoic Acid-Preservative Ethyl Lactate-Solvent
Benzyl Alcohol-Preservative Glycerin-Solvent
Benzyl Benzoate-Preservative Glycofurol-Solvent
Bronopol-Preservative Isopropyl Alcohol-Solvent
Cetrimide-Preservative Propylene Carbonate-Solvent
Cetylpyridinium Chloride-Preservative Propylene Glycol-Solvent
Chlorhexidine-Preservative Pyrrolidone-Solvent
Chlorobutanol-Preservative Triolein-Solvent
Chlorocresol-Preservative Albumin-Stabilizer
Cresol-Preservative Calcium Acetate-Stabilizer
Ethylparaben-Preservative Glycine-Stabilizer
Hexetidine-Preservative Raffinose-Stabilizer
Imidurea-Preservative Trehalose-Stabilizer
Methylparaben-Preservative Zinc Acetate-Stabilizer
Phenol-Preservative Stearyl Alcohol-Stiffening Agent
Phenoxyethanol-Preservative Wax, Cetyl Esters-Stiffening Agent
Phenylethyl Alcohol-Preservative Wax, Microcrystalline-Stiffening Agent
Phenylmercuric Acetate-Preservative Suppository Bases, Hard Fat-Suppository Base
Phenylmercuric Borate-Preservative Docusate Sodium-Surfactant
Phenylmercuric Nitrate-Preservative Macrogol 15 Hydroxystearate-Surfactant
Potassium Benzoate-Preservative Phospholipids-Surfactant
Propionic Acid-Preservative Polyoxyethylene Alkyl Ethers-Surfactant
Propylparaben-Preservative Polyoxyethylene Castor Oil Derivatives-Surfactant
Propylparaben Sodium-Preservative Polyoxyethylene Sorbitan Fatty Acid Esters-Surfactant
Sodium Benzoate-Preservative Polyoxyethylene Stearates-Surfactant
Sodium Propionate-Preservative Sodium Lauryl Sulfate-Surfactant
Sorbic Acid-Preservative Sorbitan Esters (Sorbitan Fatty Acid Esters)-Surfactant
Thimerosal-Preservative Bentonite-Suspending Agent

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 32
Calcium Silicate-Suspending Agent Erythritol-Tablet Diluent
Ceratonia-Suspending Agent Inulin-Tablet Diluent
Hectorite-Suspending Agent Lactose, Anhydrous-Tablet Diluent
Kaolin-Suspending Agent Lactose, Monohydrate-Tablet Diluent
Magnesium Aluminum Silicate-Suspending Agent Lactose, Spray-Dried-Tablet Diluent
Propylene Glycol Alginate-Suspending Agent Magnesium Carbonate-Tablet Diluent
Saponite-Suspending Agent Maltodextrin-Tablet Diluent
Sodium Hyaluronate-Suspending Agent Sodium Starch Glycolate-Tablet Disintegrant
Aspartame-Sweetening Agent Croscarmellose Sodium-Tablet Disintegrant
Dextrose-Sweetening Agent Crospovidone-Tablet Disintegrant
Fructose-Sweetening Agent Magnesium Silicate-Tablet Glidant
Glucose, Liquid-Sweetening Agent Magnesium Trisilicate-Tablet Glidant
Lactitol-Sweetening Agent Talc-Tablet Glidant
Maltitol-Sweetening Agent Calcium Stearate-Tablet Lubricant
Maltitol Solution-Sweetening Agent Starch, Sterilizable Maize-Tablet Lubricant
Maltose-Sweetening Agent Sodium Stearyl Fumarate-Tablet Lubricant
Mannitol-Sweetening Agent Stearic Acid-Tablet Lubricant
Neohesperidin Dihydrochalcone-Sweetening Agent Vegetable Oil, Hydrogenated-Tablet Lubricant
Neotame-Sweetening Agent Zinc Stearate-Tablet Lubricant
Saccharin-Sweetening Agent Magnesium Stearate-Tablet Lubricant
Saccharin Sodium-Sweetening Agent Potassium Chloride-Tonicity Contributor
Sodium Cyclamate-Sweetening Agent Sodium Chloride-Tonicity Contributor
Sorbitol-Sweetening Agent Lauric Acid-Transdermal Penetration Enhancer
Sucralose-Sweetening Agent Linoleic Acid-Transdermal Penetration Enhancer
Sucrose-Sweetening Agent Myristic Acid-Transdermal Penetration Enhancer
Sugar, Confectioner’s-Sweetening Agent Myristyl Alcohol-Transdermal Penetration Enhancer
Tagatose-Sweetening Agent Oleic Acid-Transdermal Penetration Enhancer
Thaumatin-Sweetening Agent Tricaprylin-Transdermal Penetration Enhancer
Xylitol-Sweetening Agent Aluminum Monostearate-Viscosity Imparting For Oil
Acesulfame Potassium-Sweetening Agent
Alitame-Sweetening Agent
Calcium Carbonate-Tablet Diluent
Calcium Lactate-Tablet Diluent
Calcium Phosphate, Dibasic Anhydrous-Tablet Diluent
Calcium Phosphate, Dibasic Dihydrate-Tablet Diluent
Calcium Phosphate, Tribasic-Tablet Diluent
Calcium Sulfate-Tablet Diluent
Cellulose, Microcrystalline-Tablet Diluent
Cellulose, Powdered-Tablet Diluent
Cellulose, Silicified Microcrystalline-Tablet Diluent
Starch-Tablet Diluent
Starch, Pregelatinized-Tablet Diluent
Corn Starch and Pregelatinized Starch-Tablet Diluent
Dextrates-Tablet Diluent

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 33